Rheumatoid Arthritis: A Phase 2 Study to Investigate the Safety and Efficacy of ABBV-105 Given Alone or in Combination With Upadacitinib (ABBV-599 Combination) With a Background of Conventional Synthetic DMARDs in Subjects With Active Rheumatoid Arthritis With Inadequate Response or Intolerance to Biologic DMARDs
Phase: PHASE2
Conditions: Rheumatoid Arthritis (RA)
Sponsor: AbbVie

NCT03682705

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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
9
2.1
BACKGROUND AND RATIONALE
9
2.2
BENEFITS AND RISKS TO SUBJECTS
10
3
STUDY OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES
10
3.2
PRIMARY ENDPOINT
11
3.3
SECONDARY ENDPOINTS
11
3.4
SAFETY ASSESSMENTS
11
3.5
PHARMACOKINETIC ENDPOINTS
12
3.6
BIOMARKER RESEARCH
12
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
14
5
STUDY ACTIVITIES
15
5.1
ELIGIBILITY CRITERIA
15
5.2
CONTRACEPTION RECOMMENDATIONS
19
5.3
PROHIBITED MEDICATIONS AND THERAPY
20
5.4
PRIOR AND CONCOMITANT THERAPY
22
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
23
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
24
5.7
STUDY DRUG
25
5.8
RANDOMIZATION/DRUG ASSIGNMENT
26
5.9
PROTOCOL DEVIATIONS
27
6
SAFETY CONSIDERATIONS
28
6.1
COMPLAINTS AND ADVERSE EVENTS
28
6.2
TOXICITY MANAGEMENT
32

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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
35
7.1
STATISTICAL AND ANALYTICAL PLANS
35
7.2
DEFINITION FOR ANALYSIS POPULATIONS
35
7.3
STATISTICAL ANALYSES FOR EFFICACY
35
7.4
STATISTICAL ANALYSES FOR SAFETY
37
7.5
INTERIM ANALYSIS
37
7.6
SAMPLE SIZE ESTIMATION
37
8
ETHICS
38
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
38
8.2
ETHICAL CONDUCT OF THE STUDY
38
8.3
SUBJECT CONFIDENTIALITY
38
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
38
10 DATA QUALITY ASSURANCE
39
11 COMPLETION OF THE STUDY
39
12 REFERENCES
39
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A OR CYP1A2 INHIBITORS AND INDUCERS
21
TABLE 2.
STUDY DRUG
26
TABLE 3.
AES REQUIRING SUPPLEMENTAL REPORTS
29
TABLE 4.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
33
LIST OF FIGURES
FIGURE 1.
STUDY DESIGN
13
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
41

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APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
45
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
46
APPENDIX D.
ACTIVITY SCHEDULE
47
APPENDIX E.
JOINT EVALUATION WORKSHEET EXAMPLE
49
APPENDIX F.
RHEUMATOLOGY COMMON TOXICITY CRITERIA V.2.0 EXAMPLE
51
APPENDIX G.
PROTOCOL AMENDMENT SUMMARY OF CHANGES
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
ABBV-105 is a novel, covalent Bruton's tyrosine kinase (Btk) inhibitor being developed for the treatment 
of immune-mediated inflammatory diseases including rheumatoid arthritis (RA).
Btk is a non-receptor tyrosine kinase expressed in multiple immune cell types associated with the 
pathogenesis of RA and other autoimmune diseases.  Btk is required for the propagation of pro-
inflammatory signals downstream of immunoreceptors that promote autoimmune disease 
pathogenesis.  Compared to other Btk inhibitors, CC-292 (Celgene) and ibrutinib 
(Pharmacyclics/Janssen), ABBV-105 showed better potency, superior selectivity, and less off-target 
activity which is considered favorable for administration in humans.
The hematopoietic expression and signaling function of Btk downstream of numerous receptors has 
raised interest in pharmacologic targeting of Btk for immune-mediated inflammatory diseases including 
RA.1  The potential clinical value of Btk inhibition has been supported by studies in preclinical models of 
arthritis and lupus.2,3  These have demonstrated:  1) complete abrogation of arthritis in the collagen-
induced arthritis model when initiated at disease onset, consistent with the effect of Btk inhibition on 
autoantibody production,2,3 2) efficacy in myeloid-mediated animal arthritis models, consistent with the 
effects of Btk inhibition on macrophage, mast cell, dendritic cell, and neutrophil activity,2,3 and 
3) marked reductions of proteinuria in mouse models of lupus, consistent with the effect of Btk 
inhibition on autoantibody production and/or myeloid cell activation.4-6
Upadacitinib is a novel Janus kinase (JAK) inhibitor, which displays unique selectivity for the JAK1 
receptor which is currently being developed for the treatment of adult patients with moderately to 
severely active RA (Phase 3), psoriatic arthritis (Phase 3), atopic dermatitis (Phase 3), Crohn's disease 
(Phase 3), ulcerative colitis (Phase 2), and axial spondyloarthritis (Phase 2).  As of 20 June 2017, a total of 
1232 subjects have received upadacitinib, which includes 469 healthy volunteers, 553 RA patients, and 
210 Crohn's disease patients.  Upadacitinib was generally well-tolerated, and the types of adverse 
events (AEs) seen were typical of patients treated with immunosuppressant therapies.
Clinical Hypothesis
ABBV-105 given alone or in combination with upadacitinib (as the ABBV-599 combination therapy) 
should be effective in decreasing signs and symptoms associated with active RA in patients with 
inadequate response or intolerance to biologic disease-modifying anti-rheumatic drugs (bDMARDs) by 
interfering with the JAK1/Btk pathways.  Concurrent inhibition of JAK1/Btk pathways in RA may increase 
percent of those responding as well as depth of response (relative to inhibiting either pathway alone), 
while maintaining an acceptable safety profile.

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2.2 Benefits and Risks to Subjects
Preclinical toxicology studies of ABBV-105 in animals and ex vivo human samples suggest that the 
potential risks to human subjects of ABBV-105 treatment are anemia, bleeding associated with platelet 
dysfunction, and lymphopenia.  Reductions in lymphocytes and the known mechanism of action suggest 
the potential for an increased susceptibility to infection.
In Phase 1 Studies M16-356 (single doses of ABBV-105 ranging from 2 to 125 mg), M16-357 (multiple 
doses of ABBV-105 ranging from 3 - 60 mg), and M16-044 (co-administration of upadacitinib 30 mg with 
ABBV-105 ranging from 10 - 60 mg), ABBV-105 alone or ABBV-105 co-administration with upadacitinib 
was well-tolerated with no serious adverse events (SAEs) observed in healthy adult subjects.
Taken together, the safety data from the Phase 1 program support further development of ABBV-105 
given alone or in combination with upadacitinib (ABBV-599) in Phase 2 in subjects with RA.
For safety monitoring, the following are included in the protocol:
!
Exclusion of subjects with chronic or recent infections; 
!
Screen subjects for tuberculosis (TB); exclude patients with active TB or latent TB without 
history of appropriate prophylaxis: latent TB as assessed by Interferon Gamma Release Assay 
(IGRA) QuantiFERON Tuberculosis (TB) Gold in Tube Test or equivalent (i.e., or T SPOT.TB test; as 
available and if compliant with local TB guidelines) and/or a purified protein derivative (PPD) 
test (or both if required per local guidelines).
!
Subjects will also be screened for human immunodeficiency virus (HIV) and hepatitis B and C.
!
If a subject develops a serious infection or opportunistic infection with study treatment, study 
drug should be interrupted and appropriate treatment of the infection should be initiated.
!
Review SAEs of infection on a real time basis and query for additional information as clinically 
indicated
!
A supplemental herpes zoster form will be used to collect additional information for any herpes 
zoster infections.
See Section 3.4 for information on the Data Monitoring Committee (DMC).
For further details, please see findings from completed studies, including safety data in the ABBV-105 
and upadacitinib Investigator's Brochures.7,8
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
The main objective of this dose exploratory study is to evaluate the safety and efficacy of ABBV-105 and 
ABBV-599 (ABBV-105 plus upadacitinib) vs placebo on a background of conventional synthetic disease-
modifying anti-rheumatic drugs (csDMARDs) for the treatment of signs and symptoms of RA at 12 weeks 

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in bDMARD-inadequate response (bDMARD-IR) or bDMARD-intolerant subjects with moderately to 
severely active RA and to define optimal dose(s) for further development.
3.2 Primary Endpoint
1.
The primary endpoint is the change from baseline in disease activity score (DAS)28 (C-reactive
protein [CRP]) at Week 12.
3.3 Secondary Endpoints
2.
Change from baseline in clinical disease activity index (CDAI) and simplified disease activity index 
(SDAI) at all visits;
3.
Proportion of subjects achieving Clinical Remission (CR) at Week 12.  CR is defined as DAS28 
CRP < 2.6;
4.
Proportion of subjects achieving low disease activity (LDA) at Week 12.  LDA is defined as DAS28 
CRP ≤ 3.2;
5.
Proportion of subjects achieving LDA or CR based on CDAI criteria at all visits;
6.
ACR20/50/70 response rates at all visits;
a.
ACR20/50/70 response rate will be determined based on 20%/50%/70% or greater 
improvement in Tender Joint Count (TJC) and Swollen Joint Count (SJC) and ≥ 3 of the 
5 measures of Patient's Assessment of Pain (Visual Analog Scale [VAS]), Patient's Global 
Assessment of Disease Activity (PtGA), Physician's Global Assessment of Disease Activity 
(PhGA), Health Assessment Questionnaire Disability Index (HAQ-DI), or high-sensitivity 
C-reactive protein (hsCRP);
7.
Change from baseline in individual components of American College of Rheumatology (ACR) 
response at all visits;
8.
Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation rate [ESR]) at all 
visits;
9.
Change from baseline in morning stiffness at all visits;
10. Change from baseline in HAQ-DI at all visits;
11. Proportion of subjects achieving minimal clinically important difference (MCID) in change from 
baseline in HAQ-DI (defined as change from baseline in HAQ-DI ≤ –0.3) at all visits;
12. Proportion of subjects achieving ACR/European League Against Rheumatism (EULAR) Boolean 
remission at all visits.
3.4 Safety Assessments
Routine safety evaluations include AE monitoring, physical examinations, vital sign measurements, 
electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry, and urinalysis) as a 
measure of safety and tolerability for the entire study duration.

