Clinical trial NCT03682705
Conditions: Rheumatoid Arthritis (RA)
Keywords: Elsubrutinib ABBV-105 Upadacitinib ABBV-599 Rheumatoid Arthritis
Sponsor: AbbVie
Start date: 2018-10-08; Completion date: 2020-03-26
Enrollment: 242 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a phase 2 study to evaluate the safety and efficacy of elsubrutinib (ELS) and ABBV-599 (ELS plus upadacitinib \[UPA\]) vs placebo on a background of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for the treatment of signs and symptoms of rheumatoid arthritis (RA) at 12 weeks in biological disease-modifying anti-rheumatic drugs (bDMARD)-inadequate response (bDMARD-IR) or bDMARD-intolerant participants with moderately to severely active RA and to define optimal dose for further development.

Detailed description:
This was a 12-week, randomized, double-blind, parallel-group, Phase 2, dose exploratory, multicenter study. Participants who met eligibility criteria were randomized in a 3:2:2:2:2:1 ratio to 1 of 6 treatment groups: ABBV-599 \[UPA 15 mg/ELS 60 mg\]); ELS 60 mg/UPA placebo; ELS 20 mg/UPA placebo; ELS 5 mg/UPA placebo; UPA 15 mg/ELS placebo; and ELS placebo/UPA placebo. The study included a 35-day maximum screening period and a 12-week treatment period with 30-day follow-up.

Arms: arm 1: Placebo capsule for elsubrutinib once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks arm 2: 15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; 60 mg elsubrutinib capsule once a day by mouth for 12 weeks arm 3: 60 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks arm 4: 20 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks arm 5: 5 mg elsubrutinib capsule once a day by mouth for 12 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 12 weeks arm 6: 15 mg film-coated upadacitinib tablet once a day by mouth for 12 weeks; placebo capsule for elsubrutinib once a day by mouth for 12 weeks
Interventions: intervention 1: Elsubrutinib intervention 2: Upadacitinib intervention 3: Placebo for elsubrutinib intervention 4: Placebo for upadacitinib
Intervention descriptions: intervention 1: Elsubrutinib capsule will be administered orally. intervention 2: Upadacitinib tablet will be administered orally. intervention 3: Placebo capsule for elsubrutinib will be administered orally. intervention 4: Placebo tablet for upadacitinib will be administered orally.

Protocol documents:
Prot_000.pdf: 
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
62










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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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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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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STUDY M16-063  |  Version 5.0 / EudraCT 2018-000666-10
CONFIDENTIAL INFORMATION
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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


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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.

SAP_001.pdf: 
ABBV-105
M16-063 – Statistical Analysis Plan
Version 4.0 – 23 January 2020
1
Statistical Analysis Plan for Study 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
Date:  23 January 2020
Version 4.0
NCT03682705


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M16-063 – Statistical Analysis Plan
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2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypotheses ........................................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................7
3.0
Endpoints..................................................................................8
3.1
Primary Efficacy Endpoint ........................................................................8
3.2
Secondary Efficacy Endpoints...................................................................8
3.3
Other Efficacy Endpoints.........................................................................10
3.4
Safety Endpoints ......................................................................................10
3.5
Additional Endpoint(s).............................................................................11
4.0
Analysis Populations .............................................................11
5.0
Subject Disposition................................................................11
6.0
Study Drug Duration and Compliance................................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................13
7.1
Demographics and Baseline Characteristics............................................14
7.2
Medical History .......................................................................................17
7.3
Prior and Concomitant Medications ........................................................17
8.0
Efficacy Analyses...................................................................18
8.1
General Considerations............................................................................18
8.2
Handling of Missing Data........................................................................18
8.3
Primary Efficacy Endpoint and Analyses ................................................19
8.3.1
Primary Efficacy Endpoint ......................................................................19
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint ................19
8.3.3
Primary Efficacy Analyses.......................................................................20
8.3.4
Additional Analyses of the Primary Efficacy Endpoint...........................20
8.3.5
Details for Primary Efficacy Analysis .....................................................20
8.3.5.1
Mixed-Effect Model Repeated Measure (MMRM) for Pair-Wise 
Comparison..............................................................................................20


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8.3.5.2
Historical Data Borrowing Analysis........................................................21
8.3.5.3
Dose-Response Modeling for ABBV-105...............................................22
8.4
Secondary Efficacy Analyses...................................................................24
8.5
Additional Efficacy Analyses ..................................................................24
8.6
Efficacy Subgroup Analyses....................................................................25
9.0
Safety Analyses ......................................................................26
9.1
General Considerations............................................................................26
9.2
Adverse Events ........................................................................................26
9.2.1
Treatment-Emergent Adverse Events ......................................................26
9.2.2
Adverse Event Overview .........................................................................27
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................28
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................28
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................29
9.2.6
Adverse Events of Special Interest ..........................................................29
9.2.7
Adverse Events by Maximum Severity ...................................................29
9.2.8
Adverse Events by Maximum Relationship ............................................29
9.2.9
Adverse Events by "Reasonably Possibly Related" Relationship ...........30
9.2.10
Frequent (> 5%) Adverse Events and Reasonably Possibly 
Related Adverse Events by Preferred Term in Decreasing 
Frequency.................................................................................................30
9.2.11
Listing of Adverse Events........................................................................30
9.3
Analysis of Laboratory Data....................................................................30
9.4
Analysis of Vital Signs ............................................................................32
9.5
Safety Subgroup Analyses .......................................................................33
9.6
Other Safety Analyses..............................................................................33
10.0
Other Analyses.......................................................................33
11.0
Interim Analyses....................................................................33
11.1
Data Monitoring Committee....................................................................34
12.0
Overall Type-I Error Control ..............................................34
13.0
Version History......................................................................35
14.0
References...............................................................................36


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List of Tables
Table 1.
Candidate Models ....................................................................................23
Table 2.
Subgroups for Primary Efficacy Analysis ...............................................25
Table 3.
SAP Version History Summary...............................................................35
List of Figures
Figure 1.
Study Schematic.........................................................................................6
List of Appendices
Appendix A.
Protocol Deviations..................................................................................38
Appendix B.
Definition of Adverse Events of Special Interest ....................................39
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............40
Appendix D.
Details for Historical Data Borrowing.....................................................51


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for ABBV-599 
Study M16-063.
Study M16-063 examines the efficacy and safety of ABBV-105 given alone or in 
combination with upadacitinib (ABBV-599 combination) on a background of 
conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) in subjects 
with active rheumatoid arthritis with inadequate response or intolerance to biologic 
DMARDs (bDMARDs).
The analyses of pharmacokinetics and biomarkers, if applicable, will not be covered in 
this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
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 csDMARDs for the treatment of signs and symptoms of RA at 12 weeks 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.
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 


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6
associated with active RA in patients with inadequate response or intolerance to 
bDMARDs by interfering with the JAK1/Btk pathways.  Concurrent inhibition of 
JAK1/Btk pathways in RA may increase the proportion of those responding as well as the 
depth of response, relative to inhibiting either pathway alone, while maintaining an 
acceptable safety profile.
2.2
Study Design Overview
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.
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
QD = once daily


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2.3
Treatment Assignment and Blinding
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 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)
●
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; 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.
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 biologics with multiple mechanisms of action).  Once 
approximately 35% of the total subjects have been randomized to the group who failed 
≥3 biologics with the same mechanism of action and/or ≥ 2 biologics with multiple 
mechanisms of action, further screening of those subjects may be suspended.
2.4
Sample Size Determination
The planned total sample size is 240.  Forty (40) 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 placebo combined with 20 borrowed historical placebo 
subjects (assuming a placebo mean change from baseline –0.77, and ABBV-105:  
–1.65 with common SD = 1.5) using two group t-test with one-sided significant 
level α = 0.05.  It can provide a minimum of 85% power to detect a dose-response model 
for ABBV-105 and combined placebo from 6 candidate models:  Linear, 


