Clinical trial NCT03178487
Conditions: Ankylosing Spondylitis (AS)
Keywords: Upadacitinib ABT-494 Ankylosing Spondylitis (AS) Safety Efficacy
Sponsor: AbbVie
Start date: 2017-10-24; Completion date: 2022-02-17
Enrollment: 187 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of upadacitinib in participants with active ankylosing spondylitis (AS) who have had an inadequate response to at least 2 non-steroidal anti-inflammatory drugs (NSAIDs) or intolerance to or a contraindication for NSAIDs, and who are naïve to biologic disease-modifying anti-rheumatic drugs (bDMARD).

Detailed description:
This study includes two periods: a 14-week double-blind placebo-controlled period and a 90-week open-label long-term extension period.

Eligible participants were randomly assigned in a 1:1 ratio to receive upadacitinib 15 mg or placebo for 14 weeks in Period 1.

Participants who completed Period 1 received upadacitinib 15 mg for 90 weeks in the extension period.

Arms: arm 1: Participants will receive 15 mg upadacitinib orally once a day for 14 weeks in Period 1 and continue to receive 15 mg upadacitinib orally once a day for an additional 90 weeks in Period 2. arm 2: Participants will receive matching placebo orally once a day for 14 weeks in Period 1. In Period 2 participants will receive 15 mg upadacitinib orally once a day for 90 weeks.
Interventions: intervention 1: Upadacitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet

Protocol documents:
Prot_000.pdf: 
NCT03178487


Upadacitinib
M16-098 Protocol Amendment 2
EudraCT 2017-000431-14
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
12 April 2017
Amendment 0-01 (VHP Countries)
27 June 2017
Amendment 0-02 (KR Only)
01 September 2017
Amendment 1
12 September 2017
Administrative Change 1
15 December 2017
Administrative Change 2
11 July 2018
The purpose of this amendment is to:
●
Apply administrative changes throughout the protocol.
Rationale:  Revised text to improve consistency and readability, and/or 
provide clarification.
●
Add:  events of deep vein thrombosis and pulmonary embolism have been 
reported in patients receiving JAK inhibitors including upadacitinib.  
(Section 3.2, Benefits and Risks)
Rationale: To align with the information stated in the most recent version of 
the upadacitinib Investigator's Brochure.
●
Add management of herpes zoster and added recommendation for periodic 
skin examination for patients who are at increased risk for skin cancer.  
(Section 6.1.7, Toxicity Management)
Rationale:  To align with Rinvoq® labeling.
●
Add management of thrombosis events.  (Section 5.4.1, Discontinuation of 
Individual Subjects and Section 6.1.7, Toxicity Management)
Rationale:  To add an additional safety precaution for subjects, given the 
recent concerns raised for the JAK inhibitor class regarding venous 
thromboembolic events.
●
Amend language allowing the Investigator to decide if study drug should be 
restarted if the subject experiences a study drug interruption > 7 consecutive 


Upadacitinib
M16-098 Protocol Amendment 2
EudraCT 2017-000431-14
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days during Weeks 1 through 14 (Period 1) or > 30 consecutive days.  
(Section 5.5.4, Selection and Timing of Dose for Each Subject)
Rationale:  To provide a mechanism for continuation of study drug after study 
drug interruption based on Investigator judgment instead of mandatory study 
drug discontinuation.
●
Update report signatories.  (Appendix B, List of Protocol Signatories)
Rationale:  To reflect changes in AbbVie personnel assigned to project.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix H.


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M16-098 Protocol Amendment 2
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-098
Name of Study Drug:  Upadacitinib
Phase of Development:  2/3 
Name of Active Ingredient:  Upadacitinib
Date of Protocol Synopsis:  20 December 2019
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Safety and Efficacy of Upadacitinib in Subjects with Active Ankylosing Spondylitis
Objectives:  The primary objectives of the study are:
Period 1
1.
To evaluate the efficacy of upadacitinib compared with placebo on reduction of signs and 
symptoms as measured by proportion of subjects who achieve an Assessment of SpondyloArthritis 
international Society (ASAS) 40 response at Week 14 in subjects with active ankylosing spondylitis 
(AS) who have had an inadequate response to at least two nonsteroidal anti-inflammatory drugs 
(NSAIDs) or intolerance to or a contraindication for NSAIDs, and who are biologic disease-
modifying antirheumatic drug (bDMARD)-naïve.
2.
To assess the safety and tolerability of upadacitinib in subjects with active AS who have had an 
inadequate response to at least two NSAIDs or intolerance to or a contraindication for NSAIDs, and 
who are bDMARD-naïve.
Period 2
To evaluate the safety, tolerability, and efficacy of upadacitinib through up to 2 years of treatment in 
subjects who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 107 sites worldwide
Study Population:  Adults who have a clinical diagnosis of AS and meet the modified New York 
Criteria for AS prior to study entry, who have had an inadequate response to at least two NSAIDs over 
an at least 4-week period in total at maximum recommended or tolerated doses or intolerance to or a 
contraindication for NSAIDs as defined by the Investigator, and who are bDMARD-naïve.
Number of Subjects to be Enrolled:  Approximately 170 subjects
Methodology:
This is a Phase 2/3 multicenter study that includes two periods.  Period 1 is a 14-week randomized, 
double-blind, parallel-group, placebo-controlled period designed to compare the safety and efficacy of 
upadacitinib 15 mg QD versus placebo for the treatment of subjects with active AS who have had an 
inadequate response to at least two NSAIDs over an at least 4-week period in total at maximum 
recommended or tolerated doses or intolerance to or a contraindication for NSAIDs as defined by the 
Investigator, and who are bDMARD-naïve.
Period 2 is an open-label long-term extension to evaluate the long-term safety, tolerability, and efficacy 
of upadacitinib 15 mg QD in subjects with AS who have completed Period 1.
The study duration will include a 35-day screening period; a 14-week randomized, double-blind, 
placebo-controlled period (Period 1); a 90-week open-label extension period (Period 2); and a 30-day 
follow-up visit.


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Methodology (Continued):
X-ray of the pelvis will be performed within the 35-day screening period to evaluate the sacroiliac (SI) 
joints to confirm the fulfillment of the modified New York Criteria for AS.  X-ray of the spine will also 
be performed within the 35-day screening period to assess for total spinal ankylosis; subjects with total 
spinal ankylosis are not eligible for this study.  The x-rays of the spine and pelvis will not be required 
during the Screening Period if the subject had a previous anteroposterior (AP) pelvis x-ray and lateral 
spine x-rays within 90 days of the Screening Period, provided that the x-rays are confirmed to be 
adequate for the required evaluations and are deemed acceptable by the central imaging vendor.
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of two treatment groups:
!
Group 1:  Upadacitinib 15 mg QD (n = 85)
!
Group 2:  Placebo (n = 85)
Randomization will be stratified by Screening high sensitivity C-reactive protein (hsCRP) (≤ upper limit 
of normal [ULN] vs. > ULN) and geographic region (United States [US]/Canada, Japan, Rest of the 
World [RoW]).
If entering the study on concomitant conventional-synthetic disease modifying antirheumatic drugs 
(csDMARDs) (i.e., methotrexate [MTX], leflunomide, sulfasalazine [SSZ], and/or hydroxychloroquine), 
the subject must be on a stable dose for ≥ 4 weeks prior to the first dose of study drug.  If entering the 
study on concomitant oral corticosteroids, subject must be on a stable dose of prednisone (≤ 10 mg/day) 
or oral corticosteroid equivalents for at least 14 days prior to the first dose of study drug.  The dose(s) of 
csDMARDs and corticosteroids should remain stable throughout the study (except as described for 
rescue therapy), but may be decreased only for safety reasons.
If entering the study on concomitant NSAIDs, tramadol, combination of acetaminophen and codeine or 
hydrocodone, and/or non-opioid analgesics, subject must be on stable dose(s) for at least 14 days prior to 
the first dose of study drug and should remain stable throughout the study (except as described for rescue 
therapy), but may be decreased only for safety reasons.
Starting at Week 16, subjects who do not achieve at least an ASAS 20 response at two consecutive visits 
will have the option to add or modify doses of NSAIDs, acetaminophen/paracetamol, low potency opioid 
medications (tramadol or combination of acetaminophen and codeine or hydrocodone), and/or modify 
dose of MTX or SSZ at Week 20 or thereafter.
Starting at Week 24, subjects who still do not achieve at least an ASAS 20 response at two consecutive 
visits will be discontinued from study drug treatment.
Subjects who complete the Week 14 visit (end of Period 1) will enter the open-label long-term extension 
portion of the study, Period 2 (90 weeks).  Subjects who are assigned to upadacitinib in Period 1 will 
continue to receive upadacitinib in an open-label manner.  Subjects who were randomized to placebo at 
Baseline will also receive open-label upadacitinib 15 mg QD at Week 14.
The primary analysis will be conducted after all subjects have completed Week 14 or have prematurely 
discontinued prior to Week 14.  Study sites and subjects will remain blinded to the treatment assignment 
in Period 1 for the duration of the study.
Optional samples may be collected for exploratory research at designated time points throughout the 
study.


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Methodology (Continued):
Subjects will have an x-ray of the spine at Week 104.  All subjects who meet eligibility criteria will have 
a magnetic resonance imaging (MRI) evaluation of the sacroiliac (SI) joints, as well as the cervical, 
thoracic, and lumbar regions of the spine, prior to or at the Baseline Visit, at Week 14, and Week 104.
Subjects at select sites who consent to participate in the low-dose computer tomography (CT) scan 
substudy and meet eligibility criteria will have low-dose CT scan evaluation of the whole spine (cervical, 
thoracic, and lumbar spine) prior to or at the Baseline Visit, Week 52, and Week 104.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female ≥ 18 years of age.
2.
Subject with a clinical diagnosis of AS and meeting the modified New York Criteria for AS.
3.
Subject must have baseline disease activity as defined by having a Bath Ankylosing Spondylitis 
Disease Activity Index (BASDAI) score ≥ 4 and a Patient's Assessment of Total Back Pain score 
≥4 based on a 0 – 10 Numeric Rating Scale (NRS) at the Screening and Baseline Visits.
4.
Subject has had an inadequate response to at least two 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.
5.
If entering the study on concomitant MTX, leflunomide, SSZ, and/or hydroxychloroquine, subject 
must be on a stable dose of MTX (≤ 25 mg/week) and/or SSZ (≤ 3 g/day) and/or 
hydroxychloroquine (≤400 mg/day) or leflunomide (≤ 20 mg/day) for at least 28 days prior to the 
Baseline Visit.  A combination of up to two background csDMARDs is allowed EXCEPT the 
combination of MTX and leflunomide.
6.
If entering the study on concomitant oral corticosteroids, subject must be on a stable dose of 
prednisone (≤ 10 mg/day), or oral corticosteroid equivalents, for at least 14 days prior to the 
Baseline Visit.
7.
If entering the study on concomitant NSAIDs, tramadol, combination of acetaminophen and 
codeine or hydrocodone, and/or non-opioid analgesics, subject must be on stable dose(s) for at least 
14 days prior to the Baseline Visit.
Main Exclusion:  
1.
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Prior exposure to any biologic therapy with a potential therapeutic impact on spondyloarthritis 
(SpA).
3.
Intra-articular joint injections, spinal/paraspinal injection(s), or parenteral administration of 
corticosteroids within 28 days prior to the Baseline Visit.  Inhaled or topical corticosteroids are 
allowed.
4.
Subject on any other DMARDs (other than those allowed), thalidomide, or apremilast within 
28 days or five half-lives (whichever is longer) of the drug prior to the Baseline Visit.
5.
Subject on opioid analgesics (except for combination acetaminophen/codeine or 
acetaminophen/hydrocodone which are allowed) or use of inhaled marijuana within 14 days prior to 
the Baseline Visit.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):  
6.
Subject has a history of inflammatory arthritis of different etiology other than axial SpA (including 
but not limited to rheumatoid arthritis [RA], psoriatic arthritis [PsA], mixed connective tissue 
disease, systemic lupus erythematosus, reactive arthritis, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia), or any arthritis with onset prior to 17 years of age.
7.
Laboratory values meeting the following criteria within the Screening period prior to the first dose 
of study drug:  serum aspartate transaminase (AST) > 2 × ULN; serum alanine transaminase (ALT) 
> 2 × ULN; estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of 
Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73m2; hemoglobin < 10 g/dL; total white 
blood cell (WBC) count < 2,500/μL; absolute neutrophil count (ANC) < 1,500/μL; absolute 
lymphocyte count < 800/μL; and platelet count < 100,000/μL.
Investigational Product:
Upadacitinib
Dose:
15 mg QD
Mode of Administration:
Oral
Reference Therapy:
Placebo
Dose:
N/A
Mode of Administration:
Oral
Duration of Treatment:  104 weeks
Criteria for Evaluation:
Efficacy:
The primary endpoint is the proportion of subjects with ASAS 40 response at Week 14, which is defined 
as a ≥ 40% improvement and an absolute improvement of ≥ 2 units (on a scale of 0 to 10) from Baseline 
in at least three of the following four domains:  patient's global assessment of disease activity (PtGA) 
(represented by the PtGA NRS score [0 to 10]), pain (represented by the patient's assessment of total 
back pain NRS score [0 to 10]), function (represented by the BASFI NRS score [0 to 10]), and 
inflammation (represented by the mean of the two morning stiffness related BASDAI NRS scores [mean 
of items 5 and 6 of the BASDAI (0 to 10)]), with no worsening at all in the remaining domain.
Key multiplicity adjusted secondary efficacy endpoints at Week 14 are:  
1.
Change from Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS);
2.
Change from Baseline in MRI Spondyloarthritis Research Consortium of Canada (SPARCC) 
score (Spine);
3.
Proportion of subjects with BASDAI 50 response;
4.
Change from Baseline in Ankylosing Spondylitis Quality of Life (AS QoL);
5.
Proportion of subjects with ASAS partial remission (PR);
6.
Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI);
7.
Change from Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin);
8.
Change from Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES);
9.
Change from Baseline in Work Productivity and Activity Impairment (WPAI);
10. Change from Baseline in ASAS Health Index (HI).


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Criteria for Evaluation (Continued):
Efficacy (Continued):
Additional key secondary efficacy endpoints are: 
!
Proportion of subjects with ASAS 20 response at Week 14;
!
Change from Baseline in MRI SPARCC score (SI joints) at Week 14.
Additional pre-specified endpoints are outlined in the protocol.
Pharmacokinetic:
Blood samples for assay of upadacitinib in plasma will be collected at specified study visits after 
Baseline.  Blood samples at Week 2 and Week 4 visits will be collected prior to dosing, if possible.  For 
all other visits, blood samples will be collected at any time during the visit.
Safety:
Screening assessments will include medical history, vital signs measurements, physical examination, and 
clinical laboratory tests.  The following safety evaluations will be performed during the study:  
concomitant medication review, adverse event (AE) monitoring, vital sign measurements, physical 
examination (if required), and laboratory tests.
Statistical Methods:
Efficacy:
All efficacy analyses will be carried out using the Full Analysis Set population, which includes all 
randomized subjects who receive at least one dose of study drug.
Analysis of the Primary and Key Secondary Endpoints:
Analysis of the primary and key secondary efficacy endpoints will be conducted comparing upadacitinib
15 mg QD versus placebo.  The overall type I error rate of the primary and key secondary endpoints will 
be strongly controlled.
For binary endpoints, frequencies and percentages will be reported for each treatment group.  
Comparisons between the upadacitinib group and the placebo group will be conducted using the 
Cochran-Mantel-Haenszel test, adjusting for main stratification factors.
Analysis of the Primary and Key Secondary Endpoints (Continued):
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Comparisons between the upadacitinib treatment group and the placebo group will be 
carried out using the Mixed Model for Repeated Measures (MMRM) with treatment group, visit, and 
treatment-by-visit interaction as fixed effects, and the corresponding baseline values and the main 
stratification factors as the covariates.
Analysis of Structural Disease Progression:
Progression of structural damage will be assessed using the Modified Stoke Ankylosing Spondylitis 
Spine Score (mSASSS) with conventional radiograph.  In addition, evaluation of structural changes in 
the spine will be explored in subjects who are participating in the low-dose CT scan substudy.
Long-Term Efficacy:
Long-term efficacy by time point will be summarized using descriptive statistics.


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Statistical Methods (Continued):
Pharmacokinetic:
Individual plasma concentrations of upadacitinib will be tabulated and summarized.  A non-linear 
mixed-effects modeling approach will be used to estimate the population central values and the empirical 
Bayesian estimates of the individual values for upadacitinib oral clearance (CL/F) and volume of 
distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of the data.
Safety:
Safety analyses will be carried out using the Safety Analysis Set, which includes all subjects who receive 
at least one dose of study drug.  Safety will be assessed by Treatment Emergent Adverse Events 
(TEAEs), physical examinations, laboratory assessments, and vital signs.  The number and percent of 
subjects experiencing TEAEs by treatment group will be tabulated by the Medical Dictionary for Drug 
Regulatory Activities (MedDRA®) system organ class (SOC) and preferred terms (PT).  In addition, 
summary of serious adverse events (SAEs) and TEAEs by severity and relationship to study drug as 
assessed by the Investigators will be provided.  SAEs, severe TEAEs, or TEAEs that lead to premature 
study discontinuation will be listed.  The changes in vital signs, physical examination results, and 
clinical laboratory variables at each visit as compared to baseline will be summarized.  Shift of 
laboratory values from baseline at defined time points will be tabulated.


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1.3
List of Abbreviations
ACR
American College of Rheumatology
AD
Atopic Dermatitis
ADL
Activities of Daily Living
AE
Adverse Event
ALC
Absolute Lymphocyte Count
ALT
Alanine Transaminase
ANC
Absolute Neutrophil Count
AP
Anteroposterior
AS
Ankylosing Spondylitis
ASAS
Assessment of SpondyloArthritis international Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
AST
Aspartate Transaminase
AUC
Area Under the Curve
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMIlin
Linear Bath Ankylosing Spondylitis Metrology Index
BCG
Bacille Calmette-Guérin 
bDMARD
Biologic Disease-Modifying Anti-Rheumatic Drug
BID
Twice Daily (Latin:  bis in die)
BUN
Blood Urea Nitrogen
CIA
Collagen-Induced Arthritis
CL/F
Apparent Clearance
Cmax
Maximum Observed Plasma Concentration
Cmin
Minimum Observed Plasma Concentration 
CNS
Central Nervous System
CPK
Creatine Phosphokinase
csDMARD
Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug
CRP
C-Reactive Protein
CSR
Clinical Study Report
CT
Computer Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events


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CXR
Chest X-ray
CYP
Cytochrome P450
DAS
Disease Activity Score 
DMARD
Disease-Modifying Anti-Rheumatic Drugs
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ePRO
Electronic Patient-Reported Outcome
ESR
Erythrocyte Sedimentation Rate
EU
European Union
EULAR
European League Against Rheumatism
FACIT-F
Functional Assessment of Chronic Illness Therapy – Fatigue
FAS
Full Analysis Set
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HBc Ab
Hepatitis B Core Antibodies
HBs Ab
Hepatitis B Surface Antibodies
HBs Ag
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HCV Ab
Hepatitis C Virus Antibody
HDL-C
High-density Lipoprotein Cholesterol
HI
Health Index
HIV
Human Immunodeficiency Virus
HIV Ab
Human Immunodeficiency Virus Antibody
HLA-B27
Human Leukocyte Antigen-B27
hsCRP
High Sensitivity C-reactive Protein
IAG
Imaging Acquisition Guideline
IBD
Inflammatory Bowel Disease
ICH
International Council on Harmonization
IEC
Independent Ethics Committee


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IGRA
Interferon-Gamma Release Assay
IL-17i
Interleukin-17 Inhibitor
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISI
Insomnia Severity Index
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
JAK
Janus Kinase
LDA
Low Disease Activity
LDL-C
Low-density Lipoprotein Cholesterol
MACE
Major Adverse Cardiovascular Event
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
MRI
Magnetic Resonance Imaging
mSASSS
Modified Stoke Ankylosing Spondylitis Spine Score
MTX
Methotrexate
NCI
National Cancer Institute
NK
Natural Killer
NKT
Natural Killer T
NMSC
Non-Melanoma Skin Cancer
NOAEL
No-Observed-Adverse-Effect-Level
NONMEM
Non-Linear Mixed Effect Modeling
nr-axSpA
non-radiographic Axial Spondyloarthritis
NRI
Non-Responder Imputation
NRS
Numerical Rating Scale
NSAID
Nonsteroidal Anti-inflammatory Drug
OC
Observed Cases
PCR
Polymerase Chain Reaction
PD
Premature Discontinuation
PGA
Physician's Global Assessment of Disease Activity
PK
Pharmacokinetic


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PPD
Purified Protein Derivative
PR
Partial Remission
PRN
As Needed
PRO
Patient-Reported Outcome
PsA
Psoriatic Arthritis
PT
Preferred Term
PtGA
Patient's Global Assessment of Disease Activity
QD
Once Daily (Latin:  quaqua die)
QoL
Quality of Life
QTcF
QT Interval Corrected for Heart Rate using Fridericia's Correction 
Formula
RA
Rheumatoid Arthritis
RBC
Red Blood Cell
RNA
Ribonucleic Acid
RoW
Rest of the World
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SI
Sacroiliac
SJC
Swollen Joint Count
SOC
System Organ Class
SpA
Spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
SSZ
Sulfasalazine
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
TEAE
Treatment-Emergent Adverse Event
TJC
Tender Joint Count
TNFi
Tumor Necrosis Factor Alpha Inhibitor
ULN
Upper Limit of Normal
UC
Ulcerative Colitis
US
United States
V/F
Apparent Volume of Distribution
VHP
Voluntary Harmonization Procedure
WBC
White Blood Cell


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WPAI
Work Productivity and Activity Impairment


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations ...............................................................................10
2.0
Table of Contents...................................................................15
3.0
Introduction ...........................................................................20
3.1
Differences Statement..............................................................................22
3.2
Benefits and Risks....................................................................................23
4.0
Study Objective......................................................................26
5.0
Investigational Plan...............................................................27
5.1
Overall Study Design and Plan:  Description ..........................................27
5.2
Selection of Study Population..................................................................34
5.2.1
Inclusion Criteria .....................................................................................34
5.2.2
Exclusion Criteria ....................................................................................36
5.2.3
Prior, Concomitant, and Prohibited Therapy ...........................................40
5.2.3.1
Prior Therapy ...........................................................................................40
5.2.3.2
Permitted Background AS Therapy.........................................................40
5.2.3.3
Prohibited Therapy...................................................................................42
5.2.4
Contraception Recommendations ............................................................46
5.3
Efficacy, Pharmacokinetic, Exploratory Research and Validation 
Studies, and Safety Assessments/Variables.............................................49
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................49
5.3.1.1
Study Procedures .....................................................................................49
5.3.1.2
Collection and Handling of Optional Samples for Exploratory 
Research and Validation Studies .............................................................73
5.3.2
Drug Concentration Measurements .........................................................75
5.3.2.1
Collection of Samples for Analysis .........................................................75
5.3.2.2
Measurement Methods.............................................................................76
5.3.3
Efficacy Variables....................................................................................76
5.3.3.1
Primary Variable......................................................................................76
5.3.3.2
Secondary Variable..................................................................................76


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5.3.3.3
Additional Variables ................................................................................77
5.3.4
Safety Variables.......................................................................................79
5.3.5
Pharmacokinetic Variables ......................................................................79
5.3.6
Exploratory Research Variables and Validation Studies.........................79
5.4
Removal of Subjects from Therapy or Assessment.................................80
5.4.1
Discontinuation of Individual Subjects....................................................80
5.4.2
Discontinuation of Entire Study...............................................................82
5.5
Treatments................................................................................................82
5.5.1
Treatments Administered.........................................................................82
5.5.2
Identity of Investigational Product...........................................................83
5.5.2.1
Packaging and Labeling...........................................................................83
5.5.2.2
Storage and Disposition of Study Drug ...................................................83
5.5.3
Method of Assigning Subjects to Treatment Groups...............................83
5.5.4
Selection and Timing of Dose for Each Subject......................................84
5.5.5
Blinding....................................................................................................85
5.5.5.1
Blinding of Investigational Product.........................................................85
5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)......................86
5.5.6
Treatment Compliance.............................................................................86
5.5.7
Drug Accountability.................................................................................87
5.6
Discussion and Justification of Study Design..........................................87
5.6.1
Discussion of Study Design and Choice of Control Groups....................87
5.6.2
Appropriateness of Measurements...........................................................88
5.6.3
Suitability of Subject Population .............................................................88
5.6.4
Selection of Doses in the Study ...............................................................89
6.0
Complaints .............................................................................90
6.1
Medical Complaints.................................................................................91
6.1.1
Definitions................................................................................................91
6.1.1.1
Adverse Event..........................................................................................91
6.1.1.2
Serious Adverse Events ...........................................................................92
6.1.1.3
Adverse Events of Special Interest ..........................................................93
6.1.2
Adverse Event Severity............................................................................94
6.1.3
Relationship to Study Drug......................................................................95
6.1.4
Adverse Event Collection Period.............................................................95


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6.1.5
Adverse Event Reporting.........................................................................96
6.1.6
Pregnancy.................................................................................................98
6.1.7
Toxicity Management ..............................................................................98
6.1.8
Data Monitoring Committee..................................................................103
6.1.9
Cardiovascular Adjudication Committee...............................................103
6.2
Product Complaint .................................................................................103
6.2.1
Definition ...............................................................................................103
6.2.2
Reporting................................................................................................104
7.0
Protocol Deviations..............................................................104
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................105
8.1
Statistical and Analytical Plans..............................................................105
8.1.1
Analysis Populations..............................................................................106
8.1.1.1
Full Analysis Set....................................................................................106
8.1.1.2
Per Protocol Analysis Set.......................................................................106
8.1.1.3
Safety Analysis Set ................................................................................106
8.1.2
Subject Accountability, Disposition and Study Drug Exposure............106
8.1.2.1
Subject Accountability...........................................................................106
8.1.2.2
Subject Disposition ................................................................................107
8.1.2.3
Study Drug Exposure.............................................................................107
8.1.3
Analysis of Demographic and Baseline Characteristics ........................107
8.1.4
Efficacy Analysis ...................................................................................108
8.1.4.1
Primary Efficacy Variables....................................................................108
8.1.4.2
Key Secondary Efficacy Variables ........................................................108
8.1.4.3
Additional Efficacy Variables................................................................109
8.1.4.4
Multiplicity Control for the Primary and Key Secondary 
Endpoints ...............................................................................................109
8.1.4.5
Imputation Methods...............................................................................109
8.1.4.6
Long-Term Efficacy...............................................................................110
8.1.5
Safety Analysis ......................................................................................110
8.1.5.1
General Considerations..........................................................................110
8.1.5.2
Analysis of Adverse Events...................................................................111
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE) ......................................111


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8.1.5.2.2
Serious Adverse Events and Death ........................................................112
8.1.5.3
Analysis of Laboratory and Vital Sign Data..........................................112
8.1.6
Pharmacokinetic and Exposure-Response Analyses .............................113
8.2
Determination of Sample Size ...............................................................113
8.3
Randomization Methods ........................................................................114
9.0
Ethics.....................................................................................114
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................114
9.2
Ethical Conduct of the Study.................................................................115
9.3
Subject Information and Consent...........................................................115
9.3.1
Informed Consent Form and Explanatory Material ...............................116
9.3.2
Revision of the Consent Form and Explanatory Material .....................116
10.0
Source Documents and Case Report Form 
Completion ...........................................................................117
10.1
Source Documents .................................................................................117
10.2
Case Report Forms.................................................................................117
11.0
Data Quality Assurance ......................................................120
12.0
Use of Information...............................................................121
13.0
Completion of the Study .....................................................121
14.0
Investigator's Agreement....................................................123
15.0
Reference List ......................................................................124
List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers....................................................................................................44
Table 2.
Clinical Laboratory Tests.........................................................................64
Table 3.
Identity of Investigational Product...........................................................83
Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values..................................................................................101
List of Figures
Figure 1.
Study Design............................................................................................30


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Figure 2.
Criteria for HBV DNA PCR Qualitative Testing ....................................67
Figure 3.
Adverse Event Collection ........................................................................96
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................131
Appendix B.
List of Protocol Signatories....................................................................133
Appendix C.
Modified New York Criteria for Ankylosing Spondylitis .....................134
Appendix D.
Local Requirements ...............................................................................135
Appendix E.
Study Activities......................................................................................142
Appendix F.
Optional Samples for Exploratory Research or Validation Studies.......149
Appendix G.
Latent TB Risk Assessment Form Example ..........................................150
Appendix H.
Protocol Amendment:  List of Changes.................................................151


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3.0
Introduction
Ankylosing Spondylitis
Spondyloarthritis (SpA) is a group of diseases that share common clinical, radiographic, 
and genetic features.1  This includes ankylosing spondylitis (AS), psoriatic arthritis (PsA), 
reactive arthritis, enteropathic or inflammatory bowel disease (IBD) related arthritis, and 
undifferentiated SpA.1  A more universally consistent way of categorizing SpA patients 
would be to define them by their primary and predominant clinical manifestation of axial 
or peripheral SpA.2
Axial SpA encompasses a spectrum of disease manifestations, which has been split into 
two categories, AS and non-radiographic axial SpA (nr-axSpA), due to the 1984 modified 
New York criteria, which require the presence of sacroiliitis on plain conventional 
radiographs for the classification of AS.3  Clinically, patients with AS and nr-axSpA have 
comparable clinical manifestations and burden of disease, with the sole differentiating 
characteristic between the two categories of axial SpA being the presence of sacroiliitis 
visualized by plain radiographs for the classification of AS.4,5
The Assessment of SpondyloArthritis international Society (ASAS) has proposed and 
validated new classification criteria for patients with axial SpA6 and for those with 
peripheral SpA.2
The prevalence of AS differs between regions and has been estimated to be up to 0.5%7-9
with similar estimated prevalence rates for nr-axSpA, resulting in an overall prevalence 
for axial SpA in the United States of approximately up to 1% or even higher in the overall 
population.10,11
Recently, the ASAS and European League Against Rheumatism (EULAR) have 
published updated treatment recommendations for the whole group of axial SpA.12  The 
first-line treatment of axial SpA consists of NSAIDs.  After the failure of one NSAID, a 
change to a second NSAID is recommended.  In patients with persistently high disease 
activity despite a course of two NSAIDs given over a total of at least 4 weeks, initiation of 


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a biologic disease-modifying anti-rheumatic drug (bDMARD) is recommended, and 
current practice is to start with a tumor necrosis factor alpha inhibitor (TNFi).  If TNFi 
therapy fails, switching to another TNFi or an interleukin 17 inhibitor (IL-17i) is 
recommended.  This recommendation is based on randomized controlled AS studies with 
TNFi and the IL-17i secukinumab that showed an overall good benefit-risk profile.13-20  
Several TNFi have also been successfully evaluated in nr-axSpA in controlled 
studies.17,21-23  Despite recent advances in the treatment of axial SpA, there remains a 
significant unmet medical need as only approximately 45% to 50% of patients show an 
ASAS 40 response and only approximately 15% to 20% achieve a state of remission.  In 
addition, treatment options are still limited when compared with other rheumatic diseases 
such as rheumatoid arthritis (RA) or PsA.  In axial SpA, csDMARDs and long-term 
corticosteroids are not efficacious and therefore not recommended for treatment of axial 
symptoms.12
Other than TNFi and secukinumab, ustekinumab, an IL-12/23 inhibitor, has shown 
efficacy in axial SpA in a small open-label Phase 2 trial.24  Also, recently, the JAK 
inhibitor tofacitinib has demonstrated efficacy in a placebo-controlled Phase 2 AS study, 
showing efficacy on signs and symptoms, as well as reduction of active inflammation 
both in the spine and sacroiliac (SI) joints on MRI.25
Overview of Upadacitinib (ABT-494)
Inhibition of JAK-mediated pathways is a promising approach for the treatment of 
patients with chronic inflammatory diseases such as axial SpA.  AbbVie is developing a 
small molecule inhibitor of JAK, upadacitinib, that may address the current needs.
The JAK family is composed of 4 family members:  JAK1, 2, 3, and Tyrosine kinase 2 
(Tyk2).  These cytoplasmic tyrosine kinases are associated with membrane cytokine 
receptors such as common gamma-chain receptors and the glycoprotein 130 
transmembrane proteins.26  Activation of JAK pathways initiates expression of survival 
factors, cytokines, chemokines, and other molecules that facilitate leukocyte cellular 


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trafficking and cell proliferation, which contribute to inflammatory and autoimmune 
disorders.
Hence, the JAK family has evoked considerable interest in the area of inflammatory 
diseases, leading to the development of various JAK inhibitors with different selectivity 
profiles against JAK1, JAK2, JAK3, and Tyk2.  Tofacitinib, the first in this class, has 
been approved in the United States, Europe, and in other countries for treating moderately 
to severely active RA patients.  Although tofacitinib, a non-selective JAK inhibitor, 
improves the clinical signs and symptoms and inhibits structural progression in RA 
patients, questions regarding the safety profile remain, including serious infections, herpes 
zoster reactivation, malignancies, and hematologic adverse events (AEs).
The second generation of JAK inhibitors, with different selectivity profiles against JAK1, 
JAK2, JAK3, and Tyk2, are in development.  Upadacitinib is a novel JAK1 inhibitor 
being developed for the treatment of adult patients with inflammatory diseases (RA, 
Crohn's disease [CD], ulcerative colitis [UC], atopic dermatitis [AD], and PsA).  Based on 
in vitro selectivity assays and in vivo animal models, upadacitinib has demonstrated 
inhibition of JAK1 at efficacious drug exposure levels.  The enhanced selectivity of 
upadacitinib may have the potential for an improved benefit/risk profile by mitigating 
JAK2 inhibitory effects on erythropoiesis and myelopoiesis.  Upadacitinib is also less 
potent against JAK3, an important component of lymphocyte activation and function.  As 
such, treatment with upadacitinib, a selective JAK1 inhibitor with reduced JAK3 
inhibition, could result in a decreased risk for infection (including viral reactivation) 
and/or malignancy compared to less selective JAK inhibitors.
Additional information regarding indications under study can be found in the current 
Investigator's Brochure.27
3.1
Differences Statement
Study M16-098 differs from other upadacitinib studies as it is the first study to evaluate 
the safety and efficacy of upadacitinib in subjects with AS.