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SAEs will be assessed at any dose that results in a death, inpatient hospitalization or prolongation of 
existing hospitalization, persistent or significant disability/incapacity or a congenital anomaly.
Safety data will be assessed over the course of the study.  An independent internal DMC will be created, 
and unblinded safety assessments will be conducted (Section 7.5).  This is to assess unanticipated safety 
signals with regard to novel agents ABBV-105 and ABBV-599.
An independent Cardiovascular Adjudication Committee (CAC) will adjudicate blinded cardiac and 
cerebrovascular events.  A CAC charter will be prepared separately from the protocol that will define 
objective, scope, frequency, and triggers of data reviews.
3.5 Pharmacokinetic Endpoints
ABBV-105 and upadacitinib plasma concentrations will be summarized at each sampling time point using 
descriptive statistics (Appendix D).  A mixed-effects modeling approach may be used to estimate the 
population central value and the empirical Bayesian estimates of the individual values for ABBV-105 and 
upadacitinib oral clearance (CL/F) and volume of distribution (Vss/F).  Additional parameters may be 
estimated if useful in the interpretation of the data.
3.6 Biomarker Research
Whole blood samples will be collected at specific time points (Appendix D) throughout the study to 
evaluate known and or novel disease related or drug related biomarkers.  Types of biomarkers may 
include nucleic acids, proteins, lipids, and/or metabolites.  The analyses may include but are not limited 
to prognostic, surrogate, predictive and pharmacodynamic biomarkers.  This research is exploratory in 
nature and the results may not be included with the clinical study report.  Biomarker samples will be 
collected and analyzed from all subjects, unless precluded by local regulations or restrictions.  Research 
on samples collected in Germany will be restricted to ABBV-105, upadacitinib, and RA.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a 12-week, randomized, double-blind, parallel-group, Phase 2, dose exploratory, multicenter 
study designed to assess the safety and efficacy of ABBV-105 and ABBV-599 in subjects with active RA 
who have had inadequate response to bDMARD therapy and are on stable background csDMARD 
treatment.  Subjects who meet eligibility criteria will be randomized in a 3:2:2:2:2:1 ratio to 1 of 
6 treatment groups:
!
Group 1:  Upadacitinib 15 mg and ABBV-105 60 mg administered once daily (QD) (n = 60)
!
Group 2:  ABBV-105 60 mg and upadacitinib placebo QD (n = 40)
!
Group 3:  ABBV-105 20 mg and upadacitinib placebo QD (n = 40)
!
Group 4:  ABBV-105 5 mg and upadacitinib placebo QD (n = 40)

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!
Group 5:  Upadacitinib 15 mg and ABBV-105 placebo QD (n = 40)
!
Group 6:  ABBV-105 placebo and upadacitinib placebo QD (n = 20)
The study duration will include a 35-day maximum screening period and a 12-week randomized, double 
blind, parallel-group treatment period with 30-day follow-up.  Study visits will be conducted at 
Screening, Baseline, Week 2, Week 4, Week 8, and Week 12.  For post-baseline visits, a visit window of 
± 3 days will be allowed.
The schematic of the study is shown in Figure 1.
The study population will consist of adult subjects who are at least 18 years of age with a diagnosis of RA 
for ≥ 3 months and also fulfill the 2010 ACR/EULAR classification criteria for RA.  Subjects will have been 
treated for ≥ 3 months with ≥ one bDMARD but continue to exhibit active RA or had to discontinue 
bDMARD(s) due to intolerability or toxicity, irrespective of treatment duration.
Randomization will be stratified by number of prior bDMARDs used (failed 1 or 2 biologics with the same 
mechanism of action; failed ≥ 3 biologics with the same mechanism of action and/or ≥ 2 bDMARDs with 
different mechanisms of action).  Once approximately 35% of the total subjects have been randomized 
to the second stratum, further screening of subjects in that group may be suspended.  See Section 5.1
for information regarding eligibility criteria.
This study will be conducted in approximately 240 subjects with planned interim safety reviews as 
discussed in Section 7.5.
Figure 1.
Study Design
QD = once daily

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4.2 Discussion of Study Design
Choice of Control Group
This is a parallel-group study consisting of 6 treatment groups receiving ABBV-105, ABBV-599 (a 
combination of upadacitinib and ABBV-105), upadacitinib, or matching placebo to assess the safety and 
efficacy of ABBV-105 given alone or in combination with upadacitinib (as the ABBV-599 combination) 
once daily for 12 weeks in patients with active RA who have had an inadequate response or intolerance 
to bDMARDs.  Placebo will serve as a reference for efficacy assessment while the additional efficacy of 
ABBV-599 combination will utilize in-study upadacitinib subjects as a reference (with/without historic 
data borrowed from Phase 2 and Phase 3 upadacitinib studies performed in similar populations).
Appropriateness of Measurements
Appropriate statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with RA.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
Adult subjects who are at least 18 years of age with a diagnosis of RA for ≥ 3 months and also fulfill the 
2010 ACR/EULAR classification criteria for RA and who have been treated for ≥ 3 months with 
≥1 bDMARD, but continue to exhibit active RA or had to discontinue bDMARD(s) due to intolerability or 
toxicity, irrespective of treatment duration, are eligible for this study.  The selection criteria relating to 
safety guarantee that subjects enrolled can be safely treated with ABBV-105, with or without 
upadacitinib, based on the current knowledge of these drugs.
Selection of Doses in the Study
The dose selection in this study is based on analysis of pharmacokinetic, pharmacodynamic, safety, and 
efficacy (upadacitinib only) data from Phase 1 studies in healthy volunteers for ABBV-105 and Phase 2 
and Phase 3 studies for upadacitinib.
Given the uncertainty in correlation between blood Btk occupancy and efficacy in RA patients, the low 
and middle ABBV-105 doses are intended to target exposures that would approximate mid-level and 
near maximal Btk occupancy, respectively, in a dosing interval, and the high dose is intended to 
approximate exposures at or greater than those needed to achieve maximal Btk occupancy.
In the Phase 1 ABBV-105 multiple ascending dose study (Study M16-357), the Btk occupancy at steady-
state was near 100% throughout the dosing interval at the 60 mg QD dose; in the ABBV-599 multiple 
ascending dose study (Study M16-044), the Btk occupancy of approximately 70% and 90% was 
maintained throughout the dosing interval at the 10 and 20 mg QD doses, respectively.
Following once-daily dosing of ABBV-105 5 mg, 20 mg, and 60 mg, peak Btk occupancy at steady-state is 
predicted to be 67%, 93%, and 99%, respectively, whereas steady-state trough Btk occupancy is 
predicted to be 58%, 83%, and 89%, respectively.  Therefore, the ABBV-105 doses of 5, 20, and 60 mg 
were selected to satisfy the Btk-related exposure criteria, as well as to represent exposures that were 
found to be safe and well tolerated in the Phase 1 studies.  The selected dose of the upadacitinib 
component of the ABBV-599 arm is 15 mg, based on the results of the upadacitinib RA Study M13-542.  

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In bDMARD-IR subjects with RA, upadacitinib 15 and 30 mg QD doses achieved superior responses to 
placebo in all primary and ranked secondary endpoints at Weeks 12 and 24.  The upadacitinib 30 mg 
dose provided little additional incremental benefit over the 15 mg dose.  Thus, for the ABBV-599 
treatment arm, the 15 mg QD upadacitinib dose was selected to be co-administered with ABBV-105.  A 
treatment arm of 15 mg QD upadacitinib with ABBV-105 placebo QD is included to provide an in-study 
reference to estimate the additive effect of the ABBV-599 combination relative to upadacitinib 
monotherapy.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects or their legally authorized representative must voluntarily sign and date an informed 
consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), 
prior to the initiation of any screening or study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old.
3. Laboratory values meeting the following criteria within the screening period prior to the
first dose of study drug:
!
Serum alanine transaminase (ALT) < 2 × upper limit of normal (ULN)
!
Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in 
Renal Disease (MDRD) formula > 40 mL/min/1.73 m2
!
Total white blood cell (WBC) count > 3,000/μL
!
Absolute neutrophil count (ANC) > 1,500/μL
!
Platelet count > 100,000/μL
!
Absolute lymphocyte count > 800/μL
!
Hemoglobin > 10 g/dL
Disease Activity
4. Diagnosis of RA for ≥ 3 months based on the 2010 ACR/EULAR classification criteria for RA.
5. Subject meets the following minimum disease activity criteria:
!
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) 
at Screening and Baseline Visits (Appendix E); and

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hsCRP ≥ 3 mg/L (central lab) at Screening Visit.
Subject History
6. No history of any of the following cardiovascular conditions:
!
Moderate to severe congestive heart failure (New York Heart Association Class III or IV).
!
Recent history (within past 6 months) of cerebrovascular accident (CVA), myocardial 
infarction, and/or coronary stenting.
!
Uncontrolled hypertension as defined by a persistent systolic blood pressure (BP) 
> 160 mmHg or diastolic BP > 100 mmHg.  For subjects with known hypertension, the 
subject's BP must be stable for at least 4 weeks on current, stable anti-hypertensive 
medications.
!
Prior unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) (i.e., any 
spontaneous event not directly attributable to trauma or vascular instrumentation).
!
Any other condition which, in the opinion of the Investigator, would put the subject at risk 
by participating in the protocol.
7. No history of any arthritis with onset prior to age 17 years or current diagnosis of 
inflammatory joint disease other than RA (including but not limited to gout, systemic lupus 
erythematosus, psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis and 
non-radiographic axial spondyloarthritis, reactive arthritis, overlap connective tissue diseases, 
scleroderma, polymyositis, dermatomyositis, fibromyalgia [currently with active symptoms], or 
any arthritis with onset prior to age 17 years).  Current diagnosis of secondary Sjogren's 
Syndrome is permitted.
8. Must not have been treated with intra-articular, intramuscular, intravenous, trigger point or 
tender point, intra-bursa, or intra-tendon sheath corticosteroids in the preceding 8 weeks prior 
to the first dose of study drug.
9. Must not have been treated with any investigational drug within 30 days or five half-lives of 
the drug (whichever is longer) prior to the first dose of study drug or is currently enrolled in 
another clinical study.
10. Females must not be pregnant, breastfeeding, or considering becoming pregnant during the 
study or for approximately 30 days after the last dose of study drug.
11. For all females of child-bearing potential:  a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.
12. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day 1 through at least 30 days.  Female subjects of 
non-childbearing potential do not need to use birth control.
13. Must not have any active or recurrent viral infection that, based on the Investigator's clinical 
assessment, makes the subject an unsuitable candidate for the study, including hepatitis B virus 
(HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a single episode) herpes zoster, 
disseminated (even a single episode) herpes simplex, or HIV.
Active HBV, HCV, and HIV are defined as:

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!
HBV:  Hepatitis B surface antigen (HBs Ag) positive (+) or, for hepatitis B core antibody (HBc 
Ab) positive subjects, detection of HBV DNA by polymerase chain reaction (PCR);
!
HCV:  HCV RNA detectable in any subject with anti-HCV antibody (HCV Ab);
!
HIV:  Confirmed positive anti-HIV antibody (HIV Ab) test.
14. Must not have active TB or meets TB exclusionary parameters (defined as the presence of 
active TB or latent TB not adequately treated as per protocol requirements).
Canada only:  Must not have active TB or untreated or inadequately treated latent TB
!
Must not have evidence of active TB defined in this study as the following:
i.
Documented by a positive purified protein derivative (PPD) test (≥ 5 mm induration 
between approximately 48 and 72 hours after application, regardless of vaccination 
history) and/or medical history, clinical features, and abnormal chest x-ray at screening 
consistent with active TB.
ii.
The QuantiFERON®-TB Gold test or T SPOT.TB test (as available and if compliant with 
local TB guidelines) may be used instead of the PPD test.  Patients are excluded from the 
study if the test is not negative and there is clinical evidence of active TB.
!
Must not have evidence of untreated/inadequately or inappropriately treated latent TB, 
defined in this study as the following:
i.
Documented to have a positive PPD test (≥ 5 mm induration between approximately 
48 and 72 hours after application, regardless of vaccination history), no clinical features 
consistent with active TB, and a chest x-ray with no evidence of active TB at screening; 
or
ii.
PPD test is positive and the patient has no medical history or chest x-ray findings 
consistent with active TB, the patient may have a QuantiFERON-TB Gold test or 
T SPOT.TB test (as available and if compliant with local TB guidelines).  If the test results 
are not negative, the patient will be considered to have latent TB (for purposes of this 
study); or
iii. QuantiFERON®-TB Gold test or T SPOT.TB test (as available and if compliant with local 
TB guidelines) may be used instead of the PPD test.  If the test results are positive, the 
patient will be considered to have latent TB.  If the test is not negative, the test may be 
repeated once within approximately 2 weeks of the initial value.  If the repeat test 
results are again not negative, the patient will be considered to have latent TB (for 
purposes of this study).
15. Must not have used known strong cytochrome P450 (CYP)3A or CYP1A2 inhibitors or strong 
CYP3A or CYP1A2 inducers from Screening through the end of the study.
16. Must not have had receipt of any live vaccine within 4 weeks prior to the first dose of study 
drug, or expected need of live vaccination during study participation including at least 4 weeks 
after the last dose of oral study drug.
17. Must not have a history of any malignancy except for successfully treated non-melanoma 
skin cancer (NMSC) or localized carcinoma in situ of the cervix.

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18. Must not have a history of clinically significant (per Investigator's judgment) drug or alcohol 
abuse within the last 6 months.
19. Must not have a history of gastrointestinal perforation (other than appendicitis or 
penetrating injury), diverticulitis or significantly increased risk for gastrointestinal perforation 
per investigator judgment.
20. Must not have any conditions that could interfere with drug absorption including but not 
limited to short bowel syndrome.
21. Must not be a recipient of an organ transplant.
22. Must not have history of clinically significant medical conditions or any other reason that in 
the opinion of the Investigator would interfere with the subject's participation in this study or 
would make the subject an unsuitable candidate to receive study drug.
23. Must not have had an active infection(s) requiring treatment with parenteral anti-infectives 
within 30 days, or oral anti-infectives within 14 days prior to the first dose of study drug.
24. Must not have a history of an allergic reaction or significant sensitivity to constituents of the 
study drugs (and its excipients) and/or other products in the same class.
Concomitant Medications
25. Subjects must have been treated for ≥ 3 months with ≥ 1 bDMARD therapy but continue to 
exhibit active RA or had to discontinue due to intolerability or toxicity, irrespective of treatment 
duration.
26. Subjects must have been receiving csDMARD therapy ≥ 3 months and on a stable dose for 
≥4 weeks prior to the first dose of study drug.
!
The following csDMARDs are allowed (stable dose for ≥ 4 weeks prior to the first dose of 
study drug):  oral or parenteral methotrexate (MTX) (7.5 to 25 mg/week), sulfasalazine 
(≤ 3000 mg/day), hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and 
leflunomide (≤ 20 mg/day).
!
A combination of up to two background csDMARDs is allowed EXCEPT the combination 
of MTX and leflunomide.
27. Dose of non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen/paracetamol 
must have been at a stable dose ≥ 1 week prior to the first dose of study drug; oral 
corticosteroids (equivalent to prednisone ≤ 10 mg/day) or inhaled corticosteroids for stable 
medical conditions are allowed but must have been at a stable dose ≥ 4 weeks prior to the 
first dose of study drug.
28. Subjects must have discontinued all bDMARDs prior to the first dose of study drug.  The 
washout period for bDMARDs prior to the first dose of study drug is specified below or should 
be at least five times the mean terminal elimination half-life of a drug:
!
≥ 4 weeks for etanercept, adalimumab, infliximab, certolizumab, golimumab, tocilizumab, 
and abatacept;

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!
≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pretreatment level or 
normal reference range (central lab) if pretreatment levels are not available (B cell testing 
may be completed at Screening if indicated).
29. Subjects must have discontinued all high-potency opiates at least 1 week and oral traditional 
Chinese medicine for at least 4 weeks prior to the first dose of study drug (refer to Section 5.3
for prohibited medications).
30. Subject must not have prior exposure to any JAK inhibitor for greater than 2 weeks 
(including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib). A washout 
period of ≥ 30 days is required for any JAK inhibitor prior to the first dose of study drug.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:
!
Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
!
Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.
!
Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle stimulating hormone (FSH) level > 40 IU/L.
!
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).
!
Females, of Childbearing Potential
Females of childbearing potential must avoid pregnancy while taking study drug(s) and for at 
least 30 days after the last dose of study drug.  Females must commit to one of the following 
methods of birth control with:
!
Combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal, injectable) associated with the inhibition of ovulation, initiated at 
least 30 days prior to Study Day 1.
!
Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 1 month prior to Study Day 1.
!
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure).
!
Intrauterine device (IUD).
!
Intrauterine hormone-releasing system (IUS).
!
To have a vasectomized sexual partner(s) (the vasectomized partner[s] has received medical 
assessment of the surgical success and is the sole sexual partner of the trial subject).

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To practice true abstinence (if acceptable per local requirements), defined as:  Refraining 
from heterosexual intercourse when this is in line with the preferred and usual lifestyle of 
the subject (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable).
If required per local practices, male or female condom with or without spermicide OR cap, diaphragm or 
sponge with spermicide should be used in addition to one of the highly effective birth control methods 
listed above (excluding true abstinence).  A condom is required in the following countries:  UK, Germany, 
and Spain.
The concomitant csDMARDs (i.e., MTX, sulfasalazine, etc.) that have been prescribed per standard of 
care prior to study entry and are allowed to be continued during the study for female and male subjects.  
Contraception should continue while the subject is on the concomitant csDMARD(s) and that duration of 
contraception after discontinuation of the csDMARD(s) should be based on the local label.  Additional 
local requirements may apply.
5.3 Prohibited Medications and Therapy
JAK Inhibitor
Prior exposure to JAK inhibitors (including but not limited to upadacitinib, tofacitinib [Xeljanz®], 
baricitinib [Olumiant®], and filgotinib) must not be greater than 2 weeks.
Corticosteroids
Oral corticosteroids > 10 mg prednisone/day or equivalent and intra-articular, intramuscular, 
intravenous, trigger point or tender point, intra-bursa, and intra-tendon sheath corticosteroids are NOT 
allowed during this study.
Any csDMARD/Immunosuppressive Not Listed in Section 5.4 (Prior and Concomitant Therapy)
All biologic therapies are prohibited during the study.
Subjects must have discontinued the bDMARD prior to the first dose of study drug as specified in the 
washout procedures (Eligibility Criterion #28).  For all other bDMARDs, contact the Therapeutic Area 
Medical Director for the washout period required prior to the first dose of study drug.
Examples of biologic therapies include but are not limited to the following:
!
Humira® (adalimumab)
!
Enbrel® (etanercept)
!
Remicade® (infliximab)
!
Kineret® (anakinra)
!
Rituxan® (rituximab)
!
Cimzia® (certolizumab pegol)

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!
Simponi® (golimumab)
!
Actemra® (tocilizumab)
!
Raptiva® (efalizumab)
!
Tysabri® (natalizumab)
!
Stelara® (ustekinumab)
!
Benlysta® (belimumab)
!
Orencia (abatacept)
Strong CYP3A or CYP1A2 Inhibitors or Inducers
Systemic use of known strong inhibitors or inducers of CYP3A or CYP1A2 is excluded from the Screening 
Visit through the end of the study.  The most common strong CYP3A or CYP1A2 inhibitors and inducers 
are listed in Table 1.
Table 1.
Examples of Commonly Used Strong CYP3A or CYP1A2 Inhibitors and Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Carbamazepine
Phenytoin
Rifampin
Rifapentine
St. John's Wort
Strong CYP1A2 Inhibitors
Strong CYP1A2 Inducers
Fluvoxamine
Ciprofloxacin
Enoxacin
Zafirlukast
Rifampin

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Live Vaccines
Use of live vaccines is prohibited during the study.  Examples of live vaccines include, but are not limited 
to, the following:
!
Monovalent live influenza A (H1N1) (intranasal);
!
Seasonal trivalent live influenza (intranasal);
!
Herpes zoster;
!
Rotavirus;
!
Varicella (chicken pox);
!
Measles-mumps-rubella or measles mumps rubella varicella;
!
Oral polio vaccine;
!
Smallpox;
!
Yellow fever;
!
Bacille Calmette-Guérin (BCG);
!
Typhoid.
Elective and Emergency Surgeries
Elective surgery will not be allowed during the study until the primary endpoint has been assessed.  If 
the subject undergoes emergency surgery, the study drug should be interrupted as soon as possible and 
reintroduced once the physician has examined the surgical site and determined that it has healed and 
there is no sign of infection.
5.4 Prior and Concomitant Therapy
Subjects should continue on their stable (≥ 4 weeks prior to the first dose of study drug) background 
csDMARD therapy, restricted to the following:  oral or parenteral MTX (7.5 to 25 mg/week), 
sulfasalazine (≤ 3000 mg/day), hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and 
leflunomide (≤ 20 mg/day).  Combinations of up to two csDMARDs are allowed except for the 
combination of MTX and leflunomide.
At any time, the csDMARD dose may be decreased only for safety reasons.  Subjects taking MTX should 
take a dietary supplement of oral folic acid (or equivalent, such as folinic acid) throughout study 
participation.  Folic acid dosing and timing of regimen should be followed according to Investigator's 
instructions.  AbbVie will not provide the csDMARDs (or folic acid, if taking MTX).
Subjects should continue on their stable doses of NSAIDs, acetaminophen/paracetamol, oral 
corticosteroids (equivalent to prednisone ≤ 10 mg/day), or inhaled corticosteroids.
!
If taking any of the above on a scheduled basis, they should continue to take them as they did at 
study entry with no change in dose or frequency, including on study visit days.

