A Multicenter, Randomized, Double-Blind, Study Comparing the Efficacy and Safety of Continuing Versus Withdrawing Adalimumab Therapy in Maintaining Remission in Subjects With Non-Radiographic Axial Spondyloarthritis
Phase: PHASE3
Conditions: Axial Spondyloarthritis
Sponsor: AbbVie

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
1
1.0
Title Page
Clinical Study Protocol M13-375
A Multicenter, Randomized, Double-Blind, Study 
Comparing the Efficacy and Safety of Continuing 
Versus Withdrawing Adalimumab Therapy in 
Maintaining Remission in Subjects with 
Non-Radiographic Axial Spondyloarthritis
Incorporating Amendments 1 and 2
AbbVie Investigational 
  Product:
Adalimumab
Date:
15 January 2015
Development Phase:
3b/4
Study Design:
This is a placebo-controlled, double-blind, randomized, multicountry, 
multicenter study.
EudraCT Number:
2012-000646-35
Investigators:
Multicenter Trial (Investigator information is on file at AbbVie)
Sponsor:
AbbVie Inc.
Dept. R477, Bldg. AP4
1 North Waukegan Road
North Chicago, IL  60064
Sponsor/Emergency 
  Contact:
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT01808118

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
2
1.1
Protocol Amendment:  Summary of Changes
The purpose of this amendment is to:
●
Include 6-MP in the list of stable DMARDs within the exclusion criteria.
Rationale:  azathioprine and 6-MP are considered equivalent.
●
Increase screening period from less than or equal to 30 days to 6 weeks 
(42 days).
Rationale:  to allow sites sufficient time to complete all study screening 
procedures.
●
Update IRT rounding rule in reference to ASDAS calculation.
Rationale:  more precisely calculate ASDAS to determine disease level at 
screening, remission (Weeks 16 – 28) and flare (Weeks 36 – 68).
●
Addition of Optional Blood Sample Collection Sub-Study.
Rationale:  to learn more about non-radiographic axial spondyloarthritis 
(nr-axSpA), response to adalimumab, as well as individual variability in 
response to adalimumab.
●
Correct typographical errors.
An itemized list of all changes made to the protocol under this amendment is found in 
Appendix X.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
3
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M13-375
Name of Study Drug:  Adalimumab
Phase of Development:  3b/4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  15 January 2015
Protocol Title:  A Multicenter, Randomized, Double-Blind, Study Comparing the Efficacy and Safety of 
Continuing Versus Withdrawing Adalimumab Therapy in Maintaining Remission in Subjects with 
Non-Radiographic Axial Spondyloarthritis
Objective:  The objective of this study is to evaluate the efficacy and safety of continuing versus 
withdrawing therapy with adalimumab 40 mg given every other week (eow) subcutaneously (SC) in 
maintaining remission in subjects with non-radiographic axial Spondyloarthritis (nr-axSpA).
Investigators:  Multicenter
Study Sites:  Approximately 150 sites
Study Population:  Adult subjects with nr-axSpA and objective evidence of active inflammation in the 
sacroiliac (SI) joints or spine on MRI, or elevated high sensitivity C-reactive protein (hs-CRP).
Number of Subjects to be Enrolled:  Approximately 740
Methodology:
The study duration will include a 42-day Screening Period, a 28-week open-label (OL) 40 mg 
adalimumab eow treatment period (Period 1), a 40-week double-blind, placebo-controlled treatment 
period (Period 2), with an opportunity to receive at least 12 weeks of rescue therapy (subjects who flare 
at Weeks 60, 64 and 68 will be allowed 12 weeks of rescue therapy), and a 70-day follow-up phone call.
Subjects in remission defined as meeting Ankylosing Spondylitis Disease Activity Score (ASDAS) 
Inactive Disease (ASDAS < 1.300) at Weeks 16, 20, 24 and Week 28 will be randomized in a 1:1 ratio to 
receive either blinded adalimumab 40 mg eow or matching placebo during Period 2.  Due to the
importance of the Week 16, 20 and 24 visits, two or more missed visits during this time must be 
discussed with the AbbVie Medical Monitor prior to randomization.  If a subject misses a single visit at 
Week 16, 20, or 24 the site will need to use the ASDAS parameters from the visit immediately prior to 
the missed visit.  If a subject misses the Week 28 visit, the subject must be discontinued.  Subjects not 
meeting the ASDAS Inactive Disease at Weeks 16, 20, 24 or Week 28 will be discontinued.  Subjects 
may be discontinued as early as Week 20 if they do not meet the ASDAS remission criteria using the 
Week 16 parameters.
No formal unblinded interim analysis is planned for this study that requires an adjustment to the P value.  
An interim analysis will be performed when all ongoing subjects have completed at least Week 28 of the 
study.  The primary and secondary endpoints of the study from the double-blind period will be reported at 
the completion of the study.
Subjects who flare in Period 2 (40-week double-blind period) will be allowed rescue therapy.  Flare is 
defined as 2 consecutive study visits with ASDAS ≥ 2.100.  Rescue therapy will consist of OL 
adalimumab 40 mg eow for at least 12 weeks and will continue through the duration of the subject's 
participation of the study.  After 12 weeks of rescue therapy with OL adalimumab eow, initiation of or 
change in a subject's concomitant medications for SpA including doses of DMARDs, corticosteroids, 
NSAIDs, and analgesics are permitted based on the investigator's medical judgment.  For subjects who 
meet the flare criteria at Weeks 60, 64 or 68, rescue therapy with OL adalimumab will be provided for 
12 weeks and final study visit will be at Weeks 72, 76 or 80, respectively.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
4
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject age ≥ 18 years.
2.
Subject with nr-axSpA fulfilling the Assessment of Spondyloarthritis International Society 
(ASAS) axial SpA classification criteria, but not fulfilling the radiologic criterion of the 
modified New York criteria for ankylosing spondylitis.
3.
Subject has had an inadequate response to at least 2 nonsteroidal anti-inflammatory drugs 
(NSAIDs) over a 4-week period in total at maximum recommended or tolerated doses, or has 
intolerance to or a contraindication for NSAIDs as defined by the Investigator.
4.
Subject with objective evidence of active inflammation in the SI joints or spine on MRI or 
elevated hs-CRP at screening (elevated hs-CRP is defined as any level greater than the upper 
limit of normal for the lab).
5.
Subject is a candidate for anti-TNF therapy based on the investigator's opinion.
6.
Subjects must have baseline disease activity as defined by having an ASDAS ≥ 2.100 (note, sites 
will need to use the Screening Visit hs-CRP to calculate ASDAS at Screening and Baseline 
Visits with the remainder of parameters visit-specific), BASDAI ≥ 4 and Patient's Assessment 
of Total Back Pain score ≥ 4 based on a Numeric Rating Scale (NRS) at both the Screening and 
Baseline Visits.
Main Exclusion:
1.
Subject fulfilling the radiologic criterion of the modified New York criteria for ankylosing 
spondylitis at or prior to the Screening Visit.
2.
Prior exposure to any anti-TNF therapy; any biologic therapy with a potential therapeutic impact 
on SpA, or subject has been treated with any investigational drug of chemical or biologic nature 
within a minimum of 30 days or five half-lives (whichever is longer) of the drug prior to the 
Baseline Visit.
3.
If entering the study on concomitant disease-modifying anti-rheumatic drugs (DMARDs), 
subject not on stable dose of methotrexate (≤ 25 mg per week) and/or sulfasalazine (≤ 3 g per 
day) and/or hydroxychloroquine (≤ 400 mg per day) for 28 days prior to the Baseline Visit.  All 
other oral DMARDs, with the exception of azathioprine or mercaptopurine (6-MP) are 
prohibited within 28 days prior to the Baseline Visit.
4.
If entering the study on concomitant azathioprine (AZA) or 6-MP, subject not on stable dose 
(AZA ≤ 150 mg per day or 6-MP ≤ 75 mg per day) for 28 days prior to the Baseline Visit or is 
on AZA or 6-MP and another concomitant immunosuppressive drug at study entry.
5.
If entering the study on concomitant NSAIDs, tramadol, and/or non-opioid analgesics, subject 
not on stable doses for 14 days prior to the Baseline Visit.
6.
Subject on opioid analgesics or use of marijuana within 14 days prior to the Baseline Visit.
7.
If entering the study on concomitant oral corticosteroids, subject not on stable dose of 
prednisone (≤ 10 mg per day), or oral corticosteroid equivalents, for at least 14 days prior to the 
Baseline Visit.
8.
Subject has been treated with intramuscular, intra-articular joint injection(s) or spinal/paraspinal 
injection(s) of corticosteroids in the preceding 28 days prior to the Baseline Visit.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
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Main Exclusion (Continued):
9.
Subject has undergone spinal surgery within 2 months prior to Baseline 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.
10. Subject with extra-articular manifestations (e.g., inflammatory bowel disease, psoriasis, uveitis, 
etc.) that is not clinically stable for at least 30 days prior to study entry.
11. Subject has a history of fibromyalgia or inflammatory arthritis of a different etiology other than 
SpA (e.g., rheumatoid arthritis, gout, systemic lupus erythematosus, polyarticular or systemic 
juvenile idiopathic arthritis).
Investigational Product:
Adalimumab
Dose:
40 mg eow
Mode of Administration:
SC
Reference Therapy:
Placebo
Dose:
eow
Mode of Administration:
SC
Duration of Treatment:
Length of exposure will depend on remission or flare status (20 [first time ASDAS remission will be 
calculated] to 80 weeks of treatment).
The duration of treatment will include a 28-week, OL period (adalimumab 40 mg eow), followed by a 
40-week, randomized, double-blind period (adalimumab 40 mg eow versus placebo), with an opportunity 
to receive at least 12 weeks of rescue therapy (subjects who flare at Weeks 60, 64 or 68 will be allowed 
12 weeks of rescue therapy and final study visit will be at Weeks 72, 76, or 80, respectively).
Criteria for Evaluation:
Efficacy:
The primary efficacy variable is the proportion of subjects who do not experience a flare by Week 68 of 
the study where a flare is defined as having any 2 consecutive study visits with ASDAS ≥ 2.100.
Secondary efficacy variables include the following:
At 12 weeks after initiation of Rescue Therapy
!
ASDAS Inactive Disease (ASDAS < 1.300)
!
ASDAS Major Improvement (a change from baseline ≤ –2.000)
!
ASDAS Clinically Important Improvement (a change from baseline ≤ –1.100)

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
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Efficacy (Continued):
!
ASAS20, ASAS40, ASAS 5/6 and ASAS Partial Remission
o
ASAS20 response: improvement of ≥ 20% and absolute improvement of ≥ 1 unit (on a scale 
of 0 to 10) from Baseline in ≥ 3 of the following 4 domains, with no deterioration in the 
remaining domain (defined as a worsening of ≥ 20% and a net worsening of ≥ 1 unit)
o
Patient's Global Assessment – Represented by the PTGA-disease activity NRS score 
(0 to 10)
o
Pain – Represented by the patient's assessment of total back pain NRS score (0 to 10)
o
Function – Represented by the BASFI NRS score (0 to 10)
o
Inflammation – Represented by the mean of the 2 morning stiffness-related BASDAI 
NRS scores (mean of items 5 and 6 of the BASDAI [0 to 10])
o
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 in ASAS20 with no 
deterioration in the potential remaining domain
o
ASAS partial remission: absolute score of < 2 units for each of the 4 domains identified 
above in ASAS20
o
ASAS 5/6 response:  20% improvement 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
!
Bath AS Disease Activity Index 50 (BASDAI50)
!
Health Assessment Questionnaire Modified for the Spondyloarthropathies (HAQ-S)
At Week 28 and Week 68
!
ASDAS Inactive Disease
!
ASDAS Major Improvement
!
ASDAS Clinically Important Improvement
!
ASAS20, ASAS40, ASAS 5/6 and ASAS Partial Remission
!
BASDAI50
!
HAQ-S
At Week 68 
!
Time to flare defined as ASDAS ≥ 2.100 at 2 consecutive visits
!
Time to partial flare defined as ASDAS ≥ 1.300 but < 2.100 at 2 consecutive visits
!
Proportion of subjects who reach flare definition
!
Proportion of subjects who reach partial flare definition
Other Efficacy Variables
!
Patient's Global Assessment of Disease Activity
!
Patient's Assessment of Total back pain
!
Bath AS Functional Index (BASFI)
!
Inflammation/Morning Stiffness (mean of BASDAI questions 5 and 6)

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
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Efficacy (Continued):
!
Bath AS Disease Activity Index (BASDAI)
!
ASDAS
!
hs-CRP
!
Linear Bath AS Metrology Index (BASMIlin)
!
Swollen Joint Count (66 joints)
!
Tender Joint Count (68 joints)
!
MASES
!
Plantar fascia enthesitis
!
Dactylitis
!
Physician's Global Assessment of Disease Activity
!
Patient's Global Assessment of Pain
!
Patient's Assessment of Nocturnal Back Pain
!
Anterior Uveitis
!
Short Form-36v2 Health Survey questionnaire
!
EQ-5D
!
Work Productivity and Activity Impairment – Axial Spondylorarthritis (WPAI-axial SpA)
!
SPARCC scores for MRI of the SI joint and spine
!
Proportion of subjects who regain remission on rescue therapy
!
Time to regain remission on rescue therapy
Exploratory Variables:
Each subject will have blood drawn for biomarkers at the following time points:  Baseline, Weeks 28, 68, 
time of flare (if applicable), 12 weeks post flare (if applicable), and last study visit.  The final set of 
biomarkers to be analyzed may include the following:
!
DKK-1
!
Sclerostin
!
BMP-2
!
BMP-7
The final selection of biomarkers for analysis will be based on both insights gained in the sub-study and 
available scientific knowledge at study completion.
Pharmacokinetic:
Each subject will have blood drawn for serum adalimumab concentration and anti-adalimumab antibody 
(AAA) at the following time points:  Baseline, Weeks 12, 28, 36, 52, 68, time of flare (if applicable), 
12 weeks post flare (if applicable), and last study visit.
Safety:
Screening assessments will include medical history, vital signs, physical examination, and clinical 
laboratory tests.  The following safety evaluations will be performed during the study:  concomitant 
medication review, adverse event (AE) monitoring, vital signs, physical examination (if required) and 
laboratory tests.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
8
Statistical Methods:
Efficacy:
The primary efficacy variable is the proportion of subjects who do not experience a flare in Period 2 by 
Week 68 of the study between the adalimumab and placebo groups.  Analysis will be performed using a 
two-sided chi squared test with an α = 0.05.  Subjects with missing primary efficacy endpoint response at 
Week 68 will be treated as non-responders, i.e., a "non-responder imputation" criterion will be used for 
missing data.  Descriptive statistics will also be provided for primary and secondary efficacy variables.
Pharmacokinetic:
For each scheduled time of measurement, summary statistics will be provided for the adalimumab serum 
concentration data by treatment group.  The adalimumab concentration data may be analyzed using 
nonlinear mixed effects modeling approach.  The percentage of subjects with AAA will be reported.
Safety:
Safety analyses will be carried out using the safety population, which includes all subjects who received 
at least one dose of study medication.  Treatment-emergent AEs and serious AEs (SAEs), which include 
pre- and post-treatment SAEs, will be summarized and reported.
Treatment-emergent AEs are defined as AEs that begin either on or after the first dose of the study 
medication, and up to within 70 days after the last dose of the study medication, except for those subjects 
that initiate adalimumab therapy not supplied in the context of the clinical trial after the end of study 
participation.  The number and percent of subjects experiencing AEs will be tabulated by body system 
and Medical Dictionary for Drug Regulatory Activities (MedDRA®) preferred term.  In addition, 
summary of AEs by severity and relationship to study drug will be presented.  Serious, severe, or AEs 
that lead to premature study discontinuation will be listed.
Mean change in vital signs and laboratory variables at each visit as compared to baseline will be 
summarized for all treated subjects, and compared between treatment groups using a one way Analysis of 
Variance (ANOVA).  The last evaluation prior to the first dose of study drug will be used as Baseline for 
all analyses.  For selected parameters, a listing of all subjects with any laboratory determination meeting 
Common Toxicity Criteria (CTC) of Grade 3 or higher will be provided.  Shift tables for changes from 
Baseline according to the normal range will also be provided for laboratory variables.
Sample Size:
Assuming that 50% of subjects treated with adalimumab will not experience any flare up to Week 68, 
120 subjects per arm are required for the double-blind period (Period 2) (with an adjustment for a drop-
out rate of no more than 30%) is targeted to result in at least 90% power for detecting 25% difference at 
Week 68 primary endpoint between adalimumab and placebo based on a two-sided test with significance 
level 0.05.
It is assumed that approximately 33% of the subjects enrolled into the OL period (Period 1) would meet 
ASDAS Inactive Disease at Weeks 16, 20, 24 and Week 28; therefore, a total of approximately 
740 subjects would be required to be enrolled in order to have sufficient number of subjects 
(i.e., 120 subjects per arm) for the double-blind period.  Study enrollment will be closed prior to reaching 
740 subjects should a sufficient number of subjects fulfill remission criteria and be available for 
randomization at the end of Period 1 prior to full enrollment.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
9
1.3
List of Abbreviations and Definition of Terms
Abbreviations
6-MP
6-mercaptopurine
AAA
Anti-adalimumab Antibody
ADA
Adalimumab
AE
Adverse Event
ANA
Antinuclear Antibody
ANOVA
Analysis of Variance
AP
Anteroposterior
AS
Ankylosing Spondylitis
ASAS
Assessment of Spondyloarthritis International Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
AZA
Azathioprine
BASDAI
Bath AS Disease Activity Index
BASFI
Bath AS Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BCG
Bacille Calmette-Guérin 
BM
Biomarker
BMP
Bone Morphogenetic Protein
BUN
Blood Urea Nitrogen
CD
Crohn's disease
CDC
Centers for Disease Control
CRA
Clinical Research Associate
CRF
Case Report Form
CRP
C-reactive protein
CTC
Common Toxicity Criteria
CXR
Chest X-ray
DKK-1
Dickkopf-1
DMARD
Disease-Modifying Anti-Rheumatic Drugs
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic Acid

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
10
eow
Every Other Week
EQ-5D
European Quality of Life – 5 Dimension
ESR
Erythrocyte Sedimentation Rate
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practices
HAQ-S
Health Assessment Questionnaire modified for the Spondyloarthropathies
HBc Ab
Hepatitis B core antibodies
HBs Ab
Hepatitis B surface antibodies
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HIV
Human Immunodeficiency Virus
HLA-B27
Human Leukocyte Antigen-B27
hs-CRP
High Sensitivity C-reactive Protein
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG1
Immunoglobulin G1
IGRA
Interferon-Gamma Release Assay
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine Device
IV
Intravenous
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response System
LOCF
Last Observation Carried Forward
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MTX
Methotrexate
NONMEM
Non-Linear Mixed Effect Modeling
nr-axSpA
Non-radiographic Axial Spondyloarthritis
NRS
Numerical Rating Scale
NSAID
Nonsteroidal Anti-inflammatory Drug
NYHA
New York Heart Association
OL
Open-label
PA
Posterior-anterior
PG
Pharmacogenetic

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M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
11
PK
Pharmacokinetic
POR
Proof of Receipt
PPD
Purified Protein Derivative
PsA
Psoriatic Arthritis
PTGA
Patient's Global Assessment
RA
Rheumatoid Arthritis
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SF-36V2
Short Form-36 Health Status Survey Version 2
SGOT/AST
Serum Glutamic-oxaloacetic Transaminase
SGPT/ALT
Serum Glutamic-pyruvic Transaminase
SI
Sacroiliac
SJC
Swollen Joint Count
SpA
Spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
SRM
Serum
SSZ
Sulfasalazine
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TJC
Tender Joint Count
TNF
Tumor Necrosis Factor
UC
Ulcerative Colitis
URL
Uniform Resource Locator
US
United States
WBC
White Blood Cell
WPAI-axial SpA
Work Productivity and Activity Impairment – Axial Spondylorarthritis

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M13-375 Protocol Amendment 2
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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 .....................................................................................................3
1.3
List of Abbreviations and Definition of Terms..........................................9
2.0
Table of Contents...................................................................12
3.0
Introduction ...........................................................................17
3.1
Non-Radiographic Axial Spondyloarthritis .............................................17
3.2
Current Treatments ..................................................................................17
3.3
Adalimumab Overview............................................................................19
3.4
Safety Information ...................................................................................20
3.5
Differences Statement..............................................................................20
3.6
Benefits and Risks....................................................................................21
4.0
Study Objective......................................................................21
5.0
Investigational Plan...............................................................22
5.1
Overall Study Design and Plan:  Description ..........................................22
5.2
Selection of Study Population..................................................................28
5.2.1
Inclusion Criteria .....................................................................................28
5.2.2
Exclusion Criteria ....................................................................................30
5.2.3
Prior and Concomitant Therapy...............................................................33
5.2.3.1
Prior Therapy ...........................................................................................34
5.2.3.2
Concomitant Therapy...............................................................................35
5.2.3.3
Prohibited Therapy...................................................................................36
5.2.3.4
Rescue Therapy........................................................................................37
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables.............................................................................37
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................37
5.3.1.1
Study Procedures .....................................................................................46
5.3.2
Drug Concentration, Pharmacogenic, and Biomarker 
Measurements ..........................................................................................67
5.3.2.1
Collection of Samples for Analysis .........................................................68
5.3.2.2
Handling/Processing of Samples .............................................................70

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5.3.2.3
Disposition of Samples ............................................................................72
5.3.2.4
Measurement Methods.............................................................................72
5.3.3
Efficacy Variables....................................................................................72
5.3.3.1
Primary Efficacy Variable .......................................................................72
5.3.3.2
Secondary Efficacy Variable(s) ...............................................................73
5.3.3.3
Other Efficacy Variables..........................................................................74
5.3.3.4
Exploratory Variables ..............................................................................75
5.3.4
Pharmacogenetic Variables......................................................................76
5.3.5
Safety Variables .......................................................................................76
5.4
Removal of Subjects from Therapy or Assessment .................................76
5.4.1
Discontinuation of Individual Subjects....................................................76
5.4.2
Discontinuation of Entire Study...............................................................78
5.5
Treatments................................................................................................78
5.5.1
Treatments Administered.........................................................................78
5.5.2
Identity of Investigational Product(s) ......................................................80
5.5.2.1
Packaging and Labeling...........................................................................80
5.5.2.2
Storage and Disposition of Study Drug ...................................................80
5.5.3
Method of Assigning Subjects to Treatment Groups...............................81
5.5.4
Selection and Timing of Dose for Each Subject ......................................81
5.5.5
Blinding....................................................................................................82
5.5.5.1
Blinding of Investigational Product .........................................................82
5.5.6
Treatment Compliance.............................................................................83
5.5.7
Drug Accountability.................................................................................83
5.6
Discussion and Justification of Study Design..........................................84
5.6.1
Discussion of Study Design and Choice of Control Groups....................84
5.6.2
Appropriateness of Measurements...........................................................85
5.6.3
Suitability of Subject Population .............................................................85
5.6.4
Selection of Doses in the Study ...............................................................85
6.0
Adverse Events.......................................................................85
6.1
Definitions................................................................................................86
6.1.1
Adverse Event..........................................................................................86
6.1.2
Serious Adverse Events ...........................................................................87
6.2
Adverse Event Severity............................................................................88

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6.3
Relationship to Study Drug......................................................................89
6.4
Adverse Event Collection Period.............................................................89
6.5
Adverse Event Reporting.........................................................................90
6.6
Pregnancy.................................................................................................91
6.7
Toxicity Management ..............................................................................92
7.0
Protocol Deviations................................................................92
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................93
8.1
Statistical and Analytical Plans................................................................93
8.1.1
Analysis Population .................................................................................93
8.1.2
Statistical and Analytical Plan .................................................................94
8.1.3
Analysis of Demographic Data and Baseline Disease 
Characteristics..........................................................................................95
8.1.4
Statistical Analysis of Efficacy................................................................96
8.1.4.1
Primary Efficacy Variable .......................................................................96
8.1.4.1.1
Primary Analysis of Primary Efficacy Endpoint .....................................96
8.1.4.1.2
Secondary Analysis of Primary Efficacy Endpoint .................................96
8.1.4.2
Analyses of Secondary Efficacy Variables ..............................................96
8.1.4.3
Other Exploratory Analyses.....................................................................97
8.1.5
Statistical Analyses of Safety...................................................................97
8.1.6
Pharmacokinetic Analyses .......................................................................98
8.1.7
Interim Analysis.......................................................................................99
8.2
Determination of Sample Size .................................................................99
8.3
Randomization Methods ..........................................................................99
9.0
Ethics.....................................................................................100
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................100
9.2
Ethical Conduct of the Study .................................................................100
9.3
Subject Information and Consent...........................................................101
10.0
Source Documents and Case Report Form 
Completion ...........................................................................102
10.1
Source Documents .................................................................................102
10.2
Case Report Forms.................................................................................103

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11.0
Data Quality Assurance......................................................104
12.0
Use of Information...............................................................105
13.0
Completion of the Study .....................................................106
14.0
Investigator's Agreement....................................................107
15.0
Reference List ......................................................................108
List of Tables
Table 1.
Study Activities........................................................................................38
Table 2.
Clinical Laboratory Tests.........................................................................56
Table 3. 
Identity of Investigational Products .........................................................80
List of Figures
Figure 1.
Study Design Schematic ..........................................................................23
Figure 2.
Adverse Event Collection ........................................................................90
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................110
Appendix B.
List of Protocol Signatories....................................................................112
Appendix C.
Assessment of SpondyloArthritis International Society (ASAS) 
Axial Spondyloarthritis Criteria for Classification ................................113
Appendix D.
Features of Spondyloarthritis.................................................................114
Appendix E.
Ankylosing Spondylitis Disease Activity Score (ASDAS) 
Calculation .............................................................................................115
Appendix F.
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 
NRS........................................................................................................116
Appendix G.
Patient's Assessment of Total Back Pain, NRS .....................................118
Appendix H.
Modified New York Criteria for Ankylosing Spondylitis .....................119
Appendix I.
Tender and Swollen Joint Counts ..........................................................120
Appendix J.
Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin).......122
Appendix K.
Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)............124
Appendix L.
Bath Ankylosing Spondylitis Functional Index (BASFI), NRS ............125

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Appendix M.
Physician's Global Assessment of Disease Activity, NRS ....................127
Appendix N.
Patient's Assessment of Nocturnal Back Pain, NRS..............................128
Appendix O.
Patient's Global Assessment of Disease Activity, NRS.........................129
Appendix P.
Patient's Global Assessment of Pain, NRS ............................................130
Appendix Q.
Health Assessment Questionnaire Modified for the 
Spondyloarthropathies (HAQ-S) ...........................................................131
Appendix R.
SF-36v2 Health Status Survey...............................................................135
Appendix S.
Work Productivity and Activity Impairment Questionnaire:  Axial 
Spondylorarthritis, V2.0 (WPAI:  Axial Spondyloarthritis)..................141
Appendix T.
EQ-5D (US English Version) ................................................................143
Appendix U.
70-Day Follow-Up Call – Sample .........................................................145
Appendix V.
Injection Instructions – Sample Pre-Filled Syringe ...............................146
Appendix W.
Subject Dosing Diary Sheet (Sample) ...................................................162
Appendix X.
Protocol Amendment:  List of Changes.................................................165

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3.0
Introduction
3.1
Non-Radiographic Axial Spondyloarthritis
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 related arthritis, and 
undifferentiated SpA.  Because there is an overlap of symptoms among these diseases, 
there is some variability in the way physicians may interpret and apply diagnoses in 
clinical practice.  A more universally consistent way of categorizing SpA patients would 
be to define them by their primary clinical manifestation of axial or peripheral SpA.
Axial SpA encompasses a spectrum of disease manifestations which has been split into 
2 categories—AS and non-radiographic axial SpA (nr-axSpA)—due to the 1984 modified 
New York criteria which required the presence of sacroiliitis on plain radiographs for the 
classification of AS.2,3  Clinically, patients with AS and nr-axSpA have comparable 
clinical manifestations and burden of disease4 with the sole differentiating characteristic 
between the 2 categories of axial SpA being the presence of sacroiliitis visualized by plain 
radiographs.
The Assessment of SpondyloArthritis international Society (ASAS) has proposed and 
validated new classification criteria for patients with axial SpA and for those with 
peripheral SpA.5,6  The rationale for the development of the ASAS axial SpA criteria was 
to develop criteria that were applicable to patients with or without radiographic 
sacroiliitis.7  These criteria included not only plain x-rays but also Magnetic Resonance 
Imaging (MRI) as imaging modalities for classification.5  These criteria were meant to 
facilitate the conduct of clinical trials in nr-axSpA which was considered an unmet need 
by the experts who developed the criteria.5,7
3.2
Current Treatments
There is an unmet medical need for treatment in nr-axSpA patients who fail nonsteroidal 
anti-inflammatory drug (NSAIDs).  Registry and clinical trial data indicate that AS and 

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nr-axSpA patients have comparable burden of disease that requires treatment irrespective 
of radiographic progression.4,8,9  NSAIDs are considered first line therapy for all axial 
SpA patients.10,11  Traditional disease modifying anti-rheumatic drugs (DMARDs) such as 
methotrexate (MTX) and sulfasalazine (SSZ) have not been shown to be effective for 
axial SpA.12,13  For AS patients who continue to have active disease despite NSAIDs, 
adalimumab is an approved therapy.  However, nr-axSpA patients who may have the 
same signs, symptoms, and level of disease activity as AS patients who qualify for 
adalimumab therapy, currently have no other treatment alternative to NSAIDs.  This led to 
the clinical development program for adalimumab in nr-axSpA patients who have 
moderate to severe disease as indicated by a Bath Ankylosing Spondylitis Disease 
Activity Index (BASDAI) of 4 or greater despite treatment with NSAIDs.  
Study M10-791 (ABILITY I) was a randomized, placebo controlled clinical trial of 
adalimumab in patients with nr-axSpA who have failed at least 1 NSAID, or have an 
intolerance to or contraindication for NSAIDs.  At Week 12, the ASAS40 response was 
statistically significant for adalimumab compared to placebo – 36.3% versus 14.9% 
(P < 0.001).
There are current data to suggest that continuous anti-tumor necrosis factor (anti-TNF) 
therapy is needed for nr-axSpA patients to maintain clinical response or remission over 
time.  In an investigator-initiated, randomized, placebo-controlled study of adalimumab in 
46 nr-axSpA subjects, 23 subjects attained an ASAS40 response and 9 reached ASAS 
partial remission after 52 weeks.9,14  Adalimumab was discontinued in these 23 subjects, 
and the subjects were followed for 1 year without adalimumab treatment.  Disease flare, 
defined as no longer reaching an ASAS40 response, resulted in retreatment with 
adalimumab.  Over the 1-year observation period without treatment, 19 of 23 (83%) of the 
initial ASAS40 responders had a disease flare, while only 4 of 23 (17%) maintained their 
response.  Mean duration of ASAS40 response until flare in these 19 patients was 
14.8 weeks.  Seven of the 9 (78%) subjects initially achieving ASAS partial remission 
relapsed during the 1-year observation period without treatment.  After restarting 
treatment with adalimumab, 9 of 18 (50%) subjects reached ASAS40 and 4 of 18 (22.2%) 
subjects attained ASAS partial remission after 12 weeks of retreatment.  Similar results 

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were noted in the ESTHER trial.15  This trial included 76 active axial SpA subjects with 
disease duration < 5 years and active inflammation in either the sacroiliac (SI) joints or 
spine on whole body MRI at Baseline, 39 of whom fulfilled modified New York criteria 
for AS.  Subjects received either etanercept (n = 40) or SSZ (n = 36) for 48 weeks.  At 
48 weeks, 33% (13/40) of etanercept and 11% (4/36) of SSZ subjects in study remission 
(defined by ASAS remission and absence of inflammation in the spine and SI joints on 
MRI) were taken off therapy and observed for flares.  In the etanercept group, 9 subjects 
flared (BASDAI worsening of ≥ 2 points as compared to Week 48) after a mean of 
24.4 weeks after stopping etanercept, and in the SSZ group, 3 patients flared after a mean 
of 39.6 weeks.  Approximately half of the subjects flaring after etanercept withdrawal 
responded to retreatment with etanercept (ASAS remission 56%; study remission 44%).
3.3
Adalimumab Overview
Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody 
containing only human peptide sequences.  Adalimumab is produced by recombinant 
deoxyribonucleic acid (DNA) technology in a mammalian cell expression system.  It 
consists of 1330 amino acids and has a molecular weight of approximately 
148 kilodaltons.  Adalimumab is composed of fully human heavy and light chain variable 
regions, which confer specificity to human TNF, and human IgG1 heavy chain and kappa 
light chain sequences.  Adalimumab binds with high affinity and specificity to soluble 
TNF-α but not to lymphotoxin-α (TNF-β).
TNF is a naturally occurring cytokine that is involved in normal inflammatory and 
immune responses.  Elevated levels of TNF play an important role in pathologic 
inflammation.  Adalimumab binds specifically to TNF and neutralizes the biological 
function of TNF by blocking its interaction with the p55 and p75 cell surface TNF 
receptors.  Adalimumab also modulates biological responses that are induced or regulated 
by TNF.  After treatment with adalimumab, levels of acute phase reactants of 
inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and 
serum cytokines rapidly decrease.