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3.2
Benefits and Risks
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.27  The results of all genetic toxicology testing indicate that 
upadacitinib is not genotoxic.  Embryonic and fetal development studies indicate that 
upadacitinib is teratogenic in both rats and rabbits.  Based on these findings, all women of 
childbearing potential must agree to use protocol-specified pregnancy avoidance measures 
as outlined in the protocol.
To date, upadacitinib has been studied in two Phase 2 studies in subjects with RA and is 
being evaluated in CD, UC, AD, and PsA.  Two Phase 2 studies have been completed:  
two randomized controlled trials (Study M13-550 [NCT01960855] and Study M13-537 
[NCT02066389]) in 575 subjects with moderately to severely active RA on background 
methotrexate (MTX).  Four Phase 2 studies are ongoing:  one open-label extension to the 
completed RA studies (Study M13-538 [NCT02049138]); one randomized, dose-ranging, 
placebo-controlled study in subjects with moderately to severely active CD 
(Study M13-740 [NCT02365649]); one randomized, double-blind, placebo-controlled 
study in subjects with moderately to severely active UC (Study M14-234 
[NCT02819635]); and one randomized, dose-ranging, placebo-controlled study in 
subjects with moderate to severe AD (Study M16-048 [NCT02925117]).  The Phase 3 
clinical development programs for RA and PsA have been initiated, and enrollment in the 
RA studies is ongoing.
Results are available from two RA Phase 3 clinical trials (Study M13-549 
[NCT02675426] and Study M13-542 [NCT02706847]) evaluating upadacitinib 15 mg 
QD and 30 mg QD in subjects with moderate to severe RA.  Study M13-549 evaluated 
upadacitinib compared to placebo in subjects with inadequate response to csDMARDs.  
At Week 12, among subjects receiving upadacitinib 15 mg (n = 221) or 30 mg QD 
(n = 219), 64% and 66% achieved ACR20, respectively, compared to 36% of subjects 
receiving placebo (n = 221) (P < 0.001).  Similarly, the rate of subjects achieving ACR50 
and ACR70 was also significantly higher in the upadacitinib groups – ACR50 of 38%, 


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43%, and 15% and ACR70 of 21%, 27%, and 6% in the upadacitinib 15 mg, 30 mg, and 
placebo groups, respectively (P < 0.001 for all comparisons).  Low disease activity 
(LDA), based on a DAS28 (CRP) of ≤ 3.2, was achieved by 48% of subjects receiving 
either dose of upadacitinib, compared to 17% of subjects receiving placebo (P < 0.001).28
Study M13-542 evaluated upadacitinib compared to placebo in subjects with inadequate 
response to bDMARDs.  At Week 12, among subjects receiving upadacitinib 15 mg 
(n = 164) or 30 mg QD (n = 165), 65% and 56% of subjects receiving upadacitinib 15 mg 
or 30 mg QD achieved ACR20, respectively, compared to 28% of subjects receiving 
placebo (n = 169) (P < 0.001).  Similarly, the rate of subjects achieving ACR50 and 
ACR70 was also higher in the upadacitinib groups – ACR50 of 34%, 36%, and 12% and 
ACR70 of 12%, 23%, and 7% in the upadacitinib 15 mg, 30 mg, and placebo groups, 
respectively (P < 0.001 for all comparisons except ACR70 for the 15 mg dose).  Low 
disease activity, based on a DAS28 (CRP) of ≤ 3.2, was achieved by 43% and 42% of 
subjects receiving upadacitinib 15mg and 30 mg, respectively, compared to 14% of 
subjects receiving placebo (P < 0.001).29
Data on the safety of treatment with upadacitinib are available from the Phase 2 studies in 
patients with RA.30,31  Safety data from these two Phase 2 studies (N = 575) showed that 
the types and frequencies of AEs during upadacitinib treatment were consistent with 
subjects with moderately to severely active RA receiving immunomodulatory therapy.  
The incidences of AEs were numerically higher in the upadacitinib dose groups, with a 
trend toward higher rates with higher doses of upadacitinib.  The most frequently reported 
AEs (≥ 5%) in the upadacitinib-treated subjects were urinary tract infection, headache, 
upper respiratory tract infection, and nausea.  There were 6 subjects (1.3% of total 
combined populations) with herpes zoster reactivation distributed across the upadacitinib 
dose groups, and 2 subjects (1.9%) in the placebo groups.  In these two 12-week studies, a 
total of 2 subjects in the upadacitinib treatment groups reported malignancies.  
One subject reported non-melanoma skin cancers (NMSC) (basal cell and squamous cell 
carcinoma), and 1 subject was diagnosed with lung cancer 11 days after the final 
scheduled visit and subsequently died 14 weeks after study completion.  These events 


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were reported by the Investigators as not possibly related to study drug.  No events of 
gastrointestinal perforation were reported.  Elevations of liver function tests were sporadic 
with no clear dose-response relationship observed.  
As observed with other JAK inhibitors, treatment with upadacitinib resulted in an increase 
in lipids (low-density lipoprotein cholesterol [LDL-C] and high density lipoprotein 
cholesterol [HDL-C]).  There was a trend for lower red blood cell counts, especially at the 
two highest doses (12 mg twice daily [BID] and 18 mg BID); lower white blood cell 
counts; and reductions in Natural Killer (NK) cells.  Among subjects with laboratory 
evidence of systemic inflammation (as evidenced by hsCRP > upper limit of normal 
[ULN]), treatment with lower doses of upadacitinib (3 mg BID and 6 mg BID) was 
associated with improvements in mean hemoglobin relative to placebo.  At higher doses, 
there was a reduction in mean hemoglobin; however, the mean hemoglobin levels 
remained within normal range throughout the treatment period.  In the two Phase 3 studies 
in RA (Studies M13-549 and M13-542), the safety profile was consistent with that 
observed in the upadacitinib Phase 2 clinical trials in RA.  Events of deep vein thrombosis 
and pulmonary embolism have been reported in patients receiving JAK inhibitors 
including upadacitinib.
No studies in subjects with axial SpA have been performed with upadacitinib.  The ability 
of upadacitinib to modulate inflammation and bone formation in vivo was assessed using 
collagen-induced arthritis (CIA) in rats.  The extended rat CIA preclinical model is 
supportive of inflammation-driven new bone formation in SpA.  Oral doses of 
upadacitinib at 1, 3 and 10 mg/kg BID for 4 weeks, starting at peak inflammation in the 
model, resulted in a dose-dependent inhibition of inflammation, as well as bone 
destruction and new bone formation based on paw swelling scores, microCT evaluation of 
bone, and histologic evaluation of the arthritic paw.  At the study endpoint, there was both 
significant joint destruction and periosteal bone formation in the arthritic ankle in vehicle-
treated animals.  Upadacitinib inhibition of new bone formation in an extended rat CIA 
model provides supportive data for further evaluation of upadacitinib in axial SpA.


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In summary, upadacitinib is a novel selective JAK1 inhibitor with the ability to decrease
joint inflammation and damage mediated by JAK signaling.  The Phase 2 program with 
upadacitinib in RA demonstrated efficacy for improvement in signs and symptoms of RA, 
and the safety results were consistent with those known to be associated with JAK 
inhibition.30-40  Current clinical data have not identified any new safety issues of concern 
compared to what is known about JAK inhibition in immune-mediated inflammatory 
diseases.  Upadacitinib is currently being tested in Phase 3 in RA.  Also, the Phase 2 study 
with tofacitinib established proof of mechanism of JAK inhibition in AS.25
Taken together, the data from a preclinical extended rat CIA model, the safety and 
efficacy data from the Phase 2 RA program and two Phase 3 studies in RA, as well as the 
data from the tofacitinib Phase 2 AS study, support the investigation of upadacitinib 
15 mg QD in subjects with AS.  A detailed rationale on the selection of the dose is 
provided in Section 5.6.4. The current Phase 2/3 Study M16-098 will assess the benefit-
to-risk profile of upadacitinib in subjects with active AS who have had an inadequate 
response to at least two NSAIDs or intolerance to or a contraindication for NSAIDs, and 
who are bDMARD-naïve.
4.0
Study Objective
The primary objectives of the study are:
Period 1
1.
To evaluate the efficacy of upadacitinib compared with placebo on reduction of 
signs and symptoms as measured by the proportion of subjects who achieve an 
ASAS 40 response at Week 14 in subjects with active AS who have had an 
inadequate response to at least two NSAIDs or intolerance to or a contraindication 
for NSAIDs, and who are bDMARD-naïve.
2.
To assess the safety and tolerability of upadacitinib in subjects with active AS who 
have had an inadequate response to at least two NSAIDs or intolerance to or a 
contraindication for NSAIDs, and who are bDMARD-naïve.


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Period 2
To evaluate the safety, tolerability, and efficacy of upadacitinib through up to 2 years of 
treatment in subjects who have completed Period 1.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2/3 multicenter study that includes two periods.  Period 1 is a 14-week 
randomized, double-blind, parallel-group, placebo-controlled period designed to compare 
the safety and efficacy of upadacitinib 15 mg QD versus placebo for the treatment of 
subjects with active AS who have had an inadequate response to at least two NSAIDs 
over an at least 4-week period in total at maximum recommended or tolerated doses or 
intolerance to or a contraindication for NSAIDs as defined by the Investigator, and who 
are bDMARD-naïve.
Period 2 is an open-label long-term extension to evaluate the long-term safety, 
tolerability, and efficacy of upadacitinib 15 mg QD in subjects with AS who have 
completed Period 1.
The study was designed to enroll approximately 170 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.
The study duration will include a 35-day screening period; a 14-week randomized, 
double-blind, placebo-controlled period (Period 1); a 90-week open-label extension period 
(Period 2); and a 30-day follow-up visit.
X-ray of the pelvis will be performed within the 35-day screening period to evaluate the 
SI joints to confirm the fulfillment of the modified New York Criteria for AS 
(Appendix C).  X-ray of the spine will also be performed within the 35-day screening 
period to assess for total spinal ankylosis; subjects with total spinal ankylosis are not 
eligible for this study.  The x-rays of the spine and pelvis will not be required during the 


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Screening Period if the subject had a previous anteroposterior (AP) pelvis x-ray and 
lateral spine x-rays within 90 days of the Screening Period, provided that the x-rays are 
confirmed to be adequate for the required evaluations and are deemed acceptable by the 
central imaging vendor.
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of 
two treatment groups:
●
Group 1:  Upadacitinib 15 mg QD (n = 85)
●
Group 2:  Placebo (n = 85)
Randomization will be stratified by Screening hsCRP (≤ ULN vs. > ULN) and geographic 
region (United States [US]/Canada, Japan, Rest of the World [RoW]).
If entering the study on concomitant csDMARDs (i.e., MTX, leflunomide, sulfasalazine 
[SSZ], and/or hydroxychloroquine), the subject must be on a stable dose for ≥ 4 weeks 
prior to the first dose of study drug.  If entering the study on concomitant oral 
corticosteroids, subject must be on a stable dose of prednisone (≤ 10 mg/day) or oral 
corticosteroid equivalents for at least 14 days prior to the first dose of study drug.  The 
dose(s) of csDMARDs and corticosteroids should remain stable throughout the study 
(except as described for rescue therapy), but may be decreased only for safety reasons.
If entering the study on concomitant NSAIDs, tramadol, combination of acetaminophen 
and codeine or hydrocodone, and/or non-opioid analgesics, subject must be on stable 
dose(s) for at least 14 days prior to the first dose of study drug and should remain stable 
throughout the study (except as described for rescue therapy), but may be decreased only 
for safety reasons.
Starting at Week 16, subjects who do not achieve at least an ASAS 20 response at
two consecutive visits will have the option to add or modify doses of NSAIDs, 
acetaminophen/paracetamol, low potency opioid medications (tramadol or combination of 


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acetaminophen and codeine or hydrocodone), and/or modifydose of MTX or SSZ at 
Week 20 or thereafter.
Starting at Week 24, subjects who still do not achieve at least an ASAS 20 response at 
two consecutive visits will be discontinued from study drug treatment.
Subjects who complete the Week 14 visit (end of Period 1) will enter the open-label 
long-term extension portion of the study, Period 2 (90 weeks).  Subjects who are assigned 
to upadacitinib in Period 1 will continue to receive upadacitinib 15 mg QD in an open-
label manner.  Subjects who were randomized to placebo at Baseline will also receive 
open-label upadacitinib 15 mg QD at Week 14.
The primary analysis will be conducted after all subjects have completed Week 14 or have 
prematurely discontinued prior to Week 14.  Study sites and subjects will remain blinded 
for the duration of the study (Periods 1 and 2).
Optional samples may be collected for exploratory research at designated time points 
throughout the study.
Subjects will have an x-ray of the spine at Week 104.  All subjects who meet eligibility 
criteria will have an MRI evaluation of the SI joints, as well as the cervical, thoracic, and 
lumbar regions of the spine, prior to or at the Baseline Visit, at Week 14, and Week 104.
Subjects at select sites who consent to participate in the low-dose CT scan substudy and 
meet eligibility criteria will have low-dose CT scan evaluation of the whole spine 
(cervical, thoracic, and lumbar spine) prior to or at the Baseline Visit, Week 52, and 
Week 104.
Study design schematic is shown in Figure 1.


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Figure 1.
Study Design
AS = ankylosing spondylitis; ASAS = Assessment of SpondyloArthritis international Society; BASDAI = Bath 
Ankylosing Spondylitis Disease Activity Index; bDMARD = biologic disease-modifying antirheumatic drugs; 
CT = computer tomography; hsCRP = high sensitivity C-reactive protein; MRI = magnetic resonance imaging; 
NRS = numeric rating scale; NSAIDs = nonsteroidal anti-inflammatory drugs; QD = once daily; RoW = Rest of the 
World; SSZ = Sulfasalazine; ULN = upper limit of normal; W = week
a.
Clinical diagnosis of AS and meeting the modified New York Criteria for AS.  Subject must have baseline disease 
activity as defined by having BASDAI score ≥ 4 and Patient's Assessment of Total Back Pain score ≥ 4 based on a 
0 – 10 NRS at the Screening and Baseline Visit.
b.
Stratified by geographic region (US/Canada, Japan, RoW) and hsCRP (≤ ULN vs. > ULN).
c.
The x-rays of the spine and pelvis will not be required during the Screening Period if the subject had a previous 
anteroposterior pelvis x-ray and lateral spine x-rays within 90 days of the Screening Period, provided that the 
x-rays are confirmed to be adequate for the required evaluations and are deemed acceptable by the central imaging 
vendor.
d.
For subjects at select sites who consent to participation in the low-dose CT scan substudy.


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Figure 1.
Study Design (Continued)
e.
Starting at Week 16, subjects who do not achieve at least an ASAS 20 response at two consecutive visits will have 
the option to add or modify doses of NSAIDs, acetaminophen/paracetamol, low potency opioid medications 
(tramadol or combination of acetaminophen and codeine or hydrocodone), and/or modify dose of MTX or SSZ at 
Week 20 or thereafter.
f.
Starting at Week 24, subjects who still do not achieve at least an ASAS 20 response at two consecutive visits will 
be discontinued from study drug treatment.
Screening Period
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures and then provide a signed and dated informed consent 
before undergoing the screening procedures outlined in Section 5.3.1.1.  Lab values can 
be re-tested once during the screening period.  If the re-tested lab value(s) remain(s) 
exclusionary, the subject will be considered a screen failure.  Redrawing samples if initial 
samples were unable to be analyzed would not count as a retest since an initial result was 
never obtained.
Subjects that initially screen fail for the study are permitted to re-screen once following 
re-consent.  Lab values can be re-tested once during the re-screening period.  For 
additional re-screening, AbbVie Therapeutic Area Medical Director (TA MD) approval is 
required.  All screening procedures with the possible exceptions noted below will be 
repeated during re-screening.  The subject must meet all the inclusion and none of the 
exclusion criteria at the time of re-screening in order to qualify for the study.  There is no 
minimum period of time a subject must wait to re-screen for the study.
If the subject had a complete initial screening evaluation, including the following 
assessments, these tests will not be required to be repeated for re-screening provided the 
conditions noted in Section 5.2 are met, there are no changes in the subject's medical 
history that would warrant re-testing, and no more than 90 days have passed:
●
Hepatitis B virus (HBV), Hepatitis C virus (HCV), and human 
immunodeficienty virus (HIV) serology


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●
Interferon-Gamma Release Assay (IGRA; QuantiFERON Tuberculosis [TB] 
Gold In Tube test or equivalent) and/or a purified protein derivative (PPD) test 
(or both if required per local guidelines)
●
Chest x-ray (CXR)
●
Electrocardiogram (ECG)
The x-rays of the spine and pelvis will not be required during the Screening Period if the 
subject had a previous AP pelvis x-ray and lateral spine x-rays within 90 days of the 
Screening Period, provided that the x-rays are confirmed to be adequate for the required 
evaluations and are deemed acceptable by the central imaging vendor.
Period 1 (14-Week Randomized, Double-Blind, Placebo-Controlled Treatment 
Period)
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 14 Visit.  At the 
Baseline Visit, subjects who meet all the inclusion criteria and none of the exclusion 
criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the study and 
randomized to double-blind treatment.  During this period of the study, subjects will visit 
the study site at Weeks 2, 4, 8, 12, and 14.  A ± 3 day window is permitted around 
scheduled study visits.  The last dose of oral study drug in Period 1 is taken the day prior 
to the Week 14 visit.
Period 2 (90-Week Open-Label Extension Period)
Period 2 will begin at the Week 14 visit after all assessments have been completed.  At 
Week 14, subjects on placebo will receive open-label upadacitinib 15 mg QD.  Subjects 
on upadacitinib 15 mg QD will continue to receive the same treatment in an open-label 
manner.  During Period 2, subjects will have a study visit at Weeks 16, 20, 24, 32, 40, 52, 
64, 76, 88, 96, and 104.  A ± 7 day window is permitted around scheduled study visits.  
Starting at Week 24, subjects who do not achieve at least an ASAS 20 response compared 
with Baseline at two consecutive visits will be discontinued from study drug treatment 
(see Section 5.4.1).


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Discontinuation of Study Drug and Continuation of Study Participation
Subjects may discontinue study drug treatment, but may choose to continue to participate 
in the study (refer to Section 5.4.1 for additional details).  Subjects who prematurely 
discontinue study drug should complete a Premature Discontinuation (PD) Visit as soon 
as possible, preferably within 2 weeks.  Afterwards, subjects should follow the regular 
visit schedule and adhere to all study procedures except for dispensing study drug, 
pharmacokinetic (PK) sample collection, and blood sample collection for optional 
exploratory research and validation studies.  In addition, future ASAS 20 nonresponse 
discontinuation criteria 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.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
Subjects may withdraw from the study completely (withdrawal of informed consent) for 
any reason at any time (refer to Section 5.4.1 for additional details).  If a subject 
prematurely discontinues study drug treatment AND study participation (withdrawal of 
consent), the procedures outlined for the PD Visit should be completed as soon as 
possible, preferably within 2 weeks of study drug discontinuation.  In addition, a 30-day 
follow-up visit (or phone call if a visit is not possible) should occur to determine the status 
of any ongoing AEs/serious adverse events (SAEs) or the occurrence of any new 
AEs/SAEs.
Follow-Up Period
A Follow-Up Visit (or phone call if a visit is not possible) will occur approximately 
30 days after the last dose of study drug to obtain information on any new or ongoing 
AE/SAEs and to collect vital signs and clinical laboratory tests.
Subjects will complete the Follow-Up Visit when they have either:
●
Completed the last visit of the study; OR


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●
Prematurely discontinued study drug and/or study participation and have 
completed a PD visit.  In this case the 30 day Follow-Up Visit may be a 
telephone call if a site visit is not possible.  Vital signs and laboratory tests 
may not be required.  The Follow-Up Visit is not applicable for subjects who 
discontinued study drug and continued study participation and completed at 
least one study visit at least 30 days after last dose of study drug.
5.2
Selection of Study Population
It is anticipated that approximately 170 subjects with AS will be randomized at 
approximately 107 study centers, globally.
A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria specified in Section 5.2.1 and none of the exclusion criteria specified in 
Section 5.2.2 of this protocol.
5.2.1
Inclusion Criteria
1.
Male or female ≥ 18 years of age.
2.
Subject with a clinical diagnosis of AS and meeting the modified New York 
Criteria for AS (Appendix C).2
3.
Subject must have baseline disease activity as defined by having a Bath 
Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 and a Patient's 
Assessment of Total Back Pain score ≥4 based on a 0 – 10 Numeric Rating Scale 
(NRS) at the Screening and Baseline Visits.
4.
Subject has had an inadequate response to at least two 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.
5.
Women of childbearing potential (refer to Section 5.2.4), must not have a positive 
serum pregnancy test at the Screening Visit and must have a negative urine 
pregnancy test at the Baseline Visit prior to study drug dosing.  Note:  subjects with 


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borderline serum pregnancy test at Screening must have a serum pregnancy test 
≥3 days later to document continued lack of a positive result and the subject can be 
enrolled into the study in the absence of clinical suspicion of pregnancy and other 
pathological causes of borderline results.
6.
If female, subject must be postmenopausal, OR permanently surgically sterile, OR 
for women of childbearing potential practicing at least one protocol-specified 
method of birth control (refer to Section 5.2.4), that is effective from Study Day 1 
through at least 30 days after the last dose of study drug. 
●
Additional local requirements may apply. Refer to Appendix D for local
requirements.
7.
If male, and subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 30 days after the last dose of 
oral study drug, to practice the protocol-specified contraception (refer to 
Section 5.2.4).
●
Additional local requirements may apply.  Refer to Appendix D for local 
requirements.
8.
If entering the study on concomitant MTX, leflunomide, SSZ, and/or 
hydroxychloroquine, subject must be on a stable dose of MTX (≤ 25 mg/week) 
and/or SSZ (≤ 3 g/day) and/or hydroxychloroquine (≤ 400 mg/day) or leflunomide 
(≤ 20 mg/day) for at least 28 days prior to the Baseline Visit.  A combination of up 
to two background csDMARDs is allowed EXCEPT the combination of MTX and 
leflunomide.
9.
If entering the study on concomitant oral corticosteroids, subject must be on a 
stable dose of prednisone (≤ 10 mg/day), or oral corticosteroid equivalents, for at 
least 14 days prior to the Baseline Visit.
10.
If entering the study on concomitant NSAIDs, tramadol, combination of 
acetaminophen and codeine or hydrocodone, and/or non-opioid analgesics, subject 
must be on stable dose(s) for at least 14 days prior to the Baseline Visit.


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11.
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, 
CXR, and a 12-lead ECG performed at the Screening Visit.
12.
Subjects must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study-specific procedures.  For subjects in Japan 
only:  In case of subjects under 20 years of age, the subjects and their parents or 
legal guardians must voluntarily sign and date an informed consent.
Rationale for the Inclusion Criteria
Inclusion Criteria
Rationale
1 – 4, 8 – 11
To select the appropriate subject population for this study
5 – 7
The effect of upadacitinib on pregnancy and reproduction is 
unknown
12
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Prior exposure to any JAK inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Prior exposure to any biologic therapy with a potential therapeutic impact on SpA 
(refer to Section 5.2.3.3 for examples of prohibited biologic therapy).
3.
Subject has been treated with any investigational drug within 30 days or 
five half-lives of the drug (whichever is longer) prior to the first dose of study drug 
or is currently enrolled in another clinical study.


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4.
Intra-articular joint injections, spinal/paraspinal injection(s), or parenteral 
administration of corticosteroids within 28 days prior to the Baseline Visit.  Inhaled 
or topical corticosteroids are allowed.
5.
Subject on any other DMARDs (other than those allowed), thalidomide, or 
apremilast within 28 days or five half-lives (whichever is longer) of the drug prior 
to the Baseline Visit.
6.
Subject on opioid analgesics (except for combination acetaminophen/codeine or 
acetaminophen/hydrocodone which are allowed) or use of inhaled marijuana within 
14 days prior to the Baseline Visit.
7.
Subject has a 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, fibromyalgia), or any arthritis with onset prior to 17 years of age.
8.
Subject with extra-articular manifestations (e.g., psoriasis, uveitis, or IBD) that are 
not clinically stable for at least 30 days prior to study entry.
9.
Subject has total spinal ankylosis.
10.
Subject has undergone spinal or joint surgery at joints to be assessed within this 
study within 60 days prior to the Baseline Visit or subject has been diagnosed with 
a spinal condition that may interfere with study assessments (i.e., disc herniation, 
degenerative spine disease, etc.) in the opinion of the Investigator.
11.
Subject is permanently wheelchair-bound or bedridden.
12.
Receipt of any live vaccine within 4 weeks (8 weeks in Japan) prior to the 
first dose of study drug, or expected need of live vaccination during study 
participation including at least 4 weeks (8 weeks in Japan) after the last dose of 
study drug.
13.
Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong 
CYP3A inducers from Screening through the end of the study (refer to Table 1 for 
examples of commonly used strong CYP3A inhibitors and inducers).


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14.
Use of oral traditional Chinese medicine within 4 weeks prior to the Baseline visit.
15.
Any active, chronic or recurrent viral infection that, based on the Investigator's 
clinical assessment, makes the subject an unsuitable candidate for the study, 
including hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or 
disseminated (even a single episode) herpes zoster, disseminated (even a single 
episode) herpes simplex, or human immunodeficiency virus (HIV).  HBV, HCV, 
and HIV infections are defined as:
●
HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity
on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) 
qualitative test for Hepatitis B core antibody (HBc Ab) positive (+) subjects 
(and for Hepatitis B surface antibody (HBs Ab) positive [+] subjects in Japan 
only);
●
HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV
antibody (HCV Ab).
●
HIV: confirmed positive anti-HIV antibody (HIV Ab) test.
16.
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB testing).
17.
Active infection(s) requiring treatment with parenteral anti-infectives within 
30 days, or oral anti-infectives within 14 days prior the first dose of study drug.
18.
History of any malignancy except for successfully treated NMSC or localized 
carcinoma in situ of the cervix.
19.
History of gastrointestinal perforation (other than appendicitis or penetrating 
injury), diverticulitis or significantly increased risk for gastrointestinal perforation 
per Investigator judgment.
20.
Conditions that could interfere with drug absorption including but not limited to 
short bowel syndrome.
21.
Subject has been a previous recipient of an organ transplant.


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22.
History of recent (within past 6 months) cerebrovascular accident, myocardial 
infarction, or coronary stenting.
23.
History of any condition which, in the opinion of the Investigator, would put the 
subject at risk by participating in the protocol.
24.
History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months.
25.
History of an allergic reaction or significant sensitivity to constituents of the study 
drug(s) (and their excipients) and/or other products in the same class.
26.
Subject has contraindication to MRI or any condition that would interfere with the 
ability to perform an MRI.
27.
Female subject who is breastfeeding or considering becoming pregnant during the 
study.
28.
Laboratory values meeting the following criteria within the Screening period prior 
to the first dose of study drug:
●
Serum aspartate transaminase (AST) > 2 × ULN;
●
Serum alanine transaminase (ALT) > 2 × ULN;
●
Estimated glomerular filtration rate (GFR) by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula 
< 40 mL/min/1.73 m2;
●
Hemoglobin < 10 g/dL;
●
Total white blood cell count (WBC) < 2,500/μL;
●
Absolute neutrophil count (ANC) < 1,500/μL;
●
Absolute lymphocyte count < 800/μL;
●
Platelet count < 100,000/μL.
29.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study.
30.
For Japan subjects only:  positive result of beta-D-glucan.


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Rationale for the Exclusion Criteria
Exclusion Criteria
Rationale
1 – 2, 9 – 11
To select the appropriate subject population in the study
3 – 8, 12 – 26, 28 – 30
To ensure safety of the subjects throughout the study
27
The impact of upadacitinib on pregnancies is unknown
5.2.3
Prior, Concomitant, and Prohibited Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the subject is receiving within 28 days prior to 
Screening, or receives during the study, must be recorded along with the reason for use, 
date(s) of administration including start and end dates, and dosage information including 
dose, route, and frequency on the appropriate eCRF.  Also, medications including but not 
limited to DMARDs taken for AS since date of AS diagnosis (based on subject 
recollection and available medical records) should be entered into the appropriate eCRF.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapies.
5.2.3.1
Prior Therapy
All prior drug therapies for AS since initial diagnosis must be recorded in the eCRF, along 
with the dates of first and last dose, maximum dosage taken, route of administration, and 
reason for discontinuation, if known.  Additionally, the Investigator will record history of 
response to NSAIDs (e.g., no response, inadequate response, loss of response), intolerance 
to NSAIDs, and/or contraindication for NSAIDs.
5.2.3.2
Permitted Background AS Therapy
Subjects should continue on their stable (≥ 4 weeks prior to the first dose of study drug) 
background csDMARD therapy (restricted to oral or parenteral MTX [≤ 25 mg per week], 
SSZ [≤ 3 g/day], hydroxychloroquine [≤ 400 mg/day], and leflunomide [≤20 mg/day]) 


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throughout the study.  A combination of up to two background csDMARDs is allowed 
EXCEPT the combination of MTX and leflunomide.  At any time, the csDMARD dose 
may be decreased only for safety reasons.  Subjects taking MTX should take a dietary 
supplement of oral folic acid (or equivalent such as folinic acid) throughout study 
participation.  Folic acid dosing and timing of regimen should be followed according to 
Investigator's instructions.  AbbVie will not provide the csDMARDs (or folic acid, if 
taking MTX).
Subjects should also continue on their stable doses of NSAIDs, tramadol, combination 
acetaminophen/codeine, acetaminophen/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 acetaminophen/codeine, 
acetaminophen/hydrocodone, and/or non-opioid analgesics, or oral corticosteroids may be 
decreased only 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.
●
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 the 24 hours prior to any study visit to avoid 
bias in outcome measurements.
For subjects on concomitant NSAID therapy, the NSAID eCRF should be completed.41
One intra-articular corticosteroid injection for a peripheral joint will be allowed during 
Period 1 of the study.  In Period 2, intra-articular corticosteroid injections for peripheral 
joints are allowed at the Investigator's discretion.  Once a joint is injected, it will be 
considered not evaluable/assessable ("NA") during the 90 days following injection.  PRN 
use of inhaled corticosteroids is permitted at any time.


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In the event of tolerability (or other safety) issues, the doses of these medications may be 
decreased or discontinued.
Rescue Therapy
Starting at Week 16, subjects who do not achieve at least an ASAS 20 response at
two consecutive visits will have the option to add or modify doses of NSAIDs, 
acetaminophen/paracetamol, low potency opioid medications (tramadol or combination of 
acetaminophen and codeine or hydrocodone), and/or modifydose of MTX or SSZ at 
Week 20 or thereafter (after assessments have been performed).  Change in dose or 
addition of DMARDs other than MTX or SSZ is not permitted for rescue.
Starting at Week 24, subjects who still do not achieve at least an ASAS 20 response at 
two consecutive visits will be discontinued from study drug treatment.
5.2.3.3
Prohibited Therapy
JAK Inhibitor
Prior exposure to JAK inhibitors (including but not limited to tofacitinib [Xeljanz®], 
baricitinib, and filgotinib) is not allowed.
Corticosteroids
Spinal/paraspinal and SI joint injection(s) or parenteral administration of corticosteroids 
are not allowed, and subjects must have discontinued use at least 28 days prior to the 
first dose of study drug.
Inhaled or topical corticosteroids are allowed.
Biologic Therapies
All biologic therapies with a potential therapeutic impact on SpA are prohibited during the 
study (i.e., Periods 1 and 2).
Subjects with prior exposure to bDMARDs are excluded from participation in this study.


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Examples of biologic therapies include but are not limited to the following:
●
Humira® (adalimumab)
●
Enbrel® (etanercept)
●
Remicade® (infliximab)
●
Simponi® (golimumab)
●
Cimzia® (certolizumab pegol)
●
Cosentyx® (secukinumab)
●
Taltz® (ixekizumab)
●
Stelara® (ustekinumab)
●
Orencia® (abatacept)
●
Kineret® (anakinra)
●
Rituxan® (rituximab)
●
Actemra® (tocilizumab)
●
Raptiva® (efalizumab)
●
Tysabri® (natalizumab)
●
Benlysta® (belimumab)
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors or strong CYP3A inducers is excluded 
from the Screening Visit through the end of the study (i.e., end of Period 2).  The most 
common strong CYP3A inhibitors and inducers are listed in Table 1.


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Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Avasimibe
Carbamazepine
Phenytoin
Rifampin
St. John's Wort
Opiates and Marijuana
High potency opiates or use of inhaled marijuana are not permitted during the study 
(i.e., Periods 1 and 2), 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


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Combination of acetaminophen and codeine or hydrocodone is allowed.
Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 
five half-lives of the drug (whichever is longer) prior to the first dose of study drug are 
excluded from participation in this study.  Investigational drugs are also prohibited during 
the study.
Vaccines
Although not mandated by the protocol, vaccines recommended by local guidelines 
should be considered.  If the subject and Investigator choose to administer live vaccines, 
these vaccinations must be completed (per local label) at least 4 weeks (8 weeks in Japan) 
before first dose of study drug with appropriate precautions.  Live vaccines are prohibited 
during the study.  Examples of live vaccines include but are not limited to the following:
●
Monovalent live influenza A (H1N1) (intranasal);
●
Seasonal trivalent live influenza (intranasal);
●
Herpes zoster;
●
Rotavirus;
●
Varicella (chicken pox);
●
Measles-mumps-rubella or measles mumps rubella varicella;
●
Oral polio vaccine;
●
Smallpox;
●
Yellow fever;
●
Bacille Calmette-Guérin (BCG);
●
Typhoid.
Examples of common vaccines that are inactivated, toxoid, or biosynthetic include but are 
not limited to:  injectable influenza vaccine, pneumococcal, and pertussis (Tdap) vaccines.


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Traditional Chinese Medicine
Oral traditional Chinese medicine is not permitted during the study, and subjects must 
have discontinued traditional Chinese medicine at least 4 weeks prior to the first dose of 
study drug.
5.2.4
Contraception Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy, or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.  
Postmenopausal is defined as:
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND a follicle stimulating hormone (FSH) level > 40 mIU/mL.
If the female subject is < 55 years of age AND has had no menses for ≥ 12 months AND 
has no history of permanent surgical sterilization (defined above), FSH should be tested at 
Screening.
●
If FSH is not tested, it is assumed that the subject is of childbearing potential,
and protocol-specified contraception is required.
●
If the FSH is tested and the result is consistent with post-menopausal status, 
contraception is not required.
●
If the FSH is tested and the result is consistent with pre-menopausal status, 
contraception is required, and a serum pregnancy test must be performed (see 
Section 5.3.1.1, Pregnancy Test).


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For a female subject at any age:
●
Female subjects with menses within the past 12 months are of childbearing 
potential, and FSH is therefore not required, but contraception is required.
●
Female subjects who are surgically sterile (defined above) are not of 
childbearing potential, and therefore, no FSH testing or contraception is 
required.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following highly-effective methods of birth control that is effective from Study Day 1 (or 
earlier) through at least 30 days after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 30 days prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation (Japan only:  bilateral tubal ligation only).
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical confirmation of the surgical success and is the sole sexual partner of 
the women of childbearing potential trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence (if acceptable per local requirements):  Refraining from 
heterosexual intercourse when this is in line with the preferred and usual 
lifestyle of the subject.  (Note:  Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable.)
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the highly 
effective birth control methods listed above (excluding true abstinence).


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If during the course of the study a woman becomes surgically sterile or post-menopausal 
(defined above) and complete documentation is available, contraceptive measures as 
defined above are no longer required.
It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy upadacitinib.  
Contraception requirements of the allowed background medications should be carefully 
followed during use and after discontinuation of these drugs and should be based on the 
local label.
Additional local requirements may apply.  Refer to Appendix D for local requirements for 
Canada and Korea.
Contraception Recommendation for Males
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of study drug to practice 
contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures as defined in the protocol for female study subjects of childbearing 
potential.
OR
●
True abstinence (if acceptable per local requirements):  Refraining from 
heterosexual intercourse when this is in line with the preferred and usual 
lifestyle of the subject.  (Note:  Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable.)
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of study drug. 


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Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.
It is important to note that contraception and sperm donation recommendations described 
above are specifically intended to prevent pregnancy during and after exposure to the 
investigational therapy upadacitinib.  Contraception requirements of the background 
medications should be carefully followed during use and after discontinuation of these 
drugs and should be based on the local label.
Additional local requirements may apply.  Refer to Appendix D for local requirements for 
Canada and Korea.
5.3
Efficacy, Pharmacokinetic, Exploratory Research and 
Validation Studies, and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Subjects will be allowed a visit window of ± 3 days for all study visits (with the exception 
of the Baseline Visit, as the screening window is a maximum of 35 days) up to the 
Week 14 visit.  Visits after the Week 14 visit will have a visit window of ± 7 days.
If a subject has an out of window visit, the next visit should occur as originally scheduled 
based on the first date of study drug administration (Baseline Visit).
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix E.
5.3.1.1
Study Procedures
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix E, with the exception of exploratory research 
and validation studies (discussed in Section 5.3.1.2 and summarized in tabular format in 


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Appendix F), drug concentration measurements (discussed in Section 5.3.2), the 
collection of prior and concomitant medication information (discussed in Section 5.2.3), 
and the collection of AE information (discussed in Section 6.0).  All study data will be 
recorded in source documents and on the appropriate eCRFs.
Informed Consent
At the Screening visit, the subject will sign and date a study-specific, IEC/IRB-approved 
informed consent form before any study procedures are performed or any medications are 
withheld from the subject in order to participate in this study.  Separate written consent 
will be required for each subject in order to participate in the optional exploratory 
research and validation studies.  Details regarding how informed consent will be obtained 
and documented are provided in Section 9.3.  Subjects can withdraw informed consent at 
any time.
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at both Screening and Baseline Visits.
Medical and Surgical History
A complete non-AS-related medical and surgical history, including history of alcohol and 
nicotine use, will be taken from each subject during the Screening Visit.  Additionally, a 
list of each subject's specific AS-related medical and surgical history will be recorded at 
Screening.  History of herpes zoster, herpes zoster vaccination, and hepatitis B 
vaccination status will be recorded as part of the medical history.  An updated medical 
history will be obtained prior to study drug administration at Baseline, to ensure the 
subject is still eligible for enrollment.
A detailed medical history with respect to TB risk factors will be documented in the study 
source documentation.  This information will include BCG vaccination; cohabitation with 
individuals who have had TB; and travel to, residence in, or work in TB endemic 
locations.