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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 one-sided 
significant level α = 0.05.
The planned sample size of 60 patients treated with ABBV-599 provides approximately 
94% power to detect a –1.0 difference 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 with common SD = 1.5) using 
two group t-test with one-sided significance level α = 0.05.  The sample size of 60 for 
ABBV-599 vs 20 for placebo is over-powered due to the necessary power for ABBV-105 
over placebo.
The sample size of 60 patients for ABBV-599 vs 40 for upadacitinib could produce the 
half width of 0.5 in the two-sided 90% CI of the difference in mean change from baseline, 
assuming the common SD = 1.5.  Assuming the observed difference for ABBV-599 vs 
upadacitinib is –0.45, the corresponding 90% confidence interval would be (–0.95, 0.05).
In the event that placebo variability precludes historic borrowing, comparison using only 
the in-study 20 placebo patients is estimated to still provide 68% power for pairwise 
comparison of ABBV-105 vs placebo and a minimum of 70% power in detecting a dose-
response model for ABBV-105 and placebo.
3.0
Endpoints
3.1
Primary Efficacy Endpoint
The primary endpoint is the change from baseline in disease activity score (DAS)28 
(C-reactive protein [CRP]) at Week 12.
3.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:


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1.
Change from baseline in clinical disease activity index (CDAI) and simplified 
disease activity index (SDAI) at all visits;
2.
Proportion of subjects achieving Clinical Remission (CR) at all visits.  CR is 
defined as DAS28 CRP < 2.6;
3.
Proportion of subjects achieving low disease activity (LDA) at all visits.  LDA is 
defined as DAS28 CRP ≤ 3.2;
4.
Proportion of subjects achieving LDA but not CR at all visits.  LDA but not CR is 
defined as DAS28 CRP ≤ 3.2 but ≥ 2.6;
5.
Proportion of subjects achieving CR based on CDAI criteria at all visits.  CR is 
defined as CDAI ≤ 2.8;
6.
Proportion of subjects achieving LDA based on CDAI criteria at all visits.  LDA is 
defined as CDAI ≤ 10;
7.
Proportion of subjects achieving LDA but not CR based on CDAI criteria at all 
visits.  LDA but not CR based on CDAI criteria is defined as CDAI ≤ 10 but > 2.8;
8.
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 
(PGA), Physician's Global Assessment of Disease Activity (PhGA), Health 
Assessment Questionnaire Disability Index (HAQ-DI), or high-sensitivity 
C-reactive protein (hsCRP);
9.
Change from baseline in individual components of ACR response at all visits;
10.
Change from baseline in DAS28 (CRP) and DAS28 (erythrocyte sedimentation 
rate [ESR]) at all visits;
11.
Change from baseline in morning stiffness severity (11 point scale) at all visits;
12.
Change from baseline in morning stiffness duration (in minutes) at all visits;


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13.
Proportion of subjects achieving minimal clinically important difference (MCID) in 
change from baseline in HAQ-DI (defined as change from baseline in 
HAQ-DI ≤–0.22) at all visits
14.
Proportion of subjects achieving American College of Rheumatology 
(ACR)/European League Against Rheumatism (EULAR) Boolean remission at all 
visits.  Boolean remission is defined as TJC28 ≤ 1, SJC28 ≤ 1, CRP ≤ 1 mg/dl and 
PGA ≤ 1 (in cm, 0 – 10).
3.3
Other Efficacy Endpoints
The primary and/or secondary efficacy endpoints are listed in Section 3.1 and/or 
Section 3.2, respectively.  There are no additional efficacy endpoints.
3.4
Safety Endpoints
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital 
sign measurements, electrocardiograms (ECGs), and clinical laboratory testing 
(hematology, chemistry, and urinalysis) as a measure of safety and tolerability for the 
entire study duration.
Serious AEs (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 Data 
Monitoring Committee (DMC) will be created and unblinded safety assessments will be 
conducted.  This is to assess unanticipated safety signals with regards to novel agents 
ABBV-105 and ABBV-599.  The study team, study sites and subjects will remain blinded 
for the duration of the study.
An independent external Cardiovascular Adjudication Committee (CAC) will adjudicate 
blinded cardiac, cerebrovascular and thromboembolic events.  A CAC charter will be 


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prepared separately from the protocol that will define objective, scope, frequency, and 
triggers of data reviews.
3.5
Additional Endpoint(s)
No additional endpoints will be analyzed in the SAP.  Pharmacokinetic endpoints and 
biomarker endpoints will be analyzed separately.
4.0
Analysis Populations
The following population sets will be used for the analyses.
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose 
of study drug.  Subjects will be grouped according to the treatment as randomized.  The 
FAS will be used for all efficacy and baseline characteristics analyses.
The Safety Analysis Set consists of all enrolled subjects who received at least 1 dose of 
study drug.  For the Safety Analysis Set, subjects are assigned to a treatment group based 
on the treatment received, regardless of the treatment randomized.  The Safety Analysis 
Set will be used for all safety analysis.
5.0
Subject Disposition
The number of subjects will be tabulated by country, investigator site and overall for all 
randomized subjects.
The total number of subjects who were randomized, and treated will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects randomized in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;


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●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
●
Subjects in each analysis population, as applicable;
●
Number of subjects who elect to participate in the open label extension 
Study M16-763.
In addition, the reasons for premature discontinuation (primary reason and all reasons) 
from the trial and/or from the medication collected from CRF by the following categories 
will be summarized with frequencies and percentages.  Subjects with multiple reasons for 
premature discontinuation will be counted once in the calculation of the number and 
percentage of total discontinuations ("Premature Discontinuation").
●
Adverse events,
●
Lost to follow-up,
●
Withdrew consent by subject,
●
Lack of efficacy,
●
Others.
6.0
Study Drug Duration and Compliance
A summary of study drug duration (days) will be provided by each treatment arm for the 
Safety populations.
The duration of exposure to study drug will be summarized for each group as specified 
above, with the number of subjects, mean, standard deviation, median, minimum and 
maximum values.  In addition, the number and percentage of subjects exposed to study 
drug will be summarized for the following cumulative duration intervals.


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●
≥ 1 day
●
≥ 15 days
●
≥ 29 days
●
≥ 57 days
●
≥ 85 days
The exposure to study drug is calculated as:
Exposure = (date of last study medication – date of first study medication + 1)
Compliance
Study drug compliance will be summarized for each treatment group for the FAS 
population.  The compliance is defined as the number of tablets/capsules taken (i.e., the 
difference between the number of tablets/capsules dispensed and the number of 
tablets/capsules returned) divided by the number of tablets/capsules that should have been 
taken during the treatment period.  Compliance with each study drug will be calculated for 
each subject and summarized with the mean, median, standard deviation, minimum, and 
maximum.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the FAS overall and by treatment group.  
Categorical variables will be summarized with the number and percentage of subjects; 
percentages will be calculated based on the number of non-missing observations.  
Continuous variables will be summarized with descriptive statistics (number of 
non-missing observations, mean and standard deviation, median, minimum and 
maximum).


