Clinical trial NCT03823391
Conditions: Rheumatoid Arthritis (RA)
Keywords: Rheumatoid Arthritis (RA) ABBV-3373 Adalimumab
Sponsor: AbbVie
Start date: 2019-03-27; Completion date: 2020-08-26
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the safety, tolerability, and efficacy of ABBV-3373 in participants with moderately to severely active rheumatoid arthritis (RA) on background methotrexate (MTX) compared with adalimumab.

Detailed description:
This study consists of a 12-week double-blind active-controlled phase and a 12 week double-blind extension period.

In the active-controlled period of the first 12 weeks of treatment, participants are randomized to receive either ABBV-3373 100 mg intravenously (IV) every other week (EOW) or adalimumab 80 mg subcutaneously (SC) EOW according to a 2:1 ratio.

At Week 12, the administration of ABBV-3373 was to stop to assess the durability of the observed clinical effects up to 24 weeks. Participants randomized to ABBV-3373 were to receive placebo injections, whereas participants randomized into the adalimumab arm were to continue their 80 mg dosing.

Arms: arm 1: Participants will be administered with 100 mg ABBV-3373 by intravenous infusion and placebo to adalimumab by subcutaneous injection every other week for 12 weeks. After 12 weeks, participants will receive placebo to adalimumab every other week until Week 22. arm 2: Participants will be administered with placebo to ABBV-3373 by intravenous infusion and 80 mg adalimumab by subcutaneous injection every other week for 12 weeks. After 12 weeks, participants will receive 80 mg adalimumab subcutaneously every other week until Week 22.
Interventions: intervention 1: ABBV-3373 intervention 2: Placebo for ABBV-3373 intervention 3: Adalimumab intervention 4: Placebo for adalimumab
Intervention descriptions: intervention 1: ABBV-3373 is administered as intravenous (IV) infusion intervention 2: Placebo for ABBV-3373 is administered as IV infusion intervention 3: Adalimumab is administered as subcutaneous (SC) injection intervention 4: Placebo for adalimumab is administered as subcutaneous (SC) injection

Protocol documents:
Prot_000.pdf: 
NCT03823391


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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
9
3.1
OBJECTIVES
9
3.2
PRIMARY ENDPOINT
10
3.3
SECONDARY AND ADDITIONAL ENDPOINTS
10
3.4
SAFETY ENDPOINTS
10
3.5
PHARMACOKINETIC AND IMMUNOGENICITY ENDPOINTS
11
3.6
BIOMARKER ENDPOINTS
11
4
INVESTIGATIONAL PLAN
11
4.1
OVERALL STUDY DESIGN AND PLAN
11
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
18
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
19
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
20
5.7
STUDY DRUG
21
5.8
RANDOMIZATION/DRUG ASSIGNMENT
22
5.9
PROTOCOL DEVIATIONS
23
6
SAFETY CONSIDERATIONS
23
6.1
COMPLAINTS AND ADVERSE EVENTS
23
6.2
TOXICITY MANAGEMENT
27


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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
30
7.1
STATISTICAL AND ANALYTICAL PLANS
30
7.2
DEFINITION FOR ANALYSIS POPULATIONS
30
7.3
STATISTICAL ANALYSES FOR EFFICACY
31
7.4
STATISTICAL ANALYSES FOR SAFETY
33
7.5
STATISTICAL ANALYSIS OF PHARMACOKINETIC AND IMMUNOGENITICY DATA
33
7.6
STATISTICAL ANALYSIS OF BIOMARKER DATA
33
7.7
INTERIM ANALYSIS
33
8
ETHICS
34
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
34
8.2
ETHICAL CONDUCT OF THE STUDY
34
8.3
SUBJECT CONFIDENTIALITY
34
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
34
10 DATA QUALITY ASSURANCE
34
11 COMPLETION OF THE STUDY
35
12 REFERENCES
35
LIST OF TABLES
TABLE 1.
IDENTITY OF INVESTIGATIONAL PRODUCT
22
TABLE 2.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
28
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
12
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
36
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
39


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APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
40
APPENDIX D.
ADDITIONAL ENDPOINT/ASSESSMENT DEFINITIONS
41
APPENDIX E.
JOINT EVALUATION WORKSHEET EXAMPLE
43
APPENDIX F.
REPORTED OUTCOMES VAS
44
APPENDIX G.
HEALTH ASSESSMENT QUESTIONNAIRE DISABILITY INDEX
45
APPENDIX H.
36-ITEM SHORT FORM HEALTH SURVEY SAMPLE
46
APPENDIX I.
RHEUMATOLOGY COMMON TOXICITY CRITERIA V.2.0
47
APPENDIX J.
ACTIVITY SCHEDULE
61
APPENDIX K.
SUMMARY OF CHANGES
65
APPENDIX L.
OPERATIONS MANUAL
68








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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Tumor necrosis factor (TNF)α antagonists reduce the signs and symptoms of disease by reducing 
inflammation and limiting the progression of tissue destruction and are considered effective therapies 
with established safety profiles in patients with immune-mediated inflammatory diseases, including 
rheumatoid arthritis (RA).  Nevertheless, TNFα antagonists as well as other biologics and targeted 
synthetic disease-modifying antirheumatic drugs (DMARDs) provide 50% improvement in arthritis scores 
(American College of Rheumatology 50% improvement criteria [ACR50]) for fewer than half of RA 
subjects, even in combination with methotrexate (MTX), indicating that there remains an unmet clinical 
need for improved therapies.
Glucocorticoid receptor modulators (GRMs) are potent drugs for treating many inflammatory diseases.  
In RA, GRMs such as prednisone are highly effective at reducing inflammation and fatigue as well as 
relieving pain.  However, the administration of GRMs is limited due to their side effect profile including 
(but not limited to) hypothalamic-pituitary-adrenal (HPA) axis suppression, increased rates of bone 
fracture due to osteoporosis, hyperglycemia, glaucoma, skin thinning and weight gain.1  Thus, the full 
efficacy of GRM therapy is not achieved with existing agents due to systemic side effects.
ABBV-3373 is an antibody-drug conjugate (ADC) composed of adalimumab (the active component of 
Humira®) conjugated to A-1677770, a proprietary, highly potent GRM (also referred to as the payload) 
being developed for the treatment of immune-mediated inflammatory diseases including RA.  This 
adalimumab/GRM ADC has the potential to deliver a highly potent anti-inflammatory payload selectively 
to the activated immune cells that express transmembrane TNF, and meanwhile to minimize systemic 
exposure to the free payload GRM.  Therefore, the adalimumab/GRM ADC is promising as a novel 
therapeutic agent which can achieve transformational efficacy relative to adalimumab while reducing 
side effects caused by free GRM systemic exposure.
Clinical Hypothesis
ABBV-3373 is safe and well-tolerated and provides superior efficacy in subjects with moderately to 
severely active RA on background MTX compared to adalimumab.
2.2 Benefits and Risks to Subjects
The clinical efficacy of TNF inhibitors and GRMs in the treatment of RA is well established.  Based on the 
preclinical data discussed in the ABBV-3373 Investigator's Brochure,2 ABBV-3373 is expected to 
demonstrate therapeutic benefit in treatment of RA and other immune-mediated inflammatory diseases 
with a favorable safety profile.  Preclinical toxicology of ABBV-3373 suggests that the potential risks to 
human subjects receiving ABBV-3373 treatment are consistent with known effects of adalimumab and 
glucocorticoids (GCs).  ABBV-3373 was tested in a Phase 1 single ascending dose (SAD) study in healthy 
volunteers in which 6 cohorts of subcutaneous (SC) (30, 100, 300 mg) and intravenous (IV) (30, 300, 
900 mg) successfully completed dosing.


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Medical review of the available safety data from the Phase 1 study did not identify any unexpected risk 
or trend to the healthy volunteer population.  All single doses tested to date have been well tolerated.  
For further details, please see the ABBV-3373 Investigator's Brochure.2
In clinical settings, TNF antagonists and GCs have been associated with an increased risk of serious 
infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic 
pathogens.  Opportunistic infections have included tuberculosis (TB) and histoplasmosis.  Patients will 
be closely monitored during the clinical study for any signs of infection.
Tumor necrosis factor antagonists have also been associated with an increased risk for malignancy 
(including lymphoma), hepatitis B virus (HBV) reactivation, worsening or new onset heart failure, and 
rarely central nervous system demyelinating disease, pancytopenia including aplastic anemia, and lupus-
like syndrome.
The risk of hypersensitivity reaction or other post-dose systemic reaction for humans who receive 
multiple doses of ABBV-3373 is considered a potential risk.  During Study M16-560, 1 case of 
anaphylactic shock was observed following repeated eow IV (over 3 minute bolus injection) 
administration of ABBV-3373.  The event was assessed by the investigator and AbbVie to be reasonably 
related to study drug.  The administration of biologics may lead to such reactions; therefore, patients 
will be closely monitored during and post drug administrations.
Hypertension is one of the most commonly reported events for GCs in patients, especially with high 
doses of GCs.  Therefore, blood pressure and other vital signs will be monitored during the trial.
Based on the above considerations, the risk to RA patients receiving multiple doses of ABBV-3373 is 
considered manageable and acceptable.  In addition, based on the population and disease being studied 
and the anticipation that COVID-19 related risks are not expected to differ substantially between study 
subjects and the broader population of subjects receiving treatment for RA, no change to the 
benefit/risk balance for subjects in this study is expected.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Primary
1.
To assess the safety, tolerability, and efficacy of ABBV-3373 administered every other week 
(eow) intravenously (IV) in subjects with moderately to severely active RA on background MTX.
2.
To compare clinical efficacy of ABBV-3373 with adalimumab and to test the concept that an 
anti-TNF antibody-drug-conjugate has the potential to provide superior efficacy than the 
traditional anti-TNF antibody in RA.
Secondary
3.
To compare adalimumab with synthetic placebo control to establish assay sensitivity.
4.
To assess the pharmacokinetics (PK), pharmacodynamics, and immunogenicity of ABBV-3373.
5.
To assess the duration of the treatment effect of ABBV-3373 after discontinuation.


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3.2 Primary Endpoint
The primary endpoint is the change in disease activity score (DAS)28 (C-reactive protein [CRP]) from 
Baseline (BL) at Week 12.
3.3 Secondary and Additional Endpoints
Secondary Endpoints
1.
Change in clinical disease activity index (CDAI) from BL at Week 12 
2.
Change in simplified disease activity index (SDAI) from BL at Week 12 
3.
Change in disease activity score (28 joints) (DAS28) erythrocyte sedimentation rate (ESR) from 
BL at Week 12 
4.
Achievement of low disease activity (LDA) (DAS28 [CRP] ≤3.2) at Week 12 
5.
Achievement of American College of Rheumatology (ACR) 50 at Week 12 
Additional Endpoints
1.
Change from BL in DAS28 (CRP) and DAS28 (ESR) at all visits
2.
Change from BL in CDAI at all visits
3.
Change from BL in SDAI at all visits
4.
ACR20/50/70 response rates at all visits
5.
Change from BL in individual components of ACR response at all visits
6.
Achievement of LDA at all visits.  Low disease activity is defined as DAS28 (CRP) ≤3.2, 
DAS28(ESR) ≤ 3.2, CDAI ≤ 10, SDAI ≤ 11
7.
Achievement of clinical remission at all visits.  Clinical remission is defined as DAS28 (CRP) < 2.6, 
DAS28(ESR) < 2.6, CDAI ≤ 2.8, SDAI ≤ 3.3
8.
Change in Short Form-36 (SF-36) from BL at Week 12
9.
Achievement of minimal clinically important difference (MCID) in change from BL in Health 
Assessment Questionnaire Disability Index (HAQ-DI) (defined as change from BL in Health 
Assessment Questionnaire ≤ –0.22) at all visits among subjects who have HAQ ≥ 0.22 at BL
10. Achievement of response (such as LDA) based on DAS28 (CRP), CDAI, or SDAI over time from 
Week 12 to Week 24 among subjects who have achieved DAS28 (CRP), CDAI, or SDAI response 
at Week 12
Additional endpoint definitions are provided in Appendix D.
3.4 Safety Endpoints
The following safety evaluations will be performed during the study:


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1.
Treatment-emergent adverse events, serious adverse events (SAEs), adverse events (AEs) 
leading to discontinuation, AEs of special interest
2.
Percent of subjects meeting potentially clinically significant criteria for vital signs, laboratory 
variables, physical examination findings and electrocardiogram (ECG) interval variables
3.5 Pharmacokinetic and Immunogenicity Endpoints
Serum or plasma concentrations of the conjugated ADC (ABBV-3373), total antibody, free payload 
A-1677770, and adalimumab (in the comparator arm) will be determined during the treatment period 
and drug washout period.  If sufficient data are available from the optional intensive PK sampling group, 
terminal elimination half-life may be calculated and reported.
Anti-drug antibody (ADA) to either ABBV-3373 or adalimumab will be evaluated and if confirmed 
positive, titers will be measured.  If required, samples will be analyzed for neutralizing antibodies (nAb).
3.6 Biomarker Endpoints
Biospecimens (e.g., blood, serum, and plasma) will be collected at specified time points (Appendix J) 
throughout the study to evaluate known and/or novel disease-related or drug-related biomarkers.
The analyses of biomarker samples will include but are not limited to proteins and genetic markers that 
will help to understand the subject's disease and response to study treatments.  Changes in cortisol level 
under ABBV-3373 treatment and adalimumab will be assessed.  Genes of interest will include those 
associated with PK, genes within the target pathway, or other genes believed to be related to RA and 
other inflammatory diseases.  Samples for ribonucleic acid (RNA) and proteomics will be used to 
research if any genetic variants result in changes to gene expression or protein concentrations.  
Biomarker samples will be collected and analyzed from all subjects, unless precluded by local regulations 
or restrictions.  For any samples collected in Germany, the research will be restricted to study drug and 
RA.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a randomized, double-blind, double-dummy, adalimumab active-controlled (12-week) Phase 2a
study to assess the safety, tolerability, PK, pharmacodynamics, immunogenicity and efficacy following 
multiple IV administrations of ABBV-3373 or multiple SC injections of adalimumab in subjects with RA on 
background MTX.  In the actively controlled period of the first 12 weeks of treatment, 45 subjects will 
receive either ABBV-3373 100 mg IV and the matching placebo for adalimumab SC eow or in the control 
arm the matching placebo for ABBV-3373 IV and adalimumab 80 mg SC eow (double-dummy) according 
to a 2:1 ratio.  Thereafter all subjects enter a 12-week double-blind extension period.  At Week 12, the 
administration of ABBV-3373 will stop (i.e., the last dose of ABBV-3373 will be given at Week 10) to 
assess the durability of the observed clinical effects up to 24 weeks.  To keep blinding of the study 
beyond Week 12, the subjects randomized to ABBV-3373 will receive placebo injections, whereas 


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subjects randomized into the adalimumab arm will continue their 80 mg dosing until Week 22.  At 
Week 12 and within the blinded extension period subjects who have not achieved at least a 20% 
improvement in both their swollen joint count (SJC) and tender joint count (TJC) based on 28 joint 
assessment compared with BL may be discontinued from the study at the discretion of the Investigator.  
Subsequently, standard of care may be administered at the discretion of the investigator.
After all endpoints are assessed at Week 24, a telephone contact is planned to follow up on safety 
70 days after the last dose.
After all ongoing subjects complete the Week 12 study visit, the primary analysis for the ABBV-3373 
cohort will be conducted to assess the primary/secondary endpoints and safety of this actively 
controlled period.  A final analysis will be conducted after all subjects have completed Week 24 plus 
their safety follow-up.  To maintain integrity of the trial, the study sites and subjects will remain blinded 
until the final analysis is completed.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in Appendix K.
Figure 1.
Study Schematic
∆DAS28(CRP) = change in disease activity score (DAS)28(C-reactive protein [CRP]); EOW = every other week; IV = intravenous; 
SC = subcutaneous


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See Section 5.1 for information regarding eligibility criteria.  See Section 5.8 for stratification factors for 
each cohort.
Pharmacokinetic Sampling
For ABBV-3373, blood samples for PK assessments will be collected according to the assessment 
schedule in Appendix J.  Data from the first 12 subjects treated for at least 4 doses will be used in the PK 
interim analyses.
In addition, optional PK samples will be collected from subjects who consent to participate in the more 
intensive sampling group to provide data for PK characterization following repeated administrations.  
For these subjects, in addition to the standard sampling schedule, blood samples at the following time 
points will also be collected:  Day 72, Day 73, Week 11, and Week 14.
4.2 Discussion of Study Design
Choice of Control Group
ABBV-3373 is an ADC, composed of adalimumab (the active component of Humira®) conjugated to
A-1677770, a proprietary, highly potent GRM.  In order to assess how the conjugation of adalimumab 
with the GRM impacts safety, tolerability and in particular whether it will provide additional efficacy 
versus (vs.) adalimumab, a direct comparison between the ADC and adalimumab is needed.  The chosen 
study design with adalimumab as the positive control group allows such direct comparison.  In addition, 
to compare clinical efficacy of the ADC with placebo control, and to address assay sensitivity, a synthetic 
placebo arm will be created with the propensity score matching approach using historical placebo 
subjects from similar trials with subject-level data.
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
The specific population chosen was based on the unmet medical need of subjects as defined in 
Section 5.1.
Selection of Doses in the Study
Based on the clinical hypothesis, the ADC ABBV-3373 targets the activated immune cells that express 
transmembrane TNF to deliver the highly potent GRM selectively, therefore it has the potential to 
provide superior efficacy compared to a traditional anti-TNF antibody such as adalimumab.  The dose of 
100 mg IV eow for ABBV-3373 is selected to provide a similar systemic exposure to 80 mg adalimumab 
SC eow, which is a dose previously tested in RA subjects and twice as high as the recommended clinical 
regimen of 40 mg adalimumab SC eow.  The rationale for selecting this higher dose is to increase tissue 
penetration of ABBV-3373 to successfully engage its intended target of transmembrane TNF on 
activated immune cells.  Furthermore, the doses selected for ABBV-3373 and adalimumab are expected 
to generate similar systemic exposure to ensure a fair comparison between the two.  Finally, 100 mg IV 


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ABBV-3373 is well within the range of doses that have been safely tested and well tolerated in the 
first-in-human SAD study.  Historical data with adalimumab 80 mg eow or even higher in Phase 1 and 2 
studies with adalimumab in the presence of MTX3,4 or 40 mg weekly as monotherapy in Phase 2 and 3 
studies5,6 have not shown any safety concerns.
Study Duration
For the patient population selected and the type of study drug tested, a 12-week primary endpoint to 
analyze the improvement of signs and symptoms and to assess the safety and tolerability of ABBV-3373 
is appropriate.  Preclinical data from a mouse collagen induced arthritis model2 have shown a long 
lasting effect of the ADC in comparison to adequate control groups.  Therefore, to assess the durability 
of the achieved clinical response at Week 12 in ABBV-3373-treated RA subjects, the subjects will be 
followed closely up to Week 24. While the maintenance of responses of ABBV-3373 will be monitored 
(under continuous placebo injections), subjects in the comparator arm will continue their adalimumab 
dosing to keep the blinding of the study.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects or their legally authorized representative must voluntarily sign and date an informed 
consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), 
prior to the initiation of any screening or study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, between 18 and 75 years of age inclusive at Screening.
3. Body mass index (BMI) is ≥ 18.0 to ≤ 39.9 kg/m2 after rounding to the nearest tenth.  Body 
mass index is calculated as weight in kg divided by the square of height measured in meters.
4. Laboratory values meeting the following criteria within the screening period prior to the first 
dose of study drug:
!
Serum values of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
< 2.5 × upper limit of normal (ULN);
!
Absolute neutrophil count (ANC) > 1,500/μL;
!
Creatinine < 1.5 × ULN.