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Vital Signs, Height, and Weight
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate, respiratory rate, and body temperature will be obtained at visits specified in 
Appendix E.  Vital signs should be performed before blood draws are performed.  Height 
will be measured at the Screening Visit only (with shoes off).  Body weight will be 
measured at all scheduled visits as specified in Appendix E.  All measurements will be 
recorded in metric units where applicable.
Anterior Uveitis
During the Screening period, detailed medical history of anterior uveitis, as confirmed by 
an ophthalmologist, will be documented (if applicable).  It should include the date of 
initial diagnosis; number of flares, including specific eye (right, left, or both), within the 
prior 12 months; date of the most recent flare; and treatments received in the past.
At Baseline and all subsequent visits, the Investigator will document new onset of uveitis 
and/or the number of flares, including specific eye (right, left, or both), and treatment 
received for at least one episode since the last visit.42  The corresponding AE eCRF 
should also be completed.  Initial documentation of uveitis must be confirmed by an 
ophthalmologist.  Flares following initial confirmation by an ophthalmologist can be 
subject self-reported.
Psoriasis
At Baseline and all subsequent visits, the Investigator will document prior or new 
diagnosis of psoriasis, including the current status.42  The corresponding eCRF should be 
completed.  The subject's right or left hand should be selected as the measuring device to 
estimate the area of involvement.  For purposes of clinical estimation, the total surface of 
the palm plus five digits will be assumed to be approximately equivalent to 1%.


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Inflammatory Bowel Disease
At Baseline and all subsequent visits, the Investigator will document prior or new 
diagnosis of IBD and the specific treatment since the last visit.42  The corresponding 
eCRF should be completed.
Physical Examination
A complete physical examination will be performed at the designated study visits as 
specified in Appendix E.  The physical examination at the Baseline Visit will serve as the 
baseline physical examination for the entire study.  Physical examination abnormalities 
noted by the Investigator at Baseline prior to the first dose of study drug will be recorded 
in the subject's medical history.  Abnormalities noted after the first dose of study drug will 
be evaluated and documented by the Investigator as to whether or not the abnormality is 
an AE.  All findings, whether related to an AE or part of each subject's medical history, 
will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed 
necessary by the Investigator.
12-Lead ECG
A resting 12-lead ECG will be performed at the designated study visits as specified in 
Appendix E.  A qualified physician will interpret the clinical significance of any abnormal 
finding, sign, and date each ECG.  ECG with QT interval corrected for heart rate using 
Friedericia's correction formula (QTcF) should be reported (or calculated) and 
documented in the source documents and later transcribed on to the appropriate eCRF if 
QTcF prolongation is observed.  In these cases, the baseline QTcF will need to be entered 
into the appropriate eCRF for comparison as well.  In addition, any clinically significant 
findings will be documented in the source documents and later transcribed on to the 
appropriate eCRF.  Each signed original ECG will be monitored by the responsible site 
monitor and kept with subject's source documents onsite.


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For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided source documentation is available and provided 
nothing has changed in the subject's medical history to warrant a repeat test.  If there are 
other findings that are clinically significant, the Investigator must contact the AbbVie TA 
MD before enrolling the subject.
Subjects can have a repeat ECG at any time during the study as warranted, based on the 
opinion of the Investigator.
CXR
A CXR (AP and lateral views) is required:
●
For all subjects at Screening to rule out the presence of TB or other clinically 
relevant findings.  The CXR will not be required if the subject had a previous 
normal CXR (posterior-anterior and lateral views) within 90 days of 
Screening, provided all source documentation is available at the site as 
outlined below and provided nothing has changed in the subject's medical 
history to warrant a repeat test.
●
Annually for subjects with TB risk factors as identified by the TB risk 
assessment form (Appendix G) for subjects living in areas endemic for TB or 
for subjects with newly positive PPD and/or QuantiFERON-TB Gold test.
Subjects can have a repeat CXR at any time during the study as warranted, based on the 
opinion of the Investigator.
A radiologist or qualified physician must perform an assessment of the CXR.  The 
Principal Investigator will indicate the clinical significance of any findings and will sign 
and date the report.  In the assessment of the CXR, the Principal Investigator or their 
delegate must indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.  If the CXR demonstrates changes 
suggestive of previous TB (e.g., calcified nodule, fibrotic scar, apical or basilar pleural 


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thickening) or other findings that are clinically significant, the Principal Investigator 
should contact the AbbVie TA MD before enrolling the subject.
Spine and Pelvis X-rays
Detailed instructions for performing and transmitting the study-related x-rays of spine and 
pelvis are provided in a separate Imaging Acquisition Guideline (IAG)/Site Operations 
Manual.
Handling of X-rays of Spine and Pelvis at Screening
Screening x-rays of spine (lateral views of cervical and lumbar spine) and pelvis (AP 
view) must be performed within the 35-day screening period.  The lateral spine x-rays will 
be centrally read; subjects with total spinal ankylosis are not eligible for this study.  The 
AP pelvis x-ray will also be centrally read to evaluate the SI joints for the presence of 
sacroiliitis consistent with AS based on the modified New York Criteria for AS 
(Appendix C).
The x-rays of the spine and pelvis will not be required during the Screening Period if the 
subject had a previous AP pelvis x-ray and lateral spine x-rays within 90 days of the 
Screening Period, provided that the x-rays are confirmed to be adequate for the required 
evaluations and are deemed acceptable by the central imaging vendor.
X-rays will be sent to the central imaging laboratory designated by the Sponsor.  
Digitalized images are acceptable, provided that they meet the specifications outlined in 
the IAG/Site Operations Manual.  X-rays not meeting the quality requirements must be 
repeated within the 35-day screening window.  The AP pelvis x-ray will be read by the 
central imaging vendor solely to evaluate the SI joints for the presence of sacroiliitis 
consistent with AS based on the modified New York Criteria for AS, while the x-rays of 
the spine will be read by the central imaging vendor only for the purposes of scoring for 
radiographic progression.  Subjects can only receive first dose of study drug after the 
x-rays have been centrally read and sacroiliitis is confirmed.


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Screening x-rays of spine and pelvis will serve as baseline x-rays for scoring purposes.
Handling of X-rays of Spine after Baseline
X-rays of the spine will be obtained at the Week 104 Visit (end of study).  If a subject 
prematurely discontinues the study and/or study drug, depending on the time of 
discontinuation, new x-rays of the spine may be needed.
●
Subjects who prematurely discontinue from the study and/or study drug before 
Week 76 will not have x-rays performed at the PD Visit.
○
If the subject continues study participation, the subject will follow the 
regular visit schedule, and an x-ray will be performed at the Week 104 
Visit.
●
Subjects who prematurely discontinue from the study and/or study drug at or 
after Week 76 will have x-rays performed at the PD Visit.
○
If the subject continues study participation, the subject will follow the 
regular visit schedule, but an x-ray will not be performed at the Week 104 
Visit.
The x-rays of the spine will be read by the central imaging vendor only for the purposes of 
scoring for radiographic progression.
MRI of Spine and SI Joints
All subjects who meet eligibility criteria will have an MRI evaluation of the SI joints, as 
well as the cervical, thoracic, and lumbar regions of the spine, prior to or at the Baseline 
Visit, the Week 14 Visit, as well as the Week 104 Visit.  If a site is unable to obtain the 
MRI prior to Baseline Visit, a window of 3 days post-dose will be allowed.  For the MRI 
at Week 14, a window of –7 days/+ 3 days will be allowed; for the MRI at Week 104, a 
window of ± 7 days will be allowed.  If subject has a contraindication for MRI prior to 
enrollment, the site must discuss with the AbbVie TA MD.


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Note:  If the central imaging vendor confirms a negative AP pelvic x-ray for AS, and the 
MRI has not been performed, the MRI should be cancelled as the subject would be 
considered a screen failure.
Images will be sent to the central imaging vendor designated by the Sponsor.  Procedures 
for performing and shipping the MRIs are provided in a separate manual.  The MRI will 
only be assessed by the imaging vendor for bone marrow edema.
Note:  Site staff should schedule the Week 14 MRI during the Baseline visit, if possible.  
For subjects who prematurely discontinue from the study drug for any reason, the site 
should attempt to reschedule the MRI within 2 weeks (14 days) of the PD Visit.  If the 
MRI cannot be rescheduled within 14 days of the PD Visit, the MRI will be considered 
missed.
Low-Dose Computer Tomography (CT) Scan of Spine
Subjects at select sites who consent to participate in the low-dose CT scan substudy and 
meet eligibility criteria will have low-dose CT scan evaluation of the whole spine 
(cervical, thoracic, and lumbar spine) prior to or at the Baseline Visit, Week 52, and 
Week 104.  If a site is unable to obtain the low-dose CT of the whole spine prior to 
Baseline Visit, a window of 2 weeks (14 days) post-dose will be allowed.  Images will be 
sent to the central imaging vendor designated by the Sponsor.  Procedures for performing 
and shipping the CT scans are provided in a separate manual.  The low-dose CT scans will 
only be assessed and scored by the central imaging vendor for syndesmophytes.
Note:  For subjects participating in the low-dose CT scan substudy who prematurely 
discontinue from the study drug for any reason prior to Week 104 but after Week 76 
should have a CT scan performed at or within 2 weeks of the PD Visit.
Note for the X-rays, MRI and Low-Dose CT Scan
The central imaging vendor will assess x-rays of the sacroiliac joints and the spine, MRI 
of the sacroiliac joints and the spine, and low-dose CT scans only for the purposes 


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indicated above and will not assess for any other clinically significant findings.  The 
investigator will be responsible for assessing the images for any clinically significant 
findings that may impact subject health.
TB Testing/TB Prophylaxis
The TB screening tests are diagnostic test results to be interpreted in the context of the 
subject's epidemiology, history, exam findings, etc., and it is the responsibility of the 
Investigator to determine if a subject has previous, active, or latent TB. Expert 
consultation for the evaluation and/or management of TB may be considered per 
Investigator discretion. 
At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk 
assessment form (Appendix G) and tested for TB infection by QuantiFERON-TB Gold 
test (or IGRA equivalent).  The site staff will complete the TB risk assessment form and 
enter the data into an appropriate eCRF.
●
Subjects with a negative TB test and CXR not suggestive of active TB or prior 
TB exposure may be enrolled.  If a subject had a negative QuantiFERON-TB 
Gold (or IGRA equivalent) within 90 days prior to Screening and source 
documentation is available, the test does not need to be repeated provided 
nothing has changed in the subject's medical history to warrant a repeat test.  
These cases may be discussed with the AbbVie TAMD.
●
If a subject had a negative PPD Skin Test (also known as a TB Skin Test or 
Mantoux Test) within 90 days prior to Screening and a QuantiFERON-TB 
Gold test (or IGRA equivalent) cannot be performed by Central Lab at 
Screening and source documentation is available, TB testing by PPD Skin Test 
does not need to be repeated, provided nothing has changed in the subject's 
medical history to warrant a repeat test.  These cases may be discussed with 
the AbbVie TAMD.  The results of the TB test(s) will be retained at the site as 
the original source documentation.
●
Subjects with a positive TB test must be assessed for evidence of active TB 
versus latent TB, including signs and symptoms and CXR.  Subjects with no 


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signs or symptoms and a CXR not suggestive of active TB may be enrolled 
after initiation of TB prophylaxis (see below).
●
Subjects with evidence of active TB must not be enrolled.
For subjects with a negative TB test result at Screening (or the most recent evaluation), an 
annual TB follow-up test will be performed.  If an annual TB test is newly positive 
(seroconversion), a CXR needs to be performed as soon as possible to aid in 
distinguishing active versus latent TB.  Any positive TB screen after the subject has 
started the study should be reported as an AE of latent TB or active TB (as applicable).
If the subject is experiencing signs or symptoms suspicious for TB or something has 
changed in the subject's medical history to warrant a repeat test before the next scheduled 
annual TB re-test, the case (including the TB test results) must be discussed with the 
AbbVie TA MD.
TB Testing
Additional information regarding TB testing is as follows:
●
Subjects with documentation of prior positive result of QuantiFERON-TB 
Gold Test (or equivalent) and/or PPD Skin Test are not required to repeat 
either test at Screening or during the study and should be considered positive.
●
For regions that require both PPD and QuantiFERON-TB Gold testing, both 
will be performed.  If either PPD or QuantiFERON-TB Gold results are 
positive, the TB test is considered positive. 
●
The PPD Skin Test should be utilized only when a QuantiFERON-TB Gold 
Test is not possible for any reason (unless both tests are required per local 
guidelines).
○
The PPD should be read by a licensed healthcare professional between 
48 and 72 hours after administration.  A subject who does not return within 
72 hours will need to be rescheduled for another skin test.  The reaction 
will be measured in millimeters (mm) of induration, and induration ≥ 5 mm 
is considered a positive reaction.  The absence of induration will be 
recorded as "0 mm," not "negative."  Subjects who had an ulcerating 


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reaction to the PPD in the past should not be re-exposed, and the PPD 
should be considered positive.
○
If only a PPD is placed at Screening, then the TB test to be used for the 
remainder of the study for that subject is the PPD.  Similarly, if a subject 
enters the study with a QuantiFERON-TB Gold test (or equivalent) alone, 
then the subject should have their annual TB test performed with a 
QuantiFERON-TB Gold test. 
●
If the QuantiFERON-TB Gold test is indeterminate, then the investigator 
should perform a local QuantiFERON-TB Gold test (or through the central 
laboratory if not locally available) to rule out a positive test result.  If testing 
remains indeterminate or is positive, then the subject is considered to be 
positive for the purpose of this study.  If the testing result is negative, then the 
subject is considered to be negative.
For sites participating from the Czech Republic, the following local requirements will also 
be applicable:
●
A pulmonologist will be responsible to obtain a detailed medical history with 
respect to TB exposure.  This information needs to include BCG vaccination, 
cohabitation with individuals who have had TB, and/or travel to, reside in, or 
work in TB endemic locations.  The information obtained by the 
pulmonologist must be documented in the subject's source note, dated and 
signed by the pulmonologist.
●
A pulmonologist must review the results of the QuantiFERON-TB Gold test 
and/or PPD skin test (or IGRA equivalent such as T-SPOT TB test) and the 
CXR and has to give his/her opinion about the eligibility of each subject to be 
enrolled to the study.  This opinion must be documented in writing in the 
subject's source documents.
●
All subjects with a positive QuantiFERON-TB Gold test and/or PPD test (or 
IGRA equivalent such as T-SPOT TB test) and a CXR not suggestive of active 
TB need to be approved for entry into the trial by both the Czech 
pulmonologist and the AbbVie TA MD, and all such subjects need to receive 
prophylaxis for latent TB.  Under no circumstances can a subject with a 
positive QuantiFERON-TB Gold test and/or PPD test (or IGRA equivalent 


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such as T-SPOT TB test) result and no prior history of treatment for active or 
latent TB be allowed into this trial.
TB Prophylaxis
At Screening, if the subject has evidence of latent TB infection, prophylactic treatment 
must be initiated at least 2 weeks prior to administration of study drug (or per local 
guidelines, whichever is longer).  At least 6 months of prophylaxis (or per local 
guidelines, whichever is longer) need to be completed; however, the full course of 
prophylaxis does not need to be completed prior to the first dose of study drug.
Note:  Rifampicin and Rifapentine Are Not Allowed for TB Prophylaxis
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy will be allowed to enter the study provided nothing has changed 
in the subject's medical history to warrant repeat treatment.  For subjects with completion 
of a full course of anti-TB therapy but insufficient documentation, the investigator should 
consult with the AbbVie TA MD.
During the study, subjects with new evidence of latent TB should initiate prophylactic 
treatment immediately per local guidelines and complete at least 6 months of prophylaxis 
(or per local guidelines, whichever is longer). TB prophylaxis should be initiated, and 
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.  Newly initiated prophylactic treatment should be captured in 
the eCRF and in the source documents.  Prior therapy should be captured in the eCRF.
Pregnancy Test
A serum pregnancy test will be performed for all women of childbearing potential at the 
Screening Visit.  The serum pregnancy test will be sent to and performed by the central 
laboratory.  If the serum pregnancy test is positive, the subject is considered a screen 
failure.  If the serum pregnancy test is borderline, it should be repeated ≥ 3 days later to 
determine eligibility.  If the repeat serum pregnancy test is:


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●
Positive, the subject is considered a screen failure;
●
Negative, the subject can be enrolled into the trial;
●
Still borderline ≥ 3 days later, this will be considered documentation of 
continued lack of a positive result and the subject can be enrolled into the 
study in the absence of clinical suspicion of pregnancy and other pathological 
causes of borderline results.
In Period 1, a urine pregnancy test will be performed for all women of childbearing 
potential at the Baseline Visit prior to the first dose of study drug and at all subsequent 
visits.  More frequent pregnancy tests will be performed throughout the study if required 
per local/country requirements.
●
If the baseline urine pregnancy test performed at the site is negative, then 
dosing with study drug may begin.  If the baseline urine pregnancy test 
performed at the site is positive, dosing with study drug must be withheld, and 
a serum pregnancy test is required.  The serum pregnancy test will be sent to 
and performed by the central laboratory.  If the serum pregnancy test is 
negative, study drug may be started.  If the serum pregnancy test is positive, 
study drug must be withheld, and the subject must be discontinued from the 
study.  In the event a pregnancy test comes back borderline, a repeat test is 
required.
●
If a post-baseline urine pregnancy test is positive, study drug needs to be 
temporarily discontinued, and a serum pregnancy test is required.  The serum 
pregnancy test will be sent to and performed by the central laboratory.  If the 
serum pregnancy test is negative, study drug may be restarted.  If the serum 
pregnancy test is positive, study drug must be permanently discontinued.
In Period 2, for women of childbearing potential, a urine pregnancy test will be performed 
at all visits and monthly at home between scheduled study visits.  The results of the 
monthly at home tests will be communicated to the site.  If a urine pregnancy test is 
positive, the subject must stop dosing, come in to the clinic, and have blood drawn for a 
serum pregnancy test that will be analyzed at the central laboratory.


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At each visit, the study staff should review the pregnancy avoidance recommendations 
with each subject of childbearing potential and male subjects with a partner of 
childbearing potential and document this discussion in the subject's source records.
A pregnant or breastfeeding female will not be eligible for participation in this study or be 
allowed to continue study drug.
Clinical Laboratory Tests
Samples will be obtained for the clinical laboratory tests listed in Table 2.  Unscheduled 
clinical labs may be obtained at any time during the study if deemed appropriate per 
Investigator's discretion.  A certified central laboratory will be utilized to process and 
provide results for the clinical laboratory tests. All abnormal laboratory tests that are 
considered clinically significant by the Investigator will be followed to a satisfactory 
resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing, and shipping of these samples.
Blood samples will be obtained for the laboratory tests at visits specified in Appendix E.  
Blood draws should be performed only after all clinical assessments, questionnaires, and 
vital sign determinations are obtained.
For clinic visits where samples for serum chemistry tests are collected, subjects should be 
fasting (a minimum 8-hour fast) whenever possible.  If a subject is not able to fast when 
necessary due to unforeseen circumstances, the non-fasting status will be recorded in 
study source documentation.
Urine samples will be obtained for urinalysis testing at visits specified in Appendix E.  
The central laboratory will be responsible for performing a macroscopic urinalysis (urine 
dipstick) on the collected urine specimens.  Specified abnormal macroscopic urinalyses, 
defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, or glucose 


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greater than normal, will be followed up with a microscopic analysis at the central 
laboratory.
For any laboratory test value outside the reference range that the Investigator considers to 
be clinically significant, the Investigator should apply the standard of care for medical 
evaluation and treatment per local guidelines:
●
The Investigator will repeat the test to verify the out-of-range value.
●
The Investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
A laboratory test value that requires a subject to be discontinued from the study or 
requires a subject to receive treatment will be recorded as an AE.


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Table 2.
Clinical Laboratory Tests
Hematology
(Central Lab)
Clinical Chemistrya
(Central Lab)
Urinalysisb
(Central Lab)
Other Laboratory 
Tests
Hematocrit
Hemoglobin
RBC count
WBC count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Reticulocyte count
Platelet count
BUN
Creatinine
Total bilirubin
INR (reflex only)c
ALT
AST
Alkaline phosphatase
CPK
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Inorganic phosphate
Uric acid
Cholesterol
LDL-C
HDL-C
Total protein
Glucose
Triglycerides
Albumin
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocytes
Nitrites 
Microscopic 
examination, 
if needed
Central Lab Tests:
Serum pregnancy 
(bHCG) testd
HBs Age
HBs Abe
HBc Abe
HBV DNA PCR reflex 
onlye
HCV Abe
HCV RNA reflex onlye
HIVf
QuantiFERON-TB 
Goldg
hsCRPh
FSHe,i
beta-D-glucanj
HLA-B27k
Lymphocyte subsetsl
Local Lab Tests
ESR
Urine pregnancy testm
ALT = alanine aminotransferase; AST = aspartate aminotransferase; bHCG = beta human chorionic gonadotropin; 
BUN = blood urea nitrogen; CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; ESR = erythrocyte 
sedimentation rate; FSH = follicle-stimulating hormone; HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B 
surface antibody; HBs Ag = hepatitis B surface antigen; HBV = hepatitis B virus; HCV Ab = hepatitis C virus antibody; 
HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; HLA-B27 = human leukocyte 
antigen-B27; hsCRP = high sensitivity C-reactive protein; INR = international normalized ratio; LDL-C = low-density 
lipoprotein cholesterol; NK = natural killer; NKT = natural killer T; PCR = polymerase chain reaction; RBC = red blood 
cell; RNA = ribonucleic acid; TB = tuberculosis; WBC = white blood cell
a.
Minimum 8-hour fast.  If a subject is not able to fast when necessary due to unforeseen circumstances, the 
non-fasting status will be recorded in study source documentation.
b.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A 
microscopic analysis will be performed in the event the dipstick results show leukocytes, nitrite, protein, ketones, 
or blood greater than negative, or glucose greater than normal.
c.
INR will only be measured if ALT and/or AST > 3 × ULN.
d.
A serum pregnancy test will be performed for all women of childbearing potential at the Screening Visit and if 
post-baseline urine pregnancy test turns positive.
e.
At Screening only.


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Table 2.
Clinical Laboratory Tests (Continued)
f.
Anti-HIV Ab will be performed at Screening.  The Investigator must discuss any local reporting requirements to 
local health agencies with the subject.  The site will report confirmed positive results to their health agency per 
local regulations, if necessary.  If a subject has a confirmed positive result, the Investigator must discuss with the 
subject the potential implications to the subject's health, and subject should receive or be referred for clinical care 
promptly.  A subject will not be eligible for study participation if test results indicate a positive HIV infection.  
AbbVie will not receive results from the testing and will not be made aware of any positive result.
g.
If PPD not performed.
h.
The hsCRP results after Baseline (Day 1) will not be reported to the Sponsor, Investigator, study site personnel, or 
the subject.  hsCRP will be performed by the Central Lab.  Local laboratory or site testing for hsCRP or CRP is not 
allowed after Baseline.  Results of tests such as hsCRP may be blunted in subjects taking a JAK inhibitor, thereby 
limiting the clinical utility of these tests in the setting of a possible safety assessment or adverse event 
management.  As such, local hsCRP testing should not be performed until the last subject completes Period 1.
i.
At Screening for female subjects < 55 years old.
j.
At Screening for subjects in Japan only.
k.
At Baseline only.
l.
Blood samples will be collected to assess the effects of upadacitinib inhibition on lymphocyte subsets including but 
not limited to T (CD4+ and CD8+) cells, B (CD19+) cells, NK cells, and NKT cells.  These tests will be performed 
by the Central Lab.
m.
A urine pregnancy test will be performed for all women of childbearing potential at the Baseline Visit prior to the 
first dose of study drug and all subsequent visits.  If the baseline urine pregnancy test performed at the site is 
negative, then dosing with study drug may begin.  If the baseline urine pregnancy test performed at the site is 
positive, dosing with study drug must be withheld, and a serum pregnancy test is required.  The serum pregnancy 
test will be sent to and performed by the central laboratory.  If the serum pregnancy test is positive, study drug 
must be withheld, and the subject must be discontinued from the study.  In the event a pregnancy test comes back 
borderline, a repeat test is required ≥ 3 days later to document continued lack of a positive result, and the subject 
can be enrolled into the study in the absence of clinical suspicion of pregnancy and other pathological causes of 
borderline results.  If a post-baseline urine pregnancy test is positive, study drug needs to be temporarily 
discontinued, and a serum pregnancy test is required.  The serum pregnancy test will be sent to and performed by 
the central laboratory.  If the serum pregnancy test is positive, study drug must be permanently discontinued.
Hepatitis Screen
All subjects will be tested for the presence of HBV and HCV at Screening.  In addition, 
HBV and HBC testing will be performed at the designated study visits as specified in 
Appendix E for subjects in Japan.


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Hepatitis B
Subjects will be tested for the presence of HBV at Screening using the following tests:
●
HBs Ag (Hepatitis B surface antigen)
●
HBc Ab/anti-HBc (Hepatitis B core antibody)
●
HBs Ab/anti-HBs (Hepatitis B surface antibody)
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will be tested (automatic reflex testing) for core antibodies 
(HBc Ab) and surface antibodies (HBs Ab).
●
A negative test result for HBc Ab does not require HBV DNA PCR qualitative 
testing, and the subject may be enrolled (Figure 2, Scenarios A and B).
●
For a subject who has had a HBV vaccination (should document in the medical 
history), a positive test result for HBs Ab is expected, and the subject may be 
enrolled (Figure 2, Scenario B).*
●
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic 
reflex testing) (Figure 2, Scenarios C and D; For Japan only: including 
Scenario B).
○
A result that exceeds the detection sensitivity of the central laboratory will 
be considered a positive result for HBV DNA and will be exclusionary. 
○
A subject with a negative result for HBV DNA may be enrolled.


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Figure 2.
Criteria for HBV DNA PCR Qualitative Testing
*
For subjects who have had an HBV vaccination (should be documented in the medical history), a positive test 
result for HBs Ab is expected, and these subjects may be enrolled.  For subjects without a history of HBV 
vaccination (and for subjects in Japan and China), a positive result for HBs Ab/anti-HBs requires HBV DNA PCR 
testing.
For subjects in Japan:  Subjects with positive HBs Ab and/or positive HBc Ab results 
should have HBV-DNA PCR test performed at the specified visits (Appendix E); in cases 
where recurrence of HBV-DNA is observed, the subject should be discontinued from the 
study.  This measure is not necessary in subjects with history of HBV vaccination and 
positive HBs Ab result.
Hepatitis C
Blood samples for Hepatitis C serology will be obtained at the Screening Visit.  A subject 
will not be eligible for study participation if test results indicate active Hepatitis C 
(HCV RNA detectable in any subject with anti HCV Ab).
HIV
Subjects with a known history of HIV infection are excluded from study participation.  
Anti-HIV Ab will be performed at Screening.  The Investigator must discuss any local 
reporting requirements to local health agencies with the subject.  The site will report these 


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results to their health agency per local regulations, if necessary.  If a subject has a 
confirmed positive result, the Investigator must discuss with the subject the potential 
implications to the subject's health, and subject should be referred for clinical care 
promptly.  A subject will not be eligible for study participation if test results indicate an 
HIV infection.  AbbVie will not receive results from the testing and will not be made 
aware of any positive result.
Other Laboratory Assessments
hsCRP
Blood samples for hsCRP will be obtained at visits specified in Appendix E.  The hsCRP 
results after Baseline (Day 1) will not be reported to the Sponsor, Investigator, study site 
personnel, or the subject.  hsCRP will be performed by the Central Lab.  Local laboratory 
or site testing for hsCRP or CRP is not allowed after Baseline.  Results of tests such as 
hsCRP may be blunted in subjects taking a JAK inhibitor, thereby limiting the clinical 
utility of these tests in the setting of a possible safety assessment or adverse event 
management.  As such, local hsCRP testing should not be performed until the last subject 
completes Period 1.
Lymphocyte Subsets
Blood samples will be collected at visits specified in Appendix E to assess the effects of 
ABT-494 inhibition on lymphocyte subsets including but not limited to T (CD4+ and 
CD8+) cells, B (CD19+) cells, NK cells, and NKT cells.  These tests will be performed by 
the Central Lab.
Subject Questionnaires
Subjects will complete the following questionnaires as specified in Appendix E; a 
validated translation will be provided in their local language, as applicable:
●
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)43,44
●
Bath Ankylosing Spondylitis Functional Index (BASFI)44,45


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●
Patient's Global Assessment of Disease Activity (PtGA)44,46
●
Patient's Assessment of Total Back Pain44
●
Patient's Assessment of Nocturnal Back Pain44,46
●
Patient's Global Assessment of Pain47
●
Ankylosing Spondylitis Quality of Life (AS QoL)48,49
●
ASAS Health Index (HI)50
●
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F)51
●
Insomnia Severity Index (ISI)52,53
●
Work Productivity and Activity Impairment (WPAI)54
All patient-reported outcomes (PROs) will be collected electronically.  The subject should 
complete the questionnaires before site personnel perform any clinical assessments and 
before any interaction with site personnel has occurred to avoid biasing the subject's 
response.
Tender Joint Count (TJC) and Swollen Joint Count (SJC) Assessment
TJC Assessment
An assessment of 68 joints will be done for tenderness by pressure manipulation on 
physical examination at visits specified in Appendix E.  Joint pain/tenderness will be 
classified as:  present ("1"), absent ("0"), replaced ("9"), or no assessment ("NA").
SJC Assessment
An assessment of 66 joints will be done by directed physical examination at visits 
specified in Appendix E.  The joints to be examined for swelling are the same as those 
examined for tenderness, except the hip joints are excluded.  Joint swelling will be 
classified as present ("1"), absent ("0"), replaced ("9"), or no assessment ("NA").  Any 
injected joint will be classified as "no assessment" ("NA") for 90 days from the time of 
the intra-articular injection.


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If possible, the TJC and SJC should be performed by an independent and blinded joint 
assessor who should not perform any other study-related procedures.
In order to minimize variability, the same independent joint assessor should evaluate the 
subject at each visit for the duration of the trial as much as possible.  A back-up 
independent joint assessor should be identified.  The independent joint assessors should 
be qualified medical professionals (e.g., nurse, physician's assistant, physician).  Any 
other joint assessor must be trained and competent in performing such assessments.  It is 
the responsibility of the Investigator to ensure that all assessors are qualified and trained 
to perform joint assessments.  If the independent assessor is not available, the pre-
identified back-up assessor should perform such assessments.
Dactylitis
An evaluation will be conducted at the visits specified in Appendix E to assess the 
presence or absence of dactylitis in all 20 of the subjects' digits.  The assessment should 
begin with visual inspection of the hands and feet.  For each pair of digits in which one or 
both digits appear dactylitic, the circumference of the affected digits (both right and left 
side) will be assessed using a dactylometer.  Additionally, the affected digit pairs will be 
assessed for tenderness by squeezing the digital shaft mid-way between the 
metacarpophalangeal and proximal interphalangeal joints and will be recorded as 
tenderness, yes or no.  Tenderness should not be assessed by squeezing the joint lines.  If 
a digit is missing and its contralateral digit is dactylitic, "digit absent" will be recorded for 
the missing digit.  For any digit without an available dacylometer measurement, the 
standard reference value will be utilized in calculation of the Leeds Dactylitis Index.55  
The standard reference values will not be entered into the eCRF.  A dactylometer will be 
provided to sites for use.  Digits injected with corticosteroid will be considered non-
evaluable for 90 days from the time of the injection.
The site should make every attempt to have the same qualified Investigator or designee 
conduct these assessments throughout the study for any given subject.


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Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin)
The BASMIlin will be conducted at the visits specified in Appendix E to evaluate spinal 
mobility in a subject.56
The site should make every attempt to have the same qualified Investigator or designee 
conduct these assessments throughout the study for any given subject.
Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)
The MASES evaluation will be conducted at the visits specified in Appendix E to assess 
the presence or absence of enthesitis at 13 different sites (first costochondral joint 
left/right, seventh costochondral joint left/right, posterior superior iliac spine left/right, 
anterior superior iliac spine left/right, iliac crest left/right, fifth lumbar spinous process, 
and proximal insertion of Achilles tendon left/right), noting the subjects' responses.57
The site should make every attempt to have the same qualified Investigator or designee 
conduct these assessments throughout the study for any given subject.
Physician Global Assessment of Disease Activity (PGA)
At visits specified in Appendix E, the Physician will rate global assessment of subject's 
current disease activity independent of the subject's self-assessment using a 0 – 10 NRS, 
anchored at either end by opposite adjectives.44,46
ASAS 20
The ASAS 20 calculation is required at and after the Week 16 visit to determine if a 
subject fails to achieve ASAS 20 response.  ASAS 20 response is defined as an 
improvement of ≥ 20% and absolute improvement of ≥1 unit (on a scale of 0 to 10) from 
Baseline in at least three of the following four domains, with no deterioration (where 
deterioration is defined as a worsening of ≥ 20% and a net worsening of ≥ 1 units [on a 
scale of 0 to 10]) in the remaining domain:58
●
Patient's Global Assessment – Represented by the PtGA NRS score (0 to 10);


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●
Pain – Represented by the Patient's Assessment of Total Back Pain NRS score 
(0 to 10);
●
Function – Represented by the BASFI NRS score (0 to 10);
●
Inflammation – Represented by the mean of the two morning 
stiffness related-BASDAI NRS scores (mean of items 5 and 6 of the BASDAI 
[0 to 10]).
ASAS 20 criteria will be calculated by Interactive Response Technology (IRT).
Randomization/Drug Assignment
All Screening laboratory results must be reviewed, signed, and dated by the Principal 
Investigator or Sub-investigator prior to the Baseline Visit.  Subjects will not be enrolled 
into the study if laboratory or other Screening result abnormalities are deemed clinically 
significant by the Principal Investigator or Sub-investigator.
Subjects will be eligible for randomization if they continue to meet all of the selection 
criteria (Section 5.2) at Baseline and are willing to continue in the study.
See Section 5.5.3 for details regarding the method of assigning subjects to treatment 
groups.
Subject Diary
During the Baseline Visit, subjects will be dispensed a paper subject diary and will be 
trained on how to complete the diary by site staff.  Subjects will be asked to notate their 
concomitant medication use and AEs and document date and times of doses of study drug 
taken between study visits.  The subject diary will be reviewed by site personnel with the 
subject at each visit, and a review and description of the subject diary notations will be 
documented in the subject's source documentation and recorded on the applicable eCRF.  
Replacement diaries will be dispensed as needed should a subject misplace a subject 
diary.  The completed diaries will be collected at the subject's final visit and maintained at 
the site as source documentation.


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Study Drug Dispensing, Dosing, and Compliance
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in 
Appendix E.  The first dose of study drug will be administered after all other Baseline 
(Day 1) procedures are completed.  Subjects will maintain a dosing diary for all study 
drug administered outside of the study visit (i.e., at home) to capture dosing dates and 
times.  At visits specified in Appendix E, the site personnel will review and retain a copy 
of the dosing diary, returned study drug kits, and empty study drug packaging to verify 
compliance.
All relevant dosing information will be entered into the eCRF at each visit.
Refer to Section 5.5 for additional information.
5.3.1.2
Collection and Handling of Optional Samples for 
Exploratory Research and Validation Studies
Subjects will have the option to provide samples for exploratory research and validation 
studies.  Subjects may still participate in the main study even if they decide not to 
participate in this optional exploratory research/validation study.
Exploratory research can help to improve AbbVie's understanding of how individuals 
respond to drugs and the ability to predict which subjects would benefit from receiving 
specific therapies.  In addition, exploratory research may help to improve the 
understanding of how to diagnose and assess/monitor AS by assessing 
 
.
Validation studies, including those related to the development of 
 
, may be carried out retrospectively in order to assess associations between 
.
 