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7.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics, as measured at baseline of the 
study, will be summarized.
Demographic Characteristics
●
Age (years)
●
Age category [18 – < 40 years old, 40 – < 65 years old, ≥ 65 years old]
●
Sex [male/female]
●
Race [White, Black or African American, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Asian, Other]
●
Ethnicity [Hispanic/Latino, Non-Hispanic/Latino]
●
Geographic region (North America, South/Central America, Western Europe, 
Eastern Europe, Asia, Other)
●
Weight (kg)
●
Weight Categories (< 60 kg, ≥ 60 kg)
●
Height (cm)
●
Body Mass Index (BMI) (kg/m2)
●
Body Mass Index (BMI) Category (kg/m2) (BMI < 25 vs BMI ≥ 25)
RA Medical History and Characteristics
●
Duration of RA Symptoms in years
●
Duration of RA Diagnosis in years
●
Duration of RA Diagnosis Categories (< 5 year or ≥ 5 year)
●
Prior exposure to bDMARDs (failed 1 or 2 biologics with the same mechanism 
of action; failed ≥ 3 biologics with the same mechanism of action and/or 
≥2 biologics with multiple mechanisms of action)
●
Number of prior bDMARD received (1, 2, 3, ≥ 4)
●
Concomitant csDMARDs at baseline (MTX alone, MTX and other 
csDMARDs, csDMARDs other than MTX)


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ACR and/or DAS Components at Baseline
●
Tender joint count (TJC68) defined as the number of tender joints out of 
68 assessed joints
●
Swollen joint count (SJC66) defined as the number of swollen joints out of 
66 assessed joints
●
Tender joint count (TJC28) defined as the number of tender joints out of 
28 assessed joints used for DAS28 calculation
●
Swollen joint count (SJC28) defined as the number of swollen joints out of 
28 assessed joints used for DAS28 calculation
●
Physician's global assessment of disease activity (mm on a 100-mm horizontal 
visual analogue scale [VAS])
●
Patient's assessment of pain within last week (mm on a 100-mm horizontal 
(VAS))
●
Patient's global assessment of disease activity within last 24 hours (mm on a 
100-mm horizontal VAS)
●
Health Assessment Questionnaire Disability Index of the (HAQ – DI) 
(range: 0 to 3)
●
High sensitivity C-reactive protein (hsCRP) (mg/L)
●
Erythrocyte sedimentation rate (ESR) (mm/hr)
Other Baseline RA Disease Characteristics
●
Morning stiffness (severity and duration)
●
Anti-cyclic citrullinated peptide (Anti-CCP) (units)
●
Anti-CCP status:  Positive or Negative
●
Rheumatoid Factor (RF) (units)
●
Rheumatoid Factor (RF) status:  Positive or Negative
●
Percentage of subjects on oral steroid at baseline
●
Oral steroid dose (prednisone equivalent) at baseline
●
DAS28 [ESR]


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●
DAS28 [CRP]
●
DAS28 [ESR] Categories:
a.
DAS28 [ESR] > 5.1 (High Disease Activity)
b. DAS28 [ESR] ≤ 5.1
●
DAS28 [CRP] Categories:
a.
DAS28 [CRP] > 5.1 (High Disease Activity)
b. DAS28 [CRP] ≤ 5.1
●
Clinical Disease Activity Index (CDAI)
●
CDAI categories:
a.
CDAI > 22 (High Disease Activity)
b. CDAI ≤ 22
●
Simplified Disease Activity Index (SDAI)
●
SDAI categories:
a.
SDAI > 26 (High Disease Activity)
b. SDAI ≤ 26
Clinical Tests at Screening
●
Chest x-ray
●
Tuberculin PPD skin test, QuantiFERON TB Gold test
●
Serum pregnancy test
Immunization History
●
BCG immunization
●
Herpes Zoster immunization
●
Hepatitis B immunization


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Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use (current, former, never, or unknown)
●
Alcohol Use (current, former, never, or unknown)
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  Medical history data will be summarized and 
presented for the FAS population using body systems and conditions/diagnoses as 
captured on the CRF.  The body systems will be presented in alphabetical order and the 
conditions/diagnoses will be presented in alphabetical order within each body system.  
The number and percentage of subjects with a condition/diagnosis will be summarized for 
each randomized treatment group as well as overall.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system.  No statistical comparison will be performed for medical history reporting.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by each randomized treatment 
group as well as overall for the FAS.  Prior medications are those medications taken prior 
to the first dose of study drug.  This includes medications with a start date before the 
first study drug administration date, regardless of the end date of these medications.  
Medications taken on the day of the first dose of study drug are not counted as prior
medications.  Concomitant medications are those medications, other than study drug, 
taken after the first dose of study drug and within 1 day of the last dose of study drug.  
This includes medications with a start date between first study drug administration and 
last study drug administration + 1 day, as well as, medications with a start date prior to 
first dose of study drug and which are ongoing after first dose of study drug.  Medications 
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The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
8.0
Efficacy Analyses
8.1
General Considerations
The primary and secondary efficacy endpoints will be analyzed based on the FAS.  The 
primary and secondary efficacy endpoints as specified in Section 3.0 will be tested at 
significance level alpha = 0.1 (two-sided).
For all efficacy endpoints, the descriptive statistics will be provided by treatment group.  
The statistics include number of observations, mean, standard deviation, minimum, 
median, and maximum for continuous variables; and number and percentage of subjects 
for categorical variables.
Unless otherwise specified, categorical variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) test, stratified by prior bDMARD use.  Continuous variables will be 
analyzed using Mixed-Effect Model Repeated Measure (MMRM) method.
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the correct stratum to which they should have been randomized.
"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given.
8.2
Handling of Missing Data
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Non-Responder Imputation (NRI)
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 randomized study drug will be considered as non-
responders for all subsequent visits after discontinuation.
As Observed (AO)
The 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.
Mixed-Effect Model Repeated Measure (MMRM)
MMRM analysis will be conducted for repeated continuous measurements.  Data 
collected after a subject discontinues study drug will be considered as missing.  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 
estimation is based on the assumption of data being missing at random and using the 
method of restricted maximum likelihood (REML).
8.3
Primary Efficacy Endpoint and Analyses
8.3.1
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in DAS28 (CRP) at Week 12.
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint
MMRM under assumption of data being missing at random will be used for primary 
efficacy analyses, unless otherwise specified.


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8.3.3
Primary Efficacy Analyses
The first primary analysis is to test the superiority of ABBV-599 compared to placebo at 
Week 12 using MMRM (see Section 8.3.5.1).  Two-sided 0.1 is to be used throughout in 
all efficacy analysis.
The second primary analysis is to test a pre-specified set of dose-response models among 
ABBV-105 dose groups and the placebo group at Week 12 using the Multiple 
Comparison Procedure – Modeling (MCP-Mod) method with borrowing historical 
placebo data (see Section 8.3.5.3).
8.3.4
Additional Analyses of the Primary Efficacy Endpoint
The additional analyses for the primary endpoint are
(a) comparison of ABBV-599 to each ABBV-105 dose group;
(b) comparison of ABBV-599 to the upadacitinib group;
(c) comparison of each ABBV-105 group to the placebo group.
For the comparisons (a) - (c) 90% CI from MMRM of the treatment difference will be 
used (see Section 8.3.5.1).  For comparison (b) and (c) historical data borrowing is also to 
be considered (see Section 8.3.5.2).
More details of the planned analyses can be found in Section 8.3.5 below.
8.3.5
Details for Primary Efficacy Analysis
8.3.5.1
Mixed-Effect Model Repeated Measure (MMRM) for 
Pair-Wise Comparison
In the pair-wise comparison analyses without historical data borrowing, the treatment 
mean will be estimated from MMRM method.  One MMRM model including all 
treatment groups up to visit Week 12 data will be used.