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If not taking any of the above at baseline, these should not be initiated.
!
If taking any of the above, including low potency analgesics (i.e., tramadol, codeine, 
hydrocodone, or propoxyphene) at baseline on an as needed (PRN) basis, they should continue 
to use them for the same reason and same dose each time, but they should not be taken within 
the 24 hours prior to any study visit to avoid bias in outcome measurements.
In the event of tolerability (or other safety) issues, the doses of these medications may be decreased or 
discontinued with substitution of another permitted medication from that class.  PRN use of inhaled 
corticosteroids is permitted at any time.
A long-term extension (LTE) study is planned to be conducted under a separate protocol at sites where it 
is permitted by the local Competent Authority and Ethics Committee.  Patient rollover from the initial 
randomized portion of the study will occur at Week 12 for all patients to assure comparable length of 
exposure for each different treatment.
5.5 Withdrawal of Subjects and Discontinuation of Study
Subjects can request to be discontinued from participating in the study at any time for any reason 
including but not limited to disease progression or lack of response to treatment.  The Investigator may 
discontinue any subject's participation at any time for any reason including but not limited to disease 
progression, lack of response to treatment, an AE, safety concerns, or failure to comply with the 
protocol.  See Section 6.2 for toxicity management criteria.
Subjects will have study drug discontinued immediately if any of the following occur:
!
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the Investigator or the AbbVie Therapeutic Area Medical Director (TA MD).
!
Serious infections (e.g., sepsis) that cannot be adequately controlled within 2 weeks by anti-
infective treatment or would put the subject at risk for continued participation in the trial as 
determined by the Investigator.
!
The Investigator believes it is in the best interest of the subject.
!
The subject requests withdrawal from the study.
!
Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk as determined by the AbbVie TA MD.
!
Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk, as determined by the AbbVie TA MD.
!
Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.
!
The subject becomes pregnant while on study drug.
!
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix.
!
Subject is significantly non-compliant with study procedures which would put the subject at risk 
for continued participation in the trial as determined by the Investigator or the AbbVie TA MD.

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Subject develops a gastrointestinal perforation.
In order to minimize missing data for efficacy and safety assessments, subjects who prematurely 
discontinue study drug treatment or study participation should complete a Premature Discontinuation 
visit (PD) visit.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue the study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they discontinue 
treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the PD visit should be completed as soon as possible, preferably within 2 weeks.  
In addition, if subject is willing, a 30-day follow-up phone call after the last dose of study drug may be 
completed to ensure all treatment-emergent AEs/SAEs have been resolved.
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate electronic case report form (eCRF) page.  However, these procedures should not interfere 
with the initiation of any new treatments or therapeutic modalities that the Investigator feels are 
necessary to treat the subject's condition.  Following discontinuation of study drug, the subject should 
be treated in accordance with the Investigator's best clinical judgment irrespective of whether the 
subject decides to continue participation in the study.
If a subject withdraws from the main study, biomarker research samples will continue to be stored and 
analyzed.  A subject must contact the study investigator if they no longer want their samples to be 
stored and analyzed.  Once AbbVie is notified, no new information will be collected, no new analysis will 
be started, and the samples will be destroyed unless a regulatory authority requires AbbVie to keep 
them.  However, if AbbVie (or people or companies working with AbbVie) collected any information or 
did any testing before withdrawal, AbbVie (or people or companies working with AbbVie) will still use 
and disclose such information, use the test results, and keep the data generated from the samples.

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5.7 Study Drug
ABBV-105, upadacitinib, or matching placebo manufactured by AbbVie will be administered on Day 1 
(Baseline) and should be taken at approximately the same time each day.  Subjects will be instructed to 
take study drug orally, which includes only 1 capsule of ABBV-105 or placebo from each of the 
3 dispensed bottles per day, with or without food, and only 1 tablet of upadacitinib or placebo from the 
dispensed bottle per day, with or without food.  Subjects will be instructed to take only 1 tablet from the 
dispensed tablet bottle per day.  If subjects should forget to take their ABBV-105, upadacitinib, or 
matching placebo dose at their regularly scheduled dosing time, they should take the forgotten dose as 
soon as they remember as long as it is at least 10 hours before their next scheduled dose.  Otherwise 
they should take the next dose at the next scheduled dosing time.
Subject dosing will be recorded on a subject dosing diary.  The subject will be instructed to return all 
drug containers (even if empty) to the study site personnel at each study visit.  Study site personnel will 
document compliance.
AbbVie will not supply drug other than ABBV-105, upadacitinib, or matching placebo.
ABBV-105, upadacitinib, and matching placebo will be packaged in bottles with quantities sufficient to 
accommodate study design.  Each kit will be labeled per local requirements and this label must remain 
affixed to the kit.  Upon receipt, study drug should be stored as specified on the label and kept in a 
secure location.  Each kit will contain a unique kit number.  This kit number is assigned to a subject via 
interactive response technology (IRT) and encodes the appropriate study drug to be dispensed at the 
subject's corresponding study visit.  Site staff will complete all blank spaces on the label before 
dispensing to subjects.  Study drug will only be used for the conduct of this study.

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multiple mechanisms of action).  Once approximately 35% of the total subjects have been randomized 
to the second group, further screening of those subjects may be suspended.
Once approximately 30% of total subjects have been randomized who are not on MTX, further screening 
of such subjects may be suspended.
Once approximately 30% of total subjects have been randomized who are active smokers, further 
screening of such actively smoking subjects may be suspended.
Once approximately 30% of total subjects have been randomized who are negative for both rheumatoid 
factor and anti-cyclic citrullinated peptide antibody (anti-CCP), further screening of such seronegative 
subjects may be suspended.
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment throughout the study.  To maintain the blind, the 
ABBV-105 capsules and matching placebo capsules and upadacitinib tablets and matching placebo 
tablets provided for the study will be identical in appearance.
In the event of a medical situation that requires unblinding of the study drug assignment, the 
Investigator is requested to contact the AbbVie Therapeutic Area Medical Director prior to breaking the 
blind.  However, if an urgent therapeutic intervention is necessary which warrants breaking the blind 
prior to contacting the AbbVie Therapeutic Area Medical Director, the Investigator can directly access 
the IRT system to break the blind without AbbVie notification or agreement.  Unblinding is available in 
the IRT system via the Unblind Subject transaction, which is available to the Investigator.  If the IRT 
system is unavailable, unblinding may occur by contacting EndPoint technical support via either phone 
(preferred) or email (support@endpointclinical.com).  For country-specific phone numbers, please see 
the following website:  http://www.endpointclinical.com/help-desk/.  In the event that the blind is 
broken before notification to the AbbVie Therapeutic Area Medical Director, we request that the AbbVie 
Therapeutic Area Medical Director be notified within 24 hours of the blind being broken.
5.9 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the investigator is responsible for notifying the IEC/IRB, regulatory authorities (as 
applicable), and AbbVie.

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6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaints
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or not 
the event is considered causally related to the use of the product.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
pre planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If any of the following AEs are reported, then the following supplemental report(s) must be completed.

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Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, SAEs and protocol-related nonserious AEs will be collected from the time the subject signs the 
study-specific informed consent.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local requirements.
AEs will be monitored throughout the study to identify any of special interest that may indicate a trend 
or risk to subjects.
Adverse Events of Special Interest
The following adverse events of special interest (AESI) will be monitored during the study:
!
Serious infections
!
Opportunistic infections
!
Herpes zoster
!
Tuberculosis
!
Malignancy (all types)
!
Gastrointestinal perforations
!
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event [MACE])
!
Anemia
!
Neutropenia
!
Lymphopenia
!
Increased serum creatinine and renal dysfunction
!
Hepatic events and increased hepatic transaminases
!
Elevated creatine phosphokinase (CPK)

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Embolic and thrombotic events (non-cardiac, non-CNS).
Adverse Event Severity and Relationship to Study Drug
The investigator will classify AEs according to the Rheumatology Common Toxicity Criteria v.2.0 
(Appendix F).
If no grading criteria are provided for the reported event, then the event should be as follows:
!
Mild (Grade 1):  asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
!
Moderate (Grade 2):  minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) (instrumental ADL refer to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc.).
!
Severe (Grade 3):  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL (self 
care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden);
!
Life-threatening (Grade 4):  urgent intervention indicated or death related to AE.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day after 
the site becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.5).
Information regarding the pregnancy and the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.

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6.2 Toxicity Management
The management of specific AEs and laboratory parameters is described in Table 4 and in the 
Operations Manual.
The toxicity management of the AEs including AESI consists of safety monitoring (review of AEs on an 
ongoing basis, and periodical/ad hoc review of safety issues by a safety data monitoring committee), 
interruption of study drug dosing with appropriate clinical management if applicable, and 
discontinuation of the subjects from study drug.  The management of specific AEs and laboratory 
parameters is described below.
For subjects who discontinue study drug but continue study participation and are on standard of care 
therapies, these toxicity management requirements do not apply (including alerts from the central lab) 
and any intolerability to standard of care therapies should be managed by the prescribing physician.
Serious Infections:  Subjects should be closely monitored for the development of signs and symptoms of 
infection during and after treatment with study drug.  Study drug should be interrupted if a subject 
develops a serious infection or an opportunistic infection.  A subject who develops a new infection 
during treatment with study drug should undergo prompt diagnostic testing appropriate for an 
immunocompromised subject.  As appropriate, antimicrobial therapy should be initiated, and the 
subject should be closely monitored.  Study drug may be restarted once the infection has been 
successfully treated.  Subjects who develop active TB or experience hepatitis B reactivation must be 
discontinued from study drug.  To further monitor subjects for serious infections, subjects will complete 
at-home weekly temperature monitoring.  If above 100.5 degrees Fahrenheit (38 degrees Celsius), 
subject should inform their study doctor to assess the need for further evaluation.
Canada only:  Investigators should be advised to follow local public health guidelines in order to prevent 
subjects enrolled in these trials from acquiring TB.
Serious Gastrointestinal Events:  Subjects presenting with the onset of signs or symptoms of a serious 
gastrointestinal event should be evaluated promptly for early identification of gastrointestinal 
perforation.  If the diagnosis of gastrointestinal perforation is confirmed, the subject must be 
discontinued from study drug.
Cardiovascular Events (MACE):  Subjects presenting with potential cardiovascular events should be 
carefully monitored.  These events will be reviewed and adjudicated by the independent CAC.
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in situ of the cervix must 
be discontinued from study drug.  Information including histopathological results should be queried for 
the confirmation of the diagnosis.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change considered 
clinically significant and with reasonable possibility of relationship to study drug OR a confirmed 
absolute QTcF value > 500 msec.
Management of Select Laboratory Abnormalities:  For any given laboratory abnormality, the 
Investigator should assess the subject, apply the standard of care for medical evaluation and treatment 
following any local guidelines.  Specific toxicity management guidelines for abnormal laboratory values 

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are described in Table 4 and may require an appropriate supplemental eCRF be completed.  All 
abnormal laboratory tests that are considered clinically significant by the Investigator will be followed to 
a satisfactory resolution.  If a repeat test is required per Table 4, the repeat testing must occur as soon 
as possible.
Table 4.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory Parameter
Toxicity Management Guideline
Hemoglobin
!
If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by repeat testing 
with a new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative 
etiology, interrupt study drug dosing and confirm by repeat testing with new 
sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative etiology is 
known, the subject may remain on study drug at the investigator's discretion.
!
If confirmed, continue to withhold study drug until hemoglobin value returns to 
normal reference range or its baseline value.
Absolute neutrophil 
count (ANC)
!
If confirmed < 1000 cells/μL by repeat testing with new sample, interrupt study 
drug dosing until ANC value returns to normal reference range or its baseline 
value.
!
Discontinue study drug if confirmed < 500 cells/μL by repeat testing with new 
sample.
Absolute lymphocyte 
counts (ALC)
!
If confirmed < 500 cells/μL by repeat testing with new sample, interrupt study 
drug dosing until ALC returns to normal reference range or its baseline value.
Total white blood cell 
count
!
If confirmed < 2,500 cells/μL by repeat testing with new sample, interrupt study 
drug dosing until white blood cell count returns to normal reference range or its 
baseline value.
Platelet count
!
If confirmed < 50,000 platelets/μL by repeat testing with new sample, interrupt 
study drug dosing until platelet count returns to normal reference range or its 
baseline value.

