Conditions: Rheumatoid Arthritis (RA)
Keywords: Rheumatoid Arthritis (RA) ABBV-154 AIM-RA
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 473
Healthy volunteers: no

Brief summary:
Rheumatoid Arthritis (RA) is an inflammatory disease of the joints causing pain, stiffness, swelling and loss of joint function. This study evaluated how safe and effective ABBV-154 is in participants treated for moderately to severely active RA. Adverse events and change in the disease activity were assessed.

ABBV-154 is an investigational drug being evaluated for the treatment of RA. Study doctors placed the participants in 1 of 5 treatment groups or arms; each arm received a different treatment. There was a 1 in 5 chance that participants were assigned to placebo. Participants 18-75 years of age with moderate to severe RA were enrolled. Around 425 participants were to be enrolled in the study at approximately 270 sites worldwide.

The study was comprised of a 12 week placebo-controlled period, a double-blind long term extension (LTE) period 1 of 66 weeks, a LTE period 2 of 104 weeks and a follow-up visit 70 days after the last dose of the study drug. In the LTE period 1, participants in the placebo group were re-randomized to receive ABBV-154 at 1 of 2 different doses SC every other week (EOW). Other participants remained on their previous dose and dosing regimen of ABBV-154.

There may have been a higher treatment burden for participants in this trial compared to their standard of care. Participants attended regular visits during the study at a hospital or clinic. The effect of the treatment was checked by medical assessments, blood tests, and side effects, and completing questionnaires.

Detailed description:
Participants were randomly assigned at a ratio of 1:1:1:1:1 to ABBV-154 at either 40 mg, 150 mg, 340 mg, subcutaneously (SC) EOW; 340 mg SC every 4 weeks (E4W); or placebo SC EOW. Randomization was stratified by baseline glucocorticoid (yes/no); number of prior failed biologic and/or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) (1; 2 or more); and prior anti-TNF failure (yes/no) and if yes, further stratification by prior adalimumab use (yes/no).

After 12 weeks, participants receiving placebo were re-randomized to receive ABBV-154 150 mg SC EOW or 340 mg SC EOW for the long-term extension (LTE) periods. At re-randomization, participants were stratified by baseline glucocorticoid use (yes/no) and prior adalimumab use (yes/no). Participants from the other dose groups were to continue with their respective dose and dosing regimen.

The primary analysis was conducted after all ongoing participants completed Week 12 or withdrew from the study. A final analysis was to be conducted after all participants completed LTE period 2 and a safety follow-up visit or withdrew from the study. The study was terminated before any participants entered LTE Period 2.

Arms:
arm 1: Participants in this group will receive dose A of ABBV-154 subcutaneously (SC) every other week (eow) for 12 weeks in the placebo-controlled period, 66 weeks in the long term extension (LTE) period 1 and 104 weeks in LTE period 2. arm 2: Participants in this group will receive dose B of ABBV-154 SC eow for 12 weeks in the placebo-controlled period, 66 weeks in the LTE period 1 and 104 weeks in LTE period 2. arm 3: Participants in this group will receive dose C of ABBV-154 SC eow for 12 weeks in the placebo-controlled period, 66 weeks in the LTE period 1 and 104 weeks in LTE period 2. arm 4: Participants in this group will receive dose C of ABBV-154 SC every 4 weeks (e4w) for 12 weeks in the placebo-controlled period, 66 weeks in the LTE period 1 and 104 weeks in LTE period 2. arm 5: Participants in this group will receive placebo SC eow for 12 weeks in the placebo-controlled period and will be re-randomized in 1:1 ratio to receive ABBV-154 dose B or C respectively SC eow for 66 weeks in the LTE period 1 and 104 weeks in LTE period 2.

Interventions: intervention 1: ABBV-154 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous Injection intervention 2: Subcutaneous Injection

Protocol document:
Prot_000.pdf: 


  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
9
2.1
BACKGROUND AND RATIONALE
9
2.2
BENEFITS AND RISKS TO SUBJECTS
9
3
OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
10
3.2
PRIMARY ENDPOINT
11
3.3
SECONDARY ENDPOINTS
11
3.4
ADDITIONAL EFFICACY ENDPOINTS
11
3.5
SAFETY MEASURES
12
3.6
PHARMACOKINETIC AND IMMUNOGENICITY ENDPOINTS
12
3.7
BIOMARKER RESEARCH ENDPOINTS
12
4
INVESTIGATIONAL PLAN
13
4.1
OVERALL STUDY DESIGN AND PLAN
13
4.2
DISCUSSION OF STUDY DESIGN
16
5
STUDY ACTIVITIES
16
5.1
ELIGIBILITY CRITERIA
16
5.2
CONTRACEPTION RECOMMENDATIONS
21
5.3
PROHIBITED MEDICATIONS AND THERAPY
23
5.4
PRIOR AND CONCOMITANT THERAPY
23
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
26
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
27
5.7
STUDY DRUG
28
5.8
RANDOMIZATION/DRUG ASSIGNMENT
29
5.9
PROTOCOL DEVIATIONS
29
5.10 DATA MONITORING AND GLUCOCORTICOID ADJUDICATION COMMITTEES
30
6
SAFETY CONSIDERATIONS
30
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6.1
COMPLAINTS AND ADVERSE EVENTS
30
6.2
TOXICITY MANAGEMENT
34
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
38
7.1
STATISTICAL AND ANALYTICAL PLANS
38
7.2
DEFINITION FOR ANALYSIS POPULATIONS
38
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND SECONDARY ENDPOINTS
39
7.4
STATISTICAL ANALYSES FOR EFFICACY
39
7.5
STATISTICAL ANALYSES FOR SAFETY
40
7.6
STATISTICAL ANALYSIS FOR PHARMACOKINETICS AND IMMUNOGENECITY
40
7.7
STATISTICAL ANALYSIS OF BIOMARKER DATA
41
7.8
INTERIM ANALYSIS
41
7.9
OVERALL TYPE 1 ERROR CONTROL
41
7.10 SAMPLE SIZE DETERMINATION
41
8
ETHICS
41
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTION REVIEW BOARD (IEC/IRB)
41
8.2
ETHICAL CONDUCT OF THE STUDY
41
8.3
SUBJECT CONFIDENTIALITY
42
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
42
10 DATA QUALITY ASSURANCE
42
11 COMPLETION OF THE STUDY
42
12 REFERENCES
43
LIST OF TABLES
TABLE 1.
SUGGESTED TAPERING SCHEME FOR GLUCOCORTICOID AT BASELINE
26
TABLE 2.
IDENTITY OF INVESTIGATIONAL PRODUCT
29
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
37
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LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
15
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
44
APPENDIX B.
2010 RHEMATOID ARTHRITIS CLASSIFICATION
47
APPENDIX C.
RESPONSIBILITIES OF THE INVESTIGATOR
49
APPENDIX D.
LIST OF PROTOCOL SIGNATORIES
50
APPENDIX E.
ACTIVITY SCHEDULE
51
APPENDIX F.
PROTOCOL SUMMARY OF CHANGES
60
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
Evidence suggests that tumor necrosis factor (TNF) 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, there remains an unmet clinical need for 
improved therapies as even biologic and targeted synthetic disease-modifying antirheumatic drugs 
(b/tsDMARDs) in combination with methotrexate (MTX) fail to achieve optimal disease control in some 
patients. Therefore, there is a particular need for improved therapies in refractory RA patients.
Glucocorticoids are potent drugs for treating many inflammatory diseases.  In RA, glucocorticoids such 
as prednisone are highly effective at reducing inflammation, fatigue, radiographic progression, and
relieving pain.  However, the administration of glucocorticoids is limited due to their long-term side 
effect profile including (but not limited to) hypothalamic-pituitary-adrenal axis (HPA) suppression, 
osteoporosis, hyperglycemia, glaucoma, and skin atrophy.1  Thus, the full efficacy of glucocorticoid 
therapy is often limited with existing agents due to systemic side effects.
AbbVie is developing ABBV-154, an anti-TNF antibody-drug-conjugate (ADC) composed of adalimumab 
(the active component of Humira®) conjugated to phosphorylated A-1677770, a proprietary, 
glucocorticoid receptor modulator (GRM) via an 
 linker. The A-1677770 GRM is a 
synthetic glucocorticoid receptor agonist with a steroid backbone, optimized to provide the widest 
therapeutic window in-vivo between anti-inflammatory effects and systemic glucocorticoid effects.  
Therefore, ABBV-154 has the potential to deliver an anti-inflammatory payload to activated immune 
cells that express transmembrane TNF and minimize systemic exposure to the free payload GRM.  Thus, 
ABBV-154 (adalimumab/GRM ADC) has the potential to achieve transformational efficacy relative to 
adalimumab while reducing side effects caused by systemic exposure to glucocorticoids.
2.2 Benefits and Risks to Subjects
The clinical efficacy of TNF inhibitors and glucocorticoids in the treatment of RA is well established.  
Based on the totality of the evidence from preclinical and clinical data, ABBV-154 is expected to 
demonstrate therapeutic benefit in the treatment of RA with an acceptable benefit/risk profile.
Medical review of the safety data from the Phase 1, single ascending dose study did not identify any 
safety risks in the healthy volunteer population (including Japanese and Chinese subjects).  For further 
details, please see the ABBV-154 Investigator's Brochure.2
In clinical settings, TNF antagonists and glucocorticoids have been associated with increased risk for 
serious infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic 
pathogens.  Patients with a recent history of these events will be excluded from the study.  Other known 
adverse events (AE) for glucocorticoids include hypertension, HPA suppression, decreased bone-
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formation, diabetes, and cataracts.  Signs of infection, blood pressure changes, blood glucose levels, HPA 
axis suppression, and bone mineral density will be closely monitored during the study.
TNF antagonists have also been associated with an increased risk for serious allergic reactions, including 
anaphylaxis; infusion reactions; malignancy (including nonmelanoma skin cancer, lymphoma, and 
leukemia); worsening or new onset heart failure; and rarely hepatitis B virus (HBV) reactivation, central 
nervous system events, demyelinating disease, pancytopenia (including aplastic anemia, and lupus-like 
syndrome).  Patients with a history of these events will be excluded from the study.  Signs and 
symptoms of these events will be closely monitored.
The safety profile specific to the adalimumab component of ABBV-154 is well-established for marketed 
doses.  In addition, adalimumab has been studied at doses up to 10 mg/kg IV, which is higher than the 
doses planned in this study, with a safety profile consistent to Humira® product labeling. Potential risks 
will be minimized through the selection of appropriate study subjects defined by the eligibility criteria 
and subject safety will be monitored by an unblinded independent data monitoring committee (DMC) 
and regular blinded review of safety data by the study team.  In addition, guidance for toxicity 
management and stopping rules are provided to ensure subject safety.
Based on the totality of the data, ABBV-154 is expected to demonstrate therapeutic benefit in the 
treatment of RA with an acceptable benefit-risk profile for development in the treatment of this disease.
In view of the coronavirus pandemic 2019 (COVID-19), the benefit-risk profile of various 
immunomodulatory therapies on COVID-19 are being evaluated.  Currently, the effects of ABBV-154 on 
the course of COVID-19 are not well defined.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary Objective
The primary objective is to assess the safety, tolerability, and efficacy of ABBV-154 vs. placebo on 
background MTX for the treatment of subjects with moderately to severely active RA who have had an 
inadequate response to at least one prior b/tsDMARD.
The primary efficacy objective of the study is to demonstrate a higher rate of ACR50 after 12 weeks of 
treatment with ABBV-154 when compared to placebo in the Intent-to-Treat (ITT) Population (further 
described in Section 7.2), which consists of all randomized subjects who have received at least one dose 
of study drug.  The hypothesis corresponding to the primary efficacy objective and endpoint is the 
proportion of subjects achieving ACR50 with ABBV-154 is greater than that with placebo at Week 12.  
The estimand for the primary endpoint is defined as the difference in the proportion of subjects that 
achieve ACR50 at Week 12, in each of the ABBV-154 dose groups compared with the placebo group in 
the ITT Population.
The secondary efficacy objectives of the study are to demonstrate higher efficacy of treatment with 
ABBV-154 when compared to placebo with respect to the secondary endpoints specified in Section 3.3; 
in the ITT Population. The estimands corresponding to the secondary efficacy objectives are:
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
For each of the categorical secondary endpoints, the estimands corresponding to the secondary 
efficacy objectives are defined as follows: Difference in the proportion of subjects achieving the 
endpoint, in each of the ABBV-154 groups in comparison with the placebo group in the ITT 
Population.

For each of the continuous secondary endpoints, the estimands corresponding to the secondary 
efficacy objectives are defined as follows:  Difference in the mean change from baseline of the 
endpoint, in each of the ABBV-154 dose groups in comparison with the placebo group in the ITT 
Population.
Secondary Objective
The secondary objective is to assess the pharmacokinetics (PK), pharmacodynamics, and 
immunogenicity of ABBV-154.
3.2 Primary Endpoint
The primary endpoint is the achievement of ACR50 at Week 12.
3.3 Secondary Endpoints
All secondary endpoints are at Week 12.

Change in Disease Activity Score (DAS) 28 (CRP) from Baseline;

Change in Clinical Disease Activity Index (CDAI) from Baseline;

Achievement of ACR 20;

Achievement of ACR70;

Achievement of low disease activity (LDA) defined by DAS28 (CRP) ≤ 3.2;

Achievement of LDA defined by CDAI ≤ 10;

Achievement of clinical remission (CR) defined by DAS28 (CRP) < 2.6;

Achievement of CR defined by CDAI ≤ 2.8;

Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) from Baseline.
3.4 Additional Efficacy Endpoints
The primary endpoint and all secondary endpoints will be analyzed at all visits assessed other than Week 
12.  In addition, the following endpoints will be analyzed at all visits assessed.

Change from Baseline in individual components of ACR

Change from Baseline in simplified disease activity index (SDAI)

Achievement of LDA defined as SDAI ≤ 11
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
Achievement of CR defined as SDAI ≤ 3.3

Achievement of Boolean remission based on a 28-joint count and defined as swollen joint count 
(SJC) ≤ 1, tender joint count (TJC) ≤ 1, high sensitivity C-reactive protein (hsCRP) ≤1 mg/dL, and 
Patient Global Assessment of Disease Activity ≤ 1

Change from Baseline in PROMIS Pain Interference

Change from Baseline in FLARE-RA
3.5 Safety Measures
1.
Treatment-emergent adverse events, serious adverse events (SAEs), and AEs leading to 
discontinuation of the study drug;
2.
Occurrence of potentially glucocorticoid related AEs; and
3.
Potentially clinically significant laboratory, vital signs, and electrocardiogram (ECG) variables.
3.6 Pharmacokinetic and Immunogenicity Endpoints
Serum or plasma concentrations of the conjugated ADC, total antibody, free payload A-1677770 will be 
determined at Baseline (pre-dose) and at timepoints during the treatment period as specified in the 
Activity Schedule (Appendix E).
Development of anti-drug antibody (ADA) to ABBV-154 will be evaluated and if confirmed positive, titers 
will be measured.  Samples that are confirmed positive may be further characterized in a validated 
neutralizing antibody (nAb) assay.  Immunogenicity samples will be collected at Baseline (pre-dose) and 
at timepoints as specified in the Activity Schedule (Appendix E).
3.7 Biomarker Research Endpoints
The effect of the ADC compound on glucocorticoid-related endpoints will be assessed by blood samples 
collected at specified time points (Activity Schedule, Appendix E) throughout the study.  The biomarkers 
to be analyzed include, but are not limited to:

Neuroendocrine biomarkers (cortisol) and adrenocorticotropic hormone (ACTH)

Bone formation (osteocalcin [OC], procollagen type 1 N-propeptide [P1NP]) and resorption 
(C-terminal telopeptide of type I collagen [CTX]) biomarkers

Blood leukocytes subpopulations
Provision of these biospecimens for biomarker research is mandatory, but they will not be collected 
from sites where local regulations do not allow for the collection, use, and storage of samples described 
in the protocol.
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Additional optional biospecimens (whole blood for serum, plasma, peripheral blood mononuclear cells, 
RNA, and DNA) will be collected at specified time points (Activity Schedule, Appendix E) throughout the 
study to evaluate known and/or novel disease-related or drug-related biomarkers in circulation or at 
tissue sites.  Types of biomarkers may include nucleic acids, proteins, cell populations, lipids, and/or 
metabolites, either free or in association with particular cell types.  The analyses may include but are not 
limited to soluble proteins, genomic transcripts, blood leukocyte populations, and genetic analysis to 
evaluate biomarker endpoints related to safety, disease state, and target pathway. Results from this 
optional biomarker research results may not be included in the clinical study report.  Further details 
regarding the biomarker research collection time points are located in the Operations Manual, 
Appendix G, Section 3.9.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a randomized, double-blind, Phase 2b, dose-ranging study with a 12-week Placebo-Controlled 
Period, a 66-week Double-Blind Long-Term Extension (LTE) Period 1, a 104-week LTE Period 2, and a 
70-Day Follow-up Period in adults with moderately to severely active RA and on background MTX, who 
have had an inadequate response to b/tsDMARDs treatment.
Subjects will remain on a stable dose of MTX until Week 24 (unless qualifying rescue therapy as 
described in Section 5.4); thereafter MTX may be adjusted within the range of 7.5 – 25 mg/week.  At 
Baseline, 425 subjects will be randomized to 5 treatment groups in a 1:1:1:1:1 ratio to receive ABBV-154 
at either 40 mg, 150 mg, 340 mg, subcutaneously (SC) every other week (eow); 340 mg SC every 4 weeks 
(e4w); or placebo SC eow.  Randomization will be stratified by Baseline glucocorticoid (yes/no); number 
of prior failed b/tsDMARDs (1; 2 or more); and prior anti-TNF failure (yes/no) and if yes further 
stratification by prior adalimumab use (yes/no).  At the end of the Week 12 Visit, subjects previously on 
placebo will be re-randomized and will receive ABBV-154 150 mg SC eow or ABBV-154 340 mg SC eow.  
At re-randomization, subjects will be stratified by baseline glucocorticoid use (yes/no) and prior 
adalimumab use (yes/no).  Subjects from the other dose groups will continue with their respective dose 
and dosing regimen. The enrollment for subjects with prior adalimumab use is capped at approximately 
30% of the total enrolled subjects.
Systemic glucocorticoids (dose of ≤ 7.5 mg/d prednisone equivalent at Baseline) must be tapered off 
within 4 weeks of the start of study drug.
The Primary Analysis will be conducted after all ongoing subjects have completed Week 12 or have 
withdrawn from the study.  After the Primary Analysis, additional analyses may be conducted as needed.  
A final analysis will be conducted after all subjects have completed LTE Period 2 and a safety follow-up 
visit or have withdrawn from the study.  To maintain integrity of the trial, the study sites and subjects 
will remain blinded until all subjects have either completed the last visit of LTE Period 1 or have 
withdrawn from the study.  The AbbVie study team will be unblinded to treatment assignment after the 
Primary Analysis.
The schematic of the study is shown in Figure 1.
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Further details regarding study procedures are in the Operations Manual.  See Section 5.1 for 
information regarding eligibility criteria.
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Figure 1.
Study Schematic
BL = Baseline; EOW = every other week; E4W = every 4 weeks; n = number of subjects; SC = subcutaneous
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4.2 Discussion of Study Design
Choice of Control Group
Placebo has been selected as the appropriate control group to evaluate the primary efficacy endpoints 
as double-blind, placebo-controlled study designs are generally acknowledged as standard for unbiased 
estimates of treatment differences.  There is no anticipated medical risk for subjects randomized to 
placebo with background concomitant MTX for 12 weeks.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy and 
safety-related measurements are standard for assessing disease activity in subjects with RA.  All clinical 
and laboratory procedures are standard and generally accepted.
Suitability of Subject Population
The mechanism of action of ABBV-154 has the potential to improve disease activity in RA subjects.  
While this is the first study to test ABBV-154 in RA subjects, safety results of ABBV-154 in healthy 
volunteers indicate no safety issues of concern and no dose limiting toxicity.
Selection of Doses in the Study
The dose selection in this study was informed by the safety, efficacy, PK, and pharmacodynamic results 
from a related ADC with the same mechanism of action (ABBV-3373) in a Phase 2a proof-of-concept 
study in bio-naïve RA patients on background MTX.
The 3 selected eow dosing regimens in this study (40 mg, 150 mg, and 340 mg SC) are reasonably 
separated across a wide dose range to cover the potential clinical efficacious doses and to enable a 
robust characterization of dose/exposure-response relationships for Phase 3 dose selection.  In addition, 
the 340 mg SC e4w dose regimen was chosen to provide the optionality of an eow vs. e4w dosing 
frequency for future Phase 3 trials.  All selected doses are within the range of single doses safely tested 
in the ABBV-154 First in Human Study (highest dose 600 mg intravenous) and are adequately covered by 
safety margins provided by chronic toxicology studies.  Projected ABBV-154 and A-1677770 safety 
margins for the high dose of 340 mg SC eow are at least 24-fold and 10-fold, respectively, based on 
predicted ABBV-154 human exposures and the observed toxicokinetic data in the 26-week cynomolgus 
monkey study.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all the following criteria to be included in the study.  Anything other than a positive 
response to the questions below will result in exclusion from study participation.  Additional information 
on screening (including re-screening) can be found in the Operations Manual, Appendix G.
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Consent
1. Subject must be able to understand and willing to adhere to all protocol requirements and 
voluntarily sign and date an informed consent, approved by an independent ethics committee 
(IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific 
procedures.
Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old and not more than 75 years of age at the time of 
Screening.
3. Body Mass Index (BMI) ≥ 18.0 to ≤ 39.9 kg/m2 after rounding to the nearest tenth.  BMI is 
calculated as weight in kg divided by the square of height measured in meters at the time of 
Screening.
4. Laboratory values must meet the following criteria within the Screening Period:

Serum aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN);

Serum alanine transaminase (ALT) ≤2.5 × ULN;

Estimate glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in 
Renal Disease formula ≥ 30 mL/min/1.73 m2;

Absolute neutrophil count (ANC) ≥ 1,500/µL;

Absolute lymphocyte count (ALC) ≥ 800/µL;

Platelet count ≥ 75,000/µL; 

Glycated hemoglobin (HbA1c ≤ 8.5%);

Serum potassium >3.0 mmol/L and < 5.5 mmol/L; and

Thyroid-stimulating hormone <10.0 mIU/L
Disease/RA Activity
5. Clinical diagnosis of RA with symptom onset for ≥3 months prior to Screening and fulfillment 
of the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA
(Appendix B).
6. Subject must have: ≥6 swollen joints (based on 66 joint count) and ≥6 tender joints (based on 
68 joint count) at Screening and Baseline.
7. Subject must have had inadequate response to at least one of the following prior b/tsDMARD 
treatments for RA (or corresponding biosimilar):

Tumor necrosis factor inhibitors:  adalimumab, certolizumab pegol, etanercept, 
golimumab, infliximab

Interleukin-1 receptor inhibitors:  anakinra

Interleukin-6 receptor inhibitors:  tocilizumab, sarilumab
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
CD20-directed cytolytic antibodies:  rituximab

T cell costimulation modulators:  abatacept

Janus Kinase inhibitors:  baricitinib, filgotinib, peficitinib, tofacitinib, upadacitinib

Investigational drug with positive efficacy data available from confirmatory trials, as 
agreed with the AbbVie TA MD 
8. Subjects may not have had inadequate response to more than 3 b/tsDMARDs and not more 
than 2 different mode of actions.
9. Inadequate response is defined as meeting at least one of the following criteria:
a.
Subject did not show an adequate response to b/tsDMARDs after continuous treatment of 
≥3 months; or
b.
Subject discontinued b/tsDMARDs due to intolerability or toxicity, irrespective of treatment 
duration.  Subject must not have discontinued prior adalimumab therapy due to 
intolerability or toxicity.
Note: b/tsDMARDs that were discontinued due to other reasons unrelated to inadequate 
response (good response or non-medical reasons including insurance/financial issues, trial 
ended, etc.) will not be accepted to fulfill eligibility criteria.
Subject History
10. Subject must not have a current or history of infection including:

Chronic recurring infections (s) and/or active viral infection that, based on the investigator's 
clinical assessment, makes the subject an unsuitable candidate for the study;

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;

Active tuberculosis (TB) or meets TB exclusionary parameters (See specific requirements for 
TB testing and prophylaxis in the Operations Manual [Appendix G, Section 3.15]);

Subjects in Japan only: positive result of beta-D-glucan (screening for Pneumocystis jirovecii 
infection) or two consecutive indeterminate results of beta-D-glucan during the Screening 
Period;

Human Immunodeficiency virus (HIV) infection defined as confirmed positive anti-HIV 
antibody (HIV Ab) test;

Confirmed COVID-19 infection: The Baseline visit must be at least 21 days from onset of 
signs/symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, 
defined as resolution of fever without use of antipyretics and improvement of symptoms;

Suspected COVID-19 infection: Subjects with signs/symptoms suggestive of COVID-19 
infection, known exposure, or high-risk behavior, should undergo molecular (e.g., PCR) 
testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days following 
potential exposure.
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11. Subject must not have evidence of: 

Hepatitis B virus (HBV): A positive test result for hepatis B surface antigen (HBsAg) or 
detectable HBV DNA PCR qualitative test for subjects who are hepatitis B core antibody 
(HBc Ab) positive (and for Hepatitis B surface antibody [HBs Ab] positive subjects where 
mandated by local requirements).

Hepatitis C virus (HCV):  A detectable HCV ribonucleic (RNA) acid in any subject with anti-
HCV antibody (HCV Ab);
12. Subject must not have a history of the following medical diseases or disorders.

Suspected or confirmed adrenal insufficiency;

Hypothyroidism for which the subject is not receiving physiologic replacement therapy;

Moderate to severe congestive heart failure (New York Heart Association Class III or IV);

Uncontrolled hypertension defined as confirmed systolic blood pressure >160 mm Hg or 
diastolic blood pressure >100 mm Hg at rest despite treatment;

Systemic lupus erythematosus, systemic sclerosis, inflammatory arthritis other than RA, 
inflammatory myopathies, or fibromyalgia;

Glaucoma, osteonecrosis or osteoporosis with high risk of fracture (e.g., T score ≤ -2.5 with 
history of fragility fracture);

Organ transplant which requires continued immunosuppression;

Demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease;

Any malignancy except for successfully treated non-melanoma skin cancer (NMSC) or 
localized carcinoma in situ of the cervix; and

History of any medical condition other than RA that is likely to require systemic 
glucocorticoid treatment during the study (e.g., asthma and chronic obstructive pulmonary 
disease per investigator judgement).  Inhaled glucocorticoids are allowed for stable medical 
conditions but must be at stable dose ≥ 4 weeks prior to Baseline.
13. Subjects must not have a history of allergic reaction or significant sensitivity to constituents 
of the study drug (and its excipients) and/or other products in the same class.  This includes 
anaphylactic reaction to any agent (e.g., food products or bee sting); or a reaction to any IgG 
containing product.
14. There must be no reason the investigator believes that the subject is an unsuitable 
candidate to participate in the study, receive study drug, or would be placed at risk by 
participating in the study.
15. Subjects must not have clinically significant (per investigator's judgment) drug or alcohol 
abuse within the last 12 months.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Contraception
16. Females of child-bearing potential must not have a positive serum pregnancy test at the 
Screening Visit and must have a negative urine pregnancy test at Baseline, prior to the first dose 
of study drug.  Local practices may require a serum pregnancy test at Baseline.  Subjects with a 
borderline serum pregnancy test at Screening must not have a clinical suspicion of pregnancy or 
other pathological cause of a borderline result and a serum pregnancy test ≥3 days later to
document continued lack of a positive result (unless prohibited by local requirements).
17. 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.  Local practices may require 2 methods of birth control.  Refer to Section 5.2 for 
details on contraception.  Female subjects of non-childbearing potential do not need to use 
birth control.  For the United Kingdom (UK) only:  Female subjects of childbearing potential must 
practice at least 1 protocol-specified method of birth control, that is highly effective from Study 
Day 1 through at least 150 days after the last dose of study drug.
18. Females must not be pregnant, or breastfeeding, or considering becoming pregnant and 
may not donate eggs during the study or for approximately 70 days (150 days for UK only) after 
the last dose of study drug.
19. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day 1 through 70 days (150 days for UK only) after the last dose of study 
drug, to practice the protocol-specified contraception.
20. If male, must not be considering fathering a child or donating sperm during the study or for 
approximately 70 days (150 days for UK only) after the last dose of study drug.
Prior and Concomitant Medications
21. Subjects must be on stable dose of MTX (≥ 4 weeks oral or parenteral MTX ≥15 mg to
≤25 mg per week; or MTX ≥ 10 mg per week in subjects who are intolerant of MTX at doses 
≥15 mg per week) before the first dose of study drug.  For subjects in Japan, Korea, or Taiwan a 
stable dose of MTX ≥7.5 mg per week is acceptable.
22. Subject must have discontinued oral glucocorticoids or be on a stable dose of oral 
glucocorticoid (≤ 7.5 mg per day of prednisone equivalent) for 4 weeks before the first dose of 
study drug.
23. Subjects on oral glucocorticoids (≤ 7.5 mg per day of prednisone equivalent at Baseline) 
must be willing and able to taper oral glucocorticoids to 0 mg within 4 weeks after the first dose 
of study drug.
24. Subject must have discontinued all prior b/tsDMARDs and all conventional synthetic 
(cs)DMARDs, except MTX prior to the first dose of study drug.  The washout periods required 
prior to the Baseline Visit are specified below or at least 5 times the mean terminal elimination 
half-life of a drug:

≥ 4 weeks for hydroxychloroquine, cyclosporine, minocycline, penicillamine, sulfasalazine, 
chloroquine, azathioprine, gold formulations, cyclophosphamide, tacrolimus, bucillamine, 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
iguratimod, azathioprine, mycophenolate, tocilizumab, sirukumab, sarilumab, and JAK 
inhibitors (upadacitinib, tofacitinib, baricitinib, filgotinib, ruxolitinib, peficitinib).

≥ 4 weeks for etanercept.

≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, and abatacept.

≥ 1 year for rituximab OR ≥ 6 months if B cells returned to pre-treatment level or are in the 
normal reference range at Baseline, if pre-treatment levels are not available.

≥ 8 weeks for leflunomide if no elimination procedure was followed, or adhere to an 
elimination procedure (i.e., 11 days with cholestyramine or activated charcoal as per local 
label).
25. Subject must not have been treated with any intra-articular, intramuscular, intravenous, 
trigger point or tender point, intra-bursa, or intra-tendon sheath glucocorticoid in the preceding 
8 weeks prior to the first dose of the study drug and must not have been treated with super high 
potency and/or high potency topical glucocorticoids in the preceding 1 week prior to the first 
dose of study drug.
26. 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 or is currently 
enrolled in another interventional clinical study or was previously enrolled in this study.
27. Subject must not have received any live vaccine within 4 weeks (or longer if required locally) 
prior to the first dose of study drug or have expected need of live vaccination during study 
participation including at least 70 days after the last dose of study drug.
28. Subject must have discontinued all opioid and analgesic medications, with the exception of 
non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, tramadol, combination of 
acetaminophen with codeine, or combination of acetaminophen with hydrocodone.  Subjects 
entering on analgesics must be on stable dose ≥1 week prior to the first dose of study drug.
29. Subjects must not have been treated with oral traditional Chinese medicine within 4 weeks 
prior to the first dose of study drug.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following: 

Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy
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
Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals.
2.
Postmenopausal female

Age > 55 years with no menses for 12 or more months without an alternative medical 
cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical 
cause AND a follicle-stimulating hormone level ≥30 IU/L.