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MMRM analysis will be conducted for primary endpoint.  Data collected after a subject 
discontinues study drug will be considered as missing.  The mixed model includes the 
categorical fixed effects of treatment, visit and treatment-by-visit interaction, prior 
bDMARD use, and baseline DAS28 (CRP) measurement.  An unstructured variance 
covariance matrix will be used.  The parameter estimation will be based on the 
assumption of data being missing at random and using the method of restricted maximum 
likelihood (REML).
Least-square mean (SE) and 90% confidence interval (CI) at Week 12 for each treatment 
group will be presented together with between treatment difference of least-square means 
(SE), 90% CI and p-value from t-test for the difference = 0.
8.3.5.2
Historical Data Borrowing Analysis
Historical control data will be used in the comparison of ABBV-105 vs placebo 
(borrowing placebo data) and of ABBV-599 vs upadacitinib (borrowing upadacitinib 
data).
Meta-analysis results from the historical control data will be used as prior distribution for 
control group mean and a non-informative prior will be used for treatment group mean.  
Based on posterior means and variances for treatment and control groups, the probability 
of (Treatment mean – Control mean < 0) given the data i.e., ( −	 < 0|) will 
be calculated. The details for historical data borrowing analysis is in Appendix D.
○
ABBV-105 vs Placebo (Borrowing Placebo)
Historical data for placebo group consists of 349 subjects from three clinical trials with 
similar populations, similar inclusion and exclusion criteria; and they were conducted in a 
similar way as the current study.  A meta-analysis shows that predicted mean (SD) and 
95% confidence interval for mean are –0.80 (1.5) and [–1.06, –0.54].
In the ABBV-105 vs Placebo comparisons, 20 historical placebo subjects will be 
borrowed, which targets control of Bayesian type I error rate/False Positive Rate < 10% 


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and not exceeding study placebo sample size of 20.  That is:   = 20,  = −0.80 and 
its
SE  = 1.5 √20
⁄
= 0.335.  Therefore a conjugate prior distribution for placebo would 
be N (–0.80, 0.3352).  For ABBV-105, a "flat" non-informative prior probability 
distribution will be assumed, resulting in the posterior distribution totally based on the 
data.  For supportive analysis, the dynamic borrowing based on observed bias may be 
performed as detailed in Appendix D.
○
ABBV-599 vs upadacitinib (Borrowing upadacitinib)
For the upadacitinib control group versus ABBV-599, historical data consist of 
206 subjects from two upadacitinib studies (Phase 2:  Study M13-550 Balance I and 
Phase 3:  Study M13-542 Select Beyond).  Active upadacitinib treatment group of 15 mg 
is considered.  The meta-analysis results in the predicted estimated mean (SD) and 
95% confidence interval are –2.32 (1.57) and [–2.54, –2.11].
For this comparison, 40 historical placebo subjects will be borrowed, which targets 
control of false positive rate < 10% and not exceeding the study sample size 40.  That is: 
 = 40,  = −2.32, and  = 1.57 √40
⁄
= 0.25.  Therefore the prior distribution for 
upadacitinib would be N (–2.32, 0.252).  For ABBV-599, a "flat" non-informative prior 
probability distribution will be assumed, resulting in the posterior distribution totally 
based on the data.  A dynamic borrowing based on observed bias may be performed as 
supportive analysis.
8.3.5.3
Dose-Response Modeling for ABBV-105
The dose-response relationship among ABBV-105 dose groups and the placebo group 
will be characterized for the primary endpoint using the Multiple Comparison Procedure -
Modeling (MCP-Mod) method [Pinheiro 2006, Bretz 2005].  The response based on the 
primary analysis approach above will be used, and ADDPLAN DF software will be used 
to perform the MCP-Mod analyses.  The posterior mean (SD) for placebo group (i.e., with 




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Steps of MCPMod:
1.
Choose a candidate set of S models as in Table 1.
2.
Compute the optimum contrast for each model.
3.
Use contrast test to find the significant T models while preserving FWER.
4.
Use AIC criteria to find the most significant model from the significant T models 
found from Step 3.
5.
Use the model found from Step 4 to fit observed data from the study and make 
inference (e.g., to find Minimum Effective Dose (MED) or the dose achieving 
certain amount of maximum effect), or use all significant models to make inference 
about the weighted target dose of interest.
8.4
Secondary Efficacy Analyses
Continuous efficacy variables will be analyzed using MMRM method. It will be used for 
primary inference purpose the same way as for primary efficacy endpoint analysis.
Categorical efficacy variables will be analyzed using the CMH test controlling for 
stratification variables.  The risk difference and 90% confidence intervals for the 
differences in each comparison will be constructed.  NRI imputation will be used for 
missing data imputation.  Point estimate of the response rate for each treatment group will 
also be summarized with a two-sided 90% confidence interval using Wilson's score 
method.
In addition, as observed (AO) analyses will be used as sensitivity analyses for 
DAS28 (CRP) and ACR20/50/70 response rates at all visits.
8.5
Additional Efficacy Analyses
No additional efficacy analyses are planned.


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8.6
Efficacy Subgroup Analyses
Subgroup analysis for the primary endpoint will be conducted by the subgroups specified 
in Table 2.  The difference in the primary efficacy endpoint between the treatment groups 
in each subgroup will be assessed using MMRM method.
Table 2.
Subgroups for Primary Efficacy Analysis
Subgroup Factor
Categories
Age
18 – < 40 years old
40 – < 65 years old
≥ 65 years old
Sex
Male
Female
BMI
< 25
≥ 25
Race
White
Black
Asian
Other
Baseline Rheumatoid Factor Status
Positive
Negative
Baseline Anti-CCP Antibody Status
Positive
Negative
Baseline DAS28 (CRP)
> 5.1
≤ 5.1
No. of prior anti-TNF biologics
0 1
≥ 2
Use of non-anti-TNF biologics
YES
NO
Number of prior bDMARD received
1
2
3
≥ 4
Duration of RA diagnosis
< 6 Months
6 Months – < 1 Year
1 Year – < 3 Years 
≥ 3 Years


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9.0
Safety Analyses
9.1
General Considerations
Safety analyses will include reporting of adverse events, laboratory, and vital signs 
measurements.  Safety analyses will be carried out using the Safety Analysis Set.
The following summary statistics will be presented for subjects who have both baseline 
and post-baseline values for laboratory parameters and vital signs:  the mean value at 
Baseline and at each respective protocol specified visit, and the mean, standard deviation 
and median for changes from Baseline.  Categorical data will be summarized using 
frequencies and percentages.  The number of non-missing values will be given.  Missing 
safety data will not be imputed.
A subject's actual treatment will be determined by the most frequent dose regimen 
received.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
A treatment-emergent Adverse Event (TEAE) is defined as an adverse event with an onset 
date that is on or after the first dose of study drug, and no more than 30 days after the last 
dose of study drug; or an adverse event with onset date before the first dose of study drug, 


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but increased in severity on or after the first dose of study drug, and no more than 30 days 
after the last dose of study drug.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent.  If an incomplete onset date was collected for an adverse event, the 
event will be assumed to be treatment-emergent unless there is other evidence that 
confirms that the event was not treatment-emergent (e.g., the event end date was prior to 
the study drug start date).
The number and percentage of subjects experiencing TEAEs will be summarized.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs of special interest (AESIs)
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
●
All deaths
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
For AESIs, the point estimate and 95% CI (using normal approximation) will be provided 
for the treatment difference in AE percentages.