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5. Subject must have a negative test result for hepatitis A virus immunoglobulin M (HAV-IgM), 
hepatitis B surface antigen (HBsAg), HBc Ab (subjects who have been vaccinated against 
hepatitis B [HB] and are HBs Ab positive may be enrolled), hepatitis C virus (HCV) antibody (if 
Hepatitis C RNA level is undetectable at Screening, the subject can participate in this trial), and 
human immunodeficiency virus (HIV) Ab at Screening.
6. Subject is willing and able to comply with procedures required in this protocol.
Diagnosis and Disease Activity
7. Subject has the clinical diagnosis of RA for > 3 months based on the 1987 ACR classification 
criteria or 2010 ACR/European League against Rheumatism (EULAR) criteria.
8. Subject meets the following disease activity criteria:  ≥ 4 swollen joints (based on 28 joint 
count) and ≥ 4 tender joints (based on 28 joint count) at Screening and BL Visits; and 
DAS28(CRP) ≥ 3.2 at Screening.
9. Incomplete response to MTX.  Subjects must have been on oral or parenteral MTX therapy 
≥3 months and on a stable prescription of 15 to 25 mg/week (or ≥ 10 mg/week in subjects 
intolerant of MTX at doses ≥ 15 mg/week) for ≥ 4 weeks prior to the first dose of study drug.  
Subject must be expected to be able to continue on stable dose of MTX for the duration of study 
participation.
Subject History
10. Subject must not have been previously exposed to adalimumab or other anti-TNF biologics.
11. Subject must not have been previously exposed to non-anti-TNF biologics or targeted 
synthetic DMARDs for RA, with exception of subjects exposed for less than 3 months and 
terminated not due to lack of efficacy or intolerability.
12. No history of persistent chronic or active infection(s) requiring hospitalization or treatment 
with parenteral anti-infectives within 30 days, or oral anti-infectives within 14 days prior to the 
first dose of study drug administration.
13. No history of demyelinating disease (including myelitis) or neurologic symptoms suggestive 
of demyelinating disease.
14. No history of moderate to severe congestive heart failure (CHF) (New York Heart Association 
Class III or IV).
15. No history or evidence of active TB disease or evidence of risk factors for latent TB infection 
OR a history of positive TB skin test or QuantiFERON-TB Gold In-Tube (GIT assay) within 90 days 
prior to study drug administration.
16. No history of pre-existing hyperglycemia (HbA1c > 6.5%), no history of osteoporotic 
fractures, and no high fracture risk (severe osteoporosis).
17. No history of pre-existing glaucoma, severe acne, osteonecrosis, uncontrolled hypertension, 
or peripheral edema.


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18. No history of any malignancy except for successfully treated non-melanoma skin cancer 
(NMSC) or localized carcinoma in situ of the cervix.
19. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months.
20. No history of clinically significant medical conditions or any other reason that the 
investigator determines would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug.
21. No history of an allergic reaction or significant sensitivity to any constituents of the study 
drug, or an anaphylactic reaction to any agent (e.g., food products and bee sting), or a major 
reaction to any immunoglobulin G-containing product.
22. Is not currently enrolled in another clinical study, and has not been previously enrolled in 
this study.
Contraception
23. For all females of child-bearing potential; a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at BL prior to the first dose of study drug.
24. 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 70 days after the last dose of 
study drug.  Female subjects of non-childbearing potential do not need to use birth control.
25. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study or for approximately 70 days after the last dose of study drug.
Concomitant Medications
26. Subject must have discontinued all conventional synthetic disease-modifying antirheumatic 
drugs (csDMARDs), except for MTX.  The washout periods for csDMARDs prior to the first dose 
of study are specified in Section 5.4.
27. Subject must not be on systemic GCs except for stable doses of GC (≤ 7.5 mg/d prednisone 
equivalent) in preceding 3 weeks prior to BL.
28. Subject must not have been treated with any investigational drug within 30 days or 5 half-
lives of the drug (whichever is longer) prior to the first dose of study drug.
29. Subject must not have been treated with any intra-articular, intramuscular, IV, trigger point 
or tender point, intra-bursa, or intra-tendon sheet corticosteroids in the preceding 8 weeks prior 
to the first dose of the study drug.
30. Subject must not have received 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 
12 weeks after the last dose of study drug.


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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 an 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 70 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 30 days prior to study BL Day 1.
!
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study BL 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).
!
Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).
!
Practice true abstinence, 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).


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Male subjects who are sexually active with a female partner of childbearing potential, must agree to use 
condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through at 
least 70 days after the last dose of study drug.
Contraception recommendations related to use of concomitant therapies prescribed (e.g., MTX) should 
be based on the local label.
5.3 Prohibited Medications and Therapy
The following medications are prohibited throughout the duration of the study:
!
Systemic GCs except stable doses of GC (≤ 7.5 mg/d prednisone equivalent) at BL, which have to 
be tapered off completely by end of Week 4.
!
All csDMARDs, except MTX
!
All targeted synthetic DMARDs:  Examples include but are not limited to the following:  Xeljanz® 
(tofacitinib), Olumiant® (baricitinib), Rinvoq® (upadacitinib)
!
All biologic therapies.  Examples include but are not limited to the following:  Humira® 
(adalimumab), Enbrel® (etanercept), Remicade® (infliximab), Kineret® (anakinra), Rituxan® 
(rituximab), Cimzia® (certolizumab pegol), Simponi® (golimumab), Actemra® (tocilizumab), 
Raptiva® (efalizumab), Tysabri® (natalizumab), Stelara® (ustekinumab), Benlysta® (belimumab), 
Orencia® (abatacept), Prolia® (denosumab)
!
Any intra-articular, intramuscular, parenteral, trigger point or tender point, intra-bursa, or intra-
tendon sheet corticosteroids
!
Any investigational drugs
!
Any live vaccination
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrollment or receives during the study 
must be recorded along with reasons for use; dates of administration, including start and end dates; and 
dosage information including dose, route, and frequency on the appropriate electronic case report form 
(eCRF) through the post-treatment contact (70 day follow-up call).
Non-Steroidal Anti-Inflammatory Drugs (NSAID) and low potency analgesics (i.e., tramadol, codeine, 
hydrocodeine, or propoxyphene) should continue to be used for the same reason and same dose each 
time but should not be taken within 24 hours prior to any study visit to avoid bias in outcome 
measurements.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with ABBV-3373 can be located in the 
ABBV-3373 Investigator's Brochure.2




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progression, lack of response to treatment, an AE, safety concerns, or failure to comply with the 
protocol.  See Section 6.2 for toxicity management criteria.
Subjects will have study drug discontinued immediately if any of the following occur:
!
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the Investigator or the AbbVie Therapeutic Area Medical Director (TA 
MD).
!
Serious infections (e.g., sepsis) that cannot be adequately controlled within 2 weeks by anti-
infective treatment or would put the subject at risk for continued participation in the trial as 
determined by the Investigator.
!
The Investigator believes it is in the best interest of the subject.
!
The subject requests withdrawal from the study.
!
Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk as determined by the AbbVie TA MD.
!
Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk, as determined by the AbbVie TA MD.
!
Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.
!
The subject becomes pregnant while on study drug.
!
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix.
!
Subject is significantly non-compliant with study procedures which would put the subject at risk 
for continued participation in the trial as determined by the Investigator or the AbbVie TA MD.
!
The subject develops anaphylactic reactions or anaphylactic shock.
In order to minimize missing data for efficacy and safety assessments, subjects who prematurely 
discontinue study participation should complete a Premature Discontinuation (PD) visit.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue the study participation entirely (withdrawal of informed consent).  Subjects 


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
should be advised on the continued scientific importance of their data even if they discontinue 
treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the PD visit should be completed as soon as possible, preferably within 2 weeks.  
In addition, if subject is willing, a 70-day follow-up phone call after the last dose of study drug will 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 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.
Biomarker Research
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that samples are 
withdrawn from research, samples will not be analyzed, no new biomarker analysis data will be 
collected for the withdrawn subject or added to the existing data or database(s).  Data generated from 
clinical study and/or biomarker research, before subject withdrawal of consent, will remain part of the 
study results.
5.7 Study Drug
ABBV-3373 or matching placebo manufactured by AbbVie will be administered intravenously beginning 
on Day 1 (BL).  Adalimumab or matching placebo manufactured by AbbVie will be administered 
subcutaneously beginning on Day 1 (BL).  The administration of ABBV-3373 and matching placebo by 
venipuncture has to be given slowly over 15 – 30 minutes (via infusion line or infusion pump; the study 
drug can be diluted in 50 – 100 mL isotonic saline solution for this administration).  Subjects have to be 
observed for at least 30 minutes thereafter.
AbbVie will provide study drug for ABBV-3373 or matching placebo and adalimumab or matching 
placebo.  AbbVie-provided study drug should not be substituted or alternately sourced unless otherwise 
directed by AbbVie.
ABBV-3373 and matching placebo and adalimumab or matching placebo will be packaged in cartons 
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.
AbbVie will provide instructions for drug preparation (Table 1).


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Table 1.
Identity of Investigational Product
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
ABBV-3373
Lyophilized powder 
for solution for 
infusion in vials
50 mg/mL when 
reconstituted with 
1.2 mL of sterile water 
for injection; 
1 mL extractable 
volume per vial; further 
dilution into saline for 
IV infusion
IV
AbbVie
Placebo for ABBV-3373
Lyophilized powder 
for solution for 
infusion in vials
N/A
IV
AbbVie
Adalimumab
Pre-filled syringe
80 mg/0.8 mL
SC
AbbVie
Placebo for 
Adalimumab
Pre-filled syringe
N/A
SC
AbbVie
IV = intravenous; N/A = not applicable; SC = subcutaneous
5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule generated by the statistics department at AbbVie.
Randomization will be stratified by factors listed in Section 4.1.
Forty-five subjects will be randomized to either the ABBV-3373 or adalimumab control arm according to 
a 2:1 ratio.  Randomization will be stratified by the following factors:
!
Stratification by current use of systemic GC (≤7.5 mg/d prednisone equivalent) for treatment of 
RA at BL (yes/no).
!
Stratification by prior exposure to non-anti-TNF biologics or targeted synthetic DMARDs 
(< 3 months and terminated not due to lack of efficacy or intolerance) (yes/no).
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-3373 vials and matching placebo vials, as well as adalimumab PFS and matching placebo PFS, will 
be provided for the study.  The IRT will provide access to unblinded subject treatment information in the 
case of a medical emergency.  The procedure for breaking the blind is referenced in the IRT Training 
Slides provided to each study site.


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AbbVie must be notified before the blind is broken unless identification of the study drug is required for 
medical emergency, i.e., situation in which the knowledge of the specific blinded treatment will affect 
the immediate management of the subject/patient's conditions (e.g., antidote is available).  AbbVie 
must then be notified within 24 hours of the blind being broken.  See Appendix K for contact 
information, including 24/7 AbbVie emergency contact coverage.
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 IEC/independent review board (IRB), regulatory 
authorities (as applicable), and AbbVie.
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 Complaint
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.




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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 adverse events reported from the time of study drug administration until 70 days after 
discontinuation of study drug administration will be collected, whether solicited or spontaneously 
reported by the subject.  In addition, serious adverse events and protocol-related nonserious adverse 
events 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.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Serious Adverse Event Reporting
AbbVie is committed to continue to collect safety information including those events that may occur in 
this trial in order to confirm this established safety profile and to identify any unknown potential 
adverse reactions, rare events, and those events with a long latency.  AbbVie is participating in a Food 
and Drug Administration-requested, TNF inhibitor class wide exploration of the rare appearance of 
malignancy in subjects/patients who are 30 years of age or younger at the time of diagnosis.  The risk of 
malignancy in this age group has not been established and is difficult to study due to its rarity.  AbbVie 
appreciates your attention to the additional reporting requirements needed in this unlikely event.  In the 
event of an SAE, and additionally, any nonserious event of malignancy in subjects 30 years of age and 
younger, whether related to SC study drug or not, the physician will notify Clinical Pharmacovigilance 
within 24 hours of the physician becoming aware of the event by entering the SAE or nonserious event 
of malignancy in subjects 30 years of age and younger data into the electronic data capture (EDC) 
system.  Serious adverse events and nonserious events of malignancy in subjects 30 years of age and 
younger, that occur prior to the site having access to the RAVE® EDC system or if RAVE® is not operable, 
should be documented on the SAE non-case report form forms and emailed (preferred route) or faxed 
to the Clinical Pharmacovigilance within 24 hours of being made aware of the SAE.


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Adverse Events of Special Interest
The following adverse events of special interest will be monitored during the study:
!
Serious infections, opportunistic infections, herpes zoster, and TB;
!
Malignancy (all types);
!
Cardiovascular events (e.g., major adverse cardiovascular event [MACE]);
!
Hematologic disorders (i.e., anemia, neutropenia, lymphopenia);
!
Hepatic disorders;
!
Hypersensitivity reactions, including all serious allergic reactions;
!
Demyelinating disease;
!
Systemic GC side effects (i.e., infections, skin atrophy, weight gain, cataract, hypertension, 
indigestion, hyperglycemia).
Adverse Event Severity and Relationship to Study Drug
The investigator will classify AEs according to the Rheumatology Common Toxicity Criteria v.2.0 
(Appendix I).
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day after 
the site becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.5).  If a pregnancy occurs in a study subject or in the partner of a study subject, 
information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partners will be collected from the 
date of the first dose through 70 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.


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6.2 Toxicity Management
The management of specific AEs and laboratory parameters is described in Table 2 and in the 
Operations Manual (Appendix K).
The toxicity management of the AEs including AEs of special interest consists of safety monitoring 
(review of AEs on an ongoing basis, and periodical/ad hoc review of safety issues by a safety data 
monitoring committee), interruption of study drug dosing with appropriate clinical management if 
applicable, and discontinuation of the subjects from the study drug. The management of specific AEs 
and laboratory parameters is described below.
For subjects who discontinued study drug but continued study participation and are on standard of care 
therapies, these toxicity management requirements do not apply (including alerts from the central lab) 
and any intolerability to standard of care therapies should be managed by the prescribing physician.
Management of Hypersensitivity and Serious Allergic Reactions
Subjects should be closely monitored and assessed for the development of signs and symptoms of 
hypersensitivity reactions, including anaphylaxis.  Drug administration (ABBV-3373) should be done 
slowly over 15 – 30 minutes (via infusion line or infusion pump; the study drug can be diluted in 
50 – 100 mL isotonic saline solution for this administration), and subjects should be observed for at least 
30 minutes thereafter.  Study drug should be discontinued and appropriate therapy be instituted if a 
subject develops clinically significant hypersensitivity reactions.
Hypersensitivity Testing
In the event of a suspected systemic post-dose hypersensitivity reaction, if the clinical situation allows, 
every effort should be made to obtain a serum sample within 2 hours but no later than 6 hours from 
symptom onset for additional blood tests (e.g, tryptase, ADA, nAb, total IgE, total hemolytic 
complement, etc.).  Additional details regarding hypersensitivity testing can be found in the Operations 
Manual, Section 3.12 (Appendix K).
Management of 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 a serious 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 must be permanently discontinued from study drug.
Management of Malignancy
Subjects who develop malignancy other than NMSC or carcinoma in-situ of the cervix must be 
discontinued from the study drug.  Information including histopathological results should be queried for 
the confirmation of the diagnosis.


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Management of Demyelinating Disease
Subjects must be discontinued from study drug with new onset or exacerbation of clinical symptoms 
and/or radiographic evidence of central nervous system demyelinating disease (including multiple 
sclerosis), optic neuritis, and peripheral demyelinating disease (including Guillain Barré syndrome).
Management of Hypertension
Subjects should be closely monitored for the development of hypertension before and 30 minutes after 
treatment with study drug.  Study drug should be interrupted if a subject develops serious hypertension 
in which case they should be monitored under standard of care.
Management of Hyperglycemia
Subjects should be closely monitored for the development of hyperglycemia during and after treatment 
with study drug.  Study drug should be interrupted if a subject develops a serious hyperglycemia in 
which case they should be monitored under standard of care.
Management of GC-Induced Adrenal Insufficiency
High dose or long term use of corticosteroids can produce reversible HPA axis suppression with the 
potential for GC insufficiency after withdrawal of treatment.  Drug-induced secondary adrenocortical 
insufficiency may be minimized by gradual reduction of dosage.  This type of relative insufficiency may 
persist for months after discontinuation of therapy; therefore, hormone therapy should be reinstituted 
in any situation of stress occurring during that period.
Management of Select Laboratory Abnormalities
For any given laboratory abnormality, the investigator should assess the subject, apply the standard of 
care for medical evaluation and treatment following any local guidelines.  Specific toxicity management 
guidelines for selected abnormal laboratory values are described in Table 2, and may require a 
supplemental eCRF to be completed (Section 6.1 [Complaints and AEs]).  All abnormal laboratory tests 
that are considered clinically significant by the investigator will be followed to a satisfactory resolution.  
If a repeat test is required per Table 2, the repeat testing must occur as soon as possible.
Table 2.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory 
Parameter
Toxicity Management Guideline
Hemoglobin
!
If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by repeat testing 
with new sample
!
If hemoglobin decreases ≥ 3.0 g/dL from BL, without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from BL and an alternative etiology is known, the 
subject may remain on study drug at the investigator's discretion.
!
If confirmed, continue to withhold study drug until hemoglobin value returns to 
normal reference range or its BL value.


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Laboratory 
Parameter
Toxicity Management Guideline
Absolute neutrophil 
count (ANC)
!
If confirmed < 1000/μL by repeat testing with new sample, interrupt study drug 
dosing until ANC value returns to normal reference range or its BL value.
!
Discontinue study drug if confirmed < 500/μL by repeat testing with new sample.
Absolute 
lymphocyte counts 
(ALC)
!
If confirmed < 500/μL by repeat testing with new sample, interrupt study drug 
dosing until ALC returns to normal reference range or its BL value.
Total white blood 
cell count
!
If confirmed < 2000/μL by repeat testing with new sample, interrupt study drug 
dosing until white blood cell count returns to normal reference range or its BL value.
Platelet count
!
If confirmed < 50,000/μL by repeat testing with new sample, interrupt study drug 
dosing until platelet count returns to normal reference range or its BL value.
AST or ALT
!
Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample and either a total bilirubin > 2 × ULN or an international normalized ratio 
(INR) > 1.5.
!
A separate blood sample for INR testing will be needed to measure INR at the 
time of repeat testing for ALT or AST.  A repeat test of INR is not needed for 
determination if above toxicity management criteria are met.
!
Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample along with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
!
Interrupt study drug if confirmed ALT or AST > 5 × ULN by repeat testing with new 
sample for more than 2 weeks.
!
Interrupt study drug if confirmed ALT or AST > 8 × ULN by repeat testing with new 
sample.
Subjects who meet any of the above criteria should be evaluated for an alternative 
etiology of the ALT or AST elevation and managed as medically appropriate.  The 
investigator should contact the AbbVie TA MD to discuss the management of a subject 
when an alternative etiology has been determined.  The alternative etiology should be 
documented appropriately in the eCRF; study drug should be discontinued if no 
alternative etiology can be found and ALT or AST elevations persist.
For any confirmed ALT or AST elevations > 3 ULN, complete the appropriate 
supplemental hepatic eCRF(s).
!
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA PCR 
testing at Screening who develop the following should have HBV DNA PCR testing 
performed within one week:
!
ALT > 5 × ULN OR
!
ALT or AST > 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR
!
ALT or AST > 3 × ULN along with clinical signs of possible hepatitis.
A positive result for HBV DNA PCR testing will require immediate interruption of study 
drug (unless not acceptable by local practices) and a hepatologist consultation should 
occur within 1 week for recommendation regarding subsequent treatment.


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Laboratory 
Parameter
Toxicity Management Guideline
Serum Creatinine
!
If serum creatinine is > 1.5 × the BL value and > ULN, repeat the test for serum 
creatinine (with subject in an euvolemic state) to confirm the results.  If the results 
of the repeat testing still meet this criterion, then interrupt study drug and re-start 
study drug once serum creatinine returns to ≤ 1.5 × BL value and ≤ ULN.
For the above serum creatinine elevation scenario, complete the appropriate 
supplemental renal eCRF(s).
Creatine 
Phosphokinase 
(CPK)
!
If confirmed CPK value ≥ 4 × ULN and there are no symptoms suggestive of myositis 
or rhabdomyolysis, the subjects may continue study drug at the investigator's 
discretion.
!
If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact AbbVie TA MD.
For the above CPK elevation scenarios, complete supplemental increased CPK eCRF.
Ab = antibody; ALC = Absolute lymphocyte counts; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; BL = baseline; CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; eCRF = electronic 
case report form; HB = hepatitis B; HBV = hepatitis B virus; INR = international normalized ratio; PCR = polymerase chain 
reaction; TA MD = Therapeutic Area Medical Director; ULN = upper limit of normal
Management of ECG Abnormality
Subjects should be discontinued for an ECG change considered clinically significant OR a confirmed 
absolute QT interval corrected for heart rate using Fridericia's correction formula (QTcF) value 
> 500 msec.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and secondary analyses.  
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP).  All 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 randomized subjects who received at least 1 dose of the study 
drugs.  The FAS will be used for all efficacy analyses. Subjects will be grouped according to treatment as 
randomized.  The Per-Protocol Analysis Set represents a subset of the FAS and consists of all FAS 
subjects without any major violations.  Additional analysis may be conducted on the Per-Protocol 
Analysis Set as deemed appropriate, in order to evaluate the impact of major protocol violations on the 
primary endpoint.