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 70 days (150 days for UK only) 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 Baseline (Day 1).

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to Baseline (Day 1).

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

intrauterine device.

intrauterine hormone-releasing system.

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 birth control methods listed above 
(excluding true abstinence).
Contraception recommendations related to use of concomitant therapies prescribed (e.g., MTX) should 
be based on the local label.
During the course of the study, female subjects may change from "of Childbearing Potential" to "of Non-
Childbearing Potential" if meeting criteria outlined above under "Females, Non-Childbearing Potential."  
If needed to confirm post-menopausal status after the screening visit, follicle-stimulating hormone level 
may be obtained at any time during the study.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Contraception Requirements for Males
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 Baseline (Day 1) through 
at least 70 days (150 days for UK only) after the last dose of study drug.
5.3 Prohibited Medications and Therapy
In addition to the medications listed in the eligibility criteria, prior exposure to ABBV-154 or ABBV-3373 
are NOT allowed.  The following medications are prohibited through the end of study drug 
administration:

All csDMARDs, except MTX;

All tsDMARDs:  Examples include but are not limited to the following:  Xeljanz® (tofacitinib), 
Olumiant® (baricitinib), Rinvoq® (upadacitinib), Jyseleca® (filgotinib);

All bDMARDs, including bio-originators and biosimilars.  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);

Through Week 24, oral glucocorticoids with the exception of prednisone ≤ 7.5 mg/d (or 
equivalent) at Baseline, which must be tapered to 0 within 4 weeks of Baseline unless a subject 
qualifies for rescue therapy as defined in Section 5.4;

Any intra-articular, intramuscular, parenteral, trigger point or tender point, intra-bursa, or intra-
tendon sheath glucocorticoid through Week 24 unless a subject qualified for rescue therapy 
defined in Section 5.4;

Super high potency and high potency topical glucocorticoids;

Any investigational drugs;

Any live vaccination;

Any opioid medications with exception of tramadol, combination of acetaminophen with 
codeine, or combination of acetaminophen with hydrocodone; and

Any oral traditional Chinese medicine (e.g., tripterygium glycosides, sinomenine, total glucosides 
of white paeony).
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 on the appropriate electronic case report form (eCRF) from 30 days prior to Baseline 
through the Post-Treatment Visit (70 day follow-up).  Also, medications taken for RA since the date of 
diagnosis and any glucocorticoids (based on subject recollection and/or available medical records) 
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should be entered into the appropriate eCRF inclusive of the first and last dose, dosage, route of 
administration and reason for discontinuation, if known.
Subjects must remain on stable dose of MTX until Week 24 unless qualifying for rescue therapy as 
described below.  A dietary supplement of oral folic acid (or equivalent, such as folinic acid) should be 
taken while the subject is taking MTX.
Through Week 24, NSAIDs and low potency analgesics (i.e., acetaminophen, tramadol, combination of 
acetaminophen with codeine, or combination of acetaminophen with hydrocodone) 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.
At Week 18, rescue therapy should be offered to subjects classified as non-responders (defined as not 
achieving at least 20% improvement in either TJC or SJC at both Week 14 and Week 18) or after Week 18 
for at least 2 consecutive visits as follows:  1) add or modify doses of MTX within the range of 
7.5-25 mg/week, NSAIDs, acetaminophen/paracetamol, low potency opioid medications (tramadol or 
combination of acetaminophen and codeine or hydrocodone), oral glucocorticoids (up to maximum 
dose of prednisone 10 mg/day [or equivalent]) and/or 2) receive 1 intra-articular, trigger point or tender 
point, intra-bursa, or intra-tendon sheath glucocorticoids injection every 12 weeks.
At Week 30 and later, subjects classified as non-responders (defined as not achieving at least 20% 
improvement in either TJC or SJC at both Week 24 and Week 30, or after Week 30 for at least 
2 consecutive visits) will discontinue study drug and initiate standard of care therapy at the investigator 
discretion (e.g., csDMARDs, b/tsDMARDs).
Methotrexate and oral glucocorticoids should be obtained locally as they will not be provided by 
AbbVie.
Subjects must be able to safely discontinue any prohibited medications as specified in Section 5.1.  
Subjects must consent to the study prior to discontinuing any prohibited medications for the purpose of 
meeting study eligibility.  Information regarding potential drug interactions with ABBV-154 can be 
located in the ABBV-154 Investigator's Brochure.
Vaccines
If the subject and investigator choose to receive/administer live vaccines, these vaccinations must be 
completed (as per local label) at least 28 days (or longer, if required locally) before first dose of study 
drug.  Live vaccinations are prohibited during study participation including at least 70 days after the last 
dose of study drug.  Examples of live vaccines include, but are not limited to, the following:

Monovalent live influenza A (H1N1) (intranasal);

Seasonal trivalent live influenza (intranasal);

Zostavax (herpes zoster, live attenuated);

Rotavirus;

Varicella (chicken pox);

Measles-mumps-rubella or measles-mumps-rubella-varicella;
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
Oral polio vaccine;

Smallpox;

Yellow fever;

Bacille Calmette-Guérin;

Typhoid (oral).
If the live herpes zoster vaccine is to be administered and there is no known history of primary varicella 
(chicken pox), preexisting immunity to varicella should be confirmed with antibody testing at or prior to 
Screening and prior to administration of the herpes zoster vaccine.  If screening varicella antibody 
testing is negative, the live herpes zoster vaccine should not be administered.
Administration of inactivated (non-live) vaccines is permitted prior to or during the study according to 
local practice guidelines.  Examples of common vaccines that are inactivated, toxoid or biosynthetic 
include, but are not limited to, injectable influenza vaccine, pneumococcal, Shingrix (zoster vaccine, 
recombinant, adjuvanted), and pertussis (Tdap) vaccines.
COVID-19 Pandemic -Related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-replicating viral 
vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during screening or 
the treatment period, as long as components of the vaccine are not contraindicated.
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject.
The potential impact of ABBV-154 on SARS-CoV-2 vaccination is unknown.  Therefore, study drug should 
be administered as follows:
The first dose of study drug(s) ABBV-154, when possible, is preferred to be given at least ± 7 days from 
the SARS-CoV-2 vaccine administration.
Note:  The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete 
treatment course.
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines and as more data are collected in real-world scenarios and clinical trials.
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
Operations Manual for instructions on reporting any AEs associated with the COVID-19 vaccine.
Glucocorticoid Tapering of Subjects with ≤ 7.5 mg Prednisone Equivalent at Baseline
Prednisone or glucocorticoid equivalent of up to 7.5 mg/day is allowed at Baseline.  Subjects taking 
glucocorticoids at Baseline are required to taper the dose to 0 within 4 weeks after the first dose of 
study drug.  A suggested glucocorticoid scheme for the tapering is outlined in Table 1.  Adjustment to 
the suggested glucocorticoid tapering schedule is permitted based on the local availability of 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
glucocorticoid dosage strengths and individual needs.  Signs and symptoms of adrenal insufficiency 
should be closely monitored (Section 6.2).
Table 1.
Suggested Tapering Scheme for Glucocorticoid at Baseline
Study Week
Glucocorticoid Dose at Baseline Per Day
Baseline
7 – 7.5 mg
6 mg
5 mg
4 mg
3 mg
2 mg
Week 1
5 mg
4 mg
3 mg
3 mg
2 mg
1 mg
Week 2
3 mg
3 mg
2 mg
2 mg
1 mg
1 mg
Week 3
2 mg
2 mg
1 mg
1 mg
0
0
Week 4
1 mg
1 mg
1 mg
0
0
0
Week 5 and beyond
0
0
0
0
0
0
Note:
At Week 5, subjects are required to have fully tapered from glucocorticoids.
5.5 Withdrawal of Subjects and Discontinuation of Study
AbbVie may terminate this study prematurely at any time, either in its entirety or partially (discontinue 
one or more treatment groups), or at any site.  The study may be discontinued or terminated in case of 
an unacceptable risk, any relevant toxicity, or a negative change in the risk/benefit assessment.  This 
might include the occurrence of AEs with a character, severity or frequency that is new in comparison to 
the existing risk profile.  In addition, data derived from other clinical trials or toxicological studies which 
negatively influence the benefit-risk assessment might cause discontinuation or termination of the 
study.  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.  Advance notice is 
not required by either party if the study is stopped due to safety concerns.
A subject may voluntarily withdraw from the study at any time for any reason.  An investigator may 
discontinue a subject's participation at any time for any reason.  The AbbVie Therapeutic Medical 
Director may mandate individual subject discontinuation from study drug in case of a safety concern.
Subjects must have study drug discontinued immediately if any of the following occur:

Abnormal laboratory result or AE that meets the criteria for discontinuation of study drug as 
stated in Section 6.2, or rule out safe continuation of the study drug as determined by the 
investigator or the AbbVie Therapeutic Area Medical Director.

Serious infections (e.g., sepsis) that cannot be adequately controlled within 2 weeks by anti-
infective treatment or would put the subject at risk with continuation of the study drug.

Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.

Malignancy, except for localized NMSC or carcinoma in-situ of the cervix.

The subject develops anaphylactic reactions or anaphylactic shock.

The investigator believes it is in the best interest of the subject.
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
The subject requests withdrawal from study drug or the study.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

The subject becomes pregnant while on study drug.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial as determined by the Investigator or AbbVie Therapeutic 
Medical Director.
State of Emergency or Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care. Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix G.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than described in the protocol to ensure all acceptable mitigation steps have 
been explored.
Treatment Group Changes
Treatment group changes at Week 12 (e.g., the re-randomization of subject on placebo) will be done by 
interactive response technology (IRT) to ensure double-blind integrity.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
Discontinuation of Study Drug and Continuation of Study Participation
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should be encouraged to continue to be followed for all regularly scheduled visits 
as outlined in the Appendix E, and adhere to all study procedures except for administration of study 
drug, annual TB testing, and PK sample collection, unless a subject decides to discontinue study 
participation entirely (withdrawal of informed consent).  Subjects should continue to be advised on the 
scientific importance of their data even if they discontinue treatment with study drug early.  Following 
the discontinuation of study drug, the subject should be treated in accordance with the investigator's 
best clinical judgment irrespective of whether the subject decides to continue participation in the study.
In addition, a 30-Day Follow-up Phone Call and a 70-Day Follow-up Visit after the last dose of study drug 
is required to ensure all treatment-emergent AEs/SAE 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.  This information will be recorded on the appropriate eCRF page.  This 
Follow-up Phone Call is not applicable for subjects who discontinue study drug prematurely and 
continue study participation with completion of at least 1 study visit at least 30 days after the last dose 
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of study drug.  This Follow-up Visit is not applicable for subjects who discontinue study drug prematurely 
and continue study participation with completion of at least 1 study visit at least 70 days after the last 
dose of study drug.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit should be completed as soon as possible, 
preferably within 2 weeks, and preferably prior to initiation of another therapy.
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.
If a subject withdraws from study follow up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
5.7 Study Drug
ABBV-154 or placebo only will be manufactured and provided by AbbVie.  It will be taken as SC 
injections in the abdomen or thigh beginning on Day 1 (Baseline).  The study drug (ABBV-154 or placebo) 
will always be administered by a healthcare/ trained professional up to Week 78 (end of LTE Period 1).  
For LTE Period 2, study drug will be administered to all subjects by either site medical staff on-site or by 
the subject or designee (friend, family member, or personal health care professional), if opted for home 
dosing and where locally permitted.  It should be taken at approximately the same time eow, preferably 
between 7 am and 11 am.  A 15- to 30-minute post administration observation time is required.  The 
study drug can be taken with or without food.
ABBV-154 and placebo syringes will be packaged in cartons with quantities sufficient to accommodate 
the study design.  Each prefilled syringe and carton will be labeled per local requirements and these 
labels must remain affixed to the syringe and carton.  Upon receipt, study drug should be stored as 
specified on the label (refrigerated at 2 to 8 degrees Celsius) 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.  Study drug must not be dispensed without contacting the IRT system.  Site staff will 
complete all blank spaces on the label before dispensing to subjects.  Study drug is for investigational 
use only and will only be used for the conduct of this study.
AbbVie will provide instructions for drug preparation.
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Table 2.
Identity of Investigational Product
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
ABBV-154
Solution for injection/infusion 
in pre-filled syringe
40 mg and 
150 mg
subcutaneous
AbbVie
Placebo for ABBV-154
Solution for injection/infusion 
in pre-filled syringe
Not applicable
subcutaneous
AbbVie
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.
At Baseline, 425 subjects will be randomized to 5 treatment groups in a 1:1:1:1:1 ratio to receive 
ABBV-154: 40 mg, 150 mg, 340 mg SC eow; 340 mg SC e4w, or placebo. Randomization will be stratified 
by Baseline glucocorticoid (yes/no); number of prior failed b/tsDMARDs (1; 2 or more); and prior anti-
TNF failure (yes/no) and if yes further stratification by prior adalimumab use (yes/no).  At Week 12, 
subjects assigned to placebo will be re-randomized in a 1:1 ratio to receive ABBV-154 150 mg or 
340 mg SC eow; subjects from the other dose groups will continue with their respective dose and dosing 
regimen.  Re-randomization will be stratified by baseline glucocorticoid use (yes/no) and prior 
adalimumab use (yes/no). The enrollment for subjects with prior adalimumab use is capped at 
approximately 30% of the total subjects enrolled.
All AbbVie personnel with direct oversight of the conduct and management of the trial (except for 
AbbVie Drug Supply Management Team) will be blinded to each subject's treatment through Week 12.  
The study site personnel and the subject will remain blinded throughout the study.  To maintain the 
blind, the ABBV-154 and placebo pre-filled syringes provided for the study will be identical in 
appearance.  The IRT will provide access to unblinded subject treatment information in the case of a 
medical emergency.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable), and AbbVie.
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5.10 Data Monitoring and Glucocorticoid Adjudication Committees
An external DMC will be established to safeguard the interest of trial subjects by assessing the safety of 
the interventions during the trial and well as for the monitoring the integrity and interpretability of the 
trial.  A separate DMC charter will be prepared outside of the protocol and will describe the roles and 
responsibilities of the DMC members, frequency of data reviews, and expectations for blinded 
communications.
An independent glucocorticoid adjudication committee will be established to adjudicate systemic 
glucocorticoid AEs.  A separate charter will be prepared, outside of the protocol, and will describe the 
roles and responsibilities of the adjudication committee members, frequency of data reviews, and 
expectations for blinded communications.
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 damage or not 
working properly, or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours 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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Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if 
it had occurred in a more severe form.
Hospitalization or Prolongation 
of Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not 
include an emergency room visit or admission to an outpatient 
facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results 
in fetal loss.
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, study procedure-related serious and nonserious adverse events 
will be collected from the time the subject signs the study-specific informed consent.
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
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SAR
Defined as all noxious and unintended responses to an investigation 
medicinal product (IMP) related to any dose administered that result in an 
SAE as defined above.
SUSAR
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the 
sponsor or the investigator, is unexpected (not listed in the applicable 
Reference Safety Information) and meets one of the above serious criteria. 
AbbVie will be responsible for 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.
Safety Topics of Interest
The following safety topics of interest will be monitored during the study:

Serious infections;

Opportunistic infections;

Active TB;

Serious allergic reactions;

Hypersensitivity reactions;

Malignancies;

Systemic glucocorticoid side effects;

Adrenal insufficiency; and

Iatrogenic Cushing's Syndrome.
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each AE according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE Version 5.0).3
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
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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 24 hours of site
awareness 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.
6.2 Toxicity Management
The management of specific AEs and laboratory parameters are presented in Table 3.  For subjects who 
discontinue study drug but continue study participation and are on standard of care therapies, these 
toxicity management requirements do not apply (including alerts from the central laboratory) and any 
intolerability to standard of care therapies should be managed by the prescribing physician.
Elective surgery will not be allowed during the first 24-weeks of study participation.  If the subject 
undergoes elective surgery, study drug should be interrupted at least 2 weeks prior to the planned 
surgery.  If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery.  After surgery, allow reintroduction of study drug once the physician has examined 
the surgical site and determined that it has healed and there is no sign of infection.
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.  For any hypersensitivity reaction, appropriate therapy 
should be instituted per standard of care.  Study drug should be discontinued if a subject develops 
anaphylaxis.
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 
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symptom onset for additional blood tests specified in the Operations Manual, Section 3.15 
Hypersensitivity Testing.
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.
Management of Demyelinating Disease
Subjects must be discontinued from study drug with new onset 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.  Investigators should 
consider stopping the study drug if hypertension is not successfully controlled under standard of care.
Management of Hyperglycemia
Subjects should be closely monitored for the development of hyperglycemia.  Investigators should 
manage the hyperglycemia with appropriate standard of care.
Management of Glucocorticoid Induced Adrenal Insufficiency
Subjects should be closely monitored for signs and symptoms of adrenal insufficiency (e.g., nausea, 
vomiting, lightheadedness, pale skin, unexplained weight loss, low blood pressure, electrolyte 
abnormalities [e.g., confirmed hyponatremia < 135 mmol/L, hyperkalemia > 5.5 mmol/L], etc.) and if 
adrenal insufficiency is suspected, further clinical assessment and management should follow local 
standard of care and may include measuring of cortisol levels and/or ACTH stimulation test to be 
performed at a local laboratory.  Glucocorticoid therapy with physiologic doses should be considered.  
After withdrawal of glucocorticoid therapy, adrenal insufficiency may persist for months; therefore, 
glucocorticoid therapy should be considered in any situation of stress (e.g., serious infection) occurring 
or in the months following withdrawal of study drug.
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Management of COVID-19
Subjects should be closely monitored for COVID-19.  Study drug should be interrupted if a subject 
develops a confirmed diagnosis of COVID-19.  Consider the interruption of study drug in subjects with 
signs and/or symptoms and suspicion of COVID-19.
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 3, and may require a 
supplemental eCRF to be completed (Section 6.1).  For subjects with ongoing laboratory abnormalities 
that require data entry into an eCRF, an additional eCRF related to subsequent laboratory abnormalities 
is only required if the subject has relevant changes in history (e.g., new onset signs or symptoms) or 
laboratory values that have returned to normal reference range or its Baseline value followed by 
subsequent laboratory abnormalities meeting toxicity guidelines (considered a new event).  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 the Operations Manual (Appendix G) Section 
3.15, the repeat testing must occur as soon as possible.
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Table 3.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory 
Parameter
Toxicity Management Guideline
Absolute 
neutrophil count 
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 
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.
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 new appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5% increase from 
Baseline).

Interrupt study drug if confirmed ALT or AST > 5 × ULN by repeat testing with new 
sample for more than 2 weeks.

If ALT or AST > 8 × ULN, interrupt study drug immediately, confirm by repeat testing 
with a new sample, and contact the TA MD. 
Subjects with HBc Ab+ (irrespective of HBs Ab status) or Hbs Ab+ (without a history of 
vaccination) and negative HBV DNA PCR testing at Screening who develop the following 
laboratory findings should have HBV DNA PCR testing performed within one week (based 
on initial elevated value):  

ALT> 5 × ULN OR

ALT or AST > 3 × ULN if an alternative cause is not readily identified.

Note: A separate blood sample for HBV DNA PCR testing will be needed at the 
time of repeat testing for ALT or AST.
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.
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.  If applicable, 
the alternative etiology should be documented in the eCRF.  If ALT or AST values return to 
the normal reference range or its Baseline value, study drug may be restarted.  If 
restarting study drug, documentation should include reason that rechallenge is expected 
to be safe.  If after clinically appropriate evaluation, no alternative etiology for ALT or AST 
elevation is found or the ALT or AST elevation has not resolved or is not trending down 
toward normal, the subject should be discontinued from study drug.
For any confirmed ALT or AST elevations > 3 ULN, complete the appropriate supplemental
hepatic eCRF(s).
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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).
ALC = Absolute lymphocyte counts; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; BL = baseline; DNA = deoxyribonucleic acid; eCRF = electronic case report form; HBc Ab = Hepatitis B core 
antibody; HBs Ab = Hepatitis B surface antibody; HBV = hepatitis B virus; INR = international normalized ratio; PCR = polymerase 
chain reaction; TA MD = Therapeutic Area Medical Director; ULN = upper limit of normal
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).
The primary analysis will be conducted after all ongoing subjects have completed Week 12.  This will be 
the only and final analysis for the Double-Blind, Placebo-Controlled Period.  After the primary analysis, 
additional analyses may be conducted to further inform the design of a Phase 3 program.  A final 
analysis will be conducted after all subjects have either withdrawn from the study or completed LTE 
Period 2 plus the safety follow-up visit.  To maintain integrity of the trial, the study sites and subjects will 
remain blinded until all subjects have either completed the last visit of LTE Period 1 or have withdrawn 
from the study. 
7.2 Definition for Analysis Populations
The following populations will be used for analyses:

Intent-to-treat Population includes all subjects who were randomized and received at least 
1 dose of study drug.  The ITT Population will be used for all efficacy analyses.

Safety Population in the Placebo-Controlled Period (Safety_PC) includes all subjects randomized 
and received at least 1 dose of study drug.  This population will be used for the safety analysis in 
the Placebo-Controlled Period.

All ABBV-154 Treated Population (ALL_154) includes all subjects who received at least 1 dose of 
ABBV-154 during the study.  This population will be used to provide a comprehensive summary 
of safety.
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7.3 Handling Potential Intercurrent Events for the Primary and
Secondary Endpoints
No intercurrent events will be considered for the primary and secondary endpoints.
7.4 Statistical Analyses for Efficacy
For the Placebo-Controlled Period, subjects will be analyzed according to the treatment group 
randomized.  All statistical tests will be performed at a 2-sided significance level of 0.1.  A 95% 
confidence interval of the treatment difference between each ABBV-154 dose and placebo will be 
provided.

For categorical variables, a pairwise, comparison will be made between each ABBV-154 dose 
and placebo using the Cochran-Mantel-Haenszel (CMH) test, adjusting for the actual values of 
stratification factors.  Non-Responder Imputation incorporating multiple imputation to handle 
COVID-19 (NRI-MI) will be the primary approach to handle missing data for categorical 
endpoints.

For continuous variables, the comparison will be made between each ABBV-154 dose and 
placebo based on the MMRM adjusting for treatment, visit, interaction between treatment and 
visit, actual values of stratification factors as fixed factors, and BL value as a covariate.  The 
MMRM will be the primary approach to handle missing values for continuous endpoints.
Through the Placebo-Controlled and Long-Term Extension Periods, descriptive statistics by treatment 
sequences will be provided at each visit.  Categorical endpoints will be summarized by the number and 
proportion of subjects who achieved the endpoint, as well as the 95% confidence interval.  Continuous 
endpoints will be summarized by descriptive statistics including mean, standard deviation, standard 
error, and the 95% confidence interval of the mean.  In addition, continuous endpoints through Week 24 
will be summarized using estimates from the MMRM by treatment sequence, visit, interaction between 
treatment sequence and visit, actual values of stratification as fixed factors and baseline values as a 
covariate.
Summary and Analysis of the Primary Endpoint
The primary endpoint is the achievement of ACR50 at Week 12.  It will be evaluated using the ITT 
Population based on treatment as randomized.  Comparison of the primary endpoint will be made 
between each ABBV-154 dose and placebo using the CMH test adjusting for the actual values of 
stratification factors.  NRI-MI will be the primary approach to handle missing values.  Analysis details for 
NRI-MI and other sensitivity analyses (if applicable) will be provided in the SAP.
One supplementary analysis for primary endpoints is to test a pre-specified set of dose-response models 
among ABBV-154 dose groups and the placebo group at Week 12 using the Multiple Comparison 
Procedure – Modeling approach (MCP-Mod).  Details of this method will be provided in the SAP.
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Summary and Analysis of Secondary Endpoints
Analysis of secondary efficacy endpoints will be conducted on the ITT Population based on treatment as 
randomized.
Summary and Analysis of Additional Efficacy Endpoints
Additional endpoints, as described in Section 3.3, will also be analyzed.
Subgroup Analysis for Efficacy
To evaluate the consistency of efficacy across demographic and other Baseline characteristics, the 
following subgroup analysis will be performed on the primary endpoint: 

Baseline glucocorticoid use (yes/no)

Number of prior failed b/tsDMARDs (1; 2 or more)

Prior use of failed anti-TNF (yes/no)

Prior use of adalimumab (yes/no)

Age (≤median/>median)

Sex (female/male)

Race (white/non-white)
7.5 Statistical Analyses for Safety
All safety analyses will be performed based on the Safety Population, as defined in Section 7.1.  Subjects 
will be analyzed based on the actual treatment received.  Treatment-emergent adverse events (TEAEs), 
laboratory assessments, and vital signs will be summarized.  Key safety variables will also be summarized 
on the ALL_154 Population.
A TEAE for the Safety Population is defined as an AE newly occurred or worsened after the first dose of 
study drug and within 70 days after the last dose of study drug.  The number and percentage of subjects 
experiencing TEAEs will be tabulated using the MedDRA system organ class and Preferred Term, by 
severity, and by relationship to the study drug as assessed by the investigator.  Summaries (including 
percentages and events per 100 patient years) of SAEs, deaths, and AEs leading to discontinuation will 
be provided as well.  Pre-treatment AEs will be summarized separately.
For selected laboratory parameters, a listing of all subjects with any laboratory value ≥Grade 3 of the 
Common Toxicity Criteria will be provided.  Mean change in laboratory and vital signs variables will be 
summarized.  Additional details for the safety analysis are provided in the SAP.
7.6 Statistical Analysis for Pharmacokinetics and Immunogenecity
Concentrations of conjugated ADC, total antibody, and free payload (A-1677770) will be summarized at 
each time point using descriptive statistics.
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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 (ADA) and nAb incidence and ADA titer values will be summarized for each group 
using descriptive statistics.
7.7 Statistical Analysis of Biomarker Data
Analyses may 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 may be explored for each biomarker one at 
a time, and also for combinations of biomarkers via some multivariate predictive modeling approaches.  
Analyses may be reported outside of the clinical study report.
7.8 Interim Analysis
Interim analyses may be performed in this study.
7.9 Overall Type 1 Error Control
Multiplicity from multiple comparisons is not adjusted in this Phase 2b study.
7.10 Sample Size Determination
The planned total sample size of 425 subjects (approximately 85 subjects per treatment group) provides 
at least 90% power to detect a 22% difference between ABBV-154 and placebo in ACR50 response rate 
at Week 12 (assuming a placebo ACR50 response rate of 13%), at 2-sided significance level of 0.1 based 
on Chi-square test.
8 Ethics
8.1 Independent Ethics Committee/Institution 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 
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conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix C.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care. This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  In all cases, 
these alternative measures must be allowed by local regulations and permitted by IRB/IEC.  Investigators 
should notify AbbVie if any urgent safety measures are taken to protect the subject against an 
immediate hazard.
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).
In case of state of emergency or pandemic situations (e.g., During the COVID-19 pandemic), remote 
monitoring of data may be employed if allowed by the local regulatory authority, IRB/IEC, and the study 
sites.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits to ensure human subject protection and reliability of study results.  Data will be 
generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as 70 days after the last study drug administration.
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12
REFERENCES
1.
Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. 
Pharmacol Ther. 2002;96(1):23-43.
2.
AbbVie. ABBV-154 Investigator Brochure Edition 2. 2020.
3.
National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE), Version 
5.0 2017 [cited 2019 October 16]. Available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf.
4.
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an 
American College of Rheumatology/European League Against Rheumatism collaborative 
initiative. Arthritis Rheum. 2010;62(9):2569-81.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
Antibody
ACR 20/50/70 
ACR 20/50/70 
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibody
ADC
antibody-drug conjugate
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BMD
bone mineral density
BMI
body mass index
BSAP
Bone specific alkaline phosphatase 
b/tsDMARD
biologic and targeted synthetic disease-modifying antirheumatic drugs
CDAI
clinical disease activity index
CMH
Cochran-Mantel-Haenszel
COVID-19
COVID-19
CR
clinical remission
CRF
case report form
csDMARD
conventional synthetic disease-modifying antirheumatic drug
CTX
C-terminal telopeptide of type 1 collagen
CXR
chest x-ray
DAS28
disease activity score (28 joints)
DMARD
disease-modifying antirheumatic drug
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DXA
dual-energy X-ray absorptimometry
e4w
every 4 weeks
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
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eow
every other week
ESR
erythrocyte sedimentation rate
EULAR
European League Against Rheumatism
FSH
follicle stimulating hormone
GCP
good clinical practice
GRMs
glucocorticoid receptor modulators
HAQ-DI
Health Assessment Questionnaire Disability Index
HBc Ab
Hepatitis B core antibody
HBs Ab
Hepatitis B surface antibody
HBsAg
hepatis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
HCV antibody
HIV
human immunodeficiency virus
HPA 
hypothalamic pituitary-adrenal axis suppression 
hsCRP
high-sensitivity C-reactive protein
ICH
International Council for Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IRT
Interactive response technology
ITT
Intent-to-treat
IU
International units
LCMS
liquid chromatography-mass spectrometer
LDA
low disease activity
LTE
long term extension
MACE
major adverse cardiac event
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Effect Model Repeated Measurements
MTX
methotrexate
nAb
neutralizing antibody
NMSC
non-melanoma skin cancer
NRI-MI
non-responder imputation incorporating multiple imputation to handle missing 
data due to COVID-19
NRS
numerical rating scale
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NSAID
non-steroidal anti-inflammatory drug
OC
osteocalcin
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PFS
pre-filled syringes
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
pharmacokinetic(s)
PPD
purified protein derivative
RA
rheumatoid arthritis
RNA
ribonucleic acid
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
SDAI
simplified disease activity index
SF
short form
SJC
swollen joint count
SUSAR
suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TBNK 
T/B and natural killer cells
TEAE
treatment-emergent adverse event
TJC
tender joint count
TNF
tumor necrosis factor
ULN
upper limit of normal
vs.
versus
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APPENDIX B. 2010 RHEMATOID ARTHRITIS CLASSIFICATION
The 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis4
Target population (Who should be tested?): Patients who: 1) have at least 1 joint with definite clinical synovitis 
(swelling)a and 2) with the synovitis not better explained by another diseaseb
A score of ≥ 6/10 is required for classification of a patient as having definite RA.c
Classification Criteria for Rheumatoid Arthritis (Add scores in each category) 
Score
Joint involvementd
1 large joint 
0
2-10 large joints 1
1
1-3 small joints (with or without involvement of large joints)e
2
4-10 small joints (with or without involvement of large joints)
3
> than 10 joints (at least 1 small joint)f
5
Serology (at least 1 test result is needed for classification)g
Negative rheumatoid factor and negative anti-citrullinated protein antibody ACPA
0
Low-positive rheumatoid factor or low-positive anti-citrullinated protein antibody
2
High-positive rheumatoid factor or high positive anti-citrullinated protein antibody
3
Acute-Phase Reactants (at least 1 test result is needed for classification)h
Normal CRP and normal ESR
0
Abnormal CRP or abnormal ESR
1
Duration of Symptomsi
< 6 Weeks
0
≥ 6 Weeks 
1
CRP = C-reactive protein; ESR = erythrocyte sedimentation Rate
a.
The criteria are aimed at classification of newly presenting patients.  In addition, patients with erosive disease typical of 
rheumatoid arthritis with a history compatible with prior fulfillment of the 2010 criteria should be classified as having 
rheumatoid arthritis.  Patients with longstanding disease, including those whose disease is inactive (with or without 
treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as 
having rheumatoid arthritis.
b.
Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus 
erythematosus, psoriatic arthritis, and gout.  If it is unclear about the relevant differential diagnoses to consider, an expert 
rheumatologist should be consulted.
c.
Although patients with a score of < 6/10 are not classifiable as having RA, their status can be reassessed, and the criteria 
might be fulfilled cumulatively over time.
d.
Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of 
synovitis.  Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded 
from assessment.  Categories of joint distribution are classified according to the location and number of involved joints, 
with placement into the highest category possible based on the pattern of joint involvement.
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e.
"Large joints" refers to shoulders, elbows, hips, knees, and ankles.  "Small joints" refers to the metacarpophalangeal joints, 
proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
f.
In this category, at least 1 of the involved joints must be a small joint; the other joints can include any combination of large 
and additional small joints, as well as other joints not specifically listed elsewhere (e.g., temporomandibular, 
acromioclavicular, sternoclavicular, etc.).
g.
Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; 
low-positive refers to IU values that are higher than the ULN but ≤3 times the ULN for the laboratory and assay; high-
positive refers to IU values that are >3 times the ULN for the laboratory and assay.  Where rheumatoid factor information 
is only available as positive or negative, a positive result should be scored as low-positive for rheumatoid factor.
h.
Normal/abnormal is determined by local laboratory standards.
i.
Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, swelling, 
tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.
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APPENDIX C. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M20-466:  A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and 
Efficacy of ABBV-154 in Subjects with Moderately to Severely Active Rheumatoid Arthritis with 
Inadequate Response to Biologic and/or Targeted Synthetic Disease-Modifying Anti-Rheumatic Drugs 
(b/tsDMARDs)
Protocol Date:  12 April 2022
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and 
local regulations and guidelines governing the study at the site location.  In signing the Investigator 
Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX D. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Study Project Manager
Clinical Program Development
Senior Medical Writer
Medical Writing
Group Medical Director
Immunology Therapeutic Area
Medical Director
Immunology Therapeutic Area
Associate Director
Statistics
Therapeutic Area Head
Statistics
Director
Clinical Pharmacology
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APPENDIX E. ACTIVITY SCHEDULE
The following table shows the required activities across all subject encounters.  The individual activities 
are described in detail in the Operations Manual.  Allowed modifications in case of emergency or 
pandemic situations due to COVID-19 are detailed in the Operations Manual.
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APPENDIX F. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
23 April 2021
Version 1.1 (Japan Only)
10 May 2021
Administrative Change 1
06 July 2021
Version 1.2 (United Kingdom Only)
17 September 2021
The purpose of this version is to update the following sections below.  In addition, minor typographical 
corrections or edits have been made for consistency throughout the Protocol and Operations Manual.
Summary of Protocol Changes: 

Protocol Section 1, Synopsis; Protocol Section 4.1, Overall Study Design and Plan:  Added a 104-
week LTE Period 2 and renamed the originally planned double-blind LTE period "Double-Blind, 
Long-term Extension Period 1." Corrected spelling of glucocorticoid.
Rationale:  The 2 LTEs are labeled "Double-Blind, Long-term Extension Period 1" and "Long-term 
Extension Period 2" to differentiate between them as the first LTE period is double-blind and the 
second LTE period will be blinded only until the last subject completes the last visit of Double-
Blind Long-term Extension Period 1 or withdraws from the study. The 104-week LTE Period 2 will
collect additional data for the long-term safety, tolerability, and efficacy of ABBV-154 in subjects 
with RA who have completed Double-Blind LTE Period 1.

