Clinical trial NCT04972968
Conditions: Polymyalgia Rheumatica
Keywords: Polymyalgia Rheumatica PMR ABBV-154 Glucocorticoid
Sponsor: AbbVie
Start date: 2021-09-09; Completion date: 2023-07-24
Enrollment: 181 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Polymyalgia rheumatica (PMR) is an inflammatory disease causing shoulder, hip, and neck pain and stiffness, in adults aged 50 years or older. This study evaluates how safe and effective ABBV-154 is in participants with glucocorticoid-dependent PMR. Adverse events and change in disease activity will be assessed.

ABBV-154 is an investigational drug being evaluated for the treatment of PMR. Participants will be randomized into 1 of 4 treatment groups or arms, each arm receiving a different treatment. There is a 1 in 4 chance that a participant will be assigned to placebo. Around 160 participants, of at least 50 years of age, with PMR will be enrolled in the study at approximately 95 sites worldwide.

The study is compromised of a 52 week double-blind, placebo-controlled period and a follow-up visit 70 days after the last dose of the study drug. All participants will receive a glucocorticoid taper along with the assigned dose of ABBV-154 or placebo, subcutaneously (SC) every other week (eow).

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

Detailed description:

Arms: arm 1: Participants in this group will receive dose A of ABBV-154 subcutaneously (SC) every other week (eow) for 52 weeks. In addition, participants will receive a glucocorticoid oral tablet taper. arm 2: Participants in this group will receive dose B of ABBV-154 SC eow for 52 weeks. In addition, participants will receive a glucocorticoid oral tablet taper. arm 3: Participants in this group will receive dose C of ABBV-154 SC eow for 52 weeks. In addition, participants will receive a glucocorticoid oral tablet taper. arm 4: Participants will receive placebo SC eow for 52 weeks. In addition, participants will receive a glucocorticoid oral tablet taper.
Interventions: intervention 1: ABBV-154 intervention 2: Placebo intervention 3: Glucocorticoid
Intervention descriptions: intervention 1: Subcutaneous Injection intervention 2: Subcutaneous Injection intervention 3: Oral Tablet

Protocol documents:
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
10
3
OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
11
3.2
PRIMARY ENDPOINT
12
3.3
SECONDARY ENDPOINTS
12
3.4
ADDITIONAL EFFICACY ENDPOINTS
13
3.5
SAFETY MEASURES
14
3.6
PHARMACOKINETIC AND IMMUNOGENICITY ENDPOINTS
14
3.7
BIOMARKER RESEARCH ENDPOINTS
14
4
INVESTIGATIONAL PLAN
15
4.1
OVERALL STUDY DESIGN AND PLAN
15
4.2
DISCUSSION OF STUDY DESIGN
16
5
STUDY ACTIVITIES
17
5.1
ELIGIBILITY CRITERIA
17
5.2
CONTRACEPTION RECOMMENDATIONS
23
5.3
PROHIBITED MEDICATIONS AND THERAPY
24
5.4
PRIOR AND CONCOMITANT THERAPY
25
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
28
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
29
5.7
DISEASE ACTIVITY AND FLARE ASSESSMENT
30
5.8
STUDY DRUG
31
5.9
RANDOMIZATION/DRUG ASSIGNMENT
33
5.10 PROTOCOL DEVIATIONS
34
5.11 DATA MONITORING AND ADJUDICATION COMMITTEES
34
6
SAFETY CONSIDERATIONS
35
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6.1
COMPLAINTS AND ADVERSE EVENTS
35
6.2
TOXICITY MANAGEMENT
39
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
43
7.1
STATISTICAL AND ANALYTICAL PLANS
43
7.2
DEFINITION FOR ANALYSIS POPULATIONS
43
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND SECONDARY ENDPOINTS
43
7.4
STATISTICAL ANALYSES FOR EFFICACY
44
7.5
STATISTICAL ANALYSES FOR SAFETY
45
7.6
STATISTICAL ANALYSES FOR PHARMACOKINETICS AND IMMUNOGENICITY
46
7.7
STATISTICAL ANALYSES FOR BIOMARKER DATA
46
7.8
INTERIM ANALYSIS
46
7.9
OVERALL TYPE I ERROR CONTROL
46
7.10 SAMPLE SIZE DETERMINATION
46
8
ETHICS
47
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
47
8.2
ETHICAL CONDUCT OF THE STUDY
47
8.3
SUBJECT CONFIDENTIALITY
47
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
47
10 DATA QUALITY ASSURANCE
48
11 COMPLETION OF THE STUDY
48
12 REFERENCES
48
LIST OF TABLES
TABLE 1.
INVESTIGATIONAL PRODUCT
32
TABLE 2.
NON-INVESTIGATIONAL PRODUCT
32
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
41
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LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
16
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
50
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
54
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
55
APPENDIX D.
PMR CLASSIFICATION CRITERIA
56
APPENDIX E.
SUPER-HIGH POTENCY AND HIGH POTENCY TOPICAL GLUCOCORTICOIDS
57
APPENDIX F.
ACTIVITY SCHEDULE
58
APPENDIX G.
PROTOCOL SUMMARY OF CHANGES
66
APPENDIX H.
OPERATIONS MANUAL
73
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
Polymyalgia rheumatica (PMR) is a relatively common inflammatory rheumatic disease occurring in 
adults age 50 years or older, manifesting as bilateral shoulder, hip, and neck pain and stiffness.  
Population-based studies examining the incidence of disease among residents of Olmsted County, 
Minnesota estimate the lifetime risk of developing PMR at 2.4% for women and 1.7% for men.1  
Worldwide, the incidence is highest in people of Northern European descent.  The onset is typically 
abrupt or discrete in nature; morning stiffness is prominent, and bilateral shoulder pain is the initial 
symptom in most patients.  Nonspecific symptoms such as fatigue, depression, anorexia, and sleep 
disturbance may also be present.  The symptoms that PMR patients experience impacts physical 
function and performance of activities of daily living as well as psychological well-being.2,3  Acute phase 
reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in 
almost all patients and additional nonspecific laboratory findings such as anemia of chronic disease and 
thrombocytosis may also be present.4  Approximately 16-21% of patients with PMR will develop giant 
cell arteritis (GCA), a separate but related inflammatory disease primarily affecting large vessels, at 
some point, and features of PMR are apparent in approximately 40-60% of patients diagnosed with 
GCA.5
Glucocorticoids, such as prednisone/prednisolone, are the primary treatment for PMR.  The initial 
treatment recommendation is to begin the minimum effective glucocorticoid dose within a range of 12.5 
to 25 mg/day prednisone equivalent.6  The 2015 European League Against Rheumatism 
(EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR 
provide a framework for glucocorticoid tapering but also emphasize that tapering schedules should be 
individualized based on regular monitoring of disease activity, laboratory markers, and adverse events 
(AEs).6
Glucocorticoids are highly effective at reducing inflammation and relieving pain.  However, the 
administration of glucocorticoids is limited due to their long-term systemic side effect profile including 
(but not limited to) hypothalamic-pituitary-adrenal (HPA) axis suppression, increased rates of bone 
fracture due to osteoporosis, cardiovascular events, hyperglycemia, glaucoma, skin thinning, and weight 
gain.  These adverse effects are generally dependent on dose, treatment time, concomitant and 
previous glucocorticoid intake, and individual sensitivity.  Therefore, once initial remission is achieved, 
glucocorticoids should be tapered to minimize systemic side effects.6  Unfortunately, disease flares often 
occur while tapering glucocorticoids, resulting in long-term glucocorticoid-associated morbidity.
Recent studies in patients with rheumatoid arthritis (RA) on glucocorticoids illustrate significant risks to 
patients even when used at low doses.  In a retrospective cohort study, adults with RA on low-dose 
glucocorticoids (5 mg/day or less) had a statistically significant increase in the risk of hospitalized 
infection, similar to that seen in patients on biologic therapies in other studies.7  A prospective cohort 
study of patients with RA with or without low-dose glucocorticoid treatment at least once during a 
follow-up period (median 10 years), showed patients with exposure to low-dose glucocorticoid 
experienced significantly more severe events (death, cardiovascular disease, severe infection, or 
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fracture).  The median duration of low-dose glucocorticoid treatment was 44.6 +/-40.1 months, and 
there was a time-dependent relationship between glucocorticoid treatment and the increased risk of 
these severe events.8  In a population-based cohort analysis of 87,794 adults with six immune-mediated 
inflammatory diseases with no prior cardiovascular disease, including PMR patients (n = 25,581), the 
overall absolute risk of cardiovascular disease doubled after one year of using less than 5 mg 
prednisolone per day.9
Although the 2015 EULAR/ACR recommendations for the management of PMR conditionally 
recommend use of methotrexate in addition to glucocorticoids in patients at high risk for relapse and/or 
prolonged therapy, there is a lack of strong efficacy data to support routine use of glucocorticoid-sparing 
agents in the treatment of PMR.6  In addition, the pathophysiology and disease mechanisms of PMR are 
not well delineated, leading to challenges in identifying potential therapeutic targets.  While PMR 
symptoms are generally considered to reflect inflammation in synovial and periarticular structures, 
there is some indication that muscle pathology may also contribute10,11  Some studies indicate elevated 
levels of plasma and serum tumor necrosis factor TNF12,13 and TNF in the muscle interstitium of 
symptomatic PMR patients.11
ABBV-154 as Potential Treatment for PMR
Given the substantial negative systemic effects of glucocorticoids with long-term use, even at low dose, 
and the lack of strong evidence to support the routine use of glucocorticoid-sparing agents in PMR, 
there is a clear unmet need for new therapies that would allow PMR patients to stop using 
glucocorticoids and avoid glucocorticoid-related AEs.
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 
.  Binding of the adalimumab 
portion of the ABBV-154 ADC to activated immune cells that express transmembrane TNF is intended to 
deliver the anti-inflammatory payload intracellularly.  The monoclonal antibody portion of the ADC 
provides targeted delivery, while the primary therapeutic mechanism of action in PMR is expected to be 
the intracellular GRM.  Thus, ABBV-154 is a promising novel therapeutic agent for the treatment of PMR, 
hypothesizing that delivery of the GRM payload intracellularly would allow for control of PMR disease 
activity and discontinuation of systemic glucocorticoids, thereby avoiding further adverse effects caused 
by systemic glucocorticoid exposure.
2.2 Benefits and Risks to Subjects
The clinical efficacy of glucocorticoids in the treatment of PMR is well established.  By utilizing 
expression of transmembrane TNF on activated immune cells, ABBV-154 has the potential to deliver an 
anti-inflammatory payload intracellularly, while minimizing systemic exposure to the free payload GRM.  
Based on the preclinical data discussed in the ABBV-154 Investigator's Brochure, ABBV-154 is expected 
to demonstrate a positive benefit-risk profile for the treatment of PMR.14
Medical review of the safety data from the Phase 1, single ascending dose study did not identify any 
unexpected risk or trend in the healthy volunteer population (including Japanese and Chinese subjects).  
For further details, please see the ABBV-154 Investigator's Brochure.14
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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 (AEs) associated with glucocorticoids include hypertension, HPA axis suppression, 
decreased bone formation, and cataract.  Signs of infection, blood pressure changes, HPA axis function, 
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, 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 with repeated doses up to 10 mg/kg intravenously, 
which is higher than the doses planned in this study, with consistent safety profile as labeled doses.  
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 by 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 PMR with an acceptable benefit-risk profile for development in the treatment of this 
disease.
In view of the coronavirus – 2019 (COVID-19) pandemic, the benefit-risk profiles of various 
immunomodulatory therapies on COVID-19 are being evaluated.  At this time, the effects of ABBV-154 
on the course of COVID-19 are not well defined.  Guidance regarding SARS CoV-2 vaccination is provided 
for investigators in Section 5.4.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary
The primary objective is to assess the safety and efficacy of ABBV-154 versus placebo in subjects with 
PMR, who are dependent on treatment with glucocorticoids with doses of at least 5 mg/day prednisone 
equivalent (glucocorticoid-dependent PMR).