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Laboratory Parameter
Toxicity Management Guideline
Aspartate transaminase 
(AST) or alanine 
transaminase (ALT)
!
Interrupt study drug immediately if confirmed ALT or AST > 3 × upper limit of 
normal (ULN) by repeat testing with new sample and either a total bilirubin 
> 2 × ULN or an international normalized ratio (INR) > 1.5.
!
INR will only need to be measured in subjects with ALT or AST > 3 × ULN by 
the central lab.  A repeat test of INR is not needed for determination if 
above toxicity management criteria are met.
!
Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat 
testing with new sample along with appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
!
Interrupt study drug immediately if confirmed ALT or AST > 5 × ULN by repeat 
testing with new sample for more than 2 weeks.
!
Interrupt study drug immediately if confirmed ALT or AST > 8 × ULN by repeat 
testing with new sample.
Subjects who meet any of the above criteria should be evaluated for an alternative 
etiology of the ALT or AST elevation and managed as medically appropriate.  The 
investigator should contact the AbbVie TA MD to discuss the management of a 
subject when an alternative etiology has been determined.  The alternative etiology 
should be documented appropriately in the eCRF; study drug should be discontinued 
if no alternative etiology can be found.
For any confirmed ALT or AST elevations > 3 ULN, complete supplemental hepatic 
eCRF.
!
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA at 
screening who develop the following should have HBV DNA by PCR testing 
performed within one week:
!
ALT > 5 × ULN OR
!
ALT or AST > 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR
!
ALT or AST > 3 × ULN along with clinical signs of possible hepatitis
!
A positive result for HBV DNA PCR testing in these subjects will require 
immediate interruption of study drug and a hepatologist consultation should 
occur within one week for recommendation regarding subsequent treatment.
Serum Creatinine
!
If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the test for 
serum creatinine (with subject in an euvolemic state) to confirm the results.  If 
the results of the repeat testing still meet this criterion then interrupt study 
drug and re-start study drug once serum creatinine returns to ≤ 1.5 × baseline 
value and ≤ ULN.
!
If confirmed serum creatinine ≥ 2 mg/dL interrupt study drug, and re-start study 
drug once serum creatinine returns to normal reference range or its baseline 
value.
For the above serum creatinine elevation scenarios, complete supplemental renal 
eCRF.

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Laboratory Parameter
Toxicity Management Guideline
Creatine Phosphokinase 
(CPK)
!
If confirmed CPK value ≥ 4 × ULN (if symptomatic or asymptomatic), complete 
supplemental CPK eCRF.
!
If confirmed CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug, complete supplemental CPK eCRF, and 
contact AbbVie Therapeutic Area Medical Director.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the final (Week 12) database lock.  The 
statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).  The final 
analysis will be conducted by AbbVie Statistics group at the final database lock, and the unblinded 
interim safety reviews will be conducted by the DMC at pre-specified time points as described in 
Section 7.5, Interim Analysis.
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose of randomized 
study drug.  The FAS will be used for all efficacy and baseline analyses.  Subjects will be grouped 
according to treatment as randomized.
The Safety Set consists of all enrolled subjects who received at least 1 dose of study drug.  Safety 
analyses are based on treatments actually received.
7.3 Statistical Analyses for Efficacy
Primary Endpoint Analysis
The primary endpoint is change from baseline in DAS28-CRP at Week 12.
The first primary analysis is to test the superiority of ABBV-599 compared to placebo at Week 12.
The second primary analysis is to test a pre-specified set of dose-response models (detailed in the SAP) 
among ABBV-105 dose groups and the placebo group at Week 12 using the Multiple Comparison 
Procedure – Modeling (MCP-Mod) method.9,10
Hypothesis testing in the primary analyses will be performed in a ranked fashion based on one-sided 
significance level of α = 0.05.  The other analysis for the primary endpoint includes testing the 
superiority of ABBV-599 compared to each ABBV-105 dose group, as well as to upadacitinib.  
Additionally, each ABBV-105 group will be compared vs placebo group.  All tests will be performed as 

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pairwise comparison at one-sided statistical significance level α = 0.05.  The listing of these analyses is as 
follows:
!
ABBV-599 vs placebo
!
ABBV-105 dose response
!
ABBV-599 vs each ABBV-105 dose
!
Each ABBV-105 dose vs placebo
!
ABBV-599 vs upadacitinib
In the analyses, the treatment mean will be estimated using least squares (LS) mean from Mixed-Effect 
Model Repeated Measurements (MMRM) method.  One MMRM model including all treatment groups 
up to visit Week 12 data modeling will be used.  Comparable historical placebo and upadacitinib data 
will be used to enhance the statistical power in relevant comparison analyses, which are detailed in the 
SAP.
Secondary Endpoints Analysis
Continuous efficacy variables will be analyzed using an MMRM method.  It will be used for primary 
inference purpose.  Categorical efficacy variables will be analyzed using the Cochran-Mantel-Haenszel 
(CMH) test controlling for stratification variables.  Non-responder imputation (NRI) will be used for 
primary inference purpose and as observed (AO) analyses will be used for sensitivity analysis for 
selected endpoints.
Missing Data Imputation Definition
Non-Responder Imputation:  An NRI approach will categorize any subject who has missing value for 
categorical variables at a specific visit as non-responder for that visit.  In addition, subjects who 
prematurely discontinue from study drug will be considered as non-responders for all subsequent visits 
after discontinuation.
As Observed:  AO analysis will not impute values for missing evaluations, and thus a subject who does 
not have an evaluation on a scheduled visit will be excluded from the AO analysis for that visit.  
Regardless of treatment switching or premature discontinuation of study drug, all observed data will be 
used in the analysis.
Observed Case (OC):  OC analysis will not impute values for missing evaluations and, thus, a subject who 
does not have an evaluation on a scheduled visit will be excluded from OC analysis for that visit.  In 
addition, the OC analysis will not use values after premature discontinuation of study drug.
Mixed-Effect Model Repeated Measurements (MMRM):  MMRM analysis will be conducted using 
mixed-effect model with OC analysis.  The mixed model includes the categorical fixed effects of 
treatment, visit and treatment-by-visit interaction, main stratification factors, and the continuous fixed 
covariate of baseline measurement.  An unstructured variance covariance matrix will be used.  The 
parameter estimations are based on the assumption of data being missing at random and using the 
method of restricted maximum likelihood (REML).

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7.4 Statistical Analyses for Safety
All safety analyses will be performed in the safety populations.
Pre-treatment AEs will be summarized separately.
All treatment-emergent adverse events (TEAEs), SAEs, AEs leading to discontinuation, and AESI will be 
collected during the study.  A TEAE is defined as an event with onset or worsening after the first study 
dose of study drug and within 30 days after the last dose of study drug administration.  The number and 
percentages of subjects experiencing TEAEs will be tabulated using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA®) system organ class and preferred term.  Summaries (including 
percentages and event per 100 patient-year) of SAEs, deaths, AEs leading to discontinuation, and AESI 
will be provided as well.  For selected laboratory and vital signs parameters, mean change from baseline 
and percentage of subject with evaluations meeting pre-defined criteria for Potentially Clinically 
Important values will be summarized.
7.5 Interim Analysis
An unblinded interim analysis to review safety will be conducted by an independent internal DMC at 
3 time points and ad hoc as needed:  when approximately 50% of subjects have completed Week 4 
evaluation, when approximately 80% of subjects have completed Week 4 evaluation, and when 
approximately 80% of subjects have completed Week 12 evaluation.  The sponsor, study sites and 
subjects will remain blinded for the duration of the study. The details will be given in the DMC charter or 
related SAP.
A separate DMC charter will be prepared outside of the protocol and will describe the roles and 
responsibilities of the DMC members, frequency of data reviews, and relevant safety data to be 
assessed.
7.6 Sample Size Estimation
The planned total sample size is 240.  Forty patients per arm of ABBV-105 can provide approximately 
83% power to detect a –0.88 difference in DAS28 (CRP) change from baseline for ABBV-105 vs 
20 placebo patients combined with 20 borrowed historical placebo subjects (assuming a placebo mean 
change from baseline:  –0.77, and ABBV-105:  –1.65 with common standard deviation [SD] = 1.5) using 
two group t-test with a 0.05 one-sided significance level.  It can provide minimum of 85% power to 
detect a dose-response model for ABBV-105 and combined placebo from 6 candidate models:  Linear 
(δ = 0.01), EMax (ED50 = 5 mg), Exponential (δ = 20), Logistic (ED50 = 5 mg, δ = 10), SigEMax 
(ED50 = 5 mg, h = 2), and Quadratic (δ = –0.01) using MCP-Mod with a 0.05 one-sided significant level.  
In the event that placebo variability precludes historic borrowing, comparison using only the in-study 
20 placebo patients is still estimated to provide 68% power for pairwise comparison of ABBV-105 vs 
placebo or a minimum of 70% power in detecting a dose-response model for ABBV-105 and placebo.
The planned sample size of 60 patients treated with ABBV-599 provides about 94% power to detect a 
–1.0 increase in DAS28 (CRP) LS mean change from baseline for ABBV-599 vs the group of 40 patients 
treated with ABBV-105 (assuming ABBV-105 mean change from baseline:  –1.65 and ABBV-599:  –2.65 

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with common SD = 1.5) using two group t-test with one-sided α = 0.05 significant level.  The sample size 
of 60 for ABBV-599 vs 40 for placebo is over powered due to the necessary power for ABBV-105 over 
placebo.
The 60 patients for ABBV-599 vs 40 for upadacitinib could extend around 0.5 from observed difference 
in mean change from baseline for a two-sided 90% confidence interval assuming the common SD = 1.5.  
Supposing the difference for ABBV-599 vs upadacitinib is –0.45, the 90% confidence interval of (–0.95, 
0.05) could be detected with given same size.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) guidelines, applicable regulations, and guidelines governing clinical study conduct and the 
ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of the investigator 
are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).