Protocol Section 1, Synopsis, Investigational Plan: Follow-up "Visit" changed to Follow-up 
"Period."
Rationale: To reflect the duration of follow-up, as the follow-up period is now comprised of a 
follow-up phone call and a follow-up visit as opposed to a single visit.

Protocol Section 1, Synopsis; Protocol Section 4.1, Overall Study Design and Plan; Protocol 
Section 7.1, Statistical and Analytical Plans:  Updated wording to indicate that blinded dosing 
regimens will be continued until all subjects having either completed the last visit of LTE Period 
1 or have withdrawn from the study.
Rationale:  To specify when unblinding will occur.

Protocol Section 1, Synopsis; Protocol Section 5.1, Eligibility Criteria:  Updated criterion #7 to 
include a list of b/tsDMARDs that can be considered for the criteria of inadequate response, 
including guidance for previous use of investigational drugs.  Updated note on the criterion #7 
to clarify that b/tsDMARDs discontinued due to other reasons unrelated to inadequate response 
will not be accepted to fulfill eligibility criteria.
Rationale:  To clarify which b/tsDMARDs are acceptable to fulfil the criterion #7 by mechanism of 
action, including guidance for previous use of investigational drugs. To clarify that b/tsDMARDs 
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discontinued due to other reasons unrelated to inadequate response will not be accepted to 
fulfill eligibility criterion #7.

Protocol Section 3.1, Objectives, Hypotheses, and Estimands; Protocol Section 7.2, Definition of 
Analysis Populations:  Changed the definition of ITT population from all randomized subjects to 
all subjects who were randomized and received at least 1 dose of study drug.
Rationale:  To exclude subjects from the ITT analysis if they were not dosed to be consistent with 
analysis methods used in prior clinical trials, which included all randomized subjects who 
received at least 1 dose of study drug.

Protocol Section 3.1, Objectives, Hypotheses, and Estimands; Protocol Section 7.3, Handling 
Potential Intercurrent Events for the Primary and Secondary Endpoints:  Removed the 
intercurrent event of confounding medication use for all endpoints.
Rationale:  Medications with potential to affect efficacy are either prohibited through the 
placebo-controlled period or are required to remain at stable dose (as listed in Protocol 
Section 5.1, Eligibility Criteria, and Protocol Section 5.3, Prohibited Medications and Therapy).  
Handling of intercurrent events of confounding medication use was removed to allow 
comparison to prior clinical trials that did not use this analysis method, as this study will be used 
to inform future development of ABBV-154.

Protocol Section 3.7 Biomarker Research Endpoints; Appendix E, Activity Schedule; Operations 
Manual Section 2.1, Individual Treatment Period Visit Activities; Section 3.9 Biomarker Research 
Sampling; Section 4.1 Methods and Timing of Safety Assessment; Appendix 7.3, Synovial Biopsy 
Procedures:  Removed mention of synovial biopsy/joint biopsy.
Rationale: The Optional Synovial Biopsy Substudy has been removed as it has been determined 
it will not be possible to enroll enough subjects into the Substudy to achieve scientific goals; 
without expectation for the data to provide meaningful scientific value it is not appropriate to 
perform the biopsy procedure on study subjects.

Protocol Section 4.1, Overall Study Design and Plan:  Added 70-Day Follow-up Period to the 
description of the overall study design.
Rationale: To provide clarity surrounding the planned duration of the study.

Protocol Section 4.1, Overall Study Design and Plan; Protocol Section 7.1, Statistical and 
Analytical Plans:  Updated timing of the Primary Analysis and the Final Analysis to specify it will 
occur after all ongoing subjects have completed Week 12 or have withdrawn from the study.
Rationale:  To provide clarification for analysis timing.

Protocol Section 4.1 and Figure 1:  Updated text and figure to include the 104-week LTE 
Period 2.  Updated text to clarify that subjects previously on placebo will be re-randomized.
Rationale: Figure was updated to reflect changes in the study design with the addition of the 
104-week LTE Period 2.  Updated text regarding re-randomization of placebo subjects for clarity.

Protocol Section 5.1, Eligibility Criteria:  Updated criterion #3 to add "at the time of Screening."
Rationale:  To clarify timepoint for which this criterion is to be applied.

Protocol Section 5.1, Eligibility Criteria:  Updated criterion #4 to correct units to "mIU/L."
Rationale:  To correct the typographical error.
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
Protocol Section 5.1, Eligibility Criteria, Protocol Section 5.2, Contraception Recommendations:  
Specified the duration of contraception requirements will be 150 days (5 months) after last dose 
of study drug administration for females (criterion #15) (UK only) and for males (criterion #17) 
(UK only).  Specified that females must not be pregnant, breastfeeding, or considering becoming 
pregnant and must not donate eggs for 150 days after last dose of study drug administration 
(criterion #16) (UK only), and males must not consider fathering a child or donating sperm for 
150 days after last dose of study drug administration (criterion #18) (UK only).  Updated bullet 
for Females, Childbearing Potential to add that females of childbearing potential must avoid 
pregnancy for 150 days (UK only) after the last dose of study drug.  Updated Contraception 
Requirements for Males to add that males who are sexually active with a female partner of 
childbearing potential must use male condoms through at least 150 days (UK only) after last 
dose of study drug.
Rationale:  The duration of contraception, pregnancy, and egg/sperm donation requirements 
after last dose of study drug was changed for the UK to align with local health authority request.  
The duration for each remains 70 days after the last dose of study drug administration globally, 
which represents greater than 5 times the upper limit of the mean elimination half-life, using the 
most conservative estimate of the half-life among the 3 analytes (ADC, total antibody, and 
payload) measured in circulation following subcutaneous administration of ABBV-154.  Thus, at 
70 days, no relevant systemic exposure to ABBV-154 is expected to be present.

Protocol Section 5.1, Eligibility Criteria:  Updated criterion #24 to add "interventional" to 
describe clinical study type.
Rationale:  To specify that subjects cannot be enrolled in another interventional study. 
Noninterventional studies are permitted, as they are not expected to impact safety or efficacy of 
this study.

Protocol Section 5.1, Eligibility Criteria:  For criterion #25, corrected a typographical error in the 
period of time to refrain from live vaccination after last dose of study drug from 12 weeks to 
70 days and add clarification that 4 weeks is the minimum amount of time between receipt of a 
live vaccine, but duration may be longer if required locally.
Rationale:  To align with Protocol Section 5.4 and to ensure that a live vaccination is not 
administered during periods of relevant systemic ABBV-154 exposure, as 70 days is greater than 
5 times the upper limit of the mean elimination half-life of subcutaneously administered 
ABBV-154.

Protocol Section 5.2, Contraception Recommendations:  Corrected requirement #1 for Females, 
Non-Childbearing Potential to "Premenopausal" from "Postmenopausal." Corrected the follicle-
stimulating hormone level to ≥ 30 IU/L from > 30 IU/L.
Rationale:  To correct the typographical errors.

Protocol Section 5.2, Contraception Recommendations: updated that both male and female 
condoms may be used where required by local practices in addition to the highly effective 
methods of birth control.
Rationale: To clarify that where required by local practices, both male and female condoms may 
be used in addition to the highly effective methods of birth control which are required for all 
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Females, of Childbearing Potential as either will adequately prevent the occurrence of 
pregnancy.

Protocol Section 5.2, Contraception Recommendations: Added language to allow re-testing with 
follicle-stimulating hormone after screening visit for female subjects that may change status 
from childbearing potential to non-childbearing potential during the course of the study.
Rationale: During the course of the study, females initially classified as of childbearing potential 
may become postmenopausal or permanently sterile and therefore not at risk to become 
pregnant. For subjects not at risk for pregnancy, discontinuation of required contraception and 
pregnancy testing is appropriate.

Protocol Section 5.3, Prohibited Medications and Therapy:  Changed the time period during 
which the list of prohibited medications is prohibited from "throughout the duration of the 
study" to "through the end of study drug administration."
Rationale: To clarify that subjects may receive these medications after discontinuation of study 
drug.

Protocol Section 5.3; Prohibited Medications and Therapy:  Corrected "sheet" to "sheath."
Rationale: To correct the typographical error.

Protocol Section 5.4, Prior and Concomitant Therapy: Deleted text describing b/tsDMARDs by 
mode of action and text stating all csDMARDs except for MTX must have been discontinued.
Rationale: As information on prior b/tsDMARD therapies which would qualify a subject for study 
eligibility was added to eligibility criterion #7 this information was removed from Section 5.4 to 
avoid duplication of information and potential for confusion.  The requirement for 
discontinuation of all prior b/tsDMARDs and all csDMARDs, except MTX prior to the first dose of 
study drug was deleted to remove redundancy and potential confusion as it is included in 
eligibility criterion 22 and Section 5.3, Prohibited Medications and Therapy with requirements for 
MTX stability remaining in Section 5.4.

Protocol Section 5.4, Prior and Concomitant Therapy: Clarified that at Week 30 and later, 
subjects classified as non-responders (defined as not achieving at least 20% improvement in 
either TJC or SJC at both Week 24 and Week 30, or after Week 30 for at least 2 consecutive 
visits) will discontinue study drug and initiate standard of care therapy at the investigator 
discretion.
Rationale:  To improve clarity.

Protocol Section 5.5, Withdrawal of Subjects and Discontinuation of Study:  Updated to state 
that AbbVie may terminate this study prematurely "at any time," either in its entirety or 
"partially discontinue one or more treatment groups."
Rationale:  To clarify that AbbVie may prematurely discontinue not just the entire study but one 
or more treatment groups at any time.

Protocol Section 5.5, Withdrawal of Subjects and Discontinuation of Study:  Added the following 
wording to bullet #1 regarding abnormal laboratory results or AEs that meets the criteria for 
discontinuation of study drug, "or rule out safe continuation of the study drug" as determined 
by the investigator.
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Rationale:  To clarify that the investigator or AbbVie TA MD may also determine that a subject 
must be discontinued from study drug based on abnormal laboratory result or AE, which 
prevents safe continuation of the study drug even if not stated in Section 6.2, Toxicity 
Management.

Protocol Section 5.6, Follow-Up After Subject Discontinuation of Study Drug or From Study, and 
Operations Manual Section 2.2 Post-Treatment Activities:  Added "30-Day Follow-up Phone Call" 
and to clarify those subjects for whom the Follow-up Phone Call and Follow-up Visit are not 
applicable.
Rationale:  Phone call was added to further ensure subject safety and capture of AEs/SAEs 
occurring early in the follow up period. The follow-up phone call and follow-up visit are not 
required to collect additional subject data if a subject continues in the study for at least 30 days 
or 70 days, respectively, as follow-up will occur at regular study visits.

Protocol Section 5.7, Study Drug; Operations Manual Section 6.1, Treatment Administered:  
Removed reference to 3 SC injections (2 PFS with 1.5 ml fill volume and 1 PFS with 0.4 ml fill 
volume).
Rationale:  Text on number of injections/syringes with specific volumes was removed to allow 
dispensing of fewer kits based on assigned treatment once study is unblinded, as placebo 
injections are no longer required at that time.

Protocol Section 5.7, Study Drug:  Corrected time range for study drug administration to be 
between 7 a.m. and 11 a.m.  Added sentence explaining that for LTE Period 1, the study drug 
(ABBV-154 or placebo) will always be administered by a healthcare/ trained professional and for 
LTE Period 2, study drug will be administered to all subjects by either site medical staff on-site or 
by the subject or designee (friend, family member, or personal health care professional), if 
opted for home dosing and where locally permitted.
Rationale:  To correct the typographical error for consistency with the Operations Manual.  To 
clarify the study drug administration during both LTE Period 1 and LTE Period 2.

Protocol Section 6.1, Complaints and Adverse Events:  Removed "AE" from the Hepatic eCRF.
Rationale:  The eCRF is applicable both for specified hepatic-related AEs and laboratory 
abnormalities.

Protocol Section 6.1, Complaints and Adverse Events:  Updated wording to state that pregnancy 
in a study subject must be reported to AbbVie within 24 hours of site awareness.
Rationale:  To provide clarification.

Protocol Section 6.2, Toxicity Management:  Added sentence explaining that toxicity 
management requirements do not apply to a subject who is discontinued from study drug but 
continues study participation.
Rationale:  To clarify applicability of toxicity management requirements as no ongoing risk to 
subject safety related to study drug is anticipated after discontinuation of study drug
administration.

Protocol Section 6.2, Toxicity Management: Added instructions for interruption of study drug at 
the time of elective surgery and clarified when to re-start study drug after surgery.
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Rationale: To ensure subject safety by providing instructions for interruption of study drug 
related to surgery.

Protocol Section 6.2, Toxicity Management:  Added sentence to Management of Select 
Laboratory Abnormalities explaining situations in which subjects with ongoing laboratory 
abnormalities do not require additional data entry into an eCRF.
Rationale:  To clarify and reduce duplication of eCRF data entry.

Protocol Appendix A, Study-Specific Abbreviations and Terms:  Updated abbreviations list.
Rationale:  Added missing abbreviation for PBMC and reordered abbreviations alphabetically 
where needed.

Protocol Appendix D, List of Protocol Signatories:  Updated personnel list.
Rationale: Administrative change.

Protocol Appendix E, Activity Schedule:  Updated the Activity Schedule (Appendix E) to reflect 
changes in the study design and to include additional activities for specific visits.  Updated 
abbreviations list at end of table.
Rationale: To reflect all the changes in activities scheduled on specific visits and additional 
abbreviations.

Operations Manual, Section 1 Contacts: Updated the name of the Certified Clinical Lab to 
Labcorp Central Laboratory and updated the name and contact of the Biomarker Sample storage 
from Brooks Life Sciences Brooks Receiving to Azenta Life Sciences.
Rationale:  The name of the certified clinical lab changed from Covance Central Laboratory to 
Labcorp Central Laboratory and the name of the biomarker sample storage changed to Azenta 
Life Sciences.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities; Section 2.2 Post-
Treatment Activities:  Added an extra column/dot to the column headers of the Individual Study 
Day tables.
Rationale:  To reflect the addition of the 30-day post-treatment follow-up phone call.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities:  Deleted 
subsequent instances of full terms for high-sensitivity C-reactive protein and Health Assessment 
Questionnaire Disability Index since already defined at first use and acronym provided.
Rationale:  To remove redundancy.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities:  Added 
"Rheumatoid Factor" for Week 78 visit.
Rationale:  Added to align with Activity Schedule (Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visit Activities:  Added a 7-day 
treatment period window for the LTE Period 2, starting at Week 86.
Rationale:  To inform that a longer treatment window period of 7 days will be allowed for the 
LTE Period 2. This will give flexibility to the subjects that opted for dosing at home and will 
maintain the 7-day treatment window considered safe between doses.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities: Corrected the 
spelling of "virtual."
Rationale:  To correct the typographical error.

Operations Manual, Section 2.1:  Updated study visit day tables and individual visit activities for 
LTE Period 1, LTE Period 2, 30-Day Follow-Up Phone Call, Week 182 Final Study Visit, and 70-day 
Follow-up Visit.
Rationale:  To reflect updated schedule of activities as described in the Activity Schedule 
(Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities: Corrected the AE
assessment during the Screening Period to only study procedure-related SAEs and non-serious 
AEs.
Rationale: To align with the Operations Manual Section 4.1 Methods and Timing of Safety 
Assessment.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Week 26, 28, 32, 34, 
38, 40, 44, 46, 50, 52, 56, 58, 62, 64, 68, 70, 74, 76: Added supervised training for study drug 
administration at home at Week 76 and corresponding footnote "a" to inform that if 
administration of study drug at home is not locally permitted or not opted by the subject, 
training for home administration is not required.
Rationale:  To ensure proper training for subjects which will be dosing at home during LTE Period 
2 and clarify that if administration of study drug at home is not locally permitted or not opted by 
the subject, training for home administration is not relevant.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities, Week 4 (Day 29), 
Week 8 (Day 57), Week 12 (Day 85), Week 18 (Day 127), Week 24 (Day 169), Week 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, Week 182 (Final 
Study Visit), Premature Discontinuation: Removed definition of ADA (anti-drug antibody) and 
nAb (neutralizing antibodies) abbreviations.
Rationale: Definition of ADA and nAb abbreviations were provided on Week 2 (Day 15).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Added the TB risk 
questionnaire, QuantiFeron-Tb Gold test (and/or local PPD Skin Test), and Chest X-ray to Weeks 
110 and 166.
Rationale: To ensure subject safety through annual TB assessments during administration of 
study drug.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Updated PGIC –
FLARE to Week 78 only. 
Rationale: To align with the activity schedule Appendix E for the LTE Period 1 where PGIC –
FLARE is performed at Week 78.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174: updated PGIS –
Page 66 of 123
 


  
STUDY M20-466  |  Version 2.0  |  EudraCT 2020-005303-39
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
FLARE to Weeks 30, 36, 42, 48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 
166, and 174.
Rationale: To reflect the updated schedule of activities related to the LTE Period 2 as described 
in the Activity Schedule (Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Updated the 
physical exam to Weeks 36, 48, 60, 72, 78, 86, 94, 118, 142, and 166.
Rationale: To reflect updated schedule of activities related to the LTE Period 2 as described in 
the Activity Schedule (Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Updated 12-lead 
ECG to Weeks 36, 78, and 134.
Rationale:  To reflect the updated schedule of activities related to the LTE Period 2 as described 
in the Activity Schedule (Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Updated DXA 
Scan with body composition to Week 78 and 134. Added footnote "e" to specify the window for 
obtaining DXA Scan with body composition.
Rationale: To reflect updated schedule of activities related to the LTE Period 2 as described in 
the Activity Schedule (Appendix E). To clarify the permitted window for collection of DXA Scan 
with body composition.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Week 24 (Day 169), 
Weeks 30, 36, 42, 48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174: 
added "free" to the scheduled biomarker sample of whole blood for cortisol.
Rationale: To clarify free cortisol is being tested on whole blood.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Week 24 (Day 169), 
Weeks 30, 36, 42, 48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174: 
added footnote "i" on Biomarker sample: Whole blood for free cortisol, bone markers (BSAP, 
PINP, OC and CTX), ACTH, and TBNK to inform which visits these biomarker samples are 
scheduled to be collected.
Rationale:  To reflect updated schedule of activities related to the LTE Period 2 as described in 
the Activity Schedule (Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Updated HbA1c 
to Weeks 36, 48, 60, 72, 94, 118, 142, and 166.
Rationale: To reflect updated schedule of activities related to the LTE Period 2 as described in 
the Activity Schedule (Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174: updated Lipid 
profile to Weeks 36, 48, 60, 72, 94, 118, 142, and 166.
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Rationale: To reflect updated schedule of activities related to the LTE Period 2 as described in 
the Activity Schedule (Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Revised footnote 
"a" to describe requirements for urine pregnancy testing both at scheduled visits on-site and at 
home between visits if time between visits is longer than 1 month. Added timepoints for 
collection of HbA1c and lipid profile to the table and footnote "a" removed from HbA1c and lipid 
profile.
Rationale:  To reflect updated schedule of activities related to the LTE Period 1 and 2 that 
requires urine pregnancy testing during the study at a minimum of monthly intervals and inform 
which visits the urine pregnancy tests can be collected on-site and which visits the urine 
pregnancy tests can be collected at home to ensure monthly urine pregnancy testing for females 
of childbearing potential.  Timepoints for collection of HbA1c and lipid profile were added to the 
table, therefore this information was removed from the footnote.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174: Updated 
footnote "d" added language to inform that, if necessary, HBV DNA PCR may be tested at 
unscheduled visits.
Rationale:  To inform that, if necessary, HBV DNA PCR test may be tested at unscheduled visits.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Added 
supervised training for study drug administration at home at Week 78 and corresponding
footnote "f" to inform that if administration of study drug at home is not locally permitted or 
not opted by the subject, training for home administration is not required and that subjects not 
trained for administration of study drug at home will continue to receive study drug eow in the 
clinic.
Rationale:  To ensure proper training for subjects which will be dosing at home during LTE Period 
2 and clarify that if administration of study drug at home is not locally permitted or not opted by 
the subject, training for home administration is not relevant and dosing can continue to be 
performed at the clinic eow after Week 78 (during LTE Period 2).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Added 
Dispensation of study drug for home administration and corresponding footnote "g" to state 
study drug dispensation for home administration will start at Week 78 andis only applicable 
where locally permitted or opted by the subject, and that after Week 180 study drug will no 
longer be dispensed.
Rationale:  To specify start and end of study drug dispensation for home administration and 
clarify study drug dispensation for home administration is only applicable where locally 
permitted or opted by the subject.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Added Subject 
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STUDY M20-466  |  Version 2.0  |  EudraCT 2020-005303-39
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Diary Reviewand corresponding footnote "h" to inform that subjects who opted for dosing at 
home will have their diaries reviewed.
Rationale: To inform that subjects who opted for home dosing during the LTE Period 2 will have 
their diaries reviewed at specified visits to capture dosing dates and times for dosing compliance.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Weeks 30, 36, 42, 
48, 54, 60, 66, 72, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174:  Added footnote 
"i" to inform the visit schedule for whole blood collection for free cortisol and bone markers.
Rationale:  To align with Activity Schedule (Appendix E).

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Week 182 Final 
Study Visit: Removed of PGIC – FLARE and bone biomarkers; added HbA1c and lipid profile; 
added note "a" to inform that subjects who opted for dosing at home will have their diaries 
reviewed.  Changed notes and b to b and c, respectively.
Rationale: PGIC – FLARE assessment at Week 178 will not be informative since it is based on the 
patient's recollection of disease activity at baseline and will continue to be collected at the 
Week 78 visit as previously planned.  HbA1c and lipid profile were added to have a robust safety 
assessment at the updated final study visit at Week 182. To inform that subjects who opted for 
home dosing during the LTE Period 2 will have their diaries reviewed to capture dosing dates and 
times for dosing compliance. Footnotes b and updated to align with appropriate activities.

Operations Manual, Section 2.1 Individual Treatment Period Visits Activities Week 182 Final 
Study Visit:  Added whole blood biomarker sample for free cortisol.
Rationale:  Whole blood biomarker sample for free cortisol was added to have a robust safety 
assessment at the updated final study visit at Week 182.

Operations Manual, Section 2.2 Post-Treatment Activities:  30-Day Post-treatment Follow-up 
Phone Call was added, which includes an AE assessment and prior and concomitant medications 
assessment.
Rationale:  Phone call was added to further ensure subject safety and capture of AEs/SAEs 
occurring early in the follow up period.

Operations Manual, Section 2.2 Post-Treatment Activities Post-Treatment Day 70 Visit: Added 
body weight, vital signs, whole blood biomarker sample for total and free cortisol, blood 
samples for serum conjugate ADC (serum), total antibody (serum), free A-1677770 (plasma) 
assays, and blood samples for serum ADA assays (including nAb), and ADA titer assays to the 70-
day follow-up visit.
Rationale: To ensure more robust safety data collection at follow up.  To ensure drug washout 
and assess immunogenicity during drug washout.

Operations Manual, Section 3.2, Re-Screening:  Added wording "without prior AbbVie approval" 
regarding re-screening.
Rationale:  To clarify the re-screening process.

Operations Manual, Section 3.5, Dual-Energy X-Ray Absorptiometry (DXA) Scan:  Added 
collection of Z-score for evaluation of bone mineral density and instruction that measurements 
should be obtained from the distal forearm if neither the spine nor either hip are able to be 
scanned or interpreted.  Added a Central Imaging Core Lab for central independent review of 
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STUDY M20-466  |  Version 2.0  |  EudraCT 2020-005303-39
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DXA data and modified guidance for image acquisition.  Removed performance of BMD and 
body composition assessment if DXA scan is not available.
Rationale:  To improve the robustness and interpretability of the DXA data collected.  Other 
methods of BMD and body composition assessment are not interchangeable with DXA.

Operations Manual Section 3.15 Subject Dosing Diary:  Added Operations Manual Section 3.15 
Subject dosing diary to inform when the subjects will be dispensed a diary and the process of 
diary documentation and review.
Rationale:  To inform subjects who opted for home dosing during LTE Period 2 and where locally 
permitted when they will receive a dosing diary, how they will be trained and how the dosing 
diary will be reviewed and properly documented.

Operations Manual, Section 3.16 Clinical Laboratory Tests, Table 1.  Added Follicle Stimulating 
Hormone to the table to reflect changes in Protocol Section 5.2.
Rationale:  Follicle Stimulating Hormone testing was added to align with addition of language in 
protocol section 5.2 which permits re-testing of FSH during study conduct.

Operations Manual, Section 3.16 Clinical Laboratory Tests, Pregnancy Tests (Serum and Urine): 
Updated language to align with the Protocol Section 5.2.  Added "at investigator discretion 
Follicle Stimulating Hormone may be retested after the Screening visit."
Rationale: To align with language in Protocol Section 5.2 Contraception Recommendations 
which outlines requirements for females to be considered of non-childbearing potential.  To align 
with addition of language in Protocol Section 5.2 which permits re-testing of FSH during study 
conduct.

Operations Manual, Section 3.16 Clinical Laboratory Tests, Pregnancy Tests (Serum and Urine): 
Added language to clarify requirements for serum and urine pregnancy testing during the study 
and add home urine pregnancy testing at a minimum of monthly intervals. 
Rationale: To clarify requirements for serum and urine pregnancy testing during the study and 
add home urine pregnancy testing at a minimum of monthly intervals. Greater than monthly 
intervals between on-site visits in LTE Period 2 occur; thus, specific timepoints for serum and 
urine pregnancy testing are found in the Activity Schedule (Appendix E) and Operations 
Manual Section 2.1 Individual Treatment Period Visits Activities.

Operations Manual, Section 3.16 Clinical Laboratory Tests, Hepatitis Screening:  Added language 
to Figure 1 to inform that HBV DNA PCR may be tested at unscheduled visits, if necessary.
Rationale: To provide instruction for subjects requiring HBV DNA PCR testing every 12 weeks to 
have an unscheduled visit to test HVB DNA PCR when planned visits are not at 12-week intervals. 

Operations Manual, Section 3.16 Clinical Laboratory Tests, Tuberculosis Prophylaxis:  Deleted 
duplicate "at least" and underscore between "rifampin must."
Rationale: To correct typographical errors.

Operations Manual, Section 3.16 Clinical Laboratory Tests, Hypersensitivity Testing:  Simplified 
instructions for sample collection.
Rationale: To clarify that the laboratory manual provides all the instructions necessary for 
sample collection.
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STUDY M20-466  |  Version 2.0  |  EudraCT 2020-005303-39
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Operations Manual, Section 3.19 Home Healthcare Services after Week 24:  Corrected spelling 
of healthcare.
Rationale: To correct the typographical error.

Operations Manual, Section 5.2 Treatment After End of Study: Updated last study visit to 
Week 182.
Rationale: To reflect the updated study design with the LTE Period 2.

Operations Manual, Section 6.1, Treatments Administered:  Updated section to add paragraph 
detailing training requirements for subjects or designees on home administration of study drug 
and instructions for study drug administration for LTE Period 2.
Rationale:  To provide guidance for training of subjects or designees on home administration of 
study drug and on-site and at home study drug administration for the LTE Period 2.

Operations Manual, Section 6.2, Packaging and Labeling:  Removed statement that each syringe 
and carton will be labeled as required per country requirements.
Rationale:  To remove redundant information.