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Adalimumab was first approved in the United States (US) and European Union (EU) for 
the treatment of rheumatoid arthritis (RA) in 2002 and 2003, respectively.  Additional 
indications have been approved in the US and EU including Psoriasis, PsA, AS, Crohn's 
Disease (CD), Pediatric CD, Ulcerative Colitis (UC), and Polyarticular Juvenile Idiopathic 
Arthritis.  In addition, an indication for nr-axSpA and Pediatric Enthesitis-Related 
Arthritis has been approved in the EU.  Additional updates regarding approved indications 
can be found in the current edition of the Humira Investigational Drug Brochure.
3.4
Safety Information
Adalimumab therapy has a well-established and well described safety profile based on 
extensive postmarketing experience and continued clinical trial patient exposure since the 
first approved indication in 2002 for rheumatoid arthritis.  A detailed discussion of the 
pre-clinical toxicology, metabolism, pharmacology and safety experience with 
adalimumab can be found in the current Investigator's Brochure.  AbbVie is committed to 
continue to collect safety information including those events that may occur in this trial in 
order to confirm this established safety profile and to identify any unknown potential 
adverse reactions, rare events and those events with a long latency.  AbbVie is 
participating in an FDA-requested, TNF inhibitor class wide exploration of the rare 
appearance of malignancy in patients who are 30 years old or younger at the time of 
diagnosis.  The risk of malignancy in this age group has not been established and is 
difficult to study due to its rarity.  AbbVie appreciates your attention to the additional 
reporting requirements needed in this unlikely event, outlined in Section 6.5 under 
Adverse Event (AE) Reporting.
3.5
Differences Statement
This is the first adequately powered study to evaluate the efficacy and safety of continuing 
therapy with adalimumab 40 mg every other week (eow) subcutaneous (SC) versus 
withdrawing therapy in maintaining remission in subjects with nr-axSpA.

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3.6
Benefits and Risks
There is an unmet medical need for the treatment of nr-axSpA.  The utility of TNF 
blockade with adalimumab in nr-axSpA has been established in a randomized controlled 
trial which demonstrated a safety profile similar to that observed in the extensive clinical 
and post-marketing experience of adalimumab in a wide range of disease states including 
the associated indication of AS.  The safety profile of adalimumab in this and other 
approved indications is well established.  Adverse events in the categories of 
autoimmunity, demyelinating disorders, congestive heart failure, gastrointestinal 
disorders, hematologic events, hepatic events, hypersensitivity, immunosuppression, 
infections, malignancies, respiratory thoracic and mediastinal disorders, and vascular 
disorders have been observed with adalimumab therapy.  For Study M13-375, to ensure 
nr-axSpA subjects are appropriate candidates for anti-TNF therapy subjects are required 
to meet a minimum level of disease activity at baseline (ASDAS ≥ 2.100, BASDAI ≥ 4, 
Patient's Assessment of Total Back Pain score ≥ 4), have objective evidence of active 
disease (inflammation in the SI joints or spine on MRI or elevated hs-CRP), and have had 
an inadequate response to at least 2 NSAIDs.  The investigator is referred to the current 
Investigator's Brochure where additional and more detailed information regarding 
potential risks and benefits of adalimumab can be found.  The potential benefit of the 
proposed study in nr-axSpA is that it is designed to evaluate the efficacy and safety of 
continuing versus withdrawing therapy with adalimumab 40 mg given eow SC in 
maintaining remission in subjects with nr-axSpA.  As nr-axSpA is associated with 
considerable pain, reduction in health-related quality of life, and work impairment it 
would benefit patients to know if persistent adalimumab therapy is required to maintain 
remission.
4.0
Study Objective
The objective of this study is to evaluate the efficacy and safety of continuing versus 
withdrawing therapy with adalimumab 40 mg given eow SC in maintaining remission in 
subjects with nr-axSpA.

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5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
The study duration will include a 42-day Screening Period, a 28-week open-label (OL) 
40 mg adalimumab eow treatment period (Period 1), a 40 week double-blind placebo 
controlled eow treatment period (Period 2) with an opportunity to receive at least 
12 weeks of rescue therapy (subjects that flare at Weeks 60, 64 or 68 will be allowed 
12 weeks of rescue therapy and final visits will be 72, 76 or 80 respectively), plus a 
70-day follow-up phone call.  The study design schematic is presented in Figure 1.  
Length of exposure will depend on remission or flare status (20 [first time ASDAS
remission will be calculated] to 80 weeks of treatment).

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Screening Period
Within 42 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and undergo the 
screening procedures outlined in Table 1.
Subjects cannot be enrolled until the Anteroposterior (AP) Pelvis x-ray images have been 
centrally read for the presence/absence of sacroiliitis grade ≥ 2 bilaterally or sacroiliitis 
grade 3-4 unilaterally and the report is available to the site, and the site also has the 
following results to determine fulfillment of the ASAS axial SpA criteria and objective 
evidence of active inflammation:  1) human leukocyte antigen-B27 (HLA-B27), 2) report 
from the central reading of the MRI of the SI joints and spine and 3) hs-CRP.  Note:  The 
AbbVie Medical Monitor may allow on a case-by-case basis, a subject to be enrolled 
without having the results of the MRI, HLA-B27 and/or hs-CRP as the results of these 
procedures may not be necessary to determine eligibility.  Discussion must be 
documented prior to enrolling the subject.
Subjects that initially screen-fail for the study may be permitted to re-screen following 
re-consent.  The reason for screen failure will be captured in the appropriate Electronic 
Case Report Forms (eCRFs).  All screening procedures with the possible exceptions noted 
below will be repeated.  The subject must meet all 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; however, a subject should 
only be re-screened once for this study (Note:  one additional re-screen may be approved 
by the AbbVie Medical Monitor on a case-by-case basis).  Subjects who have 
screen-failed previously and do not have a reasonable chance of meeting the 
inclusion/exclusion criteria should not be re-screened.  If the subject had completed initial 
screening evaluation assessments including a purified protein derivative (PPD) test or 
Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold In-tube test or 
T SPOT TB test), chest x-ray (CXR), MRI of the SI joints and spine, AP pelvis x-ray, 
HLA-B27, Antinuclear Antibody (ANA) or electrocardiogram (ECG), these tests will not 
be required to be repeated for the re-screening provided the conditions noted in 

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Section 5.3 are met and no more than 30 days has passed for the MRI of the SI joints and 
spine, 3 months (90 days) have passed for the PPD test or IGRA test, CXR and ECG and 
1 year (365 days) for the AP pelvis x-ray.  There is no need to redraw the HLA-B27 or 
ANA once the results are available from the central laboratory chosen for this study.  If 
re-screening requires a MRI, sites are required to contact the AbbVie Medical Monitor to 
confirm if subjects should or should not be re-screened.
Open-Label Period (Period 1)
This period will begin at the Baseline Visit (Day 1) and will end at the Week 28 Visit.  
The Baseline Visit and Day 1 should be the same day.  At this visit, subjects who meet the 
enrollment (all of the inclusion and none of the exclusion) criteria described in 
Section 5.2.1 and Section 5.2.2 will be enrolled and dispensed OL 40 mg adalimumab to 
be taken eow.  During this period of the study, the subjects will visit the study site on 
Weeks 2, 4, 8, 12, 16, 20, 24 and 28 or if they terminate early from the study.  The last 
OL dose is given at Week 26.
The ASDAS calculation in Period 1 (OL) will be done at Weeks 20, 24 and 28 (prior to 
randomization).  All ASDAS visit parameters listed in Appendix E should be used from 
each study visit (with the possible exception of hs-CRP as described below).
At Week 20, sites will enter the ASDAS parameters into IVRS/IWRS using the 
IVRS/IWRS worksheets provided separately.  At Week 20, calculation of the Week 16 
ASDAS will be done using the Week 16 visit parameters including the Week 16 hs-CRP.  
If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will 
be discontinued.
At Week 24, sites will enter the ASDAS parameters into IVRS/IWRS using the 
IVRS/IWRS worksheets provided separately.  At Week 24, calculation of the Week 20 
ASDAS will be done using the Week 20 visit parameters including the Week 20 hs-CRP.  
If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will 
be discontinued.

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At Week 28, sites will enter the ASDAS parameters into IVRS/IWRS using the 
IVRS/IWRS worksheets provided separately.  At Week 28, calculation of the Week 24 
ASDAS will be done using the Weeks 24 parameters including the Week 24 hs-CRP; the 
Week 28 ASDAS will be done using Week 28 parameters and the Week 24 hs-CRP (as 
the Week 28 results will not be available).  If any of these time points do not meet the 
criteria for remission (ASDAS < 1.300), the subject will be discontinued.
Subjects may be discontinued as early as Week 20 if they do not meet the ASDAS 
remission criteria using the Week 16 parameters.
Due to the importance of the Week 16, 20 and 24 visits, two or more missed visits during 
this time must be discussed with the AbbVie Medical Monitor prior to randomization.  If 
a subject misses a single visit at Week 16, 20 or 24 the site will need to use the ASDAS 
parameters from the visit immediately prior to the missed visit.  If the subject misses the 
Week 28 visit, the subject must be discontinued.
If a subject has an elevated hs-CRP which the investigator believes to be secondary to an 
AE and not due to nr-axSpA at Weeks 16, 20, 24 or 28, sites may repeat the hs-CRP test 
prior to the subject's next scheduled visit following a discussion with the AbbVie Medical 
Monitor.  The repeat hs-CRP results should be available to the site prior to the subject's 
next scheduled visit and will replace the visit-specific hs-CRP in the ASDAS calculation.  
Instances where AE-related hs-CRP elevation spans more than one study visit will be 
addressed on a case-by-case basis.  Note:  the AE should be reported in EDC prior to 
discussion with the AbbVie Medical Monitor.
Double-Blind Period (Period 2)
This period will begin at Week 28 and will end at Week 68.  Subjects in remission defined 
as meeting Ankylosing Spondylitis Disease Activity Score (ASDAS) Inactive Disease 
(ASDAS < 1.300) at Week 16, 20, 24 and Week 28 (described above) will be randomized 
in a 1:1 ratio to receive either blinded adalimumab 40 mg eow or matching placebo.

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During this period of the study, the subjects will visit the study site on Weeks 28, 32, 36, 
40, 44, 48, 52, 56, 60, 64 and 68 or if they discontinue early from the study.  Subjects who 
flare, defined as 2 consecutive study visits with ASDAS ≥ 2.100 in Period 2 (40-week 
double-blind period) will be allowed rescue therapy.  The earliest time a subject can meet 
the flare criteria would be at Week 36 since a subject would need to have 2 consecutive 
visits with ASDAS ≥ 2.100.  The hs-CRP from the prior visit will be used to calculate the 
ASDAS for both the prior visit and the current visit with the remainder of the ASDAS 
parameters visit-specific.  (Note:  site will need to enter the ASDAS parameters used for 
calculation outlined in Appendix E into IVRS/IWRS at Weeks 36 for that visit as well as 
the previous visit.  Source worksheets will be available for sites to use during the 
IVRS/IWRS entry).  For subjects who meet flare criteria during Period 2 and start rescue 
therapy with OL adalimumab, further calculation of ASDAS is not required.  For any 
subject missing 2 consecutive visits within the double-blind period (Period 2), the site 
must contact the AbbVie Medical Monitor for discussion regarding the subject's 
continued participation in the study.
Following the Week 28 visit, if a subject has an elevated hs-CRP which the investigator 
believes to be secondary to an AE and not due to nr-axSpA, the site may repeat the 
hs-CRP test prior to the subject's next scheduled visit following a discussion with the 
AbbVie Medical Monitor.  The repeat hs-CRP results should be available to the site prior 
to the subject's next scheduled visit and will replace the visit-specific hs-CRP in the 
ASDAS calculation.  Instances where AE-related hs-CRP elevation spans more than 
one study visit will be addressed on a case-by-case basis.  Note:  the AE should be 
reported in EDC prior to discussion with the AbbVie Medical Monitor.
Rescue Therapy
For those subjects who meet the flare criteria during the double-blind period (Period 2), 
rescue therapy will consist of OL adalimumab 40 mg eow for at least 12 weeks and will 
continue through the duration of the subject's participation of the study.  After 12 weeks 
of rescue therapy with OL adalimumab eow, initiation of or change in a subject's 
concomitant medications for SpA including doses of DMARDs, corticosteroids, NSAIDs, 

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and analgesics are permitted based on the investigator's medical judgment.  For subjects 
who meet the flare criteria at Weeks 60, 64 or 68, rescue therapy with OL adalimumab 
eow will be provided for 12 weeks and the final study visit will be at Weeks 72, 76 or 80, 
respectively.
No study drug will be administered or injected at the final visit.
Subjects may discontinue adalimumab treatment at any time during study participation.  
Subjects that end study participation early will have a Discontinuation Visit.  All subjects 
will have a follow-up phone call approximately 70 days after the last administration of 
study drug to obtain information on any new or ongoing AEs.  The 70-day follow-up 
phone call will not be required for any subject that initiates commercial adalimumab.
Subjects who prematurely discontinue should complete the procedures outlined for the 
Discontinuation Visit in Table 1 as soon as possible after the last dose of study drug and 
preferably prior to the administration of new therapies.
The study is designed to enroll approximately 740 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.  Study enrollment 
will be closed prior to reaching 740 subjects should a sufficient number of subjects fulfill 
remission criteria and be available for randomization at the end of Period 1 prior to full 
enrollment.
5.2
Selection of Study Population
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.
Subject age ≥ 18 years.

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2.
Subject with nr-axSpA fulfilling the Assessment of Spondyloarthritis International 
Society (ASAS) axial SpA classification criteria (see Appendix C and 
Appendix D), but not fulfilling the radiologic criterion of the modified New York 
criteria for ankylosing spondylitis (see Appendix H).
3.
Subject has had an inadequate response to at least 2 NSAIDs over a 4-week period 
in total at maximum recommended or tolerated doses, or subject has an intolerance 
to or a contraindication for NSAIDs as defined by the Investigator.
4.
Subject with objective evidence of active inflammation in the SI joints or spine on 
MRI or elevated high sensitivity C-reactive protein (hs-CRP) at screening (elevated 
hs-CRP is defined as any level greater than the upper limit of normal for the lab).
5.
Subject is a candidate for anti-TNF therapy based on the investigator's opinion.
6.
Subjects must have baseline disease activity as defined by having an ASDAS 
≥2.100 (note, sites will need to use the Screening Visit hs-CRP to calculate 
ASDAS at Screening and Baseline Visits with the remainder of parameters 
visit-specific), BASDAI ≥ 4 and Patient's Assessment of Total Back Pain score ≥ 4 
based on a Numeric Rating Scale (NRS) at both the Screening and Baseline Visits 
(see Appendix E, Appendix F and Appendix G, respectively).
7.
If female, subject is either not of childbearing potential, defined as postmenopausal 
for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral 
oophorectomy and/or hysterectomy) or is of childbearing potential and is practicing 
an approved method of birth control throughout the study and for 150 days after 
last dose of study drug.  The results of the serum pregnancy test performed during 
the Screening Period and urine pregnancy test performed at the Baseline Visit must 
be negative.
Examples of approved methods of birth control include the following:
●
Condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD);
●
Hormonal contraceptives for 90 days prior to study drug administration;
●
A vasectomized partner.

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8.
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 Screening;
9.
Subject has a negative TB Screening Assessment.  If the subject has evidence of a 
latent TB infection; the subject must initiate and complete at least the first 2 weeks 
(or per local guidelines, whichever is longer) of the prescribed TB prophylaxis or 
have documented completion of a course of TB prophylaxis, prior to Baseline (see 
Section 5.3.1.1).
10.
Subjects must be able and willing to self-administer SC injections or have a 
qualified person available to administer SC injections.
11.
Subjects must be able and willing to provide written informed consent and comply 
with the requirements of this study protocol.
Rationale for the Inclusion Criteria
Inclusion Criteria
Rationale
1 – 9
To select the appropriate subject population for this study.
10
To increase subject compliance potential.
11
In accordance with the harmonized Good Clinical Practice (GCP).
5.2.2
Exclusion Criteria
A subject will be excluded from the study if he/she meets any of the following criteria:
1.
Subject fulfilling the radiologic criterion of the modified New York criteria for 
ankylosing spondylitis at or prior to the Screening Visit (see Appendix H).
2.
Prior exposure to any anti-TNF therapy; any biologic therapy with a potential 
therapeutic impact on SpA, or subject has been treated with any investigational 
drug of chemical or biologic nature within a minimum of 30 days or five half-lives 
(whichever is longer) of the drug prior to the Baseline Visit.

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3.
Prior exposure to biologics that have a potential or known association with 
progressive multifocal leukoencephalopathy (i.e., natalizumab [Tysabri ®], 
rituximab [Rituxan®], or efalizumab [Raptiva®]).
4.
If entering the study on concomitant DMARDs, subject not on stable dose of MTX 
(≤ 25 mg per week) and/or SSZ (≤ 3 g per day) and/or hydroxychloroquine 
(≤400 mg per day) for 28 days prior to the Baseline Visit.  All other oral 
DMARDs, with the exception of azathioprine or mercaptopurine (6-MP), are 
prohibited within 28 days prior to the Baseline Visit.
5.
If entering the study on concomitant azathioprine (AZA) or 6-MP, subject not on 
stable dose (AZA ≤ 150 mg per day or 6-MP ≤ 75 mg per day) for 28 days prior to 
the Baseline Visit or is on AZA or 6-MP and another concomitant 
immunosuppressive drug at study entry.
6.
If entering the study on concomitant NSAIDs, tramadol, and/or non-opioid 
analgesics, subject not on stable doses for 14 days prior to the Baseline Visit.
7.
Subject on opioid analgesics or use of marijuana within 14 days prior to the 
Baseline Visit.
8.
If entering the study on concomitant oral corticosteroids, subject not on stable dose 
of prednisone (≤ 10 mg per day), or oral corticosteroid equivalents, for at least 
14 days prior to the Baseline Visit.
9.
Subject has received cyclosporine or other second line anti-rheumatic therapy 
(except MTX, SSZ, hydroxychloroquine, AZA or 6-MP) within 28 days prior to 
the Baseline Visit.
10.
Subject has been treated with intramuscular, intra-articular joint injection(s) or 
spinal/paraspinal injection(s) of corticosteroids in the preceding 28 days prior to the 
Baseline Visit.
11.
Subject has undergone spinal surgery within 2 months prior to Baseline or subject 
has been diagnosed with a spinal condition that may interfere with study 

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
32
assessments (i.e., disc herniation, degenerative spine disease, etc.) in the opinion of 
the investigator.
12.
Subject with extra-articular manifestations (e.g., inflammatory bowel disease, 
psoriasis, uveitis, etc.) that are not clinically stable for at least 30 days prior to 
study entry.
13.
Subject has a history of fibromyalgia or inflammatory arthritis of a different 
etiology other than SpA (e.g., rheumatoid arthritis, gout, systemic lupus 
erythematosus, polyarticular or systemic juvenile idiopathic arthritis).
14.
Infection(s) requiring treatment with intravenous (IV) anti-infectives within 
30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the 
Baseline Visit.
15.
Known hypersensitivity to adalimumab or its excipients as stated in the label 
(Table 3).
16.
History of demyelinating disease (including myelitis) or neurologic symptoms 
suggestive of demyelinating disease.
17.
History of invasive infection (e.g., listeriosis and histoplasmosis), human 
immunodeficiency virus (HIV).
18.
Subjects with any active viral infection that based on the investigator's clinical 
assessment makes the subject an unsuitable candidate for the study.
19.
Hepatitis B:  HBs Ag positive (+) or detected sensitivity on the HBV-DNA PCR 
qualitative test for HBc Ab/HBs Ab positive subjects (see Section 5.3.1.1).
20.
Chronic recurring infections or active TB.
21.
History of moderate to severe congestive heart failure (NYHA class III or IV), 
recent cerebrovascular accident and any other condition which would put the 
subject at risk by participation in the study.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
33
22.
Evidence of dysplasia or history of malignancy (including lymphoma and 
leukemia) other than a successfully treated non-metastatic cutaneous squamous 
cell, basal cell carcinoma or localized carcinoma in situ of the cervix.
23.
Positive pregnancy test at Screening or Baseline.
24.
Female subjects who are breast-feeding or considering becoming pregnant during 
the study.
25.
Clinically significant abnormal screening laboratory results as evaluated by the 
Investigator.
26.
History of clinically significant drug or alcohol abuse in the last 12 months.
27.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study.
The Investigator should contact the AbbVie Medical Monitor identified in Section 6.5 if 
there are any questions regarding inclusion and exclusion criteria and subject eligibility.
Rationale for the Exclusion Criteria
Exclusion Criteria
Rationale
1
To select the appropriate subject population in the study.  
2–25, 27
To avoid medical conditions, medications or procedures that may compromise 
subject safety and the ability to make causality assessments relative to 
adalimumab.
26
To increase subject compliance potential.
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at the time of screening, 
and/or receives during 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.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
34
The AbbVie study-designated physician identified in Section 6.5 should be contacted if 
there are any questions regarding concomitant or prior therapies.
In addition for patients age ≤ 30 with a reported malignancy adverse event, prior exposure 
to, or current use of, antineoplastics, or other drugs which have a risk of malignancy as 
stated in their label and other relevant dosing information to estimate total exposure will
be collected in the source documents and appropriate eCRF pages.  At the time of the 
reported malignancy adverse event, sites will be asked if any of the below prior and 
concomitant medication categories contributed to the event.  Any medications in these
categories used prior to the study will be captured on the appropriate eCRF.  Information 
on the reason for use, date(s) of administration including start and end dates, highest 
maintained dose, dosage information including dose, route and frequency, and reason for 
stopping the medication will be collected in the source documents and appropriate eCRF
pages.
Medication Categories:
●
corticosteroids
●
immunosuppressants
●
biologic agents
●
antineoplastics
●
other
5.2.3.1
Prior Therapy
All prior drug therapies for nr-axSpA, since initial diagnosis, must be recorded on the 
source documents and on the appropriate eCRF along with the dates of first and last dose, 
maximum dosage taken, route of administration and reason for discontinuation, if known.
For each subject that is screened for the study, any other medication (including, but not 
limited to, over-the-counter medicines such as aspirin, antacids, vitamins, mineral 
supplements, and herbal preparations) taken at the time of Screening through the end of 

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
35
the study must be recorded on the appropriate eCRF along with the date(s) of 
administration, reason for use, dosage, route and frequency.
5.2.3.2
Concomitant Therapy
Each vaccine and all medications except study drug, administered to a subject during the 
study should be recorded in the eCRF as a concomitant medication.
The subject may not initiate any therapies for nr-axSpA treatment during the study other 
than non-drug therapy, e.g., physiotherapy and hydrotherapy, or as outlined below.  All 
non-drug therapies administered to a subject during the study should be recorded in the 
eCRF as a concomitant medication.
Subjects may continue on stable doses of MTX, SSZ, hydroxychloroquine, AZA, 6-MP, 
prednisone and/or NSAIDs provided the stability requirements noted in Section 5.2.2 are 
met.  All current DMARDs, corticosteroids, NSAIDs and analgesics specifically 
administered for nr-axSpA will be captured on the Concomitant Medication eCRF.  Doses 
of these concomitant medications must remain stable throughout study participation 
(except as medically required due to an AE).  Dose adjustments or induction of treatment 
with these agents based on the investigator's medical judgment is only permitted after 
12 weeks of rescue therapy with OL adalimumab in subjects who meet flare criteria.  All 
dose adjustments must be recorded in the eCRF.  In addition, doses must be within the 
acceptable limits below:
●
MTX (≤ 25 mg per week)
●
SSZ (≤ 3 g per day)
●
Hydroxychloroquine (≤ 400 mg per day)
●
AZA (≤ 150 mg per day) or 6-MP (≤ 75 mg per day)
Subjects on stable doses of analgesic(s) may be allowed to continue during the study.  
However, opioid analgesics (except for tramadol) are prohibited throughout the study.  

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
36
For patients who take analgesics on an as needed basis, analgesics must be discontinued 
for at least 24 hours prior to a study visit.
One intra-articular corticosteroid injection for a peripheral joint will be allowed from 
Baseline to Week 28 and one after 12 weeks of rescue therapy.  Once a joint is injected it 
will be considered not evaluable/assessable ("NA") during the 28 days following 
injection.  No spinal, para-spinal or SI joint injections are allowed during the study.
5.2.3.3
Prohibited Therapy
The following are prohibited medications during the study:
●
All biologic therapy with a potential therapeutic impact on SpA including but 
not limited to the following (Note:  Consideration for inclusion of subjects 
who have used biologic therapy for a non-SpA indication will be considered 
on a case by case basis if discussed with the AbbVie Medical Monitor):
○
Etanercept (Enbrel®);
○
Infliximab (Remicade®);
○
Abatacept (Orencia®);
○
Anakinra (Kineret®);
○
Rituximab (Rituxan®);
○
Natalizumab (Tysabri®);
○
Tocilizumab (Actemra®);
○
Efalizumab (Raptiva®);
○
Golimumab (Simponi®);
○
Certolizumab (Cimzia®);
○
Ustekinumab (Stelara®);
○
Belimumab (Benlysta®)
●
Live vaccines (during the study and for 70 days after the last dose of study 
drug).
●
Rifampin/Pyrazinamide combination.
●
All oral DMARDs other than MTX, SSZ, AZA, 6-MP or hydroxychloroquine.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
37
●
Opioid analgesics (other than tramadol) or marijuana, except as medically 
indicated for an AE.
●
Any investigational drug of chemical or biologic nature.
Subjects may be discontinued from the study if any of the above prohibited medications 
are used during the study.
5.2.3.4
Rescue Therapy
Subjects who flare in Period 2 (40-week, double-blind period) will be allowed rescue 
therapy.  Flare is defined as 2 consecutive study visits with ASDAS ≥ 2.100.  Rescue 
therapy will consist of OL adalimumab 40 mg eow for at least 12 weeks and will continue 
through the duration of the subject's participation of the study.  For subjects who meet 
flare criteria during Period 2 and start rescue therapy with OL adalimumab, further 
calculation of ASDAS is not required.  For subjects who meet the flare criteria at 
Weeks 60, 64 or 68, rescue therapy with OL adalimumab will be provided for 12 weeks 
and final study visit will be at Weeks 72, 76 or 80, respectively.
After 12 weeks of rescue therapy with OL adalimumab eow, initiation of or change in a 
subject's concomitant medications for SpA including doses of DMARDs, corticosteroids, 
NSAIDs, and analgesics are permitted based on the investigator's medical judgment.
5.3
Efficacy, Pharmacokinetic, Pharmacogenetic and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow
Chart
Subjects will be allowed a visit window of ±7 days for all study visits (with the exception 
of the Baseline Visit as there is a maximum of 42 days screening window).
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 will be performed as outlined in the schematic presented in Table 1.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
38
Table 1.
Study Activities
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Informed 
Consent
X
Inclusion/ 
Exclusion 
Criteria
X
Xb
Medical/ 
Surgical History
X
Xb
Vital Signs/ 
Weight/ Heightc
X
X
X
X
X
X
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
X
X
X
X
X
X
Physical Exam
X
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
12-Lead ECGd
Xe
Chest X-Rayd
Xe
Xf
AP Pelvis 
X-Ray
Xe

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
39
Table 1. 
Study Activities (Continued)
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
TB Screening 
(PPD Skin Test 
OR IGRA)
Xe
Xf
Pregnancy Test
Xg
Xh
Xh,v
Xh,v
Xh,v
Xh
Xh,v Xh,v
Xh
Xh
Chemistry and 
Hematology 
X
Xi
X
X
X
X
X
X
X
X
X
X
X
Xv
Xv
X
X
Urinalysisj
X
Xi
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
HLA-B27
Xe
Antinuclear 
Antibody 
(ANA)/
reflex 
Anti-dsDNA 
antibody
Xe
HBV Screening
X
hs-CRP
X
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV
Xk

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
40
Table 1. 
Study Activities (Continued)
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Biomarkersl
X
Xv
Xv
X
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
Serum ADA 
Concentrationl
X
X
Xv
Xv
X
X
Xl
Xl
Xl
X
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
Anti-ADA 
antibody 
(AAA)l
X
X
Xv
Xv
X
X
Xl
Xl
Xl
X
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
PG Sample
Xm
MRI of the 
Spine and SI 
Joints
Xe
Xn
Xn
Xn
TJC/SJC
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASMIlin
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
MASES
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
41
Table 1. 
Study Activities (Continued)
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Plantar Fascia 
Enthesitis
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
Dactylitis
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician's 
Global 
Assessment of 
Disease 
Activity NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's 
Assessment of 
Nocturnal Back 
Pain NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's 
Assessment of 
Total Back Pain 
NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's Global 
Assessment of 
Disease 
Activity NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
42
Table 1. 
Study Activities (Continued)
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Patient's Global 
Assessment of 
Pain NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HAQ-S
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
SF-36V2 Health 
Survey
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
WPAI- axial 
SpA
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
EQ-5D 
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
Prior and 
Concomitant 
Therapy 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor AE
Xo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
ASDAS 
Calculation
X
X
Xq
Xq
Xq
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Enrollment
X
Randomization
Xq

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
43
Table 1. 
Study Activities (Continued)
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Dispense Study 
Drug 
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
X
X
X
Xs
Xs
Xs
Admin of Study 
Drugt
X
X
X
X
X
X
Optional Blood 
Sample 
Collection 
Sub-Study
X
Xy
Xy
X
Xz
Xz
Xz
Xz
Xz
Xz
Xz
Xz
Xz
Ada = Adalimumab; BL = Baseline; D = Day(s); Disc Visit = Discontinuation Visit; SCR = Screening; RT = Rescue Therapy; PF = Post Flare; F/U = Follow-up
a.
Baseline Visit is defined as Day 1, the day of first study drug administration.
b.
Medical History and Inclusion/Exclusion Criteria must be confirmed by the Investigator prior to enrollment to verify subject eligibility.
c.
Height will be measured at Screening Visit only.
d.
Subject can have a repeat CXR and/or ECG at any time during the study only if in the opinion of the investigator, clinically significant AEs develop that warrant a repeat 
exam.
e.
These procedures will not be required if the subject had a previous normal CXR, normal ECG or negative PPD within 90 days of screening provided all protocol required 
documentation is available at the site and nothing has changed in the subject's health status since the time of the test that warrants a repeat test.  MRI of the SI joint and spine 
or AP Pelvis x-ray will also not be required if the subject had a previous test within 30 days and 1 year (365 days) of Screening, respectively.  Any documentation of past 
positive PPD results may be acceptable; however, negative PPD 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 initiate and 
complete at least the first 2 weeks (or per local guidelines, whichever is longer) of the prescribed TB prophylaxis, or have documented completion of a full course of TB 
prophylaxis prior to Baseline (Section 5.3.1.1).  There is no need to redraw the HLA-B27 or ANA once the results are available from the central laboratory chosen for this 
study.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
44
Table 1. 
Study Activities (Continued)
f.
An annual PPD/IGRA test will be required for those subjects with a negative TB test at Screening.  If the annual PPD/IGRA test is positive, a CXR must be performed, the 
investigator must contact the study designated physician to review the individual data and agree on a decision whether or notadditional evaluation is needed.
g.
All females of childbearing potential will have a serum pregnancy test at Screening that is performed at the central laboratory.
h.
All females of childbearing potential will have a urine pregnancy test performed at Baseline prior to study enrollment and atstudy discontinuation/completion.  The urine 
pregnancy kit supplies will be provided to the sites via the central laboratory (where allowed by local guidelines).  Monthly pregnancy tests will beperformed throughout the 
study if required by country regulatory authorities.  Any subject with a positive urine pregnancy test must have a negative serum test performed at the central laboratory prior 
to enrollment or continuation in the study.
i.
Laboratory assessments (chemistry, hematology, hs-CRP and urinalysis) will be repeated at Baseline if the time between Screening and Baseline is greater than 14 days, or if 
the subject's health status has changed to warrant a repeat test.
j.
Dipstick 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 protein, 
ketones or blood greater than negative or glucose greater than normal.
k.
If required by country regulatory authorities to confirm eligibility, subjects will be tested for antibodies to HIV, and document that the test has been performed.  The testing is 
to be done at a local laboratory.  A subject will not be eligible for study participation if test results indicate a positiveHIV infection.  AbbVie will not receive results from the 
testing and not be made aware of any positive result.
l.
Flare is defined as 2 consecutive study visits with ASDAS ≥ 2.100.  Subjects that flare during the double-blind period (Period 2) will need the following assessments during 
the visit that flare was determined as well as 12 weeks following the determination of the flare:  biomarkers (refer to Section 5.3.1.1 for further information), serum 
adalimumab and AAA (refer to Section 5.3.2 for further information).  These assessments are in addition to the regularly scheduled assessments outlined in the table above.
m.
The pharmacogenic (PG) sample is optional.  A separate PG consent form must be signed prior to sample collection.  The PG sample is ideally collected at Baseline, but may 
be collected at any time throughout the study.
n.
Site staff should schedule the Week 28 MRI during the Baseline visit, if possible.  For subjects that are discontinued due to not fulfilling the ASDAS remission criteria at 
Weeks 20 or 24, the site should attempt to reschedule the MRI within 2 weeks (14 days) of the discontinuation visit.  If the MRI cannot be rescheduled, the Week 28 MRI will 
be considered missed.
o.
SAEs will be collected starting from time of signing informed consent; non-serious AEs will be collected starting from the 1st study drug dose.  Any AE that occurs between 
Screening and Baseline should be captured as medical history. 
p.
Site personnel will contact all subjects by telephone approximately 70 days after the last dose of study drug to determine the occurrence of AEs or SAEs.  Subjects that initiate 
adalimumab therapy not supplied in the context of the clinical trial after the end of study participation need not be contacted by phone as new AEs or SAEs should be reported 
through the mechanism used for all post marketing adverse experiences.