Primary Efficacy Objective:  The primary efficacy objective of the study is to demonstrate that 
ABBV-154 treatment results in a longer disease-free time when compared with placebo 
treatment in the Intent-to-Treat (ITT) population, which consists of all randomized subjects with 
at least one dose of study drug.
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The hypothesis corresponding to the primary efficacy objective is that the time to flare with ABBV-154 
treatment is longer than that with placebo treatment.  The estimand for the primary endpoint is defined 
as the median time to flare in the study for each ABBV-154 group versus the placebo group in the ITT
population.  Subjects will be censored at the time of the last available assessment, initiation of 
immunomodulator, or violation of protocol-allowed systemic glucocorticoid use.

Secondary Efficacy Objectives:  The secondary efficacy objectives of the study are to 
demonstrate greater efficacy with ABBV-154 treatment when compared with placebo treatment 
with respect to the secondary endpoints specified in Section 3.3, in the ITT population.
The estimands corresponding to the secondary efficacy objectives are:

For each binary secondary endpoint:  The difference in percentage of subjects achieving a 
response for each ABBV-154 group versus the placebo group in the ITT population.

For each continuous endpoint:  The mean difference between each ABBV-154 group versus 
the placebo group in the ITT population.
Secondary
The secondary objective is to assess the pharmacokinetics (PK), pharmacodynamics (PD), and 
immunogenicity of ABBV-154.
3.2 Primary Endpoint
The primary endpoint is the time to flare, where flare is defined as follows:

Presence of clinical signs and symptoms of PMR 
AND

Requirement to increase the glucocorticoid dose per investigator.
Clinical signs and symptoms of PMR are defined as shoulder and/or hip girdle pain with inflammatory 
stiffness, neck pain with inflammatory stiffness, or new or worsened limited range of motion of hips 
and/or shoulders, as outlined in Section 5.7.
3.3 Secondary Endpoints
Secondary Endpoints

Achievement of flare-free state up to Week 24

Cumulative glucocorticoid dose by 24 weeks

Change from Baseline in glucocorticoid dose at Week 24
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3.4 Additional Efficacy Endpoints
All secondary endpoints will be analyzed at all visits other than those listed.  In addition, the following 
endpoints will be analyzed at all visits assessed, per Appendix F:

Time to disease flare defined as Polymyalgia Rheumatica Activity Score (PMR-AS) increased from 
Baseline by ≥6.6.

PMR-AS = high-sensitivity CRP (hsCRP) (mg/dL) + Patient Assessment of Pain Severity 
(numeric rating scale [NRS], 0 – 10) + Physician Global Assessment of Disease Activity (NRS, 
0 – 10) + (morning stiffness duration [MST] in minutes × 0.1) + elevation of upper limbs 
(EUL) (scale of 3 – 0)

Time to disease flare defined as PMR-AS ≥9.35

Achievement of PMR-AS < 1.5 

Achievement of PMR-AS < 7 

Achievement of ESR ≤ 30 mm/h at Week 24

Achievement of hsCRP ≤ upper limit of normal (ULN) at Week 24

Change from Baseline in hsCRP

Change from Baseline in PMR-AS

Change from Baseline in MST

Change from Baseline in EUL

Change from Baseline in Physician Global Assessment of Disease Activity NRS

Change from Baseline in Patient Assessment of Pain Severity NRS

Change from Baseline in Patient Assessment of Stiffness Severity NRS

Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-
Fatigue)

Change from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)

Change from Baseline in Patient-Reported Outcomes Measurement Information System 
(PROMIS) Item Bank v 1.0 – Sleep Disturbance

Change from Baseline in Patient Assessment of Bruising Severity NRS

Change from Baseline in EuroQol 5-dimension questionnaire, 5-level (EQ-5D-5L)

Change from Baseline in Physician Assessment of Bruising Severity NRS

For subjects participating in the Wearable Device Substudy:

Change from Baseline in the following sleep parameters: total sleep time, wake after sleep 
onset, sleep efficiency, and sleep onset latency

Change from Baseline in upper limbs range of motion (UL-ROM)
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3.5 Safety Measures
1.
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and AEs leading to 
discontinuation of 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 (predose) and at timepoints during the treatment period as specified in the 
Activity Schedule (Appendix F).
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 (predose) and 
at timepoints as specified in the Activity Schedule (Appendix F).
In addition, optional PK samples will be collected from approximately 32 subjects (approximately 
8 subjects in each arm) who consent to participate in the optional PK sampling to provide additional 
data for PK characterization following repeated administrations.  For these subjects, in addition to the 
standard sampling schedule, blood samples will also be collected at the following time points:  Days 3, 4, 
87, 88, 92 (Week 13) and 99 (Week 14).
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 F) throughout the study.  The biomarkers 
to be analyzed include, but are not limited to:
 
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.
Additional optional biospecimens (whole blood for serum, plasma, peripheral blood mononuclear cells, 
ribonucleic acid [RNA], and deoxyribonucleic acid [DNA]) will be collected at specified time points 
(Activity Schedule, Appendix F) 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 
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
Study M20-370 is a randomized, double-blind, placebo-controlled, multicenter, 52-week Phase 2 study 
to assess the safety, tolerability, efficacy, PK, PD, and immunogenicity following multiple subcutaneous 
(SC) injections of ABBV-154 or placebo in 160 subjects with glucocorticoid-dependent PMR, as defined in 
Section 5.1.
The Screening Period may be up to 35 days.  At the Baseline Visit, subjects will be randomized to one of 
4 treatment arms in a 1:1:1:1 ratio, as follows:  placebo administered SC in combination with a 
glucocorticoid taper or ABBV-154 administered as 40 mg every other week (EOW), 150 mg EOW, or 
340 mg EOW in combination with a glucocorticoid taper.  The glucocorticoid taper is identical for 
placebo and active treatment groups.  Starting at Baseline, each subject will switch from oral 
glucocorticoids obtained from independent sources to oral prednisone/prednisolone provided by the 
Sponsor at the equivalent dose that the subject was taking just prior to the Baseline Visit, rounded up to 
the nearest 1 mg to a maximum of 15 mg.  Beginning at Week 3, subjects will taper 
prednisone/prednisolone per the protocol-defined glucocorticoid taper schedule to 0 mg by Week 24 
and remain off prednisone/prednisolone until the end of the Treatment Period, Week 52, unless a PMR 
flare is confirmed.  A safety follow-up visit will be performed approximately 70 days after the last 
administration of ABBV-154/placebo.
If a subject has a suspected PMR flare at any time during the study, the flare should be confirmed 
according to the protocol-defined flare definition as soon as possible, prior to initiating glucocorticoid 
rescue treatment.  Flare may be confirmed at either a scheduled visit or unscheduled visit.  PMR must 
be confirmed as the cause of flare by eliminating other causes of the subject's symptoms/signs such as 
infection or other underlying disease.  Once flare is confirmed at the visit, glucocorticoid rescue can be 
administered with the dose and subsequent tapering at the discretion of the investigator, taking into 
consideration local standard of care, the subject's preflare and/or baseline dose, and not exceeding 
15 mg/day.
Addition of immunomodulators other than glucocorticoid rescue, as outlined above, are not permitted 
for rescue.  If the investigator determines it is in the best interest of the subject to start an 
immunomodulator, the subject must discontinue study drug (ABBV-154/placebo and Sponsor-supplied 
prednisone/prednisolone; glucocorticoid will then be prescribed by the investigator as necessary, with 
dosing based on the investigator's judgement and in accordance with local standard of care).
The Primary Analysis will be performed after all subjects have either completed the Week 24 visit or 
withdrawn from the study.  Interim analyses may be performed to reassess the treatment regimens in 
this study and to inform development of future studies.
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A final analysis will be conducted after all subjects have either withdrawn from the study or completed 
Week 52 and the safety Follow-up Visit.  To maintain integrity of the trial, the study sites and subjects 
will remain blinded until the final analysis is completed.  Selected AbbVie personnel may be unblinded to 
treatment assignment to conduct interim analyses or after an interim analysis to support regulatory 
interaction; details will be included in the interim unblinding plan (IUP).
Subjects in select countries and sites where the digital health technology device is deployed and 
available may also participate in a Wearable Device Substudy.  Subjects participating in this substudy will 
wear a watch-like digital device on the wrist that will collect data reflecting the subject's UL-ROM and 
daily activity and sleep parameters (see Section 3.9 of the Operations Manual [Appendix H]).  Enrollment 
will be capped at 96 subjects.
There will be optional serial photography for subjects who consent and at sites where photography is 
available.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual (Appendix H).  See Section 5.1 for information regarding eligibility criteria.
Figure 1.
Study Schematic
EOW = every other week; PMR = polymyalgia rheumatica; SC = subcutaneous
4.2 Discussion of Study Design
Choice of Control Group
Placebo plus glucocorticoid taper (with taper duration dependent on baseline dose of glucocorticoid) 
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.  The control group in this study will follow the same glucocorticoid 
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taper as the ABBV-154 treatment groups.  Subjects are allowed to use glucocorticoid rescue if a PMR 
flare is confirmed, which is consistent with standard of care for PMR relapse.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  The key efficacy 
measures in this study are standard for assessing disease activity in subjects with PMR.  Additional 
exploratory efficacy measures were added in response to an unmet need for outcome assessments 
relevant to the PMR population based on literature review and consultation with PMR experts.  Safety 
related measures, including clinical and laboratory procedures, in this study are standard and generally 
accepted for this study population.
Suitability of Subject Population
This study will enroll adult female and male subjects who are at least 50 years of age and have been 
diagnosed with PMR.15  The study population is considered glucocorticoid-dependent.  ABBV-154 has 
the potential to improve disease activity in PMR subjects while avoiding glucocorticoid-associated 
toxicity often seen with systemic glucocorticoids.  While this is the first study to test ABBV-154 in PMR, 
safety results of ABBV-154 did not identify any unexpected risk or trend in the healthy volunteer 
population.
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 subjects on background methotrexate, in which ABBV-3373 demonstrated 
superiority over adalimumab based on comparison to a prespecified historical adalimumab mean.
The 3 SC dosing regimens (40 mg EOW, 150 mg EOW, and 340 mg EOW) selected for evaluation in this 
study 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.  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 payload 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 of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.  Additional 
information on screening (including re-screening) can be found in the Operations Manual (Appendix H).
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Consent
1. Subjects 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.
Demographics and Laboratory Assessments
2. Adult male or female, at least 50 years of age at the time of screening.
3. Body mass index (BMI) is ≥ 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.
4. Laboratory values must meet the following criteria within the Screening Period prior to the 
first dose of study drug:  