Operations Manual, Section 6.4, Selection and Timing of Dose for Each Subject:  Added 
instruction for handling of dosing of ABBV-154/placebo outside of the visit window.
Rationale:  To provide guidance for minimal timing between doses in case of unanticipated out 
of window dosing to ensure subject safety.
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SAP_001.pdf: 
A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
1 
St ati sti c al A n al y si s Pl a n f or St u d y M 2 0 -4 6 6
A R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d 
St u d y t o E v al u at e t h e S af et y a n d Effi c a c y of 
A B B V -1 5 4 i n S u bj e ct s wit h M o d er at el y t o S e v er el y 
A cti v e R h e u m at oi d Art hriti s wit h I n a d e q u at e 
R e s p o n s e t o Bi ol o gi c a n d/ or T ar g et e d S y nt h eti c 
Di s e a s e -M o dif yi n g A nti -R h e u m ati c Dr u g s 
( b/t s D M A R D s)
D at e:  1 7 A u g u st 2 0 2 2 
V er si o n 2 . 0
N C T 0 4 8 8 8 5 8 5


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 
T a bl e of C o nt e nt s
1. 0
I ntr o d ucti o n .............................................................................5
2. 0
St u d y Desi g n a n d O bjecti ves ..................................................5
2. 1
O bjecti ves, H y p ot heses a n d Esti ma n ds ..................................................... 5
2. 2
St u d y Desi g n O ver vie w ............................................................................. 6
2. 3
Treat me nt Assi g n me nt a n d Bli n di n g ......................................................... 7
2. 4
Sa m ple Size Deter mi nati o n  ........................................................................ 8
3. 0
E n d p oi nts ..................................................................................8
3. 1
Pri mar y  E n d p oi nt(s) ................................................................................... 8
3. 2
Sec o n dar y  E n d p oi nt(s) ............................................................................... 8
3. 3
Ot her Effi cac y E n d p oi nt(s) ........................................................................ 9
3. 4
Safet y E n d p oi nt(s) ................................................................................... 1 0
3. 5
A d diti o nal  E n d p oi nt(s) ............................................................................. 1 0
4. 0
A n al ysis P o p ul ati o ns .............................................................1 0
5. 0
S u bject Dis p ositi o n ................................................................1 1
6. 0
St u d y Dr u g D ur ati o n a n d C o m pli a nce ................................1 2
7. 0
De m o gr a p hics, B aseli ne C h ar acteristics, Me dic al 
Hist or y, a n d Pri or/ C o nc o mit a nt Me dic ati o ns ....................1 2
7. 1
De m o gra p hics a n d Baseli ne C haract eristics  ............................................ 1 3
7. 2
Me dical Hist or y  ....................................................................................... 1 5
7. 3
Pri or a n d C o nc o mita nt Me dicati o ns ........................................................ 1 5
8. 0
H a n dli n g of P ote nti al I nterc urre nt E ve nts f or t he 
Pri m ar y a n d Ke y Sec o n d ar y E n d p oi nts ..............................1 6
9. 0
Effic ac y A n al yses ...................................................................1 6
9. 1
Ge ner al  C o nsi derati o ns ............................................................................ 1 6
9. 2
Ha n dli n g of I nter c urre nt E ve nt a n d Missi n g Data ................................... 1 7
9. 2. 1
Missi n g Data d ue t o C O VI D- 1 9 a n d L o gistical Pr o ble ms ( Ge o-
p olitical Restricti o ns)  ............................................................................... 1 7
9. 2. 2
Ha n dli n g of missi n g data i n Cate g orical E n d p oi nts................................. 1 7
9. 2. 3
Ha n dli n g of missi n g data i n C o nti n u o us E n d p oi nts ................................ 1 9
9. 2. 4
S u m mar y of L o n g- Ter m Efficac y  ............................................................ 1 9
9. 3
Pri mar y Efficac y E n d p oi nt(s) a n d A nal yses ............................................ 2 0


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
3 
9. 3. 1
Pri mar y Efficac y E n d p oi nt(s) .................................................................. 2 0
9. 3. 2
A nal ysis of Pri mar y Effi cac y E n d p oi nt(s) ............................................... 2 1
9. 3. 3
Se nsiti vit y a n d S u p ple me ntar y A nal yses of t h e Pri mar y Efficac y 
E n d p oi nt(s) ............................................................................................... 2 2
9. 4
Sec o n dar y Efficac y E n d p oi nts a n d A nal yses .......................................... 2 2
9. 4. 1
Sec o n dar y Efficac y E n d p oi nts ................................................................. 2 2
9. 4. 2
A nal yses of Sec o n d ar y Efficac y E n d p oi nts ............................................. 2 3
9. 4. 3
Se nsiti vit y a n d S u p ple me ntar y A nal yses f or Sec o n dar y Effi cac y 
E n d p oi nts ................................................................................................. 2 5
9. 4. 4
S u p p orti ve Sec o n dar y Efficac y E n d p oi nts a n d A n al yses ........................ 2 5
9. 5
A d diti o nal Efficac y A nal yses .................................................................. 2 5
9. 6
D ose - Res p o nse M o deli n g f or A B B V- 1 5 4 ............................................... 2 5
9. 7
Efficac y S u b gr o u p A nal yses .................................................................... 2 7
1 0. 0
S afet y A n al yses ......................................................................2 7
1 0. 1
Ge ner al  C o nsi derati o ns ............................................................................ 2 7
1 0. 2
A d verse E v e nts  ........................................................................................ 2 8
1 0. 2. 1
Treat me nt - E mer ge nt A d verse E ve nts ...................................................... 2 8
1 0. 2. 2
A d verse E v e nt O ver vi e w  ......................................................................... 2 9
1 0. 2. 3
Treat me nt - E mer ge nt A d verse E ve nts b y S O C a n d/ or P T ....................... 2 9
1 0. 2. 4
Treat me nt -E mer ge nt A d verse E ve nts p er Patie nt -Years of 
E x p os ure .................................................................................................. 3 0
1 0. 2. 5
S A Es (I n cl u di n g Deat hs) a n d A d vers e E ve nts Lea di n g t o St u d y 
Dr u g  Disc o nti n uati o n ............................................................................... 3 0
1 0. 2. 6
A d verse E v e nts of S peci al I nt erest  .......................................................... 3 0
1 0. 3
A nal ysis of La b or at or y Data .................................................................... 3 1
1 0. 4
A nal ysis of Vital Si g ns  ............................................................................ 3 2
1 0. 5
Safet y S u b gr o u p A nal yses ....................................................................... 3 3
1 0. 6
Ot her Safet y A n al yses  .............................................................................. 3 4
1 1. 0
Ot her A n al yses .......................................................................3 4
1 2. 0
I nteri m A n al yses ....................................................................3 4
1 2. 1
Data M o nit ori n g C o m mittee  .................................................................... 3 5
1 3. 0
O ver all T y pe -I Err or C o ntr ol ..............................................3 5
1 4. 0
Versi o n Hist or y ......................................................................3 6


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
4 
1 5. 0
Refere nces ...............................................................................3 6
Li st of T a bl e s
Ta ble  1.
S u m mar y of t he Esti ma n d Attri b utes of t he Pri mar y Efficac y 
E n d p oi nt(s) ............................................................................................... 2 1
Ta ble  2.
S u m mar y of t he Esti ma n d Attri b utes of t he Sec o n dar y Effi cac y 
E n d p oi nts ................................................................................................. 2 4
Ta ble  3.
Ca n di date M o dels .................................................................................... 2 6
Ta ble  4.
S A P Versi o n Hist or y S u m mar y ............................................................... 3 6
Li st of Fi g ur e s
Fi g ure 1.
St u d y  Sc he matic ......................................................................................... 7
Li st of A p p e n di c e s
A p pe n di x A.
Pr ot oc ol  De viati o ns .................................................................................. 3 8
A p pe n di x B.
P ote ntiall y Cli nicall y I m p orta nt Criteria f or Safet y E n d p oi nts  ............... 3 9
A p pe n di x C.
Ra n d o m  See ds .......................................................................................... 4 0


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1. 0
I ntr o d u cti o n
T his Statistical A nal ysis Pla n ( S A P) descri bes t he statistical a nal yses f or A B B V - 1 5 4 
St u d y M 2 0- 4 6 6: A Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d St u d y t o E val uate t he 
Safet y a n d Efficac y of A B B V - 1 5 4 i n S u bjects wit h M o deratel y t o Se verel y Acti ve 
R he u mat oi d Art hritis wit h I n a de q uat e Res p o nse t o Bi ol o gic a n d/ or Tar get e d S y nt hetic 
Disease - M o dif yi n g A nti- R he u matic Dr u gs ( b/ts D M A R Ds). 
St u d y M 2 0- 4 6 6 assesses t he efficac y a n d safet y of A B B V - 1 5 4 i n s u bjects wit h 
m o deratel y t o se verel y acti ve r he u mat oi d art hritis wit h i na de q uate res p o nse t o bi ol o gic 
a n d/ or tar get e d s y nt hetic disease- m o dif yi n g a nti-r he u matic dr u gs ( b/ts D M A R Ds). 
T he a nal yses of p har mac o ki netic e n d p oi nts a n d p har mac o d y n a mic bi o mar ker e n d p oi nts 
will n ot be c o vere d i n t his S A P. 
T he S A P will n ot be u p date d i n case of a d mi nistrati ve c ha n ges or a me n d me nts t o t he 
pr ot oc ol t hat d o n ot i m pact t he a nal ysis. 
U nless n ote d ot her wise, all a nal yses will be perf or me d usi n g S A S Versi o n 9. 4 ( S A S 
I nstit ute I nc., C ar y, N C  2 7 5 1 3) or later u n d er t he U NI X o perati n g s yste m. 
2. 0
St u d y D e si g n a n d O bj e cti v e s
2. 1
O bj e cti v e s, H y p ot h e s e s a n d E sti m a n d s
T he pri mar y o bjecti ve is t o assess t he safet y, t olera bilit y, a n d efficac y of A B B V- 1 5 4 vs. 
place b o o n bac k gr o u n d met h otre xate ( M T X) f or t he treat me nt of s u bjects wit h m o deratel y 
t o se verel y acti ve r he u m at oi d art hritis ( R A) w h o ha ve ha d a n i na de q u ate res p o nse t o at 
least o ne pri or b/ts D M A R D. 
T he pri mar y efficac y o bj ecti ve of t he st u d y is t o de m o nstrate a hi g her rat e of ac hie vi n g 
5 0 % i m pr o ve me nt as meas ure d b y A merica n C oll e ge of R he u mat ol o g y res p o nse criteria 
(A C R 5 0 ) after 1 2 wee ks of treat me nt wit h A B B V - 1 5 4 w he n c o m p are d t o place b o i n t he 
I nte nt-t o- Treat (I T T) P o p ulati o n (f urt her d escri be d i n Secti o n 4. 0 ), w hic h c o nsists of all 


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ra n d o mize d s u bjects w h o recei v e d  at least o ne d ose of st u d y dr u g.  T he h y p ot hesis 
c orres p o n di n g t o t he pri mar y effi cac y o bj ecti ve a n d e n d p oi nt is t hat t he pr o p orti o n of 
s u bjects ac hie vi n g A C R 5 0 wit h A B B V- 1 5 4 is greater t ha n t hat wit h place b o at Wee k 1 2.  
T he esti ma n d f or t he pri mar y e n d p oi nt is defi ne d as t he differe nce i n t he pr o p orti o n of 
s u bjects ac hie vi n g A C R 5 0 at Wee k 1 2 i n eac h of t he A B B V - 1 5 4 d ose gr o u ps c o m pare d 
wit h t he place b o gr o u p i n t he I T T P o p ulati o n. 
T he sec o n d ar y efficac y o bjecti ves of t he st u d y are t o de m o nstrate hi g her efficac y of 
treat me nt wit h A B B V- 1 5 4 c o m pare d t o place b o wit h res pect t o t he sec o n d ar y e n d p oi nts 
s pecifie d i n Secti o n 3. 2  i n t he I T T P o p ulati o n.  T he esti ma n ds c orres p o n di n g t o t he 
sec o n dar y effi cac y o bj ecti ves are as f oll o w. 
●
F or eac h of t h e cat e g orical sec o n dar y e n d p oi nts, t he esti ma n ds c orres p o n di n g 
t o t he sec o n dar y effi cac y o bjecti ves are defi ne d as f oll o ws: Differe nce i n t h e 
pr o p orti o n of s u bjects ac hie vi n g t he e n d p oi nt i n eac h of t he A B B V- 1 5 4 gr o u ps 
i n c o m paris o n wit h t he place b o gr o u p i n t he I T T P o p ulati o n. 
●
F or eac h of t h e c o nti n u o us sec o n dar y e n d p oi nts, t he esti ma n ds c orres p o n di n g 
t o t he sec o n dar y effi cac y o bjecti ves are defi ne d as f oll o ws:  Differe nce i n t he 
mea n c ha n g e fr o m b aseli ne of t he e n d p oi nt i n eac h of t he A B B V- 1 5 4 d ose 
gr o u ps i n c o m paris o n wit h t he place b o gr o u p i n t h e I T T P o p ulati o n. 
2. 2
St u d y D e si g n O v er vi e w
T his is a ra n d o mize d, d o u ble- bli n d, P hase 2 b, d ose-ra n gi n g st u d y wit h a 1 2- wee k 
Place b o - C o ntr olle d Peri o d, a 6 6- wee k L o n g- T er m E xte nsi o n ( L T E) Peri o d 1, a n d a 
1 0 4- wee k L T E Peri o d 2 i n a d ults wit h m o deratel y t o se verel y acti ve R A a n d o n 
bac k gr o u n d M T X, w h o h a ve ha d a n i na de q u ate res p o nse t o b/ts D M A R D treat me nt.
T he Pri mar y A nal ysis will be c o n d ucte d after all o n g oi n g s u bjects ha ve c o m plete d 
Wee k  1 2 or wit h dra w n fr o m t he st u d y.  After t he Pri mar y A nal ysis, a d diti o nal a nal ys es 
ma y be c o n d uct e d as nee de d.  A fi nal a n al ysis will be c o n d ucte d after all s u bjects ha ve 
c o m plete d t he L T E Peri o d 2 a n d a safet y f oll o w- u p visit 7 0 da ys after t he l ast d ose of 


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st u d y dr u g, or ha ve wit h dra w n fr o m t he st u d y.  T he sc he matic of t he st u d y is s h o w n i n 
Fi g ure 1 . 
Fi g ure  1. 
St u d y Sc he m atic
B L = Baseli n e; E O W = e v er y ot her wee k; E 4 W = e v er y 4 wee ks; n = n u m b er of s u bjects; S C = s u b c uta n e o us
2. 3
Tr e at m e nt A s si g n m e nt a n d Bli n di n g
S u bjects will re mai n o n a sta ble d ose of M T X u ntil Wee k 2 4 ( u nless q u alif yi n g f or resc u e 
t hera p y as d escri be d i n Pr ot oc ol Secti o n 5. 4); t hereafter M T X ma y be a dj uste d wit hi n t he 
ra n ge of 7. 5 – 2 5 m g/ w ee k.  At Baseli ne, a p pr o xi matel y 4 2 5 s u bjects will be ra n d o mize d 
t o 5 treat me nt gr o u ps i n a 1: 1: 1: 1: 1 rati o t o recei v e A B B V- 1 5 4:  4 0 m g, 1 5 0 m g, 3 4 0 m g 
S C E O W ; 3 4 0 m g S C E 4 W , or place b o.  Ra n d o mizati o n will be stratifie d b y Baseli ne 
gl uc oc ortic oi d ( yes/ n o); n u m ber of pri or faile d b/ts D M A R Ds ( 1; 2 or m ore); a n d pri or 
a nti- T N F fail ure ( y es/ n o) a n d if yes f urt h er stratifi cati o n b y pri or a d ali m u ma b use 
( yes/ n o).  At Wee k 1 2, s u bjects assi g ne d t o place b o will be re-ra n d o mize d i n a 1: 1 rati o t o 
recei v e A B B V- 1 5 4 1 5 0 m g or 3 4 0 m g S C E O W ; s u bjects fr o m t he ot her d ose gr o u ps will 
c o nti n ue wit h t heir res pecti ve d ose a n d d osi n g re gi me n.  Re- ra n d o mizati o n will be 
stratifie d b y Baseli ne gl u c oc ortic oi d use ( y es/ n o) a n d pri or a d ali m u ma b use ( yes/ n o).  T h e 


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e nr oll me nt f or s u bjects wit h pri or a dali m u ma b use is ca p pe d at a p pr o xi matel y 3 0 % of t he 
t otal s u bjects e nr olle d.  S yste mic gl uc oc ortic oi ds ( d ose of ≤ 7. 5 m g/ d pre d nis o ne 
e q ui vale nt at Baseli ne) m ust be ta pere d off wit hi n 4 wee ks of t he st art of st u d y dr u g. 
All A b b Vie pers o n nel wit h direct o versi g ht of t he c o n d uct a n d ma n a ge me nt of t he trial 
(e xce pt f or A b b Vi e Dr u g S u p pl y Ma na ge me nt Tea m) will be bli n de d t o eac h s u bject's 
treat me nt t hr o u g h Wee k 1 2.  T he A b b Vie st u d y tea m will be u n bli n de d t o treat me nt 
assi g n me nt f or t he Pri mar y A nal ysis.  T h is u n bli n di n g will ta ke place after all s u bjects 
ha ve c o m plete d t h e Wee k 1 2 visit or ha ve wit h dra w n fr o m t he st u d y pri or t o Wee k 1 2.  
T o mai ntai n i nte grit y of t he trial, t he  st u d y site pers o n nel a n d t he s u bjects will re mai n
bli n de d u ntil all s u bjects ha ve eit her c o m plete d t h e last visit of L T E Peri o d 1 or ha ve 
wit h dra w n fr o m t he st u d y.  Bli n de d d osi n g re gi me ns will be c o nti n ue d u ntil t he pre vi o us 
criteria are met.  T o mai ntai n t he bli n d, t he A B B V- 1 5 4 a n d place b o pre-fille d s yri n ges 
pr o vi de d f or t he st u d y will be i de ntical i n a p peara nce.  T he I R T will pr o vi de access t o 
u n bli n de d s u bject treat m e nt i nf or mati o n i n t he cas e of a me dical e mer g e nc y. 
2. 4
S a m pl e Si z e D et er mi n ati o n
T he pla n ne d t otal sa m ple size of 4 2 5 s u bjects (a p pr o xi matel y 8 5 s u bjects per treat me nt 
gr o u p) pr o vi des at least 9 0 % p o wer t o det ect a 2 2 % differe nce bet wee n A B B V- 1 5 4 a n d 
place b o i n A C R 5 0 res p o nse rate at Wee k  1 2 (ass u mi n g a place b o A C R 5 0 res p o nse rate of 
1 3 %), at a 2-si d e d si g nifica nce le vel of 0. 1 b ase d o n C hi- s q uare test.
3. 0
E n d p oi nt s
3. 1
Pri m ar y E n d p oi nt( s)
T he pri mar y e n d p oi nt is t he ac hie v e me nt of A C R 5 0 at Wee k 1 2.
3. 2
S e c o n d ar y E n d p oi nt( s)
All sec o n dar y e n d p oi nts are at Wee k 1 2. 
●
C ha n ge i n Disease Acti vit y Sc ore ( D A S) 2 8 ( C R P) fr o m Baseli ne;


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●
C ha n ge i n Cli nical Disease Acti vit y I n d e x ( C D AI) fr o m Baseli ne;
●
Ac hie ve me nt of A C R 2 0; 
●
Ac hie ve me nt of A C R 7 0; 
●
Ac hie ve me nt of l o w dis ease acti vit y ( L D A) defi n e d b y D A S 2 8 ( C R P) ≤ 3. 2;
●
Ac hie ve me nt of L D A defi ne d b y C D AI ≤ 1 0;
●
Ac hie ve me nt of cli nical re missi o n ( C R) defi ne d b y D A S 2 8 ( C R P) < 2. 6; 
●
Ac hie ve me nt of C R defi ne d b y C D AI ≤ 2. 8;
●
C ha n ge i n t he Healt h Ass ess me nt Q uesti o n naire Disa bilit y I n de x ( H A Q- DI) 
fr o m Baseli ne. 
3. 3
Ot h er Effi c a c y E n d p oi nt( s)
T he pri mar y e n d p oi nt a n d all sec o n dar y e n d p oi nts will be a nal yze d at all visits assesse d 
ot her t ha n Wee k 1 2.  I n a d diti o n, t he f oll o wi n g e n d p oi nts will be a nal yze d at all visits 
assesse d.
●
C ha n ge fr o m Baseli ne i n i n di vi d ual c o m p o ne nts of A C R 
●
C ha n ge fr o m Baseli ne i n si m plifie d disease acti vit y i n de x ( S D AI)
●
Ac hie ve me nt of L D A defi ne d as S D AI ≤ 1 1
●
Ac hie ve me nt of C R defi ne d as S D AI ≤ 3. 3
●
Ac hie ve me nt of B o olea n re missi o n base d o n a 2 8-j oi nt c o u nt a n d defi ne d as 
s w olle n j oi nt c o u nt ( SJ C) ≤ 1, te n der j oi nt c o u nt ( TJ C) ≤ 1, hi g h se nsiti vit y 
C- reacti ve pr otei n ( hs C R P) ≤ 1 m g/ d L, a n d Patie nt Gl o bal Assess me nt of 
Disease A cti vit y ≤ 1  ( o n a 0- 1 0 n u meric rati n g scale [ N R S]) 
●
C ha n ge fr o m Baseli ne i n P R O MI S Pai n I nterfere n ce
●
C ha n ge fr o m Baseli ne i n F L A R E- R A


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3. 4
S af et y E n d p oi nt( s)
Safet y e val uati o ns i ncl u d e a d vers e e v e nt ( A E) m o nit ori n g, p h ysical e xa mi nati o ns, vital 
si g ns meas ure me nts, electr ocar di o gra ms ( E C Gs), a n d cli nical la b orat or y testi n g 
(c he mistr y, he mat ol o g y, a n d uri nal ysis). 
Safet y e n d p oi nts i ncl u de t he occ urre nce of t he f oll o wi n g: 
1.
Treat me nt -e mer ge nt a d v erse e v e nts, seri o us a d v erse e ve nts ( S A Es), a n d A Es 
lea di n g t o disc o nti n uati o n of t he st u d y dr u g 
2.
P ote ntiall y gl uc oc ortic oi d relate d A Es
3.
P ote ntiall y cli nicall y i m p orta nt  la b orat or y, vital si g ns, a n d electr o car di o gra m 
( E C G) par a meters
3. 5
A d diti o n al E n d p oi nt( s)
P har mac o ki netic, i m m u n o ge nicit y, a n d bi o mar ker researc h e n d p oi nts will be a nal yze d 
se parat el y, a n d t he c orres p o n di n g a nal ysis pla n is n ot c o vere d i n t his S A P. 
4. 0
A n al y si s P o p ul ati o n s
T he f oll o wi n g p o p ulati o n sets will be use d f or t he a nal yses. 
I nte nt-t o-Tre at (I T T) P o p ul ati o n 
T he I nte nt -t o- Treat (I T T) P o p ulati o n i ncl u des all ra n d o mize d s u bjects w h o recei v e d at 
least o ne d ose of st u d y dr u g.  T he I T T P o p ulati o n will be use d f or all efficac y a nal yses.  
S u bjects will be i ncl u de d i n t he a nal ysis acc or di n g t o t he treat me nt gr o u ps t o w hic h t he y 
are r a n d o mize d.


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S afet y P o p ul ati o n 
T he Safet y P o p ulati o n i n Place b o- C o ntr olle d Peri o d ( Safet y _ P C) i ncl u des all s u bjects 
ra n d o mize d a n d recei ve d at least 1 d ose of st u d y dr u g i n Place b o - C o ntr olle d Peri o d.  T his 
p o p ulati o n will be use d f or t he safet y a nal ysis i n t he Place b o- C o ntr olle d Peri o d. 
T he All A B B V - 1 5 4 Treate d P o p ulati o n ( AL L _ 1 5 4) i ncl u des all s u bjects w h o recei v e at 
least 1 d ose of A B B V- 1 5 4 d uri n g t he st u d y.  T his p o p ulati o n will be use d t o pr o vi de a 
c o m pre he nsi ve s u m mar y of safet y. 
F or t hese s afet y p o p ulati o ns ( Safet y _ P C a n d A L L _ 1 5 4), s u bjects are assi g ne d t o 
treat me nt gr o u ps bas e d o n t he treat me nts t he y recei ve d uri n g t he maj orit y of t heir dr u g 
e x p os ure ti me i n t he a n al ysis peri o d f or eac h s u bject i n t he res pecti ve safet y p o p ulati o n. 
5. 0
S u bj e ct Di s p o siti o n
T he t otal n u m ber of s u bj ects w h o are scree n e d, ra n d o mize d, a n d treate d will be 
s u m marize d.  Reas o ns f or e xcl usi o n, i ncl u di n g scree n fail ure, will be s u m marize d. 
A s u m mar y of s u bject acc o u nta bilit y will be pr o vi de d w here t he n u m ber of s u bjects i n 
eac h of t h e f oll o wi n g cat e g ories will be s u m marize d f or eac h treat me nt gr o u p: 
●
S u bjects ra n d o mize d i n t he st u d y; 
●
S u bjects w h o ta ke at least o ne d ose of st u d y dr u g; 
●
S u bjects w h o c o m plete pr ot oc ol- s pecifi e d treat me nt f or Place b o- C o ntr olle d 
a n d L T E Peri o ds 1 a n d 2 , res pecti vel y;
●
S u bjects w h o pre mat urel y disc o nti n ue st u d y dr u g f or Place b o- C o ntr olle d a n d 
L T E Peri o ds  1 a n d 2, res pecti vel y;
●
S u bjects w h o c o m plete st u d y partici pati o n f or Place b o- C o ntr olle d a n d L T E 
Peri o ds, 1 a n d 2, res pecti vel y;
●
S u bjects w h o pre mat urel y disc o nti n ue st u d y partici pati o n f or Place b o-
C o ntr olle d a n d L T E Peri o ds 1 a n d 2, res pecti vel y; 
●
S u bjects i n eac h a n al ysis p o p ulati o n, as a p plica ble. 


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6. 0
St u d y Dr u g D ur ati o n a n d C o m pli a n c e
F or t he P lace b o- C o ntr olle d peri o d, L T E Peri o d 1 a n d L T E Peri o d 2, as w ell as st u d y 
o verall, d urati o n of tr eat me nt will be s u m marize d f or eac h treat me nt gr o u p a n d f or all 
A B B V - 1 5 4 d ose gr o u ps c o m bi ne d.  D urati o n of treat me nt is defi ne d f or eac h s u bject as 
last d ose date mi n us first d ose date pl us 1 4 da ys.  D urati o n of treat me nt will be 
s u m marize d usi n g t he n u m ber of s u bjects treate d, mea n, sta n dar d d e viati o n, me dia n, 
mi ni m u m a n d ma xi m u m.  I n a d diti o n, t he n u m ber a n d perce nta ge of s u bjects i n eac h 
treat me nt d urati o n i nter v al (< 2 wee ks [ 1 4 d a ys], ≥ 2 wee ks [ 1 4 d a ys], ≥ 4 wee ks 
[ 2 8 da ys], ≥ 8 wee ks [5 6 da ys ], ≥ 1 2 wee ks [ 8 4 da ys], ≥ 2 4 wee ks [ 1 6 8 d a ys ], ≥ 3 6 wee ks 
[ 2 5 2 da ys], ≥ 5 2 wee ks [ 3 6 4 da ys], ≥ 7 8 wee ks [ 5 4 6 da ys], 1 0 4 wee ks [ 7 2 8 da ys], 
1 3 0 wee ks  [ 9 1 0 d a ys], a n d 1 5 6 wee ks [ 1, 0 9 2 d a ys ]) will be s u m marize d.
Treat me nt c o m plia nce will be s u m marize d b y treat me nt gr o u p a n d t otal A B B V - 1 5 4 gr o u p 
f or t he saf et y p o p ulati o ns.  Treat me nt  c o m plia nce is defi ne d as t he n u m ber of i njecti o ns 
act uall y ta ke n di vi de d b y t he n u m ber of i njecti o ns t hat s h o ul d ha ve bee n ta ke n.  All 
place b o i njecti o ns will be i ncl u de d i n t he calc ulati o n f or treat me nt c o m plia nce.  Perce nt 
c o m plia nce will be s u m marize d.
7. 0
D e m o gr a p hi c s, B a s eli n e C h ar a ct eri sti c s, M e di c al 
Hi st or y, a n d Pri or /C o n c o mit a nt M e di c ati o n s
De m o gra p hics, b aseli ne or disease c h aracteristics, me dical hist or y, a n d pri or a n d 
c o nc o mita nt me dicati o ns will be s u m marize d f or t he I T T p o p ulati o n o verall a n d b y 
treat me nt gr o u p.  Cate g orical vari a bles will be s u m marize d wit h t he n u m b er a n d 
perce nt a ge of s u bjects ; perce nt a ges will be calc ul ate d base d o n t he n u m b er of n o n-
missi n g o bser vati o ns.  C o nti n u o us varia bles will be s u m marize d wit h des cri pti ve statistics 
( n u m ber of n o n- missi n g o bser vati o ns, mea n a n d sta n dar d de viati o n, me dia n, mi ni m u m 
a n d ma xi m u m). 