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Table 1. 
Study Activities (Continued)
q.
Week 20, calculation of the Week 16 ASDAS will be done using the Week 16 visit parameters including the Week 16 hs-CRP.  If the subject does not meet the criteria for 
remission (ASDAS < 1.300), the subject will be discontinued.  At Week 24, calculation of the Week 20 ASDAS will be done using the Week 20 visit parameters including the 
Week 20 hs-CRP.  If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will be discontinued.  At Week 28,calculation of the Week 24 ASDAS 
will be done using the Week 24 parameters including the Week 24 hs-CRP; the Week 28 ASDAS will be done using Week 28 parameters and the Week 24 hs-CRP (as the 
Week 28 results will not be available).  If any of these time points do not meet the criteria for remission (ASDAS < 1.300), the subject will be discontinued.  For hs-CRP 
elevations secondary to AEs or using a previous hs-CRP, please refer to Section 5.1 or ASDAS Calculation in Section 5.3.1.1.
r.
Beginning at Week 36, ASDAS will be calculated via IVRS/IWRS for the current and previous study visit to determine fulfillment of flare criteria.  Assessments from the 
current and previous study visit will be used for the calculation except for the hs-CRP which will be based on the results from the previous study visit's blood draw for both 
calculations.  For subjects who meet flare criteria during Period 2 and start rescue therapy with OL adalimumab, further calculation of ASDAS is not required.  For any 
subject missing 2 consecutive visits within the double-blind period (Period 2) the site must contact the AbbVie Medical Monitor for discussion regarding the subject's 
continued participation in the study.
s.
Subjects would only receive study drug at Weeks 68, 72 or 76, if they flared at Week 56, 60 or 64 respectively.
t.
Study drug will be administered in the Investigator's office at Baseline, Week 2, 4, 8, 12, and Week 24 to ensure proper technique.
u.
For subjects who meet the flare criteria at Weeks 60, 64 or 68, rescue therapy with OL adalimumab will be provided for 12 weeks and final study visit will be at Weeks 72, 
76 or 80, respectively.
v.
These procedures should only be performed if the visit is the subject's last visit due to not meeting ASDAS remission criteria (Weeks 20, 24 or 28) or due to a flare and has 
received 12 weeks of rescue therapy (Weeks 72 or 76).
w.
If subject meets flare criteria, these assessments are required 12 weeks post flare in addition to assessments for the scheduled visit when the flare was identified.  If any of 
these procedures are already collected at the regularly scheduled visit, there is no need to obtain these procedures twice.
x.
Subjects who prematurely discontinue the study should complete the procedures outlined for the Discontinuation Visit as soon as possible after the last dose of study drug and 
preferably prior to the administration of new therapies.  No Discontinuation Visit procedures will be required for those subjects that complete the Week 68 visit (or Weeks 72, 
76 or 80 for those subjects who flare at Weeks 60, 64 or 68, respectively).
y.
Optional Blood Sample Collection Sub-Study only:  use a separate sub-study central lab kit.  Samples will be collected at Week 28 or at Weeks 20 or 24 only if the visit is the 
subject's last visit.  (Optional Blood Sample Collection Sub-Study samples are in addition to the regularly scheduled assessments outlined in the table above.) 
z.
Optional Blood Sample Collection Sub-Study only:  use a separate sub-study central lab kit.  In subjects who meet flare criteria during Weeks 36 – 68, samples will be 
collected only once at time of flare.  Flare is defined as 2 consecutive study visits with ASDAS ≥ 2.100.  (Optional Blood Sample Collection Sub-Study samples are in 
addition to the regularly scheduled assessments outlined in the Table above.)

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5.3.1.1
Study Procedures
The study procedures outlined in Table 1 are discussed in detail in this section, with the 
exception of the collection of AE information (discussed in Section 6.0).  All study data 
will be recorded on the appropriate eCRFs.
Informed Consent
An Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approved, 
study-specific informed consent will be reviewed, signed and dated by the subject before 
any study procedures are undertaken, or before any medications are withheld from the 
subject in order to participate in this study.  An additional consent is required for those 
subjects who agree to participate in the optional pharmacogenetic portion of the study.  
Details about how informed consent will be obtained and documented are provided in 
Section 9.3.
Inclusion/Exclusion Criteria
Subjects will be screened to ensure they meet all inclusion criteria and none of the 
exclusion criteria at both Screening and Baseline Visits.
Medical and Surgical History
A complete medical and surgical history, including history of tobacco and alcohol use, 
uveitis, inflammatory bowel disease (CD, UC only), psoriasis, spinal surgery, joint 
replacement, joint surgery or arthroscopy, will be obtained from each subject during the 
Screening Visit.  An updated medical history will be obtained at the Baseline visit prior to 
study drug administration and updated as necessary throughout the study on the eCRF.
A detailed medical history with respect to TB exposure needs to be documented.  This 
information needs to include BCG vaccination, cohabitation with individuals who have 
had TB, and/or who reside or work in TB endemic locations.

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An updated medical history will be obtained at the Baseline visit prior to study drug 
administration and updated as necessary throughout the study on the eCRF.
Vital Signs, Weight and Height
Vital sign determinations of systolic and diastolic blood pressure, pulse (counted for at 
least 30 seconds after 5 minutes in sitting position), respiratory rate, body weight, and 
body temperature will be obtained at the designated study visits in Table 1.  Vital signs 
should be measured before blood draws are performed and prior to receiving study 
medication.  Height without shoes will be measured at the Screening Visit only.
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), since the last visit.  
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 patient, self-reported.
Physical Examination
A full physical exam will be performed by medically qualified personnel at the designated 
study visits in Table 1.  Physical examination findings that are related or part of each 
subject's medical history should be captured on the appropriate eCRF page.  The physical 
exam at the Baseline visit will serve as the baseline exam for the entire study.
A symptom-directed physical examination can be performed at any other visits if, in the 
opinion of the Investigator, it is warranted by the subject's AE status or on review of 

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symptoms.  Any clinically significant physical examination findings after dosing should 
be recorded as adverse events.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at the Screening Visit.  A qualified physician 
will interpret, determine the clinical significance of any abnormal finding, sign, and date 
each ECG.  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 Clinical Research Associate (CRA) and kept with 
subject's source documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided all protocol required documentation is available 
and nothing has changed in the subject's health status since the time of the test that 
warrants a repeat test.  If there are other findings that are clinically significant, the 
Principal Investigator must contact the Medical Monitor 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.
Chest X-Ray (CXR)
All subjects will undergo a standard CXR (PA and lateral views) at the Screening Visit 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 chest x-ray within 90 days of Screening, 
provided all protocol required documentation is available at the site (as outlined below in 
Section 5.3.1.1) and nothing has changed in the subject's health status since the time of the 
test that warrants a repeat test.
Subjects can have a repeat CXR at any time during the study as warranted based on the 
opinion of the Investigator.

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A radiologist 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 chest x-ray, the Principal Investigator or their physician delegate must 
indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.
Anteroposterior Pelvis X-ray
Anteroposterior (AP) pelvis x-ray to evaluate the SI joints will be obtained during the 
Screening Period.  The AP pelvis x-ray will not be required if the subject had a previous 
AP pelvis x-ray (film with required report results must be available to the site) within 
1 year (365 days) of Screening.  The Screening Visit AP pelvis x-ray should be performed 
prior to the MRI, to rule out radiographic evidence for AS (based on the modified New 
York criteria – Appendix H) which would exclude enrollment of this subject (Note:  if the 
Central Imaging vendor confirms a positive 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).
The AP Pelvis x-ray will be assessed locally for sacroiliitis grade to determine the 
presence (positive) or absence (negative) of sacroiliitis (presence = sacroiliitis grade ≥ 2 
bilaterally or sacroiliitis grade 3-4 unilaterally) by a qualified rheumatologist or 
radiologist prior to sending the AP Pelvis x-ray to the central imaging vendor for 
assessment.
Grade
Definition
Grade 0
Normal
Grade 1
Suspicious changes
Grade 2
Minimum abnormality (small localized areas with erosion or sclerosis, 
without alteration in the joint width)
Grade 3
Unequivocal abnormality (moderate or advanced sacroiliitis with erosions, 
evidence of sclerosis, widening, narrowing, or partial ankylosis)
Grade 4
Severe abnormality (total ankylosis)

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Only x-rays negative for sacroiliitis should be sent to BioClinica (negative = bilateral 
grade ≤ 1 or if grade 2, only present unilaterally).  If the central reader's assessment does 
not match the local reader's assessment (AS versus non-AS), a second central reader 
(adjudicator), will assess the pelvis x-ray.  If adjudication is necessary, the second central 
reader's (adjudicator's) interpretation will be the final assessment sent to the site.  A 
subject cannot be enrolled until the AP pelvis x-ray has been centrally assessed for the 
presence/absence of sacroiliitis and the report is available to the site.  The imaging vendor 
will complete an imaging worksheet and return an eligibility notification report to the site 
within 48 hours of imaging vendor's receipt of the films (or within 96 hours if 
adjudication is necessary), not including BioClinica holidays or weekends.  The 
investigator will be required to review, sign and date the eligibility notification report 
prior to the subject being enrolled.
Note:  The AP Pelvis x-ray will only be assessed by the imaging vendor for sacroiliitis, 
and will not be assessed for any other clinically significant findings that may impact a 
subject's health.
Images will be sent to the central imaging vendor designated by the Sponsor.  Procedures 
for performing and shipping the AP pelvis x-rays will be provided in a separate manual.  
The central imaging vendor chosen for this study is:
BioClinica, Inc.
826 Newtown Yardley Road
Newtown, PA  18940
TB Screening
A PPD skin test (alternatively, also known as tuberculin skin test) must be placed or an 
IGRA test must be performed locally during the Screening Period for all subjects 
including those with a prior history of Bacille Calmette-Guérin (BCG) administration.

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If a subject had a negative PPD or IGRA test within 90 days prior to Screening, and all 
protocol required documentation is available, this test does not need to be repeated, 
provided nothing has changed in the subject's medical history to warrant a repeat test.
For the PPD test:
The subject will be required to have the PPD test read by a licensed healthcare 
professional 48 to 72 hours (or according to manufacturer's guide) after placement 
when the induration is maximal.  An induration (not erythema) of 5 mm or greater 
will be considered as PPD positive, irrespective of BCG status or local guidelines.  
The induration must be recorded in mm not as positive or negative.  The absence of 
induration should be recorded as "0 mm," not "negative."  (If required by specific 
counties a two-step test may be performed per local guidelines.  The result of the 
second test should be recorded.  An induration of 5 mm or greater will be considered 
as PPD positive.)
Subjects who have had an ulcerating reaction to a PPD skin test in the past should 
not be re-exposed and should not be tested at Screening but will be considered PPD 
positive.
If there are sites where the accepted testing materials are not available an alternative 
may be substituted, but the method must be submitted and approved by AbbVie prior
to use with study subjects.
A radiologist 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 chest x-ray, the Principal Investigator or their physician delegate must 
indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.  If the CXR demonstrates changes 
suggestive of previous TB (e.g., calcified nodule, fibrotic scar, apical or basilar pleural 
thickening) or other findings that are clinically significant, the Principal Investigator must 
contact the AbbVie Medical Monitor before enrolling the subject.

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If the PPD or the IGRA test is positive or the subject has a CXR indicative of latent TB, 
the subject will be required to initiate and complete at least the first 2 weeks (or per local 
guidelines, whichever is longer) of the prescribed course of Center for Disease Control 
(CDC) recommended prophylaxis or prophylaxis per local guidelines prior to starting 
study therapy.
Subjects with a prior history of latent TB that have a documented completion of the CDC 
recommended or local guideline recommended prophylaxis may be permitted to enroll.  If 
the subject has a prior history of latent TB but has not completed or received prophylaxis, 
prophylaxis must be initiated and the subject must have completed at least the 
first 2 weeks of the prescribed TB prophylaxis (or per local guidelines, whichever is 
longer) before enrolling into the study.
If the subject has a prior history of active TB they must have documentation of 
completion of CDC recommended or local guideline recommended treatment and 
documentation of resolution of the infection.
In the event both a PPD test and an IGRA test are performed, the result of the IGRA test 
will supersede the result of the PPD test.  If the IGRA test is indeterminate, the site should 
repeat the test with another blood sample or perform a PPD test.  If the second IGRA test 
is also indeterminate, the subject is considered to be positive and should initiate TB 
prophylaxis.
Newly initiated prophylactic treatment should be captured on the concomitant 
medications page in the eCRF and in the source documents.  Prior therapy should be 
captured in medical history.
For sites participating in 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 reside or work in TB 

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endemic locations.  The information obtained by the pulmonologist must be 
documented in the patient's source note, dated and signed by the 
pulmonologist.
●
A pulmonologist must review the results of the PPD skin test or the IGRA test 
and the chest x-ray and has to give his/her opinion about the eligibility of each 
patient to be enrolled to the study.  This opinion must be documented in 
writing in the patient's source documents.
●
All patients with a positive PPD or IGRA test need to be approved for entry 
into the trial by both the Czech pulmonologist and the AbbVie Medical 
Monitor and all such patients need to receive prophylaxis for latent TB.  Under 
no circumstances can a patient with a positive PPD or IGRA test result and no 
prior history of treatment for active or latent TB be allowed into this trial.
For subjects with a negative TB test at Screening, either an annual PPD or IGRA test will 
be required for any subject participating in the trial at Week 52 (Table 1).  If the annual 
TB screen is positive (PPD is positive or the IGRA test is positive), a CXR will be 
required for evaluation of active TB.  For any subject with a positive annual TB screen the 
site should contact the AbbVie Medical Monitor for further discussion.  Subjects found to 
have latent TB, will be required to start a course of CDC recommended prophylaxis or 
prophylaxis per local guidelines as soon as possible.  Subjects found to have active TB 
must discontinue study drug and receive CDC recommended or local guideline 
recommended treatment.  Any positive TB screen after the patient has started the study, 
should be reported as an AE.
An annual TB screen with PPD or IGRA testing will not be required for subjects who 
have been treated for latent or active TB or have had a positive TB test (PPD or IGRA) at 
any time (prior to the study, Screening, annual evaluation, or testing performed at any 
time point during the study).  For such subjects, annual evaluation by a physician for 
clinical signs/symptoms of active TB (including a directed TB history and physical exam 
including lungs, lymph nodes and skin) or newly identified TB risk factors will be 
required for any subject participating in the trial at Week 52.  For any subject with clinical 
signs/symptoms of active TB or newly identified TB risk factors a CXR may be required 

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for evaluation of active TB and the site should contact the AbbVie Medical Monitor for 
further discussion.  Subjects with confirmed active TB should be discontinued from the 
study and receive standard of care treatment for TB.
Pregnancy Tests
A serum pregnancy test will be performed at the Screening Visit on all female subjects of 
childbearing potential (sent and analyzed at the central lab).  At the Baseline Visit, 
subjects of childbearing potential will have a urine pregnancy test performed locally by 
designated study personnel.  If any urine pregnancy test is positive, a serum pregnancy 
test will be performed by the central laboratory.  A lactating or pregnant female will not 
be eligible for participation or continuation in this study.
Monthly pregnancy tests will be performed throughout the study if required by country 
regulatory authorities.
All women of childbearing potential will have a repeat urine pregnancy test at the final 
Study Visit performed locally by designated study personnel.
Laboratory Analyses
Blood and urine samples will be obtained for clinical laboratory tests.  Samples will be 
obtained at the designated study visits in Table 1.  Samples will be obtained for the 
laboratory tests listed in Table 2.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  The laboratory results will be provided by the central laboratory to the 
investigative site where they will be reviewed, signed and dated by the investigator and 
filed as source data.  For any abnormal value outside of the reference range, the 
investigator will indicate on the report if the result is clinically significant (CS) or not 
clinically significant (NCS).  All abnormal laboratory test results that are considered 
clinically significant by the Investigator will be followed to a satisfactory resolution.

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Blood draws should be performed after questionnaires and vital sign determinations have 
been completed but prior to any study drug administration.
Urine samples will be obtained for macroscopic urinalysis (dipstick done at the central 
lab).  Macroscopic urinalyses will include specific gravity, pH, protein, glucose, ketones, 
blood and nitrites.  A microscopic analysis will be performed in the event the dipstick 
results show protein, ketones or blood greater than negative or glucose greater than 
normal.
Clinical laboratory tests will need to be repeated at the Baseline Visit only if the time 
between the Screening Visit and the Baseline visit is greater than 14 days.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing and shipping of these samples.  The baseline laboratory test results 
for clinical assessment for a particular test will be defined as the last measurement prior to 
the initial dose of study drug.  The certified laboratory chosen for this study is:
Covance CLS
8211 SciCor Drive
Indianapolis, IN  46214-2985 USA

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Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
Specific gravity
pH
Protein
Glucose
Ketones
Blood
Nitrite
Others
Pregnancy test
HbsAg
HBsAb
HBcAb
HBV DNA PCR reflex only
hs-CRP
HLA-B27
ANA/reflex Anti-dsDNA
antibody
HLA-B27
Testing for HLA-B27 will be performed on specimens collected during the Screening 
visit.  The HLA-B27 can be used to fulfill the ASAS classification criteria (Appendix C).  
For subjects that may need to be rescreened, once results are available from the central 
laboratory chosen for this study repeat HLA-B27 testing is not required.
ANA
Testing for ANA will be performed on specimens collected during the Screening visit.  
For subjects that may need to be rescreened, once results are available from the central 
laboratory chosen for this study repeat ANA testing is not required.
Hepatitis B Testing
All subjects will be tested for the presence of the Hepatitis B Virus (HBV) at Screening.  
A positive result for the Hepatitis B surface antigen (HBs Ag) will be exclusionary.  
Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and 

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core antibodies (HBc Ab).  If test results are positive for HBc Ab or HBs Ab, HBV DNA 
PCR will be performed and any result that meets or exceeds detection sensitivity will be 
exclusionary.
High Sensitivity C-reactive Protein (hs-CRP) Test
Testing for hs-CRP will be performed on specimens collected at the designated study 
visits listed in Table 1.  The hs-CRP will be used as a parameter for the Ankylosing 
Spondylitis Disease Activity Score (ASDAS) calculation.  See the ASDAS Calculation 
section below for more details on which hs-CRP to use during the ASDAS calculations.
Following Week 36, when entering the current visit as well as the prior visit parameters to 
calculate ASDAS for flare, the site should use the prior hs-CRP results for both 
calculations.  For example, when entering the parameters for the Week 32 and Week 36 
ASDAS calculation during the Week 36 Visit, the site should use the Week 32 Visit 
hs-CRP.
HIV Testing
If required by country regulatory authorities to confirm eligibility, subjects will be tested 
for antibodies to the HIV at Screening, and document that the test has been performed.  
The testing is to be done at a local laboratory.  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.
Biomarkers
Samples will be obtained for biomarkers at the designated study visits in Table 1 and 
described in more detail under Section 5.3.2.1.  The final set of biomarkers to be analyzed 
may include the following:
●
Dickkopf-1 (DKK-1)
●
Sclerostin
●
Bone Morphogenetic Protein – 2 (BMP-2)

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●
Bone Morphogenetic Protein – 7 (BMP-7)
The final selection of biomarkers for analysis will be based on both insights gained in the 
sub-study and available scientific knowledge at study completion.
At the time of blood draw for biomarkers, subjects in certain countries (where allowed by 
local guidelines) will have the option for serum to be stored for possible future research.  
Samples will be stored frozen for future exploratory analysis of non-genetic biomarkers 
related to the subject's disease and/or response to study drug, in terms of tolerability and 
safety.  These samples may also be used for the development of diagnostic tests related to 
adalimumab (or drugs of this class).  AbbVie will store the samples in a secure storage 
space with adequate measures to protect confidentiality.  The samples will be retained for 
no longer than 5 years after completion of the study defined as the date of the last 
subject's last study visit or the actual date of follow-up contact, whichever is later (where 
allowed by local guidelines).
Biomarker analyses are considered exploratory.  Results for the primary biomarker 
analyses from the overall study and sub-study will be reported in a separate biomarker 
study report. The primary biomarker analyses do not preclude future analyses which are 
not within the scope of this study protocol and will therefore not be included in the 
separate biomarker study report.
Serum Adalimumab Concentrations
Samples will be obtained for serum adalimumab concentrations at the designated study 
visits in Table 1 and described in more detail under Section 5.3.2.1.
Anti-Adalimumab Antibodies
Samples will be obtained for anti-adalimumab antibodies at the designated study visits in 
Table 1 and described in more detail under Section 5.3.2.1.

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Pharmacogenetic Sample
Samples will be obtained for pharmacogenetic analysis at the designated study visits in 
Table 1 and described in more detail under Section 5.3.2.1.
MRI of the Spine and Sacroiliac Joints
All subjects will have an MRI evaluation of the SI joints as well as the cervical, thoracic 
and lumbar regions of the spine during the Screening Period and Week 28 Visit.  The 
Screening MRI will not be required if the subject had a previous MRI fulfilling the study 
requirements (actual MRI films must be available to the site) within 30 days of the 
Screening Visit.
(Note:  if the Central Imaging vendor confirms a positive 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).
Subjects cannot be enrolled until the Screening MRI image has been centrally read for the 
presence/absence of active inflammation in the SI joints and spine and the report is 
available to the site.  The imaging vendor will complete an imaging worksheet and return 
an eligibility notification report to the site within 48 hours of imaging vendor's receipt of 
the films.  The investigator will be required to review, sign and date the eligibility 
notification report prior to the subject being enrolled.
Note:  The MRI will only be assessed by the imaging vendor for bone marrow edema, and 
will not be assessed for any other clinically significant findings that may impact a 
subject's health.
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 central 
imaging vendor chosen for this study is:

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BioClinica, Inc.
826 Newtown Yardley Road
Newtown, PA  18940
Note:  It is expected all subjects will have a Week 28 MRI, even those subjects that are 
discontinued at Weeks 20, 24 or 28 due to lack of meeting the ASDAS remission criteria.  
Site staff should schedule the Week 28 MRI during the Baseline visit, if possible.  For 
subjects that are discontinued for any reason at Weeks 20, 24 or 28, the site should 
attempt to reschedule the MRI within 2 weeks (14 days) of the discontinuation visit.  If the 
MRI cannot be rescheduled within 14 days of the discontinuation visit, the Week 28 MRI 
will be considered missed.
Tender Joint Count (TJC)
An assessment of 68 joints will be done by physical examination at the designated study 
visits in Table 1, by pressure manipulation on physical exam.  Joint pain/tenderness will 
be classified as present ("1"), absent ("0"), replaced ("9"), or no assessment ("NA") 
(Appendix I).
A joint undergoing surgery or injected intra-articularly with corticosteroids will not be 
evaluable ("NA") for 28 days.
Site should make every attempt to have the same qualified Investigator or designee 
conduct these assessments throughout the study for any given subject.
Swollen Joint Count (SJC)
An assessment of 66 joints will be done by physical examination at the designated study 
visits in Table 1.  The joints to be examined for swelling are the same as those examined 
for tenderness, except the hip joints are excluded.  Enthesitis is not part of the swollen 
joint assessment.  Joint swelling will be classified as present ("1"), absent ("0"), replaced 
("9"), or no assessment ("NA") (Appendix I).

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A joint undergoing surgery or injected intra-articularly with corticosteroids will not be 
evaluable ("NA") for 28 days.
Site should make every attempt to have the same qualified Investigator or designee 
conduct these assessments throughout the study for any given subject.
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI will be completed at the designated study visits in Table 1.  The subject will 
assess his/her disease activity using the BASDAI which consists of NRS used to answer 
6 questions pertaining to symptoms experienced by the subject during the past week 
(Appendix F).
Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin)
The BASMIlin will be conducted at the designated study visits in Table 1 to evaluate 
spinal mobility in a subject (Appendix J).
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 designated study visits in Table 1 to 
assess the presence or absence of enthesitis at 13 different sites, noting the subjects' 
responses (Appendix K).
Site should make every attempt to have the same qualified Investigator or designee 
conduct these assessments throughout the study for any given subject.
Plantar Fascia Enthesitis
Evaluation for plantar fascia enthesitis will be conducted at the designated study visits in 
Table 1 to assess the presence or absence of plantar fascia enthesitis on the right and left 
feet.

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Site should make every attempt to have the same qualified Investigator or designee 
conduct these assessments throughout the study for any given subject.
Dactylitis
This evaluation will be conducted at the designated study visits in Table 1 to assess the 
presence or absence of dactylitis in all 20 of the subjects' digits.
Site should make every attempt to have the same qualified Investigator or designee 
conduct these assessments throughout the study for any given subject.
Bath Ankylosing Spondylitis Functional Index (BASFI)
The BASFI will be completed at the designated study visits in Table 1.  The subject will 
assess his/her ability of ten selected activities for the past week using a NRS 
(Appendix L).  This assessment should be completed prior to any other study related 
procedures being performed.
Numerical Rating Scales (NRS)
Numerical Rating Scales will be used to assess the physician and patient's global 
assessment of disease activity, as well as the patient's global assessment of pain, patient's 
assessment of nocturnal back pain, and patient's assessment of total back pain.  The left 
end of the NRS (0) signifies the absence of symptoms and the right end (10) signifies 
maximum activity in terms of the parameters assessed:
●
Physician's global assessment of disease activity (current status)
○
Physician's global assessment of patient's current disease activity 
(Appendix M).  Site should make every attempt to have the same qualified 
Investigator or designee (physician required) conduct these assessments 
throughout the study for any given subject.
●
Patient's assessment of nocturnal back pain (within the last week)
○
The patient's assessment of nocturnal back pain (Appendix N)
●
Patient's assessment of total back pain (within the last week)

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○
The patient's assessment of total back pain (Appendix G)
●
Patient's global assessment of disease activity (within last week)
○
The patient's overall assessment of disease activity within the last week 
(Appendix O)
●
Patient's global assessment of pain (within last week)
○
The patient's assessment of pain (Appendix P)
These assessments should be completed prior to any other study related procedures being 
performed in the order outlined on Table 1.
Health Outcomes Questionnaires
Subjects will complete the following questionnaires:  Health Assessment Questionnaire 
modified for the Spondyloarthropathies (HAQ-S) (Appendix Q), Short Form-36 Health 
Status Survey Version 2 (SF-36v2) (Appendix R), Work Productivity and Activity 
Impairment Questionnaire – Specific Health Problem Questionnaire (WPAI-axial SpA) 
(Appendix S), and the European Quality of Life – 5 Dimension Questionnaire (EQ-5D) 
(Appendix T).  The HAQ-S will assess the physical function and health related quality of 
life of each subject.  The SF-36v2 and EQ-5D will assess the subject's view of their 
health.  The WPAI-axial SpA will assess work related issues.  These assessments should 
be completed prior to any other study related procedures being performed in the order 
outlined on Table 1.
Prior and Concomitant Therapy Assessment
Any medication that the subject is receiving at the time of screening or receives during the 
study, must be recorded on the source documents as well as the appropriate eCRF.  
Previous prescription medications or physician-administered treatments used for 
nr-axSpA prior to study entry will be recorded.  See Section 5.2.3 for full details 
regarding documentation of prior and concomitant therapy.

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Ankylosing Spondylitis Disease Activity Score (ASDAS) Calculation
The ASDAS will be calculated for the visits outlined in Table 1.  During the Screening 
visit, the hs-CRP will be drawn and sent to the central lab.  Note:  the ASDAS calculation 
cannot be entered into IVRS/IWRS until the hs-CRP result is returned from the central 
lab.  If the subject does not meet the criteria of an ASDAS ≥ 2.100 at screening, the 
subject would be considered a screen failure and all other screening procedures should 
be cancelled.  During the Baseline Visit, the ASDAS parameters will be entered in 
IVRS/IWRS to determine if a subject met the ASDAS entry criteria.  The site will need to 
use the Screening hs-CRP for both the Screening and Baseline Visits and visit-specific 
information for the remaining parameters.
The ASDAS calculation in Period 1 (OL) will be done at Weeks 20, 24 and 28 (prior to 
randomization).  All ASDAS visit parameters listed in Appendix E should be used from 
each study visit (with the possible exception of hs-CRP as described below).
At Week 20, sites will enter the ASDAS parameters into IVRS/IWRS using the 
IVRS/IWRS worksheets provided separately.  At Week 20, calculation of the Week 16 
ASDAS will be done using the Week 16 visit parameters including the Week 16 hs-CRP.  
If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will 
be discontinued.
At Week 24, sites will enter the ASDAS parameters into IVRS/IWRS using the 
IVRS/IWRS worksheets provided separately.  At Week 24, calculation of the Week 20 
ASDAS will be done using the Week 20 visit parameters including the Week 20 hs-CRP.  
If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will 
be discontinued.
At Week 28, sites will enter the ASDAS parameters into IVRS/IWRS using the 
IVRS/IWRS worksheets provided separately.  At Week 28, calculation of the Week 24 
ASDAS will be done using the Weeks 24 parameters including the Week 24 hs-CRP; the 
Week 28 ASDAS will be done using Week 28 parameters and the Week 24 hs-CRP (as 

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the Week 28 results will not be available).  If any of these time points do not meet the 
criteria for remission (ASDAS < 1.300), the subject will be discontinued.
Subjects may be discontinued as early as Week 20 if they do not meet the ASDAS 
remission criteria using the Week 16 parameters.
Due to the importance of the Week 16, 20 and 24 visits, two or more missed visits during 
this time must be discussed with the AbbVie Medical Monitor prior to randomization.  If 
a subject misses a single visit at Week 16, 20, or 24 the site will need to use the ASDAS 
parameters from the visit immediately prior to the missed visit.  If a subject misses the 
Week 28 visit, the subject must be discontinued.
Subjects meeting the remission criteria at Weeks 16, 20, 24 and 28 will be randomized 
into Period 2.  Subjects not meeting the ASDAS Inactive Disease at Weeks 16, 20, 24 or 
28 will be discontinued.
Subjects who flare in Period 2 (40-week double-blind period) will be allowed rescue 
therapy.  Starting at Week 36 through Week 68, subjects will be assessed for flare, 
defined as 2 consecutive visits with ASDAS ≥ 2.100.  The hs-CRP from the prior visit 
will be used to calculate the ASDAS for both the prior visit and the current visit with the 
remainder of the ASDAS parameters visit-specific.  If a subject misses a visit, the site will 
need to use the ASDAS parameters from the visit immediately prior to the missed visit in 
order to determine the 2 consecutive ASDAS for assessment of flare.
If a subject has an elevated hs-CRP which the investigator believes to be secondary to an 
AE and not due to nr-axSpA, sites may repeat the hs-CRP test prior to the subject's next 
scheduled visit following a discussion with the AbbVie Medical Monitor.  The repeat 
hs-CRP results should be available to the site prior to the subject's next scheduled visit 
and will replace the visit-specific hs-CRP in the ASDAS calculation.  Instances where 
AE-related hs-CRP elevation spans more than one study visit will be addressed on a 
case-by-case basis.  Note:  the AE should be reported in EDC prior to discussion with the 
AbbVie Medical Monitor.

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Note:  site will need to enter the ASDAS parameters used for calculation outlined in 
Appendix E into IVRS/IWRS.  Source worksheets will be available for sites to use during 
the IVRS/IWRS entry.  For subjects who meet flare criteria during Period 2 and start 
rescue therapy with OL adalimumab, further calculation of ASDAS is not required.  For 
any subject missing 2 or more consecutive visits within the double-blind period (Period 2) 
the site must contact the AbbVie Medical Monitor for discussion regarding the subject's 
continued participation in the study.
Enrollment
Subjects who meet the inclusion criteria and do not meet any of the exclusion criteria will 
be enrolled into Period 1.  Subjects will not be enrolled in the study if laboratory or other 
screening results are clinically unacceptable.
As they are enrolled into the study, subjects will be assigned unique consecutive numbers 
starting with 10001, whereas, the first 3 digits represent the site number and the last 
2 digits represents a sequential number.  Site numbers will be assigned sequentially.
Randomization
During the Week 28 visit, subjects meeting ASDAS Inactive Disease (ASDAS < 1.300) at 
Weeks 16, 20, 24 and 28 will be randomized using IVRS/IWRS in a 1:1 ratio to receive 
either blinded adalimumab 40 mg eow or matching placebo.  Subjects not meeting the 
ASDAS Inactive Disease at Weeks 16, 20, 24 or 28 will be discontinued.
Dispense Study Drug
Study drug will be dispensed to subjects as outlined in Table 1 and described in more 
detail under Section 5.5.
Administration of Study Drug
Study drug will be administered in the Investigator's office at Baseline, Weeks 2, 4, 8, 12, 
and Week 24 to ensure proper technique and described in more detail under Section 5.5.

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70-Day Follow-Up Call
All subjects will be contacted approximately 70 days following their last dose of study 
drug to check for new, and update ongoing AEs or Serious AEs (SAEs) except those 
subjects that continue on adalimumab therapy after the end of study participation.  Any 
new AEs/SAEs reported during the 70-day follow-up period should be submitted to 
AbbVie.  The 70-day follow-up phone call will be recorded in source document only and 
confirmation of the contact will be faxed to AbbVie (Appendix U).  Subjects that continue 
on adalimumab therapy after study end are not required to complete the 70-day follow-up 
and any new AEs should be reported through the mechanism used for all post marketing 
adverse experiences.
Optional Blood Sample Collection Sub-Study
An Optional Blood Sample Collection Sub-Study for future research (separate from the 
blood sample collection listed above) will be offered to approximately 10 sites based on 
interest, ongoing enrollment and clinical trial conduct.  Samples will be obtained for the 
Optional Blood Sample Collection Sub-Study at up to three time points (baseline, 
remission/Week 28 [Weeks 20 or 24 if the subject's last visit], and at time of flare, if 
applicable).  Timing of blood samples to be obtained are outlined in the designated study 
visits in Table 1 and described in more detail within the "Optional Blood Sample 
Collection Sub-Study Guidelines," which will be sent separately to the approved 
sub-study sites.
5.3.2
Drug Concentration, Pharmacogenic, and Biomarker 
Measurements
Blood samples for the pharmacokinetic (PK) measurement of serum adalimumab levels 
and anti-adalimumab antibody (AAA) concentrations will be taken at the following time 
points:
●
Blood samples will be collected at Baseline, Weeks 12, 28, 36, 52, 68 or at the 
Discontinuation Visit.