Serum aspartate aminotransferase (AST) ≤2.5 × ULN;

Serum alanine transaminase (ALT) ≤2.5 × ULN;

Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in 
Renal Disease (MDRD) formula ≥30 mL/min/1.73 m2; 

Absolute neutrophil count (ANC) ≥1,500/µL;

Absolute lymphocyte count ≥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 (TSH) < 10 mIU/L.
5. Subject must have a negative test result for anti-citrullinated protein (anti-CCP) at Screening.
Disease Activity
6. Clinical diagnosis of PMR and fulfillment of the 2012 EULAR/ACR provisional classification 
criteria for PMR (see Appendix D).15 If utilizing the optional ultrasound criteria, ultrasound must 
have been assessed by a qualified physician experienced in musculoskeletal ultrasound.
7. Following a confirmed diagnosis of PMR, subject must have shown a clinical response to 
prednisone (or equivalent).
8. Subject must have had at least 2 episodes of unequivocal PMR flare while attempting to taper 
prednisone, with the dose of prednisone (or equivalent) at the time of flare ≥ 5 mg/day, prior to 
Baseline; the most recent flare must have been within 24 weeks of Baseline.  Unequivocal PMR 
flare is defined as clinical signs and symptoms of PMR (shoulder and/or hip girdle pain with 
inflammatory stiffness, neck pain with inflammatory stiffness, or new or worsened limited range 
of motion of hips and/or shoulders) that resulted in an increase in glucocorticoid dose.
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9. Subject must not exhibit clinical signs and symptoms of PMR (shoulder and/or hip girdle pain 
with inflammatory stiffness, neck pain with inflammatory stiffness, or new or worsened limited 
range of motion of hips and/or shoulders) within 2 weeks of Baseline. 
Subject History
10. Subject is judged to be in good health as determined by the Principal Investigator, based 
upon the results of medical history, laboratory profile, physical examination, chest x-ray (CXR), 
and a 12-lead ECG performed during Screening.
11. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class.  No history of anaphylactic reaction 
to any agent (e.g., food products and bee sting); or a reaction to any immunoglobulin G (IgG) 
containing product.
12. Subject must have no current or past history of infection including:

Active tuberculosis (TB) or meets TB exclusionary parameters (specific requirements for TB 
testing are provided in the Operations Manual);

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;

Active infection(s) requiring treatment with intravenous anti-infectives within 30 days, or 
oral/intramuscular anti-infectives within 14 days prior to the first dose of study drug;

Chronic recurring infection and/or active viral infection that, based on the investigator's 
clinical assessment, makes the subject an unsuitable candidate for the study;

Confirmed COVID-19:  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 in symptoms; 

Suspected COVID-19:  subjects with signs/symptoms suggestive of COVID-19, known 
exposure, or high-risk behavior should undergo molecular (e.g., polymerase chain reaction 
[PCR]) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a 
potential exposure;
13. Subjects must not have evidence of:

Hepatitis B virus (HBV):  hepatitis B surface antigen (HBs Ag) positive (+) test or detectable 
HBV deoxyribonucleic acid (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):  detectable HCV ribonucleic acid (RNA) in any subject with anti-HCV 
antibody (HCV Ab).
14. Subjects must not have any of the following medical diseases or disorders:
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
Suspected or confirmed adrenal insufficiency;

Hypothyroidism for which the subject is not receiving physiologic replacement therapy;

History of 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 mmHg at rest despite treatment;

History of an organ transplant that requires continued immunosuppression;

Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary 
stenting, and/or aorto-coronary bypass surgery;

History of GCA (based on clinical, ultrasound, and/or temporal artery biopsy diagnosis) or 
active symptoms (e.g., headache, temporal artery or scalp tenderness, jaw claudication, 
visual signs or symptoms, new or worsened extremity claudication) suggestive of GCA, per 
the investigator's judgement;

History of systemic lupus erythematosus, systemic sclerosis, inflammatory myopathies; 

Active fibromyalgia;

History of inflammatory arthritis (including but not limited to rheumatoid arthritis, psoriatic
arthritis, etc.).  A history of gout is permitted if subject has been both on stable (non-
glucocorticoid) suppressive therapy and without flares for at least two years prior to 
Baseline and is expected to remain on this therapy through the end of study drug 
administration;

History of glaucoma, osteonecrosis or osteoporosis with high risk of fracture (e.g., T-score 
≤–2.5 with history of fragility fracture); 

History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of 
demyelinating disease;

Active or suspected malignancy or history of any malignancy within the last 5 years, except 
for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of 
the cervix.  Regardless of the time since remission, subjects with any history of lymphoma, 
leukemia, melanoma, or Merkel cell carcinoma;

History of any medical condition other than PMR that is likely to require systemic 
glucocorticoid treatment during the study (e.g., asthma and chronic obstructive pulmonary 
disease [COPD] per investigator judgement).  Inhaled glucocorticoids are allowed for stable 
medical conditions but must be at stable dose ≥ 4 weeks prior to Baseline.
15. Subject must not have a history of clinically significant (per investigator's judgment) drug or 
alcohol abuse within the 12 months prior to Baseline.
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16. 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.  France only:  Subjects must be registered with a social security 
scheme.  Subjects may not fall within the scope of Article L1121-6 of the French Public Health 
Code (persons deprived of their freedom further to a judicial or administrative decision, persons 
receiving psychiatric care and persons admitted to a health and social facility for reasons 
unrelated to the study) or Article L1121-8 (adults under a legal protection order or unable to 
express their consent).
17. Wearable Device Substudy only:  Subjects must not have a history of pre-existing sleep 
disorders, including insomnia, obstructive sleep apnea, restless leg syndrome or currently on 
prescription sleep medications to participate in the sleep assessment portion of the study.  
Subjects with these histories may participate in the study as a whole if all other eligibility criteria 
are met.
Contraception
18. For all 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 serum pregnancy testing at Baseline).  Subjects 
with a borderline serum pregnancy test at Screening must have absence of clinical suspicion of 
pregnancy or other pathological causes of borderline results and a serum pregnancy test 
≥3 days later to document continued lack of a positive result (unless prohibited by local 
requirements).
19. 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 70 days after the last 
dose of study drug (local practices may require 2 methods of birth control) (refer to Section 5.2
for more detail on contraception).  Female subjects of non-childbearing potential do not need to 
use birth control.  For France and 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.
20. Females must not be pregnant, breastfeeding, or considering becoming pregnant and may 
not donate eggs during the study or for approximately 70 days (150 days for France and UK only) 
after the last dose of study drug.
21. If male, and subject is sexually active with a 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.
22. 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.
Concomitant Medications
23. Subject must be on a stable prednisone (or equivalent) dose of 5 to 15 mg/day for ≥ 2 weeks 
prior to Baseline.  Subjects may be on up to 25 mg/day at the Screening Visit provided that the 
subject is able to taper to 15 mg/day or less, with a stable dose ≥2 weeks prior to Baseline.
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24. Subject must be willing to follow the protocol-defined glucocorticoid tapering regimen.
25. Subject must not have been treated with a prior TNF antagonist (adalimumab, etanercept, 
infliximab, certolizumab, golimumab).
26. Subject must not have prior exposure to ABBV-154.
27. Subject must have discontinued use of immunomodulators other than prednisone (or 
equivalent) and hydroxychloroquine prior to Baseline.  Subject who is on current treatment 
with concomitant hydroxychloroquine must be on continuous treatment for ≥12 weeks and at 
stable dose (≤ 400 mg/day) for ≥ 4 weeks prior to Baseline and expected to remain on stable 
dose through the end of study drug administration.  Prior to Baseline, subjects who need to 
discontinue immunomodulators to comply with this criterion are required to adhere to the 
washout periods specified below or at least 5 times the mean terminal elimination half-life of a 
drug.  No minimum washout prior to Baseline is required for a biologic therapy if an 
undetectable drug level measured by a commercially available assay is documented.

≥ 1 week for anakinra;

≥ 4 weeks for methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine, tacrolimus, 
bucillamine, iguratimod, azathioprine, mycophenolate, tocilizumab, sarilumab, and JAK 
inhibitors (upadacitinib, tofacitinib, baricitinib, filgotinib, ruxolitinib, peficitinib);

≥ 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 or as per local 
label);

≥ 8 weeks for abatacept;

≥ 6 months for cyclophosphamide and other alkylating agents;

≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pretreatment level or 
normal reference range (local lab) if pretreatment levels are not available.
28. Subject must not have been treated with any intra-articular, intramuscular, intravenous, 
trigger point or tender point, intra-bursa, tendon sheath, or epidural glucocorticoids in the 
preceding 8 weeks prior to Baseline.  Subjects must not have been treated with oral 
glucocorticoids for non-PMR reasons within 8 weeks prior to Baseline.
29. Subject must not have been treated with super-high potency and/or high potency topical 
glucocorticoids (see Appendix E) in the preceding 1 week prior to Baseline.
30. 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 Baseline or is currently enrolled in another 
interventional clinical study or was previously enrolled in this study.
31. Subject must not have received any live vaccine within 4 weeks (or longer if required locally) 
prior to Baseline, or expected need of live vaccination during study participation including at 
least 70 days after the last dose of study drug.
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32. Subject must have discontinued all opioid and analgesic medications with the exception of 
nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, tramadol, combination of 
acetaminophen with codeine, or combination of acetaminophen with hydrocodone ≥1 week 
prior to Baseline.  Subjects entering on analgesics must be on stable dose ≥1 week prior to 
Baseline.
33. Subjects must not have been treated with oral traditional Chinese medicine within 4 weeks 
prior to Baseline.
5.2 Contraception Recommendations
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
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

Nonsurgical 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 (FSH) 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 France and 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 Study Day 1 (Baseline Visit).