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7. 1
D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s
C o nti n u o us de m o gra p hic varia bles i ncl u de a ge, w ei g ht, hei g ht, a n d b o d y mass i n de x 
( B MI).  Cate g orical de m o gra p hic varia bles i ncl u d e se x, et h nicit y, race, a ge ( < 4 0, 4 0 – 6 5, 
≥ 6 5 years), w ei g ht (< 6 0 , 6 0 – 1 0 0, ≥ 1 0 0 k g), B MI ( < 2 5, ≥ 2 5  - < 3 0, ≥ 3 0 k g/ m2), 
re gi o n (Asia , N ort h A merica, or r est of w orl d), t o bacc o user (c urre nt, f or m er, ne ver, 
u n k n o w n), a n d al c o h ol user (c urre nt, f or mer, n e ver, u n k n o w n). 
Disease c h aracteristics t h at will be s u m marize d as c o nti n u o us a n d cate g orical varia ble s 
are liste d bel o w:
R A Me dic al Hist or y a n d C h ar acteristi cs
●
D urati o n of R A S y m pt o ms i n years 
●
D urati o n of R A Dia g n osis i n years 
●
D urati o n of R A Dia g n osis Cate g ories ( < 5, 5 – 1 0 or ≥ 1 0 year s) 
A C R a n d/ or D A S C o m p o ne nts at B aseli ne
●
Te n der j oi nt c o u nt ( TJ C 2 8) defi ne d as t he n u m ber of te n der j oi nts o ut of 
2 8 assesse d j oi nts use d f or D A S 2 8 calc ul ati o n 
●
S w olle n j oi nt c o u nt ( SJ C 2 8) defi ne d as t he n u m ber of s w olle n j oi nts o ut of 
2 8 assesse d j oi nts use d f or D A S 2 8 calc ul ati o n 
●
Te n der j oi nt c o u nt ( TJ C 6 8) defi ne d as t he n u m ber of te n der j oi nts o ut of 
6 8 assesse d j oi nts use d f or A C R 2 0/ 5 0/ 7 0 calc ulati o n 
●
S w olle n j oi nt c o u nt ( SJ C 6 6) defi ne d as t he n u m ber of s w olle n j oi nts o ut of 
6 6 assesse d j oi nts use d f or A C R 2 0/ 5 0/ 7 0 calc ulati o n 
●
P h ysicia n's gl o bal assess me nt of disease acti vit y ( o n a 0- 1 0 N R S) 
●
Patie nt's assess me nt of pai n ( o n a 0- 1 0 N R S) 
●
Patie nt's gl o bal assess me nt of disease acti vit y ( o n a 0- 1 0 N R S) 
●
Healt h Assess me nt Q uesti o n naire Disa bilit y I n d e x of t he ( H A Q – DI) 
(ra n ge:  0 t o 3) 
●
Hi g h se nsiti vit y C -reacti ve pr otei n ( hs C R P) ( m g/ L) 


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Ot her B aseli ne R A Dise ase C h ar acteristics
●
D A S 2 8 ( C R P)
●
D A S 2 8 Cate g ories: 
○
D A S 2 8 > 5. 1 ( Hi g h Disease Acti vit y) 
○
D A S 2 8 3. 2 t o ≤ 5. 1 ( M o derate Dis ease A cti vit y)
○
D A S 2 8 < 3. 2 ( L o w Disease Acti vit y)
●
Cli nical Disease Acti vit y I n d e x ( C D AI)
●
C D AI cate g ories:
○
C D AI > 2 2 ( Hi g h Dis eas e Acti vit y) 
○
C D AI > 1 0 t o ≤ 2 2 ( M o d erate Dis ease A cti vit y)
○
C D AI ≤ 1 0 ( L o w Diseas e Acti vit y)
●
Si m plifie d Disease Acti vit y I n de x ( S D AI)
●
S D AI cate g ories:
○
S D AI > 2 6 ( Hi g h Diseas e Acti vit y)
○
S D AI > 1 1 t o ≤ 2 6 ( M o d erate Dis ease A cti vit y)
○
S D AI ≤ 1 1 ( L o w Disease Acti vit y)
●
P R O MI S Pai n I nterf ere n ce T otal Sc ore a n d ite m le vel sc ores
●
F L A R E -R A ( o v erall sc ore, J oi nt a n d Ge neral s u b d o mai n sc ores, w h et her t h e 
s u bject e x peri e nce d a n R A flare i n t he l ast 3 m o nt hs or si nce t heir last cli ni c 
visit [ N o/ Yes, O nce/ Y es, se veral ti mes], a n d w het her t he s u bject is c urre ntl y 
flari n g at baseli ne [ N o/ Y es]) 
●
R he u mat oi d Fact or ( p ositi ve: ≥ 1 0 I U/ m L, ne g ati ve: < 1 0 I U/ m L) 
●
A nti -citr ulli nate d pr otei n a nti b o d y ( A C P A) ( p ositi ve, ne gati ve) 
Pri or a n d C o nc o mit a nt Tre at m e nt U se
●
Baseli ne gl uc oc ortic oi d use ( yes/ n o) 
●
Gl uc oc ortic oi d d ose at Baseli ne 
●
Pri or faile d Bi ol o gic a n d/ or Tar get e d S y nt hetic D M A R D S ( 1; 2 or m ore) 
●
Pri or a nti -T N F fail ure ( y es/ n o ) 


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●
Pri or a nti -T N F us e ( yes/ n o) 
●
Pri or a dali m u ma b use ( y es/ n o ) 
●
Pri or n o n- a nti-T N F  bi ol o gic D M A R D use ( yes/ n o) 
●
Pri or s y nt hetic (c o n ve nti o nal a n d tar get e d) D M A R D use ( yes/ n o) 
○
Pri or c o n ve nti o nal s y nt hetic D M A R D use ( y es/ n o ) 
○
Pri or tar gete d s y nt hetic D M A R D use ( yes/ n o) 
●
D urati o n of pri or gl uc o c ortic oi d use ( m o nt h) 
●
D urati o n of pri or gl uc o c ortic oi d- free da ys bef ore ra n d o mizati o n ( da y) 
●
Pri or c u m ulati ve gl uc oc ortic oi d d ose ( m g)  
●
Pri or c u m ulati ve gl uc oc ortic oi d d ose ( m g) ( wit hi n o ne year b ef ore 
ra n d o mizati o n) 
7. 2
M e di c al Hi st or y
Me dical hist or y data will be c o de d usi n g t he Me di cal Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A).  T h e act u al versi o n of t he Me d D R A c o di n g dicti o nar y will be n ote d i n t he 
statistical ta bles a n d cli nical st u d y re p ort. T h e n u m ber a n d perce nt a ge of s u bjects i n eac h 
me dical hist or y cate g or y ( b y Me d D R A s yste m or g a n class a n d preferre d ter m) will be 
s u m marize d o ver all a n d b y treat me nt gr o u p.  T he s yste m or ga n class ( S O C) will be 
prese nte d i n al p h a betical or der, a n d t h e preferre d t er ms will be prese nt e d i n al p ha betical 
or der wit hi n eac h S O C.  S u bjects re p orti n g m ore t ha n o ne c o n diti o n/ dia g n osis will be 
c o u nte d o nl y o nce i n eac h r o w ( S O C or preferre d ter m). 
7. 3
Pri or a n d C o n c o mit a nt M e di c ati o n s
Pri or a n d c o nc o mita nt m e dicati o ns will be s u m marize d b y ge n eric n a me.  A pri or 
me dicati o n is defi ne d as a n y me dicati o n ta ke n pri or t o t he date of t he first d ose of st u d y 
dr u g.  A c o nc o mita nt me dicati o n is defi ne d as a n y me dicati o n t hat starte d pri or t o t he date 
of t he first d ose of st u d y dr u g a n d c o nti n ue d t o be ta ke n after t he first d ose of st u d y dr u g 
or a n y me dicati o n t hat st arte d o n or after t h e date of t he first d ose of st u d y dr u g, b ut n ot 
after t he d ate of t he l ast d ose of st u d y dr u g pl us 7 0 da ys.  T he  n u m ber a n d p erce nt a ge of 


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s u bjects ta ki n g me dicati o ns will be s u m marize d b y ge neric dr u g na me b ase d o n t he W orl d 
Healt h Or ga ni zati o n ( W H O) Dr u g Dicti o nar y f or b ot h pri or a n d c o nc o mit a nt me dicati o ns.  
T he sa me s u m mar y will be pr o vi de d s pecificall y f or D M A R D me dicati o ns , as well as f or 
me dicati o ns use d f or r esc ue t hera p y p er pr ot oc ol criteri o n . 
8. 0
H a n dli n g of P ot e nti al I nt er c urr e nt E v e nt s f or t h e 
Pri m ar y a n d K e y S e c o n d ar y E n d p oi nt s
N o i nterc urr e nt e ve nts ar e c o nsi der e d f or t he pri mar y a n d ke y s ec o n d ar y e n d p oi nts. 
9. 0
Effi c a c y A n al y s e s
9. 1
G e n er al C o n si d er ati o n s
All efficac y a n al ys es will be c o n d ucte d i n t he I T T P o p ulati o n.  All tests will be 2 -si de d at 
a n α  le vel of 0. 1. 
T he Pri mar y A nal ysis will be perf or me d after all o n g oi n g s u bjects ha ve c o m plete d t he 
Place b o - C o ntr olle d Peri o d , a n d t he data b ase has b ee n l oc ke d.  T his will be t he o nl y a n d 
fi nal a nal ysis f or t he pri mar y a n d sec o n dar y efficac y e n d p oi nts. 
U nless ot her wise s pecifie d, t he cate g ori cal e n d p oi nts a n d c o nti n u o us e n d p oi nts will be 
a nal yze d b y C oc hra n -M a ntel -Hae ns zel ( C M H) a n d Mi xe d M o del f or Re peate d Meas ure s 
( M M R M), res pecti vel y, a n d t he c orres p o n di n g a n al yses are s p ecifie d i n Secti o n 9. 2 . 
T w o of t he bas eli ne ra n d o mizati o n stratificati o n fact ors, p ri or a nti-T N F fail ure  a n d pri or 
a dali m u ma b use, will be c o m bi ne d i nt o a si n gle pri or a nti- T N F fail ure/a d ali m u ma b use 
fact or ( pri or a nti-T N F f ail ure wit h a dali m u ma b us e; pri or a nti -T N F fail ure wit h o ut 
a dali m u ma b use; n o pri or a nti- T N F fail ure) i n t he a nal ysis met h o d s.  Ot her ra n d o mizati o n 
stratificati o n fact ors will be use d wit h o ut c o m bi nati o n.
U nless ot her wise s pecifie d, a n y s u bject w h o is ra n d o mize d base d o n a wr o n g strat u m will 
be a nal yze d acc or di n g t o t he act ual strat u m t he s u bject bel o n gs t o. 


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" Baseli ne" refers t o t he last n o n- missi n g o bser vati o n bef ore or o n t he da y of t he first 
a d mi nistrati o n of st u d y dr u g or ra n d o mizati o n if n o st u d y dr u g is gi ve n.  O bser vati o ns o n 
t he sa me da y as t h e first a d mi nistrati o n of st u d y dr u g will be c o nsi dere d f or baseli ne, 
re gar dl ess of w het h er o bser vati o n ti me (if a v aila ble) was after t he first a d mi nistrati o n of 
st u d y dr u g ti me. 
9. 2
H a n dli n g of I nt er c urr e nt E v e nt a n d Mi s si n g D at a
9. 2. 1
Mi s si n g D at a d u e t o C O VI D -1 9 a n d L o gi sti c al Pr o bl e m s 
( G e o-p oliti c al R e stri cti o n s)
Missi n g data c o ul d occ ur d ue t o vari o us reas o ns, i ncl u di n g missi n g visits/assess me nts, 
earl y wit h dra wal fr o m t h e st u d y , or missi n g d ue t o C O VI D- 1 9 i nfecti o n or l o gistic 
restricti o n, as well as d u e t o l o gistical pr o ble ms ( ge o-p olitical restricti o ns) . 
T he C O VI D - 1 9 p a n de mi c is i nterferi n g wit h t he c o n d uct of ma n y o n g oi n g trials, wit h 
p ote ntial i m pacts o n treat me nt d urati o n a n d t he c ollecti o n, a nal ysis, a n d t he i nter pretati o n 
of cli nical trial data.  S o me pr ot oc ol -s pecifie d visits i n t he cli nical trials ma y be i m pacte d 
d ue t o C O VI D- 1 9 i nf ecti o n or l o gistical restricti o ns d uri n g t he pa n de mic.  I m pacte d visits 
d ue t o C O VI D- 1 9 will be rec or d e d i n t he data b ase.  T he pr o ba bilit y of ha vi n g misse d 
visits a n d missi n g data d ue t o C O VI D- 1 9 i nfecti o n or l o gistical restricti o ns relate d t o t he 
C O VI D - 1 9 pa n d e mic ca n be reas o n a bl y ass u me d t o be u nrelate d t o t he u n o bser ve d 
val ues.  T her ef or e, f or t h e p ur p ose of statistical a n al ysis, it is reas o na ble t o ass u me t hat 
t hese missi n g data are missi n g at ra n d o m ( M A R) a n d t he statistical m o dels t hat re q uire 
M A R ass u m pti o n are a p pr o priate.  Se nsiti vit y a nal yses will be perf or me d t o assess t he 
i m pact of missi n g data a n d t he r o b ust ness of t he c o ncl usi o n.  T he sa me l o gic is li kel y 
a p plica ble t o data missi n g d ue t o l o gistical pr o ble ms ( ge o -p olitical restricti o ns) s o t hat t he 
M A R ass u m pti o ns is als o a p plica ble. 
9. 2. 2
H a n dli n g of mi s si n g d at a i n C at e g ori c al E n d p oi nt s
●
N o n - Res p o n der I m p ut ati o n i nc or p orati n g m ulti ple i m p utati o n t o ha n dle 
C O VI D - 1 9 a n d l o gistical pr o ble ms ( ge o-p olitical restricti o ns) ( N RI-MI) will 
be t he pri mar y a p pr oac h t o ha n dle missi n g data f or cate g orical e n d p oi nts.  T he 


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N RI -MI  will cate g orize a n y s u bject w h o d oes n ot ha ve a n e val uati o n d uri n g a 
pre -s pecifie d visit wi n d o w (eit her d u e t o missi n g assess me nt or d ue t o earl y 
wit h dra wal fr o m t he st u d y) as a n o n-res p o n der f or t he visit.  T he o nl y 
e xce pti o ns ar e:  1) w he n t he s u bject is a res p o n d er b ot h bef ore a n d after t he 
visit wi n d o w, w here t he s u bject will be cate g orize d as a res p o n d er f or t he visit , 
a n d 2) w he n t h e data is missi n g d ue t o C O VI D- 1 9 i nfecti o n or l o gistical 
restricti o n, or l o gistical pr o ble ms ( ge o-p olitical restricti o ns), w hic h will t he n 
be ha n dle d b y M ulti ple I m p utati o n.  S u bjects w h ose c ha n ge/ p erce nt c ha n g e 
fr o m Baseli ne ca n n ot be calc ulate d b eca us e of a missi n g Baseli ne will be 
c o nsi dere d as a n o n-res p o n der at all p ost- bas eli ne visits i n N RI -MI a p pr o ac h. 
●
M ulti ple I m p utati o n ( MI): 
a se nsiti vit y a nal ysis f or t he pri mar y e n d p oi nt:  
Mar k o v C hai n M o nte Carl o ( M C M C) will be first a p plie d t o a u g me nt data i nt o 
m o n ot o nic missi n g patter n a n d P R O C MI will be use d t o ge nerate 3 0 datas ets 
usi n g t he re gressi o n met h o d.  T he varia bl es t o be i ncl u de d i n t he i m p utati o n 
m o del f or t he Place b o - C o ntr olle d Peri o d  are treat me nt gr o u p, stratificati o n 
fact ors at ra n d o mizati o n [Baseli ne gl uc oc ortic oi d ( yes/ n o), n u m ber of pri or 
faile d b/ts D M A R Ds ( 1; 2 or m ore), a n d a c o m bi ne d pri or a nti- T N F 
fail ure/a d ali m u ma b use fact or ( pri or a nti-T N F fail ure wit h a dali m u ma b use; 
pri or a nti- T N F fai l ur e wit h o ut a dali m u ma b use; n o pri or a nti-T N F fail ure)] , 
Baseli ne, a n d meas ure me nts at eac h visit i n t he Place b o - C o ntr olle d Peri o d .  
T he varia bl es t o be i ncl u de d i n t he i m p utati o n m o del f or t he L T E p eri o ds are 
treat me nt gr o u p, maj or strat u m [ baseli ne gl uc o c ortic oi d use ( yes/ n o) a n d pri or 
a dali m u ma b use ( yes/ n o)] , Baseli ne, a n d meas ure me nts at eac h visit i n t he 
L T E peri o ds.  T he r a n d o m see d f or M C M C a n d t he ra n d o m see d f or P R O C MI 
are s pecifie d i n A p pe n di x C .  T he i m p ute d p ost-baseli ne meas ure me nts will be 
r o u n de d t o t he sa me pr ecisi o n as t he o bser ve d dat a bef ore t he det er mi nati o n of 
res p o n der stat us.  S u bjects will be c haracterize d as res p o n ders or n o n -
res p o n ders b ase d o n t he MI i m p ute d dat asets.  Usi n g t he C oc hra n- Ma nt el -
Hae nszel ( C M H) m o del a dj uste d b y stratificati o n fact ors [Bas eli ne 
gl uc oc ortic oi d ( yes/ n o), n u m ber of pri or faile d b/ts D M A R Ds ( 1; 2 or m ore), 
a n d a c o m bi ne d pri or a nti-T N F fail ure/a d ali m u ma b use fact or ( pri or a nti-T N F 
fail ure wit h a d ali m u ma b use; pri or a nti-T N F fail ure wit h o ut a dali m u ma b use; 
n o pri or a nti- T N F fail ur e)] , t he i m p ute d e n d p oi nts will be a nal yze d usi n g eac h 
of t he 3 0 datasets.  S A S P R O C MI A N A L Y Z E will be use d t o ge nerate t he 


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fi nal i nfere n ces of t h e ris k differe n ce b et wee n eac h A B B V - 1 5 4 gr o u p a n d 
place b o.  
 
9. 2. 3  
H a n dli n g of mi s si n g d at a i n C o nti n u o u s E n d p oi nt s  
● Mi xe d M o del f or Re peate d  Meas ure s ( M M R M):  T he re p eate d meas ures 
a nal ysis will be c o n d ucte d usi n g a mi xe d m o del i ncl u di n g o bser ve d 
meas ure me nts at all visits.  F or t he Place b o- C o ntr olle d Peri o d, t he mi xe d 
m o del i ncl u des t he cate g orical fi xe d effects of treat me nt, visit a n d treat me nt -
b y- visit i nteracti o n, stratificati o n fact ors at ra n d o mizati o n [ Baseli ne 
gl uc oc ortic oi d ( yes/ n o), n u m ber of pri or faile d b/ts D M A R Ds ( 1; 2 or m ore), 
a n d a c o m bi ne d pri or a nti- T N F fail ure/a d ali m u ma b use fact or ( pri or a nti -T N F 
fail ure wit h a d ali m u ma b use; pri or a nti-T N F fail ure wit h o ut a dali m u ma b use; 
n o pri or a nti- T N F fail ur e)], a n d t he c o nti n u o us fi xe d c o vari ates of bas eli ne 
meas ure me nt.  F or L T E p eri o ds, t he mi xe d m o del i ncl u des t he cate g orical 
fi xe d eff ects of tr eat me nt, visit a n d treat me nt- b y-visit i nteracti o n, maj or 
strat u m [ baseli ne gl uc o c ortic oi d use ( yes/ n o) a n d pri or a dali m u ma b use 
( yes/ n o)], a n d t h e c o nti n u o us fi xe d c o variates of baseli ne meas ure me nt.  A n 
u nstr uct ure d varia nce- c o varia nce matri x ( U N) will be use d.  If t he m o del 
ca n n ot c o n ver ge, a n a p pr o priate c o varia nce str uct ure matri x (e. g., 
a ut ore gr essi ve ( 1) or c o m p o u n d s y m metr y) will be use d.  Para m eter esti mati o n 
is base d o n t he ass u m pti o n of data bei n g missi n g at ra n d o m a n d usi n g t he 
met h o d of restricte d m a xi m u m li keli h o o d ( R E M L).  
 
M M R M will be t he pri mar y a p pr o ac h t o t he a nal ysis of c o nti n u o us varia bles 
9. 2. 4  
S u m m ar y of L o n g -T er m Effi c a c y  
L o n g- ter m efficac y i n t he L T E p eri o ds will be s u m marize d usi n g t he As O bser ve d case 
a p pr oac h b y treat me nt se q ue nce ( A B B V- 1 5 4 4 0 m g E O W, A B B V- 1 5 4 1 5 0 m g E O W, 
A B B V - 1 5 4 3 4 0 m g E O W, A B B V- 1 5 4 3 4 0 m g E 4 W, A B B V - 1 5 4 1 5 0 m g E O W re-
ra n d o mize d fr o m Place b o, A B B V - 1 5 4 3 4 0 m g E O W re-ra n d o mize d fr o m Place b o). 
● As O bser ve d  ( AO):  T h e A O a nal ysis will be use d f or t he s u m maries of l o n g -
ter m efficac y, w hi c h will n ot i m p ute val ues f or missi n g e val uati o ns, a n d t h us a 
 


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s u bject w h o d oes n ot ha v e a n e v al uati o n o n a sc he d ule d visit will be e xcl u de d 
fr o m t he A O a n al ysis f or t hat visit.  
● N RI -MI a n d M M R M will be use d t o s u m marize s electe d cate g ori cal a n d 
c o nti n u o us efficac y varia bles, res pecti vel y, f or l o n g- ter m efficac y. 
 
9. 3  
Pri m ar y Effi c a c y E n d p oi nt ( s) a n d A n al y s e s  
9. 3. 1  
Pri m ar y Effi c a c y E n d p oi nt( s)  
T he pri mar y e n d p oi nt is t he ac hie v e me nt of A C R 5 0 at Wee k 1 2 . 
A C R criteria ar e c o m m o nl y use d sta n dar d criteria me nti o ne d i n t he g ui da nce of A merica n 
C olle ge of R he u mat ol o g y t o e val uate t he effecti ve ness of i n vesti gati o n dr u g i n R A 
cli nical trials.  It is a c o m p osite meas ure me nt calc ulate d base d o n t he i m pr o ve me nt o ve r a 
set of c ore m eas ur e me nts.  
A C R 5 0 is defi ne d as at least 5 0 % i m pr o ve me nt (c o m pare d t o bas eli ne val ues) i n te n der 
a n d s w olle n j oi nt c o u nts a n d at least 5 0 % i m pr o ve me nt i n 3 of t he re mai ni n g 5 c ore set 
meas ures ( p atie nt 's assess me nt of pai n, patie nt's gl o bal assess me nt of disease acti vit y, 
p h ysicia n's gl o bal assess me nt of disease acti vit y, H A Q- DI a n d hs C R P). 
A s u bject will be classifi e d as a n A C R 5 0 res p o n d er, if t he f oll o wi n g c o n diti o ns are met: 
1.  
≥ 5 0 % i m pr o ve me nt fr o m baseli ne i n te n der j oi nt c o u nt ( TJ C 6 8) a n d  
2.  
≥ 5 0 % i m pr o ve me nt fr o m baseli ne i n s w olle n j oi nt c o u nt ( SJ C 6 6 ) a n d 
3.  
≥ 5 0 % i m pr o ve me nt fr o m baseli ne i n at least 3 of t he f oll o wi n g 5:  
● patie nt's assess me nt of p ai n ( o n a 0- 1 0 N R S) 
● patie nt's gl o bal assess me nt of disease acti vit y ( P tG A) ( o n a 0 - 1 0 N R S) 
● p h ysicia n's gl o bal assess me nt of disease acti vit y ( P h G A) ( o n a 0- 1 0 N R S)  
● H A Q -DI  
● hs C R P  
 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
2 1  
9. 3. 2  
A n al y si s of Pri m ar y Effi c a c y E n d p oi nt( s)  
T he statistical n ull h y p ot hesis c orres p o n di n g t o t h e pri mar y e n d p oi nt is t hat t here is n o 
differe n ce b et wee n a n A B B V - 1 5 4 gr o u p a n d t he place b o gr o u p res p o nse rate i n t he 
pr o p orti o n of s u bjects ac hie vi n g A C R 5 0 at Wee k 1 2. 
A nal ysis of t he pri mar y e n d p oi nt will be c o n d ucte d i n t he I T T P o p ulati o n b ase d o n 
treat me nt as r a n d o mize d usi n g N RI -MI .  C o m paris o n of t he pri mar y e n d p oi nt will be 
ma de bet wee n eac h A B B V - 1 5 4 gr o u p a n d t he pl ace b o gr o u p usi n g t he C M H test 
a dj usti n g f or Baseli ne gl uc oc ortic oi d ( y es/ n o), n u m ber of pri or faile d b/ts D M A R Ds ( 1; 2 
or m ore) , a n d a c o m bi ne d pri or a nti-T N F fail ure/a dali m u ma b use fact or ( pri or a nti -T N F 
fail ure wit h a d ali m u ma b use; pri or a nti- T N F fail ure wit h o ut a dali m u ma b use; n o pri or 
a nti-T N F fail ur e)].  
T he attri b utes of t he esti ma n ds c orres p o n di n g t o t he pri mar y efficac y e n d p oi nt are 
s u m marize d i n Ta ble  1. 
T a ble 1. 
S u m m ar y of t he Esti m a n d Attri b utes of t he Pri m ar y Effic ac y 
E n d p oi nt (s) 
Esti m a n d L a bel  
Attri b utes of t he Esti m a n d  
Tre at m e nt  
E n d p oi nt  
P o p ul ati o n  
H a n dli n g of 
I nterc urre nt 
E ve nts (I E)  
St atistic al 
S u m m ar y  
Pri mar y:   C o m p osite 
Esti ma n d  
A B B V -1 5 4 
vs. Place b o  
A c hie ve me nt 
of A C R 5 0 at 
Wee k 1 2  
All 
ra n d o mize d 
s u bjects 
w h o 
recei ve d at 
least o ne 
d ose of 
st u d y dr u g 
(I T T 
P o p ulati o n)  
I E: n o ne c o nsi dere d  
Differe nce 
bet wee n 
A B B V -1 5 4  
a n d 
place b o i n 
t he 
pr o p orti o n 
of s u bjects 
ac hie vi n g 
A C R 5 0  at 
Wee k 1 2  
 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
2 2  
9. 3. 3  
S e n siti vit y a n d S u p pl e m e nt ar y A n al y s e s of t h e Pri m ar y 
Effi c a c y E n d p oi nt( s)  
A se nsiti vit y a nal ysis of t he pri mar y a n al ysis of t he pri mar y efficac y e n d p oi nt will be 
c o n d ucte d usi n g t he MI met h o d f or ha n dli n g missi n g data. 
A n a d diti o nal a nal ysis will be c o n d ucte d w h ere  t h e baseli ne defi niti o n f or patie nt 's 
assess me nt of pai n, Pt G A, P h G A, a n d H A Q -DI  is u p date d t o w here val ues c ollecte d u p t o 
7 da ys after t h e da y of first d ose ma y be c o nsi dere d f or t he baseli ne v al ue. 
A se par ate a n al ysis ma y be perf or me d i n t he I T T P o p ulati o n e xcl u di n g s u bjects w h o ha ve 
maj or pr ot oc ol de viati o ns i n t he Place b o- C o ntr olle d Peri o d.  T he s u bject e xcl usi o n criteria 
f or t his a nal ysis will be fi nalize d bef ore u n bli n di n g data f or t he Pri mar y A nal ysis. 
9. 4  
S e c o n d ar y Effi c a c y E n d p oi nt s a n d  A n al y s e s  
9. 4. 1  
S e c o n d ar y Effi c a c y E n d p oi nt s  
T he c o nti n u o us sec o n dar y e n d p oi nts are, at Wee k 1 2, 
● C ha n ge i n D A S 2 8 ( C R P) fr o m Baseli ne: D A S 2 8 ( C R P) is a c o m p osite i n de x 
t o assess disease acti vit y i n R A patie nts usi n g hs C R P meas ure me nt.  T he 
D A S 2 8 ( C R P) pr o vi des a sc ore bet w ee n 0. 9 6 a n d 1 0, i n dicati n g h o w acti ve t he 
r he u mat oi d art hritis is at t he ti me of meas ure m e nt. 
● D A S 2 8 ( C R P)  is calc ulate d base d o n Te n d er J oi nt C o u nt, S w olle n J oi nt C o u nt, 
Patie nt's Gl o bal Assess me nt of Disease Acti vit y ( Pt G A) ( o n a 0 - 1 0 N R S), a n d 
hs C R P (i n m g/ L). 
D A S 2 8 ( C R P) = 0. 5 6 × √( TJ C 2 8 *) + 0. 2 8 × √( SJ C 2 8 * *) + 0. 3 6 × l n( hs C R P&  
+ 1) +  0. 1 4 × Pt G A » + 0. 9 6 
* 
TJ C 2 8 refers t o t h e S u bject's t otal Te n d er J oi nt C o u nt o ut of t h e pr o vi d e d 2 8 e v al u ate d j oi nts.  
* *  
SJ C 2 8 refers t o t h e S u bject's t otal S w olle n J oi nt C o u nt o ut of t h e pr o vi d e d 2 8 e v al u ate d j oi nts.  
& 
hs C R P refers t o t h e hi g h -se nsiti vit y C- reacti v e pr otei n la b v al u e.  hs C R P u nit i n t h e D A S 2 8 ( C R P) 
e q u ati o n is e x presse d as m g/ L.  
» 
Pt G A refers t o t h e Patie nt's Gl o b al Assess me nt of Disease Acti vit y.  
W h ere √ is s q u are r o ot a n d l n is n at ural l o g. 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
2 3  
● C ha n ge i n C D AI fr o m B aseli ne: C D AI is a c o m p osite c o nti n u o us i n de x t o 
assess disease acti vit y wit h o ut usi n g hs C R P meas ure me nt.  It ca n be calc ul ate d 
base d o n TJ C 2 8, SJ C 2 8, Patie nt's Gl o bal Assess me nt of Disease Acti vit y 
( Pt G A) (o n a 0- 1 0 N R S ) a n d P h ysicia n's Gl o bal Assess me nt of Disease 
Acti vit y ( P h G A) ( o n a 0- 1 0 N R S).  It ca n be d eri v e d as f oll o ws: 
C D AI = TJ C 2 8 + SJ C 2 8 + Pt G A + P h G A . 
● C ha n ge i n t he H A Q- DI fr o m Baseli ne  
 
T he cate g orical sec o n dar y e n d p oi nts are, at Wee k 1 2, 
● Ac hie ve me nt of A C R 2 0 a n d Ac hie v e me nt of A C R 7 0 : T he defi niti o n is si milar 
t o A C R 5 0 wit h  at least 2 0 % a n d 7 0 % i m pr o ve me nt , res pecti vel y 
● Ac hie ve me nt of L D A defi ne d b y D A S 2 8 ( C R P) ≤ 3. 2  
● Ac hie ve me nt of L D A defi ne d b y C D AI ≤ 1 0  
● Ac hie ve me nt of cli nical re missi o n ( C R) defi ne d b y D A S 2 8 ( C R P) < 2. 6 
● Ac hie ve me nt of C R defi ne d b y C D AI ≤ 2. 8  
 
9. 4. 2  
A n al y s e s of S e c o n d ar y Effi c a c y E n d p oi nt s  
T he statistical n ull h y p ot hesis c orres p o n di n g t o t h e sec o n dar y e n d p oi nt is t hat t here is n o 
differe n ce b et wee n a n A B B V - 1 5 4 gr o u p a n d t he place b o gr o u p at Wee k 1 2 i n ter ms of 
res p o nse r ate f or a cate g orical e n d p oi nt a n d c h a n g e fr o m baseli ne f or a c o nti n u o us 
e n d p oi nt. 
A nal ysis of t he sec o n d ar y e n d p oi nt will be c o n d ucte d i n t he I T T P o p ulati o n base d o n 
treat me nt as r a n d o mize d.  C o m paris o n of t he sec o n dar y e n d p oi nt will be ma de bet w ee n 
eac h A B B V- 1 5 4 gr o u p a n d t he place b o gr o u p usi n g: 
● F or cate g orical varia bl e s: C M H test base d o n N RI-MI a dj uste d  b y Baseli ne 
gl uc oc ortic oi d ( yes/ n o), n u m ber of pri or faile d b/ts D M A R Ds ( 1; 2 or m ore), 
a n d a c o m bi ne d pri or a nti- T N F fail ure/a d ali m u ma b use fact or ( pri or a nti -T N F 
fail ure wit h a d ali m u ma b use; pri or a nti-T N F fail ure wit h o ut a dali m u ma b use; 
n o pri or a nti- T N F fail ur e).  
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
2 4  
● F or c o nti n u o us varia bles: M M R M me nti o ne d i n S ecti o n 9. 2  
 