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9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
The number and percentage of subjects experiencing adverse events will be tabulated by 
SOC and MedDRA PT by "as treated" treatment groups and overall.  The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC.
The following summaries of adverse events will be generated:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
●
Frequent AEs (reported in 2% of subjects or more in any treatment group)
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term (most severe incident for the severity tables and most 
related incident for the relationship tables). Subjects reporting more than one type of 
adverse event within a SOC will be counted only once for that SOC.  Subjects reporting 
more than one type of adverse event will be counted only once in the overall total.  In 
addition, if the same adverse event occurs multiple times within a subject, the highest 
severity and level of relationship to investigational product will be reported.  In addition, 
TEAEs will be summarized by PT and sorted by decreasing frequency for the total active 
group.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
TEAEs will be summarized by event rate per 100 subject years, defined as
100 * (Number of TEAEs)/(Total Patient Years)


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where total subject years is defined as the sum of the study drug exposure of all subjects 
normalized by 365.25 and rounded to 1 decimal place.
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
All serious adverse events (SAEs), deaths, and adverse events leading to discontinuation 
of study drug will be listed.  The number and percentage of subjects experiencing SAEs 
(including deaths) and adverse events leading to discontinuation of study drug will be 
tabulated by SOC and PT or each treatment group.
9.2.6
Adverse Events of Special Interest
The Adverse Events of Special Interest (AESI) categories will be summarized and 
presented by "as treated" treatment group and overall using SOC and MedDRA PT.  The 
AESI categories will be identified by the following search criteria per Standard MedDRA 
Queries (SMQs)/Company MedDRA Queries (CMQs) in Appendix B.
9.2.7
Adverse Events by Maximum Severity
TEAEs will also be summarized by maximum severity by "as treated" treatment group 
and overall.  If a subject has an AE with an unknown severity, then the subject will be 
counted in the severity category of unknown, even if the subject has another occurrence of 
the same event with a severity present.  The only exception is that if the subject has 
another occurrence of the same AE with the most extreme severity – severe.  In this case, 
the subject will be counted under the severe category.
9.2.8
Adverse Events by Maximum Relationship
TEAEs will also be summarized by maximum relationship to treatment, as assessed by the 
investigator, by "as treated" treatment group and overall.  If a subject has a TEAE with an 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 


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same TEAE with a relationship assessment of "reasonable possibility."  In this case, the 
subject will be counted under the "reasonable possibility" category.
9.2.9
Adverse Events by "Reasonably Possibly Related" 
Relationship
TEAEs and reasonably possibly related AEs occurring for more than 2% of the subjects in 
any of the treatment groups will also be summarized by MedDRA SOC and PT.  If a 
subject has an AE with an unknown relationship, then the subject will be counted in as 
'related.'
9.2.10
Frequent (> 5%) Adverse Events and Reasonably Possibly 
Related Adverse Events by Preferred Term in Decreasing 
Frequency
TEAEs and reasonably possibly related AEs occurring for more than 5% of the subjects in 
any of the treatment arms will be summarized by MedDRA PT in decreasing frequency 
separately.
9.2.11
Listing of Adverse Events
The following additional summaries of AEs will be prepared.
●
Listing of Subjects with Treatment-Emergent AESIs
●
Listing of Subjects with Pretreatment SAEs
●
Listing of Subjects with Treatment-Emergent SAEs
●
Listing of all AEs that led to discontinuation of study drug
●
Listing of all deaths.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline, where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 


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clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.
Mean change from baseline to each applicable post-baseline visit will be summarized for 
selected laboratory variables, with the number of observations, baseline mean, and visit 
mean.  The change from baseline mean, standard error, and 95% confidence interval will 
be presented for the mean change from baseline within each treatment group and 
difference between treatment groups using ANOVA model.
The baseline and post-baseline laboratory observations will be categorized as Grade 1, 
Grade 2, Grade 3, and Grade 4 according to OMERACT criteria (Rheumatology Common 
Toxicity Criteria v.2.0).  For creatine phosphokinase and creatinine, NCI CTC criteria will 
be used.
For each laboratory variable, shift tables will be generated that cross tabulate the subjects' 
as deemed appropriate by "as treated" treatment group:
●
Category of the baseline value versus category of the final value.
●
Category of the baseline value versus maximum category.
●
Category of the baseline value versus minimum category.
Note that the minimum/maximum category is used, rather than the category of the 
minimum/maximum value.  The two may be different due to variation in the reference 
range.
No statistical tests will be performed for this analysis.
Laboratory abnormalities will be evaluated based on Potentially Clinically Significant 
(PCS) criteria (Appendix C).  For each laboratory PCS criterion, the number and 
percentage of subjects who have a laboratory value meeting the criteria will be 
summarized.  Listings will be provided to summarize subject-level laboratory data for 
subjects meeting PCS criteria.


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According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation" (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver-specific function test values that meet the following 
criteria of potential clinical interest will be summarized by "as treated" treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
Total Bilirubin Level (TBL) ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
9.4
Analysis of Vital Signs
Vital sign variables include sitting systolic blood pressure, sitting diastolic blood pressure, 
pulse, body temperature, and weight.  The criteria for potentially clinically significant 
vital sign findings are presented in Appendix C.


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A treatment-emergent value is defined as a value with a date that is on or after the 
first dose of study drug, and no more than 30 days after the last dose of study drug.
The change from baseline mean, standard error, and 95% confidence interval will be 
presented for the mean change from baseline within each treatment group and difference 
between treatment groups using ANOVA model.
Vital sign variables will be evaluated based on potentially clinically significant (PCS) 
criteria (Appendix C).  For each vital sign PCS criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized.  Listings 
will be provided to summarize subject-level vital sign data for subjects meeting PCS 
criteria.
9.5
Safety Subgroup Analyses
No planned safety subgroup analyses.
9.6
Other Safety Analyses
ECG is collected at screening visit, Week 2, Week 4, Week 8, and Week 12.  ECG 
findings will be summarized by treatment group for each parameter and visit.
10.0
Other Analyses
No other analyses are planned.
11.0
Interim Analyses
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.


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11.1
Data Monitoring Committee
An internal data monitoring committee (DMC) composed of persons independent of study 
team and with relevant expertise in their field will review unblinded safety data from the 
ongoing study.  The primary responsibility of the DMC will be to protect the safety of the 
subjects participating in this study.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no alpha adjustment is needed.
12.0
Overall Type-I Error Control
Hypothesis testing in the primary analyses (see Section 8.3.3) will be performed in a 
ranked fashion as follows based on two-sided significance level of α = 0.1.
1) The superiority of ABBV-599 compared to placebo at Week 12 using MMRM.
2) The dose-response among ABBV-105 dose groups and the placebo group at 
Week 12 using MCP-Mod method.
All other tests will be performed at two-sided statistical significance level of α = 0.1 
without multiple testing α adjustment.
Since there are no efficacy analyses for early stopping planned for the DMC review, no 
alpha spending is needed due to the DMC review.