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to Study Day 1 (Baseline Visit).
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
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence, defined as:  Refraining from heterosexual intercourse when 
this is in line with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable).
If required per local practices, male or female condom with or without spermicide OR cap, diaphragm or 
sponge with spermicide should be used in addition to one of the birth control methods listed 
above(excluding true abstinence).
Contraception Requirements for Males
Male subjects who are sexually active with a female partner of childbearing potential, must agree to use 
male condoms, even if the male subject has undergone a successful vasectomy, from Study 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
Subjects must be able to safely discontinue any prohibited medications as specified in Section 5.1 and 
Section 5.4.  Subjects must be consented for the study prior to discontinuing any prohibited medications 
for the purpose of meeting study eligibility.
Intra-articular, intra-bursal, tendon sheath, trigger point or tender point, or epidural administration of 
glucocorticoids are not permitted prior to Week 24.
The following medications are prohibited through the end of study drug administration:
1.
Systemic glucocorticoids (including but not limited to oral, intravenous, intramuscular), except 
as permitted as outlined in Section 5.1, Section 5.4, and Section 5.8.
2.
Super-high potency and high potency topical glucocorticoids (see Appendix E).
3.
Corticotropin gel injection (i.e., Acthar®)
4.
Biologic Therapies:  Subjects must have discontinued biologic therapies prior to the first dose of 
study drug as specified in the washout procedures (Eligibility Criterion 27 in Section 5.1).  For all 
other biologic therapies, the required washout period is at least five times the mean terminal 
elimination half-life of the medication prior to Baseline.  No minimum washout prior to Baseline 
is required for a biologic therapy if an undetectable drug level measured by a commercially 
available assay is documented.  Therapies including but not limited to the following biologic 
therapies are prohibited medications through the end of study drug administration:
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
Abatacept

Adalimumab

Anakinra

Belimumab

Certolizumab

Dupilumab

Etanercept

Golimumab

Infliximab

Ixekizumab

Natalizumab

Rituximab

Risankizumab

Sarilumab

Secukinumab

Tocilizumab

Ustekinumab

Vedolizumab
5.
Conventional and targeted synthetic disease-modifying antirheumatic drugs (DMARDs):  
Subjects must have discontinued conventional and targeted synthetic DMARD therapies prior to 
Baseline as specified in the washout procedures (see Eligibility Criteria in Section 5.1), except for 
hydroxychloroquine.  For all other conventional or targeted synthetic DMARDs, the required 
washout period is at least five times the mean terminal elimination half-life of the medication 
prior to Baseline.
6.
Investigational drugs.
7.
Live vaccination (see Section 5.4 for examples of live vaccines).
8.
Any opiate analgesics with the exception of tramadol, combination of acetaminophen with 
codeine, or combination of acetaminophen with hydrocodone.
9.
Traditional oral 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 
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through the 70-day Post-treatment Follow-up Visit.  Also, medications taken for PMR since the date of 
diagnosis and any glucocorticoids (based on subject's recollection and available medical records) should 
be entered into the appropriate eCRF inclusive of the dates of first and last dose, dosage, route of 
administration and reason for discontinuation, if known.
Information regarding potential drug interactions with ABBV-154 can be located in the ABBV-154 
Investigator's Brochure.14
Subjects should receive oral calcium and 25-hydroxy vitamin D and/or other therapy for prevention of 
glucocorticoid-induced osteoporosis in accordance with local standard-of-care practice, unless 
contraindicated, at the discretion of the investigator.  Study participants with documented osteoporosis 
should be treated with approved drugs for osteoporosis according to local standard-of-care practice or 
clinical guidelines (e.g., National Osteoporosis Foundation or Japanese Society for Bone and Mineral 
Research).
See Section 5.8 for concomitant glucocorticoid treatment and rescue treatment for PMR flare.
Vaccines
If the subject and investigator choose to receive/administer live vaccines, these vaccinations must be 
completed (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;

Oral polio vaccine;

Smallpox;

Yellow fever;

Bacille Calmette-Guérin (BCG);

Typhoid (oral).
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.
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SARS CoV-2 Vaccination
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., messenger RNA [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 blinded study drug (ABBV-154/placebo), 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 in patients with PMR 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 (Appendix H) for instructions on reporting any AEs associated with the COVID-19 
vaccine.
Inhaled, Intraarticular, and Systemic Glucocorticoids
Inhaled glucocorticoids are allowed for stable medical conditions but must be at stable dose ≥ 4 weeks 
prior to the Baseline Visit and should remain stable throughout the study.  Short-term use (≤14 days) of 
an inhaled glucocorticoid at an increased dose/frequency such as for treatment of an AE is allowed after 
Week 24 and should not exceed 2 episodes of short-term use through Week 52.
Short-term use (≤ 7 days) of systemic glucocorticoids (including oral, intravenous, intramuscular, intra-
articular, intrabursal, tendon sheath, trigger point/tender point, or epidural administration) for non-
PMR reasons such as treatment of an AE is allowed only after Week 24, provided the total cumulative 
dose from Week 24 through Week 52 does not exceed 100 mg prednisone equivalent.
Systemic glucocorticoid use for the treatment of PMR, including rescue therapy, is discussed in 
Section 5.8.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Analgesics
NSAIDs and analgesics including 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.  After Week 24, NSAID and analgesic dosing may be changed.  Medication taken on an as-
needed basis should not be taken within 24 hours prior to any study visit to avoid bias in outcome 
measurements.
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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 Area Medical 
Director (TA MD) 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 TA MD. 

Serious infections (e.g., sepsis) that cannot be adequately controlled within 2 weeks by anti-
infective treatment or would put the subject at risk with continuation of study drug.

Subject is noncompliant 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.

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 TA MD.

Subject is prematurely unblinded to study drug assignment by the investigator or AbbVie TA 
MD.

Subject requires the addition of prohibited immunomodulatory medication for treatment of 
PMR.
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
Diagnosis of GCA.
When the blinded study drug (ABBV-154/placebo) is discontinued, the Sponsor-supplied 
prednisone/prednisolone must also be discontinued.  Prednisone/prednisolone may then be prescribed 
by the investigator, with dosing based on the investigator's judgement and in accordance with local 
standard of care.  Medications prescribed by the investigator should be documented on the 
concomitant medication eCRF.
Additional requirements related to abnormal laboratory values and selected specific AEs (safety topics 
of interest) are located in Section 6.2.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it may be 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 H.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than "planned per protocol," to ensure all acceptable mitigation steps have 
been explored.  Refer to the Operations Manual in Appendix H for details on how to handle study 
activities/procedures.
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 
(except for visits that are intended only for study drug administration [Weeks 6, 10, 14, 18, 22, 26, 30, 
34, 38, 42, 46, and 50]), unless the subject has decided to discontinue the study participation entirely 
(withdrawal of informed consent).  At the visits after study drug discontinuation, subjects should adhere 
to all study procedures except for dispensing of study drug and accountability, dosing diaries, and PK 
(conjugated ADC, total antibody, free A-1677770 assays) and immunogenicity (ADA assays) sample 
collection.  Subjects should be advised on the continued scientific importance of their data even if they 
discontinue treatment with study drug early.  Following discontinuation of study drug, the subject 
should be treated in accordance with the investigator's best clinical judgment irrespective of whether 
the subject decides to continue participation in the study.
If a subject prematurely discontinues study drug, 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.
In addition, a 30-day Follow-up Phone Call and 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 
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Phone Call is not applicable for subjects who discontinued study drug prematurely and continued study 
participation with completion of at least 1 study visit that was at least 30 days after the last dose of 
study drug.  This visit is not applicable for subjects who discontinued study drug prematurely and 
continued study participation with completion of at least 1 study visit that was 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.
In the event a subject withdraws consent from the clinical study, optional biomarker research will 
continue unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed the 
subject has withdrawn and no longer wishes biomarker samples research to continue, samples will not 
be analyzed and no new biomarker analysis data will be collected for the withdrawn subject or added to 
the existing data or database(s).  A subject may withdraw consent for optional biomarker research at 
any time and remain in the clinical study.  Data generated from clinical study and/or optional biomarker 
research, before subject withdrawal of consent, will remain part of the study results.
5.7 Disease Activity and Flare Assessment
Assessment of PMR Signs and Symptoms
Subjects will be evaluated for PMR flare by the assessment of PMR signs and symptoms at study visits 
according to the schedule of assessments and the results entered into the eCRF.  PMR signs and 
symptoms include the presence of any of the following:

Shoulder and/or hip girdle pain with inflammatory stiffness

Neck pain with inflammatory stiffness

New or worsened limited range of motion of hips and/or shoulders 
PMR must be confirmed as the cause of the clinical signs and symptoms in each subject by eliminating 
other causes such as infections, pre-existing medical conditions, and physical activity.  Signs and 
symptoms due to causes other than PMR should not be entered into the eCRF or considered as PMR 
flare.
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Once clinical signs and symptoms of PMR are confirmed for a subject, the investigator should assess if 
an increase in glucocorticoid dose is required.  If an increase in glucocorticoid dose is required, flare is 
confirmed and the subject should be offered glucocorticoid rescue as described in Section 5.8.
If a subject has a suspected flare at any time during the study, the flare should be confirmed as soon as 
possible (at a scheduled or unscheduled visit), prior to initiating glucocorticoid rescue treatment.  
Assessments at a visit where PMR flare is suspected must include assessment of PMR signs and 
symptoms, hsCRP, ESR, Patient Assessment of Pain Severity NRS, Physician Global Assessment of Disease 
Activity NRS, MST, EUL, UL-ROM and goniometer measurement for subjects in the Wearable Device 
Substudy, AE assessment, and concomitant therapy.  Additional assessments may be added per the 
investigator's medical judgement.
Other Disease Activity Assessments
Disease activity will also be assessed through collection of the ESR, PMR-AS components (i.e., hsCRP, 
Patient Assessment of Pain Severity NRS, Physician Global Assessment of Disease Activity NRS, MST, and 
EUL), and UL-ROM and goniometer measurement for subjects in the Wearable Device Substudy at study 
visits as noted in the Activity Schedule (Appendix F) and at any visit where PMR flare is suspected.  
Further details can be found in the Operations Manual (Appendix H).
5.8 Study Drug
ABBV-154 and Matching Placebo
ABBV-154 and matching placebo will be manufactured and provided by AbbVie (Table 1).  Each dose will 
be administered by a healthcare professional as 3 SC injections (2 prefilled syringes [PFS] with 1.5 mL fill 
volume and 1 PFS with 0.4 mL fill volume) in the abdomen or thigh.  Blinded study drug will be 
administered EOW at approximately the same time of day, preferably between 7 and 11 a.m., beginning 
on Day 1 (Baseline Visit).  The study drug can be taken with or without food.  A 15- to 30-minute 
observation period is required after each dose.  The last dose of ABBV-154/placebo will be given at 
Week 50.
ABBV-154 and matching 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°C) 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 study drug for the subject.  Study drug is for 
investigational use only and will only be used for the conduct of this study.
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Table 1.
Investigational Product
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
ABBV-154
Solution for Injection/infusion in 
PFS
40 mg
150 mg
subcutaneous
AbbVie
Placebo for 
ABBV-154
Solution for Injection/infusion in 
PFS
Not applicable
subcutaneous
AbbVie
PFS = prefilled syringe
Glucocorticoids
Starting at the Baseline Visit, all subjects will switch from oral glucocorticoids obtained from 
independent sources to open-label oral prednisone/prednisolone provided by the sponsor at the same 
dose they were taking just prior to the Baseline Visit, rounded up to the nearest 1 mg to a maximum of 
15 mg.  At the Baseline Visit (Day 1), the subject may take non-sponsor provided oral glucocorticoid at 
the required dose prior to randomization so that the subject does not have to delay the usual time of 
glucocorticoid dosing.  If a subject has already taken the glucocorticoid dose at home on the day of the 
Baseline Visit, dosing should not be repeated with sponsor-provided prednisone/prednisolone.  Open-
label prednisone/prednisolone will be self-administered orally (PO) once per day (QD) (Table 2).  The 
baseline dosage will be administered QD until the Week 3 visit, at which time tapering will begin as 
described in Section 6.1 of the Operations Manual (Appendix H).  Glucocorticoids should be stored as 
specified on the label (may differ by manufacturer and local requirements) in a secure location.
Table 2.
Non-Investigational Product
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Prednisone/
Prednisolone
Tablets
1 mg, 5 mg, and 10 mg
Oral
Generica
a.
Prednisone/prednisolone may be supplied by AbbVie per local requirements.
If a subject or home health nurse (if utilizing home care visits) is unable to come to the study site to pick 
up their study drug due to COVID-19 or other reasons, a direct-to-patient study drug shipment can be 
made from the study site to the subject if allowed by local regulations.  AbbVie will submit any required 
notifications to the regulatory authority as applicable.
Subjects will be instructed to return all drug containers (even if empty) to the study site personnel at 
each study visit; study site personnel will document compliance.
Glucocorticoid Tapering Schedule
Starting at Week 3, prednisone/prednisolone will be tapered to 0 mg prednisone/prednisolone per day 
according to the schedule in Section 6.1 of the Operations Manual (Appendix H), based on the 
glucocorticoid dosage at Baseline.  The glucocorticoid taper will be completed by Week 24 for all 
subjects.
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Rescue Treatment for PMR Flare
If a subject has a suspected PMR flare at any time during the study, the flare should be confirmed as 
soon as possible, prior to initiating glucocorticoid rescue treatment.  Flare may be confirmed at either a 
scheduled visit or unscheduled visit.  Assessments performed at a visit for suspected flare are listed in 
Section 5.7 and in the Operations Manual (Appendix H).  Additional assessments may be added per the 
investigator's medical judgement.  PMR must be confirmed as the cause of flare by eliminating other 
causes of the subject's symptoms/signs such as infection or other underlying disease.  Once flare is 
confirmed, glucocorticoid rescue should be administered with the dose and subsequent tapering at the 
discretion of the investigator, taking into consideration local standard of care, the subject's preflare 
and/or baseline dose, and not exceeding 15 mg/day.  The investigator must record his/her 
recommendation to increase the prednisone/prednisolone dose due to PMR flare in the eCRF, 
regardless of whether or not the subject agrees to increase his/her dose.  The specific dose of 
glucocorticoid rescue therapy taken by the subject should be documented in the eCRF.
While receiving open-label rescue treatment with prednisone/prednisolone, the subject should continue 
in the study and receive blinded study drug (ABBV-154/placebo) unless the subject meets the study drug 
discontinuation criteria (see Section 5.5).
If a subject remains on prednisone/prednisolone up to the Week 52 visit, the subject will take the last 
dose of Sponsor-supplied prednisone/prednisolone on the day prior to the Week 52 or on the day of the 
Week 52 visit and may restart individually-sourced prednisone equivalent on or after the day of the 
Week 52 visit, under the medical guidance of the investigator.
Addition of immunomodulators other than glucocorticoid rescue, as outlined above, are not permitted 
for rescue.  If the investigator determines it is in the best interest of the subject to start an 
immunomodulator, the subject must discontinue study drug treatment (ABBV-154/placebo and 
sponsor-supplied prednisone/prednisolone).  Any subsequent medications prescribed by the 
investigator should be documented on the concomitant medication eCRF.
5.9 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.  Subjects will be randomized to either placebo or 
ABBV-154 administered SC as 40 mg EOW, 150 mg EOW, or 340 mg EOW in a 1:1:1:1 ratio.
Randomization will be stratified by the following:

Glucocorticoid use at Baseline:  ≥10 mg/day; < 10 mg/day prednisone equivalent

Length of prior glucocorticoid treatment for PMR:  ≤ 1 year; > 1 year

Enrollment in optional PK sampling:  yes; no
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
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subject will remain blinded to each subject's treatment throughout the study.  Selected AbbVie 
personnel may be unblinded to treatment assignment after an interim analysis to support regulatory 
interactions; details will be included in the IUP.  To maintain the blind, the ABBV-154 and placebo 
prefilled 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.
In the event of a medical emergency that requires unblinding of the study drug assignment, the 
investigator is requested to contact the AbbVie TA MD prior to breaking the blind.  However, if an 
urgent therapeutic intervention is necessary which warrants breaking the blind prior to contacting the 
AbbVie TA MD, the investigator can directly access the IRT system to break the blind without AbbVie 
notification or agreement.  Unblinding is available in the IRT system via the Subject Unblinding by Site 
transaction, which is available only to the investigator.  If the IRT system is unavailable, unblinding may 
occur by contacting the technical support of the IRT vendor via either phone (preferred) or email 
(global.helpdesk@cenduit.com).  For country-specific phone numbers, please see the following website:  
http://www.cenduit.com.
In the event the blind is broken before notification to the AbbVie TA MD, the AbbVie TA MD should be 
notified within 24 hours of the blind being broken.  The date and reason that the blind was broken must 
be conveyed to AbbVie and recorded on appropriate eCRF.
5.10 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 the IEC/IRB, regulatory authorities (as applicable), and 
AbbVie.
5.11 Data Monitoring and Adjudication Committees
Data Monitoring Committee
An external data monitoring committee (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 further describe the roles and 
responsibilities of the DMC members, frequency and scope of the data reviews, and expectations for 
blinded communications.
Adjudication Committee
An independent Adjudication Committee will be established to adjudicate potentially glucocorticoid-
related 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.
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6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product 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.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, meet protocol-specific criteria (see 
Section 6.2 regarding toxicity management), and/or if the investigator considers them to be AEs.
Since the primary endpoint for this study is time to PMR flare, these endpoint events (shoulder and/or 
hip girdle pain with inflammatory stiffness, neck pain with inflammatory stiffness, or new or worsened 
limited range of motion of hips and/or shoulders that are not due to other causes) will not be collected 
as AEs unless they fulfill criteria for an SAE or result in a fatal outcome.  Expected manifestations of PMR 
that constitute worsening of the underlying condition are not to be recorded as AEs.
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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 treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug 
abuse.
All AEs reported from the time of study drug administration until 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 AEs 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):
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 IMP in accordance with global and local 
requirements.
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AEs 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 AEs (NCI CTCAE Version 5.0.16), which can be accessed at:
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referenc
e_5x7.pdf
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug ABBV-154 (or matching placebo) and prednisone/prednisolone:
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 after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.5).  If a pregnancy occurs in a study subject or in the partner of a study subject, 
information regarding the pregnancy and the outcome will be collected.
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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
Where "study drug" is used in this toxicity management section, study drug refers to blinded 
ABBV-154/placebo.
The management of specific AEs (safety topics of interest) and laboratory parameters are presented 
below.
For subjects who discontinue study drug but continue study participation and are on standard of care 
therapies, these toxicity management requirements do not apply (including alerts from the central 
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.  If a subject is taking 
prednisone/prednisolone, it should not be stopped for the surgery.
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 postdose hypersensitivity reaction, if the clinical situation allows, 
every effort should be made to obtain a serum sample within 2 hours but no later than 6 hours from 
symptom onset for additional blood tests specified in the Operations Manual, Section 3.19, 
Hypersensitivity Testing (Appendix H).
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 
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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 hyperglycemia with appropriate standard of care.
Management of GCA
Subjects should be closely monitored for the development of symptoms of GCA (e.g., headache, 
temporal artery or scalp tenderness, jaw claudication, visual signs or symptoms, new or worsened 
extremity claudication).  If a subject is diagnosed with GCA during the course of the study, the subject 
must be discontinued from ABBV-154/placebo and Sponsor-supplied prednisone/prednisolone, and the 
investigator must ensure the subject is promptly treated and followed appropriately for GCA per local 
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 assessment and management should follow local standard of 
care, which may include measuring cortisol levels and/or ACTH stimulation testing 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.
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.
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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 apply to blinded study 
drug (ABBV-154/placebo), and may require a supplemental eCRF to be completed (Section 6.1).  For 
subjects with ongoing laboratory abnormalities which 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 which 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, 
the repeat testing must occur as soon as possible.
Table 3.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory 
Parameter
Toxicity Management Guideline
Absolute neutrophil 
count (ANC)
If confirmed < 1000/µL by repeat testing with new sample, interrupt study drug dosing 
until ANC value returns to normal reference range or its BL value.
Discontinue study drug if confirmed < 500/µL by repeat testing with new sample.
Absolute lymphocyte 
count (ALC) 
If confirmed < 500/µL by repeat testing with new sample, interrupt study drug dosing 
until ALC returns to normal reference range or its BL value.
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.
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Laboratory 
Parameter
Toxicity Management Guideline
AST or ALT
Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample and either a total bilirubin > 2 × ULN or an international normalized ratio (INR) 
> 1.5.
A separate blood sample for INR testing will be needed to measure INR at the time of 
repeat testing for ALT or AST.  A repeat test of INR is not needed for determination if 
above toxicity management criteria are met.

Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with 
new sample along with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5% increase 
from BL).