T he attri b utes of t he esti ma n ds c orres p o n di n g t o t he ke y sec o n d ar y efficac y e n d p oi nts are 
s u m marize d i n Ta ble  2. 
T a ble 2. 
S u m m ar y of t he Esti m a n d Attri b utes of t he Sec o n d ar y Effic ac y 
E n d p oi nts  
F or bi nar y e n d p oi nt: 
Esti m a n d 
L a bel  
Attri b utes of t he Esti m a n d  
Tre at m e nt  
E n d p oi nt  
P o p ul ati o n  
H a n dli n g of  
I nterc urre nt 
E ve nts  
St atistic al 
S u m m ar y  
Bi nar y 
Sec o n dar y:  
C o m p osite 
Esti ma n d   
A B B V -1 5 4 
vs. Place b o  
Ac hie ve me nt 
of eac h 
bi nar y  
sec o n dar y 
e n d p oi nt 
res pecti vel y 
All 
ra n d o mize d 
s u bjects w h o 
recei ve d at 
least o ne d ose 
of st u d y dr u g  
(I T T 
P o p ulati o n)  
I E: n o ne 
c o nsi dere d 
Differe nce i n 
pr o p orti o n of 
s u bjects 
ac hie vi n g eac h 
bi nar y sec o n dar y 
e n d p oi nt 
 
F or c o nti n u o us e n d p oi nt: 
Esti m a n d 
L a bel  
Attri b utes of t he Esti m a n d  
Tre at m e nt  
E n d p oi nt  
P o p ul ati o n  
H a n dli n g of  
I nterc urre nt 
E ve nts  
St atistic al 
S u m m ar y  
C o nti n u o us 
Sec o n dar y:  
C o m p osite 
Esti ma n d   
A B B V -1 5 4 
vs Place b o  
C ha n ge fr o m 
Baseli ne i n 
eac h 
res pecti ve 
c o nti n u o us 
sec o n dar y 
e n d p oi nt 
All 
ra n d o mize d 
s u bjects w h o 
recei ve d at 
least o ne 
d ose of st u d y 
dr u g (I T T 
P o p ulati o n)  
I E: n o ne 
c o nsi dere d 
Differe nce i n t he 
mea n c ha n ge 
fr o m Baseli ne i n 
eac h c o nti n u o us 
sec o n dar y 
e n d p oi nt 
 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
2 5  
9. 4. 3  
S e n siti vit y a n d S u p pl e m e nt ar y A n al y s e s f or S e c o n d ar y 
Effi c a c y E n d p oi nt s  
N ot a p plica ble.  
9. 4. 4  
S u p p or ti v e S e c o n d ar y Effi c a c y E n d p oi nt s a n d A n al y s e s  
N ot a p plica ble.  
9. 5  
A d diti o n al Effi c a c y A n al y s e s  
T he pri mar y a n d all sec o n dar y efficac y vari a bles  will be a nal yze d at all visits assesse d 
ot her t ha n Wee k 1 2, i ncl u di n g i n t he L T E p eri o ds, usi n g met h o ds me nti o ne d a b o ve.  At 
ti me of t he Pri mar y A nal ysis, N RI will be use d aft er Wee k 1 2 f or all bi nar y e n d p oi nts. 
I n a d diti o n, ot her efficac y e n d p oi nts descri be d i n Secti o n 3. 3  will be a nal y ze d at all visits 
assesse d  usi n g t he sa me met h o ds as sec o n dar y e n d p oi nts. 
9. 6  
D o s e -R e s p o n s e M o d eli n g f or A B B V -1 5 4  
T he d ose-r es p o nse r elati o ns hi p a m o n g A B B V- 1 5 4 d ose gr o u ps a n d t he place b o gr o u p 
will be c haracterize d f or t he pri mar y e n d p oi nt usi n g t he M ulti ple C o m paris o n Pr oce d ure - 
M o deli n g ( M C P- M o d) met h o d [ Pi n heir o 2 0 0 6, Bretz 2 0 0 5].  T he s u m mar y le vel res p o nse 
rates base d o n t he pri mar y a nal ysis a p pr oac h a b o v e will be use d, a n d A D D P L A N D F 
s oft ware will be use d t o perf or m t he M C P- M o d a nal yses. 
A set of 6 pre- s pecifi e d sta n dar dize d ca n di dat e d ose-res p o ns e m o dels, as d escri be d i n 
Ta ble  3 will be utilize d t o e xa mi ne t he d ose -res p o nse relati o ns hi p.  A statisticall y 
si g nifica nt d ose-res p o ns e relati o ns hi p will be decl are d if at least o ne m o del is i de ntifie d 
b y t he M C P- M o d met h o d t o be statisticall y si g nifica nt at t w o -si de d α = 0. 1.  T he fitted 
d ose- res p o ns e c ur v es will be prese nte d gra p hicall y f or all statisticall y si g nifica nt m o dels 
al o n g wit h 9 5 % c o nfi de n ce ba n ds.  T h e mi ni m u m effecti ve d ose ( M E D) will be i de ntifie d 
f or eac h statisticall y si g nifica nt m o del base d o n t h e pre-s p ecifie d cli nical mea ni n gf ul 
tar get of 2 2 %.  T h e wei g hte d M E D acr oss all si g nifica nt m o dels will be cal c ulate d, wit h 
wei g ht bei n g t he i n verse of eac h ca n di dat e d ose -res p o nse m o del AI C. 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
2 6  
T a ble 3. 
C a n di d ate M o dels  
M o del  
𝒇𝒇 (𝒅𝒅,𝜽𝜽) 
d  = d ose,  
θ = M o del P ar a m eters  
𝒇𝒇𝟎𝟎 (𝒅𝒅,𝜽𝜽) 
St a n d ar dize d M o del  
I niti al V al ue(s) 
f or P ar a m eter(s)* 
Li ne ar  
E 0 + δ d  
d 
N A  
E x p o ne nti al  
𝐸𝐸0 + 𝐸𝐸1 �𝑒𝑒𝑒𝑒𝑒𝑒�𝑑𝑑
𝛿𝛿� −1 � 
𝑒𝑒𝑒𝑒𝑒𝑒�𝑑𝑑
𝛿𝛿� −1  
δ = 6 8 0  
L o gistic  
𝐸𝐸0 +
𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚
1  + 𝑒𝑒𝑒𝑒𝑒𝑒�𝐸𝐸𝐸𝐸5 0 − 𝑑𝑑
𝛿𝛿
�
 
1
1  + 𝑒𝑒𝑒𝑒𝑒𝑒�𝐸𝐸𝐸𝐸5 0 − 𝑑𝑑
𝛿𝛿
�
 
E D 5 0 = 1 5 0 , δ = 6 4. 5  
E M a x  
𝐸𝐸0 +
𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚𝑑𝑑
𝐸𝐸𝐸𝐸5 0 + 𝑑𝑑 
𝑑𝑑
𝐸𝐸𝐸𝐸5 0 + 𝑑𝑑 
E D 5 0 = 8 3. 9  
si g E M a x 
𝐸𝐸0 +
𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚𝑑𝑑ℎ
𝐸𝐸𝐸𝐸5 0
ℎ+ 𝑑𝑑ℎ 
𝑑𝑑ℎ
𝐸𝐸𝐸𝐸5 0
ℎ+ 𝑑𝑑ℎ 
E D 5 0 = 1 5 0 , h  = 3. 6  
Q u a dr atic  
𝐸𝐸0 + 𝛽𝛽1 𝑑𝑑+ 𝛽𝛽2 𝑑𝑑2  
𝑑𝑑+
𝛽𝛽2
|𝛽𝛽1 | 𝑑𝑑2  
δ = – 0. 0 0 1 
* 
F or E x p o n e ntial m o d el, t h e i nitial v al u e was d eter mi n e d b ase d o n t h e ass u m pti o n t h at A B B V -1 5 4 3 4 0  m g E O W 
will ac hie v e 9 5 % of t h e ma xi m u m efficac y of A B B V -1 5 4.  F or L o gistic, E Ma x, si g E Ma x, a n d Q u a dratic m o d el, 
t he i nitial v al u es were d eter mi n e d b ase d o n t h e ass u m pti o n t h at A B B V -1 5 4 3 4 0  m g E O W a n d A B B V -1 5 4 1 4 0  m g 
E O W will ac hie v e 9 5 % a n d 5 0 % of t h e ma xi m u m efficac y of A B B V -1 5 4, res p ecti v el y.  
 
Ste ps of M C P- M o d: 
1.  
C h o ose a ca n di dat e set of m o dels as i n  Ta ble  3. 
2.  
C o m p ute t he o pti m u m c o ntrast f or eac h m o del. 
3.  
Use c o ntrast test t o fi n d all si g nifica nt m o dels w hile preser vi n g fa mil y-wise err or 
rate (F W E R ). 
4.  
U se all si g nifica nt m o dels t o ma ke i nfere n ce a b o ut t he wei g hte d tar get d os e of 
i nterest. 
 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
2 7  
9. 7  
Effi c a c y S u b gr o u p A n al y s e s  
S u b gr o u p a nal ysis f or t h e pri mar y e n d p oi nt will b e c o n d ucte d b y t h e s u b gr o u ps s pecifie d 
bel o w.  T he diff ere n ce i n t he pri mar y efficac y e n d p oi nt bet wee n t he treat me nt gr o u ps i n 
eac h s u b gr o u p will be assesse d usi n g C M H a p pr o ac h.  Treat me nt differe n ce a n d 
c orres p o n di n g c o nfi de nce i nter val will be use d t o s u m marize t he res ult. 
● N u m ber of pri or faile d b/ts D M A R Ds  ( 1; 2 or m ore) 
● Pri or a nti -T N F  fail ure ( y es/ n o) 
● Pri or use of a dali m u ma b ( yes/ n o)  
● A ge ( < m e dia n ; ≥ me dia n  years ) 
● Se x (fe male ; male) 
● Race ( w hite ; n o n- w hite)  
● Ge o gra p hic re gi o n ( N ort h A merica, Asi a , Rest of W orl d ) 
● B MI ( < 2 5, ≥ 2 5  - < 3 0, ≥ 3 0 k g/ m2) 
● Baseli ne gl uc oc ortic oi d use  ( yes/ n o) 
 
If a n y s u b gr o u p h as fe w er t ha n 1 0 % of t he t otal s u bjects, t he n t he a nal ysis f or t his 
s u b gr o u p will n ot be perf or me d. 
1 0. 0  
S af et y A n al y s e s  
1 0. 1  
G e n er al C o n si d er ati o n s  
Safet y data will be s u m m arize d f or eac h safet y p o p ulati o n ( Safet y _ P C  a n d A L L _ 1 5 4).  
Safet y s u m maries will be prese nte d b y treat me nt gr o u p, i ncl u di n g a t otal gr o u p f or all 
s u bjects o n acti ve st u d y dr u g.  F or t he safet y anal ysis, s u bjects are assi g ne d t o a treat me nt 
gr o u p base d o n t he tr eat me nt act uall y recei ve d, re gar dless of t h e treat me nt ra n d o mize d.  
" Baseli ne" refers t o t he last n o n- missi n g o bser vati o n bef ore or o n t he da y of t he first 
a d mi nistrati o n of st u d y dr u g or ra n d o mizati o n if n o st u d y dr u g is gi ve n.  O bser vati o ns o n 
t he sa me da y as t h e first a d mi nistrati o n of st u d y dr u g will be c o nsi dere d f or baseli ne, 
 


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Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
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re gar dl ess if o bser v ati o n ti me (if a vaila ble) was after t he first a d mi nistrati o n of st u d y dr u g 
ti me. 
1 0. 2  
A d v er s e E v e nt s  
A d verse e ve nts ( A Es) will be s u m marize d a n d prese nte d usi n g pri mar y Me d D R A S yste m 
Or ga n Classes ( S O Cs) a n d preferre d t er ms ( P Ts) acc or di n g t o t he versi o n of t he Me d D R A 
c o di n g dicti o nar y use d f or t he st u d y at t he ti me of data base l oc k.  T he act ual versi o n of 
t he Me d D R A c o di n g dicti o nar y use d will be n ote d i n t he A E ta bles a n d i n t he cli nical 
st u d y re p ort.  S pecific a d verse e v e nts will be c o u nte d o nce f or eac h s u bject f or cal c ulati n g 
perce nt a ges, u nless state d ot her wise.   I n a d diti o n, if t he sa me a d v erse e ve nt occ urs 
m ulti ple ti mes wit hi n a s u bject, t he hi g hest se verit y a n d le vel of relati o ns hi p t o 
i n vesti gati o nal pr o d uct will be re p orte d. 
1 0. 2. 1  
Tr e at m e nt -E m er g e nt A d v er s e E v e nt s  
Treat me nt -e mer ge nt A Es are defi ne d as a n y A E wit h t he o nset t hat is after t he first d ose 
of st u d y dr u g a n d wit h a n o nset date n o m ore t ha n 5 half-li ves of t he st u d y dr u g (i.e., 
7 0 da ys).  E ve nts w here t he o nset date is t he sa me as t he st u d y dr u g start date are ass u me d 
t o be treat me nt-e m er ge nt , u nless t he st u d y dr u g start ti me a n d t he A E start ti me are 
c ollecte d a n d t he A E start ti me is pri or t o t he st u d y dr u g start ti me .  All treat me nt -
e mer ge nt A Es will be s u m marize d o verall, as well as b y pri mar y Me d D R A S O C a n d 
Preferre d Ter m.   T he S O Cs will be prese nte d i n al p ha betical or d er, a n d t h e P Ts will be 
prese nte d i n al p h a betical or der wit hi n eac h S O C.  
T he n u m ber a n d p erce nta ge of s u bjects e x p erie n ci n g treat me nt -e mer ge nt A Es will be 
s u m marize d. 
I n t he A L L _ 1 5 4 p o p ulati o n, treat me nt-e mer ge nt A Es are d efi ne d b ase d o n t he first d ose 
of A B B V - 1 5 4. 
 


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1 0. 2. 2  
A d v er s e E v e nt O v er vi e w  
A n o ver vie w of A Es will be prese nt e d c o nsisti n g of t he n u m ber a n d p erce nta ge of 
s u bjects e x perie n ci n g at l east o ne e v e nt f or eac h of t he f oll o wi n g A E cat e g ories: 
● A n y treat me nt -e mer ge nt A E  
● A n y treat me nt - e mer ge nt A E relate d t o st u d y dr u g acc or di n g t o t he i n vesti g at or 
● A n y se ver e ( C T C A E gra de ≥ 3) treat me nt-e mer g e nt A E  
● A n y seri o us treat me nt- e mer ge nt A E  
● A n y treat me nt - e mer ge nt A E lea di n g t o disc o nti n uati o n of st u d y dr u g 
● A n y treat me nt-e mer ge nt A E lea di n g t o deat h  
● A d verse E v e nts of S peci al I nt erest (f or mall y k n o w n as S afet y T o pics of 
Interest ) 
● All deat hs  
○ Deat hs occ urri n g ≤ 7 0 da ys  after last d ose of st u d y dr u g 
○ Deat hs occ urri n g > 7 0 d a ys after last d ose of st u d y dr u g. 
 
T he o ver vie w of A Es p er 1 0 0 patie nt- years of e x p os ure will als o be pr o vi d e d f or t he 
a b o ve cate g ories.  
1 0. 2. 3  
Tr e at m e nt - Em er g e nt A d v er s e E v e nt s  b y S O C a n d/ or P T  
Treat me nt -e mer ge nt a d v erse e v e nts will be s u m marize d b y S O C a n d P T; b y ma xi m u m 
relati o ns hi p t o st u d y dr u g as assesse d b y t he i n v esti gat or (e. g., reas o na ble p ossi bilit y or n o 
reas o na bl e p ossi bilit y) a n d S O C a n d P T; b y ma xi m u m se verit y a n d S O C a n d P T; a n d b y 
s u bject n u m ber a n d S O C a n d P T.  S pecific a d v ers e e ve nts will be c o u nte d o nce f or eac h 
s u bject f or calc ulati n g perce nta g es u nless state d ot her wise.  I n a d diti o n, if t he sa me 
a d verse e ve nt occ urs m ulti ple ti mes wit hi n a s u bject, t he hi g hest se verit y a n d le v el of 
relati o ns hi p t o i n vesti gati o nal pr o d uct will be re p orte d. 
I n a d diti o n, treat me nt-e m er ge nt a d v erse e ve nts will be s u m marize d b y P T a n d s orte d b y 
decreasi n g fr e q ue nc y f or t he t otal A B B V - 1 5 4 gr o u p. 
 


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1 0. 2. 4  
Tr e at m e nt - Em er g e nt A d v er s e E v e nt s  p er P ati e nt -Y e ar s of 
E x p o s ur e  
E x p os ure-a dj uste d A Es p er 1 0 0 patie nt- y ears will be pr o vi de d, w h ere A Es per 
1 0 0 patie nt - years of e x p os ure ar e defi n e d as t he n u m ber of A Es di vi de d b y t he t otal 
e x p os ure i n 1 0 0 patie nt- y ears.   T he st u d y dr u g e x p os ure is defi ne d as t he last d ose date 
pl us 5 × half- life ( 7 0 d a ys), mi n us t he first d ose date. 
1 0. 2. 5  
S A E s (I n cl u di n g D e at h s) a n d A d v er s e E v e nt s L e a di n g t o 
St u d y Dr u g Di s c o nti n u ati o n  
S A Es (i ncl u di n g deat hs) a n d A Es lea di n g t o st u d y dr u g disc o nti n uati o n will be 
s u m marize d b y S O C a n d P T a n d i n listi n g f or mat. 
I n a d diti o n, t he e ve nt r ate per 1 0 0 patie nt- years of e x p os ure will als o be pr o vi de d b y S O C 
a n d P T f or eac h treat me nt -e mer ge nt S A E a n d T E A E lea di n g t o st u d y dr u g 
disc o nti n uati o n. 
1 0. 2. 6  
A d v er s e E v e nt s of S p e ci al I nt er e st  
A d verse E v e nts of S peci al I nt erest ( A E SI, f or merl y k n o w n as Safet y t o pics of i nterest) 
will be s u m marize d b y S O C a n d P T a n d will be base d o n sta n dar dize d or c o m pa n y 
Me d D R A q ueries ( S M Qs or C M Qs), or base d o n a dj u dicati o n res ults.  A E SIs  t o be 
s u m marize d will f oll o w  t h ose i n dicate d i n t he latest versi o n of t he Pr o d uct Safet y 
Statistical A nal ysis Pla n  ( P S S A P) f or A B B V- 1 5 4 i n t he A E SI/ Safet y T o pics of I nterest 
secti o n.  Detaile d i nf or m ati o n a b o ut searc h criteria f or t he A E SIs  are als o pr o vi de d i n a 
ta ble i n t he sa me secti o n.  
Ta b ular listi n gs of A E SIs  will be pr o vi de d. 
I n a d diti o n, t he e ve nt r ate per 1 0 0 patie nt - years of e x p os ure will als o be pr o vi de d b y S O C 
a n d P T f or eac h A E SI. 
 


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Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
3 1  
1 0. 3  
A n al y si s of L a b or at or y D at a  
Data c ollecte d fr o m ce ntr al a n d l ocal la b orat ories, i ncl u di n g a d diti o nal la b orat or y  testi n g 
d ue t o a n S A E, will be use d i n all a nal yses , e x ce pt f or Baseli ne w h ere S A E-relate d 
la b orat or y ass ess me nts o n or bef or e t he first d ose of st u d y dr u g will be e xcl u de d.  T he 
cli nical la b orat or y tests d efi ne d i n t he pr ot oc ol o p erati o ns ma n ual (e. g., he mat ol o g y a n d 
cli nical c he mistr y) will b e s u m marize d.  
Eac h la b or at or y varia ble will be s u m marize d f or all ti me p oi nts (starti n g wit h Baseli ne) 
wit h t he n u m ber of n o n- missi n g o bser vati o ns, mea n a n d sta n dar d de viati o n, me dia n, 
mi ni m u m a n d ma xi m u m.  Mea n c ha n g e fr o m b aseli ne t o eac h a p plica ble p ost -baseli ne 
visit will be s u m marize d f or select e d la b orat or y varia bles, wit h t he n u m ber of 
o bser vati o ns, baseli ne m ea n, a n d visit mea n.  T h e c ha n ge fr o m baseli ne m ea n, sta n dar d 
err or, a n d 9 5 % c o nfi de nce i nter val will be prese nt e d f or t he mea n c h a n ge fr o m baseli ne 
wit hi n e ac h treat me nt gr o u p a n d differe nce bet wee n treat me nt gr o u ps ( A B B V- 1 5 4 vs. 
place b o)  as a p plica ble.  T his s u m mar y a n d c ha n g e fr o m baseli ne s u m mar y will be 
prese nte d  o n ce  b y treat me nt se q ue nce. 
C ha n ges i n la b orat or y p ara meters will be ta b ul ate d usi n g s hift ta bles eit her b y N CI C T C 
criteria or ot h er criteria liste d i n A p pe n di x B .  A s hift ta ble fr o m baseli ne eit her t o t he 
w orse val ue ( base d o n N CI C T C criteri a) d uri n g treat me nt or t o mi ni m u m a n d ma xi m u m 
val ue ( bas e d o n n or mal r a n ge), will be create d.  A si milar s hift ta ble will be pr o vi de d t o 
s u m marize s hifts fr o m baseli ne t o t he fi nal p ost-baseli ne val ue.  
La b orat or y a b n or malities  meeti n g C T C criteria gra de 3 a n d 4 will be s u m marize d.  
La b orat or y a b n or malities will be e val uate d b ase d o n P ote ntiall y C li nicall y I m p ort a nt 
( P CI) criteria ( base d o n N CI C T C criteria, e x ce pt f or t h ose liste d i n A p pe n di x B ).  F or 
eac h la b orat or y P CI criteri o n, t he n u m ber a n d p erce nta ge of s u bjects w h o ha ve a 
la b orat or y val u e meeti n g t he criteria will be s u m marize d.  Listi n gs will be pr o vi de d t o 
s u m marize s u bject-l e vel la b orat or y dat a f or s u bjects meeti n g P CI criteria.  I n t he 
e val uati o n of P CI  l a b orat or y val ues, t he bas eli ne v al ue f or t he A L L _ 1 5 4 p o p ulati o n will 
 


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Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
3 2  
be deter mi ne d b y t he l ast n o n- missi n g meas ure me nt rec or d e d o n or bef ore t he date of t he 
first d ose of st u d y dr u g i n t he c orr es p o n di n g A B B V - 1 5 4 treat me nt gr o u p ( w hic h ma y be 
differe nt t ha n t h e first d ose of st u d y dr u g recei ve d i n t he st u d y). 
F or t he p ur p os e of ass essi n g f or p ote ntial H y' s la w cases, t he fre q u e ncies a n d perce nt a ges 
of s u bjects wit h p ost baseli ne li ver s pecifi c f u ncti o n test val ues t hat meet t he f oll o wi n g 
criteria of p ot e ntial cli nical i nterest will be s u m marize d b y "as treate d " treat me nt gr o u p: 
● A L T > 3 × U L N  
● A L T > 5 × U L N  
● A L T > 1 0 × U L N 
● A L T > 2 0 × U L N 
● A S T > 3 × U L N  
● A S T > 5 × U L N  
● A S T > 1 0 × U L N 
● A S T > 2 0 × U L N 
● T B L > 2 × U L N  
● Al kali ne p h os p hatase > 1. 5 × U L N 
● A L T a n d/ or A S T > 3 × U L N a n d c o n c urre nt I N R > 1. 5 
● A L T a n d/ or A S T > 3 × U L N a n d c o n c urre nt T B L > 2 × U L N  
 
A listi n g of p ossi ble H y' s La w cas es, defi n e d as t h ose w h o meet all of t he f oll o wi n g 
c o n diti o ns si m ulta ne o usl y, will be pr o vi de d:  A L T > 3 × U L N or A S T > 3 × U L N t hat is 
ass ociate d wit h a n i ncrease i n bilir u bi n > 2 × U L N.  
1 0. 4  
A n al y si s of Vit al Si g n s  
Vital si g n meas ure me nts of s yst olic a n d diast olic bl o o d press ure, res pirat or y rate, p ulse 
rate, a n d b o d y te m p erat ure will be s u m marize d.   Wei g ht will be i ncl u de d i n t he 
s u m maries. 
 


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Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
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Eac h vital si g n varia ble will be s u m marize d f or all ti me p oi nts (starti n g wit h Baseli ne) 
wit h t he n u m ber of n o n- missi n g o bser vati o ns, mea n a n d sta n dar d de viati o n, me dia n, 
mi ni m u m a n d ma xi m u m.  Mea n c ha n g e fr o m b aseli ne t o eac h a p plica ble p ost -baseli ne 
visit will be s u m marize d f or eac h vital si g n varia bl e, wit h t he n u m ber of o bs er vati o ns, 
baseli ne mea n, a n d visit mea n.  T he c h a n ge fr o m baseli ne mea n, sta n d ar d err or, a n d 9 5 % 
c o nfi de nce i nter val will be prese nt e d f or t he m ea n c ha n ge fr o m baseli ne wit hi n eac h 
treat me nt gr o u p a n d differe nce b et wee n treat me nt gr o u ps ( A B B V- 1 5 4 vs. place b o) as 
a p plica ble.  T his s u m mar y a n d c ha n g e fr o m bas eli ne s u m mar y will be pres e nte d o nce b y 
treat me nt se q ue n ce. 
Vital si g n varia bles will be e val uat e d base d o n P CI criteria.  P ulse rate, b o d y te m perat ure, 
a n d res pirat or y rate will f oll o w t he criteria i n A p p e n di x B .  All ot her vital si g ns will 
f oll o w t he criteria i n t he P S S A P.  F or eac h vital si g n P CI criteri o n, t he n u m ber a n d 
perce nt a ge of s u bjects w h o ha ve a vital si g n val ue meeti n g t he criteria will be 
s u m marize d.  Listi n gs will be pr o vi de d t o s u m marize s u bject-le v el vital si g n data f or 
s u bjects meeti n g P CI criteria.  I n t he e val uati o n of P CI  vital si g n val ues f or t he A L L _ 1 5 4 
p o p ulati o n, t he baseli ne val ue will be deter mi ne d b y t he last n o n- missi n g meas ure me nt 
rec or d e d o n or bef ore t h e date of t he first d ose of st u d y dr u g i n t he c orres p o n di n g 
A B B V - 1 5 4 treat me nt gr o u p. 
1 0. 5  
S af et y S u b gr o u p A n al y s e s  
T he A E O ver vie w a n d A E b y S O C a n d P T s u m maries will be pr o vi de d f or t he 
stratificati o n varia bles: 
● Baseli ne gl uc oc ortic oi d d ose ( yes/ n o) 
● N u m ber of pri or faile d b/ts D M A R Ds  ( 1; 2 or m ore) 
 
 


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Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
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1 0. 6  
Ot h er S af et y A n al y s e s  
E C G is c ollecte d at scr ee ni n g , Wee k 1 2, Wee k 2 4, Wee k 3 6, Wee k 7 8, Wee k 1 3 4, a n d 
Wee k 1 8 2 .  E C G fi n di n gs will be s u m marize d b y treat me nt gr o u p f or eac h para meter a n d 
visit.  
D ual -e ner g y X-ra y a bs or pti m o metr y ( D X A) is c ollecte d at scree ni n g, Wee k 2 4, Wee k 7 8 , 
Wee k 1 3 4, a n d Wee k 1 8 2 .  D X A meas ure me nts, i ncl u di n g b o ne mi neral de nsit y a n d 
c orres p o n di n g T a n d Z sc ores, will be s u m marize d b y treat me nt gr o u p f or eac h visit  a n d 
als o i n t he f oll o wi n g gr o u ps: 
● Fe male p atie nts ' p ost-me n o pa usal stat us at baseli n e ( Yes/ N o)  
● B o ne pr otecti ve a g e nt stat us at baseli ne ( Yes/ N o)  
 
B o d y c o m p ositi o n meas ures of t otal fat mass ( g), t otal lea n mass ( g), t otal b o d y mass ( g), 
fat ( %), a n d lea n ( %) will als o be s u m marize d.  A d diti o nall y, t he rati o of t otal fat mass 
di vi de d b y t otal lea n mass will be i ncl u de d.  
D X A s u m maries will be prese nte d o n ce i ncl u di n g all s u bjects a n d visits w here t he s a me 
mac hi ne as scree ni n g w as use d, a n d a gai n i ncl u di n g all s u bjects a n d visits (re gar dless of 
mac hi ne s witc hi n g).  T he s u m maries will be pr o vi de d f or b ot h ce ntrall y rea d a n d l ocall y 
rea d r es ults. 
1 1. 0  
Ot h er A n al y s e s  
N ot a p plica ble.  
1 2. 0  
I nt eri m A n al y s es 
N ot a p plica ble.  
 


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Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
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1 2. 1  
D at a M o nit ori n g C o m mitt e e  
A n e xter nal D M C  will be esta blis he d t o safe g u ar d t he i nterest of trial s u bjects b y 
assessi n g t he safet y of t he i nter ve nti o ns d uri n g t he trial a n d well as f or m o nit ori n g t he 
i nte grit y a n d i nter preta bilit y of t he trial. 
A se par ate D M C c harter descri bes t he r oles a n d res p o nsi bilities of t he D M C me m bers, 
fre q ue n c y of dat a re vi e ws, rele va nt dat a t o be assesse d, a n d ge neral o perati o ns. 
Si nce t here are n o efficac y a nal yses f or earl y st o p pi n g, n o al p ha a dj ust me nt is nee de d. 
A n i nter nal i n de pe n d e nt gl uc oc ortic oi d a dj u dicati o n c o m mittee will be esta blis he d t o 
a dj u dicate s yste mic gl uc oc ortic oi d A Es .  A se p arate c harter d escri bes t he r oles a n d 
res p o nsi bilities of t he a dj u dicati o n c o m mittee me m bers, fre q u e nc y of data re vie ws, a n d 
e x pectati o ns f or bli n de d c o m m u nicati o ns. 
1 3. 0  
O v er all T y p e -I Err or C o ntr ol 
O verall T y pe- I err or c o ntr ol f or m ulti ple c o m paris o ns is n ot pla n ne d i n t his P hase 2 b 
st u d y. 
Si nce t here are n o efficac y a nal yses f or earl y st o p pi n g pla n ne d f or t he D M C re vie w a n d 
I E R C re vi e w, n o al p ha s pe n di n g is nee de d d ue t o a nal yses f or t h e D M C re vie w a n d t he 
I E R C re vi e w. 
 


