Clinical trial NCT03823378
Conditions: Rheumatoid Arthritis (RA)
Keywords: Elsubrutinib ABBV-105 Upadacitinib ABBV-599 Rheumatoid Arthritis (RA) Long-term extension (LTE)
Sponsor: AbbVie
Start date: 2019-05-13; Completion date: 2020-09-09
Enrollment: 97 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a long-term extension (LTE) study to assess the safety, tolerability, and efficacy of ABBV-105 (elsubrutinib \[ELS\]) and ABBV-599 (ELS 60 mg and upadacitinib \[UPA\] 15 mg) in participants with rheumatoid arthritis (RA) who completed Study M16-063 (NCT03682705).

Detailed description:
This was a Phase 2, double-blind, multicenter, long-term extension (LTE) study to assess the safety, tolerability, and efficacy of 3 doses of ABBV-105 (elsubrutinib \[ELS\] 5 mg, 20 mg, and 60 mg) and ABBV-599 (ELS 60 mg and upadacitinib \[UPA\] 15 mg) in adults with active rheumatoid arthritis with inadequate response or intolerance to biologic disease-modifying antirheumatic drugs (bDMARDs). Participants who successfully completed treatment in the feeder Study M16-063, a Phase 2 dose exploratory study, were eligible to participate in this study. Those who met eligibility criteria and entered this study receiving ELS, ABBV-599, or UPA from Study M16-063 continued on their previously assigned treatment through termination of this study. Participants originally randomized to placebo in Study M16-063 rolled over to ABBV-599 in a blinded fashion in this study.

Arms: arm 1: 60 mg elsubrutinib capsule once a day by mouth for 48 weeks; 15 mg film-coated upadacitinib tablet once a day by mouth for 48 weeks arm 2: 60 mg elsubrutinib capsule once a day by mouth for 48 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 48 weeks arm 3: 20 mg elsubrutinib capsule once a day by mouth for 48 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 48 weeks arm 4: 5 mg elsubrutinib capsule once a day by mouth for 48 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for 48 weeks arm 5: 15 mg film-coated upadacitinib tablet once a day by mouth for 48 weeks; placebo capsule for elsubrutinib once a day by mouth for 48 weeks arm 6: Placebo in M16-063; 60 mg elsubrutinib capsule once a day by mouth for 48 weeks and 15 mg film-coated upadacitinib tablet once a day by mouth for 48 weeks in M16-763
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: Upadacitinib placebo tablet will be administered orally.

Protocol documents:
Prot_000.pdf: 
NCT03823378


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
STUDY OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES
10
3.2
EFFICACY ENDPOINTS
10
3.3
SAFETY ENDPOINTS
11
3.4
BIOMARKER RESEARCH
12
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
13
5
STUDY ACTIVITIES
14
5.1
ELIGIBILITY CRITERIA
14
5.2
CONTRACEPTION RECOMMENDATIONS
17
5.3
PROHIBITED MEDICATIONS AND THERAPY
18
5.4
PRIOR AND CONCOMITANT THERAPY
20
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
21
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
23
5.7
STUDY DRUG
24
5.8
RANDOMIZATION/DRUG ASSIGNMENT
25
5.9
PROTOCOL DEVIATIONS
25
6
SAFETY CONSIDERATIONS
26
6.1
COMPLAINTS AND ADVERSE EVENTS
26
6.2
TOXICITY MANAGEMENT
30
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
31
7.1
STATISTICAL AND ANALYTICAL PLANS
31


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7.2
DEFINITION FOR ANALYSIS POPULATIONS
31
7.3
STATISTICAL ANALYSES FOR EFFICACY
31
7.4
STATISTICAL ANALYSES FOR SAFETY
32
7.5
INTERIM ANALYSIS
32
8
ETHICS
33
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
33
8.2
ETHICAL CONDUCT OF THE STUDY
33
8.3
SUBJECT CONFIDENTIALITY
33
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
33
10 DATA QUALITY ASSURANCE
33
11 COMPLETION OF THE STUDY
34
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A OR CYP1A2 INHIBITORS AND INDUCERS
19
TABLE 2.
STUDY DRUG
24
TABLE 3.
ADVERSE EVENTS REQUIRING SUPPLEMENTAL REPORTS
27
LIST OF FIGURES
FIGURE 1.
PERIOD 1 SCHEMATIC
13
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
35
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
37
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
38
APPENDIX D.
ACTIVITY SCHEDULE
39
APPENDIX E.
PROTOCOL AMENDMENT SUMMARY OF CHANGES
41


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APPENDIX F.
OPERATIONS MANUAL
43








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2 INTRODUCTION
2.1 Background and Rationale
Why This Study Is Being Conducted
This study will provide data on the long-term safety, tolerability, and efficacy of ABBV-105 and ABBV-599 
in rheumatoid arthritis (RA) subjects who have completed the Phase 2 study of these compounds 
(Study M16-063).  ABBV-105 is a novel, covalent Bruton's tyrosine kinase (Btk) inhibitor being developed 
for the treatment of immune-mediated inflammatory diseases including RA.  ABBV-105 may be given 
alone or in combination with upadacitinib, which is known as ABBV-599.
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, such as 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.
Upadacitinib is a novel Janus kinase (JAK) inhibitor, which displays unique selectivity for the JAK1 
receptor.  Upadacitinib 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), axial spondyloarthritis (Phase 2), and giant cell arteritis (Phase 2).  
Development of other indications of interest (i.e., dermatomyositis and/or Takayasu arteritis) are under 
discussion.  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.
ABBV-105 given alone or as the ABBV-599 combination therapy (with upadacitinib) are anticipated to be 
effective in decreasing signs and symptoms associated with active RA in patients with inadequate 
response or intolerance to biologic disease-modifying antirheumatic 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.
Clinical Hypothesis
The safety and efficacy of ABBV-105 and ABBV-599 will be maintained over an extended period of 
treatment.
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 are anemia, bleeding associated with platelet 