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●
Subjects who flare during the double-blind period (Period 2) will have blood 
samples collected at the visit that flare was determined as well as 12 weeks 
following the time of determination of flare.  Subjects who meet flare criteria 
at Weeks 36, 40, 44, 48, 52, 56, 60, 64 or 68 will have blood samples collected 
at Weeks 48, 52, 56, 60, 64, 68, 72, 76 or 80, respectively.
Blood samples for biomarker analysis will be collected at Baseline, Weeks 28, 68, time of 
flare (if applicable), 12 weeks post flare (if applicable), and last study visit.
A blood sample for the optional PG analysis is ideally collected at Baseline, but may be 
collected at anytime throughout the study.
Sites approved for the Optional Blood Sample Collection Sub-Study should refer to the 
"Optional Blood Sample Collection Sub-Study Guidelines" for collection, 
handling/processing, storage and disposition of samples.
5.3.2.1
Collection of Samples for Analysis
Serum Adalimumab Concentration and AAA Analysis
Blood samples for serum adalimumab concentration and AAA will be collected by 
venipuncture into appropriately labeled 6 mL evacuated serum collection tubes without 
gel separator.  The central laboratory will provide supplies for sample collection,
processing, storage and shipment.  Please refer to the central laboratory manual for 
specific instructions on sample collection, processing, storage and shipment.
The time that each blood sample is collected will be recorded to the nearest minute and 
entered into the appropriate eCRF.
Serum adalimumab concentration and AAA samples will be collected prior to dosing at 
the study visits specified in Table 1.

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Biomarker Analysis
Blood samples for biomarker analysis will be collected by venipuncture into appropriately 
labeled 6 mL evacuated serum collection tubes without gel separator.  The central 
laboratory will provide supplies for sample collection, processing, storage and shipment.  
Please refer to the central laboratory manual for specific instructions on sample collection, 
processing, storage and shipment.
At the time of blood draw for biomarkers, subjects in certain countries (where allowed by 
local guidelines) will have the option for serum to be stored for possible future research.  
Samples will be stored frozen for future exploratory analysis of non-genetic biomarkers 
related to the subject's disease and/or response to study drug, in terms of tolerability and 
safety.  These samples may also be used for the development of diagnostic tests related to 
adalimumab (or drugs of this class).  AbbVie will store the samples in a secure storage 
space with adequate measures to protect confidentiality.  The samples will be retained for 
no longer than 5 years after completion of the study defined as the date of the last 
subject's last study visit or the actual date of follow-up contact, whichever is later (where 
allowed by local guidelines).
The time that each blood sample is collected will be recorded to the nearest minute and 
entered into the appropriate eCRF.
Biomarker sample collection will be prior to dosing at the study visits specified in 
Table 1.
Pharmacogenetic Analysis
One 4 mL whole blood sample for DNA isolation will be collected during the Baseline 
visit (the PG sample is ideally collected at Baseline, but may be collected at anytime 
throughout the study) from each subject who consents to provide samples for 
pharmacogenetic analysis.  The procedure for obtaining and documenting informed 
consent is discussed in Section 9.3.

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The time that each blood sample is collected will be recorded to the nearest minute and 
entered into the appropriate eCRF.
5.3.2.2
Handling/Processing of Samples
The Adalimumab Concentrations, AAA, Biomarkers and PG samples will be 
handled/processed as outlined below.  At the time of blood draw for biomarkers, subjects 
in certain countries (where allowed by local guidelines) will have the option for serum to 
be stored for possible future research.  Subjects will be able to decline storing samples for 
possible future research during the consenting process discussed further in Section 9.3.
Serum Adalimumab Concentration and AAA Analysis
The blood will be allowed to clot for 30 minutes at room temperature and then centrifuged 
for approximately 10 minutes at 1100 to 1600 × g.  The collected serum volume will be 
transferred using plastic pipettes and split equally into four screw-capped polypropylene 
tubes labeled with the study drug name, type of sample (serum [SRM]), the protocol 
number, the subject number, the time point sampling relative to dosing, PK or AAA (for 
adalimumab or anti-adalimumab antibody), split number (1 or 2) and then will be stored 
frozen at –20°C or colder and remain frozen until shipped (note:  sites should ship 
split 1 and split 2 separately to the central laboratory and Samples should be shipped to 
the central lab within 4 weeks of the draw date.)  Samples will be stored frozen at 
–70°C or colder once received at the central laboratory.  Sites that do not have access to a 
–20°C or colder freezer must ship the serum samples with dry ice the same day they are 
collected.
Arrangements will be made with the central laboratory to ship samples to AbbVie for 
analysis.  The frozen samples will be eligible for disposal per AbbVie's SOPs (where 
allowed by local guidelines).
Biomarker Analysis
The blood will be allowed to clot for 30 minutes at room temperature and then centrifuged 
for approximately 10 minutes at 1100 to 1600 × g.  The collected serum volume will be 

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transferred using plastic pipettes and split equally into four (or five if a subject consents to 
the additional serum to be stored for possible future research) screw-capped 
polypropylene tubes labeled with the study drug name, type of sample (serum [SRM]), the 
protocol number, the subject number, the time point sampling relative to dosing, BM (for 
biomarker assay), aliquot number (1, 2, 3, 4 or 5 if applicable) and then will be stored 
frozen at –20°C or colder remain frozen until shipped.  Samples should be shipped to the 
central lab within 4 weeks of the draw date.  Samples will be stored frozen at –70°C or 
colder once received at the central laboratory.  Sites that do not have access to a –20°C or 
colder freezer must ship the serum samples with dry ice the same day they are collected.
At the time of blood draw for biomarkers, subjects in certain countries (where allowed by 
local guidelines) will have the option for serum to be stored for possible future research.  
Samples will be stored frozen for future exploratory analysis of non-genetic biomarkers 
related to the subject's disease and/or response to study drug, in terms of tolerability and 
safety.  These samples may also be used for the development of diagnostic tests related to 
adalimumab (or drugs of this class).  Results of exploratory analyses, if any, will not be 
reported with the study summary.  AbbVie will store the samples in a secure storage space 
with adequate measures to protect confidentiality.  The samples will be retained for no 
longer than 5 years after completion of the study defined as the date of the last subject's 
last study visit or the actual date of follow-up contact, whichever is later (where allowed 
by local guidelines).
Please refer to the central laboratory manual for specific instructions on sample collection, 
processing, storage and shipment.
Pharmacogenetic Analysis
Whole blood will be collected by standard phlebotomy technique as described below.
●
Collect approximately 4 mL of blood into an appropriately labeled 
ethylenediaminetetraacetic acid (EDTA) tube (lavender top).
●
Immediately invert the collection tube 8-10 times to reduce the likelihood of 
clot formation.

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●
Store samples at –20°C or colder within 30 minutes of blood draw until 
shipped to the central laboratory on dry ice sufficient to last during transport.
Samples will be shipped frozen to the certified central laboratory for handling prior to 
shipment to AbbVie for DNA extraction and long-term storage.
The sample collection tubes will be labeled as "PG-DNA blood," with the drug number, 
protocol number, subject number, and study day (i.e., Baseline).  AbbVie will store the 
DNA samples in a secure storage space with adequate measures to protect confidentiality.  
The samples will be retained while research on adalimumab (or drugs of this class) 
continues but no longer than 5 years defined as the date of the last subject's last study visit 
or the actual date of follow-up contact, whichever is later (where allowed by local 
guidelines).
Please refer to the central laboratory manual for specific instructions on sample collection, 
processing, storage and shipment.
5.3.2.3
Disposition of Samples
The frozen blood samples will be packed in dry ice per the central laboratory instruction 
manual.  Samples will be shipped pursuant to instructions from the central laboratory 
manual.  An inventory of the samples included will accompany the package.
5.3.2.4
Measurement Methods
Serum concentrations of adalimumab and AAA will be determined using validated ligand 
binding methods under the supervision of the Drug Analysis Department at AbbVie.
5.3.3
Efficacy Variables
5.3.3.1
Primary Efficacy Variable
The primary efficacy variable is the proportion of subjects who do not experience a flare 
during Period 2 by Week 68 of the study where a flare is defined as having any 
2 consecutive study visits with ASDAS ≥ 2.100.

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5.3.3.2
Secondary Efficacy Variable(s)
Secondary efficacy variables include the following:
At 12 Weeks after Initiation of Rescue Therapy
●
ASDAS Inactive Disease (ASDAS < 1.300)
●
ASDAS Major Improvement (a change from baseline ≤ –2.000)
●
ASDAS Clinically Important Improvement (a change from baseline ≤ –1.100)
●
ASAS20, ASAS40, ASAS 5/6 and ASAS Partial Remission
○
ASAS20 response:  improvement of ≥ 20% and absolute improvement of 
≥1 unit (on a scale of 0 to 10) from Baseline in ≥ 3 of the following 
4 domains, with no deterioration in the remaining domain (defined as a 
worsening of ≥ 20% and a net worsening of ≥ 1 unit)
●
Patient's Global Assessment – Represented by the PTGA-disease 
activity 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 2 morning 
stiffness-related BASDAI NRS scores (mean of items 5 and 6 of the 
BASDAI [0 to 10])
○
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 in ASAS20 with no deterioration in the potential remaining domain
○
ASAS partial remission:  absolute score of < 2 units for each of the 
4 domains identified above in ASAS20
○
ASAS 5/6 response:  20% improvement 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
●
Bath AS Disease Activity Index 50 (BASDAI50)

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●
Health Assessment Questionnaire Modified for the Spondyloarthropathies 
(HAQ-S)
At Week 28 and Week 68
●
ASDAS Inactive Disease
●
ASDAS Major Improvement
●
ASDAS Clinically Important Improvement
●
ASAS20, ASAS40, ASAS 5/6 and ASAS Partial Remission
●
BASDAI50
●
HAQ-S
At Week 68
●
Time to flare defined as ASDAS ≥ 2.100 at 2 consecutive visits
●
Time to partial flare defined as ASDAS ≥ 1.300 but < 2.100 at 2 consecutive 
visits
●
Proportion of subjects who reach flare definition
●
Proportion of subjects who reach partial flare definition
5.3.3.3
Other Efficacy Variables
●
Patient's Global Assessment of Disease Activity
●
Patient's Assessment of Total back pain
●
Bath AS Functional Index (BASFI)
●
Inflammation/Morning Stiffness (mean of BASDAI questions 5 and 6)
●
Bath AS Disease Activity Index (BASDAI)
●
ASDAS
●
hs-CRP
●
Linear Bath AS Metrology Index (BASMIlin)
●
Swollen Joint Count (66 joints)

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●
Tender Joint Count (68 joints)
●
MASES
●
Plantar fascia enthesitis
●
Dactylitis
●
Physician's Global Assessment of Disease Activity
●
Patient's Global Assessment of Pain
●
Patient's Assessment of Nocturnal Back Pain
●
Anterior Uveitis
●
Short Form-36v2 Health Survey questionnaire
●
EQ-5D
●
WPAI-axial SpA
●
SPARCC scores for MRI of the SI joint and spine
●
Proportion of subjects who regain remission on rescue therapy
●
Time to regain remission on rescue therapy
5.3.3.4
Exploratory Variables
Each subject will have blood drawn for Biomarkers at the following time points:  
Baseline, Weeks 28, 68, time of flare, 12 weeks following determination of flare, and last 
study visit.  The final set of biomarkers to be analyzed may include the following:
●
DKK-1
●
Sclerostin
●
BMP-2
●
BMP-7
The final selection of biomarkers for analysis will be based on both insights gained in the 
sub-study and available scientific knowledge at study completion.

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5.3.4
Pharmacogenetic Variables 
Pharmacogenetic analysis is optional and requires subject's prior consent.  DNA samples 
may be analyzed for genetic factors contributing to the subject's response to adalimumab, 
or other study treatment, in terms of pharmacokinetics, efficacy, tolerability, and safety.  
Such genetic factors may include genes for drug metabolizing enzymes, drug transport 
proteins, genes within the target pathway, or other genes believed to be related to drug 
response.  Some genes currently insufficiently characterized or unknown may be 
understood to be important at the time of analysis.  The samples may be analyzed as part 
of a multi-study assessment of genetic factors involved in the response to adalimumab or 
drugs of this class.  The samples may also be used for the development of diagnostic tests 
related to adalimumab (or drugs of this class).  The results of pharmacogenetic analyses 
may not be reported with the study summary.
5.3.5
Safety Variables
Screening assessments will include medical history, vital signs, physical examination, and 
clinical laboratory tests.  The following safety evaluations will be performed during the 
study:  concomitant medication review, AE monitoring, vital signs, physical examination 
(if required) and laboratory tests.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
A subject may withdraw from the study at any time.  The Investigator may discontinue 
any subject's participation for any reason, including an AE, safety concerns or failure to 
comply with the protocol.
Subjects will be withdrawn from the study immediately if any one of the following 
occurs:
●
Clinically significant abnormal laboratory result(s) or AE(s), as determined by 
the Investigator in consultation with the AbbVie Medical Monitor.

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●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion and exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie Medical Monitor (see Section 5.2 and 
Section 6.5).
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie 
Medical Monitor.
●
Subject is non-compliant with TB prophylaxis.
●
The subject becomes pregnant while on study medication.
●
Subject has dysplasia of the gastrointestinal tract or a malignancy, except for 
localized non melanoma skin cancer.  Discontinuation for carcinoma in-situ of 
the cervix is at the discretion of the Investigator.
●
Subject is diagnosed with lupus like syndrome, multiple sclerosis, or 
demyelinating disease.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial, as determined by the 
Investigator, in consultation with the AbbVie Medical Monitor.
●
Subject does not meet the criteria for remission at Weeks 16, 20, 24 and 28.
If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the Discontinuation Visit must be completed 
within 2 weeks of the last dose of study drug, and preferably prior to the initiation of 
another therapy.  However, these procedures should not interfere with the initiation of any 
new treatments or therapeutic modalities that the Investigator feels are necessary to treat 
the subject's condition.  Following discontinuation of the study drug, the subject will be 
treated in accordance with the Investigator's best clinical judgment.
A final phone call will be made to the subject approximately 70 days after last dose to 
determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs 
unless not required as outlined in Section 5.3.1.1.

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All attempts must be made to determine the date of the last dose of study drug and the 
primary reason for premature discontinuation.  The information will be recorded on the 
appropriate eCRF page.
For subjects that are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent.  The attempts should be documented in the 
subject's source documents.
Subjects who prematurely discontinue will not be replaced.
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
Open-Label – Period 1
Starting on Day 1 through Week 26, subjects will be administered OL adalimumab 40 mg 
eow.  Drug will be subcutaneously self-administered or administered by a qualified 
designee every other week at approximately the same time of day.  The day of the first 
dose of study drug is designated as Day 1.

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Subjects may be discontinued as early as Week 20 if they do not meet the ASDAS 
remission criteria using the Week 16 parameters.  See the ASDAS Calculation in 
Section 5.3 for more details on which hs-CRP to use during the ASDAS calculations.
Subjects meeting ASDAS Inactive Disease at Week 16, 20, 24 and Week 28 will be 
randomized 1:1 to receive either blinded adalimumab 40 mg eow or matching placebo.  
Subject not meeting ASDAS Inactive Disease at Week 16, 20, 24 or Week 28 will be 
discontinued.
Since subjects may be unfamiliar with sterile SC injection technique, qualified study site 
personnel will instruct them on proper technique and should directly observe the injection 
at the study visits at Baseline, Weeks 2, 4, 8, 12 and Week 24 to ensure proper injection 
technique (Appendix V).  This supervision will serve as a confirmation of the use of safe 
and appropriate drug injection techniques and to answer any questions related to drug 
administration.
Double-Blind – Period 2
Starting at Week 28, subjects who are eligible for randomization into Period 2 will receive 
the first dose of blinded study drug (adalimumab 40 mg eow or placebo).  The study drug 
will be provided as a sterile SC injection solution in 1 mL pre-filled syringes containing 
either adalimumab 40 mg/0.8 mL or matching placebo for adalimumab.
Rescue Therapy During Period 2
Starting at Week 36, subjects who meet the flare criteria (flare is defined as 2 consecutive 
study visits with ASDAS ≥ 2.100) will be given rescue therapy with open-label 
adalimumab 40 mg eow for at least 12 weeks and will continue through the duration of 
the subject's participation of the study.  For subjects who meet the flare criteria at Weeks 
60, 64 or 68, rescue therapy with OL adalimumab 40 mg eow will be provided for 12 
weeks and final study visit will be at Weeks 72, 76 or 80, respectively.

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5.5.2
Identity of Investigational Product(s)
The individual study drug information is presented in the following table:
Table 3. 
Identity of Investigational Products
Study Drug
Formulation
Manufacturer
Adalimumab
40 mg/0.8 mL
Adalimumab/Mannitol, Citric acid monohydrate, 
Sodium citrate, Disodium phosphate dihydrate, 
Sodium dihydrogen phosphate dihydrate, Sodium 
chloride, Polysorbate 80, Water for injections, 
Sodium Hydroxide added as necessary to adjust pH
Abbott/AbbVie
Placebo for Adalimumab
Mannitol, Citric acid monohydrate, Sodium citrate, 
Disodium phosphate dihydrate, Sodium dihydrogen 
phosphate dihydrate, Sodium chloride, Polysorbate 
80, Water for injections, Sodium Hydroxide added 
as necessary to adjust pH
Abbott/AbbVie
5.5.2.1
Packaging and Labeling
Open-label investigational product will contain 2 pre-filled syringes of adalimumab 
40 mg/0.8 mL.  Blinded investigational product will contain either 2 pre-filled syringes of 
adalimumab 40 mg/0.8 mL or 2 pre-filled syringes of placebo for adalimumab.  The type 
and amount of kits dispensed will be managed by the IVRS/IWRS.
Each pre-filled syringe and carton will be labeled as required per country requirements.  
All blank spaces on the label will be completed by site staff prior to dispensing to the 
subject.
All labels must remain affixed to study medication at all times, and should never be 
removed for any reason.
5.5.2.2
Storage and Disposition of Study Drug
Adalimumab/placebo pre-filled syringes are to be stored protected from light at 2°C to 
8°C/36°F to 46°F.  Study medication drug must not be frozen at any time.  A storage 

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temperature log is to be maintained to document proper storage conditions.  The 
refrigerator temperature must be recorded each business day.  Malfunctions or any 
temperature excursion must be reported to the Sponsor immediately.  Study medication 
should be quarantined and not dispensed until AbbVie GPRD or Abbott Temperature 
Excursion Management System (ATEMS) deems the medication as acceptable.
All clinical supplies must be stored and locked in a secure place until they are dispensed 
for subject use or are destroyed via on-site destruction (if allowed by local guidelines and 
a well-documented procedure is in place) or returned to AbbVie or third party drug 
destruction depot.
Investigational products are for investigational use only and are to be used only within the 
context of this study.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be centrally enrolled (at the Baseline Visit) and randomized (at Week 28, 
if applicable) using an IVRS/IWRS.  Before the study is initiated, the telephone number 
and call-in directions as well as the appropriate URL for the IVRS/IWRS will be provided 
to each site.
IVRS/IWRS will be maintained by:
Perceptive Informatics
Windsor Corporate Park,
50 Millstone Road
Building 100, Suite 200
East Windsor, NJ  08520
Study drug will be administered at the study visits summarized in Table 1.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study medication as outlined in Section 5.1.

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If a subject should forget to administer the injection of study medication on their regularly 
scheduled dosing date, they should take the forgotten injection as soon as they remember 
the dose was missed up to the day of their next scheduled dose.  The subject should not 
administer two doses on the same day.
In the event the incorrect dose is taken or a dose is missed, the subject should be 
instructed to contact the site to determine how to proceed with dosing.  The subject must 
record all dosing information on the Subject-Dosing Diary Sheet (Appendix W).
Doses not administered (e.g., not taken before the next dose is scheduled), should be 
recorded as not taken in the source.  The extra dose should be returned to the study site 
full.  The subject should resume their regular dosing schedule based on the first dosing 
date at Baseline.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
Period 1, defined as Baseline (Day 1) through Week 26 is OL.
All AbbVie personnel with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie Drug Supply Management Team), the Investigator, study 
site personnel and the subject will remain blinded to each subject's treatment throughout 
the double-blinded period, Week 28 through Week 68 (Period 2) of the study.  The 
IVRS/IWRS will provide access to blinded subject treatment information in case of 
medical emergency.
In the event of a medical emergency in which the Investigator believes that knowledge of 
study drug treatment is required, every effort must be made to contact the AbbVie 
Medical Monitor (Section 6.5) prior to breaking the blind.  The date and reason that the 
blind was broken must be conveyed to AbbVie and recorded on the appropriate eCRF.

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5.5.6
Treatment Compliance
The Investigator or his/her designated representatives will dispense study drug only for 
use by subjects enrolled in the study.
The subject or their qualified designee will administer all doses of study drug.  
Appropriate site staff will supervise the administration of the study drug at in-office study 
visits to ensure proper injection technique.  In order to document compliance with the 
treatment regimen, the subject will be given a subject dosing diary sheet (Appendix W) to 
record all injection dates and times.  Compliance information will be documented on the 
appropriate eCRF.  Subjects will be counseled on missed doses of medication.  Subjects 
will be instructed to return all drug containers (even if empty) to the study site.  If the 
subject does not return the subject dosing diary sheet, IP boxes and sharp containers 
(when applicable), the site should question the subject and obtain as much information as 
possible as to the dosing of the study drug.  The information should be documented on the 
source documents as per "best recollection" and when possible re-verified once the dosing 
sheet is returned before completing the applicable eCRF page.
The Investigator or his/her designated representatives will make a photocopy of the 
subject doing diary at each visit.
5.5.7
Drug Accountability
The Investigator or designee will verify that study drug supplies are received intact, at the 
appropriate temperature (except in the US, where it should be documented as cool to the 
touch), and in the correct amounts.  This will be accomplished by documenting the 
condition of the shipment, verifying the kit numbers in the package against the Proof of 
Receipt (POR) or similar document included with each drug shipment, and documenting 
this verification by signing and dating the POR or similar document.  The original POR 
Note or similar document will be kept in the site files as a record of what was received.
In addition, an accurate running inventory of study drug will be kept by the site on a Site 
Drug Accountability log including date received, the lot number, kit number(s), date  

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dispensed, subject number, and the identification with date of the person dispensing the 
drug.  For this study, unless otherwise prohibited locally, these records will be maintained 
electronically as part of the IVRS/IWRS system.
All empty IP boxes and used pre-filled syringes will be inventoried by the site and each 
subject will be given their own Sharps disposal container to store used pre-filled syringes.  
Empty IP boxes and Sharps containers should be returned by the subject at each visit for 
accountability and compliance purposes and new containers issued as necessary.  Empty 
boxes and returned Sharps containers will be retained (unless prohibited by local law) 
until the CRA is on site to confirm the returned medication.  CRAs and site staff will 
complete study medication accountability via study medication logs, source documents, 
subject dosing diary sheets, empty IP boxes and by visually inspecting the syringes in the 
Sharps container whenever possible.  Used Sharps containers should never be opened.  
Once the CRA has verified drug accountability at the site, the site staff and CRA will 
document that the used pre-filled syringes have been destroyed, using appropriate 
biohazard precautions, when appropriate.  A copy of the destruction methodology should 
be maintained at the site's facility.  Unused medication will be returned by the CRA after 
drug accountability has been completed at the site.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This clinical trial was designed to evaluate the efficacy and safety of adalimumab 40 mg 
eow versus placebo in maintaining remission in patients with nr-axSpA who achieve 
ASDAS Inactive Disease at the end of Period 1.  Based on past clinical trials of 
adalimumab in AS and in nr-axSpA patients, 28 weeks of adalimumab treatment in 
Period 1 is expected to be sufficient to identify most subjects who will respond and 
achieve remission (ASDAS Inactive Disease) with this therapy.  In Period 2, patients who 
achieve ASDAS Inactive Disease at Week 16, 20, 24 and Week 28 are randomized to 
receive either blinded adalimumab or placebo.  The primary endpoint will be the 
proportion of subjects who do not experience a flare by Week 68.  The proposed 40-week 

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duration of the double blind period is based on results of 2 prior trials that demonstrated 
the occurrence of disease flare in patients taken off anti TNF therapy. 14,15
5.6.2
Appropriateness of Measurements
Standard statistical, clinical and laboratory procedures will be utilized in this study.  
Efficacy measurements in this study have been selected or designed to assess disease 
activity in subjects with nr-axSpA.  Other than the biomarker and pharmacogenetic 
analysis which are exploratory, all clinical and laboratory procedures in this study are 
standard and generally accepted.
5.6.3
Suitability of Subject Population
Males and females at least 18 years of age with nr-axSpA who have a minimum level of 
disease activity at baseline (ASDAS ≥ 2.100, BASDAI ≥ 4, Patient's Assessment of Total 
Back Pain score ≥ 4), have objective evidence of active disease (inflammation in the SI 
joints or spine on MRI or elevated hs-CRP), have had an inadequate response or 
intolerance to two or more NSAIDs or have an intolerance to, or a contraindication for 
NSAIDs, and who meet all inclusion criteria and who do not meet any of the exclusion 
criteria are eligible for this study.
5.6.4
Selection of Doses in the Study
The recommended dose of adalimumab for adults with AS is 40 mg administered eow.  
Adalimumab is approved for the treatment of AS (in the US and EU) and approved for 
nr-axSpA (in the EU).  Adalimumab was generally well-tolerated and has demonstrated 
therapeutic efficacy compared to placebo in AS subjects in Study M03-607 (ATLAS) and 
Study M03-606 as well as in nr-axSpA subjects in Study M10-791 which were the pivotal 
studies used to support registration for these indications.
6.0
Adverse Events
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 

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any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1
Definitions
6.1.1
Adverse Event
An adverse event (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 adverse event 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 adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meets protocol specific criteria (see Section 6.7 regarding toxicity 
management) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 

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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 adverse event.
6.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (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.

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Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  
Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the 
subject.
Moderate
The adverse event causes the subject discomfort and interrupts 
the subject's usual activities.
Severe
The adverse event causes considerable interference with the 
subject's usual activities and may be incapacitating or 
life-threatening.

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6.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
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 serious 
adverse event.
6.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 70 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, serious adverse 
events will be collected from the time the subject signed the study-specific informed 
consent.  Adverse event information will be collected and recorded on the appropriate 
eCRFs.
Adverse event information will be collected as shown in Figure 2.
Subjects will be contacted approximately 70 days following study drug discontinuation 
for an assessment of any new or ongoing AEs, except those subjects that are able to 
receive commercial adalimumab treatment after the end of study participation.  These 

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subjects are not required to complete the 70-day follow-up and any new Adverse Events 
should be reported through the mechanism used for all post marketing adverse 
experiences.
There may be instances where a 70-day follow-up phone call occurs after the locking of 
the clinical database.  In this situation, any Adverse Events reported to AbbVie from this 
70-day follow-up phone call will be evaluated for inclusion in the clinical database.  All 
SAEs or Adverse Events of Special Interest, as defined by AbbVie, reported during the 
70-day follow-up phone call must be captured in the clinical database.
Figure 2.
Adverse Event Collection
SAEs
SAEs and Non-Serious AEs
Elicited and/or Spontaneously Reported
∀
∀
∀
∀
Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
70 Days
After Study 
Drug Stopped
6.5
Adverse Event Reporting
In the event of a serious adverse event, and additionally, any non-serious event of 
malignancy in subjects 30 years of age and younger, whether related to study drug or not, 
the Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being 
made aware of the serious adverse event by entering the SAE or non-serious event of 
malignancy in subjects 30 years of age and younger into the electronic data capture (EDC) 
system.  Serious adverse events and non-serious events of malignancy in subjects 30 years 
of age and younger, that occur prior to the site having access to the RAVE® system or if 
RAVE is not operable should use the SAE Non-CRF paper forms and send them (email is 
the preferred route) to Clinical Pharmacovigilance within 24 hours of being made aware 
of the adverse event.

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For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team Hotline
For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.6
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).  Pregnancies will be collected from the date of the first 
dose through 150 days following the last dose of study drug.

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Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
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.
6.7
Toxicity Management
Subjects who develop a new infection while undergoing treatment with adalimumab 
should be monitored closely.  Administration of study injections should be interrupted if a 
subject develops an infection requiring IV anti-infective treatments or if an infection 
meets the definition of "serious" (see Section 6.0 for definitions).  Study medication may 
be restarted once the physician determines that the infection has been successfully treated.  
Otherwise prohibited concomitant medications may be given if medically necessary.  
Prior to use, every attempt should be made to contact the AbbVie Study Physician for 
direction on re-introduction of adalimumab therapy after prohibited medication 
administration.
If the subject must undergo elective surgery, the study injections must be interrupted 
2 weeks prior to the surgery.  If the subject must undergo emergency surgery, the study 
injections must be interrupted at the time of the surgery.  The injectable study medication 
can recommence at least two weeks after surgery once the physician has examined the 
surgical site and determined that it has healed and there is no sign of infection.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
principal investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the Principal Investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review

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Board (IRB) regulatory authorities (as applicable) and their assigned CRO Clinical 
Monitor or the following AbbVie Clinical Members:
Primary Contact:
Alternate Contact:
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.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
8.1.1
Analysis Population
The primary and secondary efficacy variables will be analyzed for the intent-to-treat (ITT) 
population, defined as all subjects who were randomized and received at least one dose of 
double-blind study medication.  Subjects in the ITT population will be analyzed according 
to the treatment group they were randomized to.  In order to evaluate the impact of major 
protocol violations on the results of the trial, additional analysis of the primary efficacy 
variable may be conducted on the per protocol population, which consists of all ITT 
subjects who entered the double-blind period of the study and did not meet any major 
protocol violation during the OL and double-blind periods.

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The safety population consists of all subjects who received at least one dose of study 
medication.
8.1.2
Statistical and Analytical Plan
Complete and specific details of the final statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 
database lock.  The analysis will be performed using SAS (SAS Institute Inc., Cary, NC, 
USA).
Unless otherwise stated, all statistical tests will be conducted at α = 0.05 level (2 sided).  
Descriptive statistics data will be provided including but not limited to the number of 
observations, mean, standard deviation, median, minimum and maximum for continuous 
variables; and counts and percentages for discrete variables.  Primary analysis will not be 
adjusted for site effect since the subjects will be enrolled through a central randomization 
process.
All statistical comparisons for the primary efficacy endpoint will be performed at 
Week 68 (end of the placebo-controlled, i.e., double-blind period) and secondary efficacy 
endpoints will be performed at the time points specified in Section 5.3.3.2, unless 
otherwise stated.
An interim database lock is planned when all ongoing subjects have completed Week 28 
(OL, Period 1) of the study.  The OL study results (through Week 28) will be based on 
this database lock.  Efficacy and safety data from this initial OL phase will be descriptive 
and presented for exploratory purposes only and no statistical comparison will be made.  
Therefore, no adjustment to the P value will be required for this interim reporting.
Data from the subsequent double-blind period will be reported at the completion of the 
study.  All statistical comparisons for the primary and secondary endpoints will be done at 
the end of the study.

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The last available pre-treatment values recorded on or before Day 1 (the first dose of 
OL period) will be considered as the Baseline value.  To account for any missing data for 
the primary efficacy endpoint (proportion of subjects who do not experience a flare by 
Week 68), a non-responder imputation approach will be used, i.e., subjects who 
discontinue during the double-blind period (Period 2) with missing flare data will be 
imputed as having a flare.  The last observation carried forward (LOCF) rule will be used 
to impute missing continuous efficacy data at Week 68.  That is, the subject's last 
non-missing value assessed in the study while receiving double-blind study drug will be 
used in the analysis.  In addition, an analysis using only the observed or reported data will 
be performed as a sensitivity analysis for the primary endpoint.  If deemed appropriate, 
hs-CRP values obtained during the Week 28 visit, will be used for the calculation of 
ASDAS inactive disease at the Week 28 visit for a sensitivity analysis since these values 
were not available at the time of randomization.  Similarly, if deemed appropriate, 
hs-CRP values obtained at the second visit determining flare will be used for a sensitivity 
analysis since the visit-specific value was not available at the time of flare determination.
8.1.3
Analysis of Demographic Data and Baseline Disease 
Characteristics
Demographic and Baseline characteristics will be summarized and compared, among 
treatment groups.  The number of observations, mean, standard deviation, median, 
minimum and maximum will be summarized for continuous variables; and treatment 
group homogeneity will be assessed using a one-way analysis of variance (ANOVA) 
model using treatment, as the independent factor.  Discrete variables will be summarized 
via counts and percentages; and treatment group homogeneity will be evaluated using the 
appropriate chi-square method.
Duration of treatment will be summarized.  Medical History will be presented by count 
and percentage of subjects broken down by Body System and Diagnosis.

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8.1.4
Statistical Analysis of Efficacy
8.1.4.1
Primary Efficacy Variable
8.1.4.1.1
Primary Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects who do not experience a flare 
in Period 2 by Week 68 of the study, which defined as having any 2 consecutive study 
visits with ASDAS ≥ 2.100, and the response rate observed in the group randomized to 
adalimumab 40 mg eow will be compared to that in the placebo group.  The null 
hypothesis associated with this comparison states that there is no difference in response 
rates between the adalimumab and placebo groups; the alternative hypothesis is that the 
response rates are different.  The response rates will be tested using a two-sided Pearson's 
chi square test with α = 0.05.  Subjects who discontinue during the double-blind 
(Period 2) with missing flare data at Week 68 will be treated as non-responders according 
to "non-responder imputation" criterion.
8.1.4.1.2
Secondary Analysis of Primary Efficacy Endpoint
Secondary analyses of the primary endpoint will be conducted using observed case 
analysis for the proportion of subjects not experiencing a flare up to Week 68.  The 
response rates will be compared using a two sided Pearson's chi square test with α = 0.05.
8.1.4.2
Analyses of Secondary Efficacy Variables
Unless otherwise stated, all statistical comparisons of secondary efficacy variables will be 
conducted between the adalimumab group and placebo group at the 2-sided α = 0.05 
significance level.
A complete list of secondary efficacy variables is provided in Section 5.3.3.2.  Discrete 
variables will be summarized using count and percentages and will be compared between 
adalimumab and placebo groups during the double-blind and rescue periods using 
Pearson's chi square test or Fisher's exact test (if ≥ 25% of the cells have expected counts 
less than 5).