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The Safety Analysis Set consists of all subjects who received at least 1 dose of the study drugs.  For the 
Safety Analysis Set, subjects are grouped based on the treatment actually received, regardless of the 
treatment randomized.
7.3 Statistical Analyses for Efficacy
Primary Endpoint Analysis
Analysis of the primary endpoint will be conducted on the FAS based on treatment as randomized.
The primary endpoint is the change from BL in DAS28(CRP) at Week 12.  The historical mean and 
standard deviation of the change from BL in DAS28(CRP) at Week 12 in adalimumab 80 mg eow are 
estimated to be –2.13 and 1.35 respectively based on a meta-analysis of 3 historical adalimumab studies 
(Studies DE007, DE009, and DE011).
The first comparison in order to achieve the first primary objective of assessing the efficacy of 
ABBV-3373 is to compare change from BL in DAS28(CRP) at Week 12 in the ABBV-3373 group with 
–2.13, the adalimumab 80 mg eow historical mean change from BL at Week 12 based on the meta-
analysis.  The treatment mean change from BL and 90% confidence interval of ABBV-3373 will be 
estimated from Mixed Effect Model Repeated Measurements (MMRM) method including up to Week 12 
data with treatment group, visits, treatment-by-visit interaction, BL values of the primary endpoint, and 
stratification factors with observed case (OC) data.  The study will be declared positive if the comparison 
is significant and favoring ABBV-3373.
In order to achieve the second primary objective of comparing clinical efficacy of ABBV-3373 with 
adalimumab and to test the concept that an anti-TNF ADC has the potential to provide superior efficacy 
than the traditional anti-TNF antibody in RA, the second comparison is to compare ABBV-3373 with 
adalimumab for the primary efficacy endpoint with a Bayesian historical data borrowing approach.  The 
same MMRM model as described in the first comparison will be used to estimate in-study mean and 
standard deviation.  Informative normal prior for adalimumab will be determined based on historical 
adalimumab data and a non-informative prior will be used for ABBV-3373.  The prior distributions and 
estimates from MMRM model will be combined to construct the posterior distributions which will be 
used for comparison between ABBV-3373 and adalimumab.
If the adalimumab group mean is not comparable with historical adalimumab data, for example, the 
confidence intervals of the mean based on historical and in-trial data don't overlap, the Bayesian 
approach based on historical data will not be performed, and the mean difference in change from BL in 
DAS28(CRP) at Week 12 between the ABBV-3373 group and adalimumab will be estimated only based 
on in-study data with the MMRM model described above.
Historical data borrowing will only apply to the primary endpoint.
To address the secondary objectives of assay sensitivity, a synthetic placebo arm will be created with the 
propensity score matching approach using historical placebo subjects from similar trials with subject-
level data. Details will be provided in the SAP.


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Secondary Endpoints and Additional Endpoints Analyses for BL to Week 12
For the first 12 weeks of treatment period, continuous efficacy variables will be analyzed using an 
MMRM method.  Categorical efficacy variables will be analyzed using the Cochran-Mantel-Haenszel 
(CMH) test controlling for stratification variables.  Non-responder imputation (NRI) will be used for 
primary inference purpose.  Observed Case data will be summarized descriptively as a sensitivity 
analysis.
Additional Endpoints Analyses up to Week 24
Statistical inference of additional continuous endpoints at each visit up to Week 24 will be conducted 
using analysis of covariance (ANCOVA) with treatment and stratification factors as the fixed factors and 
the corresponding BL value as the covariate. Additional categorical efficacy variables up to Week 24 will 
be analyzed using the same CMH test as for the binary secondary endpoint analysis.
Details on the analyses of the primary and other efficacy endpoints will be provided in the SAP.
Sample Size Estimation
The primary endpoint is the mean change of DAS28(CRP) from BL at Week 12.  Two comparisons are 
considered.  The first one is to compare mean change in DAS28(CRP) of the ABBV-3373 group to that of 
historical adalimumab 80 mg eow, which is –2.13.  Assuming a mean DAS28(CRP) change from BL of
–2.769 to –2.982 for ABBV-3373 (corresponding to 30% to 40% more reduction than historical 
adalimumab) and a standard deviation of 1.35, 30 subjects on ABBV-3373 will provide an approximate 
81% to 96% power with a one-sample t-test and one-sided alpha = 0.05 significance level.
The second comparison is between ABBV-3373 arm and adalimumab arm with borrowed historical 
adalimumab data using a Bayesian approach.  When considering borrowing historical data, the planned 
sample size is 45 subjects (30 in ABBV-3373 and 15 in adalimumab).  The study will be considered 
successful if the posterior probability of mean difference < 0 is larger than 95%, i.e.,:
(μ	
 −μ < 0|) > 0.95.
Based on the historical mean and standard deviation from adalimumab meta-analysis, a prior 
distribution for adalimumab is N (–2.13, 0.2462) corresponding to the 30 historical subjects borrowed.  A 
noninformative prior for ABBV-3373 treatment group will be set.  Given the mean change from BL in 
DAS28 (CRP) is –2.13 for adalimumab, the probability to claim the study success is approximately 66% to 
88% if the mean change from BL in DAS28 (CRP) is –2.769 to –2.982 for ABBV-3373 (i.e., 30% to 40% 
more reduction than historical adalimumab), with at least 45 subjects for adalimumab (15 in-trial and at 
least 30 borrowed) and 30 subjects for ABBV-3373.  If both ABBV-3373 and adalimumab groups have the 
same mean change from BL of –2.13, the probability to claim study success (equivalent to type I error 
rate) is approximately 0.03 with the same sample sizes.  In the event that adalimumab variability 
precludes historic data borrowing, using only the in-study 15 adalimumab subjects and 30 ABBV-3373 
subjects will provide 43% to 63% power when ABBV-3373 in 30% to 40% more reduction than 
adalimumab respectively.


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7.4 Statistical Analyses for Safety
Safety analyses will be carried out using the Safety Analysis Set.  There will be 2 sets of planned safety 
analyses:  safety analysis by Week 12 and long-term safety analysis.  Safety will be assessed by AEs, 
laboratory assessments, and vital signs.  Frequency tables of subjects with treatment emergent AEs by 
preferred term (PT), by system organ class (SOC) and PT as in the Medical Dictionary for Regulatory 
Activities, by severity, and by relationship to the study drug as assessed by the Investigator will be 
provided.
Summaries of SAEs, deaths, AEs leading to discontinuation, and Areas of Safety Interest will be provided 
as well.  The changes from BL in clinical laboratory and vital sign values by visit will be analyzed in a 
descriptive manner.  Shift of selected laboratory values from BL to defined time points will be tabulated.  
The number and percentage of subjects meeting the criteria for potentially clinically significant 
laboratory/vital sign/ physical examination/ECG values will be summarized.
No external data borrowing will be applied for safety analyses.
7.5 Statistical Analysis of Pharmacokinetic and Immunogeniticy Data
Concentrations of conjugated ADC (ABBV-3373), total antibody, free payload A-1677770, and 
adalimumab (in the comparator arm), along with all applicable PK parameters will be summarized at 
each time point for each group using descriptive statistics.
Population PK analyses combining the data from this study and other studies may be performed and 
reported outside of the clinical study report.
Anti-drug antibody and nAb incidence and ADA titer values will be summarized for each group using 
descriptive statistics.
7.6 Statistical Analysis of Biomarker Data
Analysis will be conducted on biomarker data for the purpose of identification of prognostic, predictive, 
surrogate, and pharmacodynamic biomarkers associated with efficacy or safety.  The association of 
biomarkers to the efficacy or safety endpoints will be explored for each biomarker one at a time, and 
also for combinations of biomarkers via some multivariate predictive modeling approaches.
7.7 Interim Analysis
An interim PK analysis after 12 subjects are treated for at least 4 doses will be performed to assess 
whether the observed total antibody systemic exposure following ABBV-3373 administration is in the 
approximate range of 80 mg adalimumab exposure based on trough concentration (Ctrough) levels and if 
there is a need for dose adjustment for ABBV-3373 and replacement of already-treated subjects.


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8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (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 end-of-study is defined as last subject last visit (70 day follow-up call).
12
REFERENCES
1.
Schäcke H, Döcke WD, Asadullah K.  Mechanisms involved in the side effects of glucocorticoids.  
Pharmacol Ther.  2002;96(1):23-43.
2.
AbbVie.  ABBV-3373 Investigator's Brochure Edition 3.  September 2019.  Addendum 1, 
Edition 3.  November 2019.
3.
Keystone E, Weinblatt M, Furst D, et al.  Adalimumab, a fully human anti-TNF monoclonal 
antibody α monoclonal antibody, for treatment of rheumatoid arthritis in patients taking 
concomitant methotrexate:  The ARMADA trial.  Arthritis Rheum.  2003;48(1):35-45.
4.
Weisman M, Keystone E, Paulus H, et al.  A dose escalation study designed to demonstrate the 
safety, tolerability and efficacy of the fully human anti-TNF antibody, D2E7, given in combination 
with methotrexate (MTX) in patients with active RA (abstract 1948).  Arthritis Rheum.  
2000;43(9):S391.
5.
van de Putte LBA, Rau R, Breedveld F, et al.  Efficacy and safety of the fully human anti-tumour 
necrosis factor α monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with 
rheumatoid arthritis:  a 12 week, phase II study.  Ann Rheum Dis.  2003;62(12):1168-77.
6.
van de Putte LB, Atkins C, Malaise M, et al.  Efficacy and safety of adalimumab as monotherapy 
in patients with rheumatoid arthritis for whom previous disease modifying anti-rheumatic drug 
treatment has failed.  Ann Rheum Dis.  2004;63(5):508-16.


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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ACR
American College of Rheumatology
ACR20
American College of Rheumatology 20% improvement criteria
ACR50
American College of Rheumatology 50% improvement criteria
ADA
anti-drug antibody
ADC
antibody-drug conjugate
ADL
activities of daily living
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BL
baseline
BMI
body mass index
CDAI
clinical disease activity index
CHF
congestive heart failure
CMH
Cochran-Mantel-Haenszel
CR
clinical remission
CRF
case report form
CRP
C-reactive protein
csDMARD
conventional synthetic disease-modifying antirheumatic drug
Ctrough
trough concentration measured at the end of a dosing interval at steady state
DAS
disease activity score
DAS28
disease activity score (28 joints)
DMARD
disease-modifying antirheumatic drug
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eow
every other week
ESR
erythrocyte sedimentation rate
EULAR
European League Against Rheumatism


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FAS
full analysis set
FSH
follicle-stimulating hormone
GC
glucocorticoid
GCP
good clinical practice
GRMs
glucocorticoid receptor modulators
HAQ-DI
Health Assessment Questionnaire Disability Index
HAV
hepatitis A virus
HAV-IgM
hepatitis A virus immunoglobulin M
HB
hepatitis B
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HPA
hypothalamic-pituitary-adrenal
hs-CRP
high-sensitivity C-reactive protein
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IL
interleukin
IMP
Investigational Medicinal Product
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LDA
low disease activity
MACE
major adverse cardiac event
MCID
minimal clinically important difference
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Effect Model Repeated Measurements
MTX
Methotrexate
nAb
neutralizing antibody
NMSC
non-melanoma skin cancer
NRI
non-responder imputation
NSAID
nonsteroidal anti-inflammatory drug


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OC
observed case
QTcF
QT interval corrected for heart rate using Fridericia's correction formula
PD
premature discontinuation
PK
pharmacokinetic(s)
PT
preferred term
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SDAI
simplified disease activity index
SF-36
36-Item Short Form Health Survey
SJC
swollen joint count
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TJC
tender joint count
TNF
tumor necrosis factor
ULN
upper limit of normal
VAS
visual analogue scale
vs.
versus


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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-560:  A Randomized, Double-Blind, Double-Dummy, Active Controlled Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics, and Efficacy of ABBV-3373 in Subjects with Moderate to 
Severe Rheumatoid Arthritis
Protocol Date:  04 September 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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


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APPENDIX D. ADDITIONAL ENDPOINT/ASSESSMENT 
DEFINITIONS
Physician's Global Assessment of Disease Activity
Physician's Global Assessment of Disease Activity (visual analogue scale [VAS]) allows physicians to score 
on a 100 mm horizontal scale (0 being very low and 100 being very high) to assess the patient's current 
disease activity.
DAS28
The DAS is a combined index used to measure the disease activity in patients with RA.  The DAS provides 
a score (between 0 and 10) indicating how active the disease is at the time of measurement.  The 
calculation of the DAS28 score used either ESR or CRP.
The calculation of the DAS28 score will use ESR based on the following formula:
DAS28 (ESR) = 0.56 × √TJC28 + 0.28 × √SJC28 + 0.70 × ln(ESR) + 0.014 × PtGA
The calculation of the DAS28 score will use CRP based on the following formula:
DAS28 (CRP) = 0.56 × √TJC28 + 0.28 × √SJC28 + 0.36 × ln(CRP + 1) + 0.014 × PtGA + 0.96
PtGA represents patient's global assessment of disease activity; ESR is measured in mm/h, CRP is 
measured in mg/L, TJC28 and SJC28 represent total TJC and total SJC, respectively, based on the 
28 joints (including the left and right side of the body).
American College of Rheumatology 20/50/70 Response (ACR20/50/70)
ACR20/50/70 is defined as
!
At least 20%/50%/70% improvement in SJC compared to BL AND
!
At least 20%/50%/70% improvement in TJC compared to BL AND
!
At least 20%/50%/70% improvement in at least 3 out of the following 5 variables
1.
Patient's Assessment of RA Pain Intensity VAS
2.
Patient's Global Assessment of Disease VAS
3.
Physician's Global Assessment of Disease Activity VAS
4.
Patient's Assessment of Disability on HAQ-DI
5.
Serum high-sensitivity C-reactive protein (hs-CRP).
Clinical Disease Activity Index (CDAI)
The CDAI is a composite index for assessing disease activity based on the summation of the count of 
swollen/tender joint count of 28 joints along with patient and physician global assessment on visual 
analogue scale (VAS) (0 – 10 cm) for estimating disease activity.  It has range from 0 to 76.


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Simplified Disease Activity Index (SDAI)
The SDAI is the numerical sum of five outcome parameters:  tender and swollen joint count (based on a 
28-joint assessment), patient and physician global assessment of disease activity (VAS 0 - 10 cm) and 
level of CRP (mg/dl, normal < 1 mg/dl).  It has a range from 0 to 86.


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APPENDIX E. JOINT EVALUATION WORKSHEET EXAMPLE
JOINT
(Tick Correct Answer)
Subject Right
Subject Left
0 = Absent
1 = Present
9 = Replaced 
NA = No 
Assessment
0 = Absent
1 = Present
9 = Replaced 
NA = No 
Assessment
Pain/ 
Tenderness
Swelling
Joint
Pain/ 
Tenderness
Swelling
Joint
1.  Shoulder
0
1
0
1
9
NA
0
1
0
1
9
NA
2.  Elbow
0
1
0
1
9
NA
0
1
0
1
9
NA
3.  Wrist
0
1
0
1
9
NA
0
1
0
1
9
NA
4.  Metacarpophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
5.  Metacarpophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
6.  Metacarpophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
7.  Metacarpophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
8.  Metacarpophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
9.  Thumb Interphalangeal
0
1
0
1
9
NA
0
1
0
1
9
NA
10.  Prox. Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
11.  Prox. Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
12.  Prox. Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
13.  Prox. Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
14.  Knee
0
1
0
1
9
NA
0
1
0
1
9
NA
TOTAL Joint Count


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APPENDIX F. REPORTED OUTCOMES VAS


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APPENDIX G. HEALTH ASSESSMENT QUESTIONNAIRE 
DISABILITY INDEX


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APPENDIX H. 36-ITEM SHORT FORM HEALTH SURVEY SAMPLE


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APPENDIX I.
RHEUMATOLOGY COMMON TOXICITY CRITERIA 
V.2.0
For designation of AE terms not shown in the Rheumatology Common Toxicity Criteria v.2.0 table, the 
approach described in the header row should be used.
Rheumatology Common Toxicity Criteria v.2.0
Based on Woodworth TG, et al.  Standardizing assessment of adverse effects in rheumatology clinical 
trials II.  Status of OMERACT Drug Safety Working Group May 2006:  OMERACT 8.  Standardizing 
Assessment and Reporting of Adverse Effects in Rheumatology Clinical Trials:  Enabling Description of 
Comparative Safety Profiles for Anti-Rheumatic Therapies.


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1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
A.  Allergic/Immunologic
A1.  Allergic reaction/ 
hypersensitivity 
(includes drug fever)
Transient rash:  drug fever < 38°C:  
transient, asymptomatic 
bronchospasm
Generalised urticaria responsive to 
meds; or drug fever > 38°C, or 
reversible bronchospasm
Symptomatic bronchospasm 
requiring meds; symptomatic 
urticaria persisting with meds, 
allergy related oedema/angioedema
Anaphylaxis, laryngeal/pharyngeal 
oedema, requiring resuscitation
A2.  Autoimmune 
reaction
Seriologic or other evidence of 
autoimmune reaction, but patient 
asymptomatic:  all organ function 
normal and no treatment is 
required (e.g., vitiligo)
Evidence of autoimmune reaction 
involving a non-essential organ or 
functions, requiring treatment 
other than immunosuppressive 
drugs (e.g., hypothyroidism)
Reversible autoimmune reaction 
involving function of a major organ 
or toxicity requiring short term 
immunosuppressive treatment 
(e.g., transient colitis or anaemia)
Causes major organ dysfunction, or 
progressive, not reversible, or 
requires long term administration 
of high dose immunosuppressive 
therapy
A3.  Rhinitis (includes 
sneezing, nasal 
stuffiness, post nasal 
discharge)
Transient, non-prescription meds 
relieve
Prescription meds 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


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
B.  Cardiac
B1.  Arrhythmia
Transient, asymptomatic
Transient, but symptomatic or 
recurrent, responds to meds
Recurrent/persistent; maintenance 
prescription
Unstable, hospitalisation required, 
parenteral meds
B2.  Cardiac function 
decreased
Asymptomatic decline in resting 
ejection fraction by > 10%, but 
< 20% of baseline value
Asymptomatic decline of resting 
ejection fraction ≥ 20% of baseline 
value
CHF responsive to treatment
Severe or refractory CHF
B3.  Edema
Asymptomatic (e.g., 1 + 
feet/calves), self-limited, no 
therapy required
Symptomatic (e.g., 2 + 
feet/calves), requires therapy
Symptoms limiting function (e.g., 3 + 
feet/calves, 2 + thighs), partial relief 
with treatment prolonged
Anasarca; no response to treatment
B4.  Hypertension 
(new onset or 
worsening)
Asymptomatic, transient increase 
by > 20 mmHg (diastolic) or to 
> 150/100 if previously normal, no 
therapy required
Recurrent or persistent increase 
> 150/100 or by > 10 mmHg 
(diastolic), requiring and 
responding readily to treatment
Symptomatic increase > 150/100, 
> 20 mmHg, persistent, requiring 
multi agency therapy, difficult to 
control
Hypertensive crisis
B5.  Hypotension 
(without underlying 
diagnosis)
Transient, intermittent, 
asymptomatic, orthostatic 
decrease in blood pressure 
> 20 mmHg
Symptomatic, without 
interference with function, 
recurrent or persistent > 20 mmHg 
decrease, responds to treatment
Syncope or symptomatic, interferes 
with function, requiring therapy and 
sustained medical attention, dose 
adjustment or drug discontinuation
Shock
B6.  Myocardial 
ischaemia
Transient chest pain/ECG changes; 
rapid relief with nitro
Recurring chest pain, transient 
ECG ST-T changes; treatment 
relieves
Angina with infarction, no or 
minimal functional compromise, 
reduce dose or discontinue study 
drug
Acute myocardial infarction, 
arrhythmia 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