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dysfunction, and lymphopenia.  Reductions in lymphocytes and the known mechanism of action suggest 
the potential for an increased susceptibility to infection.
ABBV-105 alone and the ABBV-599 combination therapy (with upadacitinib) were well-tolerated with no 
serious adverse events (SAEs) observed in healthy adult subjects at various doses in 3 Phase 1 studies 
(Studies M16-356, M16-357, and M16-044).  The current study is a continuation of the Phase 2 study of 
ABBV-105 and ABBV-599 in RA (Study M16-063).  Taken together, the safety data from the Phase 1 
program and the safe and successful completion of Study M16-063 support further development of 
ABBV-105 and ABBV-599 in Phase 2 in subjects with RA.  
The data from over 4,000 RA patients treated with upadacitinib support an acceptable safety profile and 
a positive risk-benefit for treatment of adult patients with moderately to severely active RA.  
Data from the primary efficacy analyses of the 5 pivotal Phase 3 clinical studies for the upadacitinib RA 
development program consistently demonstrated the efficacy of upadacitinib 15 mg QD and 30 mg QD, 
with both doses of upadacitinib meeting all primary and ranked key secondary endpoints across all 
studies which included all lines of therapy (methotrexate [MTX]-naïve, conventional synthetic disease-
modifying antirheumatic drug [csDMARD]/MTX-inadequate responder [IR], and biologic disease-
modifying antirheumatic drug [bDMARD]-IR).  Upadacitinib 15 mg QD also demonstrated superiority 
over adalimumab across a broad range of efficacy measures.  Overall, the efficacy data in the RA 
development program provide substantial evidence to support the use of upadacitinib as monotherapy 
or in combination with MTX and/or csDMARDs for the treatment of adults with moderately to severely 
active RA.
Serious infections and herpes zoster are identified risks for upadacitinib therapy.  The rates of serious 
infections and herpes zoster for upadacitinib therapy are within the range of other marketed JAK 
inhibitor products.
In regarding to the potential for malignancy, per upadacitinib Investigator's Brochure version 18.0:
Few malignancies were reported in the controlled portions of the upadacitinib Phase 2 and 3 clinical 
studies precluding any conclusions about rates between treatment groups.  The interim rate of total 
malignancies excluding and including non-melanoma skin cancer (NMSC) on upadacitinib in the Phase 2 
open label extension Study M13-538, which includes long-term treatment data, are both 0.7 E/100 PY.  
The malignancy types reported in the clinical program have been consistent with that anticipated in the 
study population including solid tumors such as breast, prostate and lung cancer, lymphoma, and NMSC.  
A number of subjects with malignancy had pre-existing risk factors for malignancy and/or prior history of 
treatment with other immunosuppressive therapy.
The malignancy rate is higher in the upadacitinib 30 mg group compared to the 15 mg treatment group; 
however, the difference in rates is related to more cases of NMSC and not other malignancy types.
For further details, please see findings from completed studies, including safety data, in the most recent 
ABBV-105 and upadacitinib Investigator's Brochures.
For safety monitoring, the following are included in the protocol:
!
Subjects meeting discontinuation criteria as part of the M16-063 study will be excluded.


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!
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.
!
SAEs of infection will be reviewed on a real time basis and queried for additional information as 
clinically indicated.
!
A supplemental herpes zoster form will be used to collect additional information for any herpes 
zoster infections.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
The primary objective of this study is to evaluate the long-term safety, tolerability, and efficacy of 
ABBV-105 and ABBV-599 in RA subjects who have completed Study M16-063.
3.2 Efficacy Endpoints
There is no primary efficacy endpoint since this is the extension to the feeder Study M16-063.  Efficacy 
endpoints for this study, measured at each study visit, include the following:
!
Change in disease activity score (DAS)28 (C-reactive protein [CRP]) from baseline of 
Study M16-063;
!
Proportion of subjects achieving DAS Low Disease Activity (LDA), defined as DAS28 CRP ≤3.2;
!
Proportion of subjects achieving DAS Clinical Remission (CR), defined as DAS28 CRP < 2.6;
!
Change in clinical disease activity index (CDAI) from baseline of Study M16-063;
!
Proportion of subjects achieving LDA based on CDAI criteria, defined as CDAI ≤ 10;
!
Proportion of subjects achieving CR based on CDAI criteria, defined as CDAI ≤ 2.8;
!
Proportion of subjects achieving American College of Rheumatology (ACR) 20/50/70 response.  
A subject will be considered an ACR 20/50/70 responder if:
!
The swollen joint count (SJC) and tender joint count (TJC) have decreased from baseline of 
Study M16-063 by 20/50/70% or more.
!
At least 3 of the 5 remaining ACR core set measures (i.e., Patient's Assessment of Pain [using 
visual analog scale, VAS], Patient Global Assessment of Disease Activity [PtGA], Physician 
Global Assessment of Disease Activity [PhGA], Health Assessment Questionnaire Disability 
Index [HAQ-DI], and high-sensitivity C-reactive protein [hsCRP]) show reduction of 
20/50/70% or more from baseline of Study M16-063.
!
Change in individual components of ACR from baseline of Study M16-063, to include:
!
SJC,
!
TJC,


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!
Patient's Assessment of Pain (using VAS),
!
PtGA,
!
PhGA,
!
HAQ-DI, and
!
hsCRP.
!
Change in Morning Stiffness from baseline of Study M16-063.
3.3 Safety Endpoints
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.
An internal data monitoring committee (DMC) will review unblinded safety data on a cohort level 
throughout the course of the study.  A separate DMC charter has been prepared outside of the protocol 
and describes the roles and responsibilities of the DMC members, frequency of data reviews, relevant 
safety data to be assessed, and expectations for blinded communications.
The DMC will be responsible for safeguarding the interests of trial subjects by assessing the safety and, if 
appropriate, the efficacy data of the interventions during the trial, as well as for monitoring the quality 
and integrity of the clinical trial.  The DMC will provide recommendations to the AbbVie contact about 
stopping, modifying or continuing the trial without modification.  The DMC may also formulate 
recommendations relating to the selection/recruitment/retention of subjects, their management, 
improving adherence to protocol-specified regimens and retention of subjects, and the procedures for 
data management and quality control.
The DMC is a multidisciplinary group consisting of clinicians and biostatisticians who, collectively, has 
knowledge in the management of patients with rheumatoid arthritis (RA) and experience in the conduct 
and monitoring of randomized clinical trials.  The DMC reviews the available safety data, and as 
applicable, the critical efficacy endpoints, assessing risks and benefits, and recommends to the AbbVie 
Contact whether to continue without change, modify, or stop the Study M16-063 clinical trial.
All DMC members will be internal AbbVie members with expertise in clinical safety monitoring and who 
have no affiliation with ABBV-599.  Following initiation of the study, DMC members will have no 
involvement in the conduct of Study M16-063 or other ABBV-599 clinical trials outside their role on the 
DMC.  All DMC members have agreed to not discuss unblinded data with those who have involvement 
with Study M16-063 or ABBV-599 development until the Study M16-063 unblinded information is made 
available to the team.
An independent Cardiovascular Adjudication Committee (CAC) will adjudicate blinded cardiac and 
cerebrovascular events.  A CAC charter has been prepared separately from the protocol and defines
objective, scope, frequency, and triggers of data reviews.
The clinical trial is to be discontinued or terminated in case of an unacceptable risk, relevant toxicity, or 
a negative change in the risk/benefit assessment.  This might include the occurrence of adverse events 