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Continuous efficacy variables will be summarized by summary statistics (number of 
subjects, mean, 95% confidence interval, standard deviation, first quartile, median, third 
quartile, minimum, maximum).  Change from Baseline in the continuous variables will be 
compared between adalimumab and placebo groups using an analysis of covariance 
method adjusting for the Baseline score.  This will be done for both observed and LOCF 
imputed values.
Time to flare will be analyzed using a Cox proportional hazards model with treatment as a 
factor.
8.1.4.3
Other Exploratory Analyses
Analysis for other efficacy variables referenced in (Section 5.3.3.3) will be performed 
using similar methods to those described in Section 8.1.4.2.
8.1.5
Statistical Analyses of Safety
Safety analyses will be carried out using safety population, which includes all subjects 
that received at least one dose of study medication.  Treatment-emergent, and pre- and 
post-treatment AEs will be summarized and reported.  The rate of treatment-emergent 
AEs when starting OL adalimumab rescue therapy in subjects who have flared on placebo 
will be reported.
Treatment-emergent AEs are defined as AEs that begin either on or after the first dose of 
the study medication, and up to within 70 days after the last dose of the study medication, 
except for those subjects that initiate adalimumab therapy not supplied in the context of 
the clinical trial after the end of study participation.  All treatment emergent AEs will be 
coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA ®).  The 
number and percent of subjects experiencing AEs will be tabulated by system organ class 
and preferred term.  In addition, a summary of AEs by severity and relationship to study 
drug will be presented.  AEs, which are serious, severe, or life-threatening, which lead to 
premature study discontinuation will be listed and described in detail.

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Mean change in vital signs and laboratory variables at each visit as compared to baseline 
will be summarized for all treated subjects, and compared between treatment groups 
during the double-blind period using a one way ANOVA.  The last evaluation prior to the 
first dose of study drug will be used as Baseline for all analyses.  For selected parameters, 
a listing of all subjects with any laboratory determination meeting Common Toxicity 
Criteria (CTC) of Grade 3 or higher will be provided.  Shift tables for changes from 
Baseline according to the normal range will also be provided for laboratory variable.
8.1.6
Pharmacokinetic Analyses
Adalimumab concentrations will be listed by individual and time point.  For each 
scheduled time of measurement, summary statistics will be provided for the adalimumab 
serum concentration data by treatment group.  If appropriate, concentration data may be 
combined with observed concentration data from previous Humira studies, and population 
pharmacokinetic analyses will be performed to estimate adalimumab apparent clearance 
and volume of distribution.
Pharmacokinetic models will be built using a non-linear mixed-effect modeling approach 
with the Non-Linear Mixed Effect Modeling (NONMEM) software (Version V, or a 
higher version).  A stepwise addition and deletion approach will be used to assess the 
impact of covariates on model parameters.  Standard model evaluation approaches will be 
used to determine the performance of different models (e.g., objective function value 
comparison based on likelihood ratio test, visual predictive checks, magnitude of 
inter-subject and residual error etc.).  The final model will be used to produce empirical 
Bayesian estimates of the pharmacokinetic parameters for each individual, using the 
post-hoc option in NONMEM.  Individual pharmacokinetic parameters will be listed and 
summarized with appropriate statistical methods.
The percentage of subjects with AAA will be reported.
Additional pharmacokinetics/pharmacodynamic analyses may be conducted as 
appropriate.

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8.1.7
Interim Analysis
No formal unblinded interim analysis is planned for this study that requires an adjustment 
to the P value.  An interim analysis will be performed when all ongoing subjects have 
completed at least Week 28 of the study.  The primary and secondary endpoints of the 
study from the double blind period will be reported at the completion of the study.
8.2
Determination of Sample Size
Assuming that 50% of subjects treated with adalimumab will not experience any flare up 
to Week 68, 120 subjects per arm are required for the double-blind period (Period 2) (with 
an adjustment for drop out rate of no more than 30%) is targeted to result in at least 90% 
power for detecting a 25% difference at Week 68 for the primary endpoint between 
adalimumab and placebo based on a two-sided test with significance level 0.05.
It is assumed that approximately 33% of the subjects enrolled into the OL Period 
(Period 1) would meet ASDAS Inactive Disease at Weeks 16, 20, 24 and Week 28, 
therefore, a total of approximately 740 subjects would be required to be enrolled in order 
to have sufficient number of subjects (i.e., 120 subjects per arm) for the double-blind 
period.  Study enrollment will be closed prior to reaching 740 subjects should a sufficient 
number of subjects fulfill remission criteria and be available for randomization at the end 
of Period 1 prior to full enrollment.
8.3
Randomization Methods
Subjects who meet the remission criteria at Week 28 of the Open-Label Period will be 
randomized in a 1:1 ratio to receive either adalimumab 40 eow or matching placebo for 
40 weeks.

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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the clinical 
investigator are specified in Appendix A.

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9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.
At the time of blood draw for biomarkers, subjects in certain countries (where allowed by 
local guidelines) will have the option for serum to be stored for possible future research.  
The storage of these biomarker samples for possible future research is optional and 
subjects' may decline at any time.
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.
Pharmacogenetic analysis will only be performed if the subject has voluntarily signed and 
dated a separate pharmacogenetic informed consent form, approved by an IRB/IEC, after 
the nature of the testing has been explained and the subject has had the opportunity to ask 
questions.  The separate pharmacogenetic informed consent must be signed before the 
pharmacogenetic testing is performed.  If the subject does not consent to the 
pharmacogenetic testing it will not impact the subject's participation in the study.

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10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The following assessments that will be completed by the subject or physician may be 
considered source documentation:
●
SJC/TJC
●
BASDAI
●
BASFI
●
BASMIlin
●
Maastricht AS Enthesitis Score (MASES)
●
Plantar fascia enthesitis
●
Dactylitis
●
Physician's Global Assessment of Disease Activity NRS
●
Patient's Assessment of Nocturnal Back Pain NRS
●
Patient's Assessment of Total Back Pain NRS
●
SF-36v2 Health Survey
●
EQ-5D
●
WPAI-axial SpA
●
Patient's Global Assessment of Disease Activity NRS
●
Patient's Global Assessment of Pain NRS
●
Health Assessment Questionnaire modified for the Spondyloarthropathies 
(HAQ-S)

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●
Subject Dosing Diary Sheet
The adverse event eCRF data segments of:  alternate etiology, severity, frequency and 
relationship to study drug, may also be used as source and will require an Investigator 
approval on the eCRF as verification of the accuracy of the information.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an 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.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 

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principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Patient Reported Outcomes (PRO) data are collected directly onto paper source 
worksheets by the subjects.  The completion of these forms is verified by the site staff.  
The source worksheets will be entered into the EDC system by the site staff.
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.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
An Investigator's Meeting will be held with AbbVie personnel, the investigators and their 
study coordinators and the Monitors for the study.  This meeting will include a detailed 
discussion of the protocol, performance of study procedures, eCRF and Subject Diary and 
log completion, Imaging requirement, and specimen collection methods.  In addition to or 
instead of the Investigator's Meeting, the study personnel at each site may be trained on 
the study procedures by a Monitor at a study initiation visit and will be given an eCRF 
completion guideline for reference.
The CRO Monitors will monitor each site throughout the study.  Source document review 
will be performed against entries in the eCRF database and a quality assurance check will 
be performed to ensure that the investigator is complying with the protocol and 
regulations.

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All central laboratory results will be electronically transferred from the central laboratory
to the study database.
A review of the data will be conducted by a physician and clinical review team at AbbVie 
as specified in the safety review plan.
12.0
Use of Information
Any pharmacogenetic research that may be done using DNA samples from this study will
be experimental in nature and the results will not be suitable for clinical decision-making 
or patient management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different than the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic 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 pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.
Please refer to the investigator site contract for specific information related to publication 
practices.
AbbVie abides by the PhRMA Principles on Conduct of Clinical Trials and 
Communication of Clinical Trial results.  Our registrations and results disclosure adhere 
to all relevant state and federal laws.
The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (by name and subject number).  This list will be maintained at the 
site and will not be retrieved by AbbVie.

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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 and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator 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 Guidance on Investigator's Signature 
for Study Reports.
The end-of-study is defined as the date of the last subject's last study visit or the actual 
date of follow-up contact, whichever is later.

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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for Adalimumab.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Multicenter, Randomized, Double-Blind, Study Comparing the 
Efficacy and Safety of Continuing Versus Withdrawing Adalimumab 
Therapy in Maintaining Remission in Subjects with 
Non-Radiographic Axial Spondyloarthritis
Protocol Date:
15 January 2015
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)

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15.0
Reference List
1.
Khan MA.  Update on spondyloarthropathies.  Ann Intern Med.  
2002;136:896-907.
2.
Rudwaleit M, Khan MA, Sieper J.  The challenge of diagnosis and classification in 
early ankylosing spondylitis:  do we need new criteria?  Arthritis Rheum.  
2005;52(4):1000-8.
3.
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(4):361-8.
4.
Rudwaleit M, Haibel H, Baralaikos X, et al.  The early disease stage in axial 
spondylarthritis:  results from the German Spondyloarthritis Inception Cohort.  
Arthritis Rheum.  2009;60(3):717-27.
5.
Rudwaleit M, van der Heijde D, Landewé R, et al.  The development of 
Assessment of SpondyloArthritis International Society classification criteria for 
axial spondyloarthritis (part II):  validation and final selection.  Ann Rheum Dis.  
2009;68(6):777-83.
6.
Rudwaleit M, van der Heijde D, Landewé R, et al.  The Assessment of 
SpondyloArthritis international Society classification criteria for peripheral 
spondyloarthritis and for spondyloarthritis in general.  Ann Rheum Dis.  
2011;70(1):25-31.
7.
Rudwaleit M, Landewé R, van der Heijde D, et al.  The development of 
Assessment of SpondyloArthritis International Society classification criteria for 
axial spondyloarthritis (part I):  classification of paper patients by expert opinion 
including uncertainty appraisal.  Ann Rheum Dis.  2009;68:770-6.
8.
van der Heijde D, Kivitz A, Schiff MH, et al.  Efficacy and safety of adalimumab 
in patients with ankylosing spondylitis.  Results of a multicenter, randomized, 
double-blind, placebo-controlled trial.  Arthritis Rheum.  2006;54(7):2136-46.

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9.
Haibel H, Rudwaleit M, Listing J, et al.  Efficacy of adalimumab in the treatment 
of axial spondyloarthritis without radiographically defined sacroiliitis:  results of a 
twelve-week randomized, double-blind, placebo-controlled trial followed by an 
open-label extension up to week fifty-two.  Arthritis Rheum.  2008;58(7):1981-91.
10.
van der Heijde D, Sieper J, Maksymowych WP, et al.  2010 update of the 
international ASAS recommendations for the use of anti-TNF agents in patients 
with axial spondyloarthritis.  Ann Rheum Dis.  2011;70:905-8.
11.
Braun J, Davis J, Dougados M, et al.  First update of the international ASAS 
consensus statement for the use of anti-TNF agents in patients with ankylosing 
spondylitis.  Ann Rheum Dis.  2006;65:316-20.
12.
Braun J, Zochling J, Baraliakos X, et al.  Efficacy of sulfasalazine in patients with 
inflammatory back pain due to undifferentiated spondyloarthritis and early 
ankylosing spondylitis:  a multicentre randomised controlled trial.  Ann Rheum 
Dis.  2006;65:1147 53.
13.
Chen J, Liu C.  Methotrexate for ankylosing spondylitis.  Cochrane Database of 
Systematic Reviews.  2003; issue 3.  Art No:  CD004524.
14.
Amtenbrink AL, Haibel H, Rudwaleit M, et al.  Efficacy of adalimumab in the 
treatment of patients with axial spondyloarthritis (SPA) and no radiographic 
sacroiliitis:  continuous adalimumab (Humira®) therapy is necessary to prevent 
relapses after treatment withdrawal.  Ann Rheum Dis.  2008;67(Suppl II):373.
15.
Song I, Hermann K, Haibel H, et al.  Frequency and duration of drug-free 
remission after one year of Treatment with etanercept vs. sulfasalazine in early 
axial spondyloarthritis:  2 year data of the ESTHER trial [abstract].  Arthritis 
Rheum.  2011;63 Suppl 10:S992.

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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
Clinical
Clinical
Statistics
Clinical
Pharmacokinetics

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Appendix C.
Assessment of SpondyloArthritis International Society (ASAS) 
Axial Spondyloarthritis Criteria for Classification
In subjects with ≥ 3 months back pain^ and age at onset < 45 years
Sacroiliitis on imaging*
HLA-B27
plus
or
plus
≥ 1 SpA feature#
≥ 2 SpA feature#
# SpA features
●
Inflammatory back pain
●
Arthritis
●
Enthesitis (heel)
●
Uveitis
●
Dactylitis
●
Psoriasis
●
Crohn's Disease/Ulcerative 
colitis
●
Good response to NSAIDs
●
Family history for SpA
●
HLA-B27
●
Elevated CRP
*
Sacroiliitis on imaging:
active (acute) inflammation on MRI 
highly suggestive of sacroiliitis 
associated with SpA, or definite 
radiographic sacroiliitis according to 
modified New York criteria†
^
Almost daily back pain.
†
Subjects who fulfill the modified NY criteria for AS are excluded from the study.
Adapted from:  Rudwaleit M, van der Heijde D, Landewé R, et al.  The development of Assessment of 
SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (Part II):  validation 
and final selection.  Ann Rheum Dis.  2009;68:777-83.

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Appendix D.
Features of Spondyloarthritis
SpA Feature
Definition
Inflammatory back pain (IBP)
IBP according to experts:  at least 4 out of 5 parameters present:  1.  age 
at onset < 40 yrs; 2.  insidious onset; 3.  improvement with exercise; 
4.  no improvement with rest; 5.  pain at night (with improvement upon 
getting up)
Arthritis
Past or present active synovitis diagnosed by a physician
Enthesitis (heel)
Heel enthesitis:  past or present spontaneous pain or tenderness at 
examination of the site of the insertion of the Achilles tendon or plantar 
fascia at the calcaneus
Uveitis
Past or present uveitis anterior, confirmed by an ophthalmologist
Dactylitis
Past or present dactylitis, diagnosed by a physician
Inflammatory bowel disease
Past or present Crohn's disease or ulcerative colitis diagnosed by a 
gastroenterologist
Psoriasis
Past or present psoriasis (skin and/or nail lesions) diagnosed by a 
physician
Good response to NSAIDs
24 – 48 hours after a full dose of a non-steroidal anti-inflammatory drug 
(NSAID) the back pain is not present anymore or is much better
Family history for SpA
Presence in first-degree (mother, father, sisters, brothers, children) or 
second-degree (maternal and paternal grandparents, aunts, uncles, 
nieces, and nephews) relatives of any of the following:  a) ankylosing 
spondylitis, b) psoriasis, c) acute uveitis, d) reactive arthritis, 
e) inflammatory bowel disease
Elevated CRP
C-reactive protein concentration above upper normal limit in the 
presence of back pain; after exclusion of other causes for elevated CRP 
concentration
HLA-B27
Positive testing according to standard laboratory techniques
Sacroiliitis by MRI
Active inflammatory lesions of sacroiliac joints with definite bone 
marrow edema/osteitis, suggestive of sacroiliitis associated with 
spondyloarthritis
Adapted from:  Rudwaleit M, van der Heijde D, Landewé R, et al.  The development of Assessment of 
SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (Part II):  validation 
and final selection.  Ann Rheum Dis.  2009;68:777-83.
Adapted from:  Dougados M, Braun J, Burgos Vargas R, et al.  ASAS recommendations for variables to be collected in 
clinical trials/epidemiological studies of spondyloarthritis.  Ann Rheum Dis.  Epub:  2012 Jan 30.

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Appendix E.
Ankylosing Spondylitis Disease Activity Score (ASDAS) Calculation
Parameters used for the ASDAS:
1.
Patient's assessment of total back pain (BASDAI question 2)
2.
Patient global assessment of disease activity 
3.
Peripheral pain/swelling (BASDAI question 3)
4.
Duration of morning stiffness (BASDAI question 6)
5.
C-reactive protein (CRP) in mg/litre.
Calculation of ASDAS (for reference only as IVRS/IWRS will be programmed to 
calculate the ASDAS)
ASDASCRP:  0.121 × total back pain + 0.110 × patient global + 0.073 × peripheral 
pain/swelling + 0.058 × duration of morning stiffness + 0.579 × Ln(CRP+1).
References:
Lukas C, Landewé R, Sieper J, et al; Assessment of SpondyloArthritis international Society.  Development of an 
ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis.  Ann Rheum Dis.  
2009;68:18-24.
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;ii1-ii44.

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Appendix F.
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 
NRS
Please mark the box which represents your answer to each question relating to the past 
week (i.e.,
)
1.
How would you describe the overall level of fatigue/tiredness you have experienced?
0
1
2
3
4
5
6
7
8
9
10
none
very severe
2.
How would you describe the overall level of AS neck, back or hip pain you have had?
0
1
2
3
4
5
6
7
8
9
10
none
very severe
3.
How would you describe the overall level of pain/swelling in joints other than neck, back or hips you 
have had?  
0
1
2
3
4
5
6
7
8
9
10
none
very severe
4.
How would you describe the overall level of discomfort you have had from any areas tender to touch or 
pressure?
0
1
2
3
4
5
6
7
8
9
10
none
very severe
5.
How would you describe the overall level of morning stiffness you have had from the time you wake 
up?
0
1
2
3
4
5
6
7
8
9
10
none
very severe

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6.
How long does your morning stiffness last from the time you wake up?
0
1
2
3
4
5
6
7
8
9
10
0
hr
1
hr
2 or more 
hrs
Scoring of the BASDAI:
BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5 + Item 6)
                                                                                                   2             2
The BASDAI Score has a maximum value of 10.
References:
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.
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;ii1-ii44.  doi:10.1136/ard.2008.104018.

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Appendix G.
Patient's Assessment of Total Back Pain, NRS
Please place a mark in the box below to indicate your answer (i.e.,
)
What is the amount of back pain that you experienced at any time during the last week?
0
1
2
3
4
5
6
7
8
9
10
No Pain
Most severe 
pain
References:
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.
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:ii1-ii44.  doi:10.1136/ard.2008.104018.

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Appendix H.
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 I.
Tender and Swollen Joint Counts
JOINT EVALUATION
Patient Right
Patient Left
JOINT
(Mark Correct Answer)
0 = Absent
1 = Present
9 = Replaced
NA = No 
Assessment
0 = Absent
1 = Present
9 = Replaced
NA = No 
Assessment
Pain/
Tenderness
Swelling
Joint
Pain/
Tenderness
Swelling
Joint
1. Temporomandibular
0
1
0
1
9
NA
0
1
0
1
9
NA
2. Sternoclavicular
0
1
0
1
9
NA
0
1
0
1
9
NA
3. Acromio-clavicular
0
1
0
1
9
NA
0
1
0
1
9
NA
4. Shoulder
0
1
0
1
9
NA
0
1
0
1
9
NA
5. Elbow
0
1
0
1
9
NA
0
1
0
1
9
NA
6. Wrist
0
1
0
1
9
NA
0
1
0
1
9
NA
7. Metacarpophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
8. Metacarpophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
9. Metacarpophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
10. Metacarpophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
11. Metacarpophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
12. Thumb Interphalangeal
0
1
0
1
9
NA
0
1
0
1
9
NA
13. Prox. Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
14. Prox. Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
15. Prox. Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
16. Prox. Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
17. Distal Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
18. Distal Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
19. Distal Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
20. Distal Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
21. Hip
0
1
-
-
9
NA
0
1
-
-
9
NA
22. Knee
0
1
0
1
9
NA
0
1
0
1
9
NA
23. Ankle
0
1
0
1
9
NA
0
1
0
1
9
NA
24. Tarsus
0
1
0
1
9
NA
0
1
0
1
9
NA
25. Metatarsophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
26. Metatarsophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
27. Metatarsophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
28. Metatarsophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA

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JOINT EVALUATION
Patient Right
Patient Left
JOINT
(Mark Correct Answer)
0 = Absent
1 = Present
9 = Replaced
NA = No 
Assessment
0 = Absent
1 = Present
9 = Replaced
NA = No 
Assessment
Pain/
Tenderness
Swelling
Joint
Pain/
Tenderness
Swelling
Joint
29. Metatarsophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
30. Great Toe/Hallux
0
1
0
1
9
NA
0
1
0
1
9
NA
31. Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
32. Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
33. Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
34. Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA

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Appendix J.
Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin)
1.
Lateral lumbar flexion:  patient stands with heels and buttocks touching the wall, 
knees straight, shoulders back, hands by the side.  The patient is then asked to bend 
to the right side as far as possible without lifting the left foot/heel or flexing the 
right knee, and maintaining a straight posture, with heels, buttocks, and shoulders 
against the wall.  The distance from the third fingertip to the floor when patient 
bends to the side, is subtracted from the distance when the patient stands upright.  
The maneuver is repeated on the left side.
Left exact measurement (cm)_______    Right exact measurement (cm)_______
2.
Tragus-to-wall distance:  maintain same starting position as above.  The distance 
between tragus of the ear and wall during maximal effort to draw the head back 
without raising the chin above its usually carrying level is measured on both sides 
to the nearest 0.1 cm, using a rigid ruler.  Ensure no cervical extension, rotation, 
rolation, flexion or side flexion occurs.
Left exact measurement (cm)_______    Right exact measurement (cm)_______
3.
Lumbar flexion (modified Schober):  set marks in upright position at the level of 
the spinous process of L5 (found as the first process below the projected line across 
the back at the level of the top iliac crest) and 10 cm above the first mark.  Measure 
distraction of the marks when the patient bends forward as far as possible, keeping 
the knees straight.
Exact measurement (cm)_______
4.
Intermalleolar distance:  patient supine on the floor or a wide plinth, with the knees 
straight and the feet pointing straight up.  Patient is asked to separate legs along the 
resting surface as far as possible.  Distance between medial malleoli is measured.
Exact measurement (cm)_______
5.
Cervical rotation:  patient supine on plinth, head in neutral position, forehead 
horizontal (if necessary head on pillow or foam block to allow this, must be 

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documented for future reassessments).  Gravity goniometer placed centrally on the 
forehead.  Patient rotates head as far as possible, keeping shoulders still, ensure no 
neck flexion or side flexion occurs.  Rotational angled to the right and to the left is 
measured.
If you do not have a gravity goniometer:  patient sits with shoulders to the wall.  
Place goniometer to the wall above the patient's head.  Patient rotates head as 
described above.  Examiner aligns goniometer branch parallel to sagittal plane of 
the head.
Left exact measurement (degrees)_____Right exact measurement (degrees)_____
Adapted from:  van der Heijde D, et al.  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;489-493.  Epub 
2007 Aug 29.

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Appendix K.
Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)
1st Costochondral joint left/right
7th Costochondral joint left/right
Posterior superior iliac spine left/right
Anterior superior iliac spine left/right
Iliac crest left/right
5th Lumbar spinous process
Proximal insertion of Achilles tendon left/right
Reference:
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al.  Assessment of enthesitis in ankylosing spondylitis.  Ann 
Rheum Dis.  2003;62:127-32.

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Appendix L.
Bath Ankylosing Spondylitis Functional Index (BASFI), NRS
Please mark the box to indicate your level of ability with each of the following activities 
during the last week. (i.e.,
)
(An aid is a piece of equipment which helps you to perform an action or movement)
1.
Putting on your socks or tights without help or aids (e.g., sock aid).
0
1
2
3
4
5
6
7
8
9
10
easy
Impossible
2.
Bending forward from the waist to pick up a pen from the floor without an aid.
0
1
2
3
4
5
6
7
8
9
10
easy
impossible
3.
Reaching up to a high shelf without help or aids (e.g., helping hand).
0
1
2
3
4
5
6
7
8
9
10
easy
impossible
4.
Getting up out of an armless dining room chair without using your hands or any other help.
0
1
2
3
4
5
6
7
8
9
10
easy
impossible
5.
Getting up off the floor without help from lying on your back.
0
1
2
3
4
5
6
7
8
9
10
easy
impossible
6.
Standing unsupported for 10 minutes without discomfort.
0
1
2
3
4
5
6
7
8
9
10
easy
impossible

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7.
Climbing 12-15 steps without using a handrail or walking aid.  One foot at each step.
0
1
2
3
4
5
6
7
8
9
10
easy
impossible
8.
Looking over your shoulder without turning your body.
0
1
2
3
4
5
6
7
8
9
10
easy
impossible
9.
Doing physically demanding activities (e.g., physiotherapy exercises, gardening or sports).
0
1
2
3
4
5
6
7
8
9
10
easy
impossible
10. Doing a full days activities, whether it be at home or at work.
0
1
2
3
4
5
6
7
8
9
10
easy
impossible
References:
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.
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:ii1-ii44.  doi:10.1136/ard.2008.104018.

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Appendix M.
Physician's Global Assessment of Disease Activity, NRS
Please mark a box to indicate disease activity (independent of the patient's self 
assessment) (i.e.,
)
0
1
2
3
4
5
6
7
8
9
10
None
severe
References:
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.
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;ii1-ii44.  doi:10.1136/ard.2008.104018.

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Appendix N.
Patient's Assessment of Nocturnal Back Pain, NRS
Please place a mark in the box below to indicate your answer (i.e.,
)
What is the amount of back pain at night that you experienced during the last week?
0
1
2
3
4
5
6
7
8
9
10
No Pain
Most severe 
pain
References:
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.
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;ii1-ii44.  doi:10.1136/ard.2008.104018.

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Appendix O.
Patient's Global Assessment of Disease Activity, NRS
Please place a mark in the box below to indicate your answer (i.e.,
)
What is your overall assessment of your disease activity during the last week?
0
1
2
3
4
5
6
7
8
9
10
none
severe
References:
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.
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;ii1-ii44.  doi:10.1136/ard.2008.104018.

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Appendix P.
Patient's Global Assessment of Pain, NRS
Please place a mark in the box below to indicate your answer (i.e.,
)
How much pain have you had because of your condition during the last week?
0
1
2
3
4
5
6
7
8
9
10
no pain
pain as bad 
as it could be

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Appendix Q.
Health Assessment Questionnaire Modified for the 
Spondyloarthropathies (HAQ-S)
Modified Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S)
Place an "x" in the box which best describes your abilities OVER THE PAST WEEK:
WITHOUT ANY 
DIFFICULTY
WITH SOME 
DIFFICULTY
WITH MUCH 
DIFFICULTY
UNABLE 
TO DO
DRESSING AND GROOMING
Are you able to:
Dress yourself, including shoelaces 
and buttons?
0
1
2
3
Shampoo your hair?
0
1
2
3
ARISING
Are you able to:
Stand up from a straight chair?
0
1
2
3
Get in and out of bed?
0
1
2
3
EATING
Are you able to:
Cut your own meat?
0
1
2
3
Lift a full cup or glass to your
mouth?
0
1
2
3
Open a new milk carton?
0
1
2
3
WALKING
Are you able to:
Walk outdoors on a flat ground?
0
1
2
3
Climb up five steps?
0
1
2
3
Please check any AIDS OR DEVICES that you usually use for any of the above activities:
Devices used for dressing (button hook, 
zipper pull etc.)
Built up or special utensils
Crutches
Special or built up chair
Cane
Wheelchair
Walker

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Place an "x" in the box which best describes your abilities OVER THE PAST WEEK:
WITHOUT ANY 
DIFFICULTY
WITH SOME 
DIFFICULTY
WITH MUCH 
DIFFICULTY
UNABLE 
TO DO
HYGIENE
Are you able to:
Wash and dry your body?
0
1
2
3
Take a tub bath?
0
1
2
3
Get on and off the toilet?
0
1
2
3
REACH
Are you able to:
Reach and get down a 5 pound (2.3 
kilo) object (such as a bag of sugar) 
from above your head?
0
1
2
3
Bend down to pick up clothing from 
the floor?
0
1
2
3
GRIP
Are you able to:
Open car doors?
0
1
2
3
Open previously opened jars?
0
1
2
3
Turn faucets on and off?
0
1
2
3
ACTIVITIES
Are you able to:
Run errands and shop?
0
1
2
3
Get in and out of a car?
0
1
2
3
Do chores such as vacuuming or yard 
work?
0
1
2
3
Are you able to carry heavy packages 
such as grocery bags?
0
1
2
3
Are you able to sit for long periods of 
time, such as at work?
0
1
2
3
Are you able to work at a flat topped 
Table or desk?
0
1
2
3
DRIVING A CAR
Check here ________ if you DO NOT have a driver's license or a car
Are you able to look in the rear view 
mirror?
0
1
2
3
Are you able to turn your head to 
drive in reverse?
0
1
2
3

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Please check any AIDS OR DEVICES that you usually use for any of the above activities:
Raised toilet seat
Bathtub bar
Long-handled appliances for reach
Bathtub seat
Long-handled appliances in 
bathroom
Jar opener (for jars previously opened)
Please check any categories for which you usually need HELP FROM ANOTHER 
PERSON:
Hygiene
Reach
Gripping and opening 
things
Errands and chores
Your ACTIVITIES: To what extent are you able to carry out your everyday physical 
activities such as walking, climbing stairs, carrying groceries, or moving a chair?
COMPLETELY
MOSTLY
MODERATELY
A LITTLE
NOT AT ALL
Your PAIN:  How much pain have you had IN THE PAST WEEK?
On a scale of 0 to 100 (where zero represents "no pain" and 100 represents "severe pain,") 
please record the number below.
Your HEALTH:  Please rate how well you are doing on a scale of 0 to 100 (0 represents 
"very well" and 100 represents "very poor" health), please record the number below.

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How much stiffness have you had because of your illness in the past week?  Place a mark 
to indicate the severity of the stiffness.  (i.e.,
)
0
10
20
30
40
50
60
70
80
90
100
no 
stiffness
very severe 
stiffness
Reference:
Daltroy LH, Larson MG, Roberts NW, et al.  A modification of the Health Assessment Questionnaire for the 
spondyloarthropathies.  J Rheumatol.  1990;17(7):946-50.

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Appendix R.
SF-36v2 Health Status Survey
Your Health and Well-Being
This survey asks for your views about your health.  This information will help keep 
track of how you feel and how well you are able to do your usual activities.  
Thank you for completing this survey!
For each of the following questions, please mark an 
in the one box that best 
describes your answer.
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor
▼
▼
▼
▼
▼
1
2
3
4
5
2.
Compared to 1 year ago, how would you rate your health in general now?
Much better 
now than 
1 year ago
Somewhat better 
now than 
1 year ago
About the 
same as 
1 year ago
Somewhat worse 
now than 
1 year ago
Much worse 
now than 
1 year ago
▼
▼
▼
▼
▼
1
2
3
4
5
SF-36v2™ Health Survey© 1996, 2000 by Quality Metric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.  SF-36® is a registered trademark of Medical Outcomes Trust.
SF-36v2™ Standards, US Version 2.0

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3.
The following questions are about activities you might do during a typical day.  
Does your health now limit you in these activities?  If so, how much?
Yes, 
limited 
a lot
Yes, 
limited 
a little
No, not 
limited 
at all
▼
▼
▼
a. Vigorous activities, such as 
running, lifting heavy objects, 
participating in strenuous sports
1
2
3
b. Moderate activities, such as 
moving a table, pushing a 
vacuum cleaner, bowling, or 
playing golf
1
2
3
c. Lifting or carrying groceries
1
2
3
d. Climbing several flights of stairs
1
2
3
e. Climbing one flight of stairs
1
2
3
f.
Bending, kneeling, or stooping
1
2
3
g. Walking more than a mile
1
2
3
h. Walking several hundred yards
1
2
3
i.
Walking one hundred yards
1
2
3
j.
Bathing or dressing yourself
1
2
3
SF-36v2™ Health Survey© 1996, 2000 by Quality Metric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.  SF-36® is a registered trademark of Medical Outcomes Trust.
SF-36v2™ Standards, US Version 2.0

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4.
During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of your 
physical health?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
▼
▼
▼
▼
▼
a.
Cut down on the amount of time you 
spent on work or other activities
1
2
3
4
5
b.
Accomplished less than you would 
like
1
2
3
4
5
c.
Were limited in the kind of work or 
other activities
1
2
3
4
5
d.
Had difficulty performing the work 
or other activities (for example, it 
took extra effort)
1
2
3
4
5
5.
During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of any 
emotional problems (such as feeling depressed or anxious)?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
▼
▼
▼
▼
▼
a.
Cut down on the amount of time you 
spent on work or other activities
1
2
3
4
5
b.
Accomplished less than you would 
like
1
2
3
4
5
c.
Did work or other activities less 
carefully than usual
1
2
3
4
5
SF-36v2™ Health Survey© 1996, 2000 by Quality Metric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.  SF-36® is a registered trademark of Medical Outcomes Trust.
SF-36v2™ Standards, US Version 2.0

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6.
During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, 
neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
▼
▼
▼
▼
▼
1
2
3
4
5
7.
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very Severe
▼
▼
▼
▼
▼
▼
1
2
3
4
5
6
8.
During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
▼
▼
▼
▼
▼
1
2
3
4
5
SF-36v2™ Health Survey© 1996, 2000 by Quality Metric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.  SF-36® is a registered trademark of Medical Outcomes Trust.
SF-36v2™ Standards, US Version 2.0

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9.
These questions are about how you feel and how things have been with you during
the past 4 weeks.  For each question, please give the one answer that comes closest 
to the way you have been feeling.  How much of the time during the past 4 weeks?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
▼
▼
▼
▼
▼
a.
Did you feel full of life?
1
2
3
4
5
b.
Have you been very nervous?
1
2
3
4
5
c.
Have you felt so down in the dumps 
that nothing could cheer you up?
1
2
3
4
5
d.
Have you felt calm and peaceful?
1
2
3
4
5
e.
Did you have a lot of energy?
1
2
3
4
5
f.
Have you felt downhearted and 
depressed?
1
2
3
4
5
g.
Did you feel worn out?
1
2
3
4
5
h.
Have you been happy?
1
2
3
4
5
i.
Did you feel tired?
1
2
3
4
5
SF-36v2™ Health Survey© 1996, 2000 by Quality Metric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.  SF-36® is a registered trademark of Medical Outcomes Trust.
SF-36v2™ Standards, US Version 2.0

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10.
During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting friends, 
relatives, etc.)?
All of the time
Most of the time
Some of the time
A little of the time
None of the time
▼
▼
▼
▼
▼
1
2
3
4
5
11.
How TRUE or FALSE is each of the following statements for you?
Definitely 
true
Mostly 
true
Don't 
know
Mostly 
false
Definitely 
false
▼
▼
▼
▼
▼
a.
I seem to get sick a little easier 
than other people
1
2
3
4
5
b.
I am as healthy as anybody I know
1
2
3
4
5
c.
I expect my health to get worse
1
2
3
4
5
d.
My health is excellent
1
2
3
4
5
THANK YOU FOR COMPLETING THESE QUESTIONS!
SF-36v2™ Health Survey© 1996, 2000 by Quality Metric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.  SF-36® is a registered trademark of Medical Outcomes Trust.
SF-36v2™ Standards, US Version 2.0

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Appendix S.
Work Productivity and Activity Impairment Questionnaire:  Axial 
Spondylorarthritis, V2.0 (WPAI:  Axial Spondyloarthritis)
Page 1 of 2
The following questions ask about the effect of your axial spondyloarthritis on your 
ability to work and perform regular activities.  Please fill in the blanks or circle a number, 
as indicated.
1. Are you currently employed (working for pay)? ____NO
____YES
If NO, check "NO" and skip to question 6.
The next questions are about the past seven days, not including today.
2.
During the past seven days, how many hours did you miss from work because of 
problems associated with your axial spondyloarthritis?  Include hours you missed 
on sick days, times you went in late, left early, etc., because of your axial 
spondyloarthritis.  Do not include time you missed to participate in this study.
______HOURS
3.
During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study?
______HOURS
4. During the past seven days, how many hours did you actually work?
______HOURS (If "0," skip to question 6.)
5.
During the past seven days, how much did your axial spondyloarthritis affect your 
productivity while you were working?
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully 
as usual.  If axial spondyloarthritis affected your work only a little, choose a low number.  
Choose a high number if axial spondyloarthritis affected your work a great deal.