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13.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
29 May 2018
Original version
2.0
16 Jul 2018
The changes made between the second and the first version are:
! Small editorial changes for readability and to maintain consistency 
with the protocol
! Clarification of cutoff days for laboratory and vital sign values.
! An update to the DMC evaluation checkpoints.
! The addition of the OMERACT Criteria, which was referenced in the 
safety section, to the Appendix
3.0
13 June 2019
The changes made between this and the previous version are:
! An update to visits with ECG data collected in Section 9.6 to maintain 
consistency with the protocol
! Addition of an interim efficacy analysis to maintain consistency with 
the protocol
! Updated the AESI table to maintain consistency with the protocol
! Updates to the historical borrowing methods detailed in Appendix D
! Change of formatting to adhere to a new SAP template
4.0
23 Jan 2020
The change made between this and the previous version are:
! Updated Potential Clinically Important Criteria for safety endpoints in 
Appendix C
! Removed interim analysis due to protocol amendment
! Changed secondary endpoints from "Proportion of subjects achieving 
CR (DAS28 CRP) at Week 12" and "Proportion of subjects achieving 
LDA (DAS28 CRP) at Week 12" to "Proportion of subjects achieving 
CR (DAS28 CRP) at all visits" and "Proportion of subjects achieving 
LDA (DAS28 CRP) at all visits," respectively, as the summaries by 
visits are of interest.
! Added "Proportion of subjects achieving LDA (DAS28 CRP) but not 
CR at all visits" and "Proportion of subjects achieving LDA (CDAI) 
but not CR at all visits" as secondary endpoints, as these summaries 
are of interest.
! Added AO analyses for DAS28 CRP and ACR20/50/70 response rates 
at all visits as sensitivity analyses per protocol.
! Updated the criteria for Liver-Related Elevations to align with 
Immunology RA project conventions.


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14.0
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Ibrahim J, Chen M.  Power prior distribution for regression models.  Stat Sci.  
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Hobbs BP, Carlin BP, Mandrekar SJ, et al.  Hierarchical Commensurate and Power 
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Trials.  Biometrics.  2011;67(3):1047-56.
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Schmidli H, Gsteiger S, Roychoudhury S, et al.  Robust Meta-Analytic-Predictive 
Priors in Clinical Trials with Historical Control Information.  Biometrics.  
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4.
Neuenschwander B, Capkun-Niggli G, Branson M, et al.  Summarizing historical 
information on controls in clinical trials.  Clin Trials.  2010;7(1):5-18.
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Baeten D, Baraliakos X, Braun J, et al.  Anti-interleukin-17A monoclonal antibody 
secukinumab in treatment of ankylosing spondylitis:  A randomised, double-blind, 
placebo-controlled trial.  Lancet.  2013;382(9906):1705-13.
6.
Pocock SJ.  The combination of randomized and historical controls in clinical 
trials.  J Chronic Dis.  1976;29(3):175-88.
7.
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.
8.
Bretz F, Pinheiro JC, Branson M.  Combining multiple comparisons and modeling 
techniques in dose-response studies.  Biometrics.  2005;61(3):738-48.
9.
Genovese MC, Kremer J, Zamani O, et al.  Baricitinib in Patients with Refractory 
Rheumatoid Arthritis.  N Engl J Med.  2016;374(13):1243-52.
10.
Burmester GR, Blanco R, Charles-Schoeman C, et al.  Tofacitinib (CP-690,550) in 
combination with methotrexate in patients with active rheumatoid arthritis with an 
inadequate response to tumour necrosis factor inhibitors:  a randomised phase 3 
trial.  Lancet.  2013;381(9865):451-60.


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11.
Sidik K, Jonkman JN.  A comparison of heterogeneity variance estimators in 
combining results of studies.  Stat Med.  2007;26(9):1964-81.


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


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Appendix B.
Definition of Adverse Events of Special Interest
Adverse Events of Special Interest (AESI) will be identified using the following search 
criteria:
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection
CMQ
"Opportunistic Infection"
Possible Malignancy
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
"Malignant tumours"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ
Broad
Skin Malignant tumours (Broad 
SMQ) removing Melanoma CMQ
Malignancy excluding NMSC
"Malignant tumours" SMQ 
removing NMSC output
Lymphoma
SMQ
"Malignant Lymphomas"
Hepatic Disorder (Hepatic Events 
and Increased Hepatic 
Transaminases)
SMQ
Narrow
"Drug Related Hepatic Disorders"
Gastrointestinal Perforations
SMQ
Narrow
"Gastrointestinal Perforation"
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
Anemias"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia (Veliparib Product 
Specific)"
Herpes Zoster
CMQ
"Herpes Zoster"
Creatine Phosphokinase (CPK) 
Elevation
PT
Search only for the PT of "Blood 
creatine phosphokinase increased"
Renal Dysfunction
SMQ
Narrow
"Acute Renal, Failure"
Tuberculosis
CMQ
"Tuberculosis"
Adjudicated Cardiovascular Events
Output from 
CAC


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Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCS) laboratory findings are determined 
by OMERACT criteria in Table C-1, and the PCS criteria for vital sign findings are 
described in Table C-2.
Table C-1.
OMERACT Criteria
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 Antirheumatic Therapies
(Note that for L9.  CPK and L11.  Creatinine, the criteria in this table is replaced by the NCI CTC grade, as the NCI 
CTC grade is used for analysis for these two parameters.)
1 – Mild
Asymptomatic, or 
transient
Short duration 
(< 1 week)
No change in life 
style
No medication or 
OTC
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
Hospitalized > 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


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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
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


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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
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.  
Induration/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


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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
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


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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
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


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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
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


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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
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


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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 
(mmol/l)***
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 
(mmol/l)***
-
125 – 129
120 – 124
< 120
L8.  Hypokalaemia 
(mg/dl)***
-
3.0 – 3.4
2.5 – 2.9
< 2.5
L9.  CPK (also if 
polymyositis-
disease)****
> ULN – 1.5 × 
ULN
> 2.5 – 5.0 × ULN
> 5.0 – 10.0 × ULN
> 10.0 × ULN
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 – 1.5 × 
Baseline; > ULN –
1.5 × ULN
> 1.5 – 3.0 × 
Baseline; > 1.5 –
3.0 × ULN 
> 3.0 baseline; > 3.0 –
6.0 × ULN
> 6.0 × ULN


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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 – 1.5** × 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
*:
in L11, 1.5 – 1.8 × ULN is changed to 1.4 – 1.8 × ULN.
**:
in L14, 1.1 – 2.0 × ULN is changed to 1.1 – 1.5 × ULN.
***:
in L3, L7 and L8, mg/dl is changed to mmol/l.
****:
NCI CTC grade.
Table C-2.
Criteria for Potentially Clinically Significant Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and/or decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and/or increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and/or decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and/or increase ≥ 10 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and/or decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and/or increase ≥ 15 bpm from Baseline
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline


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Appendix D.
Details for Historical Data Borrowing
Statistical methods for incorporating historical data in a new study include power prior 
[Ibrahim 2000], commensurate prior [Hobbs 2011] and robust mixture prior 
[Schmidli 2014].  All these methods are Bayesian approaches.  We took a similar 
approach using meta-analytical-predictive method to summarize historical control data as 
a basis for informative prior for the control group and to determine the maximal number 
of subjects to be borrowed (effective sample size [Neuenschwander 2010]).  For the 
treatment group, we use a noninformative prior so that information for the treatment 
group only depends on in-trial data [Baeten 2013].  We systematically evaluate the impact 
of bias (defined as the difference between historical control data and concurrent control 
data) and number of historical control subjects borrowed on the (Bayesian) type I error 
rate/false positive rate and power/true positive rate.  So the number of subjects borrowed 
is determined to control the inflation (if any) of two types of error rates to a reasonable 
extent based on a reasonable range of the magnitude of bias.
D-1
Historical Data Selection and Meta-Analysis
The historical data are carefully selected based on the similarity in target population, 
mechanism of action of study drugs, concomitant medications [Pocock 1976] between 
historical trials and the trial under design.  The selection of historical trials is described in 
the following.
○
ABBV-105 vs Placebo (Borrowing Placebo)
For placebo control group vs ABBV-105 treatment group, historical data for placebo 
group are available from three clinical trials at the time of design stage of the current trial.  
These historical control data consist of 349 subjects from three clinical trials with similar 
populations (TNF and/or Bio-IR on background MTX or csDMARDs), mechanism of 
action (JAK inhibition), and study designs:  baricitinib Phase 3 study BEACON (n = 176, 
mean [SD] of DAS28-CRP change = –0.8 [1.5]) [Genovese 2016]; tofacitinib Phase 3 
study STEP (n = 118, mean (SD) = –0.6 (1.5)) [Burmester 2013]; and upadacitinib-
Phase II (n = 55, mean (SD) = –1.1 (1.6)) (AbbVie Study M13-550).  The criteria for 