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of which character, severity or frequency is new in comparison to the existing risk profile.  In addition 
any data deriving from other clinical trials or toxicological studies which negatively influence the 
risk/benefit assessment might cause discontinuation or termination of the study.
3.4 Biomarker Research
Optional samples (whole blood, serum, and plasma) will be collected at specific time points as described 
in the Activity Schedule (Appendix D) to evaluate known and or novel disease related or drug related 
biomarkers.  Types of biomarkers may include nucleic acids, proteins, lipids, and/or metabolites.  The 
objective of research is to analyze samples for biomarkers that will help to understand RA, related 
conditions, and response to treatment with ABBV-105 and upadacitinib or similar compounds.  Research 
on samples collected in Germany will be limited to RA, ABBV-105, and upadacitinib.  Research may also 
include changes in epigenetics, gene expression, and proteomics that may be associated with RA, 
related conditions, or the subject's response to treatment.  This research is exploratory in nature, and 
the results may not be included with the clinical study report.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 2, double-blind, multicenter, long-term extension (LTE) study to assess the safety, 
tolerability, and efficacy of ABBV-105 and ABBV-599 in RA subjects who have completed Study M16-063.  
Subjects who meet eligibility criteria (Section 5.1) and enter the study on ABBV-105, ABBV-599, or 
upadacitinib from Study M16-063 will continue on their previously-assigned treatment through the end 
of the LTE study.  Subjects who meet eligibility criteria and enter the study on placebo for both 
ABBV-105 and upadacitinib from Study M16-063 will receive ABBV-599.  Study drug treatment 
assignments include the following:
!
Group 1:  ABBV-599 (ABBV-105 60 mg and upadacitinib 15 mg) administered once a day (QD),
!
Group 2:  ABBV-105 60 mg and upadacitinib placebo QD,
!
Group 3:  ABBV-105 20 mg and upadacitinib placebo QD
!
Group 4:  ABBV-105 5 mg and upadacitinib placebo QD, and
!
Group 5:  Upadacitinib 15 mg and ABBV-105 placebo QD.
This study plans to enroll subjects who completed Study M16-063 at approximately 39 sites in Canada 
and the European Union.  The number, allocation, and location of sites may vary depending on 
operational aspects of the study.  Study sites and subjects will remain blinded for the duration of the 
study.
The duration of the LTE study will be approximately 52 weeks.  This includes a 48-week double-blind 
treatment period with study visits conducted at Weeks 18, 24, 30, 36, 48, and 60 from the baseline visit 
of Study M16-063.  In addition, subjects will also have a telephone follow-up call 30 days after their last 
visit to determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.


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The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual.
Figure 1.
Period 1 Schematic
QD = administered once a day
4.2 Discussion of Study Design
Choice of Control Group
Subjects will roll over from Study M16-063 and continue on their originally randomized treatment, with 
the exception of those originally randomized to placebo, who will roll over to ABBV-599.  The objective 
of this LTE study is to evaluate long term safety and efficacy of ABBV-105 and ABBV-599, and thus 
primary comparison will be relative to the safety and efficacy profile observed in each arm during the 
initial randomized study.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with RA.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
This LTE study will enroll subjects who have completed Study M16-063.  Only those subjects who have 
met all of the specified eligibility criteria will have an option to enter into the LTE study to receive 


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continued therapy, provided the subject is willing and the investigator believes that continuing therapy 
is appropriate.
Selection of Doses in the Study
Since the study is a continuation of the initial Phase 2 dose exploration study of ABBV-105 and 
ABBV-599, the doses selected for this study are the same as those used previously in Study M16-063.  
These doses were determined based on an analysis of pharmacokinetic, pharmacodynamic, and safety 
data from Phase 1 studies in healthy volunteers for ABBV-105 and Phase 2 and Phase 3 studies for 
upadacitinib, in addition to efficacy data for upadacitinib in RA.
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. Subjects have completed Study M16-063 (i.e., the preceding study of ABBV-105 and 
ABBV-599) and have not developed any laboratory or clinical discontinuation criteria as defined 
in that study.
Relevant Study M16-063 eligibility requirements applicable to Study M16-763 are as follows:
a.
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.
b.
Adult male or female, at least 18 years old.
c.
Laboratory values not meeting toxicity management criteria from the Study M16-063 study:
d.
Diagnosis of RA for ≥ 3 months based on the 2010 ACR/European League Against 
Rheumatism (EULAR) classification criteria for RA.
e.
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 


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subject's BP must be stable for at least 4 weeks on current, stable anti-hypertensive 
medications.
!
Prior unprovoked deep vein thrombosis 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.
f.
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.
g.
Must not have been treated with any investigational drug, other than those supplied in 
Study M16-063, 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, other than 
Study M16-063.
h.
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.
i.
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 in 
the Study M16-063 study as well as persistently negative urine pregnancy test throughout 
Study M16-063 and at entrance into this study.
j.
Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day 1 through at least 30 days after last dose of 
study drug.  Female subjects of non-childbearing potential do not need to use birth control.
k.
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 human 
immunodeficiency virus (HIV).
Active HBV, HCV, and HIV are defined as:
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.
l.
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).
m. 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.


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n.
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.
o.
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.
p.
Must not have a history of clinically significant (per Investigator's judgment) drug or alcohol 
abuse within the last 6 months.
q.
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.
r.
Must not have any conditions that could interfere with drug absorption including but not 
limited to short bowel syndrome.
s.
Must not be a recipient of an organ transplant.
t.
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.
u.
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.
v.
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.
w. 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.
x.
Subjects must have been receiving csDMARD therapy ≥ 3 months prior to Study M16-063 
baseline visit. 
The following csDMARDs are allowed:  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.
y.
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;
≥ 10 weeks for adalimumab, infliximab, certolizumab, golimumab, tocilizumab, and 
abatacept;
≥ 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.


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z.
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).
3. Subject is willing and/or able to comply with procedures required in this protocol.
Concomitant Medications
4. Subject must not be currently enrolled in any study (except the preceding Study M16-063) or 
planning to enroll in another interventional clinical study while participating in this study.
5. Subject must not require vaccination with any live vaccine during study participation, 
including at least 30 days after the last 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:
!
Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 1 month 
prior to study Baseline Day 1.
!
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study Baseline 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).


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!
To have a vasectomized partner(s) (the vasectomized partner[s] has received medical 
assessment of the surgical success and is the sole sexual partner of the trial subject).
!
To practice true abstinence (if acceptable per local guidelines), 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.
Concomitant conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (i.e., MTX, 
sulfasalazine, etc.) have been prescribed per standard of care prior to study entry and are allowed to be 
continued during the study.  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
Initiation of any new JAK inhibitors (including, but not limited to, tofacitinib [Xeljanz®], baricitinib 
[Olumiant®], and filgotinib) is not allowed.
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 except as described in Section 5.4 (Prior and Concomitant Therapy) for 
treatment of an RA flare, as defined by the investigator.
Any csDMARD/Immunosuppressive Therapy Not Listed in Section 5.4 (Prior and Concomitant Therapy)
All biologic therapies are prohibited during the study.  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)
!
Simponi® (golimumab)


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!
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
Live Vaccines
Use of live vaccines is prohibited during the study and must be avoided for four weeks after the last 
dose of study drug.  Examples of live vaccines include, but are not limited to, the following:


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!
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.
5.4 Prior and Concomitant Therapy
Subjects should continue on their previous background csDMARD therapy from Study M16-063, 
restricted to the following:  oral or parenteral methotrexate (7.5 to 25 mg/week), sulfasalazine 
(≤3000 mg/day), hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and/or 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 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 nonsteroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, oral corticosteroids (equivalent to prednisone ≤ 10 mg/day), or inhaled 
corticosteroids.
!
If taking any of the above on a scheduled basis, subjects should continue to take them as they 
did at study entry with no change in dose or frequency, including on study visit days.
!
If subject was not taking any of the above at baseline, these must not be initiated except where 
permitted by protocol (i.e., after Week 18).
!
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, subjects 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.
Calculation of the Clinical Disease Activity Index (CDAI) is required to determine if a subject fails to 
achieve LDA.  Calculation of CDAI will be performed at the Week 18 visit by Interactive Response 


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Technology (IRT) with input from site personnel on joint counts and PtGA and PhGA score.  The 
calculation used to determine CDAI score at Week 18 is as follows:
CDAI = TJC28 + SJC28 + PtGA (cm) + PhGA (cm)
Beginning at Week 18, subjects who fail to achieve CDAI ≤ 10 should have background medication(s) 
adjusted or initiated.  Initiation of or change in corticosteroids, NSAIDs, or acetaminophen, or 
adding/increasing csDMARD doses (restricted to oral or parenteral MTX, sulfasalazine, 
hydroxychloroquine, chloroquine, and leflunomide, except for the combination of MTX and 
leflunomide), is allowed as per local label and at investigator discretion.  If necessary, a burst of systemic 
corticosteroids (maximum dose of 0.5 mg/kg of prednisone or its equivalent) is allowed, after which 
subject should resume their usual daily oral corticosteroid dose.
Intra-articular, intramuscular, intravenous, trigger point or tender point, intra-bursa, and intra-tendon 
sheath injections of corticosteroids, at dosage and frequency per standard of care, are allowed after the 
Week 18 assessments have been performed and at time points thereafter.  For the analysis of the TJC 
and SJC, injected joints will be considered "not assessable" for 3 months from the time of the intra-
articular injection.
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.
Study drug interruption is allowed up to 30 consecutive days.  If the subject undergoes elective surgery, 
the study drug should be interrupted 2 weeks prior to the planned surgery.  If the subject must undergo 
emergency surgery, the study drug should be interrupted at the time of surgery.  In either case, study 
drug may be reintroduced once the physician has examined the surgical site and determined that it has 
healed and there is no sign of infection.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject receives during the study should be recorded through the follow-
up phone call 30 days after the last treatment visit (Week 60).
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with ABBV-105 or ABBV-599 can be located 
in the ABBV-105 or upadacitinib Investigator's Brochures.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:
!
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.
!
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.


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!
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 and continuation of 
the study drug would place the subject at risk.
!
Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.
!
Subject is non-compliant with tuberculosis (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 noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.
!
Subject develops a gastrointestinal perforation.
In addition, the following discontinuation criteria also apply:
!
Subjects not responding to therapy can discontinue study drug (or withdraw from study) at any 
time for any reason during the study in order to receive standard of care.
!
Subjects who demonstrate worsening of joint count (SJC and/or TJC) at 2 consecutive visits 
(scheduled or unscheduled) should be discontinued from study drug and treated with standard 
of care at the discretion of the clinician.
!
Starting at the Week 18 visit (after the Week 18 assessments have been performed) and at visits 
thereafter, subjects who fail to achieve at least 20% improvement in TJC and SJC should be 
discontinued.
!
Starting at the Week 18 visit (after the Week 18 assessments have been performed) and at visits 
thereafter, subjects who fail to achieve CDAI ≤ 10 should have background medication(s) 
adjusted or initiated (i.e., initiation of or change in corticosteroids, NSAIDs, acetaminophen or 
adding or increasing doses in csDMARDs [restricted to oral or parenteral MTX, sulfasalazine, 
hydroxychloroquine, chloroquine and leflunomide except the combination of MTX and 
leflunomide is allowed as per local label]).
!
Starting at the Week 18 visit (after Week 18 assessments have been performed) and at visits 
thereafter, intra-articular, intramuscular, intravenous, trigger point or tender point, intra-bursa,
and intra-tendon sheath injections of corticosteroids, dosage and frequency per standard of 
care are allowed.  For the analysis of the TJC and SJC, injected joints will be considered "not 
assessable" for 3 months from the time of the intra-articular injection.
!
Starting at the Week 24 visit and at visits thereafter, subjects achieving 20% improvement in TJC 
and SJC but not achieving CDAI ≤10 should be considered for discontinuation to standard of care 
at the discretion of the clinician.


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Subjects who prematurely discontinue study drug should complete a Premature Discontinuation (PD) 
Visit as soon as possible, preferably within 2 weeks of discontinuation.  See Section 5.6 for information 
regarding early discontinuation.
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.
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.  In addition, all future rescue- and efficacy-driven discontinuation criteria no 
longer apply.  This includes 20% TJC/SJC calculations at Weeks 12 through 24, Weeks 36 through 40 and 
Week 48 and thereafter, as well as CDAI calculation at Week 26, if applicable.  If at any point a subject 
no longer wants to provide assessments (withdrawal of informed consent) following discontinuation of 
study drug, a second PD visit is not required.
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 




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AbbVie will not supply drug other than ABBV-105, upadacitinib, and matching placebo for this study.  
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.
5.8 Randomization/Drug Assignment
All subjects were assigned a unique identification number by the IRT at the screening visit for 
Study M16-063.  Subjects who enter the study on active ABBV-105 and/or upadacitinib from 
Study M16-063 will continue on their previously-assigned treatment through the end of the LTE study.  
Subjects who previously received placebo treatment during Study M16-063 will receive ABBV-599 in the 
LTE study.
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 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 or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
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 in Table 3 are reported, the following supplemental report(s) must be 
completed.




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Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
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


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!
Lymphopenia
!
Increased serum creatinine and renal dysfunction
!
Hepatic events and increased hepatic transaminases
!
Elevated creatine phosphokinase
!
Embolic and thrombotic events (non-cardiac, non-CNS)
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each AE according to the Rheumatology Common Toxicity 
Criteria v.2.0.  If no grading criteria are provided for the reported event, then the event should be 
graded as follows:
!
Mild (Grade 1):  Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
!
Moderate (Grade 2):  Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental 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 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 the Operations Manual.
The toxicity management of AEs, including AESIs, consists of safety monitoring (review of AEs on an 
ongoing basis and periodic/ad hoc review of safety issues by a data monitoring committee [DMC]), 
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 have had study drug discontinued and are instead 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. 
Subjects 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 in a 
blinded manner.
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 QT interval corrected for heart rate using Fridericia's correction formula (QTcF) value 
> 500 msec.
Management of Select Laboratory Abnormalities:  For any given laboratory abnormality, the 
Investigator should assess the subject and apply the standard of care for medical evaluation and 