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samples may be used for 
 if needed.  The procedure for obtaining and 
documenting informed consent is discussed in Section 9.3.
Samples will be shipped to AbbVie or a designated laboratory for long-term storage 
and/or analyses.  Instructions for the preparation and shipment of the samples will be 
provided in a laboratory manual.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for assay of upadacitinib and possibly other concomitant medications will 
be collected as follows:
●
Weeks 2 and 4 prior to dosing;
●
Weeks 8, 12, 14, 24, 52, 76, and 104/PD at any time during the visit.
On Week 2 and Week 4 visit days, if possible, subjects should take the study drug dose at 
the clinic after collecting the PK blood sample, except if the subjects regularly take the 
study drug dose at night.  Those subjects who regularly take the study drug dose at night 
should continue to take study drug according to their normal schedule.  For all other 
visits, subjects can take the study drug dose on visit days at their regular schedule and not 
necessarily at the clinic.
The date and accurate time of the PK sample collection will be recorded on the lab 
requisition form.  The date and accurate time of the last two study drug doses will be 
recorded on the eCRF to the nearest minute.
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment.


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5.3.2.2
Measurement Methods
Plasma concentrations of upadacitinib will be determined by the Drug Analysis 
Department at AbbVie using a validated liquid chromatography/mass spectrometry 
method.
5.3.3
Efficacy Variables
5.3.3.1
Primary Variable
The primary endpoint is the proportion of subjects with ASAS 40 response at Week 14, 
which is defined as a ≥40% improvement and an absolute improvement of ≥2 units (on a 
scale of 0 to 10) from Baseline in at least three of the following four domains, with no 
worsening at all in the remaining domain:
●
Patient's Global Assessment – Represented by the PtGA NRS score (0 to 10);
●
Pain – Represented by the Patient's Assessment of Total Back Pain NRS score 
(0 to 10);
●
Function – Represented by the BASFI NRS score (0 to 10);
●
Inflammation – Represented by the mean of the two morning stiffness-related 
BASDAI NRS scores (mean of items 5 and 6 of the BASDAI [0 to 10]).
5.3.3.2
Secondary Variable
The key multiplicity adjusted secondary efficacy endpoints (upadacitinib versus placebo 
unless noted otherwise) at Week 14 are:
1.
Change from Baseline in Ankylosing Spondylitis Disease Activity Score 
(ASDAS);
2.
Change from Baseline in MRI Spondyloarthritis Research Consortium of Canada 
(SPARCC) score (Spine);
3.
Proportion of subjects with BASDAI 50 response (defined as 50% improvement in 
the Bath AS Disease Activity Index);


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4.
Change from Baseline in AS QoL;
5.
Proportion of subjects with ASAS partial remission (PR) (defined as an absolute 
score of ≤ 2 units for each of the four domains identified in ASAS 40);
6.
Change from Baseline in BASFI;
7.
Change from Baseline in BASMIlin;
8.
Change from Baseline in MASES;
9.
Change from Baseline in WPAI;
10.
Change from Baseline in ASAS HI.
Additional key secondary endpoints (upadacitinib versus placebo) are:
●
ASAS 20 response at Week 14;
●
Change from Baseline in MRI SPARCC score (SI joints) at Week 14.
5.3.3.3
Additional Variables
Additional endpoints are the following measurements assessed in subjects treated with 
upadacitinib versus placebo at scheduled time points other than those specified for the 
primary and key secondary variables:
●
Proportion of subjects with:
○
ASAS 20 response;
○
ASAS 40 response;
○
ASAS PR;
○
ASAS 5/6 (20% improvement from Baseline in five out of the following 
six domains:  BASFI, patient's assessment of total back pain, PtGA, 
inflammation [mean of items 5 and 6 of the BASDAI] lateral lumbar 
flexion from BASMIlin, and high sensitivity CRP [hsCRP]);
○
ASDAS Inactive Disease (ASDAS score < 1.3);
○
ASDAS Major Improvement (change from Baseline at least 2.0);


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○
ASDAS Clinically Important Improvement (change from Baseline of at 
least 1.1).
●
Change from Baseline in:
○
ASAS HI;
○
ASDAS;
○
AsQoL;
○
BASDAI;
○
BASFI;
○
BASMIlin;
○
CRP;
○
Dactylitis;
○
FACIT-F; 
○
ISI;
○
MASES;
○
Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) score with 
conventional radiograph;
○
MRI SPARCC score of SI joints;
○
MRI SPARCC score of Spine;
○
Patient's Assessment of Total Back Pain;
○
Patient's Assessment of Nocturnal Back Pain;
○
Patient's Global Assessment of Pain;
○
PGA;
○
PtGA;
○
TJC and SJC; 
○
WPAI.
Evaluation of structural changes in the spine will be explored in subjects who are 
participating in the low-dose CT scan substudy using a scoring system for 
syndesmophytes.


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5.3.4
Safety Variables
Safety evaluations include AE monitoring, physical examinations, vital sign 
measurements, and clinical laboratory testing (hematology, chemistry, and urinalysis) as a 
measure of safety and tolerability for the entire study duration.
5.3.5
Pharmacokinetic Variables
Plasma upadacitinib concentrations will be obtained at the times indicated in Appendix E.  
A non-linear mixed-effects modeling approach will be used to estimate the population 
central values and the empirical Bayesian estimates of the individual values of 
upadacitinib oral clearance (CL/F) and volume of distribution (V/F).  Additional 
parameters may be estimated if useful in the interpretation of the data.
5.3.6
Exploratory Research Variables and Validation Studies
Optional samples may be collected to conduct exploratory investigations into 
 
.  The types of 
 to be analyzed may include but are not 
limited to 
.
 
 may be used to assess and generate 
 
.  These assessments may be 
explored in the context of 
 
.  The results from these analyses are exploratory in nature and may not be 
included with the clinical study report (CSR).
The samples may also be used to 
 
  In addition, samples from this study may be stored for future use.  Samples 
may then be used to validate 
 
.


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


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●
Subject is significantly non-compliant with study procedures, which would put 
the subject at risk for continued participation as determined by the 
Investigator.
●
Subject develops a gastrointestinal perforation.
●
Subjects not responding to treatment are to be withdrawn from the trial based 
on Investigator's discretion.
●
Starting at Week 24, subjects who still do not achieve at least an ASAS 20 
response at two consecutive visits will be discontinued from study drug 
treatment.
●
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus, or 
non-cardiac, non-neurologic arterial thrombosis.
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment should complete a PD visit as soon as 
possible, preferably within 2 weeks.  Afterwards, subjects should continue to be followed 
for all regularly scheduled visits as outlined in Appendix E and adhere to all study 
procedures except for dispensing study drug, PK sample collection, blood sample 
collection for optional exploratory research and validation studies, and x-rays.  (New 
x-rays are dependent on the time of discontinuation; refer to Section 5.3.1.1 for details.)  
In addition, all future efficacy-driven discontinuation criteria no longer apply (ASAS 20 
response).  Subjects should be advised on the continued scientific importance of their data 
even if they discontinue treatment with study drug early.
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.  In addition, a 30-day follow-up visit (or phone call if 
a visit is not possible) should occur to determine the status of any ongoing AEs/SAEs or 
the occurrence of any new AEs/SAEs.  Subjects who discontinue the study prematurely 
after randomization will not be replaced.
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study drug or study participation.  The information 


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will be recorded on the appropriate eCRF page.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
Investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of study drug, the subject will be treated in accordance with the Investigator's best clinical 
judgment, irrespective of whether the subject decides to continue participation in the 
study.
Lost to Follow-Up
For subjects to be considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made, and one certified letter must be sent and documented in the subject's source 
documentation.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the Investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Study drug will be taken orally QD, beginning on Day 1 (Baseline), and should be taken 
at approximately the same time each day.  The study drug can be taken with or without 
food.


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5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 3.
Table 3.
Identity of Investigational Product
Investigational Product
Mode of Administration
Formulation
Strength
Manufacturer
ABT-494
oral
tablet
15 mg
AbbVie
ABT-494 placebo
oral
tablet
NA
AbbVie
5.5.2.1
Packaging and Labeling
ABT-494 and matching placebo will be packaged in bottles with quantities sufficient to 
accommodate study design.  Each kit label will contain a unique kit number.  This kit 
number is assigned to a subject via IRT and encodes the appropriate study drug to be 
dispensed at the subject's corresponding study visit.  Each kit will be labeled as required 
per country requirements.  Labels must remain affixed to the kits.  All blank spaces on the 
label will be completed by the site staff prior to dispensing to the subjects.
5.5.2.2
Storage and Disposition of Study Drug
ABT-494 must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  Study 
drug must not be frozen at any time.  The investigational product is for investigational use 
only and is to be used only within the context of this study.  The study drug supplied for 
this study must be maintained under adequate security and stored under the conditions 
specified on the label until dispensed for subject use or destroyed on site as appropriate.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be randomized using IRT.  Before the study is initiated, IRT directions 
will be provided to each site.
All subjects will be assigned a unique identification number by the IRT at the Screening 
Visit.  For subjects that re-screen, the Screening number assigned by the IRT at the initial 
Screening visit should be used; a new Screening number should not be requested.


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Subjects will be eligible for randomization if they continue to meet all of the selection 
criteria (Section 5.2) at Baseline and are willing to continue in the study.
Subjects will be randomized in a 1:1 ratio using IRT to receive double-blind study drug in 
one of the following treatment groups:
●
Group 1:  Upadacitinib 15 mg QD (n = 85)
●
Group 2:  Placebo (n = 85)
Randomization will be stratified by Screening hsCRP (≤ ULN vs. > ULN) and geographic 
region (US/Canada, Japan, RoW).  Subjects who were randomized to placebo at Baseline 
will receive upadacitinib 15 mg QD in an open-label manner at Week 14.
The IRT will assign a randomization number that will encode the subject's treatment 
group assignment according to the randomization schedule generated by the Statistics 
Department at AbbVie.
IRT will provide the appropriate study drug kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Section 5.3.1.1.  
Returned study drug should not be re-dispensed to any subject.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.5.1.
On dosing days that occur on study visit days, subjects should follow the regular dosing 
schedule (refer to Section 5.3.2.1 regarding Week 2 and Week 4 visits).
Each subject's dosing schedule should be closely monitored by the site at each study visit 
by careful review of the subject's dosing diary.  This will ensure that all subjects enrolled 
into the study maintain their original dosing schedule beginning with the first dose of 
study drug (Baseline/Day 1).


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If a subject should forget to take their upadacitinib (or matching placebo) dose at their 
regularly scheduled dosing time, they should take the forgotten dose as soon as they 
remember the dose was missed as long as it is at least 10 hours before their next scheduled 
dose.  If a subject only remembers the missed dose within 10 hours before next scheduled 
dose, the subject should skip the missed dose and take the next dose at the scheduled time.  
If the subject experiences a study drug interruption > 7 consecutive days during Weeks 1 
through 14 (Period 1) or > 30 consecutive days during Period 2 they should notify the 
Investigator, and the Investigator will decide if study drug should be restarted.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
All AbbVie personnel with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie Drug Supply Management Team) will remain blinded to 
each subject's treatment throughout Period 1.  The Investigator, study site personnel, and 
the subject will remain blinded to each subject's treatment assignment in Period 1 
throughout the study.  In order to maintain the blind, the upadacitinib tablets and placebo 
tablets provided for the study will be identical in appearance.  The IRT will provide 
access to unblinded subject treatment information in the case of medical emergency.
In the event of a medical situation that requires unblinding of the study drug assignment, 
the Investigator is requested to contact the AbbVie TA MD prior to breaking the blind.  
However, if an urgent therapeutic intervention is necessary that warrants breaking the 
blind prior to contacting the AbbVie TA MD, the Investigator can directly access the IRT 
system to break the blind without AbbVie notification or agreement.  Unblinding is 
available in the IRT system via the Unblind Subject transaction, which is available only to 
the Investigator.  If the IRT system is unavailable, unblinding may occur by contacting 
EndPoint technical support via either phone (preferred) or email 
(support@endpointclinical.com).  For country-specific phone numbers, please see the 
following website:  http://www.endpointclinical.com/help-desk/.  In the event that the 
blind is broken before notification to the AbbVie TA MD, it is requested that the AbbVie 


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TA MD be notified within 24 hours of the blind being broken.  The date and reason that 
the blind was broken must be conveyed to AbbVie and recorded on the appropriate eCRF.
The primary analysis will be conducted after all subjects have completed Week 14 or have 
prematurely discontinued prior to Week 14.  Study sites and subjects will remain blinded 
to the treatment assignment in Period 1 for the duration of the entire study.
5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)
An external Data Monitoring Committee (DMC) comprised of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study.  The primary responsibility of the DMC will be to protect the safety of 
the subjects participating in this study.
A separate DMC charter will be prepared outside of the protocol and will describe the 
roles and responsibilities of the DMC members, frequency of data reviews, and relevant 
safety data to be assessed.
Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.
As of 18 April 2019, with all subjects having reached the end of Period 1, and after final 
review of unblinded safety data, the DMC concluded its oversight of this study.
5.5.6
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subject dosing will be recorded on a subject dosing diary.  Subjects will be instructed to 
return all drug containers (even if empty) to the study site personnel at each clinic visit.  
The study site personnel will document compliance in the study source documents.


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5.5.7
Drug Accountability
The Investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt or similar document and by registering the arrival of drug through the 
IRT.  The original Proof of Receipt Note and the IRT confirmation sheet will be kept in 
the site files as a record of what was received.
In addition, an IRT will be used to document investigational product accountability 
including but not limited to date received, the lot number, kit number(s), date dispensed, 
subject number, and the identification of the person dispensing the drug.
All empty/used study drug packaging will be inventoried by the site and verified by the 
site monitor.  Empty/used study drug packaging should be returned by the subject at each 
visit for accountability and compliance purposes and new packaging issued as necessary.  
Empty/used packaging will be retained (unless prohibited by local law) until the site 
monitor is on site to confirm the returned study drug.  Site monitor(s) and site staff will 
complete study drug accountability via IRT, source documents, subject dosing diaries, and 
by visually inspecting the packaging whenever possible.  After drug accountability has 
been completed, used packaging and unused study drug will be destroyed on site 
according to local procedures or regulations or returned to the destruction depot by the 
site monitor (for those sites that do not meet AbbVie's documentation requirements for 
on-site destruction).  The use of a third party vendor for drug destruction must be 
pre-approved by AbbVie.  For sites performing on-site drug destruction or using a 
third party vendor for drug destruction, a copy of the destruction methodology and date of 
destruction should be maintained at the site's facility.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This study is a Phase 2 study with the quality and rigor of a Phase 3 study.  Therefore, it is 
classified as a Phase 2/3 study.  The study has 90% power on the primary efficacy 


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endpoint and is well-controlled, with randomization, blinded intervention, high-quality 
trial conduct, unbiased data analysis and interpretation, and rigorous control of the overall 
type I error rate, to provide scientifically sound data evidence in efficacy and safety.
This study includes two periods:
Period 1 is a 14-week, randomized, double-blind, placebo-controlled period to compare 
safety and efficacy of upadacitinib versus placebo in subjects with a clinical diagnosis of 
AS and meeting the modified New York Criteria for AS who have an inadequate response 
to or intolerance or contraindication for NSAIDs and are bDMARD-naïve.  Period 1 is 
designed to test superiority of upadacitinib versus placebo for achieving the primary 
endpoint (ASAS 40 response rate) at Week 14 and other secondary efficacy parameters.  
A comparative study utilizing a placebo-control design provides an unbiased assessment 
of the efficacy and safety profile of upadacitinib.
The purpose of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of 
upadacitinib 15 mg QD in subjects who have completed Period 1.  Subjects will continue 
to receive upadacitinib 15 mg QD per original randomization assignment in an open-label 
manner.  Subjects who were randomized to placebo at Baseline will receive open-label 
upadacitinib 15 mg QD at Week 14.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All 
efficacy measurements in this study are standard for assessing disease activity in subjects 
with AS.  All clinical and laboratory procedures in this study are standard and generally 
accepted.
5.6.3
Suitability of Subject Population
The intended study population is active AS patients who have had an inadequate response 
to at least two NSAIDs over an at least 4-week period in total at maximum recommended 
or tolerated doses or intolerance to or a contraindication for NSAIDs as defined by the 


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Investigator, and who are bDMARD-naïve.  The specific population chosen was 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 and meet the 
modified New York Criteria for AS.  Eligible study subjects must have a BASDAI score 
≥ 4 and a Patient's Assessment of Total Back Pain score ≥ 4 based on a 0 – 10 NRS at the 
Screening and Baseline Visits.  Subjects who enter the study on permitted concomitant 
medications(s) must have been on a stable dose for the amount of time specified in the 
inclusion criteria (Section 5.2.1) prior to the first dose of study drug.
5.6.4
Selection of Doses in the Study
This Phase 2/3 study will evaluate a single dose of upadacitinib 15 mg QD using the 
once-daily tablet formulation.
 
 
 
 
 
 
 
 
 
 
 


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Data from the tofacitinib Phase 2b study in AS demonstrated that tofacitinib 5 mg BID 
and 10 mg BID demonstrated greater clinical efficacy versus placebo in reducing the 
signs, symptoms, and objective measures of the disease.25 The 15 mg QD dose of 
upadacitinib is expected to be comparable to or better than the 5 mg BID dose of 
tofacitinib. The dose to be evaluated in this study is predicted to provide exposures that 
are lower than the No-Observed-Adverse-Effect-Level (NOAEL) exposures from the 
preclinical toxicology studies as well as the highest exposures that were previously 
evaluated and found to be safe and well tolerated in healthy volunteers in Phase 1 and in 
subjects with RA in Phase 2.
Therefore, the dose selected for Study M16-098, upadacitinib 15 mg QD dosed for up to 
104 weeks, is expected to be efficacious with an acceptable safety profile.
6.0
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.


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Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For AEs, please refer to Section 6.1.  For product 
complaints, please refer to Section 6.2.
6.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of AEs on 
a routine basis throughout the study.  The Investigator will assess and record any AE in 
detail, including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drug, and 
any action(s) taken.  For SAEs considered as having "no reasonable possibility" of being 
associated with study drug, the Investigator will provide an Other cause of the event.  For 
AEs to be considered intermittent, the events must be of similar nature and severity.  AEs, 
whether in response to a query, observed by site personnel, or reported spontaneously by 
the subject, will be recorded.
All AEs will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an AE.  Worsening in 
severity of a reported AE should be reported as a new AE.  Laboratory abnormalities and 
changes in vital signs are considered to be AEs only if they result in discontinuation from 


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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 pre-planned prior to study entry.  However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure 
is being done will be considered an AE.
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as an SAE 
within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the Investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency or 
drug abuse.
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate eCRF.
6.1.1.3
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study (see detailed 
toxicity management in Section 6.1.7):
●
Serious infections 
●
Opportunistic infections 
●
Malignancy 
●
Non-Melanoma Skin Cancer (NMSC) 
●
Malignancy excluding NMSC 
●
Lymphoma 
●
Hepatic Disorder 
●
Gastrointestinal Perforations 
●
Anemia 
●
Neutropenia 
●
Lymphopenia 


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●
Herpes Zoster 
●
Rhabdomyolysis/myopathy 
●
Creatine Phosphokinase (CPK Elevation) 
●
Renal Dysfunction 
●
Tuberculosis 
●
Adjudicated cardiovascular events 
●
Embolic and thrombotic events (non-cardiac, non-CNS)
6.1.2
Adverse Event Severity
When criteria are available, events should be graded as described in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 4.03.60
If guidance for specific events is not available, grading should be as follows:
Mild (Grade 1):  asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
Moderate (Grade 2):  minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL; instrumental ADL refer 
to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.).
Severe (Grade 3 – 5):
●
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (self-care ADL refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden); 
●
Life-threatening consequences; urgent intervention indicated; 
●
Death related to AE. 


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6.1.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:
Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is sufficient evidence 
(information) to suggest a causal relationship.
No Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is insufficient
evidence (information) to suggest a causal relationship
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the Investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the Investigator for the SAE.
6.1.4
Adverse Event Collection Period
All AEs reported from the time of study drug administration until 30 days following 
discontinuation of study drug administration have elapsed will be collected, whether 
solicited or spontaneously reported by the subject.  Subjects who discontinue study drug 
treatment but continue to participate in the study will have SAEs and nonserious AEs 
collected for the remainder of study participation.  In addition, SAEs and protocol-related 
nonserious AEs will be collected from the time the subject signed the study-specific 
informed consent.
AE information will be collected as shown in Figure 3.






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The Sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local regulations.  The reference document used for SUSAR reporting in the 
European Union (EU) countries will be the most current version of the Investigator's 
Brochure.
In Japan, the Principal Investigator will provide documentation of all SAEs to the Director 
of the investigative site and the Sponsor.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject or the partner of an 
enrolled subject, including the outcome of the pregnancy, will be collected.  Pregnancies 
in study subjects and their partners will be identified from the date of the first dose of 
study drug through 30 days following the last dose of study drug, and the pregnancy will 
be followed to outcome.
Pregnancy in a study subject is not considered an AE.  However, the medical outcome of 
an elective or spontaneous abortion, stillbirth, or congenital anomaly is considered a SAE 
and must be reported to AbbVie within 24 hours of the site becoming aware of the event.
In the event of pregnancy occurring in the partner of an enrolled subject, written informed 
consent for release of medical information from the partner must be obtained prior to the 
collection of any pregnancy-specific information, and the pregnancy will be followed to 
outcome.
6.1.7
Toxicity Management
The toxicity management of the AEs, including AEs of special interest, consists of safety 
monitoring (review of AEs on an ongoing basis and periodical/ad hoc review of safety 


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issues by a safety data monitoring committee), interruption of study drug dosing with 
appropriate clinical management if applicable, and discontinuation of the subjects from 
study drug.  The management of specific AEs and laboratory parameters is described 
below.
Note:  For subjects who discontinued study drug but continue study participation and are 
on standard of care therapies, these toxicity management requirements do not apply 
(including alerts from the central lab), and any intolerability to standard of care therapies 
should be managed by the prescribing physician.
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection or an opportunistic infection.  A 
subject who develops a new infection during treatment with study drug should undergo
prompt diagnostic testing appropriate for an immunocompromised subject.  As 
appropriate, antimicrobial therapy should be initiated, and the subject should be closely 
monitored.  Re-challenge with study drug may occur once the infection has been 
successfully treated.  If study drug has been interrupted for a serious infection for more 
than 14 consecutive days during Period 1 of the study or 30 consecutive days thereafter, 
the subject must inform the Investigator and the Investigator can determine if study drug 
can be restarted.  Subjects who develop active TB must be 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 gastrointestinal perforation should be evaluated promptly for early diagnosis and 
treatment.  If the diagnosis of gastrointestinal perforation is confirmed, the subject must 
be discontinued from study drug.
Cardiovascular Events (MACE): Subjects presenting with potential cardiovascular 
events should be appropriately assessed and carefully monitored.  These events will be 


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reviewed and adjudicated by an independent Cardiovascular Adjudication Committee in a 
blinded manner (Section 6.1.9).
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in-situ 
of the cervix must be discontinued from study drug.  Information including 
histopathological results should be queried for the confirmation of the diagnosis.  Periodic 
skin examination is recommended for subjects who are at increased risk for skin cancer.
Thrombosis Events:  Subjects who develop symptoms of thrombosis should be promptly 
evaluated and treated appropriately.  If the diagnosis of deep vein thrombosis, pulmonary 
embolus or non-cardiac, non-neurologic arterial thrombosis is confirmed, the subject must 
be discontinued from study drug.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change 
considered clinically significant and with reasonable possibility of relationship to study 
drug OR a confirmed absolute QTcF value > 500 msec.
Management of Select Laboratory Abnormalities: For any given laboratory 
abnormality, the Investigator should assess the subject and apply the standard of care for 
medical evaluation and treatment following any local guidelines.  Specific toxicity 
management guidelines for abnormal laboratory values (confirmation by repeat testing is 
required) are described in Table 4 and may require an appropriate supplemental eCRF be 
completed.  All abnormal laboratory tests that are considered clinically significant by the 
Investigator will be followed to a satisfactory resolution.


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values
Laboratory 
Parameter 
Toxicity Management Guideline
Hemoglobin
!
If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by repeat testing with a 
new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample. 
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative etiology is known, 
the subject may remain on study drug at the Investigator's discretion. 
!
If confirmed, continue to withhold study drug until hemoglobin value returns to normal 
reference range or its baseline value.
Absolute neutrophil 
count (ANC)
!
If confirmed < 1000/μL by repeat testing with new sample, interrupt study drug dosing 
until ANC value returns to normal reference range or its baseline value.
!
Discontinue study drug if confirmed < 500/μL by repeat testing with new sample.
Absolute 
lymphocyte counts 
(ALC)
!
If confirmed < 500/μL by repeat testing with new sample, interrupt study drug dosing 
until ALC returns to normal reference range or its baseline value.
Total white blood 
cell count
!
If confirmed < 2000/μL by repeat testing with new sample, interrupt study drug dosing 
until white blood cell count returns to normal reference range or its baseline value.
Platelet count
!
If confirmed < 50,000/μL by repeat testing with new sample, interrupt study drug 
dosing until platelet count returns to normal reference range or its baseline value.


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory 
Parameter 
Toxicity Management Guideline
AST or ALT
!
Discontinue study drug if confirmed ALT or AST > 3 × ULN by repeat testing with 
new sample and either a total bilirubin > 2 × ULN or an international normalized ratio 
> 1.5.
o
INR will only be measured in subjects with ALT or AST > 3 × ULN by the central 
lab by reflex testing and confirmation is not needed for consideration in toxicity 
management criteria.
!
Discontinue study drug if confirmed ALT or AST > 3 × ULN by repeat testing with 
new sample along with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
!
Discontinue study drug if confirmed ALT or AST > 8 × ULN by repeat testing with 
new sample. 
!
Discontinue study drug if confirmed ALT or AST > 5 × ULN by repeat testing with 
new sample for more than 2 weeks. 
For all of the above ALT or AST elevation scenarios, complete supplemental hepatic eCRF.
Serum Creatinine
!
If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the test for serum 
creatinine (with subject in an euvolemic state) to confirm the results.  If the results of 
the repeat testing still meet this criterion, then interrupt study drug and re-start study 
drug once serum creatinine returns to ≤ 1.5 × baseline value and ≤ULN.
!
If confirmed serum creatinine ≥ 2 mg/dL, interrupt study drug and re-start study drug 
once serum creatinine returns to normal reference range or its baseline value. 
For the above serum creatinine elevation scenarios, complete supplemental renal eCRF.
Creatine 
Phosphokinase
!
If confirmed CPK value ≥ 4 × ULN and there are no symptoms suggestive of myositis 
or rhabdomyolysis, the subjects may continue study drug at the investigator's discretion.
!
If confirmed CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact AbbVie TA MD.
For the above CPK elevation scenarios, complete supplemental CPK eCRF.
For allowed study drug interruption, the following rules apply:
Period 1
●
Allow study drug interruption up to 7 consecutive days for AEs and 
emergency surgery.  Elective surgery will not be allowed during this 14-week 
period.
●
If the subject must undergo emergency surgery, the study drug should be 
interrupted at the time of the surgery.  After emergency surgery, allow 


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reintroduction of study drug once the physician has examined the surgical site 
and determined that it has healed and there is no sign of infection.
Period 2
●
Allow study drug interruption up to 30 consecutive days for AEs and 
emergency surgery during Period 2.  PI will make determination if study drug 
should be restarted for interruptions > 30 days.
●
If the subject undergoes elective surgery, the study drug should be interrupted 
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.
●
If the subject must undergo emergency surgery, the study drug should be 
interrupted at the time of surgery.  Allow reintroduction of study drug once the 
physician has examined the surgical site and determined that it has healed and
there is no sign of infection.
6.1.8
Data Monitoring Committee
An external DMC will review unblinded safety data.  See Section 5.5.5.2 for details.
6.1.9
Cardiovascular Adjudication Committee
An independent committee of physician experts in cardiovascular adjudication will be 
utilized to assess potential cardiovascular AEs in a blinded manner as defined by the 
Cardiovascular Adjudication Committee charter.
6.2
Product Complaint
6.2.1
Definition
A product complaint is any complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.


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


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IEC/IRB regulatory authorities (as applicable) and the following AbbVie Clinical 
Contact:
Primary Contact:
Office:
Fax:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
In Japan, the Investigator will record all protocol deviations in the appropriate medical 
records at site.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The primary analysis will be conducted after all subjects have completed the Week 14 
visit or have prematurely discontinued prior to Week 14.  The analysis will be conducted 
for the comparisons of the upadacitinib group versus the placebo group.  To maintain 
integrity of the trial and avoid introduction of bias, study sites and subjects will remain 
blinded for the duration of the study.
Completed and specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 


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database lock for the primary analysis at Week 14.  The statistical analyses will be 
performed using SAS (SAS Institute Inc., Cary, NC, USA).
8.1.1
Analysis Populations
8.1.1.1
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized subjects who received at least 
one dose of study drug.  The FAS will be used for all efficacy and baseline analyses.
8.1.1.2
Per Protocol Analysis Set
The Per Protocol Analysis Set represents a subset of the FAS and consists of all FAS 
subjects who did not have any major protocol violations during the study.  Additional 
analysis may be conducted on the Per Protocol analysis set in order to evaluate the impact 
of major protocol violations.  The Per Protocol Analysis Set will be determined prior to 
the Week 14 primary analysis database lock.
8.1.1.3
Safety Analysis Set
The Safety Analysis Set consists of all subjects who received at least one dose of study 
drug.  For the Safety Analysis Set, subjects are assigned to a treatment group based on the 
treatment actually received, regardless of the treatment randomized.
8.1.2
Subject Accountability, Disposition and Study Drug 
Exposure
8.1.2.1
Subject Accountability
The following will be summarized by site and by treatment group, as well as overall:  
number of subjects randomized, the number of subjects who received at least one dose of 
study drug, the number of subjects who completed, the number of subjects who 
prematurely discontinued study drug, and the number of subjects who prematurely 
discontinued study participation.


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8.1.2.2
Subject Disposition
The number and percentage of subjects who are randomized, received at least one dose of 
study drug, prematurely discontinued study drug, prematurely discontinued study 
participation, and completed will be summarized by treatment group and overall.  Reasons 
for premature discontinuation of study drug and study participation will be summarized 
separately for all randomized subjects by treatment group and overall, with frequencies 
and percentages by reason for discontinuation.
8.1.2.3
Study Drug Exposure
Exposure to study drug will be summarized for the Safety Analysis Set.  The exposure to 
study drug will be summarized with the mean, standard deviation, median, and range for 
each treatment group.  The exposure to study drug is defined as the difference between the 
dates of the first and last doses of the study drug plus 1 day.
Study drug compliance will be summarized for each treatment group.  The compliance is 
defined as the number of tablets taken (i.e., the difference between the number of tablets 
dispensed and the number of tablets returned) during the subject's participation divided by 
the number of tablets a subject is supposed to take during the subject's participation.
8.1.3
Analysis of Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group and 
overall for the FAS.  For the purpose of this analysis, baseline data for each subject will 
be the data collected immediately prior to the first dose of study drug.
Summary statistics for continuous variables will include the number of observations, 
mean, standard deviation, median, and range.  For discrete variables, frequencies and 
percentages for each category will be summarized.
Medical history will be presented in counts and percentages of subjects, broken down by 
Body System and Diagnosis.


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Prior therapy and medication will be summarized by treatment group.  Prior therapy and 
medication will include all therapies and medications administered prior to the date of 
first dose of study drug.
Concomitant medications will also be summarized with frequencies and percentages for 
each treatment group.  All medications administered will be included.
8.1.4
Efficacy Analysis
All efficacy analyses will be carried out using the FAS population, which includes all 
randomized subjects who receive at least one dose of study drug.
8.1.4.1
Primary Efficacy Variables
Analysis of the primary endpoint will be conducted on the FAS based on treatment as 
randomized.  Comparison of the primary endpoint will be made between the upadacitinib
group and the placebo group using the Cochran-Mantel-Haenszel test, adjusting for main 
stratification factors.  For the primary analysis, Non-Responder Imputation (NRI) will be 
used.  The analysis will be repeated using Observed Cases (OC) approach.  Supportive 
analysis will also be conducted on the Per Protocol Analysis Set.
The primary efficacy analyses will also be performed in demographic subgroups, 
including age, gender, race, 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.
8.1.4.2
Key Secondary Efficacy Variables
Unless otherwise specified, comparisons are between the upadacitinib group and the 
placebo group.
For binary endpoints, frequencies and percentages will be reported for each treatment 
group.  Similar analyses as for the primary endpoint will be conducted.


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For continuous endpoints, the mean, standard deviation, median, and range will be 
reported for each treatment group.  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 factors as the covariates.
8.1.4.3
Additional Efficacy Variables
Additional efficacy variables as listed in Section 5.3.3.3 will be summarized for all visits.  
For binary endpoints, frequencies and percentages will be reported by treatment group by 
visit.  For continuous endpoints, the change from baseline mean, standard deviation, 
median, and range will be reported by treatment group by visit.
8.1.4.4
Multiplicity Control for the Primary and Key Secondary 
Endpoints
In order to preserve Type I error, a step-down approach will be used to test the primary 
and key secondary endpoints where statistical significance can be claimed for a lower-
ranked endpoint only if the previous endpoints in the sequence meet the requirements of 
significance.  The group of multiple endpoints (including proportion of subjects with 
BASDAI 50 response, proportion of subjects with ASAS partial remission, changes from 
baseline in AS QoL, BASFI, BASMIlin, MASES, and WPAI) will be tested using the 
Hochberg procedure in the ranking sequence, conditional on significance of higher-ranked 
endpoints.
8.1.4.5
Imputation Methods
The following methods will be used for missing data imputation:
Observed Cases (OC):  The OC analysis will not impute values for missing evaluations; 
thus, a subject who does not have an evaluation on a scheduled visit will be excluded from 
the OC analysis for that visit.


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Non-Responder Imputation (NRI):  NRI applies to binary endpoints only.  In NRI 
analysis, subjects who prematurely discontinue study drug will be considered 
non-responders on or after discontinuation date.
Mixed Model for Repeated Measures (MMRM):  The MMRM includes treatment, 
visit, and treatment-by-visit interaction as fixed effects, and the corresponding baseline 
values and the main stratification factors as covariate; a covariance matrix will be used to 
account for the correlation structure between visits.
The NRI approach will serve as the primary analysis approach for key binary endpoints.  
Analysis for key binary endpoints will also be repeated using OC.  The MMRM approach 
will serve as the primary analysis approach for key continuous endpoints.
8.1.4.6
Long-Term Efficacy
The efficacy endpoints of long-term efficacy analysis will be summarized for all visits, 
including visits beyond Week 14.
Long-term efficacy by time point will be summarized using descriptive statistics.  For 
binary endpoints, frequencies and percentages will be summarized.  For continuous 
endpoints, the mean and standard deviation will be reported.
8.1.5
Safety Analysis
8.1.5.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set.  Analyses will be 
conducted in primary analysis at Week 14, as well as for the entire study.
Safety analyses are based on treatments actually received.  Safety will be assessed by 
treatment-emergent adverse events (TEAEs), physical examination, laboratory 
assessments, and vital signs.  The number and percent of subjects experiencing TEAEs by 
treatment group will be tabulated by the Medical Dictionary for Drug Regulatory 
Activities (MedDRA®) system organ class (SOC) and preferred terms (PT).  In addition, 


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summary of serious AEs and TEAEs by severity and relationship to study drug as 
assessed by the Investigators will be provided.  SAEs, severe TEAEs, or TEAEs that lead 
to premature study discontinuation will be listed.  The changes in vital signs, physical 
examination results, and clinical laboratory variables at each visit as compared to baseline 
will be summarized.  Shift of laboratory values from baseline at defined time points will 
be tabulated.
Missing safety data will not be imputed.
8.1.5.2
Analysis of Adverse Events
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE)
AEs will be coded using MedDRA.  A TEAE is defined as AE that began or worsened in 
severity after initiation of study drug.
AEs starting more than 30 days following the last dose of study drug will not be included 
in summaries of TEAEs.
As a general safety summary, the number and percentage of subjects experiencing TEAEs 
will be summarized for each treatment group for the following AE categories:
●
All AEs;
●
All severe AEs;
●
All reasonably possibly related AEs;
●
All SAEs;
●
Frequent AEs (reported in 5% of subjects or more in any treatment group);
●
Frequent reasonably possibly related AEs (reported in 5% of subjects or more 
in any treatment group);
●
Discontinuations due to AEs;
●
Death.