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
B.  Cardiac (continued)
B8.  
Phlebitis/thrombosis/ 
Embolism (excludes 
injection sites)
Asymptomatic, superficial, 
transient, local, or no treatment 
required
Symptomatic, recurrent, deep vein 
thrombosis, no anticoagulant 
therapy required
Deep vein thrombosis requiring 
anticoagulant therapy
Pulmonary embolism
C.  General (Constitutional)
C1.  Fatigue/malaise 
(asthenia)
Increase over baseline; most usual 
daily functions maintained, short 
term
Limits daily function intermittently 
over time
Interferes with basic ADL, persistent
Unable to care for self, bed or 
wheelchair bound > 50% of day 
debilitating, hospitalisation
C2.  Fever (pyrexia) 
(note:  fever due to 
drug allergy should be 
coded as allergy)
Transient, few symptoms
37.7 – 38.5°C
Symptomatic, recurrent
38.6 – 39.9°C.  Relieved by meds
≥ 40°C; ≤ 24 h, persistent symptoms; 
partial response to meds.
≥ 40°C, debilitating, > 24 h, 
hospitalisation; no relief with meds
C3.  Headache
Transient or intermittent, no meds 
or relieved with OTC
Persistent, recurring, non-narcotic 
analgesics relieve
Prolonged with limited response to 
narcotic medicine
Intractable, debilitating, requires 
parenteral meds.
C4.  Insomnia
Difficulty sleeping, short term, no 
interfering with function
Difficulty sleeping interfering with 
function, use of prescription med.
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C5.  Rigors, chills
Asymptomatic, transient, no meds, 
or non-narcotic meds relieve
Symptomatic, narcotic meds 
relieve.
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C6.  Sweating 
(diaphoresis)
Episodic, transient
Frequent, short term
Frequent, drenching, disabling
Dehydration, requiring IV 
fluids/hospitalization > 24 hrs
C7.  Weight gain
5% – 9.9%
10% – 19.9%
20% – 30%
NA
C8.  Weight loss
5% – 9.9%
10% – 19.9%
20% – 30%
NA


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
D.  Dermatologic
D1.  Alopecia
Subjective, transient
Objective, fully reversible
Patchy, wig used, partly reversible
Complete, or irreversible even if 
patchy
D2.  Bullous eruption
Localised, asymptomatic
Localised, symptomatic, requiring 
treatment
Generalised, responsive to 
treatment; reversible
Prolonged, generalised, or requiring 
hospitalisation for treatment
D3.  Dry skin
Asymptomatic, controlled with 
emollients
Symptoms eventually (1 – 2 wks) 
controlled with emollients
Generalised, interfering with ADL 
> 2 wks, persistent pruritis, partially 
responsive to treatment
Disabling for extended period, 
unresponsive to ancillary therapy 
and requiring study drug 
discontinuation for relief
D4.  Injection site 
reaction
Local erythema, pain, pruritis, 
< few days
Erythema, pain, oedema, may 
include superficial phlebitis,
1 – 2 wks
Prolonged induration, superficial 
ulceration; includes thrombosis
Major ulceration necrosis requiring 
surgery
D5.  Petechiae 
(without vasculitis)
Few, transient asymptomatic
Dependent areas, persistent up to 
2 wks
Generalised, responsive to 
treatment; reversible
Prolonged, irreversible, disabling
D6.  Photosensitivity
Transient erythema
Painful erythema and oedema 
requiring topical treatment
Blistering or desquamation, requires 
systematic corticosteroids
Generalised exfoliation or 
hospitalisation
D7.  Pruritis
Localised, asymptomatic, transient, 
local treatment
Intense, or generalised, relieved 
by systematic medication
Intense or generalised; poorly 
controlled despite treatment
Disabling, irreversible
D8.  Rash (not 
bullous)
Erythema, scattered 
macular/popular eruption; pruritis 
transient; TOC or no meds
Diffuse macular/popular eruption 
or erythema with pruritus; dry 
desquamation; treatment 
required
Generalised, moist desquamation, 
requires systemic corticosteroids; 
responsive to treatment; reversible
Exfoliative or ulcerating; or requires 
hospitalisation; or parenteral 
corticosteroids


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
D.  Dermatologic (continued)
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
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


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
F.  Eye/Ophthalmologic
F1.  Cataract
Asymptomatic, no change in vision, 
non-progressive
Symptomatic, partial visual loss, 
progressive
Symptoms impairing function, vision 
loss requiring treatment, including 
surgery
NA
F2.  Conjunctivitis
Asymptomatic, transient, rapid 
response to treatment
Symptomatic, responds to 
treatment, changes not interfering 
with function
Symptoms prolonged, partial 
response to treatment, interferes 
with function
NA
F3.  Lacrimation 
increased (tearing, 
watery eyes)
Symptoms not requiring treatment, 
transient
Symptomatic, treatment required, 
reversible
Unresponsive to treatment with 
major effect on function
NA
F4.  Retinopathy
Asymptomatic, non-progressive, no 
treatment
Reversible change in vision; readily 
responsive to treatment
Disabling change in vision 
ophthalmological findings reversible, 
sight improves over time
Loss of sight
F5.  Vision changes 
(e.g., blurred, 
photophobia, night 
blindness, vitreous 
floaters)
Asymptomatic, transient, no 
treatment required
Symptomatic, vision changes not 
interfering with function, 
reversible
Symptomatic, vision changes 
interfering with function
Loss of sight
F6.  Xerophtalmia (dry 
eyes)
Mild scratchiness
Symptomatic without interfering 
with function, requires artificial 
tears
Interferes with vision/function, 
corneal ulceration
Loss of sight


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
G.  Gastrointestinal
G1.  Anorexia
Adequate food intake, minimal 
weight loss
Symptoms requiring oral 
nutritional supplementation
Prolonged, requiring iv support
Requires hospitalization for 
nutritional support
G2.  Constipation
Asymptomatic, transient, responds 
to stool softener, OTC laxatives
Symptomatic, requiring 
prescription laxatives, reversible
Obstipation requiring medical 
intervention
Bowel obstruction.  Surgery 
required.
G3.  Diarrhea
Transient, increase of
2 – 3 stools/day over pre-
treatment (no blood or mucus), 
OTC agents relieve
Symptomatic, increase
4 – 6 stools/day, nocturnal stools, 
cramping, requires treatment with 
prescription meds.
Increase > 6 stools/day, associated 
with disabling symptoms, 
e.g., incontinence, severe cramping, 
partial response to treatment.
Prolonged, dehydration, 
unresponsive to treatment, 
requires hospitalization.
G4.  Dyspepsia 
(heartburn)
Transient, intermittent, responds 
to OTC antacids, H-2 blockers
Prolonged, recurrent, requires 
prescription meds, relieved by 
meds
Persistent despite treatment, 
interferes with function, associated 
with GI bleeding
NA
G5.  GI bleed 
(gastritis, gastric or 
duodenal ulcer 
diagnosed-define 
aetiology)
Asymptomatic, endoscopic finding, 
haemocult + stools, no transfusion, 
responds rapidly to treatment
Symptomatic, transfusion ≤ 2 units 
needed; responds to treatment
Haematemesis, transfusion
3 – 4 units, prolonged interference 
with function
Recurrent, transfusion > 4 units, 
perforation, requiring surgery, 
hospitalisation
G6.  Haematochezia 
(rectal bleeding)
Haemorrhodial, asymptomatic, no 
transfusion
Symptomatic, transfusion
≤ 2 units, reversible
Recurrent, transfusion > 3 – 4 units
> 4 units, hypotension, requiring 
hospitalization
G7.  Hepatitis
Laboratory abnormalities, 
asymptomatic, reversible
Symptomatic laboratory 
abnormalities, not interfering with 
function, slowly reversible
Laboratory abnormalities persistent 
> 2 wks, symptoms interfere with 
function
Progressive, hepato-renal, 
anasarca, pre-coma or coma


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
G.  Gastrointestinal (continued)
G8.  Nausea, or 
nausea/vomiting (use 
diagnostic term)
Transient, intermittent, minimal 
interference with intake, rapid 
response to meds.
Persistent, recurrent, requires 
prescription meds, intake 
maintained
Prolonged, interferes with daily 
function and nutritional intake, 
periodic iv fluids
Hypotensive, hospitalization, 
parenteral nutrition, unresponsive 
to out-patient management
G9.  Pancreatitis
Anylase elevation, intermittent 
nausea/vomiting, transient, 
responds rapidly to treatment
Amylase elevation with abdominal 
pain, nausea, occasional vomiting, 
responsive to treatment
Severe, persistent abdominal pain 
with pancreatitic enzyme elevation, 
incomplete or slow response to 
treatment
Complicated by shock, 
haemorrhage (acute circulatory 
failure)
G10.  Proctitis
Perianal pruritus, haemorrhoids 
(new onset), transient, or 
intermittent, relieved by OTC meds
Tenesmus or ulcerations, anal 
fissure, responsive to treatment, 
minimal interference with 
function
Unresponsive to treatment, marked 
interference with function
Mucosal necrosis with 
haemorrhage, infection, surgery 
required.
H.  Musculoskeletal
H1.  Avascular 
necrosis
Asymptomatic MRI changes, non-
progressive
MRI changes and symptoms 
responsive to rest and analgesia
MRI changes, symptoms requiring 
surgical intervention
Wheelchair bound; surgical repair 
not possible
H2.  Arthralgia
Intermittent transient symptoms, 
no meds or relieved by OTC meds
Persistent or recurrent symptoms, 
resolve with meds, little effect on 
function
Severe symptoms despite meds 
impairs function
Debilitating, hospitalisation 
required for treatment
H3.  Leg cramps
Transient, intermittent, does not 
interfere with function
Recurrent symptoms, minimally 
interferes with function or sleep, 
responds to meds
Persistent, prolonged interference 
with function or sleep, partial or no 
response to meds
NA
H4.  Myalgia
Occasional; does not interfere with 
function
Frequent, requires meds (non-
narcotic); minor effects on 
function
Major change in function/lifestyle, 
narcotic pain meds
Debilitating, profound weakness, 
requires wheelchair, unresponsive 
to meds


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
I.  Neuropsychiatric
I1.  Anxiety or 
Depression (mood 
alteration)
Symptomatic, does not interfere 
with function; no meds
Frequent symptoms, responds to 
meds; interferes with ADL at times
Persistent, prolonged symptoms, 
partial or no response to meds, 
limits daily function
Suicidal ideation or danger to self
I2.  Cerebrovascular 
ischaemia
NA
Single transient ischaemic event, 
responsive to treatment
Recurrent transient ischaemic 
events
Cerebrovascular vascular accident 
with permanent disability
I3.  Cognitive 
disturbance
Subjective symptoms, transient, 
intermittent, not interfering with 
function
Objective symptoms, persisting, 
interferes with daily function 
occasionally
Persistent, or worsening objective 
symptoms; interferes with routine 
daily routine
Debilitating/disabling and 
permanent; toxic psychosis
I4.  Depressed 
consciousness 
(somnolence)
Observed, transient, intermittent, 
not interfering with function
Somnolence or sedation, 
interfering with function
Persistent, progressive, obundation, 
stupor
Coma
I5.  Inability to 
concentrate
Subjective symptoms, does not 
interfere with function
Objective findings, interferes with 
function
Persistent, prolonged objective 
findings or organic cause
NA
I6.  Insomnia (in 
absence of pain)
Occasional difficulty sleeping, 
transient intermittent, not 
interfering with function
Recurrent difficulty sleeping; 
requires meds for relief; 
occasional interference with 
function
Persistent or worsening difficulty 
sleeping; severely interferes with 
routine daily function
NA
I7.  Libido decreased
Decrease in interest
Loss of interest; influences 
relationship
Persistent, prolonged interfering 
with relationship
NA
I8.  Peripheral motor 
neuropathy
Subjective or transient loss of deep 
tendon reflexes; function 
maintained
Objective weakness, persistent, no 
significant impairment of daily 
function
Objective weakness with substantial 
impairment of function
Paralysis


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
I.  Neuropsychiatric (continued)
I9.  Peripheral sensory 
neuropathy (sensory 
disturbance)
Subjective symptoms without 
objective findings, transient, not 
interfering with function
Objective sensory loss, persistent, 
not interfering with function
Prolonged sensory loss or 
paraethesias interfering with 
function
NA
I10.  Seizure
NA
Recurrence of old seizures, 
controlled with adjustment of 
meds
Recurrence/exacerbation with 
partial response to medication
Recurrence not controlled, 
requiring hospitalization; new 
seizures
I11.  Vertigo 
(dizziness)
Subjective symptoms, transient, 
intermittent, no treatment
Objective findings, recurrent, 
meds relieve, occasionally 
interfering with function
Persistent, prolonged, interfering 
with daily function; partial response 
to medication
Debilitating without response to 
medication, hospitalization
J.  Pulmonary
J1.  Asthma
Occasional wheeze, no interference 
with activities
Wheezing, requires oral meds, 
occasional interference with 
function
Debilitating, requires nasal O2
Requires ventilator assistance
J2.  Cough
Transient, intermittent, occasional 
OTC meds relieve
Persistent, requires narcotic or 
other prescription meds for relief
Recurrent, persistent coughing 
spasms without consistent relief by 
meds, interferes with function
Interferes with oxygenation; 
debilitating
J3.  Dyspnea
Subjective, transient, no 
interference with function
Symptomatic, intermittent or 
recurring, interferes with 
exertional activities
Symptomatic during daily routine 
activities, interferes with function, 
treatment with intermittent nasal O2
relieves
Symptomatic at rest, debilitating, 
requires constant nasal O2
J4.  Pleuritic pain 
(pleurisy)
Transient, intermittent symptoms, 
no treatment or OTC meds relieve
Persistent symptoms, requires 
prescription meds for relief
Prolonged symptoms, interferes 
with function, requires frequent 
narcotic pain relief
Debilitation, requiring 
hospitalisation


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
J.  Pulmonary (continued)
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
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


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1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
L.  Chemistry
L1.  Hypercalcaemia 
(mg/dl)
1.1 × ULN – 11.5
11.6 – 12.5
12.6 – 13.5; or symptoms present
> 13.5; or associated coma
L2.  Hyperglycemia 
(mg/dl) Fasting
140 – 160
161 – 250
251 – 500
> 500, or associated with 
ketoacidosis
L3.  Hyperkalaemia 
(mg/dl)
5.5 – 5.9
6.0 – 6.4
6.5 – 7.0 or any ECG change
> 7.0 or any arrhythmia
L5.  Hypocalcaemia 
(mg/dl)
0.9 × LLN – 7.8
7.7 – 7.0
6.9 – 6.5; or associated with 
symptoms
< 6.5 or occurrence of tetany
L6.  Hypoglycemia 
(mg/dl)
55 – 64 (no symptoms)
40 – 54 (or symptoms present)
30 – 39 (symptoms impair function)
< 30 or coma
L7.  Hyponatraemia 
(mg/dl)
--
125 – 129
120 – 124
< 120
L8.  Hypokalaemia 
(mg/dl)
--
3.0 – 3.4
2.5 – 2.9
< 2.5
L9.  CPK (also if 
polymyositis-disease)
1.2 – 1.9 × ULN
2.0 – 4.0 × ULN
4.0 × ULN with weakness but 
without life-threatening signs or 
symptoms
> 4.0 × ULN with signs or symptoms 
of rhabdomyolysis or life-
threatening
L10.  Serum uric acid
1.2 – 1.6 × ULN
1.7 – 2.9 × ULN
3.0 – 5.0 × ULN or gout
NA
L11.  Creatinine 
(mg/dL)
1.1 – 1.3 × ULN
1.3 – 1.8 × ULN
1.9 – 3.0 × ULN
> 3.0 × ULN
L12.  SGOT (AST)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.1 – 8.0 × ULN
> 8.0 × ULN
L13.  SGPT (ALT)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.0 – 8.0 × ULN
> 8.0 × ULN


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
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1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation or/and dose 
reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent
Multiple meds
Hospitalized > 24 hr
Study drug discontinued
L.  Chemistry (continued)
L14.  Alkaline 
phosphatase
1.1 – 2.0 × ULN
1.6 – 3.0 × ULN
3.0 – 5.0 × ULN
> 5.0 × ULN
L15.  T. bilirubin
1.1 – 1.4 × ULN
1.5 – 1.9 × ULN
2.0 – 3.0 × ULN
> 3.0 × ULN
L16.  LDH
1.3 – 2.4 × ULN
2.5 – 5.0 × ULN
5.1 – 10 × ULN
> 10 × ULN
M.  Urinalysis
M1.  Haematuria
Micro only
Gross, no clots
Clots, transfusion < 2 units 
Transfusion required
M2.  Proteinuria (per 
24 h)
300 – 500 mg (tr/1+)
501 – 1999 mg (2+)
2 – 5.0 g (3+) nephrotic syndrome
5.0 g (4+) anasarca
M3.  WBC in urine
NA
NA
Indicating acute interstitial nephritis
Associated with acute renal failure
M4.  Uric acid crystals
Present without symptoms
NA
With stones or symptoms of stones 
(e.g., renal colic)
Causing renal outflow obstruction 
and hospitalization
ADL = activities of daily living; ANA = antinuclear antibodies; CHF = congestive heart failure; ECG = electrocardiogram; FVC = forced vital capacity; H-2 blockers = histamine-2 blockers 
IV = intravenous; LLN = lower limit of normal; MRI = magnetic resonance imaging; OTC = over-the-counter medication; SLE = systemic lupus erythematosus; ULN = upper limit of 
normal; WBC = white blood cells


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
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APPENDIX J.
ACTIVITY SCHEDULE
The following table shows the required activities the subject encounters.  The individual activities are 
described in detail in Appendix K, the Operations Manual.








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APPENDIX K. SUMMARY OF CHANGES
Previous Protocol Versions
Protocol 
Date
Version 1.0
18 October 2018
Version 1.1 (Germany Only)
07 November 2019
Version 1.1.1 (Germany Only)
20 November 2019
Version 2.0
20 November 2019
Version 3.0
20 November 2019
Version 4.0
11 March 2020
Version 4.1 (Germany Only)
12 March 2020
The purpose of this version is to remove the 
 cohort.  Minor clerical edits have been made as 
needed for consistency and clarity throughout the protocol.
Summary of Protocol Changes:
!
Title Page, removed 
 from the Title Page.
Rationale:  
 is not being studied in this protocol.
!
Synopsis, removed 
 language from the Synopsis.
Rationale:  
 is not being studied in this protocol.
!
Section 2.1, removed 
 language from this section and the clinical hypothesis.
Rationale:  
 is not being studied in this protocol.
!
Section 2.2, removed 
 language, and added language regarding COVID-19 related risks.
Rationale:  
 is not being studied in this protocol.  COVID-19 language added to indicate 
that no change to the benefit/risk balance for subjects in this study is expected.
!
Section 3.1, removed the primary and secondary objectives for the 
 cohort.
Rationale:  To clarify that the 
 cohort is not being studied in this protocol.
!
Section 3.5, revised PK and immunogenicity endpoints to remove 
Rationale:  
 is not being studied in this protocol.
!
Section 3.6, removed 
 with regard to assessment of changes in cortisol level.
Rationale:  
 is not being studied in this protocol.
!
Section 4.1, revised overall study design, including study schematic, and plan to exclude the 
 cohort.
Rationale:  
 is not being studied in this protocol.
!
Section 4.2, removed details of study conduct related to


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Rationale:  
 is not being studied in this protocol.
!
Section 5.1, removed prior and concomitant medication criteria and expectations for the 
 cohort.
Rationale:  
 is not being studied in this protocol.
!
Section 5.1, removed washout times for prior biologics/tsDMARDs for the 
 cohort, and 
shortened duration of treatment with any investigational drug prior to first dose of study drug 
to 30 days.
Rationale:  
 is not being studied in this protocol.  Thirty days is the correct duration; 
the change to 70 days in the last amendment was made in error.
!
Section 5.4, removed reference to 
 Investigator Brochure and 
 wash out 
times before baseline.
Rationale:  
 is not being studied in this protocol.
!
Section 5.7, removed details for 
 cohort dosing.
Rationale:  
 is not being studied in this protocol.
!
Section 5.8, removed information about randomization for the 
 cohort.
Rationale:  
 is not being studied in this protocol.
!
Section 6.2, removed drug administration information for 
Rationale:  
 is not being studied in this protocol.
!
Section 7.3, removed statistical analyses for efficacy for 
Rationale:  
 is not being studied in this protocol.
!
Section 7.4, removed "of each cohort" regarding the Safety Analysis Set.
Rationale:  
 is not being studied in this protocol.
!
Section 7.5, removed 
 from statistical analysis of PK and immunogenicity data.
Rationale:  
 is not being studied in this protocol.
!
Section 7.7, removed interim analysis for 
Rationale:
 is not being studied in this protocol.
!
Section 12, reference list updated.
Rationale:  References that are no longer applicable have been removed.
!
Appendix J:  revised to remove assessment/procedures related to 
 cohort.
Rationale:  
 is not being studied in this protocol.
Summary of Operations Manual Changes:
!
Title Page, removed 
 from Title Page.
Rationale:  
 is not being studied in this protocol.