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relevant historical control data selection were evaluated and met for these trials and the 
trial under design.  These studies have similar population (TNF and Bio-IR), similar 
inclusion and exclusion criteria and were conducted in the similar way as the current 
study as shown in Table D-1.
Table D-1.
Major entry criteria for historical studies and Study M16-063
Criteria
Historical Studies
Current Study
Baricitinib
(BEACON P3)
Tofacitinib
(STEP P3)
Upadacitinib 
(M13-550 P2)
ABBV-599 
(M16-063 P2)
Inc 1
Bio-IR
Bio-IR
Bio-IR
Bio-IR
Inc 2
18 years or older
18 years or older
18 years or older
18 years or older
Inc 3
Moderately to 
severely RA
Moderately to 
severely RA
Moderately to 
severely RA
Moderately to 
severely RA
Inc 4
csDMARDs
Methotrexate
Methotrexate
csDMARDs
Exc 1
haemoglobin
< 100 g/L
haemoglobin
< 90 g/L
haemoglobin
< 90 g/L
haemoglobin
< 90 g/L
Exc 2
WBC < 2.5 × 10^9/L
WBC < 3.0 × 10^9/L
WBC < 3.0 × 10^9/L
WBC
< 3.0 × 10^9/L
Exc 3
platelet
< 100 × 10^9/L
platelet
< 100 × 10^9/L
platelet
< 100 × 10^9/L
platelet
< 100 × 10^9/L
Exc 4
eGFR < 40 mL/min/
1.73 m^2
eGFR < 40 mL/min/
1.73 m^2
eGFR < 40 mL/min/
1.73 m^2
eGFR < 40 mL/min/
1.73 m^2
Exc 5
AST/ALT > 1.5 × 
ULN
AST/ALT > 1.5 × 
ULN
AST/ALT > 1.5 × 
ULN
AST/ALT > 2 × 
ULN
The meta-analysis shows that predicted estimated mean (SD) and 95% confidence interval 
for mean are –0.80 (1.5) and [–1.06, –0.54] (Figure D-1) based on Empirical Bayes 
estimator [Sidik 2007].  The estimated heterogeneity variance τ2 = 0.0297 and historical 
effective sample size (the maximum number of subjects we could borrow) is 49 
[Neuenschwander 2010].


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Figure D-1.
Meta-Analysis for Historical Placebo Data
○
ABBV-599 vs upadacitinib (Borrowing upadacitinib)
For upadacitinib control group versus ABBV-599, historical data consist of 206 subjects 
on 15 mg from two upadacitinib studies (Phase 2:  Study M13-550 Balance I and Phase 3:  
Study M13-542 Select Beyond).  Upadacitinib-Phase II gives n = 52, mean
(SD) = –2.2 (1.5), and upadacitinib-Phase III shows n = 154, mean (SD) = –2.37 (1.6).  
The meta-analysis results in the predicted mean (SD) and 95% confidence interval are
–2.32 (1.57) and [–2.54, –2.11] (Figure D-2) based on Empirical Bayes estimator 
[Sidik 2007].  Since τ2 = 0, the historical effective sample size is 206.
Figure D-2.
Meta-Analysis for Historical Upadacitinib Data


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In addition, upadacitinib-Phase III study data becomes available after this study design.  A 
sensitivity analysis will be performed to include placebo data from upadacitinib-Phase III 
study in the meta-analysis (n = 144, mean (SD) = –1.01 (1.3)).
D-2
Borrowing size and prior distribution determination
For the primary analysis, our principle for fixed borrowing historical sample size is not to 
exceed the sample size in the current study.  For placebo control borrowing, the fixed 
historical placebo borrowing sample size will not exceed 20.  The upadacitinib fixed 
historical borrowing will not exceed 40.
○
ABBV-105 vs Placebo (Borrowing Placebo)
Assume the mean for ABBV-105 is –1.65 and for placebo is –0.80 (from meta-analysis) 
so the absolute effect size is 0 = 0.85.  Let r define the relative bias from historical data, 
i.e., |	 −| = 90 where 	 is the true but unknown mean for control group (placebo) 
and  is the historical data mean calculated from meta-analysis.  To assess the bias 
impact on historical data borrowing, a reasonable limit for bias 90 would be the 
half confidence interval width from meta-analysis i.e., 90 ≤0.26.  So
9 ≤0.26 0.85
⁄
= 0.31.
Let ' =
<=
<=><? be the proportion of borrowed number of historical patients () among 
all control patients ( + 	 where 	 is the number of control group subjects in current 
study).  Let  and  be the treatment group mean and the number of subjects.  Given 9, 
and ', we can obtain Bayesian type I error rate/false positive rate (i.e., the probability 
achieving ( −	 < 0|) > 1 −A under the null hypothesis  = 	):
Φ C
±√8E4FGHIJ()KL)>HIJ()KM)NKHIJ()KL)O)>P()K4F)
O)>P()K4F)Q
R  
(1)*


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and Bayesian power/true positive rate (i.e., the probability achieving
( −	 < 0|) > 1 −A under the null hypothesis 	 − = 0):
Φ C
√8()±E4F)GHIJ()KL)>HIJ()KM)NKHIJ()KL)O)>P()K4F)
O)>P()K4F)Q
R.  
(2)*
The ± in above formula corresponds to two directions of the bias, A and 1 −7 are 
type I error and power for sample size calculation without borrowing, and S = /	 is 
the randomization ratio in current study with reduced control group due to borrowing.
* (1) and (2) could be derived as follows:
Probability of trial success = (( −	 < 0|) > 1 −A)
= Φ
⎝
⎛
	 −
W 1
 + 1 −'
 + 	
−
'( −	)
W 1
 + 1 −'
 + 	
−ΦK)(1 −A)
W 1
 +
1
 + 	
W 1
 + 1 −'
 + 	⎠
⎞
The treatment group sample size  =
8ZHIJ()KL)>HIJ()KM)[
Q\Q
]Q
which is the balanced 
sample size without borrowing.  With S = /	, the power without borrowing equals
Φ CW
8
)>P ZΦK)(1 −A) + ΦK)(1 −7)[ −ΦK)(1 −A)R.
With S = /	, |	 −| = 90 and ' =
<=
<=><?, (1) could be derived for
 −	 = 0 and (2) could be obtained from 	 − = 0.