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Additional AEs may be considered for tabulation/summary based on recommendations 
from the TA MD and Pharmacovigilance and Patient Safety as deemed appropriate.
TEAEs will be summarized and presented by SOCs and PTs using MedDRA.  The SOCs 
will be presented in alphabetical order, and the PTs will be presented in alphabetical order 
within each SOC.
TEAE will also be summarized by maximum severity and by maximum relationship.
The AEs of special interest (including but not limited to infection, opportunistic infection, 
herpes zoster, TB, gastrointestinal perforations, malignancies, MACE, renal dysfunction, 
anemia, increased CPK, and drug-related hepatic disorders) will be summarized.
All AEs leading to discontinuation of study drug will be presented in listing format.  A 
listing by treatment group of TEAEs grouped by MedDRA SOC and PT with subject 
identification numbers will be generated.
8.1.5.2.2
Serious Adverse Events and Death
All treatment-emergent SAEs and AEs leading to death will also be presented in listing 
format.  In addition, SAEs will be summarized by SOC and MedDRA PT.
8.1.5.3
Analysis of Laboratory and Vital Sign Data
Changes from baseline by visit; changes from baseline to minimum value, maximum 
value, and final values in continuous laboratory data; and vital signs will be summarized 
by treatment group.
Baseline values are defined as the last non-missing measurements recorded on or before 
the date of the first dose of study drug.
The laboratory data will be categorized as Grade 1, Grade 2, Grade 3, Grade 4, or Grade 5 
according to CTCAE criteria.  The shift tables will tabulate the number and percentage of 
subjects with baseline and post-baseline values by grade levels.  


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Summary and listings will be provided for potentially clinically significant laboratory 
values and vital signs.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Individual upadacitinib plasma concentrations at each study visit will be tabulated and 
summarized with appropriate statistical methods.
Data from this study may be combined with data from other studies for the population PK 
and exposure-response analyses.  Population PK and exposure-response analyses of only 
data from this study may not be conducted.  The following general methodology will be 
used for the population PK and exposure-response analyses.
Population PK analyses will be performed using the actual sampling time relative to 
dosing.  PK models will be built using a non-linear mixed-effects modeling (NONMEM) 
approach with NONMEM software (Version 7, or a higher version).  The CL/F and V/F 
of upadacitinib will be the PK parameters of major interest in the analyses.  If necessary, 
other parameters, including the parameters describing absorption characteristics, may be 
fixed if useful in the analysis.  The relationship between the conditional estimates of CL/F 
and V/F values with only potentially physiologically relevant or clinically meaningful 
covariates (such as subject age, sex, body weight, concomitant medications, laboratory 
markers of hepatic of renal function, etc.) will be explored using stepwise forward 
selection backward elimination approach.  Relationships between upadacitinib plasma 
exposure and clinical observations will be explored.
Results of the PK and exposure-response analyses may be summarized in a separate report 
prior to regulatory filing of upadacitinib for the treatment of AS, rather than in the CSR.  
Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
The planned sample size of 170 for this study (with 1:1 randomization ratio) provides at 
least 90% power for a 26% difference in ASAS 40 response rate (assuming a placebo 


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ASAS 40 response rate of 20%).  Power and sample size calculations are performed at 
two-sided significance level of 0.05 and accounting for a 10% dropout rate.
8.3
Randomization Methods
Subjects will be randomly assigned in a 1:1 ratio to one of the two treatment groups per 
study design diagram Figure 1.
Randomization will be stratified by Screening hsCRP (≤ ULN vs. > ULN) and geographic 
region (US/Canada, Japan, RoW).  Subjects who were randomized to placebo at Baseline 
will receive upadacitinib 15 mg QD in an open-label manner at Week 14.  See 
Section 5.5.3 for details.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
GCP requires that the protocol, any protocol amendments, the Investigator's Brochure, the 
informed consent, and all other forms of subject information related to the study (e.g.,
advertisements used to recruit subjects) and any other necessary documents be reviewed 
by an IEC/IRB.  The IEC/IRB will review the ethical, scientific, and medical 
appropriateness of the study before it is conducted.  IEC/IRB approval of the protocol, 
informed consent, and subject information and/or advertising, as relevant, will be obtained 
prior to the authorization of drug shipment to a study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain, and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP and all other applicable regulatory requirements.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies, as required by 
local regulations.  During the conduct of the study, the Investigator should promptly 


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provide written reports (e.g., ICH Expedited Reports and any additional reports required 
by local regulations) to the IEC/IRB of any changes that affect the conduct of the study 
and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct, and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the Clinical 
Investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject and answer all questions regarding this study.  Prior to any study-related screening 
procedures being performed on the subject, the informed consent statement will be 
reviewed and signed and dated by the subject, the person who administered the informed 
consent, and any other signatories according to local requirements.  A copy of the 
informed consent form will be given to the subject, and the original will be placed in the 
subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
Low-dose CT scan of the whole spine will be performed only in subjects who voluntarily 
sign written consent to participate in the low-dose CT scan substudy and meet eligibility 
criteria.  Written consent will be obtained as part of the main consent form, after the 
testing and potential risks have been explained and the subject has had an opportunity to 


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ask questions.  If the subject does not consent to the low-dose CT scan substudy, it will 
not impact the subject's participation in the main study.
Samples for exploratory research/validation studies will only be collected if the subject 
has voluntarily signed and dated the separate written consent for exploratory 
research/validation studies, approved by an IRB/IEC, after the nature of the testing has 
been explained and the subject has had an opportunity to ask questions.  The separate 
written consent must be signed before the exploratory research/validation studies samples 
are collected and testing is performed.  The separate written consent may be part of the 
main consent form.  If the subject does not consent to the exploratory research/validation 
studies, it will not impact the subject's participation in the study.
In the event a subject withdraws from the main study, optional exploratory 
research/validation samples will continue to be stored and analyzed unless the subject 
specifically withdraws consent for the optional samples.  If consent is withdrawn for the 
optional sampling, the subject must inform their study doctor, and once AbbVie is 
informed, the optional samples will be destroyed.  However, if the subject withdraws 
his/her consent and the samples have already been tested, those results will still remain as 
part of the overall research data.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the Principal Investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
Sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the Sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the Principal Investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 


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use in the study.  The Investigator will provide the information without delay to each 
subject already participating in the study and will confirm the intention of each subject to 
continue the study or not.  The Investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded to the appropriate 
source document.  The Investigator Awareness Date (SAE CRF) may serve as the source 
for this data point.  This AE data point required for eCRF completion can be entered 
directly in the eCRF.
The Investigator(s)/Institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
eCRFs must be completed for each subject screened/enrolled in this study.  These forms 
will be used to transmit information collected during the study to AbbVie and regulatory 
authorities, as applicable.  The eCRF data for this study are being collected with an EDC 
system called RAVE®, provided by the technology vendor Medidata Solutions 
Incorporated, NY, USA.  The EDC system and the study-specific eCRFs will comply with 
Title 21 CFR Part 11.  The documentation related to the validation of the EDC system is 
available through the vendor, Medidata, while the validation of the study-specific eCRFs 
will be conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.


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The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The Investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
Investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
Subject- and site-reported data must be completed for each subject screened/enrolled in 
this study.
●
The following data are being collected with an Electronic Patient-Reported 
Outcome (ePRO) system called Trialmax, provided by the technology vendor 
CRF Health of Plymouth Meeting, PA, USA:
○
Completed by Subject:
●
BASDAI
●
BASFI
●
PtGA


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●
Patient's Assessment of Total Back Pain
●
Patient's Assessment of Nocturnal Back Pain
●
Patient's Global Assessment of Pain
●
AS QoL
●
ASAS HI
●
FACIT-F
●
ISI
●
WPAI
○
Completed by Site:
●
Physician Global Assessment of Disease Activity
The ePRO system is in compliance with Title 21 CFR Part 11.  The documentation related 
to the system validation of the ePRO system is available through the vendor, CRF Health, 
while the user acceptance testing of the study-specific PRO design will be conducted and 
maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source and maintained and managed 
by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study to the site Investigator, 
as well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO system will be archived 
on appropriate data media (CD-ROM, etc.) and provided to the Investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the Investigator to make 
paper print-outs from that media.
The ePRO data will be collected by the following methods:


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Tablet Based
●
The instrument/scale will be collected electronically via a Tablet/Laptop 
device into which the subject will directly enter the required pieces of 
information.  The electronic device will be programmed to allow data entry for 
only the visits specified in the protocol and will not allow for subjects to 
complete more than one of the same assessment at any one visit.  All data 
entered on the device will be immediately stored to the device itself and 
automatically uploaded to a central server administrated by (ePRO Vendor).  
The Investigator and delegated staff will be able to access all uploaded subject-
entered data via a password-protected website, up until the generation, receipt, 
and confirmation of the study archive.
11.0
Data Quality Assurance
Prior to the initiation of the study, a meeting will be held with AbbVie personnel, the 
investigators, and appropriate site personnel.  This meeting will include a detailed 
discussion of the protocol, performance of study procedures, eCRF, subject dosing diary, 
and specimen collection methods.
The AbbVie monitor will monitor each site throughout the study.  Source document 
review will be performed against entries on the eCRF, and a quality assurance check will 
be performed to ensure that the Investigator is complying with the protocol and 
regulations.
All data hand entered in the database will be verified at AbbVie.  Any discrepancies will 
be reviewed against the eCRF and corrected online.  After completion of the entry 
process, computer logic and manual checks will be created by AbbVie to identify items 
such as inconsistent study dates.  Any necessary corrections will be made by the site to the 
eCRF.
Routine hematology, serum chemistry and serology, and urinalysis, and other tests such as 
HBV/HCV testing, will be conducted using a central laboratory (refer to Appendix E and 


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Table 2).  The data from these analyses will be electronically transferred from the central 
laboratory to the study database.
Laboratory tests including but not limited to urine pregnancy testing and ESR will be 
conducted locally by each study site (refer to Appendix E and Table 2).  Sites will provide 
AbbVie with laboratory certifications and normal ranges for each local laboratory used.  
The full name, address, phone number and fax number for each local laboratory will also 
be included.
12.0
Use of Information
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature, and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be provided to Investigators and used in scientific publications or presented at 
medical conventions.  Optional exploratory research information will be published or 
presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the Investigator (Director of the Site in Japan) 
and AbbVie.  The Investigator will provide a final report to the IEC/IRB following 
conclusion of the study and will forward a copy of this report to AbbVie or their 
representative.


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The Investigator (Director of the Site in Japan) must submit, maintain, and archive any 
records related to the study according to ICH GCP and all other applicable regulatory 
requirements.  If the Investigator (Director of the Site in Japan) is not able to retain the 
records, he/she must notify AbbVie to arrange alternative archiving options.
AbbVie will select the signatory Investigator from the Investigators who participate in the 
study.  Selection criteria for this Investigator will include level of participation, as well as 
significant knowledge of the clinical research, investigational drug, and study protocol.  
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Medicines Agency (EMA) Guidance on Investigator's 
Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for upadacitinib.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects 
with Active Ankylosing Spondylitis
Protocol Date:
20 December 2019
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
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van der Linden S, Valkenburg HA, Cats A.  Evaluation of diagnostic criteria for 
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4.
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Baeten D, Sieper J, Braun J, et al.  Secukinumab, an interleukin-17A inhibitor, in 
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Sieper J, Deodhar A, Marzo-Ortega H, et al.  Secukinumab efficacy in anti-TNF-
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20.
Sieper J and Poddubnyy D.  Axial spondyloarthritis.  Lancet.  2017 Jan 19.  pii:  
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21.
Sieper J, van der Heijde D, Dougados M, et al.  Efficacy and safety of adalimumab 
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22.
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 
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trial.  Arthritis Rheumatol.  2014;66(8):2091-102.
23.
Sieper J, van der Heijde D, Dougados M, et al.  A randomized, double-blind, 
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Poddubnyy D, Hermann KG, Callhoff J, et al.  Ustekinumab for the treatment of 
patients with active ankylosing spondylitis:  results of a 28-week, prospective, 
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van der Heijde D, Deodhar A, Wei JC, et al.  Tofacitinib in patients with 
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Murray PJ.  The Jak-STAT signaling pathway: input and output integration.  
J Immunol.  2007;178(5):2623-9.
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AbbVie.  ABT-494 Investigator's Brochure Edition 10.  19 August 2019.
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AbbVie.com.  AbbVie's Upadacitinib (ABT-494) meets all primary and ranked 
secondary endpoints in phase 3 study in rheumatoid arthritis.  Available from:  
https://news.abbvie.com/news/abbvies-upadacitinib-abt-494-meets-all-primary-
and-ranked-secondary-endpoints-in-phase-3-study-in-rheumatoid-arthritis.htm.  
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29.
AbbVie.com.  AbbVie's Upadacitinib (ABT-494) meets all primary and ranked 
secondary endpoints in second phase 3 study in rheumatoid arthritis.  Available 
from:  https://news.abbvie.com/alert-topics/immunology/abbvies-upadacitinib-abt-
494-meets-all-primary-and-ranked-secondary-endpoints-in-second-phase-3-study-
in-rheumatoid-arthritis.htm.  Accessed on:  11 September 2017.
30.
Genovese MC, Smolen JS, Weinblatt ME, et al.  Efficacy and safety of ABT-494, a 
selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis 
and an inadequate response to methotrexate.  Arthritis Rheumatol.  
2016;68(12):2857-66.
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Kremer JM, Emery P, Camp HS, et al.  A phase IIb study of ABT-494, a selective 
JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to 
anti-tumor necrosis factor therapy.  Arthritis Rheumatol.  2016;68(12):2867-77.
32.
Dougados M, van der Heijde D, Chen YC, et al.  Baricitinib in patients with 
inadequate response or intolerance to conventional synthetic DMARDs:  results 
from the RA-BUILD study.  Ann Rheum Dis.  2017;76(1):88-95.
33.
Genovese MC, Kremer J, Zamani O, et al.  Baricitinib, an oral janus kinase 
(JAK)1/JAK2 inhibitor, in patients with active rheumatoid arthritis (RA) and an 
inadequate response to TNF inhibitors:  results of the phase 3 RA-beacon study.  
Ann Rheum Dis.  2015;74 (Suppl 2):75.
34.
Fleischmann R, Kremer J, Cush J, et al.  Placebo-controlled trial of tofacitinib 
monotherapy in rheumatoid arthritis.  N Engl J.  Med.  2012;367(6):495-507.
35.
van Vollenhoven RF, Fleischmann R, Cohen S, et al.  Tofacitinib or adalimumab 
versus placebo in rheumatoid arthritis.  N Engl J Med.  2012;367(6):508-19.
36.
Burmester GR, Blanco R, Charles-Schoeman C, et al.  Tofacitinib (CP-690,550) in 
combination with methotrexate in patients with active rheumatoid arthritis with an 
inadequate response to tumour necrosis factor inhibitoes:  a randomized phase 3 
trial.  Lancet.  2013;381(9865):451-60.


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37.
Kremer J, Li ZG, Hall S, et al.  Tofacitinib in combination with nonbiologic 
disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis.  
Ann Intern Med.  2013;159(4):253-61.
38.
van der Heijde D, Tanaka Y, Fleischmann R, et al.  Tofacitinib (CP-690,550) in 
patients with rheumatoid arthritis receiving methotrexate:  twelve month data from 
a twenty-four-month phase III randomized radiographic study.  Arthritis Rheum.  
2013;65(3):559-70.
39.
Westhovens R, Taylor PC, Alten R, et al.  Filgotinib (GLPG0634/GS-6034), an 
oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) 
in patients with active rheumatoid arthritis and insufficient response to MTX:  
results from a randomised, dose-finding study (DARWIN 1).  Ann Rheum Dis.  
2016 Dec 19.  pii:  annrheumdis-2016-210104.  [Epub ahead of print].
40.
Kavanaugh A, Kremer J, Ponce L, et al.  Filgotinib (GLPG0634/GS-6034), an oral 
selective JAK1 inhibitor, is effective as monotherapy in patients with active 
rheumatoid arthritis:  results from a randomised, dose-finding study (DARWIN 2).  
Ann Rheum Dis.  2016 Dec 19.  pii:  annrheumdis-2016-210105.  [Epub ahead of 
print].
41.
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.
42.
Dougados M, Braun J, Vargas RB, et al.  ASAS recommendations for variables to 
be collected in clinical trials/epidemiological studies of spondyloarthritis.  Ann 
Rheum Dis.  2012;71(6):1103-4.
43.
Garrett S, Jenkinson T, Kennedy LG, et al.  A new approach to defining disease 
status in ankylosing spondylitis:  the Bath Ankylosing Spondylitis Disease Activity 
Index.  J Rheumatol.  1994;21:2286-91.
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Sieper J, Rudwaleit M, Baraliakos X, et al.  The Assessment of SpondyloArthritis 
international Society (ASAS) handbook:  a guide to assess spondyloarthritis.  Ann 
Rheum Dis.  2009;68 (Suppl II):ii1–ii44.


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Calin A, Garrett S, Whitelock H, et al.  A new approach to defining functional 
ability in ankylosing spondylitis:  the development of the Bath Ankylosing 
Spondylitis Functional Index.  J Rheumatol.  1994;21:2281-5.
46.
van der Heijde D, Dougados M, Davis J, et al.  Assessment in Ankylosing 
Spondylitis International Working Group/Spondylitis Association of America 
recommendations for conducting clinical trials in ankylosing spondylitis.  Arthritis 
Rheum.  2005;52(2):386-94.
47.
Hawker GA, Mian S, Kendzerska T, et al.  Measures of adult pain: Visual Analog 
Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill 
Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), 
Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), 
and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP).  Arthritis 
Care Res (Hoboken).  2011;63 (Suppl 11):S240-52.
48.
Doward LC, Spoorenberg A, Reynolds S, et al.  The development of the ASQoL:  
A quality of life instrument specific to Ankylosing Spondylitis.  Ann Rheum Dis 
2003;62(1):20-6.
49.
Helliwell P, Doward L, Whalley D, et al.  Psychometric and scaling properties of a 
new quality of life instrument specific to ankylosing spondylitis (AS).  Arthritis 
Rheum.  1999;42 (suppl):S72.
50.
Kiltz U, van der Heijde D, Boonen A, et al.  The ASAS Health Index (ASAS HI) –
a new tool to assess the health status of patients with spondyloarthritis.  Clin Exp 
Rheumatol.  2014;32 (5 Suppl 85):S-105-8.
51.
Cella D, Yount S, Sorensen M, et al.  Validation of the Functional Assessment of 
Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients 
with rheumatoid arthritis.  J Rheumatol.  2005;32(5):811-9.
52.
Morin CM.  Insomnia:  psychological assessment and management.  New York:  
Guilford Press; 1993.
53.
Bastien CH, Vallie'res A, Morin CM.  Validation of the Insomnia Severity Index as 
an outcome measure for insomnia research.  Sleep Med.  2000;2(4):297-307.


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54.
Reilly MC, Zbrozek AS, Dukes EM.  The validity and reproducibility of a work 
productivity and activity impairment instrument.  Pharmacoeconomics.  
1993;4(5):353-65.
55.
Helliwell PS, Firth J, Ibrahim GH, et al.  Development of an assessment tool for 
dactylitis in patients with psoriatic arthritis.  J Rheumatol.  2005;32(9);1745-50.
56.
van der Heijde D, Landewe R, Feldtkeller E.  Proposal of a linear definition of the 
Bath Ankylosing Spondylitis Metrology Index (BASMI) and comparison with the 
2-step and 10-step definitions.  Ann Rheum Dis.  2008;67:489-93.
57.
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al.  Assessment of 
enthesitis in ankylosing spondylitis.  Ann Rheum Dis.  2003;62(2):127-32.
58.
Anderson JJ, Baron G, van der Heijde D, et al.  Ankylosing spondylitis assessment 
group preliminary definition of short-term improvement in ankylosing spondylitis.  
Arthritis Rheum.  2001;44:1876-86.
59.
Mohamed ME, Zeng J, Song IH, et al.  Pharmacokinetics of ABT-494 with the 
once-daily extended-release tablet formulation being utilized in the ongoing 
rheumatoid arthritis phase 3 trials [abstract].  Arthritis Rheumatol.  
2016;68 (Suppl 10).  Available from:  
http://acrabstracts.org/abstract/pharmacokinetics-of-abt-494-with-the-once-daily-
extended-release-tablet-formulation-being-utilized-in-the-ongoing-rheumatoid-
arthritis-phase-3-trials/.  Accessed on:  07 March 2017.
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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the Investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Statistics
Statistics
Clinical Pharmacology and Pharmacometrics
Clinical Program Development
Bioanalysis
Medical Writing


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Appendix C.
Modified New York Criteria for Ankylosing Spondylitis
A. Diagnosis 
1.
Clinical Criteria
a.
Low back pain and stiffness for more than 3 months which improves with 
exercise, but is not relieved by rest.
b. Limitation of motion of the lumbar spine in both the sagittal and frontal planes.
c.
Limitation of chest expansion relative to normal values corrected for age and sex.
2.
Radiologic Criterion
a.
Sacroiliitis grade ≥ 2 bilaterally or sacroiliitis grade 3 – 4 unilaterally.
B. Grading 
1.
Definite ankylosing spondylitis if the radiologic criterion is associated with at least 
one clinical criterion.
2.
Probable ankylosing spondylitis if:
a.
Three clinical criteria are present.
b. The radiologic criterion is present without any signs or symptoms satisfying the 
clinical criterion.  (Other causes of sacroiliitis should be considered.)
Reference:
Van der Linden S, Valkenburg HA, Cats A.  Evaluation of diagnostic criteria for ankylosing spondylitis:  a proposal for 
modification of the New York criteria.  Arthritis Rheum.  1984;27:361-8.


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Appendix D.
Local Requirements


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Appendix E.
Study Activities
Activity
SCR
(≤35D)
BL 
(D1)
Treatment Period
Wk 
2
D15
Wk 
4
D29
Wk 
8
D57
Wk 
12
D85
Wk 
14 
D99
Wk 
16 
D113
Wk 
20 
D141
Wk 
24 
D169
Wk 
32 
D225
Wk 
40 
D281
Wk 
52 
D365
Wk 
64 
D449
Wk 
76 
D533
Wk 
88 
D617
Wk 
96 
D673
Wk 
104
D729
/PDa
30 
Day 
F/U 
Visit
Informed Consent
X
Inclusion/
Exclusion Criteria
X
Xb
Medical/Surgical 
History
X
Xb
Alcohol and 
Nicotine Use
X
X
X
X
X
X
X
X
X
X
X
Vital Signs/ 
Weight/Heightc
Xc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anterior Uveitis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Psoriasis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IBD
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
Xd
X
Chest X-Ray
Xd
Xe
Xe
AP Pelvis X-Rayf
X
Lateral Cervical-
Spine and
Lateral Lumbar-
Spine X-Rayf
X
X


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Activity
SCR
(≤35D)
BL 
(D1)
Treatment Period
Wk 
2
D15
Wk 
4
D29
Wk 
8
D57
Wk 
12
D85
Wk 
14 
D99
Wk 
16 
D113
Wk 
20 
D141
Wk 
24 
D169
Wk 
32 
D225
Wk 
40 
D281
Wk 
52 
D365
Wk 
64 
D449
Wk 
76 
D533
Wk 
88 
D617
Wk 
96 
D673
Wk 
104
D729
/PDa
30 
Day 
F/U 
Visit
MRI of Spine and 
SI Jointsg
X
X
X
Low-Dose CT Scan 
of Spineh
X
X
X
Latent TB risk 
assessment form 
Xd
Xe
Xe
TB Screening 
(QuantiFERON-TB 
Gold test and/or 
PPD Skin Test)
Xd
Xe
Xe
Pregnancy Test
Xi
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Central lab tests
  Blood chemistryk
  Hematology
  Urinalysisl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets
X
X
X
X
ESR (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FSHm
X
HBV/HCVn
X
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
HIVp
X
HLA-B27q,r
X
hsCRPs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Activity
SCR
(≤35D)
BL 
(D1)
Treatment Period
Wk 
2
D15
Wk 
4
D29
Wk 
8
D57
Wk 
12
D85
Wk 
14 
D99
Wk 
16 
D113
Wk 
20 
D141
Wk 
24 
D169
Wk 
32 
D225
Wk 
40 
D281
Wk 
52 
D365
Wk 
64 
D449
Wk 
76 
D533
Wk 
88 
D617
Wk 
96 
D673
Wk 
104
D729
/PDa
30 
Day 
F/U 
Visit
samples for 
exploratory research 
and validation 
studies (optional –
see Appendix F)t
Blood samples for 
upadacitinib PK 
assay
Xu
Xu
Xv
Xv
Xv
Xv
Xv
Xv
Xv
Subject 
questionnairesw
  BASDAI
  Total Back Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject 
questionnairesw
  BASFI
  PtGA
  Nocturnal Back 
Pain
  Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AS QoLw
X
X
X
X
X
X
X
ASAS HIw
X
X
X
X
X
X
X
X


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Activity
SCR
(≤35D)
BL 
(D1)
Treatment Period
Wk 
2
D15
Wk 
4
D29
Wk 
8
D57
Wk 
12
D85
Wk 
14 
D99
Wk 
16 
D113
Wk 
20 
D141
Wk 
24 
D169
Wk 
32 
D225
Wk 
40 
D281
Wk 
52 
D365
Wk 
64 
D449
Wk 
76 
D533
Wk 
88 
D617
Wk 
96 
D673
Wk 
104
D729
/PDa
30 
Day 
F/U 
Visit
Subject 
questionnairesw
  FACIT – F
  ISI
  WPAI
X
X
X
X
X
TJC/SJC
X
X
X
X
X
X
X
X
X
X
X
Dactylitis
X
X
X
X
X
X
X
X
X
X
X
BASMIlin
X
X
X
X
X
X
X
X
X
X
X
MASES
X
X
X
X
X
X
X
X
PGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ASAS 20 
calculationx
X
X
X
X
X
X
X
X
X
X
Prior and 
Concomitant 
Therapy 
Assessmenty
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor AEz
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Xaa
Dispense Study 
Drug 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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AE = adverse event; AP = anterior-posterior; ASAS = Assessment of SpondyloArthritis international Society; AS QoL = Ankylosing Spondylitis Quality of Life; BASDAI = Bath 
Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMIlin = Linear Bath Ankylosing Spondylitis Metrology Index; 
BL = Baseline Visit; D = Day; ECG = electrocardiogram; eCRF = electronic case report form; ESR = erythrocyte sedimentation rate; FACIT-F = Functional Assessment of 
Chronic Illness Therapy – Fatigue; FSH = follicle-stimulating hormone; F/U = Follow-Up; HBV = hepatitis B virus; HCV = hepatitis C virus; HI = health index; HIV = human 
immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; IBD = inflammatory bowel disease; IRT = Interactive Response Technology; ISI = Insomnia Severity Index; 
MASES = Maastricht AS enthesitis score; MRI = magnetic resonance imaging; NSAID = nonsteroidal anti-inflammatory drug; PD = Premature Discontinuation; 
PGA = Physician's Global Disease Activity; PK = pharmacokinetics; PPD = purified protein derivative; PtGA = Patient's Global Assessment of Disease Activity; 
SCR = Screening; SI = sacroiliac; SJC = Swollen Joint Count; TB = tuberculosis; TJC = Tender Joint Count; Wk = Week; WPAI = Work Productivity and Activity Impairment
a.
Subjects who prematurely discontinue the study or study drug should complete the procedures outlined in the PD Visit within 2 weeks of last dose of study drug and 
preferably prior to the administration of new therapies.
b.
Update Inclusion/Exclusion, prior and concomitant therapy, and Medical/Surgical History to prior to enrollment to assure subject eligibility.
c.
Height will be measured at Screening Visit only.
d.
These procedures will not be required if the subject had a previous normal ECG, normal CXR, or negative TB test within 90 days of Screening, provided all protocol-required 
documentation is available at the site and nothing has changed in the subjects health status since the time of the test that warrants a repeat test.  Any documentation of past 
positive PPD or IGRA results may be acceptable; however, negative PPD or IGRA test done more than 90 days prior to the Screening Visit will need to be repeated.  If the 
subject has a positive PPD test or IGRA test, has had a past ulcerative reaction to PPD placement, and/or a CXR consistent with prior TB exposure, the subject will be 
required to have documented completion of a full course of TB prophylaxis prior to the Baseline Visit.
Refer to Section 5.3.1.1.  Study Procedures, TB Testing for specific requirements for TB testing and TB prophylaxis.
e.
Obtain chest x-ray for subjects with TB risk factors as identified by the TB risk assessment form for subjects living in areas endemic for TB or for subjects with a newly-
positive QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.  Refer to Section 5.3.1.1, Study Procedures, TB Testing for specific requirements for TB testing 
and TB Prophylaxis.
f.
X-rays of the spine and pelvis will not be required during the Screening Period if the subject had a previous anteroposterior pelvis x-ray and lateral spine x rays within 90 days 
of the Screening Period, provided that the x-rays are confirmed to be adequate for the required evaluations and are deemed acceptable by the central imaging vendor.
g.
MRI should be performed prior to or at Baseline in subjects who meet eligibility criteria, and at Week 14 and Week 104.  If subject has a contraindication for MRI prior to 
enrollment, site must discuss with the AbbVie TA MD.  If a site is unable to obtain the MRI prior to Baseline, a window of 3 days post-dose will be allowed.
h.
Only for subjects at select sites who consent to participate in the low-dose CT scan substudy.  Low-dose CT scan of the whole spine should be performed prior to or at the 
Baseline Visit in subjects who meet eligibility criteria, Week 52, and at Week 104.  If a site is unable to obtain the low-dose CT of the whole spine prior to Baseline Visit, a 
window of 14 days post-dose will be allowed.


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i.
For all women of childbearing potential, collect serum for pregnancy test only at Screening.  If the serum pregnancy test is positive, the subject is considered a screen failure.  
If serum pregnancy test comes back borderline, a repeat test is necessary (pregnancy is an exclusion criterion).  If still borderline ≥ 3 days later, this will be considered 
documentation of continued lack of a positive result, and the subject can be enrolled into the study in the absence of clinical suspicion of pregnancy and other pathological 
causes of borderline results.  Refer to Section 5.3.1.1, Study Procedures, Pregnancy Test for additional details.
j.
For all women of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits.  More frequent pregnancy tests will be performed throughout the 
study if required per local/country requirements.  If urine pregnancy test (which is performed at the site) is negative, begin or continue dosing.  If urine pregnancy test is 
positive, withhold dosing, and perform a serum pregnancy test.  Pregnant subjects must discontinue from study drug.  Refer to Section 5.3.1.1, Study Procedures, Pregnancy 
Test for additional details.
k.
Minimum 8-hour fast.  If a subject is not able to fast when necessary due to unforeseen circumstances, the non-fasting status will be recorded in study source documentation.
l.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A microscopic analysis will be performed in the event the dipstick 
results show leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.
m.
FSH should be tested at Screening if the female subject is < 55 years of age AND has had no menses ≥ 12 months AND has no history of permanent surgical sterilization 
(defined in Section 5.2.4).
n.
In case of re-screening, there is no need to redraw HBV and HCV, provided the conditions noted in Section 5.3.1.1 are met and no more than 90 days have passed.
o.
For subjects in Japan only:  Subjects with positive HBs Ab and/or positive HBc Ab results should have HBV-DNA PCR test performed at the specified visits; in cases where 
recurrence of HBV-DNA is observed, the subject should be discontinued from the study.  This measure is not necessary in subjects with history of HBV vaccination and 
positive HBs Ab result.
p.
HIV testing will be performed at Screening.  The Investigator must discuss any local reporting requirements to local health agencies with the subject.  The site will report 
confirmed positive results to their health agency per local regulations, if necessary.  If a subject has a confirmed positive result, the Investigator must discuss with the subject 
the potential implications to the subject's health, and subject should receive or be referred for clinical care promptly.  A subject will not be eligible for study participation if 
test results indicate a positive HIV infection.  AbbVie will not receive results from the testing and will not be made aware of any positive result.
q.
In case of re-screening, there is no need to redraw HLA-B27.
r.
Result does not need to be available to the site prior to enrollment.
s.
The hsCRP results starting after Baseline (Day 1) will not be reported to the Sponsor, Investigator, study site personnel, or the subject.  Local laboratory or site testing for 
hsCRP or CRP is not allowed after Baseline.  Results of tests such as hsCRP may be blunted in subjects taking a JAK inhibitor, thereby limiting the clinical utility of these 
tests in the setting of a possible safety assessment or adverse event management.  As such, local hsCRP testing should not be performed until the last subject completes 
Period 1.
t.
Optional with signed ICF:  if the ICF is not signed, samples for exploratory research or validation studies will not be collected.  Refer to Appendix F for a description of the 
optional samples to be collected.  


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u.
Blood samples at Week 2 and Week 4 visits will be collected prior to dosing, and the subjects should take the study drug dose at the clinic after collecting the PK blood 
sample.  However, if the subject normally takes the study drug dose at a time that is after the time of the scheduled study visit, the subject should follow the regular dosing 
schedule and the PK sample should be collected at any time during the visit.
v.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.
w.
Prior to other procedures.  Will be administered to the subject on an ePRO device.
x.
ASAS 20 criteria will be calculated by IRT.
y.
For subjects on concomitant NSAID therapy, the NSAID eCRF should be completed.
z.
SAEs will be collected starting from the time of signing informed consent; non-serious AEs will be collected starting from the first day of study drug dose.  Any AE that 
occurs between Screening and Baseline Visit should be captured as medical history.
aa.
Subjects who were randomized to placebo at Baseline will receive upadacitinib 15 mg QD in an open-label manner at Week 14.


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Appendix F.
Optional Samples for Exploratory Research or Validation Studies
Activity
SCR
(≤35D)
BL 
(D1)
Treatment Period
Wk 
2
D15
Wk 
4
D29
Wk 
8
D57
Wk 
12
D85
Wk 
14 
D99
Wk 
16 
D113
Wk 
20 
D141
Wk 
24 
D169
Wk 
32 
D225
Wk 
40 
D281
Wk 
52 
D365
Wk 
64 
D449
Wk 
76 
D533
Wk 
88 
D617
Wk 
96 
D673
Wk 
104
D729
/PD
30 
Day 
F/U 
Visit


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Appendix G.
Latent TB Risk Assessment Form Example
1.
Have you or an immediate family member or other close contact ever been 
diagnosed or treated for tuberculosis?
2.
Have you lived in or had prolonged travels to countries in the following regions:
●
Africa
●
Eastern Europe
●
Asia
●
Latin America
●
Caribbean Islands 
●
Russia
3.
Have you lived or worked in a prison, homeless shelter/refugee camp, immigration 
center, health care worker in a hospital or nursing home?
4.
Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:
●
Chronic Cough
●
Chest pain, or pain with breathing or coughing
●
Blood-Streaked Sputum (coughing up blood)
●
Unexplained Weight Loss
●
Fever
●
Fatigue/Tiredness
●
Night Sweats
●
Shortness of Breath
From:  http://www mayoclinic.org/diseases-conditions/tuberculosis/symptoms-causes/dxc-20188557
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf


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Appendix H.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.2  Synopsis
Subsection Methodology:
Sixth paragraph previously read:
Randomization will be stratified by baseline high sensitivity C-reactive protein (hsCRP) 
(≤ upper limit of normal [ULN] vs. > ULN) and geographic region (United States 
[US]/Canada, Japan, Rest of the World [RoW]).
Has been changed to read:
Randomization will be stratified by Screening high sensitivity C-reactive protein (hsCRP) 
(≤ upper limit of normal [ULN] vs. > ULN) and geographic region (United States 
[US]/Canada, Japan, Rest of the World [RoW]).
Section 3.2  Benefits and Risks
Sixth paragraph
Add:  new last sentence
Events of deep vein thrombosis and pulmonary embolism have been reported in patients 
receiving JAK inhibitors including upadacitinib.
Section 5.1  Overall Study Design and Plan:  Description
Seventh paragraph previously read:
Randomization will be stratified by baseline hsCRP (≤ ULN vs. > ULN) and geographic 
region (United States [US]/Canada, Japan, Rest of the World [RoW]).
Has been changed to read:
Randomization will be stratified by Screening hsCRP (≤ ULN vs. > ULN) and geographic 
region (United States [US]/Canada, Japan, Rest of the World [RoW]).