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
CONFIDENTIAL INFORMATION
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!
Section 1, added section description for clarity, and removed 
 from Pharmacokinetic 
Lab section.
Rationale:  
 is not being studied in this protocol.
!
Section 2.1, removed study activities for 
.
Rationale:  
 is not being studied in this protocol.
!
Section 3.5, removed sections for PK and immunogenicity sampling for 
.
Rationale:  
 is not being studied in this protocol.
!
Section 3.6, removed biomarker sampling for 
.
Rationale:  
 is not being studied in this protocol.
!
Section 3.12, removed clinical laboratory testing for the 
 cohort.
Rationale:  
 is not being studied in this protocol.
!
Section 5.1, removed 
 for SUSAR reporting.
Rationale:  
 is not being studied in this protocol.
!
Section 6.1, removed section for 
 treatment administration.
Rationale:  
 is not being studied in this protocol.
!
Section 6.2, removed information on for 
 drug supply, storage, and disposition.
Rationale:  
 is not being studied in this protocol.
!
Section 6.3, removed the section for method of assigning subjects to treatment groups for the 
 cohort.
Rationale:  
 is not being studied in this protocol.
!
Section 6.4, removed the section for timing of study drug in the 
 cohort.
Rationale:  
 is not being studied in this protocol.


STUDY M16-560  |  Version 5.0 | EudraCT 2018-003053-21
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APPENDIX L.
OPERATIONS MANUAL

SAP_001.pdf: 
ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
1
Statistical Analysis Plan for Study M16-560
(ABBV-3373)
A Randomized, Double-Blind, Double-Dummy, Active 
Controlled Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of ABBV-3373 in 
Subjects with Moderate to Severe Rheumatoid 
Arthritis
Date:  08 September 2020
Version 5.0
NCT03823391


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypotheses ........................................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................8
3.0
Endpoints..................................................................................9
3.1
Primary Endpoint(s)...................................................................................9
3.2
Secondary Endpoint(s)...............................................................................9
3.3
Additional Efficacy Endpoint(s)................................................................9
3.4
Safety Endpoint(s) ...................................................................................10
3.5
Pharmacokinetic and Immunogenicity Endpoints ...................................10
4.0
Analysis Populations .............................................................10
5.0
Subject Disposition................................................................11
6.0
Study Drug Duration and Compliance................................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................13
7.1
Demographics and Baseline Characteristics............................................13
7.2
Medical History .......................................................................................16
7.3
Prior and Concomitant Medications ........................................................16
8.0
Efficacy Analyses...................................................................17
8.1
General Considerations............................................................................17
8.2
Handling of Missing Data........................................................................18
8.3
Primary Efficacy Endpoint(s) and Analyses............................................18
8.3.1
Primary Efficacy Endpoint(s) ..................................................................18
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint ................19
8.3.3
Primary Efficacy Analysis .......................................................................20
8.3.3.1
Mixed-Effect Model Repeated Measurements (MMRM) .......................20
8.3.3.2
Meta-Analysis of Adalimumab 80 mg Historical Data ...........................20
8.3.3.3
Primary Comparison 1:  Compare ABBV-3373 to a Historical 
Reference Value of Adalimumab.............................................................20


ABBV-3373
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Version 5.0 – 08 September 2020
3
8.3.3.4
Primary Comparison 2:  Compare ABBV-3373 to Adalimumab 
with Historical Data Borrowing...............................................................21
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s) ......................22
8.3.4.1
Per Protocol Analysis...............................................................................22
8.3.4.2
Analysis with Synthetic Placebo Arm .....................................................22
8.4
Secondary Efficacy Analyses...................................................................23
8.5
Additional Efficacy Analyses ..................................................................24
8.6
Subgroup Analysis ...................................................................................25
9.0
Safety Analyses ......................................................................25
9.1
General Considerations............................................................................25
9.2
Adverse Events ........................................................................................25
9.2.1
Treatment-Emergent Adverse Events ......................................................26
9.2.2
Adverse Event Overview .........................................................................26
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................27
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................27
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................28
9.2.6
Adverse Events of Special Interest ..........................................................28
9.3
Analysis of Laboratory Data....................................................................29
9.4
Analysis of Vital Signs ............................................................................32
9.5
Safety Subgroup Analyses .......................................................................33
9.6
Other Safety Analyses..............................................................................33
10.0
Other Analyses.......................................................................33
11.0
Interim Analyses....................................................................33
11.1
Data Monitoring Committee....................................................................33
12.0
Overall Type-I Error Rate Control .....................................33
13.0
Version History......................................................................34
14.0
References...............................................................................35
List of Tables
Table 1.
Anatomical Joints for DAS28 (CRP) Calculation ...................................19


ABBV-3373
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Version 5.0 – 08 September 2020
4
Table 2.
List of Laboratory Variables....................................................................29
List of Figures
Figure 1.
Study Schematic.........................................................................................7
List of Appendices
Appendix A.
Protocol Deviations..................................................................................37
Appendix B.
Definition of Adverse Events of Special Interest ....................................38
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............40
Appendix D.
Details for Historical Data Borrowing.....................................................58
Appendix E.
Details for Analysis with a Synthetic Placebo Arm.................................65


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Study M16-560 
A Randomized, Double-Blind, Double-Dummy, Active Controlled Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of ABBV-3373 in Subjects with 
Moderate to Severe Rheumatoid Arthritis.
Pharmacokinetic and exploratory biomarker analyses will be performed separately, and 
the corresponding analysis plan is not covered in this SAP.
Unless noted otherwise, all analyses will be performed using SAS Version 9.2 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the study protocol version 5 (Dated 
04 September 2020).  Details are outlined in Section 13.0.
2.0
Study Design and Objectives 
2.1
Objectives and Hypotheses
Primary objective 
1.
To assess the safety, tolerability, and efficacy of ABBV-3373 administered every 
other week (eow) intravenously (IV) in subjects with moderately to severely active 
RA on background MTX.
2.
To compare clinical efficacy of ABBV-3373 with adalimumab and to test the 
concept that an anti-TNF antibody-drug-conjugate has the potential to provide 
superior efficacy than the traditional anti-TNF antibody in RA.
Secondary objective 
3.
To compare adalimumab with synthetic control to establish assay sensitivity.


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
6
4.
To assess the pharmacokinetics (PK), pharmacodynamics and immunogenicity of 
ABBV-3373.
5.
To assess the duration of the treatment effect of ABBV-3373 after discontinuation.
2.2
Study Design Overview
M16-560 is a randomized, double-blind, double-dummy, adalimumab active-controlled 
(12-week) Phase 2a study to assess the safety, tolerability, PK, pharmacodynamics, 
immunogenicity and efficacy following multiple IV administrations of ABBV-3373 or 
multiple SC injections of adalimumab in subjects with RA on background MTX.  In the 
actively controlled period of the first 12 weeks of treatment, 45 subjects will receive either 
ABBV-3373 100 mg IV and the matching placebo for adalimumab SC eow or in the 
control arm the matching placebo for ABBV-3373 IV and adalimumab 80 mg SC eow 
(double-dummy) according to a 2:1 ratio.  Thereafter all subjects enter a 12-week double-
blind extension period.  At Week 12, the administration of ABBV-3373 will stop (i.e., the 
last dose of ABBV-3373 will be given at Week 10) to assess the durability of the 
observed clinical effects up to 24 weeks.  To keep blinding of the study beyond Week 12, 
the subjects randomized to ABBV-3373 will receive placebo injections, whereas subjects 
randomized into the adalimumab arm will continue their 80 mg dosing until Week 22.  At 
Week 12 and within the blinded extension period subjects who have not achieved at least 
a 20% improvement in both their swollen joint count (SJC) and tender joint count (TJC) 
based on 28 joint assessment compared with BL may be discontinued from the study at 
the discretion of the Investigator.  Subsequently, standard of care may be administered at 
the discretion of the investigator.
The unblinded analysis for the primary endpoint will be conducted after all subjects have 
completed Week 12. Subjects and sites will remain blinded to treatment assignment 
throughout the whole study period.
After all endpoints are assessed at Week 24, a telephone contact is planned to follow up 
on safety 70 days after the last dose.


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
7
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
ΔDAS28(CRP) = change in disease activity score (DAS)28(C-reactive protein [CRP]); EOW = every other week; 
IV = intravenous; SC = subcutaneous
2.3
Treatment Assignment and Blinding
Subjects will be randomized to ABBV-3373 100 mg IV and the matching placebo for 
adalimumab SC eow or in the control arm the matching placebo for ABBV-3373 IV and 
adalimumab 80 mg SC eow (double-dummy) in a 2:1 ratio.
Randomization will be stratified by
●
Current use of systemic glucocorticoid (GC) (≤ 7.5 mg/d prednisone 
equivalent) for treatment of RA at baseline (BL) (yes/no).


ABBV-3373
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8
●
Prior exposure to non-anti-TNF biologics or targeted synthetic DMARDs 
(< 3 months and terminated not due to lack of efficacy or intolerance) (yes/no).
2.4
Sample Size Determination
The primary endpoint is the mean change of DAS28 (CRP) from BL at Week 12.  
Two comparisons are considered.  The first one is to compare mean change in 
DAS28 (CRP) of ABBV-3373 group to that of historical adalimumab 80 mg eow, which 
is –2.13.  Assuming a mean DAS28 (CRP) change from baseline of –2.769 to –2.982 for 
ABBV-3373 (corresponding to 30% to 40% more reduction than historical adalimumab) 
and a standard deviation of 1.35, 30 subjects on ABBV-3373 will provide an approximate 
81% to 96% power with a one-sample t-test and two-sided alpha = 0.1 significance level.
The second comparison is between ABBV-3373 arm and adalimumab arm with borrowed 
historical adalimumab data using a Bayesian approach.  When considering borrowing 
historical data, the planned sample size is 45 subjects (30 in ABBV-3373 and 15 in 
adalimumab).  The study will be considered successful if the posterior probability of mean 
difference < 0 is larger than 95%, i.e.,:
μ	
 −μ < 0 > 0.95.
Based on the historical mean and standard deviation from adalimumab meta-analysis, a 
prior distribution for adalimumab is N (–2.13, 0.2462) corresponding to the 30 historical 
subjects borrowed.  A noninformative prior for ABBV-3373 treatment group will be set.  
Given the mean change from baseline in DAS28 (CRP) is –2.13 for adalimumab, the 
probability to claim the study success is approximately 66% to 88% if the mean change
from baseline in DAS28 (CRP) is –2.769 to –2.982 for ABBV-3373 (i.e., 30% to 40% 
more reduction than historical adalimumab), with at least 30 subjects for adalimumab 
(15 in-trial and at least 30 borrowed) and 30 subjects for ABBV-3373.  If both 
ABBV-3373 and adalimumab groups have the same mean change from baseline of –2.13, 
the probability to claim study success(false positive rate which is equivalent to type I error 


ABBV-3373
M16-560 – Statistical Analysis Plan
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9
rate) is approximately 0.03 with the same sample sizes.  In the event that adalimumab 
variability precludes historic data borrowing, using only the in-Study 15 adalimumab 
subjects and 30 ABBV-3373 subjects will provide 43% to 63% power when ABBV-3373 
in 30% to 40% more reduction than adalimumab respectively.
3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint is the change in disease activity score (DAS) 28 (C-reactive protein 
[CRP]) from Baseline (BL) at Week 12.
3.2
Secondary Endpoint(s)
1.
Change in clinical disease activity index (CDAI) from BL at Week 12
2.
Change in simplified disease activity index (SDAI) from BL at Week 12
3.
Change in DAS28 erythrocyte sedimentation rate (ESR) from BL at Week 12
4.
Achievement of low disease activity (LDA) (DAS28 [CRP] ≤3.2) at Week 12
5.
Achievement of American College of Rheumatology (ACR) 50 at Week 12
3.3
Additional Efficacy Endpoint(s)
1.
Change from BL in DAS28 (CRP) and DAS28 (ESR) at all visits
2.
Change from BL in CDAI at all visits
3.
Change from BL in SDAI at all visits
4.
ACR20/50/70 response at all visits
5.
Change from BL in individual components of ACR response at all visits
6.
Achievement of LDA at all visits.  Low disease activity is defined as DAS28 
(CRP) ≤ 3.2, DAS28(ESR) ≤ 3.2, CDAI ≤ 10, SDAI ≤ 11


ABBV-3373
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10
7.
Achievement of clinical remission (CR) at all visits.  Clinical remission is defined 
as DAS28 (CRP) < 2.6, DAS28 (ESR) < 2.6, CDAI ≤ 2.8, SDAI ≤ 3.3
8.
Change in Short Form-36 (SF-36) from BL at Week 12
9.
Achievement of minimal clinically important difference (MCID) in change from 
BL in Health Assessment Questionnaire Disability Index (HAQ-DI) (defined as 
change from BL in Health Assessment Questionnaire ≤ –0.22) at all visits among 
subjects who have HAQ ≥ 0.22 at BL
10.
Achievement of response (such as LDA) based on DAS28 (CRP), CDAI, or SDAI 
over time from Week 12 to Week 24 among subjects who have achieved DAS28 
(CRP), CDAI, or SDAI response at Week 12
3.4
Safety Endpoint(s)
1.
Treatment-emergent adverse events, serious adverse events (SAEs), adverse events 
(AEs) leading to discontinuation, AEs of special interest
2.
Percent of subjects meeting potentially clinically significant criteria for vital signs, 
laboratory variables, physical examination findings and electrocardiogram (ECG) 
interval variables
3.5
Pharmacokinetic and Immunogenicity Endpoints
Pharmacokinetic and exploratory biomarker analyses will be performed separately, and 
the corresponding analysis plan is not covered in this SAP.
4.0
Analysis Populations
The following population sets will be used for the analyses.


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Full Analysis Set (FAS)
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose 
of the study drug.  The FAS will be used for all efficacy and baseline analyses.  Subjects 
will be grouped according to treatment as randomized.
Per Protocol Analysis Set
The Per-Protocol Analysis Set represents a subset of the FAS and consists of all FAS 
subjects who did not meet any major protocol deviations prior to Week 12 of the study.  
Additional analysis may be conducted on the Per-Protocol Analysis Set as deemed 
appropriate, in order to evaluate the impact of major protocol deviations.  Major protocol 
deviations (ICH deviations and other clinically significant non-ICH deviations) will be 
identified prior to database lock for the primary analyses.
Safety Analysis Set
The Safety Analysis Set consists of all subjects who received at least 1 dose of the study 
drug.  For the Safety Analysis Set, subjects are assigned to a treatment group based on the 
"as treated" treatment group, regardless of the treatment randomized.  The "as treated" is 
determined by the treatment the subject received during the majority of the subject's drug 
exposure time in the analysis period.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled (randomized), and treated will 
be summarized.  Reasons for exclusion, including screen failure, 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 (randomized) in the study;
●
Subjects who took at least one dose of study drug;


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●
Subjects included in key analysis populations (Full Analysis Set and Per 
Protocol Analysis Set for primary efficacy analysis, Safety Analysis Set),
●
Subjects who completed protocol-specified treatment of the first 12 weeks 
(Only applicable for Week 12 analysis);
●
Subjects who completed protocol-specified treatment (Only applicable for 
final analysis);
●
Subjects who prematurely discontinued study drug by Week 12 (all reasons 
and primary reason) (Only applicable for Week 12 analysis);
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason) (Only applicable for final analysis);
●
Subjects who completed overall study participation.
For end of study participation, the number and percentage of subjects who completed the 
protocol defined follow-up period (or did not with associated reasons) will be summarized
overall and by treatment group.
6.0
Study Drug Duration and Compliance
For the Safety Analysis Set, duration of treatment will be summarized for each treatment 
group.  Duration of treatment is defined for each subject as last active dose date minus 
first dose date + 14, dosing interval.  Duration of treatment will be summarized using the 
number of subjects treated, mean, standard deviation, median, minimum and maximum.  
In addition, the number and percentage of subjects exposed to study drug will be 
summarized for the following duration intervals.
●
< 2 weeks (14 days)
●
≥ 2 weeks (14 days)
●
≥ 4 weeks (28 days)
●
≥ 8 weeks (56 days)
●
≥ 12 weeks (84 days)


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The duration of treatment for ABBV-3373 and for ADA will be summarized by treatment 
group for the Safety Analysis set up to Week 12, and throughout the entire study.
The duration of treatment will be summarized by the following groups:
1.
ABBV-3373 100 mg IV EOW
2.
ADA 80 mg SC EOW
Treatment compliance for ABBV-3373 and for ADA will be summarized by treatment 
group for the Safety Analysis set up to Week 12.  In addition, treatment compliance for 
ADA will be summarized by treatment group for the Safety Analysis Set between 
Week 12 and Week 24.  Treatment compliance is defined as the number of IV/injections 
actually taken divided by the number of IV/injections that should have been taken.  
Percent compliance will be summarized.
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
Main baseline demographic characteristics
●
Sex (male/female)
●
Age (years)
●
Race (White, Black or African American, Other)


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Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Geographic region (North America, Europe, 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)
ACR and/or DAS Components at Baseline
●
Tender joint count (TJC28) defined as the number of tender joints out of 
28 assessed joints used for DAS28 calculation
●
Swollen joint count (SJC28) defined as the number of swollen joints out of 
28 assessed joints used for DAS28 calculation
●
Physician's global assessment of disease activity (mm on a 100-mm horizontal 
visual analogue scale [VAS])
●
Patient's assessment of pain within a week prior to baseline (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)


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Other Baseline RA Disease Characteristics
●
Percentage of subjects on oral steroid at baseline
●
Oral steroid dose (prednisone equivalent) at baseline
●
DAS28 (CRP)
●
DAS28 (ESR)
●
DAS28 Categories:
○
DAS28 > 5.1 (High Disease Activity)
○
DAS28 ≤ 5.1
●
Clinical Disease Activity Index (CDAI)
●
CDAI categories:
○
CDAI > 22 (High Disease Activity)
○
CDAI ≤ 22
●
Simplified Disease Activity Index (SDAI)
●
SDAI categories:
○
SDAI > 26 (High Disease Activity)
○
SDAI ≤ 26
Patient Report Outcomes at Baseline
●
36-Item Short Form Health Survey (SF-36) Version 2:  physical component 
summary, mental component summary and the 8 sub-domain scores
Prior and Concomitant Treatment use
●
Prior non-anti-TNF use (Y/N)
●
Prior synthetic DMARD use (Y/N)
○
Prior conventional synthetic DMARD use (Y/N)
○
Prior targeted synthetic DMARD use (Y/N)
●
Steroid use at baseline (Y/N)


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Clinical Tests at Screening
●
Chest x-ray
●
ECG
●
Tuberculin PPD skin test, QuantiFERON TB Gold test
●
Hepatitis Testing
●
Serum pregnancy test
Immunization History
●
Hepatitis B immunization
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [user, ex-user, non-user, unknown]
●
Alcohol Use [drinker, ex-drinker, non-drinker, unknown]
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.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group.  The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC.  Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug.  A concomitant medication is defined as any medication that started prior to the date 


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of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the date of the last dose of study drug plus 14 days.  The number and percentage of 
subjects taking medications will be summarized by generic drug name based on the World 
Health Organization (WHO) Drug Dictionary for both prior and concomitant medications.
8.0
Efficacy Analyses
8.1
General Considerations
There are two sets of planned efficacy analysis:  efficacy analysis by Week 12, and 
efficacy analysis between Week 12 and 24.  All efficacy analyses will be conducted in the 
FAS Population.  In addition, Per-protocol analysis for primary endpoints will be 
performed.  All tests will be 2-sided at an alpha level of 0.1. Historical data borrowing 
will be considered with a Bayesian approach. Frequentist property will be evaluated 
where false positive rate and true positive rate will be used to represent erroneous 
conclusion rates when there is no drug effect and there is drug effect respectively.
The Primary Analysis will be performed after all ongoing subjects have completed 
Week 12 visit and the database has been locked.  This will be the only and final analysis 
for the primary and secondary efficacy endpoints as well as all other efficacy endpoints in 
DB actively controlled Period.
Unless otherwise specified, categorical variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) test, stratified by use of systemic GC (≤ 7.5 mg/d prednisone equivalent) 
for treatment of RA at BL (yes/no) and prior exposure to non-anti-TNF biologics and 
targeted synthetic DMARDs (< 3 months and terminated not due to lack of efficacy or 
intolerance) (yes/no).  Continuous variables will be analyzed using Mixed-Effect Model 
Repeat Measurement (MMRM) method.
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the actual stratum the subject belongs to.


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"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given.
8.2
Handling of Missing Data
Missing data will be imputed using the following methods for the efficacy analyses:
●
Non-Responder Imputation (NRI):  the NRI analysis will categorize any 
subject who does not have evaluation during a specific visit window as a 
non-responder for that visit.  The NRI will be the primary approach in the 
analyses of categorical variables.
●
Mixed-Effects Model Repeat Measurement (MMRM):  The MMRM analysis 
will be conducted using a mixed effects model including observed 
measurements at all visits except values after a subject prematurely 
discontinues from study drug.  The mixed effects model includes the 
categorical fixed effects of treatment, visit and treatment-by-visit interaction, 
stratification factors at randomization, and the continuous fixed covariates of 
baseline measurement.  An unstructured variance covariance matrix will be 
used.  Parameter estimation is based on the assumption of data being missing 
at random and using the method of restrictive maximum likelihood (REML).  
MMRM will be the primary approach in the analysis of continuous variables.
●
Observed Cases (OC):  The OC analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the OC analysis for that visit.  OC will exclude 
values after a subject prematurely discontinue from study drug.
8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Endpoint(s)
The primary endpoint is the change from baseline in DAS28 (CRP) at Week 12.
DAS28 (CRP) is a composite index to assess disease activity in RA patients using hsCRP 
measurement.  The DAS provides a score between 0.96 and 10, indicating how active the 
rheumatoid arthritis is at the time of measurement.