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Work Productivity and Activity Impairment Questionnaire: Axial 
Spondylorarthritis, V2.0 (WPAI: Axial Spondyloarthritis) 
(Page 2 of 2)
Consider only how much axial spondyloarthritis
affected productivity while you were working.
Axial 
Spondyloarthritis had 
no effect on my work
Axial Spondyloarthritis 
completely prevented 
me from working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6.
During the past seven days, how much did your axial spondyloarthritis affect your 
ability to do your regular daily activities, other than work at a job?
By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc.  Think about times you were limited in the 
amount or kind of activities you could do and times you accomplished less than you would 
like.  If axial spondyloarthritis affected your activities only a little, choose a low number.  
Choose a high number if axial spondyloarthritis affected your activities a great deal. 
Consider only how much axial spondyloarthritis affected your ability 
to do your regular daily activities, other than work at a job.
Axial Spondyloarthritis 
had no effect on my 
daily activities
Axial Spondyloarthritis
completely prevented me 
from doing my daily 
activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
Reference:  Reilly MC, Zbrozek AS, Dukes EM.  The validity and reproducibility of a work productivity and activity 
impairment instrument.  Pharmacoeconomics.  1993;4(5):353-65.

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Appendix T.
EQ-5D (US English Version)
By placing a checkmark in one box in each group below, please indicate which statements 
best describe your own health state today.
Mobility
I have no problems in walking about 
I have some problems in walking about 
I am confined to bed 
Self-Care
I have no problems with self-care 
I have some problems washing or dressing myself 
I am unable to wash or dress myself 
Usual Activities (e.g., work, study, housework, family or leisure activities)
I have no problems with performing my usual activities 
I have some problems with performing my usual activities 
I am unable to perform my usual activities 
Pain/Discomfort
I have no pain or discomfort 
I have moderate pain or discomfort 
I have extreme pain or discomfort 
Anxiety/Depression
I am not anxious or depressed 
I am moderately anxious or depressed 
I am extremely anxious or depressed 

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Reference:  McDowell I, Newell C.  The EuroQol Quality of Life Scale.  Measuring Health:  A Guide to Rating Scales 
and Questionnaires.  2nd ed.  1996;9:480-483.

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Appendix U.
70-Day Follow-Up Call – Sample
Site Name/Number:  ________
Subject Number:  ________
Please contact subjects that discontinue adalimumab 70 days following study drug discontinuation.
Date of Call:  ____________
Lost to Follow-Up (Please check this box if subject was not willing to provide any follow-up 
information or you were unable to speak to the subject following at least one attempt.)
No Events Reported
NA - subject continued adalimumab therapy after the end of their study participation.
List any Adverse Events (AE) and/or Serious Adverse Events (SAE) that occurred since the subject 
was last seen in clinic for this study.  If needed, provide AE/SAE details on the AE worksheet 
attached.  (Please report all SAEs to AbbVie within 24 hours of being made aware of the event.)
If events are listed above, your monitor will review and retrieve the appropriate eCRF pages during 
their next visit.
Please fax all completed forms to:
[Name] at XXX-XXX-XXXX

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Appendix V.
Injection Instructions – Sample Pre-Filled Syringe
Subject Instructions
0.8 mL dose
(Administered as a single dose-pre-filled syringe)
Protocol M13-375
Tables of Contents
Dosing Schedule
General Information & Supplies
Injection Procedures

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Study Drug Dosing Schedule
Subject Number:  _____________________________________
You will require subcutaneous (SC) injections throughout the study.  You will receive a 
kit each visit containing 2 syringes.
You will receive the following number of injections during this study:
●
Baseline visit (the first visit to receive study medication for this study) you 
will receive 1 injection at the clinic (self administer or receive help from site 
staff).
●
Weeks 2, 4, 8, 12 and 24 you will administer 1 injection at the clinic to allow 
site staff to view your injection technique.  It is possible that you may be 
discontinued at Weeks 20, 24 or 28 if you do not qualify to continue by 
meeting the remission criteria.
●
Weeks 6, 10, 14, 16, 18, 20, 22 and 26 you will administer 1 injection at home
or clinic if applicable.  Note on clinic days, you must inject study drug after all 
study procedures are performed (not prior).
●
If Randomized at Week 28, you will administer 1 injection every other week 
(eow) at home (or in clinic), Week 28 through the end of the study 
(Week 68-80 based on Rescue Therapy needed).
During the Baseline Visit through Week 26, you will receive active study medication.  
You or a trained designee will inject your study drug every other week from the Baseline 
Visit to Week 26.
During the Week 28 Visit, if you have meet criteria for Randomization, you will receive 
1 kit (2 syringes) of blinded study medication each visit from Week 28 through Week 66 
to be injected at home.  You will not administer study medication at your last visit 
(Week 68).
If you meet the criteria for flare on 2 consecutive visits, you will receive rescue therapy 
(active study drug) until the end of the study.  If you flare at Weeks 60, 64 or 68, you will 

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receive rescue therapy for 12 weeks and will receive rescue therapy until Weeks 72, 76 or 
80 respectively.  You will not administer study medication at your last visit.
Please return all used and unused syringes, the sharps container and empty boxes to the 
clinic on your next visit.  Used syringes should be placed in the special Sharps container 
provided.  All unused syringes should be returned in the original box.
If an injection is missed or something occurs where the full dose cannot be injected, 
contact your study center immediately for further instructions. Please record any missed 
doses on your subject dosing sheet.
Remember to complete your dosing sheet after each injection and to call the doctor's 
office if you are having problems administering your study medication.
General Information
●
Pre-filled syringes with study medication will be labeled "Adalimumab"
during the open-label period (Period 1) or during rescue therapy and 
"Adalimumab or Placebo" during the double-blind period (Period 2).
●
Store all pre-filled syringes in your refrigerator at 36°F to 46°F (2°C to 8°C) in 
the original container until it is used. NOT in the freezer.  Should the syringes 
accidentally become frozen, call your study doctor's office.
●
Protect the study medication from light.
●
When traveling, study medication should be stored in a cool carrier with an ice 
pack.
●
Do not use a prefilled syringe if the liquid is cloudy, discolored, or has flakes 
or particles in it.
●
Do not drop or crush the study medication. The prefilled syringe is glass.
●
Study medication should be taken at about the same time of day, on the same 
day of the week as directed by your study doctor.
●
USE A NEW SYRINGE EVERY INJECTION DAY.  There may be 
medication left in the syringe.  DO NOT RE-USE.

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●
Save all study medications.  Pre-filled syringes (used and unused) & empty 
boxes must be returned to the study center at each visit.  Used syringes will 
be disposed of in a sharps container provided to you.
●
Call your doctor IMMEDIATELY if you experience any itching, hives, 
shortness of breath, or any symptom that has you concerned.  If you are unable 
to reach your doctor or if you experience life-threatening symptoms call, 
______________________ or proceed to your nearest emergency room.
●
Keep study medication, injection supplies, and all other medicines out of the 
reach of children.
Injection Procedures (PFS)
1. Setting up for an injection
●
Find a clean flat surface.
●
Do not use if the seals on the carton are broken or missing.  Contact your study 
doctor's office if the seals are broken.
●
Take one kit with the prefilled syringe(s) of study drug from the refrigerator.  
Do not use a prefilled syringe that has been frozen or if it has been left in direct 
sunlight.
●
Return any unused syringe(s) to the refrigerator.
You will need the following items for each dose:
●
study medication in pre-filled syringe
●
alcohol prep(s) or swab(s)
●
cotton ball(s) or gauze pad(s)
●
puncture-proof sharps container for prefilled syringe disposal
The diagram below shows what a prefilled syringe looks like.  See Figure A.

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Figure A.
If you do not have all of the items you need to give yourself an injection, call your study 
physician.  Use only the items provided in the box your study drug comes in.
Do not use and call your study doctor if:
●
the seals on top and bottom of the carton are broken or missing.
●
the study medication labeling has an expired date.  Check the expiration date 
on your study medication carton and do not use if the date has passed.
●
the prefilled syringe has been frozen or left in direct sunlight.
●
the liquid in the prefilled syringe is cloudy, discolored or has flakes or particles 
in it.  Make sure the liquid is clear and colorless.
For your protection, it is important that you follow these instructions.

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2. Choosing and preparing an injection site
●
Wash and dry your hands well
●
Choose an injection site:
○
on the front of your thighs or
○
your lower abdomen (belly).  If you choose your abdomen, you should 
avoid the area 2 inches around your belly button (navel). See Figure B.
Figure B.

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●
Choose a different site each time you give yourself an injection.  Each new 
injection should be given at least one inch from a site you used before.
●
Do not inject into skin that is:
○
sore (tender)
○
bruised
○
red
○
hard
○
scarred or where you have stretch marks
●
If you have psoriasis, you should try not to inject directly into any raised, 
thick, red or scaly skin patches or lesions on your skin.
●
You may find it helpful to keep notes on the location of your injection sites.
●
Do not inject through your clothes.
●
Wipe the injection site with an alcohol prep (swab) using a circular motion.
●
Do not touch this area again before giving the injection. Allow the skin to dry 
before injecting. Do not fan or blow on the clean area.
3. How to prepare your study drug dose for injection with a Prefilled Syringe
●
Check the fluid level in the syringe:
○
Always hold the prefilled syringe by the body of the syringe.  Hold the 
syringe with the covered needle pointing down.  See Figure C.

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Figure C.
Hold the syringe at eye level.  Look closely to make sure that the amount of liquid in the 
syringe is the same or close to the 0.8 mL line for the 40 mg prefilled syringe.  See 
Figure D.

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Figure D.
●
The top of the liquid may be curved. If the syringe does not have the correct 
amount of liquid, do not use that syringe. Call your study doctor.
●
Remove the needle cover:
○
Hold the syringe in one hand.  With the other hand gently remove the 
needle cover.  See Figure E.
○
Throw away the needle cover.

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Figure E.
●
Do not touch the needle with your fingers or let the needle touch anything.
●
Turn the syringe so the needle is facing up and hold the syringe at eye level 
with one hand so you can see the air in the syringe. Using your other hand, 
slowly push the plunger in to push the air out through the needle. See 
Figure F.

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Figure F.
●
You may see a drop of liquid at the end of the needle.  This is normal.
●
Do not shake the syringe.
4. Injecting Study Drug
●
Hold the body of the prefilled syringe in one hand between the thumb and 
index fingers. Hold the syringe in your hand like a pencil. See Figure G.

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Figure G.
●
Do not pull back on the plunger at any time.
●
With your other hand, gently squeeze an area of the cleaned area of skin and 
hold it firmly.  See Figure H.

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Figure H.
●
Using a quick, dart-like motion, insert the needle into the squeezed skin at 
about a 45-degree angle. See Figure I.

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Figure I.
●
After the needle is in, let go of the skin.  Pull back gently on the plunger.
If blood appears in the syringe:
●
It means that you have entered a blood vessel.
●
Do not inject study drug.
●
Pull the needle out of the skin while keeping the syringe at the same angle.
●
Press a cotton ball or gauze pad over the injection site and hold it for 
10 seconds.  See Figure J.

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Figure J.
●
Do not use the same syringe and needle again.  Throw away the needle and 
syringe in your special sharps container.
●
Do not rub the injection site.  You may have slight bleeding.  This is normal.
●
Repeat Steps 1 through 12 with a new prefilled syringe.
If no blood appears in the syringe:
●
Slowly push the plunger all the way in until all of the liquid is injected and the 
syringe is empty.
●
Pull the needle out of the skin while keeping the syringe at the same angle.
●
Press a cotton ball or gauze pad over the injection site and hold it for 
10 seconds.  Do not rub the injection site. You may have slight bleeding.  
This is normal.
●
Dispose of the syringe right away into your special sharps container. See 
Figure K.
●
Do not throw the needle, or syringe, in the household trash.  Do not recycle.
●
Do not try to touch the needle.

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Figure K.
●
For the safety and health of you and others, needles and used syringes must 
never be re-used.
●
Always keep the sharps container out of the reach of children.
●
The used alcohol pads, cotton balls, dose trays and packaging may be placed in 
your household trash.
●
When you go to your study visit tape the cap or lid of the sharps container 
down so it does not come off and take it to your visit.  Do not throw the 
container in the household trash.  Do not recycle.

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Appendix W.
Subject Dosing Diary Sheet (Sample)
To be completed for every study dose administered.  Study medication should be taken at 
about the same time of day, on the same day of the week as directed by your study doctor.  
Please record the date, time of study drug administration, kit number, dose administered, 
injection location, initials of person administering study medication, and any comments.  
Instructions on proper study medication administration will be provided by your study 
doctor and should be followed for every injection.  Call the doctor's clinic if you are 
having problems administering your study medication.
Please bring your Sheet with you to each clinic visit.
If you have any questions or concerns at any time, please call the study coordinator or 
physician at the following number(s):
Subject Study Number:  _____________

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Date
day/mm/yr
Day or 
Week#
Time of Study 
Drug 
Administrationa
Kit 
Number
Dose (mL) 
Administered
Injection 
Site 
(abdomen 
or thigh)
Initials of 
Person 
Administering 
Study 
Medication
Comments
31/MAY/12
EXAMPLE
0 9:3 0 hrs
123456
0.8 mL
abdomen
PG
Clinic 
injection
Baseline
: 
  hrs
Week 2
: 
  hrs
Week 4
: 
  hrs
Week 6
: 
  hrs
Week 8
: 
  hrs
Week 10
: 
  hrs
Week 12
: 
  hrs
Week 14
: 
  hrs
Week 16
: 
  hrs
Week 18
: 
  hrs
Week 20
: 
  hrs
Week 22
: 
  hrs
Week 24
: 
  hrs
Week 26
: 
  hrs
Week 28
: 
  hrs
Week 30
: 
  hrs
Week 32
: 
  hrs
Week 34
: 
  hrs
Week 36
: 
  hrs
Week 38
: 
  hrs
Week 40
: 
  hrs
Week 42
: 
  hrs
Week 44
: 
  hrs
Week 46
: 
  hrs
Week 48
: 
  hrs
Week 50
: 
  hrs
Week 52
: 
  hrs
Week 54
: 
  hrs
Week 56
: 
  hrs
Week 58
: 
  hrs

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Date
day/mm/yr
Day or 
Week#
Time of Study 
Drug 
Administrationa
Kit 
Number
Dose (mL) 
Administered
Injection 
Site 
(abdomen 
or thigh)
Initials of 
Person 
Administering 
Study 
Medication
Comments
Week 60
: 
  hrs
Week 62
: 
  hrs
Week 64
: 
  hrs
Week 66
: 
  hrs
Week 68
: 
  hrs
Week 70
: 
  hrs
Week 72
: 
  hrs
Week 74
: 
  hrs
Week 76
: 
  hrs
Week 78
: 
  hrs
a.
Please note the time in military time (e.g., 22:00 hrs etc.)

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Appendix X.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Sponsor/Emergency 
  Contact:
Has been changed to read:
Sponsor/Emergency 
  Contact:

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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M13-375
Name of Study Drug:  Adalimumab
Phase of Development:  3b/4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  04 December 2013
Protocol Title:  A Multicenter, Randomized, Double-Blind, Study Comparing the Efficacy and Safety of 
Continuing Versus Withdrawing Adalimumab Therapy in Maintaining Remission in Subjects with 
Non-Radiographic Axial Spondyloarthritis
Objective:  The objective of this study is to evaluate the efficacy and safety of continuing versus 
withdrawing therapy with adalimumab 40 mg given every other week (eow) subcutaneously (SC) in 
maintaining remission in subjects with non-radiographic axial Spondyloarthritis (nr-axSpA).
Investigators:  Multicenter
Study Sites:  Approximately 150 sites
Study Population:  Adult subjects with nr-axSpA and objective evidence of active inflammation in the 
sacroiliac (SI) joints or spine on MRI, or elevated high sensitivity C-reactive protein (hs-CRP).
Number of Subjects to be Enrolled:  Approximately 740

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Methodology:
The study duration will include a 30-day Screening Period, a 28-week open-label (OL) 40 mg 
adalimumab eow treatment period (Period 1), a 40-week double-blind, placebo-controlled treatment 
period (Period 2), with an opportunity to receive at least 12 weeks of rescue therapy (subjects who flare 
at Weeks 60, 64 and 68 will be allowed 12 weeks of rescue therapy), and a 70-day follow-up phone call.
Subjects in remission defined as meeting Ankylosing Spondylitis Disease Activity Score (ASDAS) 
Inactive Disease (ASDAS < 1.3) at Weeks 16, 20, 24 and Week 28 will be randomized in a 1:1 ratio to 
receive either blinded adalimumab 40 mg eow or matching placebo during Period 2.  Due to the 
importance of the Week 16, 20 and 24 visits, two or more missed visits during this time must be 
discussed with the AbbVie Medical Monitor prior to randomization.  If a subject misses a single visit at 
Week 16, 20, or 24 the site will need to use the ASDAS parameters from the visit immediately prior to 
the missed visit.  If a subject misses the Week 28 visit, the subject must be discontinued.  Subjects not 
meeting the ASDAS Inactive Disease at Weeks 16, 20, 24 or Week 28 will be discontinued.  Subjects 
may be discontinued as early as Week 20 if they do not meet the ASDAS remission criteria using the 
Week 16 parameters.
No formal unblinded interim analysis is planned for this study that requires an adjustment to the P value.  
An interim analysis will be performed when all ongoing subjects have completed at least Week 28 of the 
study.  The primary and secondary endpoints of the study from the double-blind period will be reported at 
the completion of the study.
Subjects who flare in Period 2 (40-week double-blind period) will be allowed rescue therapy.  Flare is 
defined as 2 consecutive study visits with ASDAS ≥ 2.1.  Rescue therapy will consist of OL adalimumab 
40 mg eow for at least 12 weeks and will continue through the duration of the subject's participation of 
the study.  After 12 weeks of rescue therapy with OL adalimumab eow, initiation of or change in a 
subject's concomitant medications for SpA including doses of DMARDs, corticosteroids, NSAIDs, and 
analgesics are permitted based on the investigator's medical judgment.  For subjects who meet the flare 
criteria at Weeks 60, 64 or 68, rescue therapy with OL adalimumab will be provided for 12 weeks and 
final study visit will be at Weeks 72, 76 or 80, respectively.

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Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject age ≥ 18 years.
2.
Subject with nr-axSpA fulfilling the Assessment of Spondyloarthritis International Society 
(ASAS) axial SpA classification criteria, but not fulfilling the radiologic criterion of the 
modified New York criteria for ankylosing spondylitis.
3.
Subject has had an inadequate response to at least 2 nonsteroidal anti-inflammatory drugs 
(NSAIDs) over a 4-week period in total at maximum recommended or tolerated doses, or has 
intolerance to or a contraindication for NSAIDs as defined by the Investigator.
4.
Subject with objective evidence of active inflammation in the SI joints or spine on MRI or 
elevated hs-CRP at screening (elevated hs-CRP is defined as any level greater than the upper 
limit of normal for the lab).
5.
Subject is a candidate for anti-TNF therapy based on the investigator's opinion.
6.
Subjects must have baseline disease activity as defined by having an ASDAS ≥ 2.1 (note, sites 
will need to use the Screening Visit hs-CRP to calculate ASDAS at Screening and Baseline 
Visits with the remainder of parameters visit-specific), BASDAI ≥ 4 and Patient's Assessment 
of Total Back Pain score ≥ 4 based on a Numeric Rating Scale (NRS) at both the Screening and 
Baseline Visits.
Main Exclusion:
1.
Subject fulfilling the radiologic criterion of the modified New York criteria for ankylosing 
spondylitis at or prior to the Screening Visit.
2.
Prior exposure to any anti-TNF therapy; any biologic therapy with a potential therapeutic impact 
on SpA, or subject has been treated with any investigational drug of chemical or biologic nature 
within a minimum of 30 days or five half-lives (whichever is longer) of the drug prior to the 
Baseline Visit.
3.
If entering the study on concomitant disease-modifying anti-rheumatic drugs (DMARDs), 
subject not on stable dose of methotrexate (≤ 25 mg per week) and/or sulfasalazine (≤ 3 g per 
day) and/or hydroxychloroquine (≤ 400 mg per day) for 28 days prior to the Baseline Visit.  All 
other oral DMARDs are prohibited within 28 days prior to the Baseline Visit.
4.
If entering the study on concomitant azathioprine (AZA), subject not on stable dose (≤ 150 mg 
per day) for 28 days prior to the Baseline Visit or is on AZA and another concomitant 
immunosuppressive drug at study entry.
5.
If entering the study on concomitant NSAIDs, tramadol, and/or non-opioid analgesics, subject 
not on stable doses for 14 days prior to the Baseline Visit.
6.
Subject on opioid analgesics or use of marijuana within 14 days prior to the Baseline Visit.
7.
If entering the study on concomitant oral corticosteroids, subject not on stable dose of 
prednisone (≤ 10 mg per day), or oral corticosteroid equivalents, for at least 14 days prior to the 
Baseline Visit.
8.
Subject has been treated with intramuscular, intra-articular joint injection(s) or spinal/paraspinal 
injection(s) of corticosteroids in the preceding 28 days prior to the Baseline Visit.
9.
Subject has undergone spinal surgery within 2 months prior to Baseline 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.

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Main Exclusion (Continued):
10. Subject with extra-articular manifestations (e.g., inflammatory bowel disease, psoriasis, uveitis, 
etc.) that is not clinically stable for at least 30 days prior to study entry.
11. Subject has a history of fibromyalgia or inflammatory arthritis of a different etiology other than 
SpA (e.g., rheumatoid arthritis, gout, systemic lupus erythematosus, polyarticular or systemic 
juvenile idiopathic arthritis).
Investigational Product:
Adalimumab
Dose:
40 mg eow
Mode of Administration:
SC
Reference Therapy:
Placebo
Dose:
eow
Mode of Administration:
SC
Duration of Treatment:
Length of exposure will depend on remission or flare status (20 [first time ASDAS remission will be 
calculated] to 80 weeks of treatment).
The duration of treatment will include a 28-week, OL period (adalimumab 40 mg eow), followed by a 
40-week, randomized, double-blind period (adalimumab 40 mg eow versus placebo), with an opportunity 
to receive at least 12 weeks of rescue therapy (subjects who flare at Weeks 60, 64 or 68 will be allowed 
12 weeks of rescue therapy and final study visit will be at Weeks 72, 76, or 80, respectively).
Criteria for Evaluation:
Efficacy:
The primary efficacy variable is the proportion of subjects who do not experience a flare by Week 68 of 
the study where a flare is defined as having any 2 consecutive study visits with ASDAS ≥ 2.1.
Secondary efficacy variables include the following:
At 12 weeks after initiation of Rescue Therapy
!
ASDAS Inactive Disease (ASDAS < 1.3)
!
ASDAS Major Improvement (a change from baseline ≤ –2.00)
!
ASDAS Clinically Important Improvement (a change from baseline ≤ –1.10)

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Efficacy (Continued):
!
ASAS20, ASAS40, ASAS 5/6 and ASAS Partial Remission
o
ASAS20 response: improvement of ≥ 20% and absolute improvement of ≥ 1 unit (on a scale 
of 0 to 10) from Baseline in ≥ 3 of the following 4 domains, with no deterioration in the 
remaining domain (defined as a worsening of ≥ 20% and a net worsening of ≥ 1 unit)
o
Patient's Global Assessment – Represented by the PTGA-disease activity NRS score 
(0 to 10)
o
Pain – Represented by the patient's assessment of total back pain NRS score (0 to 10)
o
Function – Represented by the BASFI NRS score (0 to 10)
o
Inflammation – Represented by the mean of the 2 morning stiffness-related BASDAI 
NRS scores (mean of items 5 and 6 of the BASDAI [0 to 10])
o
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 in ASAS20 with no 
deterioration in the potential remaining domain
o
ASAS partial remission: absolute score of < 2 units for each of the 4 domains identified 
above in ASAS20
o
ASAS 5/6 response:  20% improvement 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
!
Bath AS Disease Activity Index 50 (BASDAI50)
!
Health Assessment Questionnaire Modified for the Spondyloarthropathies (HAQ-S)
At Week 28 and Week 68
!
ASDAS Inactive Disease
!
ASDAS Major Improvement
!
ASDAS Clinically Important Improvement
!
ASAS20, ASAS40, ASAS 5/6 and ASAS Partial Remission
!
BASDAI50
!
HAQ-S
At Week 68 
!
Time to flare defined as ASDAS ≥ 2.1 at 2 consecutive visits
!
Time to partial flare defined as ASDAS ≥ 1.3 but < 2.1 at 2 consecutive visits
!
Proportion of subjects who reach flare definition
!
Proportion of subjects who reach partial flare definition
Other Efficacy Variables
!
Patient's Global Assessment of Disease Activity
!
Patient's Assessment of Total back pain
!
Bath AS Functional Index (BASFI)
!
Inflammation/Morning Stiffness (mean of BASDAI questions 5 and 6)

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Efficacy (Continued):
!
Bath AS Disease Activity Index (BASDAI)
!
ASDAS
!
hs-CRP
!
Linear Bath AS Metrology Index (BASMIlin)
!
Swollen Joint Count (66 joints)
!
Tender Joint Count (68 joints)
!
MASES
!
Plantar fascia enthesitis
!
Dactylitis
!
Physician's Global Assessment of Disease Activity
!
Patient's Global Assessment of Pain
!
Patient's Assessment of Nocturnal Back Pain
!
Anterior Uveitis
!
Short Form-36v2 Health Survey questionnaire
!
EQ-5D
!
Work Productivity and Activity Impairment – Axial Spondylorarthritis (WPAI-axial SpA)
!
SPARCC scores for MRI of the SI joint and spine
!
Proportion of subjects who regain remission on rescue therapy
!
Time to regain remission on rescue therapy
Each subject will have blood drawn for biomarkers at the following time points:  Baseline, Week 28, time 
of flare (if applicable), 12 weeks post flare (if applicable), and last study visit.  The biomarkers may 
include the following:
!
DKK-1
!
Sclerostin
!
BMP-2
!
BMP-7
Pharmacokinetic:
Each subject will have blood drawn for serum adalimumab concentration and anti-adalimumab antibody 
(AAA) at the following time points:  Baseline, Weeks 12, 28, 36, 52, 68, time of flare (if applicable), 
12 weeks post flare (if applicable), and last study visit.
Safety:
Screening assessments will include medical history, vital signs, physical examination, and clinical 
laboratory tests.  The following safety evaluations will be performed during the study:  concomitant 
medication review, adverse event (AE) monitoring, vital signs, physical examination (if required) and 
laboratory tests.

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Statistical Methods:
Efficacy:
The primary efficacy variable is the proportion of subjects who do not experience a flare in Period 2 by 
Week 68 of the study between the adalimumab and placebo groups.  Analysis will be performed using a 
two-sided chi squared test with an α = 0.05.  Subjects with missing primary efficacy endpoint response at 
Week 68 will be treated as non-responders, i.e., a "non-responder imputation" criterion will be used for 
missing data.  Descriptive statistics will also be provided for primary and secondary efficacy variables.
Pharmacokinetic:
For each scheduled time of measurement, summary statistics will be provided for the adalimumab serum 
concentration data by treatment group.  The adalimumab concentration data may be analyzed using 
nonlinear mixed effects modeling approach.  The percentage of subjects with AAA will be reported.
Safety:
Safety analyses will be carried out using the safety population, which includes all subjects who received 
at least one dose of study medication.  Treatment-emergent AEs and serious AEs (SAEs), which include 
pre- and post-treatment SAEs, will be summarized and reported.
Treatment-emergent AEs are defined as AEs that begin either on or after the first dose of the study 
medication, and up to within 70 days after the last dose of the study medication, except for those subjects 
that initiate adalimumab therapy not supplied in the context of the clinical trial after the end of study 
participation.  The number and percent of subjects experiencing AEs will be tabulated by body system 
and Medical Dictionary for Drug Regulatory Activities (MedDRA®) preferred term.  In addition, 
summary of AEs by severity and relationship to study drug will be presented.  Serious, severe, or AEs 
that lead to premature study discontinuation will be listed.
Mean change in vital signs and laboratory variables at each visit as compared to baseline will be 
summarized for all treated subjects, and compared between treatment groups using a one way Analysis of 
Variance (ANOVA).  The last evaluation prior to the first dose of study drug will be used as Baseline for 
all analyses.  For selected parameters, a listing of all subjects with any laboratory determination meeting 
Common Toxicity Criteria (CTC) of Grade 3 or higher will be provided.  Shift tables for changes from 
Baseline according to the normal range will also be provided for laboratory variables.
Sample Size:
Assuming that 50% of subjects treated with adalimumab will not experience any flare up to Week 68, 
120 subjects per arm are required for the double-blind period (Period 2) (with an adjustment for a drop-
out rate of no more than 30%) is targeted to result in at least 90% power for detecting 25% difference at 
Week 68 primary endpoint between adalimumab and placebo based on a two-sided test with significance 
level 0.05.
It is assumed that approximately 33% of the subjects enrolled into the OL period (Period 1) would meet 
ASDAS Inactive Disease at Weeks 16, 20, 24 and Week 28; therefore, a total of approximately 
740 subjects would be required to be enrolled in order to have sufficient number of subjects 
(i.e., 120 subjects per arm) for the double-blind period.  Study enrollment will be closed prior to reaching 
740 subjects should a sufficient number of subjects fulfill remission criteria and be available for 
randomization at the end of Period 1 prior to full enrollment.

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Has been changed to read:
AbbVie Inc.
Protocol Number:  M13-375
Name of Study Drug:  Adalimumab
Phase of Development:  3b/4
Name of Active Ingredient:  Adalimumab
Date of Protocol Synopsis:  15 January 2015
Protocol Title:  A Multicenter, Randomized, Double-Blind, Study Comparing the Efficacy and Safety of 
Continuing Versus Withdrawing Adalimumab Therapy in Maintaining Remission in Subjects with 
Non-Radiographic Axial Spondyloarthritis
Objective:  The objective of this study is to evaluate the efficacy and safety of continuing versus 
withdrawing therapy with adalimumab 40 mg given every other week (eow) subcutaneously (SC) in 
maintaining remission in subjects with non-radiographic axial Spondyloarthritis (nr-axSpA).
Investigators:  Multicenter
Study Sites:  Approximately 150 sites
Study Population:  Adult subjects with nr-axSpA and objective evidence of active inflammation in the 
sacroiliac (SI) joints or spine on MRI, or elevated high sensitivity C-reactive protein (hs-CRP).
Number of Subjects to be Enrolled:  Approximately 740
Methodology:
The study duration will include a 42-day Screening Period, a 28-week open-label (OL) 40 mg 
adalimumab eow treatment period (Period 1), a 40-week double-blind, placebo-controlled treatment 
period (Period 2), with an opportunity to receive at least 12 weeks of rescue therapy (subjects who flare 
at Weeks 60, 64 and 68 will be allowed 12 weeks of rescue therapy), and a 70-day follow-up phone call.
Subjects in remission defined as meeting Ankylosing Spondylitis Disease Activity Score (ASDAS) 
Inactive Disease (ASDAS < 1.300) at Weeks 16, 20, 24 and Week 28 will be randomized in a 1:1 ratio to 
receive either blinded adalimumab 40 mg eow or matching placebo during Period 2.  Due to the 
importance of the Week 16, 20 and 24 visits, two or more missed visits during this time must be 
discussed with the AbbVie Medical Monitor prior to randomization.  If a subject misses a single visit at 
Week 16, 20, or 24 the site will need to use the ASDAS parameters from the visit immediately prior to 
the missed visit.  If a subject misses the Week 28 visit, the subject must be discontinued.  Subjects not 
meeting the ASDAS Inactive Disease at Weeks 16, 20, 24 or Week 28 will be discontinued.  Subjects 
may be discontinued as early as Week 20 if they do not meet the ASDAS remission criteria using the 
Week 16 parameters.
No formal unblinded interim analysis is planned for this study that requires an adjustment to the P value.  
An interim analysis will be performed when all ongoing subjects have completed at least Week 28 of the 
study.  The primary and secondary endpoints of the study from the double-blind period will be reported at 
the completion of the study.
Subjects who flare in Period 2 (40-week double-blind period) will be allowed rescue therapy.  Flare is 
defined as 2 consecutive study visits with ASDAS ≥ 2.100.  Rescue therapy will consist of OL 
adalimumab 40 mg eow for at least 12 weeks and will continue through the duration of the subject's 
participation of the study.  After 12 weeks of rescue therapy with OL adalimumab eow, initiation of or 
change in a subject's concomitant medications for SpA including doses of DMARDs, corticosteroids, 
NSAIDs, and analgesics are permitted based on the investigator's medical judgment.  For subjects who 
meet the flare criteria at Weeks 60, 64 or 68, rescue therapy with OL adalimumab will be provided for 
12 weeks and final study visit will be at Weeks 72, 76 or 80, respectively.