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treatment following any local guidelines.  Specific toxicity management guidelines for abnormal 
laboratory values are described in the operations manual 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, the repeat testing 
must occur as soon as possible.
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 database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all subjects who completed Study M16-063 and received at least 
1 dose of assigned study drug in Study M16-763.  The FAS will be used for efficacy and baseline analyses.  
Subjects will be grouped according to treatments as randomized for Study M16-063.
The Safety Analysis Set also includes all subjects who completed Study M16-063 and received at least 
one dose of assigned study drug in Study M16-763.  Subjects will be grouped according to treatments 
actually received in Study M16-763.  The Safety Analysis Set will be used for safety analyses.  
7.3 Statistical Analyses for Efficacy
Analysis of efficacy endpoints will be conducted on the FAS based on treatments as randomized for 
Study M16-063.  The analysis will be based on As Observed data, and no imputation will be conducted.  
The analysis treatment groups will be described as follows indicating from Study M16-063 to extension 
Study M16-763:
!
Group 1:  ABBV-599 to ABBV-599
!
Group 2:  ABBV-105 60 to 105 60 mg
!
Group 3:  ABBV-105 20 to 105 20 mg
!
Group 4:  ABBV-105 5 to 105 5 mg
!
Group 5:  Upadacitinib 15 to Upadacitinib 15 mg, and
!
Group 6:  Placebo to ABBV-599
!
Group 7:  All ABBV-599 (Group 1 and 6)
The baseline for all efficacy analyses in this study will be the baseline in Study M16-063.


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There is no primary efficacy endpoint and no formal statistical tests will be applied.  Only descriptive 
statistics will be used for all efficacy endpoints.  Descriptive statistics will be provided for each treatment 
group for all visits.  These include the number of observations, mean with 95% confidence interval, 
standard deviation, median, minimum and maximum for continuous endpoints (or the change from 
baseline measurements), and frequencies and percentages with 95% confidence interval for binary 
endpoints.  
No missing data imputation will be applied.  All efficacy analyses will be based on As Observed analysis, 
and thus a subject who does not have an evaluation at the primary analysis time point will not be 
included.
Details on efficacy analyses are provided in the SAP.
Sample Size Estimation
This is the LTE study for Study M16-063.  All eligible subjects who completed Study M16-063 will be 
enrolled in this study if the subject signs and dates the informed consent.  Based on discontinuation 
criteria mandating efficacy, it is estimated that 20 - 60% of subjects (i.e., between 40 and 120 subjects) 
will ultimately complete the LTE.
7.4 Statistical Analyses for Safety
All safety analyses will be performed in the Safety Analysis Set.
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 long-term safety and efficacy will be conducted after the 
Study M16-063 unblinded Week 12 database lock and analysis.  The descriptive statistics will be 
presented for key efficacy and safety endpoints with all available data at the interim analysis.  Detailed 
interim analyses are provided in the SAP.


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8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to 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 Council 
for Harmonisation of Technical Requirements for 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).
10 DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.


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11 COMPLETION OF THE STUDY
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 submit, maintain, and archive any records related to the study according to ICH 
GCP and all other applicable regulatory requirements.  If the investigator is not able to retain the 
records, he/she must notify AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the study.  
Selection criteria for this investigator will include level of participation as well as significant knowledge 
of the clinical research, investigational drug, and study protocol.  The signatory investigator for the study 
will review and sign the final study report in accordance with the European Medicines Agency Guidance 
on Investigator's Signature for Study Reports.
The end of study is defined as the date of the last subject's last contact, which will be a follow-up phone 
call 30 days after the last dose.


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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
ACR
American College of Rheumatology
AE
adverse event
ADL
activities of daily living
AESI
adverse event(s) of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCG
Bacille Calmette-Guérin
bDMARD
biologic disease-modifying antirheumatic drug
Btk
Bruton's tyrosine kinase
CAC
Cardiovascular Adjudication Committee
CDAI
Clinical Disease Activity Index
CNS
central nervous system
CR
clinical remission
CRP
C-reactive protein
csDMARD
conventional synthetic disease-modifying antirheumatic drug
CYP1A2
cytochrome P450 1A2 isoform
CYP3A
cytochrome P450 3A isoform
DAS
disease activity score
DAS28
disease activity score (28 joints)
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
EudraCT
European Clinical Trials Database
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HAQ-DI
Health Assessment Questionnaire Disability Index
HBV, HCV
hepatitis B virus, hepatitis C virus
HIV
human immunodeficiency virus
hsCRP
high-sensitivity C-reactive protein
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use


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IEC
independent ethics committee
IGRA
interferon gamma release assay
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
LTE
long-term extension
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MTX
methotrexate
NMSC
non-melanoma skin cancer
NSAID
nonsteroidal anti-inflammatory drug
PD
premature discontinuation
PhGA
Physician's Global Assessment of Disease Activity
PtGA
Patient's Global Assessment of Disease Activity
PRN
as needed (pro re nata)
QD
once a day
QTc
corrected QT
QTcF
Fridericia-corrected QT interval
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SJC
swollen joint count
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
tuberculosis
TEAE
treatment-emergent adverse event
TJC
tender joint count
ULN
upper limit of normal
VAS
visual analog scale


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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-763:  ABBV-105, Given Alone or in Combination with Upadacitinib (ABBV-599), in Adult 
Subjects with Active Rheumatoid Arthritis Who Have Completed a Preceding Phase 2 Randomized 
Controlled Trial
Protocol Date:  06 February 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (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
Data and Statistical Sciences
Data and Statistical Sciences
Clinical Pharmacology and 
Pharmacometrics
Medical Writing






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APPENDIX E. PROTOCOL AMENDMENT SUMMARY OF 
CHANGES
Previous Protocol Version
Protocol 
Date
Version 1.0
06 August 2018
Version 1.1 (Canada Only)
12 October 2018
Version 2.0
12 October 2018
Version 2.1 (VHP)
17 December 2018
Version 3.0
17 January 2019
!
Added CDAI efficacy endpoints to Section 3.2.
Rationale:  To add endpoints that use a disease activity index that is not influenced by CRP, 
who's synthesis by the liver is directly blocked by JAK inhibition.
!
Added further detail to Eligibility Criterion 2j in Section 5.1.
Rationale:  To clarify proper birth control practices that are to be followed during the study.
!
Removed "relative to baseline from Study M16-063" from discontinuation criteria around 
worsening of SJC and/or TJC, subjects failing to achieve at least 20% improvement in SJC and TJC 
starting at Week 18, and subjects who fail to achieve CDAI ≤10 starting at Week 18
(Section 5.5).
Rationale:  To clarify discontinuation criteria.
!
Added further detail to study drug discontinuation instructions in Section 5.6.
Rationale:  To ensure study drug discontinuation processes are clear.
!
Added clarification to the study drug dispensation instructions in Section 5.7.
Rationale:  To ensure that study drug is properly dispensed.
!
Added information around the Safety Analysis set to Section 7.2 and Section 7.4.
Rationale:  To clarify the Safety Analysis Set parameters.
!
Added an All ABBV-599 efficacy analysis set and clarifying language in Section 7.3.
Rationale:  To run an efficacy analysis on all subjects who received study drug.
!
Added an Interim Analysis (Section 7.5).
Rationale:  To explain the planned, unblinded interim analysis that will be conducted after the 
Study M16-063 Week 12 database lock.
!
Removed Troponin and Troponin + CK MB testing from Section 3.11 of the Operations Manual 
(Protocol Appendix F).