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Table D-2.
Bayesian type I error/false positive rate (Error I) and power/true 
positive rate for ABBV-105 vs Placebo
Borrowing 
# of 
Subjects
^ = %. _
^ = %. `
^ = %. a
Error I
Power
Error I
Power
Error I
Power
–
+
–
+
–
+
–
+
–
+
–
+
0
0.05
0.05
0.65
0.65
0.05
0.05
0.65
0.65
0.05
0.05
0.65
0.65
10
0.028
0.041
0.741
0.793
0.023
0.049
0.712
0.816
0.019
0.058
0.682
0.838
20
0.021
0.040
0.796
0.868
0.014
0.053
0.753
0.896
0.010
0.071
0.706
0.920
30
0.018
0.041
0.831
0.907
0.011
0.060
0.780
0.934
0.007
0.085
0.722
0.955
40
0.016
0.044
0.853
0.929
0.010
0.067
0.798
0.954
0.005
0.099
0.734
0.971
50
0.016
0.047
0.868
0.943
0.009
0.074
0.811
0.965
0.005
0.113
0.742
0.980
Borrowing 
# of 
Subjects
^ = %. b
^ = %. c
^ = %. d
Error I
Power
Error I
Power
Error I
Power
–
+
–
+
–
+
–
+
–
+
–
+
0
0.05
0.05
0.65
0.65
0.05
0.05
0.65
0.65
0.05
0.05
0.65
0.65
10
0.015
0.069
0.651
0.858
0.012
0.080
0.619
0.876
0.010
0.094
0.587
0.893
20
0.007
0.093
0.655
0.939
0.004
0.119
0.600
0.954
0.003
0.150
0.544
0.967
30
0.004
0.118
0.657
0.970
0.002
0.158
0.588
0.980
0.001
0.206
0.515
0.988
40
0.003
0.142
0.660
0.982
0.001
0.195
0.579
0.990
0.001
0.258
0.495
0.994
50
0.002
0.163
0.662
0.989
0.001
0.227
0.573
0.994
0.000
0.303
0.481
0.997
*
For sample size = 40:20 (k = 2), α = 0.05, 1 – β = 80%, δ = 0.85.
Table D-2 shows the Bayesian type I error rate/false positive rate and power/true positive 
rate for different number of borrowing and different relative bias (r = 0.1 - 0.6) given 
sample size = 40:20 (k = 2), α = 0.05, 1 – β = 80%, δ = 0.85.  For r ≤ 0.4, with the sample 
size = 40:20 (k = 40/20 = 2) for ABBV-105 and placebo respectively, we could borrow up 
to 20 historical placebo subjects while controlling type I error rate/false positive 
rate < 10% and not exceeding in study placebo sample size.  For example, for r = 0.3, 
borrowing 20 will control false positive rate at 7%.
Therefore, for this analysis with historical data borrowing, we would borrow historical 
data:   = 20,  = −0.80, and its SE  = 1.5 √20
⁄
= 0.335.  That is, the prior 
distribution for placebo would be N (–0.80, 0.3352).  For ABBV-105, a "flat" non-


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informative prior probability distribution will be assumed, that is the posterior distribution 
is totally from the data.
A supportive analysis will also be performed as dynamic borrowing based on the observed 
r and Table D-2.  For example, if r = 0.2, we will borrow up to 50 historical sample size.  
On the other hand, if r = 0.5 in positive (+) direction, we just borrow 10; if r = 0.5 in 
negative (–) direction, we will not borrow (borrow 0).  Overall, if borrowing provides a 
true positive rate above 65% and false positive rate less than 10%, we conduct dynamic 
historical borrowing by picking up the appropriate borrowing sample size to achieve 
maximum true positive rate.
○
ABBV-599 vs Upadacitinib
Assume the mean for ABBV-599 is –2.65 and for upadacitinib is –2.32 so the absolute 
effect size is δ = 0.33.  To control the bias with historical data borrowing, a reasonable 
limit for bias 90 would be the half confidence interval width from meta-analysis i.e.,
90 ≤0.215 e9 9 ≤0.65.  With the same formula as for ABBV-105 vs placebo, we 
obtained the Bayesian type I error/false positive rate and power/true positive rate in 
Table D-3 for r = 0.6/0.65/0.7, respectively.
Table D-3.
Bayesian type I error/false positive rate (Error I) and power/true 
positive rate for ABBV-599 vs Upa
Borrowing 
# of 
Subjects
^ = %. d
^ = %. d5
^ = %. f
Error I
Power
Error I
Power
Error I
Power
–
+
–
+
–
+
–
+
–
+
–
+
0
0.05
0.05
0.34
0.34
0.05
0.05
0.34
0.34
0.05
0.05
0.34
0.34
10
0.028
0.057
0.298
0.422
0.027
0.059
0.294
0.427
0.026
0.061
0.289
0.432
20
0.018
0.066
0.273
0.497
0.017
0.070
0.264
0.507
0.016
0.073
0.256
0.517
30
0.012
0.076
0.254
0.561
0.011
0.081
0.243
0.574
0.010
0.087
0.233
0.587
40
0.009
0.087
0.241
0.612
0.008
0.093
0.228
0.628
0.008
0.100
0.216
0.643
50
0.007
0.097
0.231
0.654
0.007
0.105
0.217
0.671
0.006
0.114
0.204
0.688
*
For sample size = 60:40 (k = 1.5), α = 0.05, 1 – β = 39%, δ = 0.33.


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Table D-3 shows the Bayesian type I error rate/false positive rate and power/true positive 
rate for different number of borrowing and different relative bias given sample 
size = 60:40 (k = 1.5), α = 0.05, 1 – β = 39%, δ = 0.33.  For r ≤ 0.65 in positive direction, 
sample size = 60:40 for ABBV-599 and upadacitinib respectively, we could borrow 
40 historical placebo subjects while controlling type I error rate < 10% and no more than 
in study sample size 40.  Therefore for historical data borrowing analysis, we have
 = 40,  = −2.32, and its SE  = 1.57 √40
⁄
= 0.25.  That is, the prior distribution 
for upadacitinib would be N (–2.32, 0.252).  For ABBV-599, a "flat" non-informative 
prior probability distribution will be assumed.  That is the posterior distribution is totally 
based on the observed data.
In addition, a supportive analysis using dynamic borrowing will also be performed based 
on the observed r and extended Table D-3 (not presented).  For example, if bias is positive 
and r = 0.6, we could borrow 50 historical sample size to control false positive rate within 
10%.  On the other hand, if bias is negative, we will not borrow (borrow 0).  Overall, if 
borrowing provides a true positive rate above 34% and the false positive rate 
less than 10%, we conduct dynamic historical borrowing by picking up the appropriate 
borrowing sample size to achieve maximum true positive rate.
D-3
Analysis Methods
The prior distributions discussed in Section D-2 will be combined with the observed data 
in the trial to obtain posterior distributions for the treatment and control groups.  The 
probability of Treatment mean – Control mean < 0 given the observed data i.e.,
( −	 < 0|) will be calculated.
Let  = (,), ⋯, ,<) be the data and ,n~p(, 8).  Then ,̅~p(,
\Q
< ). If σ2 is a constant, 
we have the likelihood for the data
r(|) =  -(|) ∝p(,̅,
\Q
< ).


ABBV-105
M16-063 – Statistical Analysis Plan
Version 4.0 – 23 January 2020
59
The conjugate prior for μ is supposed to be
-() ∝p(', '
8).
Then the posterior is given by
-(|) = r(|)-() ∝p(<, <
8) where
< =
\Q
<\FQ>\Q ' +
<\FQ
<\FQ>\Q ,̅ and
<
8 =
)
t
uQ> J
uFQ
=
\Q\FQ
<\FQ>\Q.
If ( −	 < 0|) > 0.95, the treatment group will be claimed as significantly 
better than the control group. This is equivalent to the hypothesis test of  −	 = 0 at 
one-sided A = 0.05 significant level.
Notice that (', '
8) are prior parameters determined from historical data borrowing and 
meta-analysis (see Section D-2).  G,̅,
\Q
< N are LSMean and SE from MMRM based on data 
in the study.  For treatment group, a "flat" non-informative prior probability distribution 
will be assumed, that is the posterior distribution is totally based on the observed data.