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Section 5.2.3.2  Permitted Background AS Therapy
Fourth paragraph, third sentence previously read:
Once a joint is injected, it will be considered not evaluable/assessable ("NA") during the 
28 days following injection.  
Has been changed to read:
Once a joint is injected, it will be considered not evaluable/assessable ("NA") during the 
90 days following injection.  
Section 5.3.1.1  Study Procedures
Subsection TB Testing/TB Prophylaxis
Second paragraph, first sentence previously read:
At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk 
assessment form (Appendix G) and tested for TB infection by QuantiFERON-TB Gold 
test.  
Has been changed to read:
At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk 
assessment form (Appendix G) and tested for TB infection by QuantiFERON-TB Gold 
test (or IGRA equivalent).  
Section 5.3.1.1  Study Procedures
Subsection TB Testing/TB Prophylaxis
Second paragraph, first bullet
Add:  new second and third sentence
If a subject had a negative QuantiFERON-TB Gold (or IGRA equivalent) within 90 days 
prior to Screening and source documentation is available, the test does not need to be 
repeated provided nothing has changed in the subject's medical history to warrant a repeat 
test.  These cases may be discussed with the AbbVie TAMD.


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Section 5.3.1.1  Study Procedures
Subsection TB Testing/TB Prophylaxis
Second paragraph, second bullet, first sentence previously read:
If a subject had a negative PPD Skin Test (also known as a TB Skin Test or Mantoux 
Test) within 90 days prior to Screening and a QuantiFERON-TB Gold test cannot be 
performed by Central Lab at Screening and source documentation is available, TB testing 
by PPD Skin Test does not need to be repeated, provided nothing has changed in the 
subject's medical history to warrant a repeat test.  
Has been changed to read:
If a subject had a negative PPD Skin Test (also known as a TB Skin Test or Mantoux 
Test) within 90 days prior to Screening and a QuantiFERON-TB Gold test (or IGRA 
equivalent) cannot be performed by Central Lab at Screening and source documentation is 
available, TB testing by PPD Skin Test does not need to be repeated, provided nothing 
has changed in the subject's medical history to warrant a repeat test.  
Section 5.4.1  Discontinuation of Individual Subjects
Second paragraph
Add:  new last bullet
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus, or non-cardiac, non-
neurologic arterial thrombosis.
Section 5.5.3  Method of Assigning Subjects to Treatment Groups
Fifth paragraph, first sentence previously read:
Randomization will be stratified by baseline hsCRP (≤ ULN vs. > ULN) and geographic 
region (US/Canada, Japan, RoW).  
Has been changed to read:
Randomization will be stratified by Screening hsCRP (≤ ULN vs. > ULN) and geographic 
region (US/Canada, Japan, RoW).  


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Section 5.5.4  Selection and Timing of Dose for Each Subject5.5.4 Selection and 
Timing of Dose for Each Subject
Last paragraph, last sentence previously read:
If the subject experiences a study drug interruption > 7 consecutive days during Weeks 1 
through 14 (Period 1) or > 30 consecutive days after Week 14 (Period 2), they should 
notify the Investigator, and study drug should be discontinued.
Has been changed to read:
If the subject experiences a study drug interruption > 7 consecutive days during Weeks 1 
through 14 (Period 1) or > 30 consecutive days during Period 2 they should notify the 
Investigator, and the Investigator will decide if study drug should be restarted.
Section 5.5.5.2  Blinding of Data for Data Monitoring Committee (DMC)
Add:  new last paragraph
As of 18 April 2019, with all subjects having reached the end of Period 1, and after final 
review of unblinded safety data, the DMC concluded its oversight of this study.
Section 6.1.1.1  Adverse Event
Second paragraph, last sentence previously read:
Laboratory abnormalities and changes in vital signs are considered to be AEs only if they 
result in discontinuation from the study, necessitate therapeutic medical intervention, 
and/or if the Investigator considers them to be AEs.
Has been changed to read:
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.


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Section 6.1.2  Adverse Event Severity
First paragraph previously read:
When criteria are available, events should be graded as described in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).60
Has been changed to read:
When criteria are available, events should be graded as described in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03.60
Section 6.1.7  Toxicity Management
Third paragraph, sixth sentence previously read:
If study drug has been interrupted for a serious infection for more than 14 consecutive 
days during Period 1 of the study or 30 consecutive days thereafter, the subject must be 
discontinued from study drug.  
Has been changed to read:
If study drug has been interrupted for a serious infection for more than 14 consecutive 
days during Period 1 of the study or 30 consecutive days thereafter, the subject must 
inform the Investigator and the Investigator can determine if study drug can be restarted.  
Section 6.1.7  Toxicity Management
Add:  new fourth paragraph
Herpes Zoster:  If a subject develops herpes zoster, consider temporarily interrupting 
study drug until the episode resolves.
Section 6.1.7  Toxicity Management
Sixth paragraph
Add:  new last sentence
Periodic skin examination is recommended for subjects who are at increased risk for skin 
cancer.


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Section 6.1.7  Toxicity Management
Add:  new seventh paragraph
Thrombosis Events:  Subjects who develop symptoms of thrombosis should be promptly 
evaluated and treated appropriately.  If the diagnosis of deep vein thrombosis, pulmonary 
embolus or non-cardiac, non-neurologic arterial thrombosis is confirmed, the subject must 
be discontinued from study drug.
Table 4.  Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory Parameter "Serum Creatinine"
First bullet, last sentence previously read:
If the results of the repeat testing still meet this criterion, then interrupt study drug and re-
start study drug once serum creatinine returns to ≤ 1.5 × baseline value and > ULN.
Has been changed to read:
If the results of the repeat testing still meet this criterion, then interrupt study drug and re-
start study drug once serum creatinine returns to ≤ 1.5 × baseline value and ≤ ULN.
Section 6.1.7  Toxicity Management
Subsection Period 2
First bullet
Add:  new last sentence
PI will make determination if study drug should be restarted for interruptions > 30 days.
Section 8.3  Randomization Methods
Last paragraph, first sentence previously read:
Randomization will be stratified by baseline hsCRP (≤ ULN vs. > ULN) and geographic 
region (US/Canada, Japan, RoW).  
Has been changed to read:
Randomization will be stratified by Screening hsCRP (≤ ULN vs. > ULN) and geographic 
region (US/Canada, Japan, RoW).  


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Section 15.0  Reference List
Reference 27 and 60 previously read:
27.
AbbVie.  ABT-494 Investigator's Brochure Edition 6.1.  12 May 2016.
60.
National Cancer Institute.  CTCAE v. 4.0.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc.  
Accessed on:  10 August 2017.
Has been changed to read:
27.
AbbVie.  ABT-494 Investigator's Brochure Edition 10.  19 August 2019.
60.
National Cancer Institute.  CTCAE v. 4.03.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc.  
Accessed on:  10 August 2017.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Pharmacovigilance and Patient Safety
Statistics
Clinical Pharmacology and Pharmacometrics
Clinical Program Development
Bioanalysis
Medical Writing


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Has been changed to read:
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Statistics
Statistics
Clinical Pharmacology and Pharmacometrics
Clinical Program Development
Bioanalysis
Medical Writing
Appendix E.  Study Activities
Table note "t."
Delete:  last sentence
Sample collected at Screening will be for the stool sample only.

SAP_001.pdf: 
Upadacitinib
M16-098 – Statistical Analysis Plan
Version 3.0 – 20 August 2020
1
1.0
Title Page
Statistical Analysis Plan
Study M16-098
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and 
Efficacy of Upadacitinib in Subjects with Active 
Ankylosing Spondylitis
Date:  20 August 2020
Version 3.0
NCT03178487


Upadacitinib
M16-098 – Statistical Analysis Plan
Version 3.0 – 20 August 2020
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................7
4.0
Study Objectives, Design and Procedures.............................7
4.1
Study Objectives ........................................................................................7
4.2
Overall Study Design and Plan..................................................................8
4.3
Sample Size..............................................................................................12
4.4
Week 14 Analysis and Database Lock.....................................................12
4.5
Long-term Analysis and Database Locks ................................................12
4.6
Data Monitoring Committee (DMC) Activities.......................................12
5.0
Analysis Populations and Analysis Windows .....................13
5.1
Analysis Populations................................................................................13
5.2
Analysis Windows ...................................................................................13
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............16
6.1
Demographics and Baseline Characteristics............................................16
6.2
Medical History .......................................................................................19
6.3
Prior Treatment and Concomitant Medications.......................................19
6.4
Protocol Deviations..................................................................................20
7.0
Patient Disposition.................................................................20
8.0
Study Drug Exposure and Compliance...............................22
8.1
Study Drug Exposure...............................................................................22
8.2
Compliance ..............................................................................................23
9.0
Efficacy Analysis....................................................................24
9.1
General Considerations............................................................................24
9.1.1
Efficacy Analysis at Different Phases of the Study.................................24
9.1.2
Handling for Missing Data and Intercurrent Event..................................24
9.2
Efficacy Analysis for Period 1.................................................................26
9.2.1
Primary Efficacy Analysis .......................................................................26
9.2.2
Supplementary Analysis of Primary Efficacy Variable...........................27
9.2.3
Key Secondary Efficacy Analyses...........................................................27


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9.2.4
Exploratory Efficacy Analyses ................................................................30
9.2.5
Handling of Multiplicity ..........................................................................32
9.2.6
Efficacy Subgroup Analysis ....................................................................33
9.3
Long-Term Efficacy Analysis..................................................................34
9.4
Efficacy Variables Definitions and Conventions.....................................34
9.4.1
Ankylosing Spondylitis Disease Activity Score (ASDAS) .....................34
9.4.2
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ...........36
9.4.3
BASDAI50...............................................................................................37
9.4.4
ASAS20, ASAS40, ASAS 5/6, and ASAS Partial Remission ................37
9.4.5
Bath Ankylosing Spondylitis Functional Index (BASFI)........................38
9.4.6
High Sensitivity C-Reactive Protein........................................................39
9.4.7
Bath Ankylosing Spondylitis Metrology Index (Linear).........................39
9.4.8
Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)..............40
9.4.9
Dactylitis..................................................................................................41
9.4.10
Work Productivity and Activity Impairment Questionnaire:  Axial 
Spondyloarthritis, Version 2.0 (WPAI-Axial Spondyloarthritis) ............41
9.4.11
Joint Evaluation .......................................................................................44
9.4.12
Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) ...........45
9.4.13
ASAS Health Index (HI)..........................................................................48
9.4.14
Functional Assessment of Chronic Illness Therapy – Fatigue 
Scale (FACIT-F) ......................................................................................49
9.4.15
Insomnia Severity Index (ISI)..................................................................50
9.4.16
SpondyloArthritis Research Consortium of Canada (SPARCC) 
scores........................................................................................................52
9.4.17
Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)...........54
9.4.18
Other Efficacy Variables..........................................................................55
10.0
Safety Analysis.......................................................................55
10.1
General Considerations............................................................................55
10.2
Analysis of Adverse Events.....................................................................57
10.2.1
Analysis of Adverse Events Prior to Protocol-Defined Treatment 
Switching .................................................................................................57
10.2.1.1
Adverse Events Overview........................................................................57
10.2.1.2
Adverse Events by System Organ Class and Preferred Term..................58


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10.2.1.3
TEAEs by Maximum Severity.................................................................59
10.2.1.4
TEAEs by Relationship............................................................................59
10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and Preferred 
Term.........................................................................................................59
10.2.1.6
Adverse Events of Special Interest ..........................................................59
10.2.2
Analysis of Long-Term Adverse Event ...................................................61
10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................62
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT ........................................................................63
10.2.2.3
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................63
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation ........................64
10.3
Analysis of Laboratory Data....................................................................64
10.3.1
Variables and Units..................................................................................64
10.3.2
Analysis of Laboratory Data for Period 1................................................66
10.3.2.1
Assessment of Mean Change from Baseline and Percentage 
Change from Baseline in Clinical Laboratory Variables.........................67
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................67
10.3.2.3
Assessment of Potentially Clinical Significant Laboratory Values .........68
10.3.2.4
Assessment of Liver Elevations...............................................................68
10.3.3
Analysis of Long-Term Laboratory Data.................................................69
10.3.3.1
Assessment of Mean Change from Baseline and Percentage 
Change from Baseline in Clinical Laboratory Variables.........................69
10.3.3.2
Assessment of Potentially Clinical Significant Laboratory Values .........69
10.3.3.3
Assessment of Liver Elevations...............................................................70
10.4
Analysis of Vital Signs ............................................................................71
10.4.1
Variables and Criteria Defining Abnormality..........................................71
10.4.2
Analysis of Vital Sign for Period 1..........................................................71
10.4.3
Analysis of Long-Term Vital Sign...........................................................72


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11.0
Statistical Analysis to Account for the Impact of 
COVID-19 Pandemic.............................................................72
12.0
Version History......................................................................74
13.0
References...............................................................................75
14.0
Appendix.................................................................................76
List of Tables
Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ASAS 
Components, BASDAI, BASFI and ASDAS components) and 
Safety Analysis of Vital Signs for Period 1.............................................14
Table 2.
Analysis Windows for Safety Analysis of lab values for Period 1..........15
Table 3.
Analysis Windows for Efficacy Analysis for Period 1 (for ASAS 
HI)............................................................................................................15
Table 4.
Analysis Windows for Efficacy Analysis for Period 1 (for AS 
QoL and MASES)....................................................................................15
Table 5.
Analysis Windows for Efficacy Analysis for Period 1 (for 
FACIT-F, ISI, WPAI, BASMI, TJC/SJC and Dactylitis)........................16
Table 6.
Analysis Windows for Efficacy Analysis for Period 1 (for MRI 
joints and spine SPARCC).......................................................................16
Table 7.
Subgroups for Efficacy Analysis .............................................................34
Table 8.
Anatomical Joints Assessed.....................................................................45
Table 9.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................60
Table 10.
List of Laboratory Variables....................................................................65
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Findings..........71
Table 12.
SAP Version History Summary...............................................................74
List of Figures
Figure 1.
Study Design............................................................................................11
Figure 2.
Graphical Multiple Testing Procedure.....................................................33


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List of Appendices
Appendix A.
ASAS-NSAID Intake Score for Axial Spondyloarthritis ........................77
Appendix B.
EAER and Normal Approximation Based 95% Confidence 
Interval .....................................................................................................80
Appendix C.
Analysis of Categorical Endpoints...........................................................81
Appendix D.
Analysis of Continuous Endpoints using Mixed Effect Model 
Repeat Measurement (MMRM)...............................................................84
Appendix E.
Tipping Point Analysis ............................................................................85
Appendix F.
Geographic Region ..................................................................................87
Appendix G.
Low Dose CT Imaging.............................................................................88


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the Data and Statistical Science Department for Upadacitinib Study M16-098.  It provides 
details to further elaborate on statistical methods as outlined in the protocol.  
Pharmacokinetic and 
 analyses will be performed separately, and the 
corresponding analysis plan is documented separately.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC 27513).
4.0
Study Objectives, Design and Procedures
4.1
Study Objectives
Period 1
1.
To evaluate the efficacy of upadacitinib compared with placebo on reduction of 
signs and symptoms as measured by proportion of subjects who achieve an 
Assessment of SpondyloArthritis international Society (ASAS) 40 response at 
Week 14 in subjects with active ankylosing spondylitis (AS) who have had an 
inadequate response to at least two nonsteroidal anti-inflammatory drugs (NSAIDs) 
or intolerance to or a contraindication for NSAIDs, and who are biologic disease-
modifying antirheumatic drug (bDMARD)-naïve.
2.
To assess the safety and tolerability of upadacitinib in subjects with active AS who 
have had an inadequate response to at least two NSAIDs or intolerance to or a 
contraindication for NSAIDs, and who are bDMARD-naïve.
Period 2
To evaluate the safety, tolerability, and efficacy of upadacitinib through up to 2 years of 
treatment in subjects who have completed Period 1 under global protocol V2. After Week 
104, subjects in France, Germany, Belgium, Finland, and Netherlands only will be 


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evaluated for safety and tolerability of upadacitinib every 12 weeks until the end of the 
study as defined in the country specific protocols V2.01, V2.02 and V2.03.
4.2
Overall Study Design and Plan
This is a Phase 2/3, multicenter study that includes two periods.  Period 1 is the 14-week 
randomized, double-blind, parallel-group, placebo-controlled period designed to compare 
the safety and efficacy of Upadacitinib 15 mg QD versus placebo for the treatment of 
signs and symptoms of subjects with active AS who have had an inadequate response to at 
least two NSAIDs over an at least 4-week period in total at maximum recommended or 
tolerated doses or intolerance to or a contraindication for NSAIDs as defined by the 
Investigator, and who are bDMARDs-naïve.  Period 2 is an open label long-term
extension to evaluate the long-term safety, tolerability, and efficacy of Upadacitinib 
15 mg QD in subjects with AS who have completed Period 1.
The study is designed to enroll approximately 170 subjects at approximately 110 study 
centers worldwide to meet scientific and regulatory objectives without enrolling an undue 
number of subjects in alignment with ethical considerations.  
The study duration includes a 35-day screening period; a 14-week randomized, double-
blind, placebo-controlled treatment period (Period 1); a 90-week open label extension 
period (Period 2); and a 30-day follow-up visit. After Week 104, subjects in France, 
Germany, Belgium, Finland, and Netherlands will be evaluated for safety and tolerability 
of upadacitinib every 12 weeks until the end of the study.
X-rays of the pelvis will be performed within the 35-day screening period to evaluate the 
SI joints to confirm the fulfillment of the modified New York Criteria for AS.  X-rays of 
the spine will also be performed within the 35-day screening period to assess for total 
spinal ankylosis; subjects with total spinal ankylosis are not eligible for this study.  The 
x-rays of the spine and pelvis will not be required during the Screening Period if the 
subject had a previous anteroposterior (AP) pelvis x-ray and lateral spine x-rays within 


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90 days of the Screening Period, provided that the x-rays are confirmed to be adequate for 
the required evaluations and are deemed acceptable by the central imaging vendor.
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of 
two treatment groups:
●
Group 1:  Upadacitinib 15 mg QD, N = 85 (Day 1 to Week 14) → 
Upadacitinib 15 mg QD (Week 14 and thereafter)
●
Group 2:  Placebo, N = 85 (Day 1 to Week 14) → Upadacitinib 15 mg QD 
(Week 14 and thereafter)
Randomization is stratified by screening hsCRP (≤ ULN vs. > ULN) and geographic 
region (United States [US]/Canada, Japan, Rest of the World [RoW]).
Starting at Week 16, subjects who do not achieve at least an ASAS 20 response at
two consecutive visits will have the option to add or modify doses of NSAIDs, 
acetaminophen/paracetamol, low potency opioid medications (tramadol or combination of 
acetaminophen and codeine or hydrocodone), and/or modifydose of MTX or SSZ at 
Week 20 or thereafter. ASAS 20 calculation for rescue therapy no longer applies post 
Week 104.
Starting at Week 24, subjects who still do not achieve at least an ASAS 20 response at 
two consecutive visits will be discontinued from study drug treatment. ASAS 20 
calculation for discontinuation criteria no longer applies post Week 104.
Subjects who complete the Week 14 visit (end of Period 1) will enter the open-label long-
term extension portion of the study, Period 2.  Subjects who are assigned to Upadacitinib 
in Period 1 will continue to receive Upadacitinib 15 mg QD in an open-label manner.  
Subjects who were randomized to placebo at Baseline will also receive open label 
upadacitinib 15 mg QD at Week 14.
The primary analysis will be conducted after all subjects have completed Week 14 or have 
prematurely discontinued prior to Week 14.  


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Optional samples may be collected for exploratory research at designated time points 
throughout the study.
Subjects will have an x-ray of the spine at Week 104.  All subjects who meet eligibility 
criteria will have an MRI evaluation of the SI joints, as well as the cervical, thoracic, and 
lumbar regions of the spine, prior to or at the Baseline Visit, at Week 14, and Week 104.
Subjects at select sites who consent to participate in the low-dose computer tomography 
(CT) scan sub-study and meet eligibility criteria will have low-dose CT scan evaluation of 
the whole spine (cervical, thoracic, and lumbar spine) prior to or at the Baseline Visit, 
Week 52, and Week 104.
Study design schematic is shown in Figure 1.


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Figure 1.
Study Design
AS = ankylosing spondylitis; ASAS = Assessment of SpondyloArthritis international Society; BASDAI = Bath 
Ankylosing Spondylitis Disease Activity Index; bDMARD = biologic disease-modifying antirheumatic drugs;
CT = computer tomography; hsCRP = high sensitivity C-reactive protein; MRI = magnetic resonance imaging;
NRS = numeric rating scale; NSAIDs = nonsteroidal anti-inflammatory drugs; QD = once daily; RoW = Rest of the 
World; SSZ = Sulfasalazine; ULN = upper limit of normal; W = week
a.
Clinical diagnosis of AS and meeting the modified New York Criteria for AS.  Subject must have baseline disease 
activity as defined by having BASDAI score ≥ 4 and Patient's Assessment of Total Back Pain score ≥ 4 based on a 
0 – 10 NRS at the Screening and Baseline Visit.
b.
Stratified by geographic region (US/Canada, Japan, RoW) and hsCRP (≤ ULN vs. > ULN).
c.
The x-rays of the spine and pelvis will not be required during the Screening Period if the subject had a previous 
anteroposterior pelvis x-ray and lateral spine x-rays within 90 days of the Screening Period, provided that the x-
rays are confirmed to be adequate for the required evaluations and are deemed acceptable by the central imaging 
vendor.
d.
For subjects at select sites who consent to participation in the low-dose spine CT scan sub-study.
e.
Starting at Week 16, subjects who do not achieve at least an ASAS 20 response at two consecutive visits will have 
the option to add or modify doses of NSAIDs, acetaminophen/paracetamol, low potency opioid medications 
(tramadol or combination of acetaminophen and codeine or hydrocodone), and/or modify dose of MTX or SSZ at 
Week 20 or thereafter.  ASAS 20 calculation for rescue therapy no longer applies post Week 104.


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Figure 1.
Study Design (Continued)
f.
Starting at Week 24, subjects who still do not achieve at least an ASAS 20 response at two consecutive visits will 
be discontinued from study drug treatment.  ASAS 20 calculation for discontinuation criteria no longer applies post 
Week 104.
g.
After Week 104, subjects in France, Germany, Belgium, Finland, and Netherlands will be evaluated for safety and 
tolerability of upadacitinib every 12 weeks until the end of the study.
4.3
Sample Size
The planned total sample size of 170 can provide at least 90% power to detect a 26% 
difference in ASAS 40 response rates at Week 14 (assuming a placebo ASAS 40 response 
rate of 20%), at two-sided α = 0.05 and accounting for 10% dropout rate.  
4.4
Week 14 Analysis and Database Lock
An unblinded analysis will be conducted after all subjects have completed Period 1 
(Week 14) or have prematurely discontinued prior to Week 14. 
4.5
Long-term Analysis and Database Locks
A Week 104 analysis will be conducted after all subjects have completed Week 104 or 
have prematurely discontinued prior to Week 104.  This will be the final efficacy analysis 
for the entire study. Safety analysis will include data collected up to Week 104 or 
premature discontinuation for every subject. 
At the final database lock when the study completes, updated long-term safety analysis 
will be conducted.
4.6
Data Monitoring Committee (DMC) Activities
An independent external Data Monitoring Committee (DMC) is used to review unblinded 
safety data at regular intervals during the conduct of the study.  The DMC will provide 
recommendations to an AbbVie Point of Contact on whether to continue, modify, or 
terminate studies after each review.  When needed, high-level unblinded efficacy data 
may also be requested by the DMC and be reviewed so that the DMC can assess benefit: 
risk of any emerging safety differences.


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5.0
Analysis Populations and Analysis Windows
5.1
Analysis Populations
Full Analysis Set (FAS)
The Full Analysis Set (FAS) includes all randomized subjects who received at least 
one dose of study drug.  The FAS will be used for all efficacy and baseline analyses.
Per Protocol Analysis Set
The Per Protocol Analysis Set represents a subset of the FAS and consists of all FAS 
subjects who did not meet any major protocol deviations up to Week 14 in Period 1 of the 
study.  Additional analysis of the primary efficacy endpoint will be conducted on the Per 
Protocol analysis set, in order to evaluate the impact of major protocol deviations.
Major protocol deviations (ICH deviations and other clinically significant non-ICH 
deviations) will be identified prior to database lock.
Safety Analysis Set
The Safety Analysis Set consists of all subjects who received at least one dose of study 
drug.  For the Safety Analysis Set, subjects are assigned to a treatment group based on the 
"as treated" treatment group, regardless of the treatment randomized.  The "as treated" is 
determined by the treatment the subject received during the majority of the subject's drug 
exposure time in the analysis period.
5.2
Analysis Windows
Definition of Study Days (Days Relative to the First Dose of Study Drug)
Study Days are calculated for each collection date relative to the date of the first dose of 
study drug.  It is defined as the number of days between the date of the first dose of study 
drug and the collection date.  Study days are negative values when the collection date of 
interest is prior to the first study drug dose date.  Study days are positive values when the 
collection date of interest is on or after the first study drug dose date.  The day of the 


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first dose of study drug is defined as Study Day 1, while the day prior to the first study 
drug dose is defined as Study Day –1 (there is no Study Day 0).  Study days are used to 
map actual study visits to the protocol-specified study visits.
Definition of Analysis Windows
The following rules will be applied to assign actual subject visits to protocol-specified 
visits.  For each protocol-specified study visit, a target study day will be identified to 
represent the corresponding visit along with a window around the target day.  Windows 
will be selected in a non-overlapping fashion so that a collection date does not fall into 
multiple visit windows.  If a subject has two or more actual visits in one visit window, the 
visit closest to the target day will be used for analysis.  If two visits are equidistant from 
the target day, then the later visit will be used for analysis. 
The visit window and the target study day for each protocol-specified visit in Period 1 are 
displayed in Table 1 and Table 3 (depending on the different visit schedules of different 
endpoints).  Visit windows for protocol-specified visits in Period 2 are defined similarly. 
Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ASAS 
Components, BASDAI, BASFI and ASDAS components) and Safety 
Analysis of Vital Signs for Period 1
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
2
2
15
22
4
23
29
43
8
44
57
71
12
72
85
92
14
93
99
First dose date of Period 2 
a.
Day of first dose of study drug.


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Table 2.
Analysis Windows for Safety Analysis of lab values for Period 1
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
4
2
29
43
8
44
57
71
12
72
85
92
14
93
99
First dose date of Period 2
a.
Day of first dose of study drug.
Table 3.
Analysis Windows for Efficacy Analysis for Period 1 (for ASAS HI)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
2
2
15
22
4
23
29
43
8
44
57
78
14
79
99
First dose date of Period 2 
a.
Day of first dose of study drug.
Table 4.
Analysis Windows for Efficacy Analysis for Period 1 (for AS QoL 
and MASES)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
4
2
29
43
8
44
57
78
14
79
99
First dose date of Period 2 
a.
Day of first dose of study drug.


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Table 5.
Analysis Windows for Efficacy Analysis for Period 1 (for FACIT-F, 
ISI, WPAI, BASMI, TJC/SJC and Dactylitis)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
14
2
99
First dose date of Period 2 
a.
Day of first dose of study drug.
Table 6.
Analysis Windows for Efficacy Analysis for Period 1 (for MRI 
joints and spine SPARCC)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
3
14
4
99
First dose date of Period 2 
a.
Day of first dose of study drug.
If first dose date of Period 2 is missing, the Upper Bound of Week 14 will be set at 
Day 106, which is half way of Week 14 and next visit Week 16.
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
6.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics information will be collected at the Baseline 
visit of the study and will be summarized for the FAS.  The number of observations, 
mean, standard deviation, median, minimum and maximum will be summarized for 
continuous variables.  Categorical or discrete variables will be summarized via 
frequencies and percentages.  Summary statistics will be computed for each treatment 
group and overall.
Main Demographic and Baseline Characteristics
●
Sex (male, female)
●
Age (years)


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●
Age Categories (< 40, [40, 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 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
●
Duration (years) since AS diagnosis 
●
Duration of AS diagnosis categories (< 5 years or ≥ 5 years)
●
HLA-B27 (positive, negative)
●
Usage and number of different prior NSAIDS (discontinued prior to baseline)
●
Usage and number of different baseline NSAIDs (started prior to baseline and 
ongoing at baseline)
●
Number and percentage of previous disorders at baseline (Psoriasis, 
Inflammatory Bowel Disease, Uveitis)
ASAS and/or ASDAS Components at Baseline
●
Patient's assessment of total back pain (BASDAI Question 2 NRS score 0 - 10)
●
Patient global assessment of disease activity (NRS score 0 - 10)
●
Peripheral pain/swelling (BASDAI Question 3 NRS score 0 - 10)
●
Duration of morning stiffness (BASDAI Question 6 NRS score 0 - 10)
●
High sensitivity C-reactive protein (hsCRP) (mg/L) 
●
Patient's assessment of total back pain (NRS score 0 - 10)


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●
Function – Represented by the BASFI (NRS score 0 - 10)
●
Inflammation (mean of items 5 and 6 of BASDAI NRS scores 0 - 10)
●
Lateral lumbar flexion from BASMI
●
Erythrocyte sedimentation rate (ESR) (mm/hr)
Other Baseline AS Disease Characteristics
●
Continuous ASDAS (CRP) 
●
ASDAS(CRP) categories (ASDAS(CRP) > 3.5 vs ≤ 3.5)
●
MRI SPARCC score (Spine) 
●
MRI SPARCC score (SI joints)
●
BASMI
●
Continuous MASES
●
Presence of Enthesitis (MASES > 0)
●
Tender Joint Count (TJC68)
●
Swollen Joint Count (SJC66)
●
Presence of dactylitis (yes/no)
●
Total dactylitis count out of subjects with presence of dactylitis
●
mSASSS
Patient Reported Outcomes at Baseline
●
BASDAI
●
FACIT-F
●
ISI total score and score categories
●
WPAI
●
AS QoL
●
ASAS HI 
●
Patient's Assessment of Nocturnal Back Pain (NRS score 0 - 10)
●
Physician's Global Assessment of Disease Activity (NRS score 0 - 10)
●
Patient's Global Assessment of Pain (NRS score 0 - 10)


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Clinical Tests at Screening
●
Chest x-ray
●
12-Lead ECG
●
AP Pelvis X-Ray
●
Tuberculosis test result (PPD positive or QuantiFERON positive)
●
Anterior Uveitis
Immunization History
●
BCG immunization
●
Herpes Zoster immunization
●
Hepatitis B immunization
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [user, ex-user, non-user, unknown]
●
Alcohol Use [drinker, ex-drinker, non-drinker, unknown]
6.2
Medical History
Medical history data will be summarized and presented for FAS population using body 
systems and conditions/diagnoses as captured on the CRF.  The body systems will be 
presented in alphabetical order and the conditions/diagnoses will be presented in 
alphabetical order within each body system.  The number and percentage of subjects with 
a particular condition/diagnosis will be summarized for each randomized treatment group 
as well as overall.  Subjects reporting more than one condition/diagnosis within a body 
system will be counted only once for that body system.  No statistical comparison will be 
performed for medical history reporting.
6.3
Prior Treatment and Concomitant Medications
Prior and concomitant medications will be summarized by each randomized treatment 
group as well as overall for FAS.  Prior medications are those medications taken prior to 


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the first dose of study drug.  This includes medications with a start date before the 
first study drug administration date, regardless of the end date of these medications.  
Medications taken on the day of the first dose of study drug are not counted as prior 
medications.  Concomitant medications are those medications, other than study drug, 
taken after the first dose of study drug and within 1 day of the last dose of study drug.  
This includes medications with a start date between first study drug administration and 
last study drug administration + 1 day, as well as, medications with a start date prior to 
first dose of study drug and which are ongoing after first dose of study drug.  Medications 
taken on the day of the first dose of study drug are counted as concomitant medications.  
The concomitant NSAIDs will also be reported using equivalent NSAID score and 
accumulative NSAID intake score (the derivation is detailed in Appendix A).
The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
6.4
Protocol Deviations
Protocol deviations based on ICH deviation criteria are categorized as follows:
1.
Those who entered the study even though they did not satisfy the entry criteria
2.
Those who developed withdrawal criteria during the study and were not withdrawn
3.
Those who received the wrong treatment or incorrect dose, and
4.
Those who received an excluded or prohibited concomitant medication.
The protocol deviations listed above will be summarized and listed by treatment group.
7.0
Patient Disposition
The following will be summarized by randomized treatment group as well as overall:


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


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Period 2
Period 2 patient disposition and reason for discontinuation will be summarized for overall 
Upadacitinib 15 mg QD treatment in Period 2.
Among the subjects who entered Period 2 participation (regardless of whether subject 
prematurely discontinued study drug in Period 1), the number and percentage of subjects 
completed and prematurely discontinued study participation in Period 2 will be 
summarized.  Among the subjects who entered Period 2 on study drug, the number and 
percentage of subjects completed and prematurely discontinued study drug in Period 2 
will be summarized.
For subjects who prematurely discontinued study drug or study participation, the reason 
for discontinuation will be summarized by the following categories (as collected in CRF):
●
Adverse event (AE)
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy
●
Other
Subjects may have more than one reason for discontinuing; both the primary reason and 
all reasons will be summarized.
8.0
Study Drug Exposure and Compliance
8.1
Study Drug Exposure
The duration of exposure to study drug will be summarized for the safety analysis set by 
the randomized treatment groups (placebo group vs Upadacitinib 15 mg QD) in Period 1.  
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 


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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
8.2
Compliance
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 days that the subject was in 
treatment.