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Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject age ≥ 18 years.
2.
Subject with nr-axSpA fulfilling the Assessment of Spondyloarthritis International Society 
(ASAS) axial SpA classification criteria, but not fulfilling the radiologic criterion of the 
modified New York criteria for ankylosing spondylitis.
3.
Subject has had an inadequate response to at least 2 nonsteroidal anti-inflammatory drugs 
(NSAIDs) over a 4-week period in total at maximum recommended or tolerated doses, or has 
intolerance to or a contraindication for NSAIDs as defined by the Investigator.
4.
Subject with objective evidence of active inflammation in the SI joints or spine on MRI or 
elevated hs-CRP at screening (elevated hs-CRP is defined as any level greater than the upper 
limit of normal for the lab).
5.
Subject is a candidate for anti-TNF therapy based on the investigator's opinion.
6.
Subjects must have baseline disease activity as defined by having an ASDAS ≥ 2.100 (note, sites 
will need to use the Screening Visit hs-CRP to calculate ASDAS at Screening and Baseline 
Visits with the remainder of parameters visit-specific), BASDAI ≥ 4 and Patient's Assessment 
of Total Back Pain score ≥ 4 based on a Numeric Rating Scale (NRS) at both the Screening and 
Baseline Visits.
Main Exclusion:
1.
Subject fulfilling the radiologic criterion of the modified New York criteria for ankylosing 
spondylitis at or prior to the Screening Visit.
2.
Prior exposure to any anti-TNF therapy; any biologic therapy with a potential therapeutic impact 
on SpA, or subject has been treated with any investigational drug of chemical or biologic nature 
within a minimum of 30 days or five half-lives (whichever is longer) of the drug prior to the 
Baseline Visit.
3.
If entering the study on concomitant disease-modifying anti-rheumatic drugs (DMARDs), 
subject not on stable dose of methotrexate (≤ 25 mg per week) and/or sulfasalazine (≤ 3 g per 
day) and/or hydroxychloroquine (≤ 400 mg per day) for 28 days prior to the Baseline Visit.  All 
other oral DMARDs, with the exception of azathioprine or mercaptopurine (6-MP) are 
prohibited within 28 days prior to the Baseline Visit.
4.
If entering the study on concomitant azathioprine (AZA) or 6-MP, subject not on stable dose 
(AZA ≤ 150 mg per day or 6-MP ≤ 75 mg per day) for 28 days prior to the Baseline Visit or is 
on AZA or 6-MP and another concomitant immunosuppressive drug at study entry.
5.
If entering the study on concomitant NSAIDs, tramadol, and/or non-opioid analgesics, subject 
not on stable doses for 14 days prior to the Baseline Visit.
6.
Subject on opioid analgesics or use of marijuana within 14 days prior to the Baseline Visit.
7.
If entering the study on concomitant oral corticosteroids, subject not on stable dose of 
prednisone (≤ 10 mg per day), or oral corticosteroid equivalents, for at least 14 days prior to the 
Baseline Visit.
8.
Subject has been treated with intramuscular, intra-articular joint injection(s) or spinal/paraspinal 
injection(s) of corticosteroids in the preceding 28 days prior to the Baseline Visit.

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Main Exclusion (Continued):
9.
Subject has undergone spinal surgery within 2 months prior to Baseline 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.
10. Subject with extra-articular manifestations (e.g., inflammatory bowel disease, psoriasis, uveitis, 
etc.) that is not clinically stable for at least 30 days prior to study entry.
11. Subject has a history of fibromyalgia or inflammatory arthritis of a different etiology other than 
SpA (e.g., rheumatoid arthritis, gout, systemic lupus erythematosus, polyarticular or systemic 
juvenile idiopathic arthritis).
Investigational Product:
Adalimumab
Dose:
40 mg eow
Mode of Administration:
SC
Reference Therapy:
Placebo
Dose:
eow
Mode of Administration:
SC
Duration of Treatment:
Length of exposure will depend on remission or flare status (20 [first time ASDAS remission will be 
calculated] to 80 weeks of treatment).
The duration of treatment will include a 28-week, OL period (adalimumab 40 mg eow), followed by a 
40-week, randomized, double-blind period (adalimumab 40 mg eow versus placebo), with an opportunity 
to receive at least 12 weeks of rescue therapy (subjects who flare at Weeks 60, 64 or 68 will be allowed 
12 weeks of rescue therapy and final study visit will be at Weeks 72, 76, or 80, respectively).
Criteria for Evaluation:
Efficacy:
The primary efficacy variable is the proportion of subjects who do not experience a flare by Week 68 of 
the study where a flare is defined as having any 2 consecutive study visits with ASDAS ≥ 2.100.
Secondary efficacy variables include the following:
At 12 weeks after initiation of Rescue Therapy
!
ASDAS Inactive Disease (ASDAS < 1.300)
!
ASDAS Major Improvement (a change from baseline ≤ –2.000)
!
ASDAS Clinically Important Improvement (a change from baseline ≤ –1.100)

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Efficacy (Continued):
!
ASAS20, ASAS40, ASAS 5/6 and ASAS Partial Remission
o
ASAS20 response: improvement of ≥ 20% and absolute improvement of ≥ 1 unit (on a scale 
of 0 to 10) from Baseline in ≥ 3 of the following 4 domains, with no deterioration in the 
remaining domain (defined as a worsening of ≥ 20% and a net worsening of ≥ 1 unit)
o
Patient's Global Assessment – Represented by the PTGA-disease activity NRS score 
(0 to 10)
o
Pain – Represented by the patient's assessment of total back pain NRS score (0 to 10)
o
Function – Represented by the BASFI NRS score (0 to 10)
o
Inflammation – Represented by the mean of the 2 morning stiffness-related BASDAI 
NRS scores (mean of items 5 and 6 of the BASDAI [0 to 10])
o
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 in ASAS20 with no 
deterioration in the potential remaining domain
o
ASAS partial remission: absolute score of < 2 units for each of the 4 domains identified 
above in ASAS20
o
ASAS 5/6 response:  20% improvement 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
!
Bath AS Disease Activity Index 50 (BASDAI50)
!
Health Assessment Questionnaire Modified for the Spondyloarthropathies (HAQ-S)
At Week 28 and Week 68
!
ASDAS Inactive Disease
!
ASDAS Major Improvement
!
ASDAS Clinically Important Improvement
!
ASAS20, ASAS40, ASAS 5/6 and ASAS Partial Remission
!
BASDAI50
!
HAQ-S
At Week 68 
!
Time to flare defined as ASDAS ≥ 2.100 at 2 consecutive visits
!
Time to partial flare defined as ASDAS ≥ 1.300 but < 2.100 at 2 consecutive visits
!
Proportion of subjects who reach flare definition
!
Proportion of subjects who reach partial flare definition
Other Efficacy Variables
!
Patient's Global Assessment of Disease Activity
!
Patient's Assessment of Total back pain
!
Bath AS Functional Index (BASFI)
!
Inflammation/Morning Stiffness (mean of BASDAI questions 5 and 6)

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Efficacy (Continued):
!
Bath AS Disease Activity Index (BASDAI)
!
ASDAS
!
hs-CRP
!
Linear Bath AS Metrology Index (BASMIlin)
!
Swollen Joint Count (66 joints)
!
Tender Joint Count (68 joints)
!
MASES
!
Plantar fascia enthesitis
!
Dactylitis
!
Physician's Global Assessment of Disease Activity
!
Patient's Global Assessment of Pain
!
Patient's Assessment of Nocturnal Back Pain
!
Anterior Uveitis
!
Short Form-36v2 Health Survey questionnaire
!
EQ-5D
!
Work Productivity and Activity Impairment – Axial Spondylorarthritis (WPAI-axial SpA)
!
SPARCC scores for MRI of the SI joint and spine
!
Proportion of subjects who regain remission on rescue therapy
!
Time to regain remission on rescue therapy
Exploratory Variables:
Each subject will have blood drawn for biomarkers at the following time points:  Baseline, Weeks 28, 68, 
time of flare (if applicable), 12 weeks post flare (if applicable), and last study visit.  The final set of 
biomarkers to be analyzed may include the following:
!
DKK-1
!
Sclerostin
!
BMP-2
!
BMP-7
The final selection of biomarkers for analysis will be based on both insights gained in the sub-study and 
available scientific knowledge at study completion.
Pharmacokinetic:
Each subject will have blood drawn for serum adalimumab concentration and anti-adalimumab antibody 
(AAA) at the following time points:  Baseline, Weeks 12, 28, 36, 52, 68, time of flare (if applicable), 
12 weeks post flare (if applicable), and last study visit.
Safety:
Screening assessments will include medical history, vital signs, physical examination, and clinical 
laboratory tests.  The following safety evaluations will be performed during the study:  concomitant 
medication review, adverse event (AE) monitoring, vital signs, physical examination (if required) and 
laboratory tests.

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Statistical Methods:
Efficacy:
The primary efficacy variable is the proportion of subjects who do not experience a flare in Period 2 by 
Week 68 of the study between the adalimumab and placebo groups.  Analysis will be performed using a 
two-sided chi squared test with an α = 0.05.  Subjects with missing primary efficacy endpoint response at 
Week 68 will be treated as non-responders, i.e., a "non-responder imputation" criterion will be used for 
missing data.  Descriptive statistics will also be provided for primary and secondary efficacy variables.
Pharmacokinetic:
For each scheduled time of measurement, summary statistics will be provided for the adalimumab serum 
concentration data by treatment group.  The adalimumab concentration data may be analyzed using 
nonlinear mixed effects modeling approach.  The percentage of subjects with AAA will be reported.
Safety:
Safety analyses will be carried out using the safety population, which includes all subjects who received 
at least one dose of study medication.  Treatment-emergent AEs and serious AEs (SAEs), which include 
pre- and post-treatment SAEs, will be summarized and reported.
Treatment-emergent AEs are defined as AEs that begin either on or after the first dose of the study 
medication, and up to within 70 days after the last dose of the study medication, except for those subjects 
that initiate adalimumab therapy not supplied in the context of the clinical trial after the end of study 
participation.  The number and percent of subjects experiencing AEs will be tabulated by body system 
and Medical Dictionary for Drug Regulatory Activities (MedDRA®) preferred term.  In addition, 
summary of AEs by severity and relationship to study drug will be presented.  Serious, severe, or AEs 
that lead to premature study discontinuation will be listed.
Mean change in vital signs and laboratory variables at each visit as compared to baseline will be 
summarized for all treated subjects, and compared between treatment groups using a one way Analysis of 
Variance (ANOVA).  The last evaluation prior to the first dose of study drug will be used as Baseline for 
all analyses.  For selected parameters, a listing of all subjects with any laboratory determination meeting 
Common Toxicity Criteria (CTC) of Grade 3 or higher will be provided.  Shift tables for changes from 
Baseline according to the normal range will also be provided for laboratory variables.
Sample Size:
Assuming that 50% of subjects treated with adalimumab will not experience any flare up to Week 68, 
120 subjects per arm are required for the double-blind period (Period 2) (with an adjustment for a drop-
out rate of no more than 30%) is targeted to result in at least 90% power for detecting 25% difference at 
Week 68 primary endpoint between adalimumab and placebo based on a two-sided test with significance 
level 0.05.
It is assumed that approximately 33% of the subjects enrolled into the OL period (Period 1) would meet 
ASDAS Inactive Disease at Weeks 16, 20, 24 and Week 28; therefore, a total of approximately 
740 subjects would be required to be enrolled in order to have sufficient number of subjects 
(i.e., 120 subjects per arm) for the double-blind period.  Study enrollment will be closed prior to reaching 
740 subjects should a sufficient number of subjects fulfill remission criteria and be available for 
randomization at the end of Period 1 prior to full enrollment.

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Section 1.3  List of Abbreviations and Definition of Terms
Add:  new abbreviation
6-MP
6-mercaptopurine
Section 3.3  Adalimumab Overview
Last paragraph, second and third sentence previously read:
Additional indications have been approved in the US and EU including Psoriasis, PsA, 
AS, Crohn's Disease (CD), Ulcerative Colitis (UC), and Polyarticular Juvenile Idiopathic 
Arthritis.  In addition, an indication for nr-axSpA has been approved in the EU.
Has been changed to read:
Additional indications have been approved in the US and EU including Psoriasis, PsA, 
AS, Crohn's Disease (CD), Pediatric CD, Ulcerative Colitis (UC), and Polyarticular 
Juvenile Idiopathic Arthritis.  In addition, an indication for nr-axSpA and Pediatric 
Enthesitis-Related Arthritis has been approved in the EU.
Section 3.6  Benefits and Risks
Fifth sentence previously read:
For Study M13-375, to ensure nr-axSpA subjects are appropriate candidates for anti-TNF 
therapy subjects are required to meet a minimum level of disease activity at baseline 
(ASDAS ≥ 2.1, BASDAI ≥ 4, Patient's Assessment of Total Back Pain score ≥ 4), have 
objective evidence of active disease (inflammation in the SI joints or spine on MRI or 
elevated hs-CRP), and have had an inadequate response to at least 2 NSAIDs.
Has been changed to read:
For Study M13-375, to ensure nr-axSpA subjects are appropriate candidates for anti-TNF 
therapy subjects are required to meet a minimum level of disease activity at baseline 
(ASDAS ≥ 2.100, BASDAI ≥ 4, Patient's Assessment of Total Back Pain score ≥ 4), have 
objective evidence of active disease (inflammation in the SI joints or spine on MRI or 
elevated hs-CRP), and have had an inadequate response to at least 2 NSAIDs.

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Section 5.1  Overall Study Design and Plan:  Description
First paragraph, first sentence previously read:
The study duration will include a 30-day Screening Period, a 28-week open-label (OL) 
40 mg adalimumab eow treatment period (Period 1), a 40 week double-blind placebo 
controlled eow treatment period (Period 2) with an opportunity to receive at least 
12 weeks of rescue therapy (subjects that flare at Weeks 60, 64 or 68 will be allowed 
12 weeks of rescue therapy and final visits will be 72, 76 or 80 respectively), plus a 
70-day follow-up phone call.  
Has been changed to read:
The study duration will include a 42-day Screening Period, a 28-week open-label (OL) 
40 mg adalimumab eow treatment period (Period 1), a 40 week double-blind placebo 
controlled eow treatment period (Period 2) with an opportunity to receive at least 
12 weeks of rescue therapy (subjects that flare at Weeks 60, 64 or 68 will be allowed 
12 weeks of rescue therapy and final visits will be 72, 76 or 80 respectively), plus a 
70-day follow-up phone call.  
Figure 1.  Study Design Schematic
First and second table note previously read:
*
Subjects who meet remission criteria (ASDAS inactive disease < 1.3) at Weeks 16, 20, 24 and 28 will be 
randomized to Period 2.  Subjects not meeting remission criteria will be discontinued at Weeks 20, 24 or 28.
**
Subjects who flare (ASDAS ≥ 2.1 for 2 consecutive study visits) during the double-blind period (Period 2) can 
receive rescue therapy with OL ADA 40 mg eow for at least 12 weeks and will continue through the duration of the 
subject's participation of this study.  The earliest time a subject can meet the flare criteria would be at Week 36 
since a subject would need to have 2 consecutive visits with ASDAS ≥ 2.1.  Subjects who flare at Weeks 60, 64 or 
68, rescue therapy with OL adalimumab will be provided for 12 weeks and final study visit will be at Weeks 72, 76 
or 80 respectively.

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Has been changed to read:
*
Subjects who meet remission criteria (ASDAS inactive disease < 1.300) at Weeks 16, 20, 24 and 28 will be
randomized to Period 2.  Subjects not meeting remission criteria will be discontinued at Weeks 20, 24 or 28.
**
Subjects who flare (ASDAS ≥ 2.100 for 2 consecutive study visits) during the double-blind period (Period 2) can 
receive rescue therapy with OL ADA 40 mg eow for at least 12 weeks and will continue through the duration of the 
subject's participation of this study.  The earliest time a subject can meet the flare criteria would be at Week 36 
since a subject would need to have 2 consecutive visits with ASDAS ≥ 2.100.  Subjects who flare at Weeks 60, 64 
or 68, rescue therapy with OL adalimumab will be provided for 12 weeks and final study visit will be at Weeks 72, 
76 or 80 respectively.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Period
First paragraph previously read:
Within 30 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and undergo the 
screening procedures outlined in Table 1.
Has been changed to read:
Within 42 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and undergo the 
screening procedures outlined in Table 1.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Period
Third paragraph, seventh and eight sentence previously read:
If the subject had completed initial screening evaluation assessments including a purified 
protein derivative (PPD) test or Interferon-Gamma Release Assay (IGRA; QuantiFERON-
TB Gold In-tube test or T SPOT TB test), chest x-ray (CXR), MRI of the SI joints and 
spine, AP pelvis x-ray, HLA-B27, or electrocardiogram (ECG), these tests will not be 
required to be repeated for the re-screening provided the conditions noted in Section 5.3 
are met and no more than 30 days has passed for the MRI of the SI joints and spine, 
3 months (90 days) have passed for the PPD test or IGRA test, CXR and ECG and 1 year 

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(365 days) for the AP pelvis x-ray.  There is no need to redraw the HLA-B27 once the 
results are available from the central laboratory chosen for this study.  
Has been changed to read:
If the subject had completed initial screening evaluation assessments including a purified 
protein derivative (PPD) test or Interferon-Gamma Release Assay (IGRA; QuantiFERON-
TB Gold In-tube test or T SPOT TB test), chest x-ray (CXR), MRI of the SI joints and 
spine, AP pelvis x-ray, HLA-B27, Antinuclear Antibody (ANA) or electrocardiogram 
(ECG), these tests will not be required to be repeated for the re-screening provided the 
conditions noted in Section 5.3 are met and no more than 30 days has passed for the MRI 
of the SI joints and spine, 3 months (90 days) have passed for the PPD test or IGRA test, 
CXR and ECG and 1 year (365 days) for the AP pelvis x-ray.  There is no need to redraw 
the HLA-B27 or ANA once the results are available from the central laboratory chosen 
for this study.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Period (Period 1)
Third paragraph, last sentence previously read:
At Week 20, calculation of the Week 16 ASDAS will be done using the Week 16 visit 
parameters including the Week 16 hs-CRP.  If the subject does not meet the criteria for 
remission (ASDAS < 1.3), the subject will be discontinued.
Has been changed to read:
At Week 20, calculation of the Week 16 ASDAS will be done using the Week 16 visit 
parameters including the Week 16 hs-CRP.  If the subject does not meet the criteria for 
remission (ASDAS < 1.300), the subject will be discontinued.

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Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Period (Period 1)
Fourth paragraph, last sentence previously read:
If the subject does not meet the criteria for remission (ASDAS < 1.3), the subject will be 
discontinued.
Has been changed to read:
If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will 
be discontinued.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Period (Period 1)
Fifth paragraph, last sentence previously read:
If any of these time points do not meet the criteria for remission (ASDAS < 1.3), the 
subject will be discontinued.
Has been changed to read:
If any of these time points do not meet the criteria for remission (ASDAS < 1.300), the 
subject will be discontinued.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Open-Label Period (Period 1)
Add:  new last paragraph
If a subject has an elevated hs-CRP which the investigator believes to be secondary to an 
AE and not due to nr-axSpA at Weeks 16, 20, 24 or 28, sites may repeat the hs-CRP test 
prior to the subject's next scheduled visit following a discussion with the AbbVie Medical 
Monitor.  The repeat hs-CRP results should be available to the site prior to the subject's 
next scheduled visit and will replace the visit-specific hs-CRP in the ASDAS calculation.  
Instances where AE-related hs-CRP elevation spans more than one study visit will be 
addressed on a case-by-case basis.  Note:  the AE should be reported in EDC prior to 
discussion with the AbbVie Medical Monitor.

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Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Period (Period 2)
First paragraph, last sentence previously read:
Subjects in remission defined as meeting Ankylosing Spondylitis Disease Activity Score 
(ASDAS) Inactive Disease (ASDAS < 1.3) at Week 16, 20, 24 and Week 28 (described 
above) will be randomized in a 1:1 ratio to receive either blinded adalimumab 40 mg eow 
or matching placebo.
Has been changed to read:
Subjects in remission defined as meeting Ankylosing Spondylitis Disease Activity Score 
(ASDAS) Inactive Disease (ASDAS < 1.300) at Week 16, 20, 24 and Week 28 (described 
above) will be randomized in a 1:1 ratio to receive either blinded adalimumab 40 mg eow 
or matching placebo.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Period (Period 2)
Second paragraph, second and third sentence previously read:
Subjects who flare, defined as 2 consecutive study visits with ASDAS ≥ 2.1 in Period 2 
(40-week double-blind period) will be allowed rescue therapy.  The earliest time a subject 
can meet the flare criteria would be at Week 36 since a subject would need to have 
2 consecutive visits with ASDAS ≥ 2.1.
Has been changed to read:
Subjects who flare, defined as 2 consecutive study visits with ASDAS ≥ 2.100 in Period 2 
(40-week double-blind period) will be allowed rescue therapy.  The earliest time a subject 
can meet the flare criteria would be at Week 36 since a subject would need to have 
2 consecutive visits with ASDAS ≥ 2.100.

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Section 5.1  Overall Study Design and Plan:  Description
Subsection Double-Blind Period (Period 2)
Add:  new last paragraph
Following the Week 28 visit, if a subject has an elevated hs-CRP which the investigator 
believes to be secondary to an AE and not due to nr-axSpA, the site may repeat the 
hs-CRP test prior to the subject's next scheduled visit following a discussion with the 
AbbVie Medical Monitor.  The repeat hs-CRP results should be available to the site prior 
to the subject's next scheduled visit and will replace the visit-specific hs-CRP in the 
ASDAS calculation.  Instances where AE-related hs-CRP elevation spans more than one 
study visit will be addressed on a case-by-case basis.  Note:  the AE should be reported in 
EDC prior to discussion with the AbbVie Medical Monitor.
Section 5.2.1  Inclusion Criteria
Criterion 6 previously read:
Subjects must have baseline disease activity as defined by having an ASDAS ≥2.1 (note, 
sites will need to use the Screening Visit hs-CRP to calculate ASDAS at Screening and 
Baseline Visits with the remainder of parameters visit-specific), BASDAI ≥ 4 and 
Patient's Assessment of Total Back Pain score ≥ 4 based on a Numeric Rating Scale 
(NRS) at both the Screening and Baseline Visits (see Appendix E, Appendix F and 
Appendix G, respectively).
Has been changed to read:
Subjects must have baseline disease activity as defined by having an ASDAS ≥2.100 
(note, sites will need to use the Screening Visit hs-CRP to calculate ASDAS at Screening 
and Baseline Visits with the remainder of parameters visit-specific), BASDAI ≥ 4 and 
Patient's Assessment of Total Back Pain score ≥ 4 based on a Numeric Rating Scale 
(NRS) at both the Screening and Baseline Visits (see Appendix E, Appendix F and 
Appendix G, respectively).

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Section 5.2.2  Exclusion Criteria
Criterion 4, last sentence previously read:
All other oral DMARDs, with the exception of azathioprine, are prohibited within 28 days 
prior to the Baseline Visit.
Has been changed to read:
All other oral DMARDs, with the exception of azathioprine or mercaptopurine (6-MP), 
are prohibited within 28 days prior to the Baseline Visit.
Section 5.2.2  Exclusion Criteria
Criterion 5 previously read:
If entering the study on concomitant azathioprine (AZA), subject not on stable dose 
(≤150 mg per day) for 28 days prior to the Baseline Visit or is on AZA and another 
concomitant immunosuppressive drug at study entry.
Has been changed to read:
If entering the study on concomitant azathioprine (AZA) or 6-MP, subject not on stable 
dose (AZA ≤ 150 mg per day or 6-MP ≤ 75 mg per day) for 28 days prior to the Baseline 
Visit or is on AZA or 6-MP and another concomitant immunosuppressive drug at study 
entry.
Section 5.2.2  Exclusion Criteria
Criterion 9 previously read:
Subject has received cyclosporine or other second line anti-rheumatic therapy (except 
MTX, SSZ, hydroxychloroquine or AZA) within 28 days prior to the Baseline Visit.
Has been changed to read:
Subject has received cyclosporine or other second line anti-rheumatic therapy (except 
MTX, SSZ, hydroxychloroquine, AZA or 6-MP) within 28 days prior to the Baseline 
Visit.

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Section 5.2.3.2  Concomitant Therapy
Third paragraph, first sentence previously read:
Subjects may continue on stable doses of MTX, SSZ, hydroxychloroquine, AZA, 
prednisone and/or NSAIDs provided the stability requirements noted in Section 5.2.2 are 
met.
Has been changed to read:
Subjects may continue on stable doses of MTX, SSZ, hydroxychloroquine, AZA, 6-MP, 
prednisone and/or NSAIDs provided the stability requirements noted in Section 5.2.2 are 
met.
Section 5.2.3.2  Concomitant Therapy
Second paragraph, last bullet previously read:
●
AZA (≤ 150 mg per day)
Has been changed to read:
●
AZA (≤ 150 mg per day) or 6-MP (≤ 75 mg per day)
Section 5.2.3.3  Prohibited Therapy
Fourth and fifth bullet previously read:
●
All oral DMARDs other than MTX, SSZ, AZA or hydroxychloroquine.
●
Opioid analgesics (other than tramadol) or marijuana.
Has been changed to read:
●
All oral DMARDs other than MTX, SSZ, AZA, 6-MP or hydroxychloroquine.
●
Opioid analgesics (other than tramadol) or marijuana, except as medically 
indicated for an AE.

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Section 5.2.3.4  Rescue Therapy
First paragraph, second sentence previously read:
Flare is defined as 2 consecutive study visits with ASDAS ≥ 2.1.  
Has been changed to read:
Flare is defined as 2 consecutive study visits with ASDAS ≥ 2.100.  
Section 5.3.1  Efficacy and Safety Measurements Assessed and Flow Chart
First paragraph previously read:
Subjects will be allowed a visit window of ±7 days for all study visits (with the exception 
of the Baseline Visit as there is a maximum of 30 days screening window).
Has been changed to read:
Subjects will be allowed a visit window of ±7 days for all study visits (with the exception 
of the Baseline Visit as there is a maximum of 42 days screening window).

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Table 1.  Study Activities
Previously read:
Activity
SCR
(<30 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Informed 
Consent
X
Inclusion/ 
Exclusion 
Criteria
X
Xb
Medical/ 
Surgical History
X
Xb
Vital Signs/ 
Weight/ Heightc
X
X
X
X
X
X
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
X
X
X
X
X
X
Physical Exam
X
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
12-Lead ECGd
Xe
Chest X-Rayd
Xe
Xf
AP Pelvis 
X-Ray
Xe

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Activity
SCR
(<30 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
TB Screening 
(PPD Skin Test 
OR 
QuantiFERON-
TB Gold Test)
Xe
Xf
Pregnancy Test
Xg
Xh
Xh,v
Xh,v
Xh,v
Xh
Xh,v Xh,v
Xh
Xh
Chemistry and 
Hematology 
X
Xi
X
X
X
X
X
X
X
X
X
X
X
Xv
Xv
X
X
Urinalysisj
X
Xi
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
HLA-B27
Xe
Antinuclear 
Antibody 
(ANA)/
reflex 
Anti-dsDNA 
antibody
X
HBV Screening
X
hs-CRP
X
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV
Xk

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Activity
SCR
(<30 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Biomarkers 
(DKK-1, 
Sclerostin, BMP
2, and/or 
BMP-7)l
X
Xv
Xv
X
Xl
Xl
Xl
Xl
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
Serum ADA 
Concentrationl
X
X
Xv
Xv
X
X
Xl
Xl
Xl
X
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
Anti-ADA 
antibody 
(AAA)l
X
X
Xv
Xv
X
X
Xl
Xl
Xl
X
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
PG Sample
Xm
MRI of the 
Spine and SI 
Joints
Xe
Xn
Xn
Xn
TJC/SJC
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASMIlin
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
MASES
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X

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Activity
SCR
(<30 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Plantar Fascia 
Enthesitis
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
Dactylitis
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician's 
Global 
Assessment of 
Disease 
Activity NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's 
Assessment of 
Nocturnal Back 
Pain NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's 
Assessment of 
Total Back Pain 
NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's Global 
Assessment of 
Disease 
Activity NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Activity
SCR
(<30 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Patient's Global 
Assessment of 
Pain NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HAQ-S
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
SF-36V2 Health 
Survey
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
WPAI- axial 
SpA
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
EQ-5D 
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
Prior and 
Concomitant 
Therapy 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor AE
Xo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
ASDAS 
Calculation
X
X
Xq
Xq
Xq
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Enrollment
X
Randomization
Xq

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
194
Activity
SCR
(<30 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Dispense Study 
Drug 
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
X
X
X
Xs
Xs
Xs
Admin of Study 
Drugt
X
X
X
X
X
X
Ada = Adalimumab; BL = Baseline; D = Day(s); Disc Visit = Discontinuation Visit; SCR = Screening; RT = Rescue Therapy; PF = Post Flare; F/U = Follow-up
a.
Baseline Visit is defined as Day 1, the day of first study drug administration.
b.
Medical History and Inclusion/Exclusion Criteria must be confirmed by the Investigator prior to enrollment to verify subject eligibility.
c.
Height will be measured at Screening Visit only.
d.
Subject can have a repeat CXR and/or ECG at any time during the study only if in the opinion of the investigator, clinically significant AEs develop that warrant a repeat 
exam.
e.
These procedures will not be required if the subject had a previous normal CXR, normal ECG or negative PPD within 90 days of screening provided all protocol required 
documentation is available at the site and nothing has changed in the subject's health status since the time of the test thatwarrants a repeat test.  MRI of the SI joint and spine 
or AP Pelvis x-ray will also not be required if the subject had a previous test within 30 days and 1 year (365 days) of Screening, respectively.  Any documentation of past 
positive PPD results may be acceptable; however, negative PPD 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 initiate and 
complete at least the first 2 weeks (or per local guidelines, whichever is longer) of the prescribed TB prophylaxis, or have documented completion of a full course of TB 
prophylaxis prior to Baseline (Section 5.3.1.1).  There is no need to redraw the HLA-B27 once the results are available from the central laboratory chosen for this study.
f.
An annual PPD/QuantiFERON-TB Gold test will be required for those subjects with a negative TB test at Screening.  If the annual PPD/QuantiFERON-TB Gold test is 
positive, a CXR must be performed, the investigator must contact the study designated physician to review the individual dataand agree on a decision whether or not 
additional evaluation is needed.
g.
All females of childbearing potential will have a serum pregnancy test at Screening that is performed at the central laboratory.
h.
All females of childbearing potential will have a urine pregnancy test performed at Baseline prior to study enrollment and at study discontinuation/completion.  The urine 
pregnancy kit supplies will be provided to the sites via the central laboratory (where allowed by local guidelines).  Monthlypregnancy tests will be performed throughout the 
study if required by country regulatory authorities.  Any subject with a positive urine pregnancy test must have a negative serum test performed at the central laboratory prior 
to enrollment or continuation in the study.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
195
i.
Laboratory assessments (chemistry, hematology, hs-CRP and urinalysis) will be repeated at Baseline if the time between Screening and Baseline is greater than 14 days, or if 
the subject's health status has changed to warrant a repeat test.
j.
Dipstick 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 protein, 
ketones or blood greater than negative or glucose greater than normal.
k.
If required by country regulatory authorities to confirm eligibility, subjects will be tested for antibodies to HIV, and document that the test has been performed.  The testing is 
to be done at a local laboratory.  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 not be made aware of any positive result.
l.
Flare is defined as 2 consecutive study visits with ASDAS ≥ 2.1.  Subjects that flare during the double-blind period (Period 2) will need the following assessments during the 
visit that flare was determined as well as 12 weeks following the determination of the flare:  biomarkers, which may include the following:  (Dickkopf-1 [DKK-1], Sclerostin, 
Bone Morphogenetic Protein [BMP]-2, BMP-7), serum adalimumab and AAA (refer to Section 5.3.2 for further information).  These assessments are in addition to the 
regularly scheduled assessments outlined in the Table above.
m.
The pharmacogenic (PG) sample is optional.  A separate PG consent form must be signed prior to sample collection.  The PG sample is ideally collected at Baseline, but may 
be collected at anytime throughout the study.
n.
Site staff should schedule the Week 28 MRI during the Baseline visit, if possible.  For subjects that are discontinued due tonot fulfilling the ASDAS remission criteria at 
Weeks 20 or 24, the site should attempt to reschedule the MRI within 2 weeks of the discontinuation visit.  If the MRI cannot be rescheduled, the Week 28 MRI will be 
considered missed.
o.
SAEs will be collected starting from time of signing informed consent; non-serious AEs will be collected starting from the 1st study drug dose.  Any SAE that occurs between 
Screening and Baseline should be captured as medical history. 
p.
Site personnel will contact all subjects by telephone approximately 70 days after the last dose of study drug to determine the occurrence of AEs or SAEs.  Subjects that initiate 
adalimumab therapy not supplied in the context of the clinical trial after the end of study participation need not be contacted by phone as new AEs or SAEs should be reported 
through the mechanism used for all post marketing adverse experiences.
q.
Week 20, calculation of the Week 16 ASDAS will be done using the Week 16 visit parameters including the Week 16 hs-CRP.  If the subject does not meet the criteria for 
remission (ASDAS < 1.3), the subject will be discontinued.  At Week 24, calculation of the Week 20 ASDAS will be done using the Week 20 visit parameters including the 
Week 20 hs-CRP.  If the subject does not meet the criteria for remission (ASDAS < 1.3), the subject will be discontinued.  At Week 28, calculation of the Week 24 ASDAS 
will be done using the Week 24 parameters including the Week 24 hs-CRP; the Week 28 ASDAS will be done using Week 28 parameters and the Week 24 hs-CRP (as the 
Week 28 results will not be available).  If any of these time points do not meet the criteria for remission (ASDAS < 1.3), the subject will be discontinued.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
196
r.
Beginning at Week 36, ASDAS will be calculated via IVRS/IWRS for the current and previous study visit to determine fulfillment of flare criteria.  Assessments from the 
current and previous study visit will be used for the calculation except for the hs-CRP which will be based on the results from the previous study visit's blood draw for both 
calculations.  For subjects who meet flare criteria during Period 2 and start rescue therapy with OL adalimumab, further calculation of ASDAS is not required.  For any 
subject missing 2 consecutive visits within the double-blind period (Period 2) the site must contact the AbbVie Medical Monitor for discussion regarding the subject's 
continued participation in the study.
s.
Subjects would only receive study drug at Weeks 68, 72 or 76, if they flared at Week 56, 60 or 64 respectively.
t.
Study drug will be administered in the Investigator's office at Baseline, Week 2, 4, 8, 12, and Week 24 to ensure proper technique.
u.
For subjects who meet the flare criteria at Weeks 60, 64 or 68, rescue therapy with OL adalimumab will be provided for 12 weeks and final study visit will be at Weeks 72, 
76 or 80, respectively.
v.
These procedures should only be performed if the visit is the subject's last visit due to not meeting ASDAS remission criteria (Weeks 20, 24 or 28) or due toa flare and has 
received 12 weeks of rescue therapy (Weeks 72 or 76).
w.
If subject meets flare criteria, these assessments are required 12 weeks post flare in addition to assessments for the scheduled visit when the flare was identified.  If any of 
these procedures are already collected at the regularly scheduled visit, there is no need to obtain these procedures twice.
x.
Subjects who prematurely discontinue the study should complete the procedures outlined for the Discontinuation Visit as soon as possible after the last dose of study drug and 
preferably prior to the administration of new therapies.  No Discontinuation Visit procedures will be required for those subjects that complete the Week 68 visit (or Weeks 72, 
76 or 80 for those subjects who flare at Weeks 60, 64 or 68, respectively).