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10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The 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 end-of-study is defined as the date of the last subject's last visit.
12
REFERENCES
1.
Flemming A.  Target discovery:  blocking Btk in B-cell disorders.  Nat Rev Drug Discov.  
2010;9(9):681.
2.
Chang BY, Huang MM, Francesco M, et al.  The Bruton tyrosine kinase inhibitor PCI-32765 
ameliorates autoimmune arthritis by inhibition of multiple effector Cells.  Arthritis Res Ther.  
2011;13(4):R115.
3.
Di Paolo JA, Huang T, Balazs M, et al.  Specific Btk inhibition suppresses B cell- and myeloid cell-
mediated arthritis.  Nat Chem Biol.  2011;7(1):41-50.
4.
Hutcheson J, Vanarsa K, Bashmakov A, et al.  Modulating proximal cell signaling by targeting Btk 
ameliorates humoral autoimmunity and end-organ disease in murine lupus.  Arthritis Res Ther.  
2012;14(6):R243.
5.
Mina-Osorio P, LaStant J, Keirstead N, et al.  Suppression of glomerulonephritis in lupus-prone 
NZB x NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase.  Arthritis Rheum.  
2013;65(9):2380-91.
6.
Rankin AL, Seth N, Keegan S, et al.  Selective inhibition of Btk prevents murine lupus and 
antibody-mediated glomerulonephritis.  J Immunol.  2013;191(9):4540-50.
7.
AbbVie.  ABBV-105 Investigator's Brochure Edition 1.  09 November 2016.

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8.
Abbvie.  Upadacitinib Investigator's Brochure Edition 7.  20 June 2017.
9.
Pinheiro J, Bornkamp B, Bretz F.  Design and analysis of dose-finding studies combining multiple 
comparisons and modeling procedures. J Biopharm Stat.  2006;16(5):639-56.
10. Bretz F, Pinheiro JC, Branson M.  Combining multiple comparisons and modeling techniques in 
dose-response studies.  Biometrics.  2005;61(3):738-48.

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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ACR
American College of Rheumatology
ADL
activities of daily living
AE
adverse event
AESI
adverse event of special interest
ALC
absolute lymphocyte counts
ALT
alanine transaminase
ANC
absolute neutrophil count
anti-CCP
anti-cyclic citrullinated peptide antibody
AO
as observed
AST
aspartate transaminase
bDMARD-IR
biologic disease-modifying anti-rheumatic drugs – inadequate response
bDMARD
biologic disease-modifying anti-rheumatic drug
BP
blood pressure
Btk
Bruton's tyrosine kinase
CAC
Cardiovascular Adjudication Committee
CDAI
clinical disease activity index
CL/F
apparent clearance or apparent oral clearance
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CPK
creatine phosphokinase
CR
clinical remission
CRP
C-reactive protein
csDMARD
conventional synthetic disease-modifying anti-rheumatic drug
CVA
cerebrovascular accident
CYP
cytochrome P450
CXR
chest x-ray
DAS
disease activity score
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DVT
deep vein thrombosis

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ECG
electrocardiogram
eCRF
electronic case report form
ESR
erythrocyte sedimentation rate
EULAR
European League Against Rheumatism
FAS
full analysis set
FSH
follicle stimulating hormone
GCP
good clinical practice
GFR
glomerular filtration rate
HAQ-DI
Health Assessment Questionnaire Disability Index
HBc Ab
hepatitis B core antibody
HBs Ag
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
anti-HCV antibody
Hgb
hemoglobin
HIV
human immunodeficiency virus
HIV Ab
HIV antibody
hsCRP
high-sensitivity C-reactive protein
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
IRT
interactive response technology
IU
international unit
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JAK
Janus kinase
LDA
low disease activity
LS
least squares
LTE
long-term extension
MACE
major adverse cardiovascular event
MCID
minimal clinically important difference
MCP-Mod
Multiple Comparison Procedure – Modeling

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MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-Effect Model Repeated Measurements
MTX
methotrexate
NMSC
non-melanoma skin cancer
NRI
non-responder imputation
NSAID
non-steroidal anti-inflammatory drug
OC
observed case
PCR
polymerase chain reaction
PD
premature discontinuation
PE
pulmonary embolism
PhGA
Physician's Global Assessment of Disease Activity
PtGA
Patient's Global Assessment of Disease Activity
PK
Pharmacokinetic(s)
PPD
purified protein derivative
QD
once daily
QTc
corrected QT
QTcF
QT interval corrected for heart rate using Fridericia's correction formula
PRN
as needed (pro re nata)
RA
rheumatoid arthritis
REML
restricted maximum likelihood
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDAI
simplified disease activity index
SUSAR
suspected unexpected serious adverse reactions
SJC
swollen joint count
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TBNKM
T lymphocytes, B lymphocytes, natural killer lymphocytes, and monocytes
TEAE
treatment-emergent adverse event
TJC
tender joint count
ULN
upper limit of normal

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VAS
visual analog scale
Vss/F
apparent volume of distribution at steady state
WBC
white blood cell

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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-063:  A Phase 2 Study to Investigate the Safety and Efficacy of ABBV-105 Given Alone or in 
Combination with Upadacitinib (ABBV-599 Combination) with a Background of Conventional Synthetic 
DMARDs in Subjects with Active Rheumatoid Arthritis with Inadequate Response or Intolerance to 
Biologic DMARDs
Protocol Date:  15 October 2019
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)

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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Immunology
Clinical Program Development
Study Project Management
Medical Writing
Data and Statistical Sciences
Clinical Pharmacology and Pharmacometrics

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JOINT
(Tick Correct Answer)
Subject Right
Subject Left
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
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
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
TOTAL Joint Count

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APPENDIX F. RHEUMATOLOGY COMMON TOXICITY CRITERIA 
V.2.0 EXAMPLE
For designation of adverse event terms not shown in the Rheumatology Common Toxicity Criteria v.2.0 
table, the approach described in Row 1 should be used.

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Rheumatology Common Toxicity Criteria v.2.0
Based on Woodworth TG, et al.  Standardizing assessment of adverse effects in rheumatology clinical trials II.  Status of OMERACT Drug Safety Working Group May 2006:  
OMERACT 8.  Standardizing Assessment and Reporting of Adverse Effects in Rheumatology Clinical Trials:  Enabling Description of Comparative Safety Profiles for Anti-
Rheumatic Therapies
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve.  (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation, or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent.
Multiple meds
Hospitalised > 24 hr
Study drug discontinued
A.  Allergic/Immunologic
A1.  Allergic reaction/ 
hypersensitivity 
(includes drug fever)
Transient rash:  drug fever < 38°C:  
transient, asymptomatic 
bronchospasm
Generalised urticaria responsive to 
meds; or drug fever > 38°C, or 
reversible bronchospasm
Symptomatic bronchospasm 
requiring meds; symptomatic 
urticaria persisting with meds, 
allergy related oedema/angioedema
Anaphylaxis, laryngeal/pharyngeal 
oedema, requiring resuscitation
A2.  Autoimmune 
reaction
Seriologic or other evidence of 
autoimmune reaction, but patient 
asymptomatic:  all organ function 
normal and no treatment is 
required (e.g., vitiligo)
Evidence of autoimmune reaction 
involving a non-essential organ or 
functions, requiring treatment 
other than immunosuppressive 
drugs (e.g., hypothyroidism)
Reversible autoimmune reaction 
involving function of a major organ 
or toxicity requiring short term
immunosuppressive treatment 
(e.g., transient colitis or anaemia)
Causes major organ dysfunction, or 
progressive, not reversible, or 
requires long term administration 
of high dose immunosuppressive 
therapy
A3.  Rhinitis (includes 
sneezing, nasal 
stuffiness, post nasal 
discharge)
Transient, non-prescription meds 
relieve
Prescription med. required, slow
Corticosteroids or other prescription 
med. with persistent disabling 
symptoms such as impaired exercise 
tolerance
NA
A4.  Serum sickness
Transient, non-prescription meds 
relieve
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Prolonged; symptoms only partially 
relieved by meds; parenteral 
corticosteroids required
Major organ dysfunction, requires 
long-term high-dose 
immunosuppressive therapy 

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A.  Allergic/Immunologic (continued)
A5.  Vasculitis
Localised, not requiring treatment; 
or rapid response to meds; 
cutaneous
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Generalised, parenteral 
corticosteroids required or/and
short duration hospitalisation
Prolonged, hospitalisation, ischemic 
changes, amputation
B.  Cardiac
B1.  Arrhythmia
Transient, asymptomatic
Transient, but symptomatic or 
recurrent, responds to meds
Recurrent/persistent; maintenance 
prescription
Unstable, hospitalisation required, 
parenteral meds
B2.  Cardiac function 
decreased
Asymptomatic decline in resting 
ejection fraction by > 10%, but 
< 20% of baseline value
Asymptomatic decline of resting 
ejection fraction ≥ 20% of baseline 
value
CHF responsive to treatment
Severe or refractory CHF
B3.  Edema
Asymptomatic
(e.g., 1 + feet/calves), self-limited, 
no therapy required
Symptomatic
(e.g., 2 + feet/calves), requires 
therapy
Symptoms limiting function (e.g., 3 + 
feet/calves, 2 + thighs), partial relief 
with treatment prolonged
Anasarca; no response to treatment
B4.  Hypertension 
(new onset or 
worsening)
Asymptomatic, transient increase 
by > 20 mmHg (diastolic) or to 
> 150/100 if previously normal, no 
therapy required
Recurrent or persistent increase 
> 150/100 or by > 10 mmHg 
(diastolic), requiring and 
responding readily to treatment
Symptomatic increase > 150/100, 
> 20 mmHg, persistent, requiring 
multi agency therapy, difficult to 
control
Hypertensive crisis
B5.  Hypotension 
(without underlying 
diagnosis)
Transient, intermittent, 
asymptomatic, orthostatic 
decrease in blood pressure 
> 20 mmHg
Symptomatic, without interference 
with function, recurrent or 
persistent > 20 mmHg decrease, 
responds to treatment
Syncope or symptomatic, interferes 
with function, requiring therapy and 
sustained medical attention, dose 
adjustment or drug discontinuation
Shock
B6.  Myocardial 
ischaemia
Transient chest pain/ECG changes; 
rapid relief with nitro
Recurring chest pain, transient ECG 
ST-T changes; treatment relieves
Angina with infarction, no or 
minimal functional compromise, 
reduce dose or discontinue study 
drug
Acute myocardial infarction, 
arrthymia or/and CHF