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9.0
Efficacy Analysis
9.1
General Considerations
There are two sets of planned efficacy analysis: efficacy analysis for Period 1 and long-
term efficacy analysis.  All efficacy analyses will be carried out using the FAS population.
9.1.1
Efficacy Analysis at Different Phases of the Study
Efficacy Analysis for Period 1
Standard efficacy analysis by randomized treatment groups (Upadacitinib 15 mg QD and 
the placebo group) will be performed on efficacy data for Period 1.  No protocol-defined 
treatment switching will occur in Period 1.  Formal statistical inference will be generated, 
and results from this set of analysis will be used as the key efficacy findings of this study.
Long-Term Efficacy Analysis
Long-term efficacy analysis will be performed on As Observed data (defined in 
Section 9.1.2) by randomized treatment group sequence as described below:
1.
Placebo →Upadacitinib 15 mg QD
2.
Upadacitinib 15 mg QD →Upadacitinib 15 mg QD
There will be no statistical testing; only descriptive statistics and confidence intervals will 
be provided.
9.1.2
Handling for Missing Data and Intercurrent Event
Non-Responder Imputation (NRI) Approach
The NRI approach will handle data for binary variables as follows.
●
Subjects who prematurely discontinue from study drug will be considered as 
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●
In addition, any subject with any missing value for binary variables at a 
specific visit will be treated as non-responder for that visit.
The NRI data handling will be used for the primary estimand (refer to Section 9.2.1) for 
binary variables.
As Observed (AO)
The AO data handling will not impute values for missing evaluations, and thus a subject 
who does not have an evaluation on a scheduled visit will be excluded from the AO 
analysis for that visit.  Regardless of premature discontinuation of study drug, all 
observed data will be used in the analysis. The AO data handling will be used to facilitate 
the supplementary analysis for both binary and continuous variables (refer to 
Section 9.2.2 and Section 9.2.3 where the corresponding supplementary estimand for the 
primary and ranked secondary endpoints is described respectively).
Mixed Effect Model Repeat Measurement (MMRM)
The repeated measure analysis will be conducted using mixed model including observed 
data at all visits.  For the MMRM analysis, data collected after premature discontinuation 
of study drug will be excluded.  The mixed model includes the categorical fixed effects of 
treatment, visit and treatment-by-visit interaction, main stratification factors at 
randomization 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).  MMRM will be used for the primary estimand 
of continuous variables (refer to Section 9.2.3).
Longitudinal Analysis for Long-Term Efficacy: MMRM and Generalized Linear
Mixed Model (GLMM) 
The repeated measure analysis will be conducted using mixed model including AO 
measurements at all visits.  MMRM will be used for continuous endpoints and GLMM 
will be used for binary endpoints. The mixed models will include the categorical fixed 


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effects of treatment, visit and treatment-by-visit interaction, and stratification factor 
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. The categorical fixed effect of subject's discontinuation status and other 
baseline covariates may also be included in the model as appropriate. Unstructured, 
Toeplitz, compound symmetry, or other covariance structures may be considered.
9.2
Efficacy Analysis for Period 1
9.2.1
Primary Efficacy Analysis
The primary efficacy endpoint for regulatory purposes is ASAS 40 response at Week 14. 
The primary estimand is the difference in the proportion of AS patients who achieved 
ASAS 40 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.
Analysis of the primary endpoint will be conducted on the FAS based on randomized 
treatment groups (Upadacitinib 15 mg QD and the placebo group).  Point estimate and 
95% CI using normal approximation will be provided for the response rate for each 
randomized treatment group.  Comparisons of the primary endpoint will be made between 
Upadacitinib and the placebo group using the Cochran-Mantel-Haenszel (CMH) test 
adjusting for stratification factor of hsCRP level (≤ ULN vs. > ULN).  Point estimate, 
95% CI using normal approximation and p-value for the treatment comparison will be 
presented.  The nominal p-value constructed using the CMH test will be provided.  The 
multiplicity adjusted (as described in Section 9.2.5) testing results (significant or not 
significant) will also be provided.  For the primary estimand, NRI data handling as 
defined in Section 9.1.2 will be used.  To facilitate the interpretation of the estimand, the 
number and percentage of non-responders for ASAS40 will be summarized into 
three categories:
1.
Subjects who discontinue study drug by Week 14


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2.
Subjects who didn't discontinue study drug but missing Week 14 ASAS 
40 measurements
3.
Subjects with ASAS 40 measurements observed and on study drug at Week 14 but 
didn't meet ASAS 40 response criteria
9.2.2
Supplementary Analysis of Primary Efficacy Variable
For the primary efficacy endpoint, the same CMH analysis as detailed in Section 9.2.1
will be repeated using As Observed (AO) data handling without any imputation as 
supplementary analysis.  This will be conducted on the FAS based on randomized 
treatment groups.  The corresponding estimand for the supplementary analysis is the 
difference in the proportion of AS 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, received study drug 
and have the efficacy measurement at Week 14 visit.
In addition to the supplementary analysis based on AO data, to explore various missing 
data assumptions including missing not at random (MNAR), tipping point analysis will 
also be conducted for the primary endpoint.  Details of the analysis are outlined in 
Appendix E.
Supportive analysis will also be conducted on the Per Protocol Analysis Set using the 
CMH model and NRI data handling.
9.2.3
Key Secondary Efficacy Analyses
The key multiplicity adjusted secondaryefficacy endpoints at Week 14 are:
1.
Change from Baseline in Ankylosing Spondylitis Disease Activity Score 
(ASDAS(CRP));
2.
Change from Baseline in MRI Spondyloarthritis Research Consortium of Canada 
(SPARCC) score (Spine);


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3.
Proportion of subjects with BASDAI 50 response (defined as 50% improvement in 
the Bath AS Disease Activity Index);
4.
Change from Baseline in AS QoL;
5.
Proportion of subjects with ASAS partial remission (PR) (defined as an absolute 
score of ≤2 units for each of the four domains identified in ASAS 40);
6.
Change from Baseline in BASFI;
7.
Change from Baseline in BASMIlin;
8.
Change from Baseline in MASES (for subjects with baseline enthesitis);
9.
Change from Baseline in WPAI (the overall work impairment due to SpA);
10.
Change from Baseline in ASAS HI.
Additional key secondary endpoints are:
●
ASAS 20 response at Week 14.
●
Change from Baseline in MRI SPARCC score (SI joints) at Week 14.
For binary endpoints, frequencies and percentages will be reported for each randomized 
treatment group.  The primary estimand is the same as that for the primary efficacy 
endpoint as defined in Section 9.2.1, except for the definition of the efficacy 
measurement.  NRI data handling will be used to analyze the primary estimand.
Supplementary analysis using AO data handling will also be conducted.  The 
corresponding supplementary estimand is the same as defined in Section 9.2.2 except for 
the definition of the efficacy measurement.  To explore various missing data assumptions 
including missing not at random (MNAR), tipping point analysis will also be conducted 
for ASAS 20 at Week 14 and details of the analysis are outlined in Appendix E.
Point estimate and 95% CI using normal approximation will be provided for the response 
rate for each randomized treatment group.  Treatment comparisons will be made between 


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upadacitinib and the placebo group using the Cochran-Mantel-Haenszel.  The CMH test 
adjusts for the main stratification factor of hsCRP level (≤ ULN vs. > ULN).  Point 
estimate, 95% CI using normal approximation and the p-value for the treatment difference 
will be presented.
For continuous key secondary efficacy endpoints, the estimand is the difference in mean 
change from baseline at Week 14 under the assumption that patients with missing data 
including those due to premature discontinuation of study drug can have their 
measurements at Week 14 predicted by their observed data and the observed data for 
other patients for their respective assessments during follow-up.  The comparison is 
Upadacitinib 15 MG QD vs placebo for patients randomized and treated with at least 
one dose of study drug.
For the primary estimand of the continuous key secondary efficacy endpoints, statistical 
inference will be conducted using the MMRM model and the associated data handling as 
described in Section 9.1.2, with the main stratification factor of hsCRP level (≤ ULN vs. 
> ULN).  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.
The supplementary analysis for secondary continuous variables will be conducted on AO 
cases using the analysis of covariance (ANCOVA) model with treatment and the 
stratification factor of hsCRP (≤ ULN vs. > ULN) as the fixed factor and the 
corresponding baseline value as the covariate.  The corresponding estimand is the 
difference in the mean change from baseline in the efficacy endpoints at Week 14 
regardless of premature discontinuation of study drug.  The comparison will be the 
Upadacitinib 15 MG QD vs placebo for patients randomized and treated with at least 
one dose of study drug and have the efficacy measurement available at Week 14.  To 
explore various missing data assumptions including missing not at random (MNAR), the 
tipping point analysis will also be conducted using multiple imputation (MI) as additional 
supplementary analysis.  Details of the tipping point analysis are outlined in Appendix E.


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9.2.4
Exploratory Efficacy Analyses
Additional endpoints are the following measurements assessed in subjects treated with 
upadacitinib versus placebo at scheduled time points other than those specified for the 
primary and key secondary variables:
●
Proportion of subjects with:
○
ASAS 20 response;
○
ASAS 40 response;
○
ASAS PR;
○
ASAS 5/6 (20% improvement from Baseline in five out of the following 
six domains:  BASFI, patient's assessment of total back pain, PtGA, 
inflammation [mean of items 5 and 6 of the BASDAI] lateral lumbar 
flexion from BASMIlin, and high sensitivity CRP [hsCRP]);
○
Inactive Disease based on ASDAS(CRP) and ASDAS(ESR) (ASDAS 
score < 1.3);
○
Low Disease based on ASDAS(CRP) and ASDAS(ESR) (ASDAS score 
< 2.1);
○
Major Improvement based on ASDAS(CRP) and ASDAS(ESR) (a change 
from Baseline ≤ –2.0);
○
Clinically Important Improvement based on ASDAS(CRP) and 
ASDAS(ESR) (a change from Baseline ≤–1.1);
○
Resolution of dactylitis (for subjects with baseline presence of dactylitis);
●
Change from Baseline in:
○
ASAS HI;
○
ASDAS(CRP) and ASDAS(ESR) respectively;
○
AsQoL;
○
BASDAI;
○
BASFI;
○
BASMIlin;
○
CRP;


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○
Total dactylitis count (for subjects with baseline presence of dactylitis);
○
FACIT-F;
○
ISI;
○
MASES (for subjects with baseline MASES > 0);
○
Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) score 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 NRS score 0 - 10;
○
Inflammation (mean of items 5 and 6 of BASDAI NRS scores 0 - 10);
○
Patient's assessment of total back pain (BASDAI Question 2 NRS score 
0 - 10);
○
Peripheral pain/swelling (BASDAI Question 3 NRS score 0 - 10);
○
Duration of morning stiffness (BASDAI Question 6 NRS score 0 - 10);
○
Patient's Global Assessment of Disease Activity NRS score 0 - 10;
○
TJC68 and SJC66;
○
WPAI (all 4 dimension scores);
●
Categories in ISI
For binary endpoints, point estimate and 95% CI using normal approximation will be 
provided for the response rate for each randomized treatment group.  Point estimate, 95% 
CI and p-value will be provided for the treatment comparison between Upadacitinib and 
the placebo group, where the 95% CI will be based on normal approximation and the 
p-value will be based on the CMH test adjusting for stratification factor of hsCRP level.  
Only the nominal p-value will be provided.  NRI data handling will be used.


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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, hsCRP level (≤ULN vs. 
> ULN) and baseline value as covariate.  Only the nominal p-value 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)), supplementary 
analysis will be conducted using AO data handling. Analysis of covariance (ANCOVA) 
model will be employed with treatment and the stratification factor of hsCRP level 
(≤ULN vs. > ULN) as the fixed factor and the corresponding baseline values as the 
covariate.
For categorical (more than 2 categories) endpoints, number and percentage for each 
category will be provided for each randomized treatment group.  P-value will be provided 
for the treatment comparison between Upadacitinib and the placebo group using the 
extended Cochran-Mantel-Haenszel test adjusting for stratification factor of hsCRP level 
(≤ ULN vs. > ULN).  Only the nominal p-value will be provided.  No missing data 
imputation will be used.
Evaluation of structural changes in the spine will be explored in subjects who are 
participating in the low-dose CT scan sub-studyusing a scoring system for 
syndesmophytes.  Analysis for this sub-study is described in Appendix G.
9.2.5
Handling of Multiplicity
In order to preserve Type I error, a step-down approach will be used to test the primary 
and ranked key secondary endpoints where statistical significance can be claimed for a 
lower ranked endpoint only if the previous endpoint in the sequence meets the 
requirements of significance.  Specifically, the testing will utilize the endpoint sequence 
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in following Figure 2, using α of 0.05.  The group of multiple endpoints (including
proportion of subjects with BASDAI 50 response, proportion of subjects with ASAS
partial remission, changes from baseline in AS QoL, BASFI, BASMIlin, MASES, and
WPAI) will be tested using the Hochberg procedure, conditional on significance of higher-
ranked endpoints.
Figure 2.
Graphical Multiple Testing Procedure
9.2.6
Efficacy Subgroup Analysis
The primary efficacy endpoint will be examined in the subgroups listed in Table 7 below.  
Treatment difference between Upadacitinib and the placebo group will be presented with 
point estimate and 95% confidence interval using normal approximation.  No p-value will 
be provided for subgroup analysis.  If any of the resulting subgroups has fewer than 20% 


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of the planned study size (i.e., < 34 subjects), the subgroup analyses for that variable will 
not be presented.  A forest plot will be provided for the subgroup analyses.
Table 7.
Subgroups for Efficacy Analysis
Subgroup Factor
Categories
Age
< 40, [40, 65), ≥ 65
Sex
Male or Female
BMI
< 25, ≥ 25
Race
White vs non-White 
Geographic Region
North America, Europe, Other
hsCRP level at screening
≤ ULN vs > ULN
9.3
Long-Term Efficacy Analysis
Assessments to evaluate long-term efficacy will be analyzed for all efficacy 
measurements at scheduled visits.
Descriptive statistics will be provided for each randomized treatment group sequence as 
defined in Section 9.1.1.  These include the number of observations, mean, standard 
deviation, 95% CI, for continuous endpoints; and frequencies and percentages with 95% 
CI using normal approximation for binary endpoints.  Plot for each randomized treatment 
group sequence over time will be provided for primary and ranked secondary endpoints.  
These efficacy analyses will be based on As Observed (AO) analysis.  In addition, 
longitudinal analysis will be performed using MMRM or GLMM as described in Section 
9.1.2 for all endpoints except for radiographic endpoints.  Point estimates and 95% CI 
from the model will be provided for each treatment group sequence.
9.4
Efficacy Variables Definitions and Conventions
9.4.1
Ankylosing Spondylitis Disease Activity Score (ASDAS)
Parameters used for the calculation of ASDAS:
1.
Patient's assessment of total back pain (BASDAI Question 2 NRS score 0 - 10)


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2.
Patient global assessment of disease activity NRS score 0 - 10
3.
Peripheral pain/swelling (BASDAI Question 3 NRS score 0 - 10)
4.
Duration of morning stiffness (BASDAI Question 6 NRS score 0 - 10)
5.
high-sensitivity C-reactive protein (hs-CRP) in mg/L.
Calculation of ASDAS:
ASDAShs-CRP = 
0.121 × total back pain + 0.110 × patient global + 0.073 
× peripheral pain/swelling + 0.058 × duration of morning 
stiffness + 0.579 × Ln(hs-CRP+1).
Note:  When the conventional CRP is below the limit of detection or when the high 
sensitivity CRP is < 2 mg/L, the constant value of 2 mg/L should be used to calculate 
ASDAS-CRP
ASDASESR = 
0.113 × patient global + 0.293 × √ESR + 0.086 × peripheral 
pain/swelling + 0.069 × duration of morning stiffness 
+ 0.079× total back pain.
ASDAS score is categorized in to the following ASDAS Disease Activity States:
●
ASDAS Inactive Disease:  ASDAS < 1.3
●
ASDAS Low Disease:  ASDAS < 2.1
●
ASDAS High Disease:  2.1 ≤ ASDAS ≤ 3.5
●
ASDAS Very High Disease:  ASDAS > 3.5
ASDAS Response categories are defined as follows:
●
ASDAS Major Improvement (a change from baseline ≤ –2.0)
●
ASDAS Clinically Important Improvement (a change from baseline ≤ –1.1)


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9.4.2
Bath Ankylosing Spondylitis Disease Activity Index 
(BASDAI)
BASDAI consists of the following 6 questions; Questions 1 through 5 have responses that 
can range from 0 (none) to 10 (very severe); Question 6 have response range from 0 (0 hr) 
to 10 (2 or more hrs), and 5 represents 1 hr.
Q1. How would you describe the overall level of fatigue/tiredness you have 
experienced?
Q2. How would you describe the overall level of AS neck, back or hip pain you 
have had?
Q3. How would you describe the overall level of pain/swelling in joints, other than 
neck, back or hips you have had?
Q4. How would you describe the overall level of discomfort you have had from 
any areas tender to touch or pressure?
Q5. How would you describe the overall level of morning stiffness you have had 
from the time you wake up?
Q6. How long does your morning stiffness last from the time you wake up?
Scoring of the BASDAI
BASDAI will be reported 0 to 10.  The score has a maximum value of 10 and is calculated 
as follows:
BASDAI Score = 0.2 (Q1 + Q2 + Q3 + Q4 + Q5/2 + Q6/2)
If one of the 5 items (Questions 1 – Question 4, inflammation) is missing, then the score 
is the mean of the 4 non-missing items (total of 4 non-missing items divided by 4).  If 
more than 1 of the 5 items is missing, then the BASDAI score is missing.


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Note:  Question 5 and Question 6 jointly constitute Item 5 (inflammation).  If both 
Questions 5 and 6 are missing, and questions 1 through 4 are non-missing, then only 
one item will be considered missing.  The BASDAI score can still be calculated as the 
mean of Questions 1 – 4. 
However, if, for example, both Question 6 and Question 1 are missing, then 2 items will 
be considered missing, as the inflammation calculation would be incomplete.  The 
BASDAI score would then be considered missing in this case.
9.4.3
BASDAI50
BASDAI50 is a categorical response based on BASDAI that represents a 50% 
improvement in BASDAI from baseline.
9.4.4
ASAS20, ASAS40, ASAS 5/6, and ASAS Partial Remission
Parameters used for the ASAS responses:
●
Patient's Global Assessment – Represented by the PTGA-disease activity 
(NRS score 0 - 10)
●
Pain – Represented by the patient's assessment of total back pain (NRS score 
0 - 10)
●
Function – Represented by the BASFI (NRS score 0 - 10)
●
Inflammation – Represented by the mean of the 2 morning stiffness-related 
BASDAI (mean of items 5 and 6 of the BASDAI NRS score 0 – 10)
ASAS20 Response
Improvement of ≥ 20% and absolute improvement of ≥ 1 unit (on a scale of 0 to 10) from 
Baseline in ≥ 3 of the above 4 domains, with no deterioration in the remaining domain 
(defined as a worsening of ≥ 20% and a net worsening of ≥ 1 unit).


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ASAS40 Response
Improvement of ≥ 40% and absolute improvement of ≥ 2 units (on a scale of 0 to 10) from 
Baseline in ≥ 3 of the 4 domains above with no deterioration (defined as a net worsening 
of > 0 units) in the potential remaining domain.
ASAS Partial Remission
Absolute score of ≤ 2 units for each of the 4 domains identified above.
ASAS 5/6 Response
Improvement of ≥ 20% from Baseline in 5 out of the following 6 domains:  BASFI, 
patient's assessment of total back pain, PTGA-disease activity, inflammation (mean of 
Items 5 and 6 of the BASDAI]), lateral lumbar flexion from BASMI, and hs-CRP.
9.4.5
Bath Ankylosing Spondylitis Functional Index (BASFI)
The Bath Ankylosing Spondylitis Functional Index (BASFI) consists of the following 
10 questions, each with a response ranging from 0 (easy) to 10 (impossible).
1.
Putting on your socks or tights without help or aids (e.g., sock-aid).
2.
Bending forward from the waist to pick up a pen from the floor without an aid.
3.
Reaching up to a high shelf without help or aids (e.g., helping hand).
4.
Getting up out of an armless dining room chair without using your hands or any 
other help.
5.
Getting up off the floor without help from lying on your back.
6.
Standing unsupported for 10 minutes without discomfort.
7.
Climbing 12 to 15 steps without using a handrail or walking aid.  One foot on each 
step.
8.
Looking over your shoulder without turning your body.


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9.
Doing physically demanding activities (e.g., physiotherapy, exercises, gardening, 
or sports).
10.
Doing a full day's activities whether at home or at work. 
Scoring of BASFI
The BASFI score will be derived based on the average of Questions 1 through 10.  If up 
to 2 items are missing, corresponding scores will be replaced with the mean of the 
remaining non-missing items.  If 3 or more items are missing, BASFI will be considered 
missing.
9.4.6
High Sensitivity C-Reactive Protein 
The high-sensitivity C-reactive protein (hs-CRP) is a laboratory parameter and is an 
efficacy variable in axial spondyloarthritis.  The abnormal and normal values will be 
determined according to the normal ranges provided by the laboratory for hs-CRP; in this 
study a normal CRP is defined as ≤ 2.87 mg/L.
9.4.7
Bath Ankylosing Spondylitis Metrology Index (Linear)
The Linear BASMI (BASMIlin) composite score will be calculated using the BASMI 
components.
Scoring of BASMIlin
The table below presents the components of BASMIlin and assessment ranges for score.


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Score
0
Between 0 and 10
10
Lateral Lumbar flexion (cm)
A ≥ 21.1
(21.1 – A)/2.1
A ≤ 0.1
Tragus to wall distance (cm)
A ≤ 8
(A – 8)/3
A ≥ 38
Lumbar flexion (modified Schober) (cm)
A ≥ 7.4
(7.4 – A)/0.7
A ≤ 0.4
Intermalleolar distance (cm)
A ≥ 124.5
(124.5 – A)/10
A ≤ 24.5
Cervical rotation (°)
A ≥ 89.3
(89.3 – A)/8.5
A ≤ 4.3
BASMIlin = Assessment measurements for tragus to wall, cervical rotation and lateral lumbar flexion are the means of 
the left and right measurements
A = assessment measurement
Scores for each assessment range from 0 to 10, and the BASMIlin total score will be the 
average of the 5 assessment scores.  If 1 item is missing, the BASMIlin will be calculated 
as the mean of remaining 4 items.  Hence, the range of the BASMIlin total score should be 
between 0 and 10.  If 2 or more items are missing, then the BASMIlin score will be 
considered missing.
9.4.8
Maastricht Ankylosing Spondylitis Enthesitis Score 
(MASES)
The Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) will be measured at 
the designated study visits listed in the protocol.  To assess the presence or absence of 
enthesitis at 13 different sites, noting the subjects' responses.
Scoring of MASES
The following left and right locations will be graded for presence (1) or absence (0) of 
enthesitis:  1st Costochondral joint, 7th Costochondral joint, Posterior Superior Iliac Spine, 
Anterior Superior Iliac Spine, Iliac Crest, Proximal Insertion of Achilles tendon; the 
5th Lumbar Spinous process will also be graded for enthesitis yielding a total score 
ranging 0 – 13.  If one or more locations are missing, the score will be calculated using 
available data.  If all locations are missing, then MASES is set to be missing.


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9.4.9
Dactylitis
The Dactylitis scores will be the presence of Dactylitis at baseline, the total Dactylitis 
count (out of subjects with baseline presence of Dactylitis) and the resolution of Dactylitis 
(out of subjects with baseline presence of Dactylitis).
The presence of Dactylitis at baseline is defined as the following:
At least one affected and tender digit with circumference increase over reference digit 
≥10%.
The dactylitis count will be calculated as the number of digits (hands and feet) with 
presence of dactylitis.  The count ranges from 0 to 20.  
The Leeds Dactylitis Index (LDI) is a score based on finger circumference and tenderness, 
assessed and summed across all dactylitic digits.  For each of 20 digits of a subject, a digit 
final score needs to be calculated first.  For an unaffected digit, the digit final score is set 
to be 0.  For an affected digit, the digit final score is calculated as (A/B-1)*100*C if A/B 
≥1.1, and 0 if A/B < 1.1, where A denotes the circumference of the digit, B the reference 
circumference, and C the tenderness score.  The reference circumference can be either the 
circumference of the unaffected contralateral digit if available, or from a reference table if 
otherwise.  LDI is the sum of the digit final scores over all 20 digits.
The proportion of subjects with resolution of dactylitis is defined as the proportion of 
subjects with LDI = 0.
9.4.10
Work Productivity and Activity Impairment Questionnaire:  
Axial Spondyloarthritis, Version 2.0 (WPAI-Axial 
Spondyloarthritis)
The Work Productivity and Activity Impairment Questionnaire:  Axial Spondyloarthritis, 
V2.0 (WPAI-Axial SpA) was developed to measure the effect of overall health and 
specific symptoms on productivity at work and outside of work.  It consists of 
6 questions.  A lower WPAI-Axial SpA score indicates an improvement.  The 


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WPAI-Axial SpA is collected at the designated study visits listed in the protocol.  The 
WPAI-Axial SpA coding and scoring methods are described in the following:
A description of the six questions asked in the WPAI-Axial SpA is as follows:
Questions:
Q1. Currently employed? (Yes/No).
Q2. Hours missed from work due to Axial Spondyloarthritis.
Q3. Hours missed due to other reasons.
Q4. Hours actually worked.
Q5. Degree Axial Spondyloarthritis affected productivity while working.
Q6. Degree Axial Spondyloarthritis affected regular activities other than job.
The following 6 measures will be derived based on the responses from the 6 questions.  
The 4 main impairment scores (S1 to S4) are expressed as percent impairment based on 
the above questions.
Scores:
S0.
Employment:  defined below in missing data handling conventions
S1.
Absenteeism:  Percent work time missed due to SpA: 
S2.
Presenteeism:  Percent impairment while working due to SpA: 
!∀
#
∃%
&
∋
(
4
2
2
100
Q
Q
Q
!∀
#
∃%
&
( 10
5
100
Q


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S3.
Percent overall work impairment due to SpA:
!
∀
#
∃
%
&
(
)
∗
+
,
−
.
∋
/
∋
∋
(
10
5
4
2
2
1
4
2
2
100
Q
Q
Q
Q
Q
Q
Q
S4.
Percent activity impairment due to SpA: 
!∀
#
∃%
&
( 10
6
100
Q
S5.
Did subject miss work (defined below).  This is needed to derive the 
proportion of subjects who missed work.
Missing Data Handling Conventions
When calculating the WPAI:  Axial SpA scores, the following computational notes should 
be followed.
●
Define Employment as a binary YES or NO variable where YES corresponds 
to "Employed" and NO corresponds to "Not Employed."
○
A subject will be considered "employed" at a given visit if Q1 = YES or 
Q2 > 0 or Q4 > 0.
○
A subject will be considered "unemployed" at a given visit if Q1 = NO and 
no positive hours recorded under Q2 and Q4 (i.e., if Q1 = NO AND Q2 ≤ 0 
AND Q4 ≤ 0, then UNEMPLOYED).
○
Employment status for a subject will be considered "missing" at a given 
visit if Q1 = missing and no positive hours recorded under Q2 and Q4.
●
If a subject is "unemployed" or employment status is "missing," then S1, S2, 
and S3 will be set to "missing."
●
If Q2 = 0 and Q4 = 0 or missing then Q2/(Q2 + Q4) = missing 
(i.e., S1 = missing).
●
If Q2 = 0 and Q4 = 0, then set S3 to missing.
●
If Q2 is missing or Q4 is missing, then set S1 and S3 to missing.


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●
If Q4 = missing, then DO NOT set Q5 = missing.
●
If Q5 is missing, then apply the following rules:
○
If Q2 > 0, Q4 = 0, and Q5 = missing, then S3 = 100%.
○
If Q2 = 0, Q4 > 0, and Q5 = missing, then S3 is missing.
○
If Q2 > 0, Q4 > 0, and Q5 = missing, then S3 is missing.
●
Determine if a subject missed work (based on Q2) in order to analyze the 
proportion of subjects who missed work:
○
Create a binary (yes or no) "missed work" variable.
○
A subject will be considered as yes to missed work if Q2 is greater than 0.
○
If Q2 = missing, then MISSED WORK = missing.
○
If Q2 > 0, then MISSED WORK = "yes."
○
If Q2 = 0, then MISSED WORK = "no."
○
Therefore, the proportion of subjects who missed work will be counted 
based on the number of subjects with MISSED WORK = YES.
9.4.11
Joint Evaluation
Anatomical joints are evaluated for swelling and tenderness at the designated study visits 
listed in the protocol.  The 34 anatomical joints in Table 8 are assessed in both the left and 
right side of the body for tenderness.  The joints to be examined for swelling are the same 
as those examined for tenderness, with the exception of the hip joints.


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Table 8.
Anatomical Joints Assessed
Temporomandibular
Sternoclavicular
Acromio-Clavicular
Shoulder
Elbow
Wrist
Metacarpophalangeal I
Metacarpophalangeal II
Metacarpophalangeal 
III
Metacarpophalangeal 
IV
Metacarpophalangeal V
Thumb Interphalangeal
Proximal 
Interphalangeal II
Proximal 
Interphalangeal III
Proximal 
Interphalangeal IV
Proximal 
Interphalangeal V
Distal Interphalangeal 
II
Distal Interphalangeal 
III
Distal Interphalangeal 
IV
Distal Interphalangeal 
V
Hipa
Knee
Ankle
Tarsus
Metatarsophalangeal I
Metatarsophalangeal II
Metatarsophalangeal III
Metatarsophalangeal IV
Metatarsophalangeal V
Great Toe/Hallux
Interphalangeal II
Interphalangeal III
Interphalangeal IV
Interphalangeal V
a.
Hip joints are not assessed for swelling.
At each study visit, a joint evaluator will assess whether a particular joint is "tender or 
painful," where presence of tenderness is scored as "1" and the absence of tenderness is 
scored as "0," provided the joint was not replaced ("9") or could not be assessed ("NA") 
due to other reasons (e.g., post-corticosteroid joint injection).  The total tender joint count 
(TJC68) will be derived as the sum of all "1s" thus collected and no penalty will be 
considered for the joints not assessed or those which have been replaced.  A similar 
method will be followed for the derivation of total swollen joint count (SJC66).  Thus, the 
range for TJC68 will be 0 to 68 and 0 to 66 for SJC66.
9.4.12
Ankylosing Spondylitis Quality of Life Questionnaire 
(ASQoL)
Scoring the ASQoL
Each statement on the ASQoL is given a score of "1" or "0."  A score of "1" is given 
where the item is affirmed, indicating adverse QoL.  All item scores are summed to give a 
total score or index.  Scores can range from 0 (good QoL) to 18 (poor QoL).  Cases with 
more than three missing responses (i.e., more than 20%) cannot be allocated a total score.  
For cases with between one and three missing responses, the total score is calculated as 


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follows:  T=18x/18-m where:  T is the total score, x is the total score for the items 
affirmed and m is the number of missing items.
The 18 statements of the questionnaire are listed below.


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Please read each item carefully and tick the one response that applies best to you at the moment
1. 
My condition limits the places I can go
Yes □
No □
2. 
I sometimes feel like crying
Yes □
No □
3. 
I have difficulty dressing
Yes □
No □
4. 
I struggle to do jobs around the house
Yes □
No □
5. 
It's impossible to sleep
Yes □
No □
6. 
I am unable to join in activities with my friends/family
Yes □
No □
7. 
I am tired all the time
Yes □
No □
8. 
I have to keep stopping what I am doing to rest
Yes □
No □
9. 
I have unbearable pain
Yes □
No □
10.
It takes a long time to get going in the morning
Yes □
No □
11.
I am unable to do jobs around the house
Yes □
No □
12.
I get tired easily
Yes □
No □
13.
I often get frustrated
Yes □
No □
14.
The pain is always there
Yes □
No □
15.
I feel I miss out on a lot
Yes □
No □
16.
I find it difficult to wash my hair
Yes □
No □
17.
My condition gets me down
Yes □
No □
18.
I worry about letting people down
Yes □
No □


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9.4.13
ASAS Health Index (HI)
The ASAS HI is a linear composite measure with a dichotomous response option:  "I 
agree" and "I do not agree."  Each statement on the ASAS HI is given a score of "1" = "I 
agree" or "0" = "I do not agree."  The total sum of the ASAS HI ranges from 0-17, with a 
lower score indicating a better health status.  Please note that item 7 and 8 are not 
applicable to all patients.  For those patients who ticked the response "not applicable," the 
sum score is analyzed based on n = 16 or n = 15 respectively.  A total score can be 
analyzed if no more than 20% of the data (i.e., 3 items) are missing.  The total score is 
calculated as follows for respondents with on to a maximum of three missing responses:
Sum.score = x/(17-m)*17, where x is the item summation score and m is the number of 
missing items and m ≤ 3.  Cases with more than three missing responses (m > 3) cannot 
be allocated a total score and the total score will be set as missing.
The following table lists the 17 items:
Item 
1. Pain sometimes disrupts my normal activities.
2. I find it hard to stand for long.
3. I have problems running.
4. I have problems using toilet facilities.
5. I am often exhausted. 
6. I am less motivated to do anything that requires physical effort.
7. I have lost interest in sex.
8. I have difficulty operating the pedals in my car.
9. I am finding it hard to make contact with people.
10. I am not able to walk outdoors on flat ground.
11. I find it hard to concentrate.
12. I am restricted in traveling because of my mobility.
13. I often get frustrated.
14. I find it difficult to wash my hair.
15. I have experienced financial changes because of my rheumatic disease. 


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16. I sleep badly at night.
17. I cannot overcome my difficulties.
9.4.14
Functional Assessment of Chronic Illness Therapy – Fatigue 
Scale (FACIT-F)
Fatigue is one of the most frequent complaints of the elderly and is strongly associated 
with loss of independence and decreased physical activity and functional decline.  
One validated tool to measure fatigue is FACIT Fatigue Scale v4.  The FACIT Fatigue 
Scale is a short, 13-item, easy to administer tool that measures an individual's level of 
fatigue during their usual daily activities over the past week.  Each of the fatigue and 
impact of fatigue items are measured on a four point Likert scale.  The FACIT Fatigue 
Scale is ranged from 0 to 52 and the higher the score, the better the quality of life.
Score for each item is calculated by either subtracted from 4 or adding 0 depending on 
whether it is a reversal item or not.  FACIT Fatigue Scale is then calculated by adding up 
all item scores, multiplied by 13 and divided by the number of items answered.  It is 
essentially a prorated subscale if there are missing values for some items.  If less than or 
equal to 50% of the items are answered (e.g., 6 out of 13), the proration is not acceptable 
and the scale will not be computed.
Below is a list of statements that other people with your illness have said are important.  
By circling one (1) number per line, please indicate how true each statement has been for 
you during the past 7 days.


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Not at 
All
A little 
bit
Some-
what
Quite a 
bit
Very 
much
I feel fatigued
0
1
2
3
4
I feel weak all over 
0
1
2
3
4
I feel listless ("washed out")
0
1
2
3
4
I feel tired 
0
1
2
3
4
I have trouble starting things because I am tired
0
1
2
3
4
I have trouble finishing things because I am tired 
0
1
2
3
4
I have energy
0
1
2
3
4
I am able to do my usual activities
0
1
2
3
4
I need to sleep during the day
0
1
2
3
4
I am too tired to eat 
0
1
2
3
4
I need help doing my usual activities
0
1
2
3
4
I am frustrated by being too tired to do the things 
I want to do
0
1
2
3
4
I have to limit my social activity because I am 
too tired
0
1
2
3
4
9.4.15
Insomnia Severity Index (ISI)
ISI is a 7 item questionnaire that assess, (1) difficulty with sleep onset, (2) difficulty with 
sleep maintenance (3) problem with early awakening, (4) satisfaction with sleep pattern, 
(5) interference with daily functioning as a result of sleep problems, (6) noticeability of 
sleep problem to others, and (7) degree of distress caused by sleep problem.  The severity 
of insomnia items are rated on a Likert type of scale, (0) "None," 1- "Mild," 2-
"Moderate," 3- "Severe" and 4- "Very Severe."  Other items on satisfaction, noticeability 
on impairment, worry/distress about sleep and interference are similarly rated on 5-point 
likert type scale form.  See an ISI example below:
For each question, please CIRCLE the number that best describes your answer.
Please rate the CURRENT (i.e., LAST 2 WEEKS) SEVERITY of your insomnia 
problem(s).