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Rationale:  Asymptomatic CPK elevation is a known JAK inhibitor class effect and is described in 
the Rinvoq USPI and SmPC.  Testing asymptomatic subjects with more specific tests designed 
only for those with suspicion for myocardial infarction (CK-MB and troponin is not warranted and 
may lead to unnecessary cardiac evaluations and patient anxiety).
!
Added clarification around which type of herpes zoster vaccine the instructions are referring to 
in Section 3.11 of the Operations Manual (Protocol Appendix F).
Rationale:  To ensure it's understood that this requirement only applies to those taking a live 
herpes zoster vaccine.
!
Remove reference to liver biopsies from Section 4.1 of the Operations Manual (Protocol 
Appendix F).
Rationale:  To clarify that there are no liver biopsies at Screening or any time during the Study.
In addition to these modifications, the Amendment contains the following minor changes:
Update Section 2.1 to align with current upadacitinib development program.
Update wording in Section 2.1 and Section 2.2 for clarity.
Update wording in Section 3.3 to clarify that separate DMC and CAC charters have been prepared 
outside of the protocol.
Update wording around study drug discontinuation in Section 6.2 for clarity.
Update Sponsor/Emergency Medical Contact throughout.
Update to protocol signatories (Appendix C, List of Protocol Signatories).
Added Appendix F to align with the updated AbbVie Protocol template.
Update abbreviations throughout for consistency.


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APPENDIX F. OPERATIONS MANUAL

SAP_001.pdf: 
ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
1
Statistical Analysis Plan
Study M16-763
A Phase 2, Multicenter, Double-Blind, Parallel Group 
Long Term Extension Study in Rheumatoid Arthritis 
Subjects Who Have Completed a Preceding Phase 2 
Randomized Controlled Trial with ABBV-105 Given 
Alone or in Combination with Upadacitinib 
(ABBV-599)
Date:  10 Feb 2020
Version 2.0
NCT03823378


ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
2
Table of Contents
Table of Contents ...........................................................................................2
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypotheses ........................................................................5
2.2
Study Design Overview .............................................................................5
2.3
Treatment Assignment and Blinding .........................................................6
2.4
Sample Size Determination........................................................................7
3.0
Endpoints..................................................................................7
3.1
Primary Efficacy Endpoint ........................................................................7
3.2
Secondary Efficacy Endpoints...................................................................7
3.3
Other Efficacy Endpoints...........................................................................9
3.4
Safety Endpoints ........................................................................................9
3.5
Additional Endpoint(s)...............................................................................9
4.0
Analysis Populations ...............................................................9
5.0
Subject Disposition................................................................10
6.0
Study Drug Duration and Compliance................................11
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................13
7.1
Demographics and Baseline Characteristics............................................13
7.2
Medical History .......................................................................................16
7.3
Prior and Concomitant Medications ........................................................17
8.0
Efficacy Analyses...................................................................17
8.1
General Considerations............................................................................17
8.2
Handling of Missing Data........................................................................18
8.3
Primary Efficacy Endpoint and Analyses ................................................18
8.4
Secondary Efficacy Analyses...................................................................18
8.5
Additional Efficacy Analyses ..................................................................18
8.6
Efficacy Subgroup Analyses....................................................................19
9.0
Safety Analyses ......................................................................19
9.1
General Considerations............................................................................19
9.2
Adverse Events ........................................................................................19


ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
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9.2.1
Treatment-Emergent Adverse Events ......................................................20
9.2.2
Adverse Event Overview .........................................................................20
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................21
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................22
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................22
9.2.6
Adverse Events of Special Interest ..........................................................22
9.2.7
Adverse Events by Maximum Severity ...................................................22
9.2.8
Adverse Events by Maximum Relationship ............................................23
9.2.9
Adverse Events by "Reasonably Possibly Related" Relationship ...........23
9.2.10
Frequent (> 5%) Adverse Events and Reasonably Possibly 
Related Adverse Events by Preferred Term in Decreasing 
Frequency.................................................................................................23
9.2.11
Listing of Adverse Events........................................................................23
9.3
Analysis of Laboratory Data....................................................................24
9.4
Analysis of Vital Signs ............................................................................26
9.5
Safety Subgroup Analyses .......................................................................26
9.6
Other Safety Analyses..............................................................................26
10.0
Other Analyses.......................................................................27
11.0
Interim Analysis.....................................................................27
12.0
Overall Type-I Error Control ..............................................27
13.0
Version History......................................................................28
14.0
References...............................................................................28
List of Tables
Table 1.
SAP Version History Summary...............................................................28
Table C-1.
OMERACT Criteria.................................................................................32
Table C-2.
Criteria for Potentially Clinically Significant Vital Sign Values.............48
List of Figures
Figure 1.
Study Schematic.........................................................................................6


ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
4
List of Appendices
Appendix A.
Protocol Deviations..................................................................................29
Appendix B.
Definition of Adverse Events of Special Interest ....................................30
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............31


ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for ABBV-599 
Study M16-763.
Study M16-763 evaluates the long-term safety, tolerability, and efficacy of ABBV-105 
and ABBV-599 in RA subjects who have completed Study M16-063.
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 primary objective of this study is to evaluate the long-term safety, tolerability, and 
efficacy of ABBV-105 and ABBV-599 in RA subjects who have completed 
Study M16-063.  
Clinical Hypothesis
The safety and efficacy of ABBV-105 and ABBV-599 will be maintained over an 
extended period of treatment.
2.2
Study Design Overview
This is a Phase 2, double-blind, multicenter, long-term extension (LTE) study to assess 
the safety, tolerability, and efficacy of ABBV-105 and ABBV-599 in RA subjects who 
have completed Study M16-063.
The schematic of the study is shown in Figure 1.  


ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
6
Figure 1.
Study Schematic
QD = once daily
2.3
Treatment Assignment and Blinding
Subjects who meet eligibility criteria as specified in Section 5.1 of the protocol and enter 
the study on ABBV-105, ABBV-599, or upadacitinib from Study M16-063 will continue 
on their previously-assigned treatment through the end of the LTE study.  Subjects who 
meet eligibility criteria and enter the study on placebo for both ABBV-105 and 
upadacitinib from Study M16-063 will receive ABBV-599.  Study drug treatment 
assignments include the following:
●
Group 1: ABBV-599 (ABBV-105 60 mg and upadacitinib 15 mg) 
administered once a day (QD),
●
Group 2:  ABBV-105 60 mg and upadacitinib placebo QD,


ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
7
●
Group 3:  ABBV-105 20 mg and upadacitinib placebo QD
●
Group 4:  ABBV-105 5 mg and upadacitinib placebo QD, and
●
Group 5:  Upadacitinib 15 mg and ABBV-105 placebo QD.
This study plans to enroll subjects who completed Study M16-063 at approximately 
39 sites in Canada and the European Union.  The number, allocation, and location of sites 
may vary depending on operational aspects of the study.  Study sites and subjects will 
remain blinded for the duration of the study.
The duration of the LTE study will be approximately 52 weeks.  This includes a 48-week 
double-blind treatment period with study visits conducted at Weeks 18, 24, 30, 36, 48, 
and 60 from the baseline visit of Study M16-063.  In addition, subjects will also have a 
telephone follow-up call 30 days after their last visit to determine the status of any 
ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.
2.4
Sample Size Determination
This is the LTE study for Study M16-063.  All eligible subjects who completed 
Study M16-063 will be enrolled in this study if the subject signs and dates the informed 
consent.  Based on discontinuation criteria mandating efficacy, it is estimated that 
20 - 60% of subjects (i.e., between 40 and 120 subjects) will ultimately complete the LTE.
3.0
Endpoints
3.1
Primary Efficacy Endpoint
There is no primary efficacy endpoint since this is the extension to the feeder 
Study M16-063.
3.2
Secondary Efficacy Endpoints
1.
Change in disease activity score (DAS)28 (C-reactive protein [CRP]) from baseline 
of Study M16-063;
2.
DAS Low Disease Activity (LDA), defined as DAS28 CRP ≤ 3.2;


ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
8
3.
DAS Clinical Remission (CR), defined as DAS28 CRP < 2.6;
4.
Change in clinical disease activity index (CDAI) from baseline of Study M16-063;
5.
LDA based on CDAI criteria, defined as CDAI ≤ 10;
6.
CR based on CDAI criteria, defined as CR ≤ 2.8;
7.
American College of Rheumatology (ACR) 20/50/70 response.  A subject will be 
considered an ACR 20/50/70 responder if:
○
The swollen joint count (SJC) and tender joint count (TJC) have decreased 
from baseline of Study M16-063 by 20/50/70% or more.
○
At least 3 of the 5 remaining ACR core set measures show reduction of 
20/50/70% or more from baseline of Study M16-063.
●
Patient's Assessment of Pain [using visual analog scale, VAS],
●
Patient Global Assessment of Disease Activity [PtGA], 
●
Physician Global Assessment of Disease Activity [PhGA], 
●
Health Assessment Questionnaire Disability Index [HAQ-DI]
●
High-sensitivity C-reactive protein [hsCRP]) 
8.
Change in individual components of ACR from baseline of Study M16-063, to 
include:
○
SJC,
○
TJC,
○
Patient's Assessment of Pain (using VAS),
○
PtGA,
○
PhGA,
○
HAQ-DI, and
○
hsCRP.
9.
Change in Morning Stiffness Severity (11 point scale) from baseline of 
Study M16-063.


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10.
Change in Morning Stiffness Duration (Hours and Minutes) from baseline of 
Study M16-063
3.3
Other Efficacy Endpoints
The secondary efficacy endpoints are listed in 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, electrocardiogram (ECG), and clinical laboratory testing 
(hematology, chemistry, and urinalysis) as a measure of safety and tolerability for the 
entire study duration.  
An internal independent data monitoring committee (IDMC) will review unblinded safety 
data on a cohort level throughout the course of the study.  A separate IDMC charter will 
be prepared outside of the protocol and will describe the roles and responsibilities of the 
IDMC members, frequency of data reviews, relevant safety data to be assessed, and 
expectations for blinded communications.
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
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.


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The Full Analysis Set (FAS) includes all subjects who enrolled in Study M16-763 and 
received at least 1 dose of assigned study drug.  The FAS will be used for efficacy and 
baseline analyses.  Subjects will be grouped according to treatments as randomized for 
Study M16-063.
The Safety Analysis Set consists of all subjects who enrolled in Study M16-763 and 
received at least 1 dose of assigned study drug.  Subjects will be grouped according to 
treatments actually received in Study M16-763. The Safety Analysis Set will be used for 
safety analyses.  
5.0
Subject Disposition
The number of subjects will be tabulated by country, investigator site and overall for all 
enrolled subjects.
The total number of subjects who were enrolled 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 enrolled in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
●
Subjects in each analysis population.
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").


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●
Adverse events,
●
Lost to follow-up,
●
Withdrew consent by subject,
●
Lack of efficacy,
●
Other.
6.0
Study Drug Duration and Compliance
A summary of study drug duration (days) will be provided by each treatment arm for the 
Safety Analysis Set.
The duration of exposure to study drug will be summarized by groups as specified below.
●
Group 1:  ABBV-599 Always 
●
Group 2:  ABBV-105 60 mg
●
Group 3:  ABBV-105 20 mg
●
Group 4:  ABBV-105 5 mg
●
Group 5:  Upadacitinib
●
Group 6:  ABBV-599 After Placebo
●
Group 7:  Placebo (Not present in Study M16-763)
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 Study M16-063/763 combined and for Study M16-763 
treatment period only respectively.  For Study M16-063/763 combined, the following 
duration intervals will be used:
●
≥ 1 day
●
≥ 15 days
●
≥ 29 days


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●
≥ 57 days
●
≥ 85 days
●
≥ 127 days
●
≥ 169 days
●
≥ 211 days
●
≥ 252 days
●
≥ 336 days
●
≥ 420 days
The exposure to study drug in days for Study M16-063/763 combined period is calculated 
as:
Exposure = (date of last study medication in Study M16-763 – date of first study 
medication in Study M16-063 + 1)
For Study M16-763 only, the following duration intervals will be used:
●
≥ 1 day
●
≥ 42 days
●
≥ 85 days
●
≥ 127 days
●
≥ 168 days
●
≥ 252 days
●
≥ 336 days
The exposure to study drug in days for Study M16-763 period only is calculated as:
Exposure = (date of last study medication in Study M16-763 – date of first study 
medication in Study M16-763 + 1)


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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).
7.1
Demographics and Baseline Characteristics
The following demographic and baseline characteristics, as measured at baseline of the 
Study M16-063 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, 
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●
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)
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 
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●
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]
●
DAS28 [CRP]
●
CDAI
●
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
●
CDAI categories:


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a.
CDAI > 22 (High Disease Activity)
b. CDAI ≤ 22
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
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 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.