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 BL 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).
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 restart 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).
Ab = antibody; ALC = absolute lymphocyte counts; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; BL = baseline; CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; eCRF = electronic 
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case report form; HB = hepatitis B; HBs = hepatitis B surface; 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 performed after all subjects have either completed the Week 24 visit or 
withdrawn from the study.
The final analysis will be conducted after all subjects have either withdrawn from the study or 
completed Week 52 and the safety Follow-up Visit.  To maintain integrity of the trial, the study sites and 
subjects will remain blinded until the final analysis is completed.  Selected AbbVie personnel may be 
unblinded to treatment assignment after an interim analysis to support regulatory interactions and 
future development decisions; details will be included in the IUP.
7.2 Definition for Analysis Populations
The following population will be used for the efficacy analysis:

Intent-to-Treat (ITT) Population:  The ITT Population includes all subjects who were randomized 
and received at least 1 dose of study drug.  The ITT Population will be analyzed as randomized 
(i.e., according to the randomized treatment assignment).
The following population will be used for the safety analysis:

Safety Population:  The Safety Population includes all subjects who were randomized and 
received at least 1 dose of study drug.  The Safety Population will be analyzed as treated 
(i.e., according to the actual treatment received).
7.3 Handling Potential Intercurrent Events for the Primary and 
Secondary Endpoints
Primary endpoint:

Subjects will be censored at the time of immunomodulator initiation or violation of protocol-
allowed systemic glucocorticoid use.
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Categorical secondary endpoints:

Subjects will be considered as not achieving the response after the initiation of rescue 
medication, immunomodulator or violation of protocol-allowed systemic glucocorticoid use.
Continuous endpoint:

No intercurrent event will be considered in the analysis of glucocorticoid dose.
7.4 Statistical Analyses for Efficacy
Efficacy analysis will be performed by the subject's randomized treatment group.  All statistical tests will 
be performed at a 2-sided significance level of 0.1.  A 95% confidence interval (CI) of the treatment 
difference between each ABBV-154 dose and placebo will be provided.  The actual value of stratification 
factors will be used in the analysis.  Enrollment in the optional PK sampling is not expected to impact 
any of the efficacy endpoints and will thus not be used as a stratification factor in the analysis.

For time-to-event endpoints, comparison of number of events will be made between each 
ABBV-154 dose and placebo based on log-rank test stratified by stratification factors.  The point 
and CI estimate of median time to event and event-free rate for each group will be reported 
based on Kaplan-Meier curves.  Hazard ratio and its corresponding CI for each ABBV-154 group 
compared with placebo will be estimated using Cox regression analysis adjusting for 
stratification factors.  For all analyses of time-to-event endpoints, subject without an event at 
the time of the analysis will be administratively censored at the time of the last available 
assessment.

For categorical variables, pairwise comparison will be made between each ABBV-154 dose and 
placebo using the Cochran-Mantel-Haenszel (CMH) test, adjusting for stratification factors.  
Nonresponder imputation incorporating multiple imputation (NRI-MI) to handle COVID-19 will 
be the primary approach to handle missing data for categorical endpoints.

For continuous variables other than glucocorticoid dose, the comparison will be made between 
each ABBV-154 dose and placebo based on the mixed effect model repeated measures (MMRM) 
adjusting for visit, interaction between treatment and visit, actual values of stratification factors 
as fixed factors, and baseline value as a covariate.  The MMRM will be the primary approach to 
handle missing values for continuous endpoints.

For analyses of glucocorticoid dose, comparison will be made between each ABBV-154 dose and 
placebo based on the analysis of covariance (ANCOVA) adjusting for stratification factors as 
fixed factors, and baseline glucocorticoid dose as a covariate.
Summary and Analysis of the Primary Endpoints
The primary endpoint is the time to flare.  The time origin is the first dose of study drug and the time of 
first flare will be use for the analysis.  Comparison of the primary endpoint will be made between each 
ABBV-154 dose and placebo using the log-rank test adjusting for stratification factors.  The point and CI 
estimate of median time to flare and flare-free rate for each group will be reported based on Kaplan-
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Meier curves.  Hazard ratio and its corresponding CI for each ABBV-154 group versus placebo will be 
estimated using Cox regression analysis adjusting for stratification factors.
One supplementary analysis for the primary endpoints is to test a prespecified set of dose-response 
models among ABBV-154 dose groups and the placebo group at Week 24 using the Multiple Comparison 
Procedure – Modeling (MCP-Mod) method.
Summary and Analysis of Secondary Endpoints
Analysis of secondary endpoints are described above.
Summary and Analysis of Additional Efficacy Endpoints
Analysis of additional efficacy endpoints are described above.
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 (≥10 mg/day; < 10 mg/day prednisone equivalent)

Length of prior glucocorticoid treatment for PMR (≤ 1 year; > 1 year)

Age (≤median; > median)

Sex (female; male)

Race (white; nonwhite)
In addition, change from Baseline in glucocorticoid dose at Week 24 will be analyzed by the following 
subgroup:

Glucocorticoid status at Week 24 (glucocorticoid free; not glucocorticoid free)
7.5 Statistical Analyses for Safety
All safety analyses will be performed using the Safety Population, as defined in Section 7.2.  Data will be 
analyzed based on the actual treatment subjects received.  TEAEs, laboratory assessments, and vital 
signs will be summarized.  Details will be described in the SAP.
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 Medical Dictionary for Regulatory Activities (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 also be provided.  Pretreatment AEs will be summarized 
separately.
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For selected laboratory parameters, a listing of all subjects with any laboratory value that is Grade ≥3 of 
NCI CTCAE 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 Analyses for Pharmacokinetics and Immunogenicity
Concentrations of conjugated ADC, total antibody, and free payload (A-1677770) will be summarized for 
each time point using descriptive statistics.
Population PK analyses combining the data from this study and other studies may be performed and 
reported outside of the clinical study report.
ADA and nAb incidence and ADA titer values will be summarized for each group using descriptive 
statistics.
7.7 Statistical Analyses for Biomarker Data
 
7.8 Interim Analysis
Interim analyses may be performed to reassess the treatment regimens in this study and to inform 
development of future studies.
7.9 Overall Type I Error Control
Overall Type I error control is not planned in this Phase 2 study.
7.10 Sample Size Determination
A total of 37 flares in the highest dose of ABBV-154 group and placebo group would provide more than 
90% power to detect a hazard ratio of 0.296 at 2-sided significance level of 0.1.  The hazard ratio of 
0.296 is determined under the assumption that flares would occur during the tapering and within 
12 weeks after the end of tapering (up to Week 36), and 70% and 30% of subjects will remain flare-free 
by Week 36 in the highest dose of ABBV-154 group and placebo group, respectively.
Based on an Emax model with ED50 of 150 mg, a total of 74 flares are expected for the Primary Analysis.  A 
sample size of 40 subjects in each of the ABBV-154 and placebo arms is planned to ensure appropriate 
accrual of flares.  A sample size re-estimation may be considered at an interim analysis prior to 
unblinding of the study team.  The sample size increase will be capped at approximately 100 subjects.
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8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki. Responsibilities of 
the investigator are specified in Appendix B.
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 
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currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
In case of a state of emergency or pandemic situations, (e.g., COVID-19 pandemic), remote monitoring 
of data may be employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit or the actual date of follow-up 
contact, whichever is later
12
REFERENCES
1.
Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset rheumatoid 
arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 
2011;63(3):633-9.
2.
Mackie SL, Hughes R, Walsh M, et al. "An impediment to living life": why and how should we 
measure stiffness in polymyalgia rheumatica? PLoS One. 2015;10(5):e0126758.
3.
Mackie SL, Twohig H, Neill LM, et al. The OMERACT Core Domain Set for Outcome Measures for 
Clinical Trials in Polymyalgia Rheumatica. J Rheumatol. 2017;44(10):1515-21.
4.
Hazleman B. Laboratory investigations useful in the evaluation of polymyalgia rheumatica (PMR) 
and giant cell arteritis (GCA). Clin Exp Rheumatol. 2000;18(4 Suppl 20):S29-31.
5.
Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet. 
2008;372(9634):234-45.
6.
Dejaco C, Singh YP, Perel P, et al. 2015 Recommendations for the management of polymyalgia 
rheumatica: a European League Against Rheumatism/American College of Rheumatology 
collaborative initiative. Ann Rheum Dis. 2015;74(10):1799-807.
7.
George MD, Baker JF, Winthrop K, et al. Risk for Serious Infection With Low-Dose 
Glucocorticoids in Patients With Rheumatoid Arthritis : A Cohort Study. Ann Intern Med. 
2020;173(11):870-8.
8.
Roubille C, Coffy A, Rincheval N, et al. Ten-year analysis of the risk of severe outcomes related to 
low-dose glucocorticoids in early Rheumatoid Arthritis. Rheumatology (Oxford). 2020.
9.
Pujades-Rodriguez M, Morgan AW, Cubbon RM, et al. Dose-dependent oral glucocorticoid 
cardiovascular risks in people with immune-mediated inflammatory diseases: A population-
based cohort study. PLoS Med. 2020;17(12):e1003432.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
10.
Kreiner F, Galbo H. Elevated muscle interstitial levels of pain-inducing substances in 
symptomatic muscles in patients with polymyalgia rheumatica. Pain. 2011;152(5):1127-32.
11.
Kreiner F, Langberg H, Galbo H. Increased muscle interstitial levels of inflammatory cytokines in 
polymyalgia rheumatica. Arthritis Rheum. 2010;62(12):3768-75.
12.
Kreiner F, Galbo H. Insulin sensitivity and related cytokines, chemokines, and adipokines in 
polymyalgia rheumatica. Scand J Rheumatol. 2010;39(5):402-8.
13.
Cutolo M, Montecucco CM, Cavagna L, et al. Serum cytokines and steroidal hormones in 
polymyalgia rheumatica and elderly-onset rheumatoid arthritis. Ann Rheum Dis. 
2006;65(11):1438-43.
14.
AbbVie. ABBV-154 Investigator Brochure Edition 2. 2020.
15.
Dasgupta B, Cimmino MA, Maradit-Kremers H, et al. 2012 provisional classification criteria for 
polymyalgia rheumatica: a European League Against Rheumatism/American College of 
Rheumatology collaborative initiative. Ann Rheum Dis. 2012;71(4):484-92.
16.
US Department of Health and Human Services NIoH, National Cancer Institute. Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 2017 [cited 10 Feb 2020]. Available 
from: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf.
17.
Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135-40.
18.
National Psoriasis Foundation. Potency chart  [cited 2021 16 Apr 2021]. Available from: 
https://www.psoriasis.org/potency-chart/.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ACR
American College of Rheumatology
ADA
Anti-drug antibody
ADC
Antibody-drug-conjugate
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance 
Anti-CCP
Anti-citrullinated protein 
AST
Aspartate aminotransferase
BAP
Bone-specific alkaline phosphatase
BL
Baseline
BMD
Bone mineral density
BMI
Body mass index
BUN
Blood urea nitrogen
CH50
Total hemolytic complement
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disorder
COVID-19
Coronavirus – 2019
CPK
Creatinine phosphokinase
CRP
C-reactive protein
 