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
197
Has been changed to read:
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Informed 
Consent
X
Inclusion/ 
Exclusion 
Criteria
X
Xb
Medical/ 
Surgical History
X
Xb
Vital Signs/ 
Weight/ Heightc
X
X
X
X
X
X
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
X
X
X
X
X
X
Physical Exam
X
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
12-Lead ECGd
Xe
Chest X-Rayd
Xe
Xf
AP Pelvis 
X-Ray
Xe

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
198
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
TB Screening 
(PPD Skin Test 
OR IGRA)
Xe
Xf
Pregnancy Test
Xg
Xh
Xh,v
Xh,v
Xh,v
Xh
Xh,v Xh,v
Xh
Xh
Chemistry and 
Hematology 
X
Xi
X
X
X
X
X
X
X
X
X
X
X
Xv
Xv
X
X
Urinalysisj
X
Xi
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
HLA-B27
Xe
Antinuclear 
Antibody 
(ANA)/
reflex 
Anti-dsDNA 
antibody
Xe
HBV Screening
X
hs-CRP
X
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV
Xk

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
199
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Biomarkersl
X
Xv
Xv
X
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
Serum ADA 
Concentrationl
X
X
Xv
Xv
X
X
Xl
Xl
Xl
X
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
Anti-ADA 
antibody 
(AAA)l
X
X
Xv
Xv
X
X
Xl
Xl
Xl
X
Xl
Xl
Xl
X
Xl
Xv
Xv
X
X
PG Sample
Xm
MRI of the 
Spine and SI 
Joints
Xe
Xn
Xn
Xn
TJC/SJC
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASMIlin
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
MASES
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
200
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Plantar Fascia 
Enthesitis
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
Dactylitis
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician's 
Global 
Assessment of 
Disease 
Activity NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's 
Assessment of 
Nocturnal Back 
Pain NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's 
Assessment of 
Total Back Pain 
NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's Global 
Assessment of 
Disease 
Activity NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
201
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Patient's Global 
Assessment of 
Pain NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HAQ-S
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
SF-36V2 Health 
Survey
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
WPAI- axial 
SpA
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
EQ-5D 
X
X
Xv
Xv
X
X
X
X
Xv
Xv
X
X
Prior and 
Concomitant 
Therapy 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor AE
Xo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
ASDAS 
Calculation
X
X
Xq
Xq
Xq
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Enrollment
X
Randomization
Xq

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
202
Activity
SCR
(≤42 D)
BLa
(D1)
Open-Label - Period 1
Double-Blind – Period 2
12
Weeks
PFw
RT for 
Those that 
Flare at 
Week 60–68u
Disc  
Visi x
70-
Day 
F/U 
Call
Week
Week
2
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
Dispense Study 
Drug 
X
X
X
X
X
X
X
Xq
X
X
X
X
X
X
X
X
X
Xs
Xs
Xs
Admin of Study 
Drugt
X
X
X
X
X
X
Optional Blood 
Sample 
Collection 
Sub-Study
X
Xy
Xy
X
Xz
Xz
Xz
Xz
Xz
Xz
Xz
Xz
Xz
Ada = Adalimumab; BL = Baseline; D = Day(s); Disc Visit = Discontinuation Visit; SCR = Screening; RT = Rescue Therapy; PF = Post Flare; F/U = Follow-up
a.
Baseline Visit is defined as Day 1, the day of first study drug administration.
b.
Medical History and Inclusion/Exclusion Criteria must be confirmed by the Investigator prior to enrollment to verify subject eligibility.
c.
Height will be measured at Screening Visit only.
d.
Subject can have a repeat CXR and/or ECG at any time during the study only if in the opinion of the investigator, clinically significant AEs develop that warrant a repeat 
exam.
e.
These procedures will not be required if the subject had a previous normal CXR, normal ECG or negative PPD within 90 days of screening provided all protocol required 
documentation is available at the site and nothing has changed in the subject's health status since the time of the test that warrants a repeat test.  MRI of the SI joint and spine 
or AP Pelvis x-ray will also not be required if the subject had a previous test within 30 days and 1 year (365 days) of Screening, respectively.  Any documentation of past 
positive PPD results may be acceptable; however, negative PPD 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 initiate and 
complete at least the first 2 weeks (or per local guidelines, whichever is longer) of the prescribed TB prophylaxis, or have documented completion of a full course of TB 
prophylaxis prior to Baseline (Section 5.3.1.1).  There is no need to redraw the HLA-B27 or ANA once the results are available from the central laboratory chosen for this 
study.
f.
An annual PPD/IGRA test will be required for those subjects with a negative TB test at Screening.  If the annual PPD/IGRA test is positive, a CXR must be performed, the 
investigator must contact the study designated physician to review the individual data and agree on a decision whether or not additional evaluation is needed.
g.
All females of childbearing potential will have a serum pregnancy test at Screening that is performed at the central laboratory.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
203
h.
All females of childbearing potential will have a urine pregnancy test performed at Baseline prior to study enrollment and at studydiscontinuation/completion.  The urine 
pregnancy kit supplies will be provided to the sites via the central laboratory (where allowed by local guidelines).  Monthly pregnancy tests will be performed throughout the 
study if required by country regulatory authorities.  Any subject with a positive urine pregnancy test must have a negative serum test performed at the central laboratory prior 
to enrollment or continuation in the study.
i.
Laboratory assessments (chemistry, hematology, hs-CRP and urinalysis) will be repeated at Baseline if the time between Screening and Baseline is greater than 14 days, or if 
the subject's health status has changed to warrant a repeat test.
j.
Dipstick 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 protein, 
ketones or blood greater than negative or glucose greater than normal.
k.
If required by country regulatory authorities to confirm eligibility, subjects will be tested for antibodies to HIV, and document that the test has been performed.  The testing is 
to be done at a local laboratory.  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 not be made aware of any positive result.
l.
Flare is defined as 2 consecutive study visits with ASDAS ≥ 2.100.  Subjects that flare during the double-blind period (Period 2) will need the following assessments during 
the visit that flare was determined as well as 12 weeks following the determination of the flare:  biomarkers (refer to Section 5.3.1.1 for further information), serum 
adalimumab and AAA (refer to Section 5.3.2 for further information).  These assessments are in addition to the regularly scheduled assessments outlined in the table above.
m.
The pharmacogenic (PG) sample is optional.  A separate PG consent form must be signed prior to sample collection.  The PG sample is ideally collected at Baseline, but may 
be collected at any time throughout the study.
n.
Site staff should schedule the Week 28 MRI during the Baseline visit, if possible.  For subjects that are discontinued due tonot fulfilling the ASDAS remission criteria at 
Weeks 20 or 24, the site should attempt to reschedule the MRI within 2 weeks (14 days) of the discontinuation visit.  If the MRI cannot be rescheduled, the Week 28 MRI will 
be considered missed.
o.
SAEs will be collected starting from time of signing informed consent; non-serious AEs will be collected starting from the 1st study drug dose.  Any AE that occurs between 
Screening and Baseline should be captured as medical history. 
p.
Site personnel will contact all subjects by telephone approximately 70 days after the last dose of study drug to determine the occurrence of AEs or SAEs.  Subjects that initiate 
adalimumab therapy not supplied in the context of the clinical trial after the end of study participation need not be contacted by phone as new AEs or SAEs should be reported 
through the mechanism used for all post marketing adverse experiences.
q.
Week 20, calculation of the Week 16 ASDAS will be done using the Week 16 visit parameters including the Week 16 hs-CRP.  If the subject does not meet the criteria for 
remission (ASDAS < 1.300), the subject will be discontinued.  At Week 24, calculation of the Week 20 ASDAS will be done usingthe Week 20 visit parameters including the 
Week 20 hs-CRP.  If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will be discontinued.  At Week 28, calculation of the Week 24 ASDAS 
will be done using the Week 24 parameters including the Week 24 hs-CRP; the Week 28 ASDAS will be done using Week 28 parameters and the Week 24 hs-CRP (as the 
Week 28 results will not be available).  If any of these time points do not meet the criteria for remission (ASDAS < 1.300), the subject will be discontinued.  For hs-CRP 
elevations secondary to AEs or using a previous hs-CRP, please refer to Section 5.1 or ASDAS Calculation in Section 5.3.1.1.

Adalimumab
M13-375 Protocol Amendment 2
EudraCT 2012-000646-35
204
r.
Beginning at Week 36, ASDAS will be calculated via IVRS/IWRS for the current and previous study visit to determine fulfillment of flare criteria.  Assessments from the 
current and previous study visit will be used for the calculation except for the hs-CRP which will be based on the results from the previous study visit's blood draw for both 
calculations.  For subjects who meet flare criteria during Period 2 and start rescue therapy with OL adalimumab, further calculation of ASDAS is not required.  For any 
subject missing 2 consecutive visits within the double-blind period (Period 2) the site must contact the AbbVie Medical Monitor for discussion regarding the subject's 
continued participation in the study.
s.
Subjects would only receive study drug at Weeks 68, 72 or 76, if they flared at Week 56, 60 or 64 respectively.
t.
Study drug will be administered in the Investigator's office at Baseline, Week 2, 4, 8, 12, and Week 24 to ensure proper technique.
u.
For subjects who meet the flare criteria at Weeks 60, 64 or 68, rescue therapy with OL adalimumab will be provided for 12 weeks and final study visit will be at Weeks 72, 
76 or 80, respectively.
v.
These procedures should only be performed if the visit is the subject's last visit due to not meeting ASDAS remission criteria (Weeks 20, 24 or 28) or due to a flare and has 
received 12 weeks of rescue therapy (Weeks 72 or 76).
w.
If subject meets flare criteria, these assessments are required 12 weeks post flare in addition to assessments for the scheduled visit when the flare was identified.  If any of 
these procedures are already collected at the regularly scheduled visit, there is no need to obtain these procedures twice.
x.
Subjects who prematurely discontinue the study should complete the procedures outlined for the Discontinuation Visit as soon as possible after the last dose of study drug and 
preferably prior to the administration of new therapies.  No Discontinuation Visit procedures will be required for those subjects that complete the Week 68 visit (or Weeks 72, 
76 or 80 for those subjects who flare at Weeks 60, 64 or 68, respectively).
y.
Optional Blood Sample Collection Sub-Study only:  use a separate sub-study central lab kit.  Samples will be collected at Week 28 or at Weeks 20 or 24 only if the visit is the 
subject's last visit.  (Optional Blood Sample Collection Sub-Study samples are in addition to the regularly scheduled assessments outlined in the table above.) 
z.
Optional Blood Sample Collection Sub-Study only:  use a separate sub-study central lab kit.  In subjects who meet flare criteria during Weeks 36 – 68, samples will be 
collected only once at time of flare.  Flare is defined as 2 consecutive study visits with ASDAS ≥ 2.100.  (Optional Blood Sample Collection Sub-Study samples are in 
addition to the regularly scheduled assessments outlined in the Table above.)

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Section 5.3.1.1  Study Procedures
Subsection Chest X-Ray (CXR)
Last paragraph previously read:
In the assessment of the chest x-ray, a radiologist must note the presence or absence of 
(1) calcified granulomas, (2) pleural scarring/thickening, and (3) signs of active TB.  The 
Principal Investigator will indicate the clinical significance of any findings and will sign 
and date the report.
Has been changed to read:
A radiologist 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 chest x-ray, the Principal Investigator or their physician delegate must 
indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.
Section 5.3.1.1  Study Procedures
Subsection Anteroposterior Pelvis X-ray
Fourth paragraph, fifth and sixth sentence previously read:
The imaging vendor will complete an imaging worksheet and return an eligibility 
notification report to the site within 48 hours of imaging vendor's receipt of the films (or 
within 96 hours if adjudication is necessary).  The investigator will be required to review, 
sign and date the eligibility notification report.
Has been changed to read:
The imaging vendor will complete an imaging worksheet and return an eligibility 
notification report to the site within 48 hours of imaging vendor's receipt of the films (or 
within 96 hours if adjudication is necessary), not including BioClinica holidays or 
weekends.  The investigator will be required to review, sign and date the eligibility 
notification report prior to the subject being enrolled.

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Section 5.3.1.1  Study Procedures
Subsection TB Screening
Sixth paragraph, first and second sentence previously read:
In the assessment of the chest x-ray, a radiologist must note the presence or absence of 
(1) calcified granulomas, (2) pleural scarring/thickening, and (3) signs of active TB.  The 
Principal Investigator will indicate the clinical significance of any findings and will sign 
and date the report. 
Has been changed to read:
A radiologist 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 chest x-ray, the Principal Investigator or their physician delegate must 
indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.
Section 5.3.1.1  Study Procedures
Subsection ANA
Add:  new subsection
ANA
Testing for ANA will be performed on specimens collected during the Screening visit.  
For subjects that may need to be rescreened, once results are available from the central 
laboratory chosen for this study repeat ANA testing is not required.
Section 5.3.1.1  Study Procedures
Subsection Biomarkers
First paragraph, last sentence previously read:
The samples collected may include the following:
Has been changed to read:
The final set of biomarkers to be analyzed may include the following:

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Section 5.3.1.1  Study Procedures
Subsection Biomarkers
Add:  new second paragraph
The final selection of biomarkers for analysis will be based on both insights gained in the 
sub-study and available scientific knowledge at study completion.
Section 5.3.1.1  Study Procedures
Subsection Biomarkers
Delete:  fourth sentence in second paragraph
Results of exploratory analyses, if any, will not be reported with the study summary.
Section 5.3.1.1  Study Procedures
Subsection Biomarkers
Second paragraph, last sentence previously read:
The samples will be retained for no longer than 5 years after completion of the study 
(where allowed by local guidelines).
Has been changed to read:
The samples will be retained for no longer than 5 years after completion of the study 
defined as the date of the last subject's last study visit or the actual date of follow-up 
contact, whichever is later (where allowed by local guidelines).
Section 5.3.1.1  Study Procedures
Subsection Biomarkers
Add:  new last paragraph
Biomarker analyses are considered exploratory.  Results for the primary biomarker 
analyses from the overall study and sub-study will be reported in a separate biomarker 
study report.  The primary biomarker analyses do not preclude future analyses which are 
not within the scope of this study protocol and will therefore not be included in the 
separate biomarker study report.

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Section 5.3.1.1  Study Procedures
Subsection MRI of the Spine and Sacroiliac Joints
Third paragraph, last sentence previously read:
The investigator will be required to review, sign and date the eligibility notification report.
Has been changed to read:
The investigator will be required to review, sign and date the eligibility notification report 
prior to the subject being enrolled.
Section 5.3.1.1  Study Procedures
Subsection MRI of the Spine and Sacroiliac Joints
Last paragraph, second and third sentence previously read:
For subjects that are discontinued due to not fulfilling the ASDAS remission criteria at 
Weeks 20 or 24, the site should attempt to reschedule the MRI within 2 weeks of the 
discontinuation visit.  If the MRI cannot be rescheduled, the Week 28 MRI will be 
considered missed.
Has been changed to read:
For subjects that are discontinued for any reason at Weeks 20, 24 or 28, the site should 
attempt to reschedule the MRI within 2 weeks (14 days) of the discontinuation visit.  If the 
MRI cannot be rescheduled within 14 days of the discontinuation visit, the Week 28 MRI 
will be considered missed.
Section 5.3.1.1  Study Procedures
Subsection Numerical Rating Scales (NRS)
First bullet, first sub-bullet, second sentence previously read:
Site should make every attempt to have the same qualified Investigator or designee (MD
or DO required) conduct these assessments throughout the study for any given subject.

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Has been changed to read:
Site should make every attempt to have the same qualified Investigator or designee 
(physician required) conduct these assessments throughout the study for any given 
subject.
Section 5.3.1.1  Study Procedures
Subsection Ankylosing Spondylitis Disease Activity Score (ASDAS) Calculation
First paragraph, fourth sentence previously read:
If the subject does not meet the criteria of an ASDAS ≥ 2.1 at screening, the subject would 
be considered a screen failure and all other screening procedures should be cancelled.
Has been changed to read:
If the subject does not meet the criteria of an ASDAS ≥ 2.100 at screening, the subject 
would be considered a screen failure and all other screening procedures should be 
cancelled.
Section 5.3.1.1  Study Procedures
Subsection Ankylosing Spondylitis Disease Activity Score (ASDAS) Calculation
Third paragraph, last sentence previously read:
If the subject does not meet the criteria for remission (ASDAS < 1.3), the subject will be 
discontinued.
Has been changed to read:
If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will 
be discontinued.
Section 5.3.1.1  Study Procedures
Subsection Ankylosing Spondylitis Disease Activity Score (ASDAS) Calculation
Fourth paragraph, last sentence previously read:
If the subject does not meet the criteria for remission (ASDAS < 1.3), the subject will be 
discontinued.

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Has been changed to read:
If the subject does not meet the criteria for remission (ASDAS < 1.300), the subject will 
be discontinued.
Section 5.3.1.1  Study Procedures
Subsection Ankylosing Spondylitis Disease Activity Score (ASDAS) Calculation
Fifth paragraph, last sentence previously read:
If any of these time points do not meet the criteria for remission (ASDAS < 1.3), the 
subject will be discontinued.
Has been changed to read:
If any of these time points do not meet the criteria for remission (ASDAS < 1.300), the 
subject will be discontinued.
Section 5.3.1.1  Study Procedures
Subsection Ankylosing Spondylitis Disease Activity Score (ASDAS) Calculation
Eighth paragraph, second sentence previously read:
Starting at Week 36 through Week 68, subjects will be assessed for flare, defined as 
2 consecutive visits with ASDAS ≥ 2.1.  
Has been changed to read:
Starting at Week 36 through Week 68, subjects will be assessed for flare, defined as 
2 consecutive visits with ASDAS ≥ 2.100.  
Section 5.3.1.1  Study Procedures
Subsection Ankylosing Spondylitis Disease Activity Score (ASDAS) Calculation
Add:  new tenth paragraph
If a subject has an elevated hs-CRP which the investigator believes to be secondary to an 
AE and not due to nr-axSpA, sites may repeat the hs-CRP test prior to the subject's next 
scheduled visit following a discussion with the AbbVie Medical Monitor.  The repeat 
hs-CRP results should be available to the site prior to the subject's next scheduled visit 

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and will replace the visit-specific hs-CRP in the ASDAS calculation.  Instances where 
AE-related hs-CRP elevation spans more than one study visit will be addressed on a 
case-by-case basis.  Note:  the AE should be reported in EDC prior to discussion with the 
AbbVie Medical Monitor.
Section 5.3.1.1  Study Procedures
Subsection Randomization
First sentence previously read:
During the Week 28 visit, subjects meeting ASDAS Inactive Disease (ASDAS < 1.3) at 
Weeks 16, 20, 24 and 28 will be randomized using IVRS/IWRS in a 1:1 ratio to receive 
either blinded adalimumab 40 mg eow or matching placebo.
Has been changed to read:
During the Week 28 visit, subjects meeting ASDAS Inactive Disease (ASDAS < 1.300) at 
Weeks 16, 20, 24 and 28 will be randomized using IVRS/IWRS in a 1:1 ratio to receive 
either blinded adalimumab 40 mg eow or matching placebo.
Section 5.3.1.1  Study Procedures
Subsection Optional Blood Sample Collection Sub-Study
Add:  new subsection
Optional Blood Sample Collection Sub-Study
An Optional Blood Sample Collection Sub-Study for future research (separate from the 
blood sample collection listed above) will be offered to approximately 10 sites based on 
interest, ongoing enrollment and clinical trial conduct.  Samples will be obtained for the 
Optional Blood Sample Collection Sub-Study at up to three time points (baseline, 
remission/Week 28 [Weeks 20 or 24 if the subject's last visit], and at time of flare, if 
applicable).  Timing of blood samples to be obtained are outlined in the designated study 
visits in Table 1 and described in more detail within the "Optional Blood Sample 
Collection Sub-Study Guidelines," which will be sent separately to the approved 
sub-study sites.

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Section 5.3.2  Drug Concentration Measurements
Section title previously read:
Drug Concentration Measurements
Has been changed to read:
Drug Concentration, Pharmacogenic, and Biomarker Measurements
Section 5.3.2  Drug Concentration Measurements
Second paragraph previously read:
Blood samples for biomarker analysis will be collected at Baseline, Week 28, time of flare 
(if applicable), 12 weeks post flare (if applicable), and last study visit.
Has been changed to read:
Blood samples for biomarker analysis will be collected at Baseline, Weeks 28, 68, time of 
flare (if applicable), 12 weeks post flare (if applicable), and last study visit.
Section 5.3.2  Drug Concentration Measurements
Add:  new last paragraph
Sites approved for the Optional Blood Sample Collection Sub-Study should refer to the 
"Optional Blood Sample Collection Sub-Study Guidelines" for collection, 
handling/processing, storage and disposition of samples.
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Biomarker Analysis
Delete:  fourth sentence in second paragraph
Results of exploratory analyses, if any, will not be reported with the study summary.

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Section 5.3.2.1  Collection of Samples for Analysis
Subsection Biomarker Analysis
Second paragraph, last sentence previously read:
The samples will be retained for no longer than 5 years after completion of the study 
(where allowed by local guidelines).
Has been changed to read:
The samples will be retained for no longer than 5 years after completion of the study 
defined as the date of the last subject's last study visit or the actual date of follow-up 
contact, whichever is later (where allowed by local guidelines).
Section 5.3.2.2  Handling/Processing of Samples
Subsection Biomarker Analysis
Second paragraph, last sentence previously read:
The samples will be retained for no longer than 5 years after completion of the study 
(where allowed by local guidelines).
Has been changed to read:
The samples will be retained for no longer than 5 years after completion of the study 
defined as the date of the last subject's last study visit or the actual date of follow-up 
contact, whichever is later (where allowed by local guidelines).
Section 5.3.2.2  Handling/Processing of Samples
Subsection Pharmacogenetic Analysis
Third paragraph, last sentence previously read:
The samples will be retained while research on adalimumab (or drugs of this class) 
continues but no longer than 5 years (where allowed by local guidelines).
Has been changed to read:
The samples will be retained while research on adalimumab (or drugs of this class) 
continues but no longer than 5 years defined as the date of the last subject's last study visit 

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or the actual date of follow-up contact, whichever is later (where allowed by local 
guidelines).
Section 5.3.2.4  Measurement Methods
Previously read:
Serum concentrations of adalimumab, AAA and biomarkers will be determined using 
validated ligand binding methods under the supervision of the Drug Analysis Department 
at AbbVie.
Has been changed to read:
Serum concentrations of adalimumab and AAA will be determined using validated ligand 
binding methods under the supervision of the Drug Analysis Department at AbbVie.
Section 5.3.3.1  Primary Efficacy Variable
Previously read:
The primary efficacy variable is the proportion of subjects who do not experience a flare 
during Period 2 by Week 68 of the study where a flare is defined as having any 
2 consecutive study visits with ASDAS ≥ 2.1.
Has been changed to read:
The primary efficacy variable is the proportion of subjects who do not experience a flare 
during Period 2 by Week 68 of the study where a flare is defined as having any 
2 consecutive study visits with ASDAS ≥ 2.100.
Section 5.3.3.2  Secondary Efficacy Variable(s)
Subsection At 12 Weeks after Initiation of Rescue Therapy
First, second and third bullet previously read:
●
ASDAS Inactive Disease (ASDAS < 1.3)
●
ASDAS Major Improvement (a change from baseline ≤ –2.00)
●
ASDAS Clinically Important Improvement (a change from baseline ≤ –1.10)

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Has been changed to read:
●
ASDAS Inactive Disease (ASDAS < 1.300)
●
ASDAS Major Improvement (a change from baseline ≤ –2.000)
●
ASDAS Clinically Important Improvement (a change from baseline ≤ –1.100)
Section 5.3.3.2  Secondary Efficacy Variable(s)
Subsection At Week 68
First and second bullet previously read:
●
Time to flare defined as ASDAS ≥ 2.1 at 2 consecutive visits
●
Time to partial flare defined as ASDAS ≥ 1.3 but < 2.1 at 2 consecutive visits
Has been changed to read:
●
Time to flare defined as ASDAS ≥ 2.100 at 2 consecutive visits
●
Time to partial flare defined as ASDAS ≥ 1.300 but < 2.100 at 2 consecutive 
visits
Section 5.3.3.3  Other Efficacy Variables
Previously read:
5.3.3.3
Other Efficacy Variables
●
Patient's Global Assessment of Disease Activity
●
Patient's Assessment of Total back pain
●
Bath AS Functional Index (BASFI)
●
Inflammation/Morning Stiffness (mean of BASDAI questions 5 and 6)
●
Bath AS Disease Activity Index (BASDAI)
●
ASDAS
●
hs-CRP
●
Linear Bath AS Metrology Index (BASMIlin)
●
Swollen Joint Count (66 joints)
●
Tender Joint Count (68 joints)

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●
MASES
●
Plantar fascia enthesitis
●
Dactylitis
●
Physician's Global Assessment of Disease Activity
●
Patient's Global Assessment of Pain
●
Patient's Assessment of Nocturnal Back Pain
●
Anterior Uveitis
●
Short Form-36v2 Health Survey questionnaire
●
EQ-5D
●
WPAI-axial SpA
●
SPARCC scores for MRI of the SI joint and spine
●
Proportion of subjects who regain remission on rescue therapy
●
Time to regain remission on rescue therapy
Each subject will have blood drawn for Biomarkers at the following time points:  
Baseline, Week 28, time of flare, 12 weeks following determination of flare, and last 
study visit.  The biomarkers may include the following:
●
DKK-1
●
Sclerostin
●
BMP-2
●
BMP-7
Has been changed to read:
5.3.3.3
Other Efficacy Variables
●
Patient's Global Assessment of Disease Activity
●
Patient's Assessment of Total back pain
●
Bath AS Functional Index (BASFI)
●
Inflammation/Morning Stiffness (mean of BASDAI questions 5 and 6)

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●
Bath AS Disease Activity Index (BASDAI)
●
ASDAS
●
hs-CRP
●
Linear Bath AS Metrology Index (BASMIlin)
●
Swollen Joint Count (66 joints)
●
Tender Joint Count (68 joints)
●
MASES
●
Plantar fascia enthesitis
●
Dactylitis
●
Physician's Global Assessment of Disease Activity
●
Patient's Global Assessment of Pain
●
Patient's Assessment of Nocturnal Back Pain
●
Anterior Uveitis
●
Short Form-36v2 Health Survey questionnaire
●
EQ-5D
●
WPAI-axial SpA
●
SPARCC scores for MRI of the SI joint and spine
●
Proportion of subjects who regain remission on rescue therapy
●
Time to regain remission on rescue therapy
5.3.3.4
Exploratory Variables
Each subject will have blood drawn for Biomarkers at the following time points:  
Baseline, Weeks 28, 68, time of flare, 12 weeks following determination of flare, and last 
study visit.  The final set of biomarkers to be analyzed may include the following:
●
DKK-1
●
Sclerostin
●
BMP-2
●
BMP-7

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The final selection of biomarkers for analysis will be based on both insights gained in the 
sub-study and available scientific knowledge at study completion.
Section 5.3.5  Safety Variables
Last sentence previously read:
The following safety evaluations will be performed during the study:  concomitant 
medication review, adverse event (AE) monitoring, vital signs, physical examination (if 
required) and laboratory tests.
Has been changed to read:
The following safety evaluations will be performed during the study:  concomitant 
medication review, AE monitoring, vital signs, physical examination (if required) and 
laboratory tests.
Section 5.5.1  Treatments Administered 
Subsection Rescue Therapy During Period 2
First sentence previously read:
Starting at Week 36, subjects who meet the flare criteria (flare is defined as 2 consecutive 
study visits with ASDAS ≥ 2.1) will be given rescue therapy with open-label adalimumab 
40 mg eow for at least 12 weeks and will continue through the duration of the subject's 
participation of the study.
Has been changed to read:
Starting at Week 36, subjects who meet the flare criteria (flare is defined as 2 consecutive 
study visits with ASDAS ≥ 2.100) will be given rescue therapy with open-label 
adalimumab 40 mg eow for at least 12 weeks and will continue through the duration of 
the subject's participation of the study.

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Section 5.5.2.2  Storage and Disposition of Study Drug
Second paragraph previously read:
All clinical supplies must be stored and locked in a secure place until they are dispensed 
for subject use or are returned to AbbVie.
Has been changed to read:
All clinical supplies must be stored and locked in a secure place until they are dispensed 
for subject use or are destroyed via on-site destruction (if allowed by local guidelines and 
a well-documented procedure is in place) or returned to AbbVie or third party drug 
destruction depot.
Section 5.6.3  Suitability of Subject Population
Previously read:
Males and females at least 18 years of age with nr-axSpA who have a minimum level of 
disease activity at baseline (ASDAS ≥ 2.1, BASDAI ≥ 4, Patient's Assessment of Total 
Back Pain score ≥ 4), have objective evidence of active disease (inflammation in the SI 
joints or spine on MRI or elevated hs-CRP), have had an inadequate response or 
intolerance to two or more NSAIDs or have an intolerance to, or a contraindication for 
NSAIDs, and who meet all inclusion criteria and who do not meet any of the exclusion 
criteria are eligible for this study.
Has been changed to read:
Males and females at least 18 years of age with nr-axSpA who have a minimum level of 
disease activity at baseline (ASDAS ≥ 2.100, BASDAI ≥ 4, Patient's Assessment of Total 
Back Pain score ≥ 4), have objective evidence of active disease (inflammation in the SI 
joints or spine on MRI or elevated hs-CRP), have had an inadequate response or 
intolerance to two or more NSAIDs or have an intolerance to, or a contraindication for 
NSAIDs, and who meet all inclusion criteria and who do not meet any of the exclusion 
criteria are eligible for this study.

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Section 6.5  Adverse Event Reporting
First paragraph, last sentence previously read:
Serious adverse events and non-serious events of malignancy in subjects 30 years of age 
and younger, that occur prior to the site having access to the RAVE® system or if RAVE 
is not operable should use the SAE Non-CRF paper forms and send them to Clinical 
Pharmacovigilance within 24 hours of being made aware of the adverse event.
Has been changed to read:
Serious adverse events and non-serious events of malignancy in subjects 30 years of age 
and younger, that occur prior to the site having access to the RAVE® system or if RAVE 
is not operable should use the SAE Non-CRF paper forms and send them (email is the 
preferred route) to Clinical Pharmacovigilance within 24 hours of being made aware of 
the adverse event.
Section 6.5  Adverse Event Reporting
"Primary Study Designated Physician" contact information previously read:

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Has been changed to read:
Section 8.1.2  Statistical and Analytical Plan
Fourth paragraph, first sentence previously read:
An interim database lock is planned when all ongoing subjects have completed Week 28 
of the study.  
Has been changed to read:
An interim database lock is planned when all ongoing subjects have completed Week 28 
(OL, Period 1) of the study.  
Section 8.1.4.1.1  Primary Analysis of Primary Efficacy Endpoint
First sentence previously read:
The primary efficacy endpoint is the proportion of subjects who do not experience a flare 
in Period 2 by Week 68 of the study, which defined as having any 2 consecutive study 
visits with ASDAS ≥ 2.1, and the response rate observed in the group randomized to 
adalimumab 40 mg eow will be compared to that in the placebo group.
Has been changed to read:
The primary efficacy endpoint is the proportion of subjects who do not experience a flare 
in Period 2 by Week 68 of the study, which defined as having any 2 consecutive study 

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visits with ASDAS ≥ 2.100, and the response rate observed in the group randomized to 
adalimumab 40 mg eow will be compared to that in the placebo group.
Section 9.3  Subject Information and Consent
Add:  new fifth paragraph
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.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Statistics
Clinical
Pharmacokinetics
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Statistics
Clinical
Pharmacokinetics