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Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
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1 4. 0  
V er si o n Hi st or y  
T a ble 4. 
S A P Versi o n Hist or y S u m m ar y  
Versi o n  
D ate  
S u m m ar y  
1. 0  
0 4 A u g ust  2 0 2 1  
Ori gi nal versi o n  
2. 0  
1 7 A u g ust  2 0 2 2  
•  
U p date d t o reflect pr ot oc ol versi o n 2 c ha n ges, 
i ncl u di n g: 
o  
Re m o val of i nterc urre nt e ve nts  
o  
A d diti o n of L T E Peri o d 2  
o  
I T T p o p ulati o n n o w re q uires at least 1 d ose of 
st u d y treat me nt 
•  
C ha n ge d cate g ories f or s o me baseli ne 
de m o gra p hics/c haracteristics  
•  
A d de d s u m mar y of pri or a n d c o nc o mita nt D M A R D, 
i n a d diti o n t o all me dicati o ns 
•  
A d de d l o gistical pr o ble ms ( ge o -p olitical restricti o ns) 
t o N RI-MI, i n a d diti o n t o C O VI D -1 9  
•  
C ha n ge d O bser ve d Cases l o n g -ter m efficac y t o As 
O bser ve d  
•  
C ha n ge d cate g ories f or efficac y a n d safet y s u b gr o u p 
a nal yses f or baseli ne gl uc oc ortic oi d d ose  
•  
Clarifie d treat me nt e mer ge nce defi niti o n f or a d verse 
e ve nts 
•  
C ha n ge d Safet y T o pics of I nterest t o A d verse E ve nts 
of S pecial I nterest  
•  
Clarifie d P ote ntiall y Cli nical I m p orta nt criteria f or 
la bs a n d vital si g ns 
•  
C orrecte d H y 's La w cases 
•  
Clarifie d i ncl u de d varia bles i n vital si g ns a nal ysis  
•  
A d de d details f or D X A a nal ysis  
 
1 5. 0  
R ef er e n c e s  
1.  
R u bi n D B, Sc he n ker N.  I nter val esti mati o n fr o m m ulti pl y -i m p ute d data:  a case 
st u d y usi n g a gric ult ure i n d ustr y c o des.  J A m Stat Ass oc.  1 9 8 7; 8 1: 3 6 6- 7 4. 
2.  
F D A G ui da n ce o n C o n d uct of Cli nical Trials of Me dical Pr o d ucts d uri n g C O VI D-
1 9 Pa n de mic - G ui da nce f or I n d ustr y, I n v esti gat ors, a n d I nstit uti o nal Re vie w 
B oar ds.  F D A.  2 0 2 0.  
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
3 7  
3.  
Statistical C o nsi derati o ns f or Cli nical Trials D uri n g t he C O VI D - 1 9 P u blic Healt h 
E mer ge nc y - G ui da nce f or I n d ustr y.  F D A.  2 0 2 0.  
4.  
P oi nts t o c o nsi der o n i m plicati o ns of C or o na vir us disease ( C O VI D- 1 9) o n 
met h o d ol o gical as pects of o n g oi n g cli nical trials.  E M A.  2 0 2 0. 
5.  
Gra ha m J W, Olc h o ws ki A E, Gilreat h T D.  H o w ma n y i m p utati o ns are reall y 
nee de d ?  S o me practical clarificati o ns of m ulti ple i m p utati o n t he or y.  Pre v Sci.  
2 0 0 7; 8( 3): 2 0 6- 1 3.  
6.  
R u bi n D B, Sc he n ker N.  I nter val esti mati o n fr o m m ulti pl y- i m p ute d data:  a case 
st u d y usi n g a gric ult ure i n d ustr y c o des.  J A m Stat Ass oc.  1 9 8 7; 8 1: 3 6 6- 7 4. 
7.  
W hite I R, R o yst o n P, W o o d A M.  M ulti ple i m p utati o n usi n g c hai ne d e q uati o ns:  
Iss u es a n d g ui da nce f or practice.  Stat Me d.  2 0 1 1; 3 0( 4): 3 7 7- 9 9. 
8.  
Pi n heir o J, B or n ka m p B, Bretz F.  D esi g n a n d a n al ysis of d ose-fi n di n g st u dies 
c o m bi ni n g m ulti ple c o m paris o ns a n d m o deli n g pr oce d ures.  J Bi o p har m Stat.  
2 0 0 6; 1 6( 5): 6 3 9- 5 6. 
9.  
Bretz F, Pi n heir o J C, Bra ns o n M.  C o m bi ni n g m ulti ple c o m paris o ns a n d m o deli n g 
tec h ni q ues i n d ose-r es p o nse st u dies.  Bi o metrics.  2 0 0 5; 6 1( 3): 7 3 8- 4 8. 
 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
3 8  
A p pe n di x  A.  
Pr ot oc ol D e vi ati o ns 
T he n u m ber a n d p erce nta ge of s u bjects w h o re p ort e d at least o ne of t he f oll o wi n g 
pr ot oc ol de viati o n cate g ories will be pr o vi de d. 
● S u bject e ntere d i nt o t he st u d y e ve n t h o u g h s/ he di d n ot satisf y e ntr y criteri a. 
● S u bject de vel o pe d wit h dra wal criteria d uri n g t he st u d y a n d was n ot 
wit h dra w n . 
● S u bject recei v e d wr o n g treat me nt or i nc orrect d ose of st u d y. 
● S u bject t o o k pr o hi bite d c o nc o mita nt me dicati o n . 
 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
3 9  
A p pe n di x  B.  
P ote nti all y Cli nic all y I m p ort a nt Criteri a f o r S afet y E n d p oi nts 
T he P CI criteria f or selecte d la b orat or y v aria bles are descri be d i n Ta ble B 1  i nstea d of 
usi n g N CI C T C.  
T a ble B 1. 
P ote nti all y Cli nic all y I m p ort a nt Criteri a f o r  Selecte d  L a b or at or y 
V al ues  
L a b or at or y  Test  
C ate g or y  
H b A 1c  
< 6. 5 %  
≥ 6. 5 % t o < 8 %  
≥ 8 %  
H D L  
< 1. 0 3 m m ol/ L  
≥ 1. 0 3 m m ol/ L  
L D L  
< 3. 3 6 m m ol/ L  
≥ 3. 3 6 t o <  4. 1 4 m m ol/ L  
≥ 4. 1 4 m m ol/ L  
 
T he P CI criteria f or selecte d vital si g n  varia ble s ( p ulse rate, bo d y te m perat ure, a n d 
res pirat or y r ate) are d escri be d i n Ta ble B 2. 
T a ble B 2. 
Criteri a f or P ot e nti all y Cli nic all y I m p ort a nt Vit al Si g n V al ues  
Vit al Si g n  
C ate g or y  
Criteri a f or P ote nti al Cli nic all y I m p ort a nt Vit al Si g ns  
P ulse  
L o w  
Val ue ≤ 5 0 b p m a n d decrease ≥ 1 5 b p m fr o m Baseli ne  
 
Hi g h  
Val ue ≥ 1 2 0 b p m a n d i ncrease ≥ 1 5 b p m fr o m Baseli ne  
B o d y te m perat ure  
Hi g h  
> 3 9. 0 de grees C ( 1 0 2. 3 de grees F)  
Res pirat or y rate  
L o w  
< 1 0 breat hs/ mi n  
 
Hi g h  
> 2 4 breat hs/ mi n  
 
 


 A B B V -1 5 4  
M 2 0 -4 6 6 – Statistical A nal ysis Pla n  
Versi o n 2 . 0 –  1 7  A u g ust 2 0 2 2  
 
 
4 0  
A p pe n di x  C.  
R a n d o m See ds  
I n case of n o n-c o n v er g e n ce, t he r a n d o m see d will be u p date d b y a d di n g 1 0 0 0 0 at eac h 
atte m pt u ntil c o n ver ge nce of m o del ha p pe ns. 
A.   Ra n d o m See ds f or N RI-MI  
E n d p oi nts  
R a n d o m See d  
M C M C pr oce d ure  
P R O C MI  
TJ C 6 8  
1 0 0 0 1  
2 0 0 0 1  
SJ C 6 6  
1 0 0 0 2  
2 0 0 0 2  
TJ C 2 8  
1 0 0 0 3  
2 0 0 0 3  
SJ C 2 8  
1 0 0 0 4  
2 0 0 0 4  
Patie nt's Assess me nt of Pai n  
1 0 0 0 5  
2 0 0 0 5  
Patie nt's Gl o bal Assess me nt of Disease Acti vit y  
1 0 0 0 6  
2 0 0 0 6  
P h ysicia n's Gl o bal Assess me nt of Disease Acti vit y  
1 0 0 0 7  
2 0 0 0 7  
H A Q -DI  
1 0 0 0 8  
2 0 0 0 8  
hs C R P  
1 0 0 0 9  
2 0 0 0 9  
 
B.   Ra n d o m See ds f or MI 
E n d p oi nts  
R a n d o m See d  
M C M C pr oce d ure  
P R O C MI  
TJ C 6 8  
4 0 0 0 1  
5 0 0 0 1  
SJ C 6 6  
4 0 0 0 2  
5 0 0 0 2  
Patie nt's Assess me nt of Pai n  
4 0 0 0 5  
5 0 0 0 5  
Patie nt's Gl o bal Assess me nt of Disease Acti vit y  
4 0 0 0 6  
5 0 0 0 6  
P h ysicia n's Gl o bal Assess me nt of Disease Acti vit y  
4 0 0 0 7  
5 0 0 0 7  
H A Q -DI  
4 0 0 0 8  
5 0 0 0 8  
hs C R P  
4 0 0 0 9  
5 0 0 0 9  
 
 


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
1 9
fi nal i nfere n ces of t h e ris k differe n ce b et wee n eac h A B B V - 1 5 4 gr o u p a n d 
place b o.
9. 2. 3
H a n dli n g of mi s si n g d at a i n C o nti n u o u s E n d p oi nt s
●
Mi xe d M o del f or Re peate d Meas ure s ( M M R M):  T he re p eate d meas ures 
a nal ysis will be c o n d ucte d usi n g a mi xe d m o del i ncl u di n g o bser ve d 
meas ure me nts at all visits. F or t he Place b o- C o ntr olle d Peri o d, t he mi xe d 
m o del i ncl u des t he cate g orical fi xe d effects of treat me nt, visit a n d treat me nt -
b y- visit i nteracti o n, stratificati o n fact ors at ra n d o mizati o n [ Baseli ne 
gl uc oc ortic oi d ( yes/ n o), n u m ber of pri or faile d b/ts D M A R Ds ( 1; 2 or m ore), 
a n d a c o m bi ne d pri or a nti- T N F fail ure/a d ali m u ma b use fact or ( pri or a nti -T N F 
fail ure wit h a d ali m u ma b use; pri or a nti-T N F fail ure wit h o ut a dali m u ma b use; 
n o pri or a nti- T N F fail ure)], a n d t he c o nti n u o us fi xe d c o vari ates of bas eli ne 
meas ure me nt.  F or L T E p eri o ds, t he mi xe d m o del i ncl u des t he cate g orical 
fi xe d eff ects of tr eat me nt, visit a n d treat me nt- b y-visit i nteracti o n, maj or 
strat u m [ baseli ne gl uc o c ortic oi d use ( yes/ n o) a n d pri or a dali m u ma b use 
( yes/ n o)], a n d t h e c o nti n u o us fi xe d c o variates of baseli ne meas ure me nt.  A n 
u nstr uct ure d varia nce- c o varia nce matri x ( U N) will be use d.  If t he m o del 
ca n n ot c o n ver ge, a n a p pr o priate c o varia nce str uct ure matri x (e. g., 
a ut ore gr essi ve ( 1) or c o m p o u n d s y m metr y) will be use d.  Para m eter esti mati o n 
is base d o n t he ass u m pti o n of data bei n g missi n g at ra n d o m a n d usi n g t he 
met h o d of restricte d m a xi m u m li keli h o o d ( R E M L).
M M R M will be t he pri mar y a p pr o ac h t o t he a nal ysis of c o nti n u o us varia bles 
9. 2. 4
S u m m ar y of L o n g -T er m Effi c a c y
L o n g- ter m efficac y i n t he L T E p eri o ds will be s u m marize d usi n g t he As O bser ve d case 
a p pr oac h b y treat me nt se q ue nce ( A B B V- 1 5 4 4 0 m g E O W, A B B V- 1 5 4 1 5 0 m g E O W, 
A B B V - 1 5 4 3 4 0 m g E O W, A B B V- 1 5 4 3 4 0 m g E 4 W, A B B V - 1 5 4 1 5 0 m g E O W re-
ra n d o mize d fr o m Place b o, A B B V - 1 5 4 3 4 0 m g E O W re-ra n d o mize d fr o m Place b o).
●
As O bser ve d  ( AO): T h e A O a nal ysis will be use d f or t he s u m maries of l o n g -
ter m efficac y, w hi c h will n ot i m p ute val ues f or missi n g e val uati o ns, a n d t h us a 


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 0
s u bject w h o d oes n ot ha v e a n e v al uati o n o n a sc he d ule d visit will be e xcl u de d 
fr o m t he A O a n al ysis f or t hat visit.
●
N RI -MI a n d M M R M will be use d t o s u m marize s electe d cate g ori cal a n d 
c o nti n u o us efficac y varia bles, res pecti vel y, f or l o n g- ter m efficac y.
9. 3
Pri m ar y Effi c a c y E n d p oi nt ( s) a n d A n al y s e s
9. 3. 1
Pri m ar y Effi c a c y E n d p oi nt( s)
T he pri mar y e n d p oi nt is t he ac hie v e me nt of A C R 5 0 at Wee k 1 2 . 
A C R criteria ar e c o m m o nl y use d sta n dar d criteria me nti o ne d i n t he g ui da nce of A merica n 
C olle ge of R he u mat ol o g y t o e val uate t he effecti ve ness of i n vesti gati o n dr u g i n R A 
cli nical trials.  It is a c o m p osite meas ure me nt calc ulate d base d o n t he i m pr o ve me nt o ve r a 
set of c ore m eas ur e me nts. 
A C R 5 0 is defi ne d as at least 5 0 % i m pr o ve me nt (c o m pare d t o bas eli ne val ues) i n te n der 
a n d s w olle n j oi nt c o u nts a n d at least 5 0 % i m pr o ve me nt i n 3 of t he re mai ni n g 5 c ore set 
meas ures ( p atie nt 's assess me nt of pai n, patie nt's gl o bal assess me nt of disease acti vit y, 
p h ysicia n's gl o bal assess me nt of disease acti vit y, H A Q- DI a n d hs C R P). 
A s u bject will be classifi e d as a n A C R 5 0 res p o n d er, if t he f oll o wi n g c o n diti o ns are met: 
1.
≥ 5 0 % i m pr o ve me nt fr o m baseli ne i n te n der j oi nt c o u nt ( TJ C 6 8) a n d
2.
≥ 5 0 % i m pr o ve me nt fr o m baseli ne i n s w olle n j oi nt c o u nt ( SJ C 6 6 ) a n d
3.
≥ 5 0 % i m pr o ve me nt fr o m baseli ne i n at least 3 of t he f oll o wi n g 5:
●
patie nt's assess me nt of p ai n ( o n a 0- 1 0 N R S) 
●
patie nt's gl o bal assess me nt of disease acti vit y ( P tG A) ( o n a 0 - 1 0 N R S) 
●
p h ysicia n's gl o bal assess me nt of disease acti vit y ( P h G A) ( o n a 0- 1 0 N R S)
●
H A Q -DI
●
hs C R P


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 1
9. 3. 2
A n al y si s of Pri m ar y Effi c a c y E n d p oi nt( s)
T he statistical n ull h y p ot hesis c orres p o n di n g t o t h e pri mar y e n d p oi nt is t hat t here is n o 
differe n ce b et wee n a n A B B V - 1 5 4 gr o u p a n d t he place b o gr o u p res p o nse rate i n t he 
pr o p orti o n of s u bjects ac hie vi n g A C R 5 0 at Wee k 1 2. 
A nal ysis of t he pri mar y e n d p oi nt will be c o n d ucte d i n t he I T T P o p ulati o n b ase d o n 
treat me nt as r a n d o mize d usi n g N RI -MI .  C o m paris o n of t he pri mar y e n d p oi nt will be 
ma de bet wee n eac h A B B V - 1 5 4 gr o u p a n d t he pl ace b o gr o u p usi n g t he C M H test 
a dj usti n g f or Baseli ne gl uc oc ortic oi d ( y es/ n o), n u m ber of pri or faile d b/ts D M A R Ds ( 1; 2 
or m ore) , a n d a c o m bi ne d pri or a nti-T N F fail ure/a dali m u ma b use fact or ( pri or a nti -T N F 
fail ure wit h a d ali m u ma b use; pri or a nti- T N F fail ure wit h o ut a dali m u ma b use; n o pri or 
a nti-T N F fail ur e)].
T he attri b utes of t he esti ma n ds c orres p o n di n g t o t he pri mar y efficac y e n d p oi nt are 
s u m marize d i n Ta ble  1. 
T a ble 1. 
S u m m ar y of t he Esti m a n d Attri b utes of t he Pri m ar y Effic ac y 
E n d p oi nt (s)
Esti m a n d L a bel
Attri b utes of t he Esti m a n d
Tre at m e nt
E n d p oi nt
P o p ul ati o n
H a n dli n g of 
I nterc urre nt 
E ve nts (I E)
St atistic al 
S u m m ar y
Pri mar y:   C o m p osite 
Esti ma n d
A B B V -1 5 4 
vs. Place b o
A c hie ve me nt 
of A C R 5 0 at 
Wee k 1 2
All 
ra n d o mize d 
s u bjects 
w h o 
recei ve d at 
least o ne 
d ose of 
st u d y dr u g 
(I T T 
P o p ulati o n)
I E: n o ne c o nsi dere d
Differe nce 
bet wee n 
A B B V -1 5 4
a n d 
place b o i n 
t he 
pr o p orti o n 
of s u bjects 
ac hie vi n g 
A C R 5 0 at 
Wee k 1 2


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 2
9. 3. 3
S e n siti vit y a n d S u p pl e m e nt ar y A n al y s e s of t h e Pri m ar y 
Effi c a c y E n d p oi nt( s)
A se nsiti vit y a nal ysis of t he pri mar y a n al ysis of t he pri mar y efficac y e n d p oi nt will be 
c o n d ucte d usi n g t he MI met h o d f or ha n dli n g missi n g data. 
A n a d diti o nal a nal ysis will be c o n d ucte d w h ere  t h e baseli ne defi niti o n f or patie nt 's 
assess me nt of pai n, Pt G A, P h G A, a n d H A Q -DI is u p date d t o w here val ues c ollecte d u p t o 
7 da ys after t h e da y of first d ose ma y be c o nsi dere d f or t he baseli ne v al ue. 
A se par ate a n al ysis ma y be perf or me d i n t he I T T P o p ulati o n e xcl u di n g s u bjects w h o ha ve 
maj or pr ot oc ol de viati o ns i n t he Place b o- C o ntr olle d Peri o d.  T he s u bject e xcl usi o n criteria 
f or t his a nal ysis will be fi nalize d bef ore u n bli n di n g data f or t he Pri mar y A nal ysis. 
9. 4
S e c o n d ar y Effi c a c y E n d p oi nt s a n d A n al y s e s
9. 4. 1
S e c o n d ar y Effi c a c y E n d p oi nt s
T he c o nti n u o us sec o n dar y e n d p oi nts are, at Wee k 1 2,
●
C ha n ge i n D A S 2 8 ( C R P) fr o m Baseli ne: D A S 2 8 ( C R P) is a c o m p osite i n de x 
t o assess disease acti vit y i n R A patie nts usi n g hs C R P meas ure me nt.  T he 
D A S 2 8 ( C R P) pr o vi des a sc ore bet w ee n 0. 9 6 a n d 1 0, i n dicati n g h o w acti ve t he 
r he u mat oi d art hritis is at t he ti me of meas ure m e nt.
●
D A S 2 8 ( C R P)  is calc ulate d base d o n Te n d er J oi nt C o u nt, S w olle n J oi nt C o u nt, 
Patie nt's Gl o bal Assess me nt of Disease Acti vit y ( Pt G A) ( o n a 0 - 1 0 N R S), a n d 
hs C R P (i n m g/ L). 
D A S 2 8 ( C R P) = 0. 5 6 × √( TJ C 2 8 *) + 0. 2 8 × √( SJ C 2 8 * *) + 0. 3 6 × l n( hs C R P&
+ 1) +  0. 1 4 × Pt G A » + 0. 9 6 
* 
TJ C 2 8 refers t o t h e S u bject's t otal Te n d er J oi nt C o u nt o ut of t h e pr o vi d e d 2 8 e v al u ate d j oi nts.
* *
SJ C 2 8 refers t o t h e S u bject's t otal S w olle n J oi nt C o u nt o ut of t h e pr o vi d e d 2 8 e v al u ate d j oi nts.
& 
hs C R P refers t o t h e hi g h -se nsiti vit y C- reacti v e pr otei n la b v al u e.  hs C R P u nit i n t h e D A S 2 8 ( C R P) 
e q u ati o n is e x presse d as m g/ L.
» 
Pt G A refers t o t h e Patie nt's Gl o b al Assess me nt of Disease Acti vit y.
W h ere √
is s q u are r o ot a n d l n is n at ural l o g.


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 3
●
C ha n ge i n C D AI fr o m B aseli ne: C D AI is a c o m p osite c o nti n u o us i n de x t o 
assess disease acti vit y wit h o ut usi n g hs C R P meas ure me nt.  It ca n be calc ul ate d 
base d o n TJ C 2 8, SJ C 2 8, Patie nt's Gl o bal Assess me nt of Disease Acti vit y 
( Pt G A) (o n a 0- 1 0 N R S ) a n d P h ysicia n's Gl o bal Assess me nt of Disease 
Acti vit y ( P h G A) ( o n a 0- 1 0 N R S).  It ca n be d eri v e d as f oll o ws: 
C D AI = TJ C 2 8 + SJ C 2 8 + Pt G A + P h G A . 
●
C ha n ge i n t he H A Q- DI fr o m Baseli ne
T he cate g orical sec o n dar y e n d p oi nts are, at Wee k 1 2,
●
Ac hie ve me nt of A C R 2 0 a n d Ac hie v e me nt of A C R 7 0 : T he defi niti o n is si milar 
t o A C R 5 0 wit h at least 2 0 % a n d 7 0 % i m pr o ve me nt , res pecti vel y
●
Ac hie ve me nt of L D A defi ne d b y D A S 2 8 ( C R P) ≤ 3. 2
●
Ac hie ve me nt of L D A defi ne d b y C D AI ≤ 1 0
●
Ac hie ve me nt of cli nical re missi o n ( C R) defi ne d b y D A S 2 8 ( C R P) < 2. 6 
●
Ac hie ve me nt of C R defi ne d b y C D AI ≤ 2. 8
9. 4. 2
A n al y s e s of S e c o n d ar y Effi c a c y E n d p oi nt s
T he statistical n ull h y p ot hesis c orres p o n di n g t o t h e sec o n dar y e n d p oi nt is t hat t here is n o 
differe n ce b et wee n a n A B B V - 1 5 4 gr o u p a n d t he place b o gr o u p at Wee k 1 2 i n ter ms of 
res p o nse r ate f or a cate g orical e n d p oi nt a n d c h a n g e fr o m baseli ne f or a c o nti n u o us 
e n d p oi nt. 
A nal ysis of t he sec o n d ar y e n d p oi nt will be c o n d ucte d i n t he I T T P o p ulati o n base d o n 
treat me nt as r a n d o mize d.  C o m paris o n of t he sec o n dar y e n d p oi nt will be ma de bet w ee n 
eac h A B B V- 1 5 4 gr o u p a n d t he place b o gr o u p usi n g: 
●
F or cate g orical varia bl e s: C M H test base d o n N RI-MI a dj uste d  b y Baseli ne 
gl uc oc ortic oi d ( yes/ n o), n u m ber of pri or faile d b/ts D M A R Ds ( 1; 2 or m ore), 
a n d a c o m bi ne d pri or a nti- T N F fail ure/a d ali m u ma b use fact or ( pri or a nti -T N F 
fail ure wit h a d ali m u ma b use; pri or a nti-T N F fail ure wit h o ut a dali m u ma b use; 
n o pri or a nti- T N F fail ur e).


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 4
●
F or c o nti n u o us varia bles: M M R M me nti o ne d i n S ecti o n 9. 2
T he attri b utes of t he esti ma n ds c orres p o n di n g t o t he ke y sec o n d ar y efficac y e n d p oi nts are 
s u m marize d i n Ta ble  2. 
T a ble 2. 
S u m m ar y of t he Esti m a n d Attri b utes of t he Sec o n d ar y Effic ac y 
E n d p oi nts
F or bi nar y e n d p oi nt: 
Esti m a n d 
L a bel
Attri b utes of t he Esti m a n d
Tre at m e nt
E n d p oi nt
P o p ul ati o n
H a n dli n g of 
I nterc urre nt 
E ve nts
St atistic al 
S u m m ar y
Bi nar y 
Sec o n dar y:
C o m p osite 
Esti ma n d   
A B B V -1 5 4 
vs. Place b o
Ac hie ve me nt 
of eac h 
bi nar y
sec o n dar y 
e n d p oi nt 
res pecti vel y
All 
ra n d o mize d 
s u bjects w h o 
recei ve d at 
least o ne d ose 
of st u d y dr u g
(I T T 
P o p ulati o n)
I E: n o ne 
c o nsi dere d
Differe nce i n 
pr o p orti o n of 
s u bjects 
ac hie vi n g eac h 
bi nar y sec o n dar y 
e n d p oi nt
F or c o nti n u o us e n d p oi nt: 
Esti m a n d 
L a bel
Attri b utes of t he Esti m a n d
Tre at m e nt
E n d p oi nt
P o p ul ati o n
H a n dli n g of 
I nterc urre nt 
E ve nts
St atistic al 
S u m m ar y
C o nti n u o us 
Sec o n dar y:
C o m p osite 
Esti ma n d   
A B B V -1 5 4 
vs Place b o
C ha n ge fr o m 
Baseli ne i n 
eac h 
res pecti ve 
c o nti n u o us 
sec o n dar y 
e n d p oi nt
All 
ra n d o mize d 
s u bjects w h o 
recei ve d at 
least o ne 
d ose of st u d y 
dr u g (I T T 
P o p ulati o n)
I E: n o ne 
c o nsi dere d
Differe nce i n t he 
mea n c ha n ge 
fr o m Baseli ne i n 
eac h c o nti n u o us 
sec o n dar y 
e n d p oi nt


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 5
9. 4. 3
S e n siti vit y a n d S u p pl e m e nt ar y A n al y s e s f or S e c o n d ar y 
Effi c a c y E n d p oi nt s
N ot a p plica ble.
9. 4. 4
S u p p or ti v e S e c o n d ar y Effi c a c y E n d p oi nt s a n d A n al y s e s
N ot a p plica ble.
9. 5
A d diti o n al Effi c a c y A n al y s e s
T he pri mar y a n d all sec o n dar y efficac y vari a bles will be a nal yze d at all visits assesse d 
ot her t ha n Wee k 1 2, i ncl u di n g i n t he L T E p eri o ds, usi n g met h o ds me nti o ne d a b o ve.  At 
ti me of t he Pri mar y A nal ysis, N RI will be use d aft er Wee k 1 2 f or all bi nar y e n d p oi nts. 
I n a d diti o n, ot her efficac y e n d p oi nts descri be d i n Secti o n 3. 3 will be a nal y ze d at all visits 
assesse d  usi n g t he sa me met h o ds as sec o n dar y e n d p oi nts. 
9. 6
D o s e -R e s p o n s e M o d eli n g f or A B B V -1 5 4
T he d ose-r es p o nse r elati o ns hi p a m o n g A B B V- 1 5 4 d ose gr o u ps a n d t he place b o gr o u p 
will be c haracterize d f or t he pri mar y e n d p oi nt usi n g t he M ulti ple C o m paris o n Pr oce d ure - 
M o deli n g ( M C P- M o d) met h o d [ Pi n heir o 2 0 0 6, Bretz 2 0 0 5].  T he s u m mar y le vel res p o nse 
rates base d o n t he pri mar y a nal ysis a p pr oac h a b o v e will be use d, a n d A D D P L A N D F 
s oft ware will be use d t o perf or m t he M C P- M o d a nal yses. 
A set of 6 pre- s pecifi e d sta n dar dize d ca n di dat e d ose-res p o ns e m o dels, as d escri be d i n 
Ta ble  3 will be utilize d t o e xa mi ne t he d ose -res p o nse relati o ns hi p.  A statisticall y 
si g nifica nt d ose-res p o ns e relati o ns hi p will be decl are d if at least o ne m o del is i de ntifie d 
b y t he M C P- M o d met h o d t o be statisticall y si g nifica nt at t w o -si de d α = 0. 1.  T he fitted 
d ose- res p o ns e c ur v es will be prese nte d gra p hicall y f or all statisticall y si g nifica nt m o dels 
al o n g wit h 9 5 % c o nfi de n ce ba n ds.  T h e mi ni m u m effecti ve d ose ( M E D) will be i de ntifie d 
f or eac h statisticall y si g nifica nt m o del base d o n t h e pre-s p ecifie d cli nical mea ni n gf ul 
tar get of 2 2 %.  T h e wei g hte d M E D acr oss all si g nifica nt m o dels will be cal c ulate d, wit h 
wei g ht bei n g t he i n verse of eac h ca n di dat e d ose -res p o nse m o del AI C. 


A B B V -1 5 4
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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 6
T a ble 3. 
C a n di d ate M o dels
M o del
𝒇𝒇(𝒅𝒅,𝜽𝜽)
d = d ose,
θ = M o del P ar a m eters
𝒇𝒇𝟎𝟎(𝒅𝒅,𝜽𝜽)
St a n d ar dize d M o del
I niti al V al ue(s)
f or P ar a m eter(s)*
Li ne ar
E 0 + δ d
d 
N A
E x p o ne nti al
𝐸𝐸0 + 𝐸𝐸1 �𝑒𝑒𝑒𝑒𝑒𝑒�𝑑𝑑
𝛿𝛿�−1 �
𝑒𝑒𝑒𝑒𝑒𝑒�𝑑𝑑
𝛿𝛿�−1
δ = 6 8 0
L o gistic
𝐸𝐸0 +
𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚
1 + 𝑒𝑒𝑒𝑒𝑒𝑒�𝐸𝐸𝐸𝐸5 0 −𝑑𝑑
𝛿𝛿
�
1
1 + 𝑒𝑒𝑒𝑒𝑒𝑒�𝐸𝐸𝐸𝐸5 0 −𝑑𝑑
𝛿𝛿
�
E D 5 0 = 1 5 0 , δ = 6 4. 5
E M a x
𝐸𝐸0 +
𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚𝑑𝑑
𝐸𝐸𝐸𝐸5 0 + 𝑑𝑑
𝑑𝑑
𝐸𝐸𝐸𝐸5 0 + 𝑑𝑑
E D 5 0 = 8 3. 9
si g E M a x
𝐸𝐸0 +
𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚𝑑𝑑ℎ
𝐸𝐸𝐸𝐸5 0
ℎ+ 𝑑𝑑ℎ
𝑑𝑑ℎ
𝐸𝐸𝐸𝐸5 0
ℎ+ 𝑑𝑑ℎ
E D 5 0 = 1 5 0 , h = 3. 6
Q u a dr atic
𝐸𝐸0 + 𝛽𝛽1 𝑑𝑑+ 𝛽𝛽2 𝑑𝑑2
𝑑𝑑+
𝛽𝛽2
|𝛽𝛽1 | 𝑑𝑑2
δ = – 0. 0 0 1 
* 
F or E x p o n e ntial m o d el, t h e i nitial v al u e was d eter mi n e d b ase d o n t h e ass u m pti o n t h at A B B V -1 5 4 3 4 0 m g E O W 
will ac hie v e 9 5 % of t h e ma xi m u m efficac y of A B B V -1 5 4. F or L o gistic, E Ma x, si g E Ma x, a n d Q u a dratic m o d el, 
t he i nitial v al u es were d eter mi n e d b ase d o n t h e ass u m pti o n t h at A B B V -1 5 4 3 4 0 m g E O W a n d A B B V -1 5 4 1 4 0 m g 
E O W will ac hie v e 9 5 % a n d 5 0 % of t h e ma xi m u m efficac y of A B B V -1 5 4, res p ecti v el y.
Ste ps of M C P- M o d: 
1.
C h o ose a ca n di dat e set of m o dels as i n Ta ble  3. 
2.
C o m p ute t he o pti m u m c o ntrast f or eac h m o del. 
3.
Use c o ntrast test t o fi n d all si g nifica nt m o dels w hile preser vi n g fa mil y-wise err or 
rate (F W E R ). 
4.
U se all si g nifica nt m o dels t o ma ke i nfere n ce a b o ut t he wei g hte d tar get d os e of 
i nterest.