CXR
Chest x-ray
D
Day
DMARD
Disease-modifying antirheumatic drug
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DXA
Dual-energy x-ray absorptiometry
E4W
Every 4 weeks
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ECG
Electrocardiogram
eCRF
Electronic case report form
ED50
Dose that produces half of Emax
EDC
Electronic data capture
Emax
Maximum effect attributable to the drug
EOW
Every other week
ePRO
Electronic patient-reported outcome
ESR
Erythrocyte sedimentation rate
EUL
Elevation of upper limbs
EULAR
European League Against Rheumatism
EQ-5D-5L
EuroQol 5-dimension questionnaire, 5-level
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy – Fatigue
FSH
Follicle-stimulating hormone
GCA
Giant cell arteritis
GCP
Good clinical practice
GFR
Glomerular filtration rate
GRM
Glucocorticoid receptor modulator
HAQ-DI
Health Assessment Questionnaire Disability Index
HAV
Hepatitis A virus
HB
Hepatitis B
HbA1c
Glycated hemoglobin
HBc
Hepatitis B core
HBc Ab
Hepatitis B core antibody
HBc Ab+
Hepatitis B core antibody positive
HBs
Hepatitis B surface
HBs Ab
Hepatitis B surface antibody
HBs Ab+
Hepatitis B surface antibody positive
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCV Ab
HCV antibody
HDL
High density lipoprotein
HIV
Human immunodeficiency virus
HPA
Hypothalamic-pituitary-adrenal
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hsCRP
High-sensitivity C-reactive protein
IA
Interim analysis
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IgG
immunoglobulin G
IgE
immunoglobulin E
IMP
Investigation medicinal product
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-Treat
IUD
Intrauterine device
IUP
Interim unblinding plan
IUS
Intrauterine hormone-releasing system
LCMS
Liquid chromatography-mass spectrometry
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
MACE
Major adverse cardiac event
MCP-Mod
Multiple Comparison Procedure – Modeling
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Effect Model Repeated Measurements
mRNA
Messenger ribonucleic acid
MST
Morning stiffness
nAb
Neutralizing antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NMSC
Nonmelanoma skin cancer
NRI-MI
Nonresponder imputation incorporating multiple imputation
NRS
Numeric rating scale
NSAIDs
Nonsteroidal anti-inflammatory drugs
PBMC
Peripheral blood mononuclear cells
PD
Pharmacodynamic(s)
PFS
Prefilled syringe(s)
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PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
Pharmacokinetic(s)
PMR
Polymyalgia rheumatica
PMR-AS
Polymyalgia Rheumatica Activity Score 
PO
Orally
PPD
Purified protein derivative
PRO
Patient-reported outcome
PROMIS
Patient-Reported Outcomes Measurement Information System
QD
Once daily
RA
Rheumatoid arthritis
RBC
Red blood cell
RF
Rheumatoid factor
RNA
Ribonucleic acid
RSI
Reference Safety Information
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAR
Serious Adverse Reaction(s)
SC
Subcutaneous
SF-8b
Short Form 8b
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
TNF
Tumor necrosis factor
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
UL-ROM
Upper limbs range of motion
US
Ultrasound
VAS
Visual analog scale
W
Week
WBC
White blood cell
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M20-370:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to 
Evaluate the Safety and Efficacy of ABBV-154 in Subjects with Polymyalgia Rheumatica (PMR) 
Dependent on Glucocorticoid Treatment
Protocol Date:  21 February 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 C. 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 & Pharmacometrics
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APPENDIX D. PMR CLASSIFICATION CRITERIA
The 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 
provisional classification criteria for PMR are shown below.15
PMR Classification Criteria Scoring Algorithm – Required Criteria: Age 50 years or older, bilateral shoulder 
aching and abnormal CRP and/or ESRa
Points 
without US 
(0 – 6)
Points 
with USb
(0 – 8)
Morning stiffness duration > 45 minutes
2
2
Hip pain or limited range of motion
1
1
Absence of RF and anti-CCP antibody
2
2
Absence of other joint involvement
1
1
At least one shoulder with subdeltoid bursitis and/or biceps tenosynovitis 
and/or glenohumeral synovitis (either posterior or axillary) and at least 
one hip with synovitis and/or trochanteric bursitis
Not applicable
1
Both shoulders with subdeltoid bursitis, biceps tenosynovitis or 
glenohumeral synovitis
Not applicable
1
Anti-CCP = anti-citrullinated protein; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; PMR = polymyalgia 
rheumatica; RF = rheumatoid factor; US = ultrasound
a.
A score of 4 or more is categorized as PMR in the algorithm without US and a score of 5 or more is categorized as PMR in 
the algorithm with US.
b.
Optional US criteria.
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APPENDIX E. SUPER-HIGH POTENCY AND HIGH POTENCY 
TOPICAL GLUCOCORTICOIDS
Potency
Generic Name(s)
Brand Name(s)
Vehicle Type(s)
Strength (%, 
except as noted)
Super-high
Clobetasol proprionate
Clobex
Lotion
0.05
Temovate
Cream, gel, 
ointment
0.05
Temovate E
Cream, emollient 
base
0.05
Olux-E, Tovet
Foam
0.05
Cormax
Solution
0.05
Betamethasone 
dipropionate, augmented
Diprolene
Gel, lotion, ointment 
(optimized)
0.05
Halobetasol proprionate
Ultravate
Cream, lotion, 
ointment
0.05
Fluocinonide
Vanos
Cream
0.1
Diflucortolone valerate
Nerisone Forte
Ointment, cream
0.3
Flurandrenolide
Cordran
Tape
4 mcg/sq cm
High
Betamethasone 
diproprionate
Diprolene AF
Cream, augmented 
formulation
0.05
Diprosone
Ointment
0.05
Clobetasol proprionate
Impoyz
Cream
0.025
Halobetasol proprionate
Bryhali
Lotion
0.01
Desoximetasone
Topicort
Cream, ointment, 
spray
0.25
Topicort
Gel, cream
0.05
Diflorasone diacetate
ApexiCon, Florone
Ointment, cream
0.05
ApexiCon E
Cream, emollient
0.05
Fluocinonide
Lidex
Cream, gel, 
ointment, solution
0.05
Halcinonide
Halog
Cream, ointment, 
solution
0.1
Amcinonide
Cyclocort, Amcort
Ointment
0.1
Source:
Ference 200917, National Psoriasis Foundation18
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APPENDIX F. ACTIVITY SCHEDULE
The following table shows the required activities for subjects throughout the study.
The individual activities are described in detail in the Operations Manual (Appendix H).  Modifications 
allowed due to COVID-19 are detailed in the Operations Manual.
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c.
Subjects in Wearable Device Substudy to wear digital device for 1 week after each site visit with UL-ROM assessment (Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36).  
Daily activity and sleep parameters will be measured.  Subject performs UL-ROM at home during the 1st hour after getting out of bed each day for specified weeks.  Subject will 
perform UL-ROM and goniometer assessments at site visits indicated.  
d.
If prednisone/prednisolone is required for rescue treatment, it will be dispensed after PMR flare is confirmed (see Section 5.8).  Subjects should record all rescue prednisone 
dosing on the prednisone/prednisolone dosing diary. If a subject remains on prednisone/prednisolone rescue treatment up to Week 52, the last dose of Sponsor-supplied 
prednisone/prednisolone will be taken one day prior to the Week 52 visit and individually-sourced prednisone equivalent may be restarted the day of the Week 52 visit, under 
the medical guidance of the investigator.  If necessary, the subject may take sponsor provided prednisone/prednisolone (from Week 50 dispensation) on the day of the Week 
52 visit so subject does not have to delay the usual time of glucocorticoid dosing.
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APPENDIX G. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
13 May 2021
Version 2.0
13 July 2021
Version 2.1 (UK only)
29 September 2021
Version 2.2 (France only)
19 October 2021
Version 2.3 (Germany only)
23 November 2021
The purpose of this version is to update the following sections below.  In addition, minor typographical 
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 including 
Figure 1, Section 5.9, Randomization/Drug Assignment; Section 7.10, Sample Size 
Determination; Operations Manual, Section 6.3, Method of Assigning Subjects to Treatment 
Groups:  Changed the randomization ratio from 2:1:1:1 to 1:1:1:1 and the total subjects to be 
enrolled from 200 to 160.
Rationale:  To reduce the proportion of placebo subjects to match the number of subjects in 
each ABBV-154 dose group.  Reduction in the number of placebo patients maintains the power 
for the primary endpoint.

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, Investigational Plan; Protocol Section 4.1, Overall Study Design and 
Plan and Operations Manual Section 3.9, Wearable Device Substudy:  Changed the enrollment 
cap for the Wearable Device Substudy from 120 to 96.
Rationale:  To align with the change in the randomization ratio and the reduction of number of 
subjects in the placebo arm.

Protocol Section 1, Synopsis, Key Eligibility Criteria; Protocol Section 4.2, Discussion of Study 
Design and Section 5.1, Eligibility Criteria:  Deleted upper age limit of 80 (criterion #2).
Rationale:  To align the study population with the known epidemiology of PMR.

Protocol Section 1, Synopsis, Investigational Plan; Protocol Section 5.1, Eligibility Criteria:  
Deleted dosage specifications for clinical response to prednisone or equivalent from 
criterion #7.
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Rationale:  To align with 2015 EULAR/ACR treatment recommendations and real-world practice, 
which may include intramuscular injections of glucocorticoid with initial higher doses > 25 mg/d 
prednisone equivalent.

Protocol Section 3.6, Pharmacokinetic and Immunogenicity Endpoints: Changed the number of 
subjects needed for collecting the optional PK samples from approximately 40 to approximately 
32 subjects (approximately 8 subjects in each arm).
Rationale:  To align with the change in the randomization ratio and the reduction of number of 
subjects in the placebo arm.

Protocol Section 4.1, Overall Study Design and Plan and Operations Manual, Section 3.9 
Wearable Device Substudy:  Removed requirement to participate in the Wearable Device 
Substudy as a condition for overall study participation in subjects who otherwise qualify for the 
Substudy.
Rationale:  To allow subjects the option to participate in the main study in the case they do not 
choose to participate in the Wearable Device Substudy.

Protocol Section 4.1, Overall Study Design and Plan and Figure 1, and Section 7.8, Interim 
Analysis:  Modified plan for Interim analyses.
Rationale:  To reduce the number of planned interim analyses to reassess the treatment 
regimens in this study and to inform the development of future studies and allow flexibility in 
interim analysis timing to account for variability in the observed enrollment rate.

Protocol Section 5.1, Eligibility Criteria: Updated history of GCA to specify a diagnosis may be 
based on clinical, ultrasound, and/or temporal artery biopsy.
Rationale: To clarify the definition of history of GCA considered exclusionary for this study, for 
which diagnosis may be established clinically, or by ultrasound and/or temporal artery biopsy 
even if clinical symptoms of GCA were not present.

Protocol Section 5.1, Eligibility Criteria:  Changed criterion #14 to exclude active fibromyalgia.
Rationale:  To allow subjects with inactive fibromyalgia to participate in the study, as inactive 
fibromyalgia is not considered a confounder and will not affect subject safety.

Protocol Section 5.1, Eligibility Criteria:  Moved wording in criterion #14 regarding inflammatory 
arthritis to a new bullet and added wording to allow subjects with stable gout to participate in 
the study.
Rationale:  The bullet was reorganized to address inflammatory arthritis in a separate point 
from other rheumatic diseases excluded.  To allow subjects with stable gout to participate in the 
study, as stable gout controlled on suppressive therapy and without recent flare is not expected 
to interfere with interpretation of PMR flare and will not affect subject safety.