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DAS28 (CRP) can be calculated based on Tender Joint Count, Swollen Joint Count, 
Patient's Global Assessment of Disease Activity (PtGA) (in mm), and hsCRP (in mg/L).
DAS28 (CRP) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(hsCRP& + 1) 
+ 0.014 × PtGA» + 0.96
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
&
hsCRP refers to the high-sensitivity C-reactive protein lab value.  hsCRP unit in the DAS28 (CRP) equation is 
expressed as mg/L.
»
PtGA refers to the Patient's Global Assessment of Disease Activity.
Where √is square root and ln is natural log.
Table 1.
Anatomical Joints for DAS28 (CRP) Calculation
Shoulder
Elbow
Wrist
Thumb Interphalangeal
Metacarpophalangeal I
Metacarpophalangeal II
Metacarpophalangeal III
Metacarpophalangeal IV
Metacarpophalangeal V
Proximal 
Interphalangeal II
Proximal 
Interphalangeal III
Proximal 
Interphalangeal IV
Proximal 
Interphalangeal V
Knee
To calculate observed DAS28 scores, the observed component value will be calculated 
first.  Then the components will be included in the calculation per the DAS formula 
selected.  If any observed component is missing in a window, then the observed 
DAS28 score will be missing.
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint
If any observed component of DAS28 is missing in a window, then the observed 
DAS28 score will be missing.
MMRM described in Section 8.2 will be the primary imputation approach in the analysis 
of the primary endpoint.


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8.3.3
Primary Efficacy Analysis
The null hypothesis is that there is no difference in change from BL in DAS28 (CRP) at 
Week 12 between ABBV-3373 and adalimumab.
The alternative hypothesis is that change from BL in DAS28 (CRP) at Week 12 for 
ABBV-3373 is different from adalimumab.
8.3.3.1
Mixed-Effect Model Repeated Measurements (MMRM)
An MMRM model including up to Week 12 data with treatment group, visits, treatment-
by-visit interaction, BL values and stratification factors will be used to estimate mean and 
standard deviation of each treatment group, and the treatment difference between 
two treatment groups based on in-study data.  An unstructured variance covariance matrix 
will be used.  The parameter estimations are based on the assumption of data being 
missing at random and using the method of restricted maximum likelihood (REML).
Least-square mean, SE and 90% confidence interval (CI) at Week 12 for each treatment 
group will be presented together with least-square means (SE), 90% CI of the treatment 
difference and 2-sided p-value from t-test for the difference = 0.
8.3.3.2
Meta-Analysis of Adalimumab 80 mg Historical Data
The historical mean, 95% confidence interval and standard deviation of the change from 
BL in DAS28 (CRP) at Week 12 in adalimumab 80 mg eow are estimated to be –2.13 
(–2.29, –1.96) and 1.35 respectively based on a meta-analysis consisting of 242 subjects 
from 3 historical adalimumab studies (Studies DE007, DE009, and DE011) with similar 
populations, similar inclusion and exclusion criteria; for details, see Appendix D.
8.3.3.3
Primary Comparison 1:  Compare ABBV-3373 to a Historical 
Reference Value of Adalimumab
The first comparison in order to achieve the primary objective of assessing the efficacy of 
ABBV-3373 is to compare change from baseline in DAS28 (CRP) at Week 12 in the 
ABBV-3373 group with –2.13, the adalimumab 80 mg eow historical mean change from 


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BL at Week 12 based on the meta-analysis.  The mean of the ABBV-3373 treatment 
group estimated from the above MMRM model will be compared to –2.13, and 90% CI 
and p-value will be provided.
8.3.3.4
Primary Comparison 2:  Compare ABBV-3373 to 
Adalimumab with Historical Data Borrowing
The second comparison is between ABBV-3373 arm and adalimumab arm with borrowed 
historical adalimumab data using a Bayesian historical borrowing approach.  Meta-
analysis results from the historical data will be used as prior distribution for control group 
mean and a non-informative prior will be used for treatment group mean. Based on 
posterior means and variances for treatment and control groups, (!" −!# < 0|%)
will be calculated where !" and !# are treatment mean and control mean respectively. 
The details for historical data borrowing analysis is in Appendix D.
Based on the historical mean and standard deviation from adalimumab meta-analysis, 
30 historical adalimumab subjects will be borrowed, which targets control of false 
positive rate < 10% and not exceeding total sample size of 45 in the current study. That 
is: number of borrowed subjects *+ = 30, historical mean from meta-analysis !/ =
−2.13 and its SE 4+ = 1.35 √30
⁄
= 0.246. Therefore a conjugate prior distribution for 
adalimumab is N (–2.13, 0.2462).  A 'flat' noninformative prior will be used for 
ABBV-3373 treatment group, which results in the posterior distribution totally based on 
the data.  The prior distributions and estimates of mean of each treatment group from the 
MMRM model above will be combined to construct the posterior distributions which will 
be used for comparison between ABBV-3373 and adalimumab.  Based on posterior 
distribution of means for treatment and control groups, the probability of Treatment mean 
– Control mean < 0 given the observed data i.e., (!" −!# < 0|%) will be calculated.
If (!" −!# < 0|) > 0.95, the treatment group will be claimed as significantly 
better than the control group. For sensitivity analysis, the dynamic borrowing based on 
observed bias may be performed as detailed in Appendix D.


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If the adalimumab group mean is not comparable with historical adalimumab data, for 
example, the confidence intervals of the mean based on historical and in-trial data don't 
overlap, the Bayesian approach based on historical data may not be performed, and the 
mean difference in change from baseline in DAS28 (CRP) at Week 12 between the 
ABBV-3373 group and adalimumab will be estimated only based on in-study data with 
the MMRM model described above.
Historical data borrowing will only apply to the primary endpoint.
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s)
8.3.4.1
Per Protocol Analysis
The primary analyses above may also be conducted on the Per Protocol Analysis Set.
8.3.4.2
Analysis with Synthetic Placebo Arm
Study M16-560 has two treatment arms, the investigational drug ABBV-3373 and 
adalimumab as an active control.  Since the trial doesn't have a placebo arm, subject-level 
historical placebo data will be used to estimate the treatment effect of ABBV-3373 or 
adalimumab against placebo to establish the assay sensitivity of the study.  Historical 
placebo data of the change from baseline in DAS28(CRP), the primary endpoint, from 
3 recent AbbVie studies with similar populations, entry criteria and study designs:  
upadacitinib Phase 2 study (Study M13-537), upadacitinib Phase 3 studies SELECT-
COMPARE (Study M14-465) and SELECT-NEXT (Study M13-549) are selected to 
construct a synthetic placebo arm through propensity score matching.  For details of entry 
criteria of these studies, see Appendix E.
The propensity scores will be estimated for in-trial subjects and historic placebo subjects 
using penalized maximum likelihood estimation (PMLE) (Firth, 1993) with selected 
common baseline demographics and characteristics variables shared by Study M16-560 
and the three historical studies.  The full list of baseline variables can be found in 
Appendix E. The "nearest neighbor matching" will be performed based on a distance 
measure, caliper, calculated from the logistic regression for propensity score estimates.  


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The intention is to match 45 to 90 placebo subjects corresponding to 1 or 2 synthetic 
placebo subject(s) matched with each ABBV-3373 or adalimumab treated subject.
Pairwise comparison between the in-trial data of the ABBV-3373 or adalimumab 
treatment group and the synthetic placebo arm will be performed based on matched 
dataset.  Each of ABBV-3373 and adalimumab groups will be compared with all matched 
placebo subjects separately.  Change from baseline in DAS28 (CRP) at Week 12 will be 
analyzed with the matched dataset by an MMRM model including data collected during 
the common study visits up to Week 12 (i.e., Weeks 2, 4, 8, 12) with treatment group, 
study visits, and treatment-by-visit interaction.  An unstructured variance covariance 
matrix will be used.  The parameter estimations will be based on the assumption of data 
being missing at random and using the method of restricted maximum likelihood 
(REML).  Least-square mean difference, 90% CI and p-value will be presented.
If only very few placebo patients can be matched with treated subjects in Study M16-560 
and analysis based on matched dataset is deemed not appropriate, alternative methods 
such as propensity score stratified analysis will be considered.
Further details of analyses and implementation using synthetic placebo control are 
described in Appendix E.
8.4
Secondary Efficacy Analyses
Secondary efficacy endpoints are listed in Section 3.2.
Continuous efficacy variables will be analyzed using the same MMRM model as for the 
primary endpoint analysis with data up to Week 12.  LS mean and 90% CI of each 
treatment group and between-treatment-group difference will be reported. P-value for the 
treatment comparison will be presented.
Categorical efficacy variables will be analyzed using the Cochran-Mantel-Haenszel 
(CMH) test controlling for stratification variables.  Point estimate and 90% CI using 
normal approximation will be provided for the response rate for each randomized 


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treatment group.  Point estimate, 90% CI of treatment difference using normal 
approximation and p-value for the treatment comparison will be presented.  For the 
primary analysis, non-responder imputation (NRI) will be used.
Secondary endpoints may also be analyzed between ABBV-3373 or adalimumab and the 
synthetic placebo arm with the matched data sets described in Section 8.3.4.2 as needed.  
If conducted, continuous endpoints between ABBV-3373 or adalimumab and the 
synthetic placebo arm will be analyzed using the same MMRM model as described in 
Section 8.3.4.2, and binary endpoints between ABBV-3373 or adalimumab and the 
synthetic placebo arm will be analyzed using Chi-square test with non-responder 
imputation (NRI).
8.5
Additional Efficacy Analyses
Additional efficacy endpoints are listed in Section 3.3.
Continuous efficacy variables will be analyzed using the same MMRM model as for the 
primary endpoint analysis with data up to Week 12.  In addition, statistical inference of 
continuous endpoints at each visit up to Week 24 will be conducted using analysis of 
covariance (ANCOVA) with treatment, stratification factors and the corresponding 
baseline value as the covariates.  LS mean and 90% CI of each treatment group and 
between-treatment-group difference will be reported. P-value for the treatment 
comparison will be presented.
Categorical efficacy variables up to Week 24 will be analyzed using the same Cochran-
Mantel-Haenszel (CMH) test as for the binary secondary endpoint analysis.  For the 
primary analysis, non-responder imputation (NRI) will be used.  Point estimate and 
90% CI using normal approximation will be provided for the response rate for each 
randomized treatment group.  Point estimate of treatment difference, 90% CI using 
normal approximation and p-value for the treatment comparison will be presented.
Plots by randomized treatment group over time will be provided for selected efficacy 
endpoints.


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8.6
Subgroup Analysis
●
No efficacy subgroup analysis is planned.
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Analysis Set.  Safety summaries will be 
presented by treatment group.  For the safety analysis, subjects are assigned to a treatment 
group based on the treatment actually received, regardless of the treatment randomized.  A 
subject's actual treatment will be determined by the most frequent dose regimen received.
Safety analyses will be carried out using the Safety Analysis Set.  Safety analyses will 
include reporting of adverse events, laboratory, vital signs and ECG measurements.  
Missing safety data will not be imputed.  No external data borrowing will be applied for 
safety analyses.
There are two sets of planned safety analyses:  safety analysis up to Week 12 by "as 
treated" treatment groups of ABBV-3373 and ADA 80 mg EOW, and long-term safety 
analysis which includes safety analysis of the extension period (Week 12 to 24) by "as 
treated" treatment groups of PBO and ADA 80 mg EOW, and the safety analysis adjusted 
by cumulative active treatment exposure groups (ABBV-3373 and ADA 80 mg EOW).
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.


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9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with the onset that is after the first dose 
of study drug and with an onset date no more than 5 half-lives of the study drug 
(i.e., 70 days).  Events where the onset date is the same as the study drug start date are 
assumed to be treatment-emergent.  If an incomplete onset date was collected for an 
adverse event, the event will be assumed to be treatment-emergent unless there is other 
evidence that confirms that the event was not treatment-emergent (e.g., the event end date 
was prior to the study drug start date).  All treatment-emergent AEs will be summarized 
overall, as well as by primary MedDRA SOC and Preferred Term.  The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.  In addition, treatment-emergent AEs per 100 patient-years of study 
exposure will be presented by treatment group for AE overview.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent AE of Special Interest
●
All deaths
○
Deaths occurring ≤ 70 days after last dose of study drug
○
Deaths occurring > 70 days after last dose of study drug.


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The point estimate and 90% CI (using normal approximation) will be provided for the 
treatment difference in AE percentages.
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
An overview of treatment-emergent AEs per 100 patient-years of study exposure will be 
presented by treatment group for the same AE categories.  The point estimate and 90% CI 
(using normal approximation) will be provided for the treatment difference in AE rates 
per 100 patient-years.
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by 
subject number and SOC and PT.  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.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the ABBV-3373 group.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided for AE overview, where 
AEs per 100 patient-years of exposure are defined as the number of AEs divided by the 
total study drug exposure in 100 patient-years.  The study drug exposure is defined as the 
last dose date plus 5 × half-life (70 days), minus the first dose date.
The point estimate and 90% CI (using normal approximation) will be provided for the 
treatment difference in AE rates per 100 patient-years.


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9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs, deaths and AEs leading to study drug discontinuation will be summarized by SOC 
and PT and in listing format.
9.2.6
Adverse Events of Special Interest
Adverse events of special interest will be summarized by SOC and PT and will be based 
on standardized or company MedDRA queries (SMQs or CMQs). Adverse events of 
special interest are categorized as follows:
●
Serious infections, opportunistic infections, herpes zoster, and TB;
●
Malignancy (all types);
●
Cardiovascular events (e.g., major adverse cardiovascular event [MACE]);
●
Hematologic disorders (i.e., anemia, neutropenia, lymphopenia);
●
Hepatic disorders;
●
Hypersensitivity reactions, including all serious allergic reactions;
●
Demyelinating disease;
●
Systemic GC side effects (i.e., infections, skin atrophy, weight gain, cataract, 
hypertension, indigestion, hyperglycemia).
Detailed information about the search criteria are provided in Appendix B.
Tabular listings of selected adverse events of special interest will be provided.  Additional 
AEs may be considered for tabulation/summary based on recommendations from Clinical 
and Safety as deemed appropriate.
Treatment-emergent AESIs per 100 patient-years of study exposure will also be presented 
by treatment group.


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9.3
Analysis of Laboratory Data
All laboratory parameters to be collected in this study are listed below.  Laboratory 
parameters will be reported using the standard international (SI) units.
Table 2.
List of Laboratory Variables
Laboratory Variables
Hematology
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
HbA1c
Chemistry
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Albumin
Alanine transaminase (SGPT/ALT)
Aspartate transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium


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Table 2.
List of Laboratory Variables (Continued)
Laboratory Variables
Chemistry (continued)
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Lactate dehydrogenase (LDH)
Creatinine phosphokinase (CPK)
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Other
hs-CRP
ESR
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and
clinical chemistry) will be summarized.
For each laboratory variable, mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 


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error, and 90% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between treatment groups.
Changes in laboratory parameters will be tabulated using shift tables by Rheumatology 
Common Toxicity Criteria v2.0.  A shift table from baseline to the worst post-baseline 
category (maximum toxicity grade) during treatment will be created.  A similar shift table 
will be provided to summarize shifts from baseline to the final post-baseline value.  No 
statistical tests will be performed for this analysis.
For total cholesterol and triglycerides, the following categories according to National 
Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines 
will be used. Shift tables from baseline to the maximum or to the minimum or to the final 
post-baseline value during treatment will be created.  
●
Total cholesterol (< 5.17, ≥5.17 and < 6.21, ≥6.21 mmol/L)
●
Triglycerides (< 1.69, ≥1.69 and < 2.26, ≥2.26 mmol/L)
Potentially Clinically Significant (PCS) Laboratory abnormalities meeting Rheumatology 
Common Toxicity Criteria (Appendix C) grade 3 and 4 will be summarized.  For 
creatinine phosphokinase and creatinine, NCI CTC criteria will be used.  Only subjects 
with worsening in grade compared to baseline grade will be captured.
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.
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


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●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions simultaneously, will be provided:  ALT > 3 × ULN or AST > 3 × ULN that is 
associated with an increase in bilirubin ≥ 2 × ULN and alkaline phosphatase < 2 × ULN.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, weight and 
body temperature will be summarized.
For each vital sign variable, mean change from baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
baseline mean, and visit mean.  The change from baseline mean, standard error, and 
90% confidence interval will be presented for the mean change from baseline within each 
treatment group and difference between treatment groups.
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.


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9.5
Safety Subgroup Analyses
No safety subgroup analysis is planned.
9.6
Other Safety Analyses 
ECG is collected at baseline visit, Week 12 and Week 24.  ECG findings will be 
summarized by treatment group for each parameter and visit.
10.0
Other Analyses
No other analysis is planned.
11.0
Interim Analyses
There will not be an interim efficacy analysis for this study.
11.1
Data Monitoring Committee
There will be no DMC in this study.
12.0
Overall Type-I Error Rate Control
Multiplicity for multiple comparison is not adjusted in this POC study.  For the primary 
endpoint, the first comparison between ABBV-3373 and adalimumab 80 mg historical 
mean using single arm test provides control of type I error rate at alpha = 0.1 (2-sided).  
For the second comparison between ABBV-3373 and adalimumab 80 mg using historical 
data borrowing, the false positive rate will be capped at alpha = 0.1 (1-sided).


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13.0
Version History
Version
Date
Summary
1.0
13 June 2019
Original version
2.0
12 November 2019
Version 2
3.0
02 December 2019
Version 3
4.0
17 April 2020
Version 4
5.0
08 September 2020
Version 5
This SAP includes changes from the previous version of the SAP (version 1.0, approved 
on 13 June 2019, version 2.0, approved on 12 November 2019, version 3.0 approved on 
02 December 2019, version 4.0 approved on 17 April 2020).  High level updates in this 
SAP include:
●
Title:  Removed 
 in title
Rationale:  To align with protocol version 5.0
●
Section 1.0:  Removed 
 in introduction part
Rationale:  To align with protocol version 5.0
●
Section 2.0:  Removed the specification of 'ABBV-3373 cohort' for this SAP
Rationale:  To align with protocol version 5.0
●
Section 2.1:  Removed the specification of 'ABBV-3373 cohort' for this SAP
Rationale:  To align with protocol version 5.0
●
Section 2.2:  Removed the specification of 'ABBV-3373 cohort' for this SAP
Rationale:  To align with protocol version 5.0
●
Section 6.0:  Removed the wording "cumulative" for exposure duration 
interval analysis
Rationale: Wording updated for clarity.
●
Section 6.0:  Updated treatment label for ADA 80 mg SC EOW group
Rationale: Wording updated for accuracy
●
Section 8.1:  Added wording "actively controlled" to clarify the scope of 
primary analysis.
Rationale:  Wording updated for clarity and accuracy.


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●
Appendix B, Table B-1:  Added search criteria for Herpes Zoster
Rationale:  To increase accuracy.
●
Appendix B, Table B-1:  Updated the AESI term "Opportunistic Infection 
Excluding TB" as "Opportunistic Infection Excluding TB and Herpes Zoster"
Rationale:  To increase accuracy for the description of AESI term.
14.0
References
1.
Ibrahim J, Chen M.  Power prior distribution for regression models.  Statistical 
Science.  2000;15:46-60.
2.
Hobbs BP, Carlin BP, Mandrekar SJ, et al.  Hierarchical Commensurate and Power 
Prior Models for Adaptive Incorporation of Historical Information in Clinical 
Trials.  Biometrics.  2011;67(3):1047-56.
3.
Schmidli H, Gsteiger S, Roychoudhury S, et al.  Robust Meta-Analytic-Predictive 
Priors in Clinical Trials with Historical Control Information.  Biometrics.  
2014;70(4):1023-32.
4.
Neuenschwander B, Capkun-Niggli G, Branson M, et al.  Summarizing historical 
information on controls in clinical trials.  Clin Trials.  2010;7(1):5-18.
5.
Pocock S.  The combination of randomized and historical controls in clinical trials.  
J Chronic Dis.  1976;29(3):175-88.
6.
Genovese MC, Kremer J, Zamani O, et al.  Baricitinib in Patients with Refractory 
Rheumatoid Arthritis.  N Engl J Med.  2016;374(3):1243-52.
7.
Burmester GR, Blanco R, Charles-Schoeman C, et al.  Tofacitinib (CP-690,550) in 
combination with methotrexate in patients with active rheumatoid arthritis with an 
inadequate response to tumour necrosis factor inhibitors:  a randomised Phase 3 
trial.  Lancet.  2013;381(9865):451-60.
8.
Sidik K, Jonkman JN.  A comparison of heterogeneity variance estimators in 
combining results of studies.  Stat Med.  2007;26(9):1964-81.