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7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by each 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 taken on the day of the 
first dose of study drug are counted as concomitant medications.
The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
8.0
Efficacy Analyses
8.1
General Considerations
Analysis of efficacy endpoints will be conducted on the FAS.  
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.
The analysis treatment groups will be described as follows indicating from 
Study M16-063 to extension Study M16-763:
●
Group 1:  ABBV-599 to ABBV-599


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●
Group 2:  ABBV-105 60 to ABBV-105 60 mg
●
Group 3:  ABBV-105 20 to ABBV-105 20 mg
●
Group 4:  ABBV-105 5 to ABBV-105 5 mg, and
●
Group 5:  Upadacitinib to Upadacitinib
●
Group 6:  Placebo to ABBV-599
●
Group 7:  All ABBV-599 (Group 1 and 6)
"Baseline" refers to the last non-missing observation before the first administration of 
study drug in Study M16-063 or randomization in Study M16-063 if no study drug is 
given.
8.2
Handling of Missing Data
The analysis will be based on As Observed data, and no imputation will be conducted.  
8.3
Primary Efficacy Endpoint and Analyses
There are no primary efficacy endpoints or analyses for this study.
8.4
Secondary Efficacy Analyses
Descriptive statistics will be provided for each treatment group for all visits.  These 
include the number of observations, mean with 95% confidence interval, standard 
deviation, median, minimum and maximum for continuous endpoints; and frequencies 
and percentages with 95% confidence interval using Wilson score1 for binary endpoints.  
No missing data imputation will be applied.  All efficacy analyses will be based on As 
Observed (AO) analysis, and thus a subject who does not have an evaluation at the 
primary analysis time point will not be included.
8.5
Additional Efficacy Analyses
No additional efficacy analyses are planned.


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8.6
Efficacy Subgroup Analyses
No subgroup analyses will be performed.
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.
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.
TEAEs will be summarized using subject data from Study M16-763 and a combination of 
data from Studies M16-063 and M16-763 that includes any subject receiving a dose in 
Study M16-763, respectively.  Only the datasets from Studies M16-063 and M16-763 that 
includes any subject receiving a dose in Study M16-763 will be used for per 100 patient 
years of exposure analyses (for the Study M16-763 study).


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9.2.1
Treatment-Emergent Adverse Events
To summarize data from Study M16-763 only, 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 from Study M16-763, and no more than 30 days after the last dose of study 
drug from Study M16-763.
To summarize a combination of data from Studies M16-063 and M16-763, 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 from Study M16-063, and no more than 30 days 
after the last dose of study drug from Study M16-763.
Events where the onset date is the same as Study M16-063 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
The number and percentage of subjects experiencing TEAEs will be summarized by 
treatment group as specified in Section 6.0 and overall.
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


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●
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.
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 


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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 occurring during Study M16-063 and Study M16-763 will be summarized by 
event rate per 100 subject years, defined as
100 * (Number of TEAEs)/(Total Patient Years)
where total patient 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 


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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 
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


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●
Listing of Subjects with Pretreatment SAEs
●
Listing of Subjects with Treatment-Emergent SAEs
●
Listing of Treatment-Emergent 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.  
Baseline is defined as the last available measurement before Study M16-063 study drug 
administration. The 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, at each visit in Study M16-063 and Study M16-763 for each treatment group.  An 
ANOVA model with only treatment as a factor, not controlling for baseline, will be used 
to test statistical significance for the mean change from baseline among different arms.
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.


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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.
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


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●
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.
Mean changes from Baseline to post-baseline visits will be summarized with the baseline 
mean, the visit mean, change from baseline mean, standard deviation, and median.  An 
ANOVA model with only treatment as a factor, not controlling for baseline, will be used 
to test statistical significance for the mean change from baseline.  
The number and percentage of subjects meeting the criteria for potentially clinically 
significant vital sign values will be summarized.
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 Weeks 18, 24, 30, 36, 48, and 60.  ECG findings will be summarized 
by treatment group for each parameter and visit.


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10.0
Other Analyses
No other analyses are planned.
11.0
Interim Analysis
An interim analysis to review long-term safety and efficacy will be conducted after 
Study M16-063 Week 12 database lock and analysis. The descriptive statistics will be 
presented for key efficacy and safety endpoints with all available data at the interim 
analysis. Key efficacy endpoints include DAS28(CRP), CDAI, ACR20/50/70, Patient's 
Assessment of Pain [using visual analog scale, VAS], and HAQ-DI. Key safety endpoints 
include overview of TEAE, TEAEs reasonably possibly related to study drug, SAEs, 
TEAE leading to death, AESIs, mean change from baseline for hematology and 
chemistry, PCS for hematology and chemistry and liver-related elevations.  
Unblinded interim analyses for safety will be conducted by a DMC to review safety.  The 
sponsor, study sites and subjects will remain blinded for the duration of the study until the 
database lock of Study M16-063.
An internal data monitoring committee (DMC) 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 has been prepared outside of 
the protocol and describes the roles and responsibilities of the DMC members, frequency 
of data reviews, relevant safety data to be assessed, and expectations for blinded 
communications.
12.0
Overall Type-I Error Control
No hypothesis tests will be conducted for the efficacy analysis. 


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13.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
30 Jan 2019
Original version
2.0
07 Feb 2020
The changes made between the second and the first version are:
! Change of formatting to adhere to a new SAP template
! Small editorial changes for readability and to maintain consistency
with the protocol
! An update to include interim analysis.
! Updated the criteria for Liver-Related Elevations to align with 
Immunology RA project conventions
14.0
References
1.
Julious SA.  Two-sided confidence intervals for the single proportion:  comparison 
of seven methods by Robert G. Newcombe. Stat Med.  2005;24(21):3383-4.


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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.


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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
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
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


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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 Antirheumatic Therapies
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


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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 Antirheumatic Therapies
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
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


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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 Antirheumatic Therapies
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


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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 Antirheumatic Therapies
C7.  Weight gain
5% – 9.9%
10% – 19.9%
20% – 30%
NA
C8.  Weight loss
5% – 9.9%
10% – 19.9%
20% – 30%
NA
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


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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 Antirheumatic Therapies
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
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


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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 Antirheumatic Therapies
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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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
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


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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 Antirheumatic Therapies
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)


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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 Antirheumatic Therapies
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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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
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


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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 Antirheumatic Therapies
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
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


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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 Antirheumatic Therapies
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
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


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Version 2.0 – 10 February 2020
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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 Antirheumatic Therapies
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


ABBV-105
M16-763 – Statistical Analysis Plan
Version 2.0 – 10 February 2020
46
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
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
1.4* – 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 – 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.


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*** In L3, L7 and L8, mg/dl is changed to mmol/l.
****
For CPK and Creatinine NCI CTC grading will be used.  For CPK therefore the following gradings apply:  Grade 1:  > ULN – 2.5 × ULN; Grade 2:  > 2.5 – 5.0 × ULN;
Grade 3:  > 5.0 – 10.0 × ULN; Grade 4:  > 10.0 × ULN; For Creatinine the following gradings apply:  Grade 1:  > 1 – 1.5 × Baseline; > ULN – 1.5 × ULN; 
Grade 2:  > 1.5 – 3.0 × Baseline; > 1.5 – 3.0 × ULN; Grade 3:  > 3.0 baseline; > 3.0 – 6.0 × ULN; Grade 4:  > 6.0 × ULN


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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