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9. 7
Effi c a c y S u b gr o u p A n al y s e s
S u b gr o u p a nal ysis f or t h e pri mar y e n d p oi nt will b e c o n d ucte d b y t h e s u b gr o u ps s pecifie d 
bel o w.  T he diff ere n ce i n t he pri mar y efficac y e n d p oi nt bet wee n t he treat me nt gr o u ps i n 
eac h s u b gr o u p will be assesse d usi n g C M H a p pr o ac h.  Treat me nt differe n ce a n d 
c orres p o n di n g c o nfi de nce i nter val will be use d t o s u m marize t he res ult. 
●
N u m ber of pri or faile d b/ts D M A R Ds  ( 1; 2 or m ore) 
●
Pri or a nti -T N F fail ure ( y es/ n o) 
●
Pri or use of a dali m u ma b ( yes/ n o)  
●
A ge ( < m e dia n ; ≥me dia n years ) 
●
Se x (fe male ; male)
●
Race ( w hite ; n o n- w hite)
●
Ge o gra p hic re gi o n ( N ort h A merica, Asi a , Rest of W orl d ) 
●
B MI ( < 2 5, ≥ 2 5  - < 3 0, ≥ 3 0 k g/ m2) 
●
Baseli ne gl uc oc ortic oi d use  ( yes/ n o) 
If a n y s u b gr o u p h as fe w er t ha n 1 0 % of t he t otal s u bjects, t he n t he a nal ysis f or t his 
s u b gr o u p will n ot be perf or me d. 
1 0. 0
S af et y A n al y s e s
1 0. 1
G e n er al C o n si d er ati o n s
Safet y data will be s u m m arize d f or eac h safet y p o p ulati o n ( Safet y _ P C  a n d A L L _ 1 5 4).  
Safet y s u m maries will be prese nte d b y treat me nt gr o u p, i ncl u di n g a t otal gr o u p f or all 
s u bjects o n acti ve st u d y dr u g.  F or t he safet y anal ysis, s u bjects are assi g ne d t o a treat me nt 
gr o u p base d o n t he tr eat me nt act uall y recei ve d, re gar dless of t h e treat me nt ra n d o mize d.
" Baseli ne" refers t o t he last n o n- missi n g o bser vati o n bef ore or o n t he da y of t he first
a d mi nistrati o n of st u d y dr u g or ra n d o mizati o n if n o st u d y dr u g is gi ve n.  O bser vati o ns o n 
t he sa me da y as t h e first a d mi nistrati o n of st u d y dr u g will be c o nsi dere d f or baseli ne, 


A B B V -1 5 4
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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 8
re gar dl ess if o bser v ati o n ti me (if a vaila ble) was after t he first a d mi nistrati o n of st u d y dr u g 
ti me.
1 0. 2
A d v er s e E v e nt s
A d verse e ve nts ( A Es) will be s u m marize d a n d prese nte d usi n g pri mar y Me d D R A S yste m 
Or ga n Classes ( S O Cs) a n d preferre d t er ms ( P Ts) acc or di n g t o t he versi o n of t he Me d D R A 
c o di n g dicti o nar y use d f or t he st u d y at t he ti me of data base l oc k.  T he act ual versi o n of 
t he Me d D R A c o di n g dicti o nar y use d will be n ote d i n t he A E ta bles a n d i n t he cli nical 
st u d y re p ort.  S pecific a d verse e v e nts will be c o u nte d o nce f or eac h s u bject f or cal c ulati n g 
perce nt a ges, u nless state d ot her wise.   I n a d diti o n, if t he sa me a d v erse e ve nt occ urs 
m ulti ple ti mes wit hi n a s u bject, t he hi g hest se verit y a n d le vel of relati o ns hi p t o 
i n vesti gati o nal pr o d uct will be re p orte d. 
1 0. 2. 1
Tr e at m e nt -E m er g e nt A d v er s e E v e nt s
Treat me nt -e mer ge nt A Es are defi ne d as a n y A E wit h t he o nset t hat is after t he first d ose 
of st u d y dr u g a n d wit h a n o nset date n o m ore t ha n 5 half-li ves of t he st u d y dr u g (i.e., 
7 0 da ys).  E ve nts w here t he o nset date is t he sa me as t he st u d y dr u g start date are ass u me d 
t o be treat me nt-e m er ge nt , u nless t he st u d y dr u g start ti me a n d t he A E start ti me are 
c ollecte d a n d t he A E start ti me is pri or t o t he st u d y dr u g start ti me .  All treat me nt -
e mer ge nt A Es will be s u m marize d o verall, as well as b y pri mar y Me d D R A S O C a n d 
Preferre d Ter m.   T he S O Cs will be prese nte d i n al p ha betical or d er, a n d t h e P Ts will be 
prese nte d i n al p h a betical or der wit hi n eac h S O C.
T he n u m ber a n d p erce nta ge of s u bjects e x p erie n ci n g treat me nt -e mer ge nt A Es will be 
s u m marize d.
I n t he A L L _ 1 5 4 p o p ulati o n, treat me nt-e mer ge nt A Es are d efi ne d b ase d o n t he first d ose 
of A B B V - 1 5 4. 


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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
2 9
1 0. 2. 2
A d v er s e E v e nt O v er vi e w
A n o ver vie w of A Es will be prese nt e d c o nsisti n g of t he n u m ber a n d p erce nta ge of 
s u bjects e x perie n ci n g at l east o ne e v e nt f or eac h of t he f oll o wi n g A E cat e g ories:
●
A n y treat me nt -e mer ge nt A E
●
A n y treat me nt - e mer ge nt A E relate d t o st u d y dr u g acc or di n g t o t he i n vesti g at or 
●
A n y se ver e ( C T C A E gra de ≥ 3) treat me nt-e mer g e nt A E
●
A n y seri o us treat me nt- e mer ge nt A E
●
A n y treat me nt - e mer ge nt A E lea di n g t o disc o nti n uati o n of st u d y dr u g 
●
A n y treat me nt-e mer ge nt A E lea di n g t o deat h
●
A d verse E v e nts of S peci al I nt erest (f or mall y k n o w n as S afet y T o pics of 
Interest ) 
●
All deat hs
○
Deat hs occ urri n g ≤ 7 0 da ys  after last d ose of st u d y dr u g 
○
Deat hs occ urri n g > 7 0 d a ys after last d ose of st u d y dr u g. 
T he o ver vie w of A Es p er 1 0 0 patie nt- years of e x p os ure will als o be pr o vi d e d f or t he 
a b o ve cate g ories.
1 0. 2. 3
Tr e at m e nt - Em er g e nt A d v er s e E v e nt s
b y S O C a n d/ or P T
Treat me nt -e mer ge nt a d v erse e v e nts will be s u m marize d b y S O C a n d P T; b y ma xi m u m 
relati o ns hi p t o st u d y dr u g as assesse d b y t he i n v esti gat or (e. g., reas o na ble p ossi bilit y or n o 
reas o na bl e p ossi bilit y) a n d S O C a n d P T; b y ma xi m u m se verit y a n d S O C a n d P T; a n d b y 
s u bject n u m ber a n d S O C a n d P T.  S pecific a d v ers e e ve nts will be c o u nte d o nce f or eac h 
s u bject f or calc ulati n g perce nta g es u nless state d ot her wise.  I n a d diti o n, if t he sa me 
a d verse e ve nt occ urs m ulti ple ti mes wit hi n a s u bject, t he hi g hest se verit y a n d le v el of 
relati o ns hi p t o i n vesti gati o nal pr o d uct will be re p orte d. 
I n a d diti o n, treat me nt-e m er ge nt a d v erse e ve nts will be s u m marize d b y P T a n d s orte d b y 
decreasi n g fr e q ue nc y f or t he t otal A B B V - 1 5 4 gr o u p. 


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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
3 0
1 0. 2. 4
Tr e at m e nt - Em er g e nt A d v er s e E v e nt s
p er P ati e nt -Y e ar s of 
E x p o s ur e
E x p os ure-a dj uste d A Es p er 1 0 0 patie nt- y ears will be pr o vi de d, w h ere A Es per 
1 0 0 patie nt - years of e x p os ure ar e defi n e d as t he n u m ber of A Es di vi de d b y t he t otal 
e x p os ure i n 1 0 0 patie nt- y ears.   T he st u d y dr u g e x p os ure is defi ne d as t he last d ose date 
pl us 5 × half- life ( 7 0 d a ys), mi n us t he first d ose date. 
1 0. 2. 5
S A E s (I n cl u di n g D e at h s) a n d A d v er s e E v e nt s L e a di n g t o 
St u d y Dr u g Di s c o nti n u ati o n
S A Es (i ncl u di n g deat hs) a n d A Es lea di n g t o st u d y dr u g disc o nti n uati o n will be 
s u m marize d b y S O C a n d P T a n d i n listi n g f or mat. 
I n a d diti o n, t he e ve nt r ate per 1 0 0 patie nt- years of e x p os ure will als o be pr o vi de d b y S O C 
a n d P T f or eac h treat me nt -e mer ge nt S A E a n d T E A E lea di n g t o st u d y dr u g 
disc o nti n uati o n. 
1 0. 2. 6
A d v er s e E v e nt s of S p e ci al I nt er e st 
A d verse E v e nts of S peci al I nt erest ( A E SI, f or merl y k n o w n as Safet y t o pics of i nterest) 
will be s u m marize d b y S O C a n d P T a n d will be base d o n sta n dar dize d or c o m pa n y 
Me d D R A q ueries ( S M Qs or C M Qs), or base d o n a dj u dicati o n res ults.  A E SIs  t o be 
s u m marize d will f oll o w  t h ose i n dicate d i n t he latest versi o n of t he Pr o d uct Safet y 
Statistical A nal ysis Pla n ( P S S A P) f or A B B V- 1 5 4 i n t he A E SI/ Safet y T o pics of I nterest 
secti o n.  Detaile d i nf or m ati o n a b o ut searc h criteria f or t he A E SIs  are als o pr o vi de d i n a 
ta ble i n t he sa me secti o n.
Ta b ular listi n gs of A E SIs  will be pr o vi de d. 
I n a d diti o n, t he e ve nt r ate per 1 0 0 patie nt - years of e x p os ure will als o be pr o vi de d b y S O C 
a n d P T f or eac h A E SI. 


A B B V -1 5 4
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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
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1 0. 3
A n al y si s of L a b or at or y D at a
Data c ollecte d fr o m ce ntr al a n d l ocal la b orat ories, i ncl u di n g a d diti o nal la b orat or y testi n g 
d ue t o a n S A E, will be use d i n all a nal yses , e x ce pt f or Baseli ne w h ere S A E-relate d 
la b orat or y ass ess me nts o n or bef or e t he first d ose of st u d y dr u g will be e xcl u de d.  T he 
cli nical la b orat or y tests d efi ne d i n t he pr ot oc ol o p erati o ns ma n ual (e. g., he mat ol o g y a n d 
cli nical c he mistr y) will b e s u m marize d.
Eac h la b or at or y varia ble will be s u m marize d f or all ti me p oi nts (starti n g wit h Baseli ne) 
wit h t he n u m ber of n o n- missi n g o bser vati o ns, mea n a n d sta n dar d de viati o n, me dia n, 
mi ni m u m a n d ma xi m u m. Mea n c ha n g e fr o m b aseli ne t o eac h a p plica ble p ost -baseli ne 
visit will be s u m marize d f or select e d la b orat or y varia bles, wit h t he n u m ber of 
o bser vati o ns, baseli ne m ea n, a n d visit mea n.  T h e c ha n ge fr o m baseli ne m ea n, sta n dar d 
err or, a n d 9 5 % c o nfi de nce i nter val will be prese nt e d f or t he mea n c h a n ge fr o m baseli ne 
wit hi n e ac h treat me nt gr o u p a n d differe nce bet wee n treat me nt gr o u ps ( A B B V- 1 5 4 vs. 
place b o) as a p plica ble.  T his s u m mar y a n d c ha n g e fr o m baseli ne s u m mar y will be 
prese nte d o n ce  b y treat me nt se q ue nce. 
C ha n ges i n la b orat or y p ara meters will be ta b ul ate d usi n g s hift ta bles eit her b y N CI C T C 
criteria or ot h er criteria liste d i n A p pe n di x B .  A s hift ta ble fr o m baseli ne eit her t o t he 
w orse val ue ( base d o n N CI C T C criteri a) d uri n g treat me nt or t o mi ni m u m a n d ma xi m u m 
val ue ( bas e d o n n or mal r a n ge), will be create d.  A si milar s hift ta ble will be pr o vi de d t o 
s u m marize s hifts fr o m baseli ne t o t he fi nal p ost-baseli ne val ue.
La b orat or y a b n or malities meeti n g C T C criteria gra de 3 a n d 4 will be s u m marize d.
La b orat or y a b n or malities will be e val uate d b ase d o n P ote ntiall y C li nicall y I m p ort a nt 
( P CI) criteria ( base d o n N CI C T C criteria, e x ce pt f or t h ose liste d i n A p pe n di x B ).  F or 
eac h la b orat or y P CI criteri o n, t he n u m ber a n d p erce nta ge of s u bjects w h o ha ve a 
la b orat or y val u e meeti n g t he criteria will be s u m marize d.  Listi n gs will be pr o vi de d t o 
s u m marize s u bject-l e vel la b orat or y dat a f or s u bjects meeti n g P CI criteria.  I n t he 
e val uati o n of P CI  l a b orat or y val ues, t he bas eli ne v al ue f or t he A L L _ 1 5 4 p o p ulati o n will 


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
3 2
be deter mi ne d b y t he l ast n o n- missi n g meas ure me nt rec or d e d o n or bef ore t he date of t he 
first d ose of st u d y dr u g i n t he c orr es p o n di n g A B B V - 1 5 4 treat me nt gr o u p ( w hic h ma y be 
differe nt t ha n t h e first d ose of st u d y dr u g recei ve d i n t he st u d y). 
F or t he p ur p os e of ass essi n g f or p ote ntial H y' s la w cases, t he fre q u e ncies a n d perce nt a ges 
of s u bjects wit h p ost baseli ne li ver s pecifi c f u ncti o n test val ues t hat meet t he f oll o wi n g 
criteria of p ot e ntial cli nical i nterest will be s u m marize d b y "as treate d" treat me nt gr o u p: 
●
A L T > 3 × U L N
●
A L T > 5 × U L N
●
A L T > 1 0 × U L N 
●
A L T > 2 0 × U L N 
●
A S T > 3 × U L N
●
A S T > 5 × U L N
●
A S T > 1 0 × U L N 
●
A S T > 2 0 × U L N 
●
T B L > 2 × U L N
●
Al kali ne p h os p hatase > 1. 5 × U L N 
●
A L T a n d/ or A S T > 3 × U L N a n d c o n c urre nt I N R > 1. 5 
●
A L T a n d/ or A S T > 3 × U L N a n d c o n c urre nt T B L > 2 × U L N
A listi n g of p ossi ble H y' s La w cas es, defi n e d as t h ose w h o meet all of t he f oll o wi n g 
c o n diti o ns si m ulta ne o usl y, will be pr o vi de d:  A L T > 3 × U L N or A S T > 3 × U L N t hat is 
ass ociate d wit h a n i ncrease i n bilir u bi n > 2 × U L N.
1 0. 4
A n al y si s of Vit al Si g n s
Vital si g n meas ure me nts of s yst olic a n d diast olic bl o o d press ure, res pirat or y rate, p ulse 
rate, a n d b o d y te m p erat ure will be s u m marize d.   Wei g ht will be i ncl u de d i n t he 
s u m maries.


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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
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Eac h vital si g n varia ble will be s u m marize d f or all ti me p oi nts (starti n g wit h Baseli ne) 
wit h t he n u m ber of n o n- missi n g o bser vati o ns, mea n a n d sta n dar d de viati o n, me dia n, 
mi ni m u m a n d ma xi m u m. Mea n c ha n g e fr o m b aseli ne t o eac h a p plica ble p ost -baseli ne 
visit will be s u m marize d f or eac h vital si g n varia bl e, wit h t he n u m ber of o bs er vati o ns, 
baseli ne mea n, a n d visit mea n.  T he c h a n ge fr o m baseli ne mea n, sta n d ar d err or, a n d 9 5 % 
c o nfi de nce i nter val will be prese nt e d f or t he m ea n c ha n ge fr o m baseli ne wit hi n eac h 
treat me nt gr o u p a n d differe nce b et wee n treat me nt gr o u ps ( A B B V- 1 5 4 vs. place b o) as 
a p plica ble.  T his s u m mar y a n d c ha n g e fr o m bas eli ne s u m mar y will be pres e nte d o nce b y 
treat me nt se q ue n ce. 
Vital si g n varia bles will be e val uat e d base d o n P CI criteria.  P ulse rate, b o d y te m perat ure, 
a n d res pirat or y rate will f oll o w t he criteria i n A p p e n di x B .  All ot her vital si g ns will 
f oll o w t he criteria i n t he P S S A P.  F or eac h vital si g n P CI criteri o n, t he n u m ber a n d 
perce nt a ge of s u bjects w h o ha ve a vital si g n val ue meeti n g t he criteria will be 
s u m marize d.  Listi n gs will be pr o vi de d t o s u m marize s u bject-le v el vital si g n data f or 
s u bjects meeti n g P CI criteria.  I n t he e val uati o n of P CI  vital si g n val ues f or t he A L L _ 1 5 4 
p o p ulati o n, t he baseli ne val ue will be deter mi ne d b y t he last n o n- missi n g meas ure me nt 
rec or d e d o n or bef ore t h e date of t he first d ose of st u d y dr u g i n t he c orres p o n di n g 
A B B V - 1 5 4 treat me nt gr o u p. 
1 0. 5
S af et y S u b gr o u p A n al y s e s
T he A E O ver vie w a n d A E b y S O C a n d P T s u m maries will be pr o vi de d f or t he 
stratificati o n varia bles: 
●
Baseli ne gl uc oc ortic oi d d ose ( yes/ n o) 
●
N u m ber of pri or faile d b/ts D M A R Ds  ( 1; 2 or m ore) 


A B B V -1 5 4
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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
3 4
1 0. 6
Ot h er S af et y A n al y s e s
E C G is c ollecte d at scr ee ni n g , Wee k 1 2, Wee k 2 4, Wee k 3 6, Wee k 7 8, Wee k 1 3 4, a n d 
Wee k 1 8 2 .  E C G fi n di n gs will be s u m marize d b y treat me nt gr o u p f or eac h para meter a n d 
visit.
D ual -e ner g y X-ra y a bs or pti m o metr y ( D X A) is c ollecte d at scree ni n g, Wee k 2 4, Wee k 7 8 , 
Wee k 1 3 4, a n d Wee k 1 8 2 .  D X A meas ure me nts, i ncl u di n g b o ne mi neral de nsit y a n d 
c orres p o n di n g T a n d Z sc ores, will be s u m marize d b y treat me nt gr o u p f or eac h visit  a n d 
als o i n t he f oll o wi n g gr o u ps: 
●
Fe male p atie nts ' p ost-me n o pa usal stat us at baseli n e ( Yes/ N o)
●
B o ne pr otecti ve a g e nt stat us at baseli ne ( Yes/ N o)
B o d y c o m p ositi o n meas ures of t otal fat mass ( g), t otal lea n mass ( g), t otal b o d y mass ( g), 
fat ( %), a n d lea n ( %) will als o be s u m marize d. A d diti o nall y, t he rati o of t otal fat mass 
di vi de d b y t otal lea n mass will be i ncl u de d.  
D X A s u m maries will be prese nte d o n ce i ncl u di n g all s u bjects a n d visits w here t he s a me 
mac hi ne as scree ni n g w as use d, a n d a gai n i ncl u di n g all s u bjects a n d visits (re gar dless of 
mac hi ne s witc hi n g).  T he s u m maries will be pr o vi de d f or b ot h ce ntrall y rea d a n d l ocall y 
rea d r es ults.
1 1. 0
Ot h er A n al y s e s
N ot a p plica ble.
1 2. 0
I nt eri m A n al y s es 
N ot a p plica ble.


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M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
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1 2. 1
D at a M o nit ori n g C o m mitt e e
A n e xter nal D M C will be esta blis he d t o safe g u ar d t he i nterest of trial s u bjects b y 
assessi n g t he safet y of t he i nter ve nti o ns d uri n g t he trial a n d well as f or m o nit ori n g t he 
i nte grit y a n d i nter preta bilit y of t he trial.
A se par ate D M C c harter descri bes t he r oles a n d res p o nsi bilities of t he D M C me m bers, 
fre q ue n c y of dat a re vi e ws, rele va nt dat a t o be assesse d, a n d ge neral o perati o ns. 
Si nce t here are n o efficac y a nal yses f or earl y st o p pi n g, n o al p ha a dj ust me nt is nee de d. 
A n i nter nal i n de pe n d e nt gl uc oc ortic oi d a dj u dicati o n c o m mittee will be esta blis he d t o 
a dj u dicate s yste mic gl uc oc ortic oi d A Es .  A se p arate c harter d escri bes t he r oles a n d 
res p o nsi bilities of t he a dj u dicati o n c o m mittee me m bers, fre q u e nc y of data re vie ws, a n d 
e x pectati o ns f or bli n de d c o m m u nicati o ns. 
1 3. 0
O v er all T y p e -I Err or C o ntr ol
O verall T y pe- I err or c o ntr ol f or m ulti ple c o m paris o ns is n ot pla n ne d i n t his P hase 2 b 
st u d y. 
Si nce t here are n o efficac y a nal yses f or earl y st o p pi n g pla n ne d f or t he D M C re vie w a n d 
I E R C re vi e w, n o al p ha s pe n di n g is nee de d d ue t o a nal yses f or t h e D M C re vie w a n d t he 
I E R C re vi e w. 


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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
3 6
1 4. 0
V er si o n Hi st or y
T a ble 4. 
S A P Versi o n Hist or y S u m m ar y
Versi o n
D ate
S u m m ar y
1. 0
0 4 A u g ust 2 0 2 1
Ori gi nal versi o n
2. 0
1 7 A u g ust 2 0 2 2
•
U p date d t o reflect pr ot oc ol versi o n 2 c ha n ges, 
i ncl u di n g:
o
Re m o val of i nterc urre nt e ve nts
o
A d diti o n of L T E Peri o d 2
o
I T T p o p ulati o n n o w re q uires at least 1 d ose of 
st u d y treat me nt
•
C ha n ge d cate g ories f or s o me baseli ne 
de m o gra p hics/c haracteristics
•
A d de d s u m mar y of pri or a n d c o nc o mita nt D M A R D, 
i n a d diti o n t o all me dicati o ns
•
A d de d l o gistical pr o ble ms ( ge o -p olitical restricti o ns) 
t o N RI-MI, i n a d diti o n t o C O VI D -1 9
•
C ha n ge d O bser ve d Cases l o n g -ter m efficac y t o As 
O bser ve d
•
C ha n ge d cate g ories f or efficac y a n d safet y s u b gr o u p 
a nal yses f or baseli ne gl uc oc ortic oi d d ose
•
Clarifie d treat me nt e mer ge nce defi niti o n f or a d verse 
e ve nts
•
C ha n ge d Safet y T o pics of I nterest t o A d verse E ve nts 
of S pecial I nterest
•
Clarifie d P ote ntiall y Cli nical I m p orta nt criteria f or 
la bs a n d vital si g ns
•
C orrecte d H y 's La w cases
•
Clarifie d i ncl u de d varia bles i n vital si g ns a nal ysis
•
A d de d details f or D X A a nal ysis
1 5. 0
R ef er e n c e s
1.
R u bi n D B, Sc he n ker N.  I nter val esti mati o n fr o m m ulti pl y -i m p ute d data:  a case 
st u d y usi n g a gric ult ure i n d ustr y c o des.  J A m Stat Ass oc.  1 9 8 7; 8 1: 3 6 6- 7 4. 
2.
F D A G ui da n ce o n C o n d uct of Cli nical Trials of Me dical Pr o d ucts d uri n g C O VI D-
1 9 Pa n de mic - G ui da nce f or I n d ustr y, I n v esti gat ors, a n d I nstit uti o nal Re vie w 
B oar ds.  F D A.  2 0 2 0.  


A B B V -1 5 4
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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
3 7
3.
Statistical C o nsi derati o ns f or Cli nical Trials D uri n g t he C O VI D - 1 9 P u blic Healt h 
E mer ge nc y - G ui da nce f or I n d ustr y.  F D A.  2 0 2 0.  
4.
P oi nts t o c o nsi der o n i m plicati o ns of C or o na vir us disease ( C O VI D- 1 9) o n 
met h o d ol o gical as pects of o n g oi n g cli nical trials.  E M A.  2 0 2 0. 
5.
Gra ha m J W, Olc h o ws ki A E, Gilreat h T D.  H o w ma n y i m p utati o ns are reall y 
nee de d ?  S o me practical clarificati o ns of m ulti ple i m p utati o n t he or y.  Pre v Sci.  
2 0 0 7; 8( 3): 2 0 6- 1 3.  
6.
R u bi n D B, Sc he n ker N.  I nter val esti mati o n fr o m m ulti pl y- i m p ute d data:  a case 
st u d y usi n g a gric ult ure i n d ustr y c o des.  J A m Stat Ass oc.  1 9 8 7; 8 1: 3 6 6- 7 4. 
7.
W hite I R, R o yst o n P, W o o d A M.  M ulti ple i m p utati o n usi n g c hai ne d e q uati o ns:  
Iss u es a n d g ui da nce f or practice.  Stat Me d.  2 0 1 1; 3 0( 4): 3 7 7- 9 9. 
8.
Pi n heir o J, B or n ka m p B, Bretz F.  D esi g n a n d a n al ysis of d ose-fi n di n g st u dies 
c o m bi ni n g m ulti ple c o m paris o ns a n d m o deli n g pr oce d ures.  J Bi o p har m Stat.  
2 0 0 6; 1 6( 5): 6 3 9- 5 6. 
9.
Bretz F, Pi n heir o J C, Bra ns o n M.  C o m bi ni n g m ulti ple c o m paris o ns a n d m o deli n g 
tec h ni q ues i n d ose-r es p o nse st u dies.  Bi o metrics.  2 0 0 5; 6 1( 3): 7 3 8- 4 8. 


A B B V -1 5 4
M 2 0 -4 6 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
3 8
A p pe n di x A.
Pr ot oc ol D e vi ati o ns 
T he n u m ber a n d p erce nta ge of s u bjects w h o re p ort e d at least o ne of t he f oll o wi n g 
pr ot oc ol de viati o n cate g ories will be pr o vi de d. 
●
S u bject e ntere d i nt o t he st u d y e ve n t h o u g h s/ he di d n ot satisf y e ntr y criteri a. 
●
S u bject de vel o pe d wit h dra wal criteria d uri n g t he st u d y a n d was n ot 
wit h dra w n . 
●
S u bject recei v e d wr o n g treat me nt or i nc orrect d ose of st u d y. 
●
S u bject t o o k pr o hi bite d c o nc o mita nt me dicati o n . 


A B B V -1 5 4
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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
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A p pe n di x B.
P ote nti all y Cli nic all y I m p ort a nt Criteri a f o r S afet y E n d p oi nts 
T he P CI criteria f or selecte d la b orat or y v aria bles are descri be d i n Ta ble B 1  i nstea d of 
usi n g N CI C T C.
T a ble B 1. 
P ote nti all y Cli nic all y I m p ort a nt Criteri a f o r Selecte d  L a b or at or y 
V al ues
L a b or at or y Test
C ate g or y
H b A 1c
< 6. 5 %
≥6. 5 % t o < 8 %
≥8 %
H D L
< 1. 0 3 m m ol/ L
≥1. 0 3 m m ol/ L
L D L
< 3. 3 6 m m ol/ L
≥3. 3 6 t o < 4. 1 4 m m ol/ L
≥4. 1 4 m m ol/ L
T he P CI criteria f or selecte d vital si g n varia ble s ( p ulse rate, bo d y te m perat ure, a n d 
res pirat or y r ate) are d escri be d i n Ta ble B 2. 
T a ble B 2. 
Criteri a f or P ot e nti all y Cli nic all y I m p ort a nt Vit al Si g n V al ues
Vit al Si g n
C ate g or y
Criteri a f or P ote nti al Cli nic all y I m p ort a nt Vit al Si g ns
P ulse
L o w
Val ue ≤ 5 0 b p m a n d decrease ≥ 1 5 b p m fr o m Baseli ne
Hi g h
Val ue ≥ 1 2 0 b p m a n d i ncrease ≥ 1 5 b p m fr o m Baseli ne
B o d y te m perat ure
Hi g h
> 3 9. 0 de grees C ( 1 0 2. 3 de grees F)
Res pirat or y rate
L o w
< 1 0 breat hs/ mi n
Hi g h
> 2 4 breat hs/ mi n


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Versi o n 2 . 0 – 1 7 A u g ust 2 0 2 2
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A p pe n di x C.
R a n d o m See ds
I n case of n o n-c o n v er g e n ce, t he r a n d o m see d will be u p date d b y a d di n g 1 0 0 0 0 at eac h 
atte m pt u ntil c o n ver ge nce of m o del ha p pe ns. 
A.   Ra n d o m See ds f or N RI-MI
E n d p oi nts
R a n d o m See d
M C M C pr oce d ure
P R O C MI
TJ C 6 8
1 0 0 0 1
2 0 0 0 1
SJ C 6 6
1 0 0 0 2
2 0 0 0 2
TJ C 2 8
1 0 0 0 3
2 0 0 0 3
SJ C 2 8
1 0 0 0 4
2 0 0 0 4
Patie nt's Assess me nt of Pai n
1 0 0 0 5
2 0 0 0 5
Patie nt's Gl o bal Assess me nt of Disease Acti vit y 
1 0 0 0 6
2 0 0 0 6
P h ysicia n's Gl o bal Assess me nt of Disease Acti vit y
1 0 0 0 7
2 0 0 0 7
H A Q -DI
1 0 0 0 8
2 0 0 0 8
hs C R P
1 0 0 0 9
2 0 0 0 9
B.   Ra n d o m See ds f or MI 
E n d p oi nts
R a n d o m See d
M C M C pr oce d ure
P R O C MI
TJ C 6 8
4 0 0 0 1
5 0 0 0 1
SJ C 6 6
4 0 0 0 2
5 0 0 0 2
Patie nt's Assess me nt of Pai n
4 0 0 0 5
5 0 0 0 5
Patie nt's Gl o bal Assess me nt of Disease Acti vit y 
4 0 0 0 6
5 0 0 0 6
P h ysicia n's Gl o bal Assess me nt of Disease Acti vit y
4 0 0 0 7
5 0 0 0 7
H A Q -DI
4 0 0 0 8
5 0 0 0 8
hs C R P
4 0 0 0 9
5 0 0 0 9