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9.
Schäcke H, Döcke WD, Asadullah K.  Mechanisms involved in the side effects of 
glucocorticoids.  Pharmacol Ther.  2002;96(1):23-43.
10.
Genovese MC, Fleischmann R, Kivitz AJ, et al.  Sarilumab plus methotrexate in 
patients with active rheumatoid arthritis and inadequate response to methotrexate:  
results of a Phase III study.  Arthritis Rheumatol.  2015;67(6):1424-37.
11.
Taylor PC, Keystone EC, van der Heijde D, et al.  Baricitinib versus placebo or 
adalimumab in rheumatoid arthritis.  N Engl J Med.  2017;376(7):652-62.
12.
Westhovens R, Taylor PC, Alten R, et al.  Filgotinib (GLPG0634/GS-6034), an 
oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) 
in patients with active rheumatoid arthritis and insufficient response to MTX:  
results from a randomised, dose-finding study (DARWIN 1).  Ann Rheum Dis.  
2017;76(6):998-1008.
13.
Rosenbaum PR, Rubin DB.  Constructing a control group using multivariate 
matched sampling methods that incorporate the propensity score.  Am Stat.  
1985;39(1): 33-8.
14.
Austin PC.  Optimal caliper widths for propensity-score matching when estimating 
differences in means and differences in proportions in observational studies.  
Pharm Stat.  2011;10(2):150-61.
Appendix


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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:
Table B-1.
AESI SMQs/CMQs/PTs Search Criteria
Adverse Event of Interest
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Infections
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection Excluding TB and 
Herpes Zoster
CMQ
"Opportunistic Infections excluding 
Tuberculosis and Herpes Zoster"
Tuberculosis
CMQ
"Tuberculosis (Including Investigations)"
Active Tuberculosis
CMQ
"Active Tuberculosis"
Tuberculosis Conversion
CMQ
"Tuberculosis (Including Investigations)"
Herpes Zoster
CMQ
"Herpes Zoster"
Malignancies
Malignancies
SMQ
Narrow
"Malignancies"
Lymphoma
SMQ
Broad
"Malignant Lymphomas"
Hepatosplenic T-Cell Lymphomas
(HSTCL)
CMQ
"Hepatosplenic T-Cell Lymphoma"
Non-Melanoma Skin Cancer (NMSC)
SMQ
Broad
"Skin Neoplasms, Malignant and
Unspecified" And Add the Preferred 
Terms "Squamous Cell Carcinoma" and 
"Bowen's Disease" to this Search
Cardiovascular Events
Myocardial Infarction
SMQ
Broad
"Myocardial infarction"
Cerebrovascular Accident
SMQ
Broad
"Central nervous system vascular 
disorders"
Congestive Heart Failure
SMQ
Broad
"Cardiac Failure"
Hematologic Disorders
Hematologic Disorders Including
Pancytopenia
SMQ
Broad
"Haematopoietic Cytopenias"
Hepatic Events
Liver Failure and Other Liver Events 
(Except Gall Bladder Related Events)
SMQ
Broad
"Drug Related Hepatic Disorders –
Comprehensive Search"


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Table B-1.
AESI SMQs/CMQs/PTs Search Criteria (Continued)
Adverse Event of Interest
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Allergic Reactions
Allergic Reactions Including 
Hypersensitivity, Angioedema, and
Anaphylaxis
1) SMQ
2) SMQ
3) SMQ
1) Narrow
2) Broad 
3) Broad
1) "Hypersensitivity"
2) "Anaphylactic Reaction" and 
3) "Angioedema" and PT "Drug reaction 
with Eosinophilia and systemic 
Syndrome"
Stevens-Johnson Syndrome
SMQ
Narrow
"Severe Cutaneous Adverse Reactions"
Erythema Multiforme
SMQ
Narrow
"Severe Cutaneous Adverse Reactions"
Demyelinating Disease
Demyelinating Disorders Including 
Multiple Sclerosis, Guillain-Barré 
Syndrome, and Optic Neuritis and Others
SMQ
Broad
"Demyelination"
Systemic Glucocorticoid Events
Systemic Glucocorticoid Events
NA
NA
Medical review and adjudication of the 
events


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Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints
Table C-1.
Rheumatology Common Toxicity Criteria v2.0
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
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


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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
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
A4.  Serum sickness
Transient, non-prescription 
meds relieve
Symptomatic, slow response 
to meds (e.g., oral 
corticosteroids)
Prolonged; symptoms only partially 
relieved by meds; parenteral 
corticosteroids required
Major organ dysfunction, 
requires long-term high-dose 
immunosuppressive therapy
A5.  Vasculitis
Localised, not requiring 
treatment; or rapid response 
to meds; cutaneous
Symptomatic, slow response
to meds (e.g., oral 
corticosteroids)
Generalised, parenteral 
corticosteroids required or/and short 
duration hospitalisation
Prolonged, hospitalisation, 
ischemic changes, amputation
B.  Cardiac
B1.  Arrhythmia
Transient, asymptomatic
Transient, but symptomatic or 
recurrent, responds to meds
Recurrent/persistent; maintenance 
prescription
Unstable, hospitalisation 
required, parenteral meds
B2.  Cardiac function decreased
Asymptomatic decline in 
resting ejection fraction by 
> 10%, but < 20% of 
baseline value
Asymptomatic decline of 
resting ejection fraction 
≥20% of baseline value
CHF responsive to treatment
Severe or refractory CHF
B3.  Edema
Asymptomatic (e.g., 1 + 
feet/calves), self-limited, no 
therapy required
Symptomatic (e.g., 2 + 
feet/calves), requires therapy
Symptoms limiting function (e.g., 3 + 
feet/calves, 2 + thighs), partial relief 
with treatment prolonged
Anasarca; no response to 
treatment


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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
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
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
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
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


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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
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
C6.  Sweating (diaphoresis)
Episodic, transient
Frequent, short term
Frequent, drenching, disabling
Dehydration, requiring IV 
fluids/hospitalization > 24 hrs
C7.  Weight gain
5% – 9.9%
10% – 19.9%
20% – 30%
NA
C8.  Weight loss
5% – 9.9%
10% – 19.9%
20% – 30%
NA
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


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Version 5.0 – 08 September 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
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
D5.  Petechiae (without 
vasculitis)
Few, transient asymptomatic
Dependent areas, persistent up 
to 2 wks
Generalised, responsive to treatment; 
reversible
Prolonged, irreversible, 
disabling
D6.  Photosensitivity
Transient erythema
Painful erythema and oedema 
requiring topical treatment
Blistering or desquamation, requires 
systematic corticosteroids
Generalised exfoliation or 
hospitalisation
D7.  Pruritis
Localised, asymptomatic, 
transient, local treatment
Intense, or generalised, 
relieved by systematic 
medication
Intense or generalised; poorly 
controlled despite treatment
Disabling, irreversible
D8.  Rash (not bullous)
Erythema, scattered 
macular/popular eruption; 
pruritis transient; TOC or no 
meds
Diffuse macular/popular 
eruption or erythema with 
pruritus; dry desquamation; 
treatment required
Generalised, moist desquamation, 
requires systemic corticosteroids; 
responsive to treatment; reversible
Exfoliative or ulcerating; or 
requires hospitalisation; or 
parenteral corticosteroids
D9.  
Induration/fibrosis/Thickening 
(not sclerodermal)
Localized, high density on 
palpation, reversible, no 
effect on ADL and not 
disfiguring
Local areas < 50% body 
surface, not disfiguring, 
transient interference with 
ADL, reversible
Generalized, disfiguring, interferes 
with ADL, reversible
Disabling, irreversible, systemic 
symptoms
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


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 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
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
E2.  Sense of smell
Slightly altered
Markedly altered
Complete loss, reversible
Complete loss, without recovery
E3.  Stomatitis
Asymptomatic
Painful, multiple, can eat
Interferes with nutrition, slowly 
reversible
Requires enteral support; 
residual dysfunction
E4.  Taste disturbance 
(dysgeusia)
Transiently altered; metallic
Persistently altered; limited 
effect on eating
Disabling, effect on nutrition
NA
E5.  Tinnitus
Intermittent, transient, no 
interference with function
Requires treatment, reversible
Disabling, or associated with hearing 
loss
Irreversible deafness
E6.  Voice changes (includes 
hoarseness, loss of voice, 
laryngitis)
Intermittent hoarseness, able 
to vocalise
Persistent hoarseness, able to 
vocalise
Whispered speech, slow return of 
ability to vocalise
Unable to vocalize for extended
E7.  Xerostomia (dry mouth)
Transient dryness
Relief with meds
Interferes with nutrition, slowly 
reversible
Extended duration interference
with nutrition, requires 
parenteral nutrition
F.  Eye/Ophthalmologic
F1.  Cataract
Asymptomatic, no change in 
vision, non-progressive
Symptomatic, partial visual 
loss, progressive
Symptoms impairing function, vision 
loss requiring treatment, including 
surgery
NA


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
47
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
F2.  Conjunctivitis
Asymptomatic, transient, 
rapid response to treatment
Symptomatic, responds to 
treatment, changes not 
interfering with function
Symptoms prolonged, partial 
response to treatment, interferes with 
function
NA
F3.  Lacrimation increased 
(tearing, watery eyes)
Symptoms not requiring 
treatment, transient
Symptomatic, treatment 
required, reversible
Unresponsive to treatment with 
major effect on function
NA
F4.  Retinopathy
Asymptomatic, non-
progressive, no treatment
Reversible change in vision; 
readily responsive to 
treatment
Disabling change in vision 
ophthalmological findings reversible, 
sight improves over time
Loss of sight
F5.  Vision changes (e.g., blurred, 
photophobia, night blindness, 
vitreous floaters)
Asymptomatic, transient, no 
treatment required
Symptomatic, vision changes 
not interfering with function, 
reversible
Symptomatic, vision changes 
interfering with function
Loss of sight
F6.  Xerophtalmia (dry eyes)
Mild scratchiness
Symptomatic without 
interfering with function, 
requires artificial tears
Interferes with vision/function, 
corneal ulceration
Loss of sight
G.  Gastrointestinal
G1.  Anorexia
Adequate food intake, 
minimal weight loss
Symptoms requiring oral 
nutritional supplementation
Prolonged, requiring iv support
Requires hospitalization for 
nutritional support


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
48
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
G2.  Constipation
Asymptomatic, transient, 
responds to stool softener, 
OTC laxatives
Symptomatic, requiring 
prescription laxatives, 
reversible
Obstipation requiring medical 
intervention
Bowel obstruction.  Surgery 
required
G3.  Diarrhea
Transient, increase of 
2 – 3 stools/day over pre-
treatment (no blood or 
mucus), OTC agents relieve
Symptomatic, increase 
4 – 6 stools/day, nocturnal 
stools, cramping, requires 
treatment with prescription 
meds
Increase > 6 stools/day, associated 
with disabling symptoms, 
e.g., incontinence, severe cramping, 
partial response to treatment
Prolonged, dehydration, 
unresponsive to treatment, 
requires hospitalization
G4.  Dyspepsia (heartburn)
Transient, intermittent,
responds to OTC antacids, 
H-2 blockers
Prolonged, recurrent, requires 
prescription meds, relieved by 
meds
Persistent despite treatment, 
interferes with function, associated 
with GI bleeding
NA
G5.  GI bleed (gastritis, gastric or 
duodenal ulcer diagnosed-define 
aetiology)
Asymptomatic, endoscopic 
finding, haemocult + stools, 
no transfusion, responds 
rapidly to treatment
Symptomatic, transfusion 
≤2 units needed; responds to 
treatment
Haematemesis, transfusion 3 –
4 units, prolonged interference with 
function
Recurrent, transfusion > 4 units, 
perforation, requiring surgery, 
hospitalisation
G6.  Haematochezia (rectal 
bleeding)
Haemorrhodial, 
asymptomatic, no 
transfusion
Symptomatic, transfusion 
≤2 units, reversible
Recurrent, transfusion > 3 – 4 units
> 4 units, hypotension, requiring 
hospitalization


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
49
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
G7.  Hepatitis
Laboratory abnormalities, 
asymptomatic, reversible
Symptomatic laboratory 
abnormalities, not interfering 
with function, slowly 
reversible
Laboratory abnormalities persistent 
> 2 wks, symptoms interfere with 
function
Progressive, hepato-renal, 
anasarca, pre-coma or coma
G8.  Nausea, or nausea/vomiting 
(use diagnostic term)
Transient, intermittent, 
minimal interference with 
intake, rapid response to 
meds
Persistent, recurrent, requires 
prescription meds, intake 
maintained
Prolonged, interferes with daily 
function and nutritional intake, 
periodic iv fluids
Hypotensive, hospitalization, 
parenteral nutrition, 
unresponsive to out-patient 
management
G9.  Pancreatitis
Anylase elevation, 
intermittent 
nausea/vomiting, transient, 
responds rapidly to 
treatment
Amylase elevation with 
abdominal pain, nausea, 
occasional vomiting, 
responsive to treatment
Severe, persistent abdominal pain 
with pancreatitic enzyme elevation, 
incomplete or slow response to 
treatment
Complicated by shock, 
haemorrhage (acute circulatory 
failure)
G10.  Proctitis
Perianal pruritus, 
haemorrhoids (new onset), 
transient, or intermittent, 
relieved by OTC meds
Tenesmus or ulcerations, anal 
fissure, responsive to 
treatment, minimal 
interference with function
Unresponsive to treatment, marked 
interference with function
Mucosal necrosis with 
haemorrhage, infection, surgery 
required


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
50
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
H.  Musculoskeletal
H1.  Avascular necrosis
Asymptomatic MRI 
changes, non-progressive
MRI changes and symptoms 
responsive to rest and 
analgesia
MRI changes, symptoms requiring 
surgical intervention
Wheelchair bound; surgical 
repair not possible
H2.  Arthralgia
Intermittent transient 
symptoms, no meds or 
relieved by OTC meds
Persistent or recurrent 
symptoms, resolve with meds, 
little effect on function
Severe symptoms despite meds 
impairs function
Debilitating, hospitalisation 
required for treatment
H3.  Leg cramps
Transient, intermittent, does 
not interfere with function
Recurrent symptoms, 
minimally interferes with 
function or sleep, responds to 
meds
Persistent, prolonged interference 
with function or sleep, partial or no 
response to meds
NA
H4.  Myalgia
Occasional; does not 
interfere with function
Frequent, requires meds (non-
narcotic); minor effects on 
function
Major change in function/lifestyle, 
narcotic pain meds
Debilitating, profound weakness, 
requires wheelchair, 
unresponsive to meds
I.  Neuropsychiatric
I1.  Anxiety or Depression (mood 
alteration)
Symptomatic, does not 
interfere with function; no 
meds
Frequent symptoms, responds 
to meds; interferes with ADL 
at times
Persistent, prolonged symptoms, 
partial or no response to meds, limits 
daily function
Suicidal ideation or danger to 
self


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
51
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
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


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
52
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
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


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
53
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
J2.  Cough
Transient, intermittent, 
occasional OTC meds 
relieve
Persistent, requires narcotic or 
other prescription meds for 
relief
Recurrent, persistent coughing 
spasms without consistent relief by 
meds, interferes with function
Interferes with oxygenation; 
debilitating
J3.  Dyspnea
Subjective, transient, no 
interference with function
Symptomatic, intermittent or 
recurring, interferes with 
exertional activities
Symptomatic during daily routine 
activities, interferes with function, 
treatment with intermittent nasal O2
relieves
Symptomatic at rest, debilitating, 
requires constant nasal O2
J4.  Pleuritic pain (pleurisy)
Transient, intermittent 
symptoms, no treatment or 
OTC meds relieve
Persistent symptoms, requires 
prescription meds for relief
Prolonged symptoms, interferes with 
function, requires frequent narcotic 
pain relief
Debilitation, requiring 
hospitalisation
J5.  Pneumonitis (pulmonary 
infiltrates)
Asymptomatic radiographic 
changes, transient, no 
treatment required
Symptomatic, persistent, 
requiring corticosteroids
Symptomatic, requiring treatment 
including O2
Debilitating, not reversible; or 
requiring assisted ventilation
J6.  Pulmonary function 
decreased (FVC or carbon 
monoxide diffusion capacity –
DLCO)
76% – 90% of pre-treatment 
value
51% – 75% of pre-treatment 
value
26% – 50% of pre-treatment value
≤ 25% of pre-treatment value


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 2020
54
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
Laboratory Data
K.  Haematology
K1.  Hgb (g/dl) decrease from 
pre-treatment
1.0 – 1.4
1.5 – 2.0
2.1 – 2.9, or Hgb < 8.0, > 7.0
≥ 3.0; or Hgb < 7.0
K2.  Leukopenia (total WBC) 
× 1000
3.0 – 3.9
2.0 – 2.9
1.0 – 1.9
< 1.0
K3.  Neutropenia (× 1000)
1.5 – 1.9
1.0 – 1.4
0.5 – 0.9
< 0.5
K4.  Lymphopenia (× 1000)
1.5 – 1.9
1.0 –1.4
0.5 – 0.9
< 0.5
K5.  Platelets (× 1000)
75 – LLN
50 – 74.9
20 – 49.9; platelet transfusion 
required
< 20; recurrent platelet 
transfusions
L.  Chemistry
L1.  Hypercalcaemia (mg/dl)
1.1 × ULN – 11.5
11.6 – 12.5
12.6 – 13.5; or symptoms present
> 13.5; or associated coma
L2.  Hyperglycemia (mg/dl) 
Fasting
140 – 160
161 – 250
251 – 500
> 500, or associated with 
ketoacidosis
L3.  Hyperkalaemia (mg/dl)***
5.5 – 5.9
6.0 – 6.4
6.5 – 7.0 or any ECG change
> 7.0 or any arrhythmia


ABBV-3373
M16-560 – Statistical Analysis Plan
Version 5.0 – 08 September 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
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
L5.  Hypocalcaemia (mg/dl)
0.9 × LLN – 7.8
7.7 – 7.0
6.9 – 6.5; or associated with 
symptoms
< 6.5 or occurrence of tetany
L6.  Hypoglycemia (mg/dl)
55 – 64 (no symptoms)
40 – 54 (or symptoms present)
30 – 39 (symptoms impair function)
< 30 or coma
L7.  Hyponatraemia (mmol/l)***
-
125 – 129
120 – 124
< 120
L8.  Hypokalaemia (mg/dl)***
-
3.0 – 3.4
2.5 – 2.9
< 2.5
L9.  CPK (also if polymyositis-
disease
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


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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
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
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


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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 decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 15 mmHg from Baseline
High
Value ≥ 105 mmHg and increase ≥ 15 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Body temperature
High
> 39.0 degrees C (102.3 degrees F)
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline


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Appendix D.
Details for Historical Data Borrowing 
Statistical methods for incorporating historical data in a new study include power prior 
[Ibrahim 2000], commensurate prior [Hobbs 2011] and robust mixture prior 
[Schmidli 2014].  All these methods are Bayesian approaches.  We took a similar 
approach using meta-analytical-predictive method to summarize historical control data as 
a basis for informative prior for the control group and to determine the maximal number 
of subjects to be borrowed (effective sample size [Neuenschwander 2010]).  For the 
treatment group, we use a noninformative prior so that information for the treatment 
group only depends on in-trial data.  We systematically evaluate the impact of bias 
(defined as the difference between historical control data and concurrent control data) and 
number of historical control subjects borrowed on the false positive rate and true positive 
rate.  So the number of subjects borrowed is determined to control the inflation (if any) of 
two types of error rates to a reasonable extent based on a reasonable range of the 
magnitude of bias.
D-1
Historical Data Selection and Meta-Analysis
The historical data are carefully selected based on the similarity in target population, 
mechanism of action of study drugs, concomitant medications [Pocock 1976] between 
historical trials and the trial under design.  The selection of historical trials is described in 
the following. 
Historical data for adalimumab 80 mg group are available from three clinical trials at the 
time of design stage of the current trial.  These historical control data consist of 
242 subjects from three AbbVie Adalimumab studies with similar populations 
(DMARD-IR or MTX-IR) and mechanism of action:  Study DE007 (n = 70, mean [SD] of 
DAS28 (CRP) change from BL = –2.1 [1.3]); Study DE009 (n = 70, mean (SD) of 
DAS28 (CRP) change from BL = –2.23 (1.16)); and Study DE011 (n = 102, mean (SD) of 
DAS28 (CRP) change from BL = –2.04 (1.49)).  The criteria for relevant historical 
control data selection were evaluated and met for these trials and the trial under design.  