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Insomnia Problem
None
Mild
Moderate
Severe
Very Severe
1.  Difficulty falling asleep
0
1
2
3
4
2.  Difficulty staying asleep
0
1
2
3
4
3.  Problem waking up too early
0
1
2
3
4
4. How SATISFIED/DISSATISFIED are you with your CURRENT sleep pattern?
Very Satisfied
Satisfied
Moderately 
Satisfied
Dissatisfied
Very Dissatisfied
0
1
2
3
4
5. How NOTICEABLE to others do you think your sleep problem is in terms of 
impairing the quality of your life?
Not at All
Noticeable
A Little
Somewhat
Much
Very Much 
Noticeable
0
1
2
3
4
6. How WORRIED/DISTRESSED are you about your current sleep problem?
Not at All
Worried
A Little
Somewhat
Much
Very Much 
Worried
0
1
2
3
4
7. To what extent do you consider your sleep problem to INTERFERE with your 
daily functioning (e.g., daytime fatigue, mood, ability to function at work/daily 
chores, concentration, memory, mood, etc.)?
Not at All
Interfering
A Little
Somewhat
Much
Very Much 
Interfering
0
1
2
3
4
Guidelines for Scoring/Interpretation:
Add the scores for all seven items (questions 1 + 2 + 3 + 4 + 5 + 6 + 7) = _____ your total 
score. If there is one or two missing items, their value can be replaced with the average 


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score of the remaining items. If there are more than two items with no responses, it is
preferred to consider the total score missing.
Total score categories:
0 – 7 = No clinically significant insomnia
8 – 14 = Subthreshold insomnia
15 – 21 = Clinical insomnia (moderate severity)
22 – 28 = Clinical insomnia (severe)
9.4.16
SpondyloArthritis Research Consortium of Canada 
(SPARCC) scores
SPARCC scores for spine and sacroiliac (SI) joints are calculated by adding up the 
dichotomous outcomes from evaluations of the presence, depth and intensity of bone 
marrow edema lesions of the spine and SI joints, respectively.
SPARCC Assessment of Spine Scoring
In the SPARCC assessment of the MRI of the spine, the entire spine is evaluated for 
active inflammation (bone marrow edema) using the STIR image sequence.  
23 discovertebral units (DVUs) are assessed by each reviewer per subject and timepoint, 
and the six most severely affected DVUs are selected by each reviewer and used to 
calculate the MRI Spine SPARCC score.  For each of the six DVUs, 3 consecutive 
sagittal slices are assessed in four quadrants in order to evaluate the extent of 
inflammation in all three dimensions. 
1.
Each quadrant is scored for presence of increased signal on STIR
●
1 = increased signal
●
0 = normal signal


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2.
Presence, on each of the sagittal slices, of a lesion exhibiting high signal intensity 
(comparable to cerebrospinal fluid) in any disco-vertebral unit is given an 
additional score of 1.
3.
Slices that included a lesion demonstrating continuous increased signal of depth 
≥1 cm extending from the endplate are to be scored as +1 per slice.
The maximum possible score for any individual slice is 6, with a maximum score for all 
6 discovertebral units being 108.
SPARCC Assessment of SI Joint Scoring
Scoring is conducted on 6 consecutive slices of the STIR image sequence.  All lesions 
within the iliac bone and within the sacrum up to the sacral foramina are to be scored.  
The SI joint is divided into 4 quadrants:  upper iliac, lower iliac, upper sacral and lower 
sacral.  Each consecutive slice is scored separately for the right and left joint in all 
four quadrants as follows:
1.
Each quadrant is scored for presence of increased signal on STIR
●
1 = increased signal
●
0 = normal signal
2.
Joints that include a lesion exhibiting intense signal on the STIR sequence are 
scored as +1 per slice.
3.
Joints that included a lesion demonstrating continuous increased signal of depth 
≥1 cm from the articular surface are be scored as +1 per slice.
The maximum possible score for any individual slice is 12, with a maximum score for all 
6 slices being 72.


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Adjudication by a third reader
Should adjudication be required for a given case, another reviewer, different from the 
reviewers who performed primary assessments will make a third, independent assessment.  
There will be a single dedicated adjudicator performing all adjudication reads.
The 2 closest of the 3 readings (2 primary readers and adjudicator) will determine the final 
score.
9.4.17
Modified Stoke Ankylosing Spondylitis Spine Score 
(mSASSS)
The modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) is a scoring method 
that measure radiographic progression in the spine of patients with ankylosing spondylitis.  
The mSASSS has a range of 0 to 72, which is derived from scoring the anterior site of the 
lumbar spine from the lower border of T12 to the upper border of S1 and the anterior site 
of the cervical spine from the lower border of C2 to the upper border of T1 as either 
0 (normal), 1 (erosion, sclerosis, or squaring), 2 (syndesmophyte), 3 (bridging 
syndesmophyte), or NA vertebral body not evaluable.
Selection of Scores and Adjudication of mSASSS
X-ray of spinal films will be read by two independent readers who are blinded to both 
treatment and time point.  The blinded data read will be performed to compare 
radiographic progression (from Baseline to the follow-up timepoint, e.g., Year 2). 
Adjudication trigger:  If the follow-up mSASSS progression scores of read 1 and read 2
differ by 
 mSASSS points for a given subject, a third independent reader (adjudicator) 
will perform an adjudication read and score that subject.  The 2 closest of the 3 readings 
(2 primary reader and adjudicator) will determine the final score.
Handling of missing joints in the mSASSS  
If a score at any location (vertebral unit, VU) is missing, the method described below will 
be used for deriving mSASSS. 


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●
If the score for a location is missing at Baseline, this location will not 
contribute to the calculation of mSASSS for this subject at any visit within the 
reading session (even if the score for this location is available at postbaseline 
visits). 
●
If the score for a location is missing at all post-baseline visits within a reading 
session, this location will not contribute to the calculation of mSASSS for this 
subject at any visit within the reading session (even if the score for this 
location is available at Baseline). 
●
If the score for a location is available at Baseline and at least one postbaseline 
visit, missing scores for this location at any other post-baseline visit will be 
imputed assuming no progression from the previous time point with available 
score.
9.4.18
Other Efficacy Variables
●
Patient's Global Assessment of Disease Activity NRS [0 - 10]
○
No activity is indicated by 0 and severe activity by 10.
●
Patient's Assessment of Total Back Pain NRS [0 - 10]
○
No pain is indicated by 0 and most severe pain by 10.
●
Physician's Global Assessment of Disease Activity NRS [0 - 10]
○
No activity is indicated by 0 and severe activity by 10.
●
Patient's Assessment of Nocturnal Back Pain NRS [0 - 10]
○
No pain is indicated by 0 and worst possible pain by 10.
●
Patient's Global Assessment of Pain NRS [0 - 10]
○
No pain is indicated by 0 and severe pain by 10.
10.0
Safety Analysis
10.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set.  There are two sets of 
planned safety analysis:  safety analysis for Period 1, and long-term safety analysis.


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Safety Analysis for Period 1
Standard safety analysis by the "as treated" treatment groups of Upadacitinib 15 mg QD 
and placebo group will be performed on safety data in Period 1.  No protocol-defined 
treatment switching will occur prior to these time points.
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 be summarized by "as treated" treatment group.  Frequency tables of subjects 
meeting criteria for potentially clinically significant vital sign values and for potentially 
clinically significant laboratory values will be provided by treatment group.  Missing 
safety data will not be imputed.
Long-Term Safety Analysis
Long-term safety analyses that account for protocol-defined treatment switching include 
reporting of AE rate adjusted by cumulative exposure, descriptive summary in laboratory 
parameters and vital sign variables, and rate of potentially clinically significant laboratory 
and vital signs values.  The treatment-emergent adverse event (TEAE) rate per 
100 patient-years of exposure will be presented by actual treatment received at the time of 
AE (as described in Section 10.2.2).  Listing of subjects with TEAEs by SOC and PT will 
be provided.  All continuous laboratory parameters and vital signs variables at each visit 
will be summarized by "as treated" treatment group sequences defined as follows.  
Frequency tables and listings of subjects meeting criteria for potentially clinically 
significant vital sign values and for potentially clinically significant laboratory values will 
be provided by actual treatment received at the time of event.  Missing safety data will not 
be imputed.
"As treated" treatment group sequences:


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1.
Placebo →Upadacitinib 15 mg QD
2.
Upadacitinib 15 mg QD →Upadacitinib 15 mg QD
10.2
Analysis of Adverse Events
A treatment-emergent Adverse Event (TEAE) is defined as an adverse event with an onset 
date that is after the first dose of study drug, and no more than 30 days 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 event data will be presented by SOCs and PTs using MedDRA Version 19.1 or 
most up to date version.  All adverse event tables will be sorted in alphabetical order by 
SOC and PT and descending percentages for each treatment group.
10.2.1
Analysis of Adverse Events Prior to Protocol-Defined
Treatment Switching
10.2.1.1
Adverse Events Overview
The number and percentage of subjects experiencing TEAEs will be summarized by 
treatment groups for the following AE categories.
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs of special interest


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●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
For TEAEs of special interest, 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.
10.2.1.2
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing adverse events will be tabulated by 
SOC and MedDRA PT by treatment groups.  The SOCs will be presented in alphabetical 
order, and the PTs will be presented in alphabetical order within each SOC.
The following summaries of adverse events will be generated:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
●
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 
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10.2.1.3
TEAEs by Maximum Severity
TEAEs will also be summarized by maximum severity by treatment groups.  If a subject 
has an AE with an unknown severity, then the subject will be counted in the severity 
category of unknown, even if the subject has another occurrence of the same event with a 
severity present.  The only exception is 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.
10.2.1.4
TEAEs by Relationship
TEAEs will also be summarized by relationship to Upadacitinib and Placebo, as assessed 
by the investigator, by treatment groups.  If a subject has a TEAE with an unknown 
relationship, then the subject will be counted in the relationship category of "unknown," 
even if the subject has another occurrence of the same event with a relationship present.  
The only exception is if the subject has another occurrence of the same TEAE with a 
relationship assessment of "reasonable possibility."  In this case, the subject will be 
counted under the "reasonable possibility" category.
10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and 
Preferred Term
TEAEs and reasonably possibly related AEs occurring for more than 2% of the subjects in 
any of the treatment groups will be summarized by MedDRA PT in decreasing frequency 
separately.
10.2.1.6
Adverse Events of Special Interest
The Adverse Events of Special Interest (AESI) categories will be summarized and 
presented by treatment groups using SOC and MedDRA PT.  The AESI categories will be 
identified by the following search criteria per Standard MedDRA Queries 
(SMQs)/Company MedDRA Queries (CMQs) in Table 9 below.  Adjudicated 


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cardiovascular events will be summarized and presented by treatment group using the 
CAC adjudicated categories.
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" Narrow 
SMQ removing NMSC output
Lymphoma
SMQ
Broad
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic 
Disorders"
Adjudicated Gastrointestinal 
Perforations
Based on 
adjudicated 
results (the 
identification 
of events to be 
adjudicated are 
described in 
the GI 
Perforation 
charter)
Anemia
CMQ
"Non-Hemolytic and Non-
Aplastic Anemias"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia (Veliparib 
Product Specific)"


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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
Herpes Zoster
CMQ
"Herpes Zoster"
Creatine Phosphokinase (CPK) 
Elevation
PT
Search only for the PT of 
"Blood creatine 
phosphokinase increased"
Renal Dysfunction
SMQ
Narrow
"Acute Renal, Failure"
Active Tuberculosis
CMQ
"Active Tuberculosis"
Adjudicated Cardiovascular Events
Output from 
CAC
MACE* 
Undetermined/Unknown Cause 
of Deaths 
Other Cardiovascular events
Adjudicated Thrombotic Events
Output from 
CAC
Venous Thromboembolic 
Events**
Other Venous Thrombosis 
Arterial Thromboembolic Events
(non-cardiac, non-neurologic)
*
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).
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
10.2.2
Analysis of Long-Term Adverse Event
Long-term adverse events will be analyzed using event rates adjusted by cumulative 
exposure and will be based on the actual treatment received at the time of AE occurrence.  
According to the study design, randomized placebo subjects switch to Upadacitinib 15 mg 


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QD when entering Period 2, this analysis will be reported for Any Upadacitinib 15 mg 
QD subjects.  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 occurred under Upadacitinib 15 mg QD exposure from subjects 
starting on Upadacitinib 15 mg QD and subjects switching from placebo to Upadacitinib 
15 mg QD.
Exposure-Adjusted Event Rate (EAER)
To adjust for potentially different follow-up time between treatment groups, EAER will 
be provided.  For the purpose of event rate calculation, the numerator will be the total 
number of AEs reported for the event (i.e., a subject can contribute more than one event to 
the numerator) and the denominator will be the total exposure time among subjects under 
the treatment group.  The number of AEs reported (numerator), the total number of years 
of study drug exposure (denominator), and the exposure-adjusted AE event rate per 
100 patient-years calculated as ([numerator (days)/denominator])/365.25 • 100 will be 
presented for each treatment group.  The EAER will be the main approach to evaluate 
AEs in the long-term analysis.
In addition, the exposure-adjusted incidence rate (censored at first event) will be 
conducted for AESI endpoints as deemed appropriate for long-term analysis.
10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure
An overview of AEs per 100 patient-years of study exposure will be presented for Any 
Upadacitinib 15 mg QD for the following AE categories.
●
All TEAEs 
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events 
●
TEAEs reasonably possibly related to study drug
●
TEAEs of special interest


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●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
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 Any Upadacitinib 15 mg QD group.
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
For TEAE of special interest, the point estimate and 95% CI (using normal 
approximation) will be provided for the Any Upadacitinib 15 mg QD group in AE rate per 
100 patient-years (refer to Appendix B).
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT
For the Any Upadacitinib 15 mg QD treatment group, the TEAE rate per 100 patient-
years of exposure as outlined in Section 10.2.2.1 will be calculated overall, for each SOC 
and each PT, for each of the following events:
●
All TEAEs 
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events 
●
TEAEs reasonably possibly related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
10.2.2.3
Adverse Events of Special Interest Rates per
100 Patient-Years of Study Drug Exposure
The Adverse Events of Special Interest (AESI) categories will be summarized and 
presented for the Any Upadacitinib 15 mg QD treatment group using SOC and MedDRA 
PT (for adjudicated cardiovascular events, the CAC adjudicated categories will be used).  


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The AESI categories will be identified per Standard MedDRA Queries (SMQs)/Company 
MedDRA Queries (CMQs). 
The Adverse Events of Special Interest (AESI) rate per 100 patient-years of exposure as 
outlined in Section 10.2.2.1 will be calculated overall, for each SOC and each PT, for 
each of the AESI listed in Section 10.2.1.6.  
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation
All serious adverse events (SAEs), deaths, and adverse events leading to discontinuation 
of study drug will be listed.
10.3
Analysis of Laboratory Data
10.3.1
Variables and Units
All laboratory parameters to be collected in this study are listed below.  Laboratory 
parameters will be reported using the standard international (SI) units.


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Table 10.
List of Laboratory Variables
Laboratory Variables
Hematology
White Blood Cell (WBC) Count
Red Blood Cell (RBC) Count
Hemoglobin
Hematocrit
Platelets count
Neutrophils
Basophils
Eosinophils
Lymphocytes
Monocytes
Bands
Chemistry
Total Bilirubin
Alkaline Phosphatase (ALP)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Uric acid
Sodium
Potassium
Calcium
Inorganic Phosphorus
Creatine Phosphokinase (CPK)
Chloride
Bicarbonate


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Table 10.
List of Laboratory Variables (Continued)
Laboratory Variables
Chemistry (Continued)
Cholesterol
LDL cholesterol
HDL cholesterol
LDL/HDL ratio
Cholesterol/HDL ratio
Urinalysis
Specific Gravity
pH
Protein
Glucose
Ketones
Blood
Microscopic Examination (if needed)
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Other
hs-CRP
QuantiFERON-TB Golda
ESR
a.
For annual follow-up QFT is captured only for those with negative QFT at Screening.
10.3.2
Analysis of Laboratory Data for Period 1
The laboratory data will be summarized by the "as treated" treatment groups 
(Upadacitinib 15 mg QD and placebo group).


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10.3.2.1
Assessment of Mean Change from Baseline and Percentage 
Change from Baseline in Clinical Laboratory Variables
Analyses of 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 and percent 
change from baseline between different treatment groups for selected laboratory 
parameters.  Mean difference from placebo and associated 95% CIs will be presented.  
The analysis applies to the following laboratory parameters of clinical interest: 
hemoglobin, platelets, lymphocytes, neutrophils, creatinine, creatine phosphokinase 
(CPK), LDL, HDL, the ratio of LDL to HDL, and total cholesterol.
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables
The baseline and post-baseline laboratory observations will be categorized as Low, 
Normal, and High according to normal ranges.  The shift tables will tabulate the number 
and percentage of subjects with baseline and post-baseline values by these categories.  
For each laboratory variable, shift tables will be generated that cross tabulate the subjects' 
as deemed appropriate by treatment groups:
●
Shift from baseline high or normal to minimum post-baseline low; shift from 
baseline low or normal to maximum post-baseline high.
●
Shift from baseline high or normal to final post-baseline low; shift from 
baseline low or normal to final post-baseline high.
Note that the minimum/maximum category is used, rather than the category of the 
minimum/maximum value.  The two may be different due to variation in the reference 
range.


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No statistical tests will be performed for this analysis.
10.3.2.3
Assessment of Potentially Clinical Significant Laboratory 
Values
The criteria for potentially clinically significant laboratory values will be determined by 
CTCAE criteria of Grade 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.  
10.3.2.4
Assessment of Liver Elevations
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation" (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by "as treated" treatment group:
●
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


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●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
10.3.3
Analysis of Long-Term Laboratory Data
10.3.3.1
Assessment of Mean Change from Baseline and Percentage 
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 10.1.  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 and percentage change from baseline in 
hemoglobin, lymphocytes, neutrophils, creatinine, creatine phosphokinase (CPK), LDL, 
HDL, the ratio of LDL to HDL, and total cholesterol.  
10.3.3.2
Assessment of Potentially Clinical Significant Laboratory 
Values
Long-term laboratory data will also be summarized based on the number and percentage 
of subjects meeting the criteria for potentially clinical significant laboratory values for the 
Any Upadacitinib 15 mg QD group as described in Section 10.2.2. 
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 14, lab values under 
upadacitinib 15 mg QD exposure would be evaluated against the baseline value defined as 
above.


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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.
10.3.3.3
Assessment of Liver Elevations
The frequencies and percentages of subjects with post-baseline liver-specific function test 
values that meet the following criteria of potential clinical interest will be summarized for 
Any Upadacitinib 15 mg QD group as described in Section 10.2.2:
●
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
A listing of potentially clinically significant liver elevations based on criteria specified 
above will be provided.  For each of these subjects, the whole course of the respective 
parameter will be listed.


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10.4
Analysis of Vital Signs
10.4.1
Variables and Criteria Defining Abnormality
Vital sign variables include sitting systolic blood pressure, sitting diastolic blood pressure, 
pulse rate, respiratory rate, body temperature, and weight.  The criteria for potentially 
clinically significant vital sign findings are presented in Table 11.
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Findings
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 15 mmHg from Baseline
High
Value ≥ 105 mmHg and increase ≥ 15 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Respiratory Rate
Low
< 10 rpm
High
> 24 rpm
Body temperature
High
> 39.0°C (102.3°F)
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
10.4.2
Analysis of Vital Sign for Period 1
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 potentially 
clinically significant vital sign values will be summarized by "as treated" treatment group.


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10.4.3
Analysis of Long-Term Vital Sign
Analyses of mean change from baseline in continuous vital signs variables which are 
measured longitudinally will be performed by visits and by "as treated" treatment group 
sequences as described in Section 10.1.  For each change from baseline analysis, the 
following summary statistics will be presented for each treatment group:  sample size, 
baseline mean, visit mean, and the mean, standard deviation, and median of the changes 
from baseline.
Long-Term Vital Sign will also be summarized based on the number and percentage of 
subjects meeting the criteria for potentially clinical significant vital sign values for the 
Any Upadacitinib 15 mg QD group as described in Section 10.2.2.  Similar baseline 
definition as described in Section 10.3.3.2 will be applied.
A listing of all subjects with any vital sign values meeting the criteria for potentially 
clinically significant vital signs will be provided.  For each of these subjects, the whole 
course of the respective parameter will be listed.
11.0
Statistical Analysis to Account for the Impact of 
COVID-19 Pandemic
This section presents the changes in statistical analysis to handle the missing data due to 
COVID-19 and the additional data collected related to COVID-19. The Week 14 DBL 
was completed in Feb 2019. The Week 64 database lock was completed in Feb 2020. 
The analyses specified in this section applies to future database locks. 
Patient Disposition
Reasons for premature discontinuation of study drug/study will be updated to add two 
additional reasons related to COVID-19:
●
COVID-19 Infection
●
COVID-19 Logistical restrictions


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The number and percentage of subjects who prematurely discontinued from study 
drug/study due to COVID-19 infection or COVID-19 logistical restrictions will be 
summarized by randomized treatment group.
Summary of COVID-19 Impacted Visits
Types of missing 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
Efficacy Analyses
With respect to the COVID-19 pandemic, it would be reasonable to assume that missed 
visits and missing data due to self-quarantine or local government restrictions on travel or 
limitations on healthcare resources will impact subjects across treatment arms in a similar 
fashion and adopt the Missing at Random (MAR) assumption for missing data handling.
A sensitivity analysis will be conducted to handle this using AO data. MMRM will be 
used for continuous endpoints and GLMM defined in section 9.1.2 will be used for binary 
endpoints.
Safety Analyses
COVID-19 related AEs occurring on or after February 1, 2020 and COVID-19 related 
deaths occurred on or after February 1, 2020 will be collected.
Listings of subjects with AEs related to COVID-19 infection will be provided.


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12.0
Version History
Table 12.
SAP Version History Summary
Version
Date
Summary
1.0
12 Apr 2018
Original version
2.0
20 Dec 2018
Incorporated FDA's comment
3.0
20 August 2020
Incorporating updates 1)  the study duration is extended for 
France, Belgium, Finland, Netherlands and Germany in 
protocol amendment 2.01, 2.02 and 2.03; 2) Add Week 104 
data base lock (DBL) and final lock; 3) in statistical analysis 
related to COVID-19;4) add appendix G for low dose CT 
sub-study analysis plan 5) Update ASDAS Low Disease 
definition for Week 104 DBL 6) Include incident rate for all 
AESI for future DBL


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13.0
References
1.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
2.
National Cancer Institute.  CTCAE v. 4.0.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc.  
Accessed on:  August 10, 2017.
3.
Dougdos M, Paternotte S, Braun J, et al.  ASAS recommendations for collecting, 
analyzing and reporting NSAID intake in clinical trials/epidemiological studies in 
axial spondyloarthritis.  Ann Rheum Dis.  2011;70(2):249-51.
4.
Machado PM, Landewé R, Heijde DV, et al.  Ankylosing Spondylitis Disease 
Activity Score (ASDAS):  2018 update of the nomenclature for disease activity 
states.  Ann Rheum Dis.  2018 Feb 16.  pii:  annrheumdis-2018-213184.  doi:  
10.1136/annrheumdis-2018-213184.  [Epub ahead of print].
5.
Stokes ME, Davis CS, Koch GG.  Chapter 4 of Categorical data analysis using 
SAS.  SAS institute.  2012.
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.


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14.0
Appendix
Appendix A
ASAS-NSAID Intake Score for Axial Spondyloarthritis
Appendix B
Exposure adjusted AE rate and normal approximation based 95% confidence 
interval
Appendix C
Analysis of Categorical Endpoints
Appendix D
Analysis of Continuous Endpoints using Mixed Effect Model Repeat 
Measurement (MMRM)
Appendix E
Tipping Point Analysis
Appendix F
Geographic Region
Appendix G
Low Dose CT Sub-study Analysis Plan


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Appendix A.
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, the following information is 
required:
(1) the 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 table the weight factor will be determined based on medical review using the 
local label as a guide.
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
Indometacin
100/150
Ketoprofen
100/200
Meloxicam
100/15
Nimesulide
100/200
Phenylbutazone
100/400
Piroxicam
100/20
Tenoxicam
100/20


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(2) the dose:  mg per intake
(3) the 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
(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; 70:249–251), 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.


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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 B.
EAER and Normal Approximation Based 95% Confidence Interval
Assume the occurrence of TEAE of special interest follows a Possion distribution and let 
λ denote the rate of occurrence of TEAE under the total exposure time for a treatment 
group. Let n be the number of AEs reported in Any Upadacitinib 15 mg QD group.  Let T
be the total number of days exposed to study drug summed across all treated subjects in 
Any upadacitinib 15 mg QD group.  Under the assumption that n follow Possion 
distribution with parameters λT, the = n/T. 
Using normal approximation, the 95% confidence interval can be calculated by (Liu GF,
et al. 2006.):
   ± ⍺/

Where  = 




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Appendix C.
Analysis of Categorical Endpoints
Binary endpoints
The point estimate of the response rate for each treatment group is calculated as ̂ =

 
where k denotes the number of responders in the treatment group and N denotes the total 
number of subjects in the treatment group.  The corresponding 95% CI is based on normal 
approximation, that is ̂ ± .

 ̂(1 −̂), where . denotes the 97.5% quantile of 
the standard normal distribution.  This is implemented by obtaining the Wald asymptotic 
confidence limits using the SAS procedure PROC FREQ with the BINOMIAL option.  
The SAS code example is as follows:
proc freq data=TESTData1;
  by TRTP;
  tables RESP / binomial(level="1") alpha=0.05;
  weight COUNT/zero;
  output out=CI(keep= L_BIN U_BIN) binomial;
run;
Note:
The input dataset is cell count data, with variable RESP denoting response status ("1" as responder and "0" as 
non-responder) and variable COUNT denoting the number of subjects with the corresponding response status.
The treatment difference is calculated as ̂ −̂
, and the corresponding 95% CI for the 
treatment difference is based on normal approximation, that is ̂ −̂
 ±
.

" ̂(1 −̂) +

 ̂
(1 −̂
). This is implemented by obtaining the Wald 
asymptotic confidence limits using the SAS procedure PROC FREQ with the RISKDIFF 
option. The SAS code example is as follows:
proc freq data=TESTData1;
  tables TRTP*RESP / riskdiff alpha=0.05;
  weight COUNT/zeros;
  where TRTP in ('PLACEBO','UPA 15MG');
  output out=diff(keep= _RDIF1_ L_RDIF1 U_RDIF1) riskdiff1;
run;
Note:
The input dataset is cell count data, with variable RESP denoting response status ("1" as responder and "0" as 
non-responder) and variable COUNT denoting the number of subjects with the corresponding response status.
TRTP denotes the treatment group.


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The p-value for the treatment comparison is based on the Cochran-Mantel-Haenszel 
(CMH) test adjusting for stratification factor. This is implemented using the SAS 
procedure PROC FREQ with the CMH option. The p-value from the "general association 
statistic" is used. The SAS code example is as follows:
proc freq data=TESTData3;
  tables STRATA*TRTP*RESP_VALUE / cmh;
run;
Note:
The input dataset is subject-level data, with variable RESP_VALUE denoting the subject's response status 
("1" as responder and "0" as non-responder). TRTP denotes the treatment group and STRATA denotes the 
strata for a given subject.
Categorical endpoints with more than 2 categories
The extended Cochran-Mantel-Haenszel test is used to assess the association among a set 
of $2-by-% tables, where % is the number of levels in the ordinal categorical endpoints.  
For the case of insomnia severity index (ISI) which has % = 4 levels, the extended CMH 
test is stratified by hsCRP level that has $ = 2 strata.  The analysis is to assess the 
association between treatment and ISI, adjusting for the hsCRP level.
The following PROC FORMAT declaration is to ensure that the ISI categories are 
properly ordered in the analysis.
/*PROC FORMAT to ensure that the ISI categories are correctly ordered*/
proc format;
value ISIcat
1 = "No clinically significant insomnia"
2 = "Subthreshold insomnia"
3 = "Clinical insomnia (moderate severity)"
4 = "Clinical insomnia (severe)";
run;
Denote &'() the number of subjects who are in hsCRP stratum ℎ (ℎ= 1, … , $), treatment 
group , (, = 1,2) and have ISI category . (. = 1, … , %). Also suppose {0', … , 0'1} is a 
set of scores associated with each level of the response variable in stratum ℎ. In this 


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analysis, we use the SAS default "integer scores" such that {0', … , 0'1} = {1, … %} for 
ℎ= 1, … , $.
The sum of strata scores for treatment  , = 1 is
344  = 5 5 0')&')
1
)6
7
'6
Under the null hypothesis of no association, 344 has the expected value and variance
8{344|:} = 5 &'4;' = ;∗ 
7
'6
,
={344|:} = 5 &'4(&' −&'4)
&' −1
>' = >∗
7
'6
,
where ;' = ∑
(0')&'4)/&')
1
)6
is the finite subpopulation mean and >' =
∑
@0') −;'A

1
)6
(&'4)/&') is the variance of scores for stratum ℎ.
The extended CMH test statistic is
BCDE =
(344 −;∗)
>∗
which has an approximate chi-square distribution with one degree of freedom. The 
following PROC FREQ implements the test for ISI and the test statistics BCDE
corresponds to "Row mean scores differ" in the output.
/*ORDER=FORMATTED is critical*/
proc freq data=ISI order=formatted;
table hsCRP*Treatment*ISIcat / cmh nocum nocol nopercent;
run;


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Appendix D.
Analysis of Continuous Endpoints using Mixed Effect Model 
Repeat Measurement (MMRM)
The repeated measure analysis will be conducted using mixed model including observed 
data at all visits.  For the MMRM analysis, data collected after premature discontinuation 
of study drug will be excluded.  The mixed model includes the categorical fixed effects of 
treatment, visit and treatment-by-visit interaction, main stratification factors at 
randomization 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 is implemented using the SAS procedure PROC MIXED.  The LSMEANS 
statement provides the least-squares means and corresponding 95% CIs for each treatment 
group at each visit, as well as the least-squares means, corresponding 95% CIs and 
p-values for treatment comparisons at each visit.  The SAS code example is as follows:
proc mixed data=CData;
    class TRTP AVISIT STRATA USUBJID;
    model CHG = TRTP AVISIT BASE STRATA TRTP*AVISIT / DDFM=kr htype = 3;
    repeated AVISIT / subject = USUBJID type=un;
    lsmeans TRTP*AVISIT/ cl diff;
    ods output lsmeans=lsmean_output;
run;
Note:
The input dataset is per subject per visit. USUBJID is the unique subject number, TRTP denotes the treatment 
group, STRATA denotes the strata, and AVISIT denotes the visit. CHG denotes the change from baseline 
value and BASE denotes the baseline value.


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Appendix E.
Tipping Point Analysis
Tipping Point Analysis for binary endpoint ASAS40 ( and ASAS 20)
To assess the robustness of the primary analysis using NRI data handling, tipping point 
analysis is conducted on the primary endpoint ASAS40.  The analysis is conducted using 
As Observed data handling.
Let M1 be the number of subjects missing ASAS40 status in the placebo group, and let M2
be the number of subjects missing ASAS40 status in the upadacitinib group.  Let X1 be 
the number of subjects imputed as ASAS40 responders out of the M1 subjects with 
missing ASAS40 status in the placebo group – the rest are imputed as non-responders.  
X1 can take values from 0 to M1.  Similarly define X2.  Given each pair of (X1, X2), we 
can obtain the p-value for the treatment comparison of upadacitinib versus placebo using 
the combined observed data and imputed data for each treatment group.  If one pair of 
parameters are found to just reverse the study conclusion, in terms of p-value larger than 
0.05 (the original p-value < 0.05), then these parameters are called the tipping point. 
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 
ranked secondary endpoints at the primary time point.  The tipping point analyses are 
two-dimensional, i.e., assumptions about the missing outcomes on the upadacitinib 
treatment group and the placebo group are allowed to vary independently.  In addition, the 
focus is on scenarios where missing outcomes on upadacitinib are worse than the imputed 
values on upadacitinib, while missing outcomes on placebo are better than the imputed 
values on placebo.  Missing values are first imputed via multiple imputation (MI) under 
MAR, and then a shift parameter is applied to the imputed values (a different shift 
parameter may be specified for each treatment group).  (The MI imputation is performed 
upon AO data).  This is implemented by PROC MI using the MNAR statement.  For a 
given pair of shift parameters, the SAS code example is as follows:


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PROC MI DATA=DATA WIDE OUT=OUTMI NIMPUTE=5 SEED=12345     
     MINMAXITER=1000;     
     CLASS TRTP COVCAT;     
     MONOTONE;     
     VAR TRTP COVCON COVCAT  WEEK_2 WEEK_4 WEEK_8 WEEK_12;   
     MONOTONE REG( WEEK_2  = TRTP COVCON COVCAT );      
     MONOTONE REG( WEEK_4  = TRTP WEEK_2 COVCON COVCAT );     
     MONOTONE REG( WEEK_8  = TRTP WEEK_2 WEEK_4 COVCON COVCAT );     
     MONOTONE REG( WEEK_12 = TRTP WEEK_2 WEEK_4 WEEK_8 COVCON COVCAT );     
     MNAR ADJUST (WEEK_12 / SHIFT=&SJ1 ADJUSTOBS=(TRTP='PLACEBO'));
     MNAR ADJUST (WEEK_12 / SHIFT=&SJ2 ADJUSTOBS=(TRTP='UPA 15MG'));
RUN;
Note:
The input dataset is the same as that used for MI analysis. The macro variables SJ1 and SJ2 denote the shift 
parameters for the placebo group and the upadacitinib group respectively.
In cases where the shifted values are smaller than the minimum or larger than maximum 
value of the endpoints, (i.e., out of range), the minimum or maximum value is used in 
further analysis steps. For each pair of shift parameters, the same analysis as the primary 
MI analysis is then conducted to obtain the p-values for the upadacitinib treatment group 
versus the placebo group. If one pair of shift parameters are found to just reverse the 
study conclusion, in terms of p-value larger than 0.05 (the original p-value < 0.05), then 
the shift parameters are identified as the tipping point. The results for a grid of shift 
parameter combinations are provided in tabular format.


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Appendix F.
Geographic Region
Below table lists the countries considered for each geographic region.
Geographic Region
Countries
Asia
Japan, South Korea
Eastern Europe
Croatia, Czech Republic, Hungary, Poland
North America
Canada, United States
Other
Australia, New Zealand
Western Europe
Belgium, Denmark, Finland, France, Germany, Netherlands, 
Portugal, Spain Sweden, United Kingdom


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Appendix G.
Low Dose CT Imaging
Per study protocol, subjects enrolled into Study M16-098 can choose to enroll into a sub-
study in which low dose CT imaging of the spine is performed. The analysis population 
for low dose CT includes all the subjects who consented to the sub-study, were 
randomized, with at least one dose of study drug, and with at least one measurement of 
low dose CT.  Analysis will be conducted using As Observed (AO) cases.
Each subject enrolled in the low dose CT sub-study should be measured at baseline, Week 
52 and Week 104.  The summary of the low dose CT score change from baseline to Week 
52 or Week 104 will be summarized by treatment group sequence as defined in section 
9.1.1 and the overall group. The descriptive statistics min, max, mean, SD, and the 95% 
CI of mean for each group at each visit will be provided. The CT scans are evaluated for 
the full spine (cervical, thoracic, and lumbar spine) by the central image reading and the 
scoring of the low dose CT Syndesmophyte is described below.
At each timepoint, the reviewer will score a total of 23 vertebral units (VUs), from C2-S1, 
in the coronal and sagittal planes. In the sagittal view, the anterior and posterior rim of a 
vertebra can be assessed whereas the left and right rim can be assessed in the coronal 
view.
By scoring images in the sagittal and coronal planes, 8 quadrants are assessed per VU 
(i.e., per VU lower and upper borders: coronal - left rim, coronal - right rim, sagittal -
anterior rim, and sagittal - posterior rim). With 8 quadrants per vertebral unit, 23 VUs per 
spine, and a max score of 3 per quadrant, the maximum possible score for a subject is 552 
(ACR, 2016, de Bruin, 2017).
A syndesmophyte is defined as a bony spur arising from the vertebral body close to the 
vertebral endplate in a vertical configuration with an angle of ≥ 45-degrees in relation to 
the horizontal endplate. For each quadrant, the reviewer will enter a syndesmophyte score 
as follows:
0 = no syndesmophyte present


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1 = a syndesmophyte is present that does not reach 50% of the intervertebral disc 
space (IDS)
2 = the syndesmophyte reaches or crosses 50% of the IDS
3 = the syndesmophyte bridges the IDS
A value of 3 is, per definition, scored in both quadrants on opposite sides of the 
intervertebral disc space. If a VU is not visible (e.g., poor film quality, missing imaging,) 
at the timepoint, the individual VU will be coded as 'Not Visible' (N). If images at the 
timepoint show a VU with surgical fusion, then the VU will be scored 'Surgically 
Modified' (S). No numerical values will be provided for these locations and will be 
considered as missing. 
If a score at any location (vertebral unit) is missing, the method described below will be 
used for deriving syndesmophyte score.  
●
If the score for a location is missing at Baseline, this location will not 
contribute to the calculation of total syndesmophyte score for this subject at 
any visit within the reading session (even if the score for this location is 
available at postbaseline visits).  
●
If the score for a locationis missing at all post-baseline visits within a reading 
session, this location will not contribute to the calculation of total 
syndesmophyte score for this subject at any visit within the reading session 
(even if the score for this locationis available at Baseline).  
●
If the score for a location is available at Baseline and at least one postbaseline 
visit, missing scores for this location at any other post-baseline visit will be 
imputed assuming no progression from the previous time point with available 
score.