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B.  Cardiac (continued)
B7.  Pericarditis/ 
pericardial effusion
Rub heard, asymptomatic
Detectable effusion by 
echocardiogram, symptomatic 
NSAID required
Detectable on chest x-ray, dyspnoea; 
or pericardiocentesis; requires 
corticosteroids
Pulsus alternates with low cardiac 
output; requires surgery
B8.  
Phlebitis/thrombosis/ 
Embolism (excludes 
injection sites)
Asymptomatic, superficial, 
transient, local, or no treatment 
required
Symptomatic, recurrent, deep vein 
thrombosis, no anticoagulant 
therapy required
Deep vein thrombosis requiring 
anticoagulant therapy
Pulmonary embolism
C.  General (Constitutional)
C1.  Fatigue/malaise 
(asthenia)
Increase over baseline; most usual 
daily functions maintained, short 
term
Limits daily function intermittently 
over time
Interferes with basic ADL, persistent
Unable to care for self, bed or 
wheelchair bound > 50% of day 
debilitating, hospitalisation
C2.  Fever (pyrexia) 
(note:  fever due to 
drug allergy should be 
coded as allergy)
Transient, few symptoms
37.7 – 38.5°C
Symptomatic, recurrent
38.6 – 39.9°C.  Relieved by meds
≥ 40°C; ≤ 24 h, persistent symptoms; 
partial response to meds.
≥ 40°C, debilitating, > 24 h, 
hospitalisation; no relief with meds
C3.  Headache
Transient or intermittent, no meds 
or relieved with OTC
Persistent, recurring, non-narcotic 
analgesics relieve
Prolonged with limited response to 
narcotic medicine
Intractable, debilitating, requires 
parenteral meds.
C4.  Insomnia
Difficulty sleeping, short term, no 
interfering with function
Difficulty sleeping interfering with 
function, use of prescription med.
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C5.  Rigors, chills
Asymptomatic, transient, no 
meds, or non-narcotic meds 
relieve
Symptomatic, narcotic meds 
relieve.
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C6.  Sweating 
(diaphoresis)
Episodic, transient
Frequent, short term
Frequent, drenching, disabling
Dehydration, requiring IV 
fluids/hospitalization > 24 hrs
C7.  Weight gain
5% – 9.9%
10% – 19.9%
20% – 30%
NA
C8.  Weight loss
5% – 9.9%
10% – 19.9%
20% – 30%
NA

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D.  Dermatologic
D1.  Alopecia
Subjective, transient
Objective, fully reversible
Patchy, wig used, partly reversible
Complete, or irreversible even if 
patchy
D2.  Bullous eruption
Localised, asymptomatic
Localised, symptomatic, requiring 
treatment
Generalised, responsive to 
treatment; reversible
Prolonged, generalised, or requiring 
hospitalisation for treatment
D3.  Dry skin
Asymptomatic, controlled with 
emollients
Symptoms eventually (1 – 2 wks) 
controlled with emollients
Generalised, interfering with ADL 
> 2 wks, persistent pruritis, partially 
responsive to treatment
Disabling for extended period, 
unresponsive to ancillary therapy 
and requiring study drug 
discontinuation for relief
D4.  Injection site 
reaction
Local erythema, pain, pruritis, 
< few days
Erythema, pain, oedema, may 
include superficial phlebitis,
1 – 2 wks
Prolonged induration, superficial 
ulceration; includes thrombosis
Major ulceration necrosis requiring 
surgery
D5.  Petechiae 
(without vasculitis)
Few, transient asymptomatic
Dependent areas, persistent up to 
2 wks
Generalised, responsive to 
treatment; reversible
Prolonged, irreversible, disabling
D6.  Photosensitivity
Transient erythema
Painful erythema and oedema 
requiring topical treatment
Blistering or desquamation, requires 
systematic corticosteroids
Generalised exfoliation or 
hospitalisation
D7.  Pruritis
Localised, asymptomatic, 
transient, local treatment
Intense, or generalised, relieved by 
systematic medication
Intense or generalised; poorly 
controlled despite treatment
Disabling, irreversible
D8.  Rash (not 
bullous)
Erythema, scattered 
macular/popular eruption; pruritis 
transient; TOC or no meds
Diffuse macular/popular eruption 
or erythema with pruritus; dry 
desquamation; treatment required
Generalised, moist desquamation, 
requires systemic corticosteroids; 
responsive to treatment; reversible
Exfoliative or ulcerating; or requires 
hospitalisation; or parenteral 
corticosteroids
D9.  Indurartion/ 
fibrosis/Thickening 
(not sclerodermal)
Localized, high density on 
palpation, reversible, no effect on 
ADL and not disfiguring
Local areas < 50% body surface, not 
disfiguring, transient interference 
with ADL, reversible
Generalized, disfiguring, interferes 
with ADL, reversible
Disabling, irreversible, systemic 
symptoms
E.  Ear/Nose/Throat
E1.  Hearing loss
Transient, intermittent, no 
interference with function
Symptomatic, treatment required, 
reversible
Interferes with function; incomplete 
response to treatment
Irreversible deafness
E2.  Sense of smell
Slightly altered
Markedly altered
Complete loss, reversible
Complete loss, without recovery
E3.  Stomatitis
Asymptomatic
Painful, multiple, can eat
Interferes with nutrition, slowly 
reversible
Requires enteral support; residual 
dysfunction
E4.  Taste disturbance 
(dysgeusia)
Transiently altered; metallic
Persistently altered; limited effect 
on eating
Disabling, effect on nutrition
NA

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E.  Ear/Nose/Throat (continued)
E5.  Tinnitus
Intermittent, transient, no 
interference with function
Requires treatment, reversible
Disabling, or associated with hearing 
loss
Irreversible deafness
E6.  Voice changes 
(includes hoarseness, 
loss of voice, 
laryngitis)
Intermittent hoarseness, able to 
vocalise
Persistent hoarseness, able to 
vocalise
Whispered speech, slow return of 
ability to vocalise
Unable to vocalize for extended
E7.  Xerostomia (dry 
mouth)
Transient dryness
Relief with meds
Interferes with nutrition, slowly 
reversible
Extended duration interference 
with nutrition, requires parenteral 
nutrition
F.  Eye/Ophthalmologic
F1.  Cataract
Asymptomatic, no change in 
vision, non-progressive
Symptomatic, partial visual loss, 
progressive
Symptoms impairing function, vision 
loss requiring treatment, including 
surgery
NA
F2.  Conjunctivitis
Asymptomatic, transient, rapid 
response to treatment
Symptomatic, responds to 
treatment, changes not interfering 
with function
Symptoms prolonged, partial 
response to treatment, interferes 
with function
NA
F3.  Lacrimation 
increased (tearing, 
watery eyes)
Symptoms not requiring 
treatment, transient
Symptomatic, treatment required, 
reversible
Unresponsive to treatment with 
major effect on function
NA
F4.  Retinopathy
Asymptomatic, non-progressive, 
no treatment
Reversible change in vision; readily 
responsive to treatment
Disabling change in vision 
ophthalmological findings reversible, 
sight improves over time
Loss of sight
F5.  Vision changes 
(e.g., blurred, 
photophobia, night 
blindness, vitreous 
floaters)
Asymptomatic, transient, no 
treatment required
Symptomatic, vision changes not 
interfering with function, reversible
Symptomatic, vision changes 
interfering with function
Loss of sight
F6.  Xerophtalmia (dry 
eyes)
Mild scratchiness
Symptomatic without interfering 
with function, requires artificial 
tears
Interferes with vision/function, 
corneal ulceration
Loss of sight

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G.  Gastrointestinal
G1.  Anorexia
Adequate food intake, minimal 
weight loss
Symptoms requiring oral 
nutritional supplementation
Prolonged, requiring iv support
Requires hospitalization for 
nutritional support
G2.  Constipation
Asymptomatic, transient, 
responds to stool softener, OTC 
laxatives
Symptomatic, requiring 
prescription laxatives, reversible
Obstipation requiring medical 
intervention
Bowel obstruction.  Surgery 
required.
G3.  Diarrhea
Transient, increase of
2 – 3 stools/day over pre-
treatment (no blood or mucus), 
OTC agents relieve
Symptomatic, increase
4 – 6 stools/day, nocturnal stools, 
cramping, requires treatment with 
prescription meds.
Increase > 6 stools/day, associated 
with disabling symptoms, 
e.g., incontinence, severe cramping, 
partial response to treatment.
Prolonged, dehydration, 
unresponsive to treatment, 
requires hospitalization.
G4.  Dyspepsia 
(heartburn)
Transient, intermittent, responds 
to OTC antacids, H-2 blockers
Prolonged, recurrent, requires 
prescription meds, relieved by 
meds
Persistent despite treatment, 
interferes with function, associated 
with GI bleeding
NA
G5.  GI bleed 
(gastritis, gastric or 
duodenal ulcer 
diagnosed-define 
aetiology)
Asymptomatic, endoscopic 
finding, haemocult + stools, no 
transfusion, responds rapidly to 
treatment
Symptomatic, transfusion ≤ 2 units 
needed; responds to treatment
Haematemesis, transfusion
3 – 4 units, prolonged interference 
with function
Recurrent, transfusion > 4 units, 
perforation, requiring surgery, 
hospitalisation
G6.  Haematochezia 
(rectal bleeding)
Haemorrhodial, asymptomatic, no 
transfusion
Symptomatic, transfusion
≤ 2 units, reversible
Recurrent, transfusion > 3 – 4 units
> 4 units, hypotension, requiring 
hospitalization
G7.  Hepatitis
Laboratory abnormalities, 
asymptomatic, reversible
Symptomatic laboratory 
abnormalities, not interfering with 
function, slowly reversible
Laboratory abnormalities persistent 
> 2 wks, symptoms interfere with 
function
Progressive, hepato-renal, 
anasarca, pre-coma or coma
G8.  Nausea, or 
nausea/vomiting (use 
diagnostic term)
Transient, intermittent, minimal 
interference with intake, rapid 
response to meds.
Persistent, recurrent, requires 
prescription meds, intake 
maintained
Prolonged, interferes with daily 
function and nutritional intake, 
periodic iv fluids
Hypotensive, hospitalization, 
parenteral nutrition, unresponsive 
to out-patient management
G9.  Pancreatitis
Anylase elevation, intermittent 
nausea/vomiting, transient, 
responds rapidly to treatment
Amylase elevation with abdominal 
pain, nausea, occasional vomiting, 
responsive to treatment
Severe, persistent abdominal pain 
with pancreatitic enzyme elevation, 
incomplete or slow response to 
treatment
Complicated by shock, 
haemorrhage (acute circulatory 
failure)
G10.  Proctitis
Perianal pruritus, haemorrhoids 
(new onset), transient, or 
intermittent, relieved by OTC 
meds
Tenesmus or ulcerations, anal 
fissure, responsive to treatment, 
minimal interference with function
Unresponsive to treatment, marked 
interference with function
Mucosal necrosis with 
haemorrhage, infection, surgery 
required.