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These studies have similar population (DMARD-IR or MTX-IR), similar inclusion and 
exclusion criteria as shown in Table D-1. 
Table D-1.
Major entry criteria for historical studies and Study M16-560
Criteria
Historical Studies
Current Study
DE007
DE009
DE011
ABBV-3373 
(M16-560)
Inc 1
RA as defined by 
the 1987-revised 
ACR criteria
RA as defined by 
the 1987-revised 
ACR criteria
RA as defined by 
the 1987-revised 
ACR criteria
RA for > 3 months as
defined by 1987 ACR 
or 2010 ACR/EULAR
Inc 2
DMARD-IR
MTX and DMARD-
IR
DMARD-IR
MTX-IR
Inc 3
18 years or older
18 years or older
18 years or older
Between 18 and 
75 years
Inc 4
At least 
10/66 swollen 
joints; At least 
12/68 tender joints
At least 
6/66 swollen joints; 
At least 9/68 tender 
joints
At least 
10/66 swollen 
joints; At least 
12/68 tender joints
At least 4/28 swollen 
joints; At least 
4/28 tender joints
Exc 1
Male:  
Haemoglobin < 8.5 
g/dl Female:  
Haemoglobin 
< 8.0 g/dl
Male:  Haemoglobin
< 9.0 g/dl Female:  
Haemoglobin 
< 8.5 g/dl
Male:  Haemoglobin 
< 8.5 g/dl Female:  
Haemoglobin 
< 8.0 g/dl
Exc 2
WBC < 3 × 10^9/L
WBC 
< 3.0 × 10^9/L
WBC 
< 3.0 × 10^9/L
Exc 3
platelet 
< 150 × 10^9/L
platelet 
< 100 × 10^9/L
platelet 
< 150 × 10^9/L
Exc 4
AST/ALT 
> 2× ULN
AST/ALT 
> 2 × ULN
AST/ALT 
> 2 × ULN
AST/ALT 
≥2.5 × ULN
The meta-analysis shows that predicted estimated mean (SD) and 95% confidence interval 
for mean are –2.13 (1.35) and [–2.29, –1.96] (Figure D-1) based on Empirical Bayes 
estimator [Sidik 2007].  Between-trial variability is very small, and historical effective 
sample size (the maximum number of subjects we could borrow) is 242 [Neuenschwander 
2010].


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Figure D-1.
Meta-Analysis for Historical Adalimumab Data
D-2
Borrowing size and prior distribution determination
For the primary analysis, our principle for borrowing historical sample size is not to 
exceed the total sample size in the current study while keeping reasonable false positive 
rate and true positive rate with borrowing.
Assuming the mean DAS28 (CRP) change from baseline of –2.769 to –2.982 for 
ABBV-3373 (corresponding to 30% to 40% more reduction than historical adalimumab) 
and of –2.13 for historical adalimumab 80 mg eow, so the absolute effect size 9 is from 
0.639 to 0.852.  Let !# −!+ define the bias from historical data, where !# is the true but 
unknown mean for control group (adalimumab 80 mg) and !+ is the historical data mean 
calculated from meta-analysis.  To assess the bias impact on historical data borrowing, a 
reasonable limit for bias would be the half confidence interval width from meta-analysis 
i.e.|!# −!+| ≤0.165.
Let ; =
<=
<=><? be the proportion of borrowed number of historical patients *+ among all 
control patients *+ + *# where *# is the number of control group subjects in current 
study).  Let !" and *" be the treatment group mean and the number of subjects. Given A, 
and ;, false positive rate (i.e., the probability achieving (!" −!# < 0|%) > 0.95
under the null hypothesis !" = !#) and true positive rate (i.e., the probability achieving 


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(!" −!# < 0|%) > 0.95 under the alternative hypothesis !# −!" = 9) can be 
derived from the following formula:
Φ
⎝
⎛
!# −!"
4E 1
*" + 1 −;
*+ + *#
−
;(!+ −!#)
4E 1
*" + 1 −;
*+ + *#
−Φ
F(0.95)
E 1
*" +
1
*+ + *#
E 1
*" + 1 −;
*+ + *#⎠
⎞


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Table D-2.
False positive rate and true positive rate for ABBV-3373 vs 
adalimumab: δ = 0.852
IJ −IK
Borrowing 15 subjects
Borrowing 30 subjects
Borrowing 45 subjects
False 
Positive 
Rate
True 
Positive 
Rate
False 
Positive 
Rate
True 
Positive 
Rate
False 
Positive 
Rate
True 
Positive 
Rate
–0.4
0.108
0.944
0.173
0.986
0.226
0.994
–0.35
0.093
0.934
0.144
0.98
0.185
0.991
–0.3
0.08
0.922
0.118
0.974
0.149
0.987
–0.25
0.069
0.909
0.095
0.965
0.119
0.981
–0.2
0.058
0.895
0.076
0.955
0.092
0.973
–0.165
0.052
0.884
0.065
0.946
0.077
0.967
–0.13
0.046
0.873
0.054
0.936
0.063
0.958
–0.1
0.041
0.862
0.047
0.927
0.053
0.95
–0.07
0.037
0.851
0.04
0.916
0.045
0.941
–0.03
0.032
0.835
0.032
0.9
0.035
0.926
0
0.029
0.822
0.027
0.886
0.029
0.913
0.03
0.026
0.809
0.023
0.871
0.024
0.899
0.07
0.022
0.79
0.018
0.85
0.018
0.877
0.1
0.019
0.776
0.015
0.832
0.014
0.858
0.13
0.017
0.76
0.013
0.813
0.012
0.838
0.165
0.015
0.742
0.01
0.789
0.009
0.812
0.2
0.013
0.723
0.008
0.763
0.007
0.784
0.25
0.01
0.695
0.006
0.724
0.004
0.74
0.3
0.008
0.665
0.004
0.682
0.003
0.691
0.35
0.007
0.634
0.003
0.637
0.002
0.639
0.4
0.005
0.603
0.002
0.59
0.001
0.584
Table D-2 shows the false positive rate and true positive rate for different number of 
borrowing and different bias within ± 0.4 given sample size = 30:15, 9 = 0.852.  With the 
sample size = 30:15 (k = 30/15 = 2) for ABBV-3373 and adalimumab respectively, 
30 historical adalimumab subjects could be borrowed while controlling false positive rate 
< 10% and not exceeding in study total sample size.  For example, for


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!# −!+ = – 0.165 with 9 = 0.852, borrowing 30 will control false positive rate at 6.5%.
Therefore, for this analysis with historical data borrowing, we would borrow historical 
data:  *+ = 30, !+ = −2.13, and its SE 4+ = 1.35 √30
⁄
= 0.246.  That is, the prior 
distribution for adalimumab would be N(–2.13, 0.2462).  For ABBV-3373, a "flat" non-
informative prior probability distribution will be assumed, that is the posterior distribution 
is totally from the data. 
In addition, a supportive analysis using dynamic borrowing may be performed based on 
the observed bias and Table D-2.  For example, if observed bias = –0.165 we can borrow 
up to 45 historical sample size to control the false positive rate within 10%.  On the other 
hand, if bias = –0.25, we just borrow 30; if bias = –0.4, we will not borrow (borrow 0) due 
to unreasonable false positive rate inflation.  If the bias is positive and borrowing provides 
a true positive rate above 70%, then up to 45 will be borrowed to achieve the maximum 
true positive rate.  If the bias is positive (for example, 0.3) and the true positive rate loss 
with borrowing is greater than 10% compared with the target power (80%) with up to 45 
borrowed, then we will not borrow due to unreasonable true positive rate loss.
D-3
Analysis Methods
The prior distributions discussed in Section D-2 will be combined with the observed data 
in the trial to obtain posterior distributions for the treatment and control groups.  The 
probability of Treatment mean – Control mean < 0 given the observed data 
i.e., (!" −!# < 0|%) will be calculated.
Let % = (QF, ⋯, Q<) be the data and Q~T(!, 4U). Then Q̅~T(!,
WX
< ).  If 4U is a constant, 
we have the likelihood for the data
Y(!|%) =  Z(%|!) ∝T(Q̅,
WX
< ).
The conjugate prior for μ is supposed to be


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Z(!) ∝T(!;, 4;
U).
Then the posterior is given by
Z(!|%) = Y(!|%)Z(!) ∝T(!<, 4<
U) where 
!< =
WX
<W\X>WX !; +
<W\X
<W\X>WX Q̅ and
4<
U =
F
]
^X> _
^\X
=
WXW\X
<W\X>WX.
If (!" −!# < 0|%) > 0.95, the treatment group will be claimed as significantly 
better than the control group. This is equivalent to the hypothesis test of !" −!# = 0 at 
one-sided ` = 0.05 significant level.
Notice that !;, 4;
U are prior parameters determined from historical data borrowing and 
meta-analysis (see Section D-2).  (Q̅,
WX
< ) are LSMean and SE from MMRM based on data 
in the study.  For treatment group, a "flat" non-informative prior probability distribution 
will be assumed, that is the posterior distribution is totally based on the observed data.


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Appendix E.
Details for Analysis with a Synthetic Placebo Arm
Study M16-560 has two treatment arms, the investigational drug ABBV-3373 and 
adalimumab as an active control.  Since the trial doesn't have a placebo arm, subject-level 
historical placebo data will be borrowed to estimate the treatment effect of ABBV-3373 or 
adalimumab against placebo to establish the assay sensitivity of the study.  Historical 
placebo data of the change from baseline in DAS28(CRP), the primary endpoint, from 
three recent similar AbbVie studies are selected to construct a synthetic placebo arm 
through propensity score matching.  Pairwise comparison between the in-trial data of the 
ABBV-3373 or adalimumab treatment group and the synthetic placebo arm will be 
performed based on matched dataset.
In this section, we will describe how historical placebo data are selected, the analysis plan 
and implementation plan. 
E1.
Historical Data Selection 
The historical data are carefully selected based on the similarity in target population, entry 
criteria, prior and concomitant medications, years conducted between historical trials and 
Study M16-560. 
Subject-level historical placebo data consists of subjects from 3 recent AbbVie clinical 
trials with similar populations (MTX/csDMARD-IR on background MTX or 
csDMARDs), entry criteria and study designs:  upadacitinib Phase 2 study 
(Study M13-537), upadacitinib Phase 3 studies SELECT-COMPARE (Study M14-465) 
and SELECT-NEXT (Study M13-549).  837 placebo subjects with non-missing Week 12 
DAS28 (CRP) change from baseline values are identified.  To enhance trial similarity, for 
the two Phase 3 studies of upadacitinib, the placebo patients with prior biologics use or 
without prior synthetic DMARDs use or without concomitant MTX use prior to Week 12 
will be removed.


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The criteria for relevant historical control data selection were evaluated and met for these 
trials and Study M16-560.  The main eligibility criteria for these studies are shown in 
Table E1-1. 
Table E1-1.
Historical Placebo Data Selection– main eligibility criteria
Criteria
Current Study
Study M13-549
Study M14-465
Study M13-537
M16-560
Inc 1
csDMARDs - IR
MTX - IR
MTX – IR
MTX-IR
Inc 2
18 years or older
18 years or older
18 years or older
between 18 and 
75 years
Inc 3
Moderately to severely 
RA
Moderately to severely 
RA
Active RA
Moderately to 
severely RA
Inc 4
Background meds: 
csDMARDs
Background meds: 
MTX
Background meds: 
MTX
Background 
meds: MTX
Exc 1
Hemoglobin < 10 g/dL
Hemoglobin < 10 g/dL
Hemoglobin 
< 9 gm/dL
Exc 2
WBC < 2,500/μL
WBC < 2,500/μL
WBC < 3,000/μL
Exc 3
Platelet count 
< 100,000/μL
Platelet count 
< 100,000/μL
Platelet count 
< 100,000/μL
Exc 4
eGFR 
< 40 mL/min/1.73 m^2
eGFR 
< 40 mL/min/1.73 m^2
eGFR 
< 40 mL/min/1.73 m^2
Exc 5
AST/ALT > 2 × ULN
AST/ALT > 2 × ULN
AST/ALT 
> 1.5 × ULN
AST/ALT 
≥2.5 × ULN
A meta-analysis shows that predicted estimated mean (SD) for placebo based on these 
studies are –1.14 (1.23) based on a random effect model.  
E2.
Pairwise comparison between ABBV-3373/adalimumab and 
placebo with synthetic placebo arm using propensity score 
analysis
E2.1.
Propensity Score estimation
Propensity score method will be used to balance the population-level baseline 
characteristics between in trial data and historic placebo group.  In order to calculate 
propensity scores, selected common baseline demographics and characteristics variables 


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among Study M16-560 and the three upadacitinib studies will be used as covariates in 
propensity score estimation. 
Main baseline demographic characteristics can include:
●
Sex (male/female)
●
Race (White, Non-White)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Geographic region (North America, Other)
●
Age (years)
●
Body Mass Index (BMI) (kg/m2)
Main baseline disease characteristics and medications can include:
●
Steroid use at baseline (Y/N)
●
Number of prior synthetic DMARDs (1/Greater than 1)
●
Duration of RA Diagnosis in years
●
Tender joint count (TJC28) defined as the number of tender joints out of 
28 assessed joints used for DAS28 calculation
●
Swollen joint count (SJC28) defined as the number of swollen joints out of 
28 assessed joints used for DAS28 calculation
●
Physician's global assessment of disease activity (mm on a 100-mm horizontal 
visual analogue scale [VAS])
●
Patient's assessment of pain within last week (mm on a 100-mm horizontal 
(VAS)
●
Patient's global assessment of disease activity within last 24 hours (mm on a 
100-mm horizontal VAS)
●
Health Assessment Questionnaire Disability Index of the (HAQ – DI) (range:  
0 to 3)
●
High sensitivity C-reactive protein (hsCRP) (mg/L)
●
DAS28 (CRP)


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Covariate balance will be checked between all subjects enrolled in Study M16-560 and 
historical placebo subjects specified in Section E1. 
Propensity score is the probability of a patient being assigned to a treatment instead of the 
other one conditional on a given set of baseline characteristics.  It is determined by a 
logistic regression with all above common baseline covariates.  To reduce any potential 
bias due to rare events (45 subjects getting active treatment vs. > 700 getting placebo), 
propensity scores will be estimated using penalized maximum likelihood estimation 
(PMLE) (Firth, 1993).  Sensitivity analysis of PS estimation can be considered.  Overlap 
of PS between the in-trial data and synthetic placebo control will be assessed using 
histogram and descriptive statistics.
E2.2.
Analysis using placebo synthetic control with propensity 
score matching
Propensity score matching method (Rosenbaum and Rubin, 1985) matches treatment 
patients with synthetic placebo subjects based on propensity scores such that matched 
treatment subjects and placebo subjects are comparable in terms of covariates used in 
propensity score determination.  This process mimics randomization to create 
two comparable groups with a caution of limitation that the matching is conditional on 
included covariates. The "nearest neighbor matching" will be performed based on a 
distance measure, caliper, calculated from the propensity scores estimates.  We will start 
the matching with the optimal caliper 0.2, which was recommended by Austin (2011), 
with the intention to match 45 to 90 placebo subjects.  If this is not possible under the 
optimal caliper, other caliper values may also be considered.  If multiple placebo subjects 
have propensity scores that are equally close to that of an ABBV-3373 or adalimumab 
treated subject exceeding the matching ratio, prespecified number of these placebo 
subjects will be selected at random.  Subjects who are not selected in the matching 
process will be excluded from further analysis.  Following matching, baseline covariates 
will be summarized for subjects in Study M16-560 and matched historical placebo 
subjects to ensure balance is generally achieved.


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Analysis will be based on matched dataset.  Each of ABBV-3373 and adalimumab group 
will be compared with all matched placebo subjects separately.  Change from baseline in 
DAS28(CRP) at Week 12 will be analyzed with the matched datasets to compare each 
treated group and the synthetic placebo group by an MMRM model including data 
collected during the common study visits up to Week 12 (i.e., Weeks 2, 4, 8, 12) with 
treatment group, study visits, and treatment-by-visit interaction.  An unstructured variance 
covariance matrix will be used.  The parameter estimations will be based on the 
assumption of data being missing at random and using the method of restricted maximum 
likelihood (REML).  Least-square mean difference, 90% CI and p-value will be presented.  
Other endpoints may also be analyzed with the matched data sets. 
Table E2-1 shows the power for two-group comparison between adalimumab and placebo 
under different matching ratios assuming 100% actively treated subjects can be matched.  
When all of the 45 treated subjects in Study M16-560 are matched to synthetic placebo 
subjects according to the matching ratios of 1:1 and 1:2, the statistical power of the 
pairwise comparison between adalimumab and placebo ranges from 78% to 83% based on 
two-sided test with alpha of 0.1, assuming a common standard deviation of 1.35 and the 
mean of adalimumab and placebo to be –2.13 and –1.14 respectively based on meta-
analysis results.
Table E2-1.
The power for adalimumab vs. synthetic placebo control.
Matching Ratio 
(Treated:Placebo)
N_3373:N_ADA:N_PBO
Two-Group Comparison 
Power (ADA vs. PBO)
1:1
30:15:45
78%
1:2
30:15:90
83%
If only very few placebo patients can be matched with treated subjects in Study M16-560 
and analysis based on matched dataset is deemed not appropriate, alternative methods 
such as stratified analysis will be considered.


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E3.
Implementation
To reduce operational bias and maintain study validity, the propensity score calculation 
and matching described in Section E2 will be conducted by an independent statistician 
who is removed from Study M16-560 study.  Prior to the last subject first dose, the study 
team and the independent statistician will meet as needed and agree on the statistical 
details of each step above, with any question (must be unrelated to treatment assignment 
information and in trial and historical subjects outcome) from the independent statistician 
resolved during the meeting(s). 
The process to implement the propensity score analysis is summarized in Figure E3.1.  
Each step is described in detail below.  These steps should happen after Study M16-560 
enrollment is finished and prior to the Week 12 database lock.
Figure E3-1.
Flowchart of Implementation


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1. Input baseline datasets of Study M16-560 
A dataset of Study M16-560 containing study ID, de-identified subject IDs, and baseline 
characteristics will be delivered to the independent statistician by the study team.  No 
post-baseline data should be contained in this dataset.  No randomization code is 
accessible to the study team or independent statistician.  
2. Input integrated baseline dataset of historical placebo subjects
A dataset integrating the baseline characteristics from the three studies with historical 
placebo subjects specified in Section E2.1 will be delivered to the independent statistician 
by the study team.  No post-baseline data should be contained.  In addition, study IDs and 
subject IDs in this dataset will be de-identified by the study programing team before 
delivery to the independent statistician. 
3. Post-baseline dataset of historical placebo subjects
A dataset integrating the change from baseline in DAS28 (CRP) data at Weeks 2, 4, 8, 12 
from the three studies with historical placebo subjects specified in Section E2.1 will be 
generated.  Subject ID, change value and visit will be included.  This dataset is to be kept 
by study team for the final analysis and should not be accessible to the independent 
statistician.  
4. Propensity score analysis and communication with study team
Prior to enrollment completion, the study team and the independent statistician will meet 
as needed and agree on the final PS analysis rules (for example, matching ratio, matching 
caliper) of each step in Section E2.  Any question (must be unrelated to treatment 
assignment information) from the independent statistician will also be addressed during 
these meeting(s).
After Study M16-560 enrollment is finished, the input datasets will be delivered to the 
independent statistician for PS estimation and matching, without accessing the subject-


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level post-baseline data (including primary endpoint data) of selected historical placebo 
subjects and Study M16-560 subjects.  The independent statistician will check the 
covariate balance before and after matching is performed to make sure the balance is 
improved following the matching.
5. Final covariate datasets
The resultant datasets (matched) containing subject-level covariate data will be delivered 
by the independent statistician to the study team prior to the Week 12 database lock for 
analysis.  Matched datasets should discard those unmatched subjects.  The analysis-ready 
datasets should include variables such as re-identified subject ID, baseline characteristics, 
propensity score. 
There is no plan to share interim data with external experts or with Regulatory Agencies 
(prior to study completion and availability of final study results).  
6. Final data analysis
After database lock, the study programming team will merge the final output datasets with 
datasets containing post-baseline data of ABBV-3373/adalimumab and historical placebo 
subjects and perform the analyses as specified Section E2.