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H.  Musculoskeletal
H1.  Avascular 
necrosis
Asymptomatic MRI changes, non-
progressive
MRI changes and symptoms 
responsive to rest and analgesia
MRI changes, symptoms requiring 
surgical intervention
Wheelchair bound; surgical repair 
not possible
H2.  Arthralgia
Intermittent transient symptoms, 
no meds or relieved by OTC meds
Persistent or recurrent symptoms, 
resolve with meds, little effect on 
function
Severe symptoms despite meds 
impairs function
Debilitating, hospitalisation 
required for treatment
H3.  Leg cramps
Transient, intermittent, does not 
interfere with function
Recurrent symptoms, minimally 
interferes with function or sleep, 
responds to meds
Persistent, prolonged interference 
with function or sleep, partial or no 
response to meds
NA
H4.  Myalgia
Occasional; does not interfere 
with function
Frequent, requires meds (non-
narcotic); minor effects on function
Major change in function/lifestyle, 
narcotic pain meds
Debilitating, profound weakness, 
requires wheelchair, unresponsive 
to meds
I.  Neuropsychiatric
I1.  Anxiety or 
Depression (mood 
alteration)
Symptomatic, does not interfere 
with function; no meds
Frequent symptoms, responds to 
meds; interferes with ADL at times
Persistent, prolonged symptoms, 
partial or no response to meds, 
limits daily function
Suicidal ideation or danger to self
I2.  Cerebrovascular 
ischaemia
NA
Single transient ischaemic event, 
responsive to treatment
Recurrent transient ischaemic 
events
Cerebrovascular vascular accident 
with permanent disability
I3.  Cognitive 
disturbance
Subjective symptoms, transient, 
intermittent, not interfering with 
function
Objective symptoms, persisting, 
interferes with daily function 
occasionally
Persistent, or worsening objective 
symptoms; interferes with routine 
daily routine
Debilitating/disabling and 
permanent; toxic psychosis
I4.  Depressed 
consciousness 
(somnolence)
Observed, transient, intermittent, 
not interfering with function
Somnolence or sedation, 
interfering with function
Persistent, progressive, obundation, 
stupor
Coma
I5.  Inability to 
concentrate
Subjective symptoms, does not 
interfere with function
Objective findings, interferes with 
function
Persistent, prolonged objective 
findings or organic cause
NA
I6.  Insomnia (in 
absence of pain)
Occasional difficulty sleeping, 
transient intermittent, not 
interfering with function
Recurrent difficulty sleeping; 
requires meds for relief; occasional 
interference with function
Persistent or worsening difficulty 
sleeping; severely interferes with 
routine daily function
NA
I7.  Libido decreased
Decrease in interest
Loss of interest; influences 
relationship
Persistent, prolonged interfering 
with relationship
NA
I8.  Peripheral motor 
neuropathy
Subjective or transient loss of 
deep tendon reflexes; function 
maintained
Objective weakness, persistent, no 
significant impairment of daily 
function
Objective weakness with substantial 
impairment of function
Paralysis

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I.  Neuropsychiatric (continued)
I9.  Peripheral sensory 
neuropathy (sensory 
disturbance)
Subjective symptoms without 
objective findings, transient, not 
interfering with function
Objective sensory loss, persistent, 
not interfering with function
Prolonged sensory loss or 
paraethesias interfering with 
function
NA
I10.  Seizure
NA
Recurrence of old seizures, 
controlled with adjustment of 
medication
Recurrence/exacerbation with 
partial response to medication
Recurrence not controlled, 
requiring hospitalization; new 
seizures
I11.  Vertigo 
(dizziness)
Subjective symptoms, transient, 
intermittent, no treatment
Objective findings, recurrent, meds 
relieve, occasionally interfering 
with function
Persistent, prolonged, interfering
with daily function; partial response 
to medication
Debilitating without response to 
medication, hospitalization
J.  Pulmonary
J1.  Asthma
Occasional wheeze, no 
interference with activities
Wheezing, requires oral meds, 
occasional interference with 
function
Debilitating, requires nasal O2
Requires ventilator assistance
J2.  Cough
Transient, intermittent, occasional 
OTC meds relieve
Persistent, requires narcotic or 
other prescription meds for relief
Recurrent, persistent coughing 
spasms without consistent relief by 
meds, interferes with function
Interferes with oxygenation; 
debilitating
J3.  Dyspnea
Subjective, transient, no 
interference with function
Symptomatic, intermittent or 
recurring, interferes with 
exertional activities
Symptomatic during daily routine 
activities, interferes with function, 
treatment with intermittent nasal O2
relieves
Symptomatic at rest, debilitating, 
requires constant nasal O2
J4.  Pleuritic pain 
(pleurisy)
Transient, intermittent symptoms, 
no treatment or OTC meds relieve
Persistent symptoms, requires 
prescription meds for relief
Prolonged symptoms, interferes 
with function, requires frequent 
narcotic pain relief
Debilitation, requiring 
hospitalisation
J5.  Pneumonitis 
(pulmonary 
infiltrates)
Asymptomatic radiographic 
changes, transient, no treatment 
required
Symptomatic, persistent, requiring 
corticosteroids
Symptomatic, requiring treatment 
including O2
Debilitating, not reversible; or 
requiring assisted ventilation
J6.  Pulmonary 
function decreased 
(FVC or carbon 
monoxide diffusion 
capacity – DLCO)
76% – 90% of pre-treatment value
51% – 75% of pre-treatment value
26% – 50% of pre-treatment value
≤ 25% of pre-treatment value

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Laboratory Data
K.  Haematology
K1.  Hgb (g/dl) 
decrease from pre-
treatment
1.0 – 1.4
1.5 – 2.0
2.1 – 2.9, or Hgb < 8.0, > 7.0
≥ 3.0; or Hgb < 7.0
K2.  Leukopenia (total 
WBC) × 1000
3.0 – 3.9
2.0 – 2.9
1.0 – 1.9
< 1.0
K3.  Neutropenia 
(× 1000)
1.5 – 1.9
1.0 – 1.4
0.5 – 0.9
< 0.5
K4.  Lymphopenia 
(× 1000)
1.5 – 1.9
1.0 –1.4
0.5 – 0.9
< 0.5
K5.  Platelets (× 1000)
75 – LLN
50 – 74.9
20 – 49.9; platelet transfusion 
required
< 20; recurrent platelet transfusions
L.  Chemistry
L1.  Hypercalcaemia 
(mg/dl)
1.1 × ULN – 11.5
11.6 – 12.5
12.6 – 13.5; or symptoms present
> 13.5; or associated coma
L2.  Hyperglycemia 
(mg/dl) Fasting
140 – 160
161 – 250
251 – 500
> 500, or associated with 
ketoacidosis
L3.  Hyperkalaemia 
(mg/dl)
5.5 – 5.9
6.0 – 6.4
6.5 – 7.0 or any ECG change
> 7.0 or any arrhythmia
L5.  Hypocalcaemia 
(mg/dl)
0.9 × LLN – 7.8
7.7 – 7.0
6.9 – 6.5; or associated with 
symptoms
< 6.5 or occurrence of tetany
L6.  Hypoglycemia 
(mg/dl)
55 – 64 (no symptoms)
40 – 54 (or symptoms present)
30 – 39 (symptoms impair function)
< 30 or coma
L7.  Hyponatraemia 
(mg/dl)
--
125 – 129
120 – 124
< 120
L8.  Hypokalaemia 
(mg/dl)
--
3.0 – 3.4
2.5 – 2.9
< 2.5

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L.  Chemistry (continued)
L9.  CPK (also if 
polymyositis-disease)
1.2 – 1.9 × ULN
2.0 – 4.0 × ULN
4.0 × ULN with weakness but 
without life-threatening signs or 
symptoms
> 4.0 × ULN with signs or symptoms 
of rhabdomyolysis or life-
threatening
L10.  Serum uric acid
1.2 – 1.6 × ULN
1.7 – 2.9 × ULN
3.0 – 5.0 × ULN or gout
NA
L11.  Creatinine 
(mg/dL)
1.1 – 1.3 × ULN
1.3 – 1.8 × ULN
1.9 – 3.0 × ULN
> 3.0 × ULN
L12.  SGOT (AST)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.1 – 8.0 × ULN
> 8.0 × ULN
L13.  SGPT (ALT)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.0 – 8.0 × ULN
> 8.0 × ULN
L14.  Alkaline 
phosphatase
1.1 – 2.0 × ULN
1.6 – 3.0 × ULN
3.0 – 5.0 × ULN
> 5.0 × ULN
L15.  T. bilirubin
1.1 – 1.4 × ULN
1.5 – 1.9 × ULN
2.0 – 3.0 × ULN
> 3.0 × ULN
L16.  LDH
1.3 – 2.4 × ULN
2.5 – 5.0 × ULN
5.1 – 10 × ULN
> 10 × ULN
M.  Urinalysis
M1.  Haematuria
Micro only
Gross, no clots
Clots, transfusion < 2 units 
Transfusion required
M2.  Proteinuria (per 
24 h)
300 – 500 mg (tr/1+)
501 – 1999 mg (2+)
2 – 5.0 g (3+) nephrotic syndrome
5.0 g (4+) anasarca
M3.  WBC in urine
NA
NA
Indicating acute interstitial nephritis
Associated with acute renal failure
M4.  Uric acid crystals
Present without symptoms
NA
With stones or symptoms of stones 
(e.g., renal colic)
Causing renal outflow obstruction 
and hospitalization
OTC = over-the-counter medication; ADL = activities of daily living; IV = intravenous; ECG = electrocardiogram; CHF = congestive heart failure; MRI = magnetic resonance imaging; 
Hb = haemglobin; LLN = lower limit of normal; ULN = upper limit of normal; WBC = white blood cells; SLE = systemic lupus erythematosus; ANA = antinuclear antibodies; 
H-2 blockers = histamine-2 blockers; FVC = forced vital capacity

p. 62 of 62
STUDY M16-063  |  Version 5.0 / EudraCT 2018-000666-10
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX G. PROTOCOL AMENDMENT SUMMARY OF 
CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
25 May 2018
Version 2.0
11 July 2018
Version 3.0
05 October 2018
Version 4.0
11 March 2019
The purpose of this Amendment is to update the following:
Protocol
!
Update Section 4.1, Section 7.1, and Section 7.5 to remove interim efficacy analysis wording.
Rationale:  The interim efficacy analysis is removed as the study has enrolled more slowly than 
anticipated and, as a result, the interim efficacy analysis would not save enough time to be 
worthwhile in terms of designing the next Phase of the ABBV-599 Rheumatoid Arthritis Program.
!
Update Sponsor/Emergency Medical Contact info and Appendix C, List of Protocol Signatories.
Rationale: Revised due to personnel change.
!
Minor typographical corrections made for clarity.