Protocol Section 5.1, Eligibility Criteria: Revised criterion #14 requirements related to current 
and prior malignancy.
Rationale:  To allow subjects with a remote history (> 5 years) of malignancy to participate in 
the clinical trial but continue to exclude potential subjects with a history of specific malignancies 
consistent with the warnings section of the adalimumab Summary of Product Characteristics.
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
Protocol Section 5.1, Eligibility Criteria:  Added wording to criterion #16 for France only 
regarding requirement for subjects to be registered with a social security scheme and that 
subjects may not fall within the scope of Article L1121-6 and Article L1121-8 of the French Public 
Health Code.
Rationale:  To align with French regulations.

Protocol Section 5.1, Eligibility Criteria and 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 19) (France and UK only) and for males 
(criterion 21) (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 20) (France and UK only), and males must not consider fathering a 
child or donating sperm for 150 days after last dose of study drug administration (criterion #22) 
(UK only).
Rationale:  The duration of contraception, pregnancy, and egg/sperm donation requirements 
after last dose of study drug was changed for France and 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 five times the upper limit of the mean elimination half-
life, using the most conservative estimate of the half-life among the three 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, Criterion #27; Section 5.3 Prohibited Medications and 
Therapy:  Added language to permit hydroxychloroquine use at a stable dose.
Rationale:  Allow use of hydroxychloroquine at stable dose as it is not expected to impact study 
efficacy assessments or subject safety.

Protocol Section 5.1, Eligibility Criteria:  For criterion #27, added sulfasalazine to the list of 
immunomodulators requiring washout prior to Baseline.
Rationale:  Washout of 4 weeks was specified for sulfasalazine as it was previously omitted.

Protocol Section 5.1, Eligibility Criteria:  For criterion #30, added the word "interventional" to 
describe clinical study.
Rationale:  To specify that subjects cannot be enrolled in another interventional study.  Non-
interventional studies are permitted, as they are not expected to impact safety or efficacy of this 
study.

Protocol Section 5.1, Eligibility Criteria:  For criterion #31, 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 
five times the upper limit of the mean elimination half-life of subcutaneously administered 
ABBV-154.
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
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:  Deleted sentence stating that 
prohibited medications could be used to treat AEs when no medical alternative is available.
Rationale: To clarify that use of a prohibited medication is considered prohibited at any time as 
specified in Section 5.3.

Protocol Section 5.5, Withdrawal of Subjects and Discontinuation of Study:  Added language to 
clarify that AbbVie may prematurely discontinue the study at any time, including discontinuing 
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 "or rule out 
safe continuation of the study drug" to abnormal laboratory result reason for study 
discontinuation.
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; 
Appendix F, Activity Schedule; Operations Manual Section 2.4, Individual Post-Treatment Period 
Visit Activities:  Added a phone call to the subject to assess AEs/SAEs at 30 days after the last 
dose of study drug.
Rationale:  Phone call was added to further ensure subject safety and capture of AEs/SAEs 
occurring early in the follow up period.

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, clarified when to re-start study drug after surgery, and added 
guidance to continue prednisone/prednisolone in a subject who undergoes surgery.
Rationale:  To ensure subject safety by providing instructions for interruption of study drug 
before and after surgery.  To clarify that prednisone should not be held for surgery to prevent 
adrenal insufficiency in subjects who have been on long-term systemic glucocorticoid therapy.
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
Protocol Section 6.2, Toxicity Management:  Added sentence 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 Section 7.1, Statistical and Analytical Plans:  Added text to describe that interim 
analysis will support future development decisions.
Rationale: To clarify the reason for interim unblinding should it occur.

Protocol Section 7.10, Sample Size Determination:  Changed the sample size from 200 subjects 
total to 40 subjects in each of the ABBV-154 and placebo arms.
Rationale:  To reflect the change in randomization ratio and clarify the sample size calculation 
was based on subjects per arm rather than total number of subjects.

Protocol Section 7.10, Sample Size Determination:  Changed the total number of flares from 64 
to 37 for the highest dose and placebo arms and from 101 to 74 for all treatment arms 
combined.
Rationale:  The expected total number of flares is reduced as the result of changing the 
randomization ratio and sample size.

Protocol Section 7.10, Sample Size Determination:  Revised the timing of the possible sample 
size re-estimation to be at one interim analysis to occur prior to unblinding of the study team.
Rationale:  To align with modifications to remove specific timing and number of planned interim 
analyses and clarify that sample size re-estimation will occur before the study team is unblinded. 

Protocol Appendix A, Study Specific Abbreviations and Terms:  Corrected the terms for hepatitis 
surface antibody abbreviation.
Rationale:  To correct a typographical error.

Protocol Appendix C, List of Protocol Signatories:  Updated list of protocol signatories.
Rationale:  Administrative change.

Protocol Appendix F, Activity Schedule:  Added additional column for the 30-day follow-up
phone call to assess adverse events and prior/concomitant therapy and added "Visit" to 70-day 
follow-up column header.
Rationale:  Added a 30-day follow-up call and clarified that the 70-day follow-up is a visit to 
ensure all treatment-emergent AEs/SAE have been resolved.

Protocol Appendix F, Activity Schedule (including footnote c); Operations Manual, Section 2.1 
Individual Treatment Period Visit Activities (footnotes); Operations Manual, Section 3.9 
Wearable Device Substudy:  Reduced the duration of time during which subjects participating in 
the Wearable Device Substudy wear the device.
Rationale:  To limit data collection for this substudy to the one week after site visits at which UL-
ROM is performed to reduce subject burden and increase subject compliance to substudy 
procedures.
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
Protocol Appendix F, Activity Schedule; Operations Manual Section 2.4, Individual Post-
Treatment Period Visit Activities:  Added body weight and vital signs collection to 70-day follow-
up visit.
Rationale:  To ensure more robust safety data collection at follow up.

Protocol Appendix F, Activity Schedule; Operations Manual Section 2.1 Individual Treatment 
Period Visit Activities and Section 3.19, Clinical Laboratory Tests, Table 1:  Added collection of 
25-hydroxyvitamin D to the Baseline Visit and to Table 1, Clinical Laboratory Tests.
Rationale:  To collect additional data on subjects Baseline status which may affect bone mineral 
density.

Protocol Appendix F, Activity Schedule; Operations Manual Section 2.4, Individual Post-
Treatment Period Visit Activities:  Added PK and immunogenicity sample collection at the 70-day 
Follow-Up Visit.
Rationale:  To ensure drug washout and assess immunogenicity during drug washout.

Operations Manual, Section 1, Contacts: Updated Clinical Lab and Biomarker Sample Storage 
contact information.
Rationale:  Administrative change.

Operations Manual, Section 2.1, Individual Treatment Period Visit Activities:  All individual study 
day headers were updated to include an additional column.
Rationale:  Added for alignment with the 30-day phone call column in the Study Activity Table.

Operations Manual, Section 2.1, Individual Treatment Period Visit Activities:  For screening visit, 
changed reference for Section 3.6 to 3.5, describing chest x-ray.
Rationale:  To correct typographical error.

Operations Manual, Section 2.2 Premature Discontinuation Visit, Footnote b:  Footnote was 
removed.
Rationale:  Footnote was not applicable to the premature discontinuation visit anymore since 
subjects no longer wear the device continuously.

Operations Manual Section 3.2, Rescreening:  Added additional opportunity for rescreening of 
subjects with the AbbVie Therapeutic Area Medical Director/Scientific Director approval.
Rationale:  To allow subjects who have already been screened twice the opportunity to rescreen 
on a case-by-case basis, if appropriate.

Operations Manual Section 3.2, Rescreening:  Added FSH to the list of testing not required to be 
repeated if rescreening a subject within 14 days from the sample collection date of the previous 
screen.
Rationale:  To reduce unnecessary procedures, as FSH would not be expected to change 
significantly in 14 days.

Operations Manual Section 3.6, 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 the spine nor either hip are able to be scanned or 
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interpreted.  Added a Central Imaging Core Lab for central independent review of DXA data and 
modified guidance for image acquisition.
Rationale:  To improve the robustness and interpretability of the DXA data collected.

Operations Manual Section 3.8, Patient-Reported Outcomes, Patient Global Impression of 
Severity (PGIS):  Corrected upper limit of scoring scale and verbal anchors.
Rationale:  To correct typographical errors and omissions in upper limit of scoring scale and 
verbal anchors.

Operations Manual Section 3.9, Wearable Device Substudy, Daily Activity and Sleep Assessment 
at Home:  Added instruction for when subjects are to press the event marker.
Rationale:  To provide clarity on when the assessment is to be completed.

Operations Manual, Section 3.14, Vital Signs:  Added language to specify that blood pressure 
and pulse rate should be measured after the subject has been sitting for at least 3 minutes to 
replace deleted sentence "measurements should be assessed consistently throughout the 
study."
Rationale:  To provide clarity and ensure consistency of the procedure used to assess blood 
pressure and pulse, which can be affected by positional changes and activity.

Operations Manual Section 3.20, Subject Withdrawal from Study:  Added language to specify 
that subjects discontinued from study drug and continuing study participation no longer follow 
rescue treatment parameters.
Rationale:  To clarify that rescue treatment does not apply to subjects discontinued from study 
drug and continuing study participation.

Operations Manual 3.22 Home Healthcare Service:  Added option for home healthcare visits 
provided by a study nurse or third-party vendor beginning with Week 6.
Rationale:  To provide greater flexibility for study subjects.
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SAP_001.pdf: 
ABBV-154
M20-370 – Statistical Analysis Plan
Version 2.0 – 03 August 2022
1
Statistical Analysis Plan for Study M20-370
A Phase 2, Randomized, Double-Blind, Placebo-
Controlled, Dose-Ranging Study to Evaluate the 
Safety and Efficacy of ABBV-154 in Subjects with 
Polymyalgia Rheumatica (PMR) Dependent on 
Glucocorticoid Treatment
Date:  03 August 2022
Version 2.0
NCT04972968


ABBV-154
M20-370 – Statistical Analysis Plan
Version 2.0 – 03 August 2022
2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives, Hypotheses and Estimands .....................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................9
3.0
Endpoints..................................................................................9
3.1
Primary Endpoint(s)...................................................................................9
3.2
Secondary Endpoint(s)...............................................................................9
3.3
Other Efficacy Endpoint(s)......................................................................10
3.4
Safety Endpoint(s) ...................................................................................11
3.5
Additional Endpoint(s).............................................................................11
4.0
Analysis Populations .............................................................11
5.0
Subject Disposition................................................................12
6.0
Study Drug Duration and Compliance................................13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................13
7.1
Demographics and Baseline Characteristics............................................13
7.2
Medical History .......................................................................................15
7.3
Prior and Concomitant Medications ........................................................16
8.0
Handling of Potential Intercurrent Events for the 
Primary and Secondary Endpoints......................................16
9.0
Efficacy Analyses...................................................................17
9.1
General Considerations............................................................................17
9.2
Handling of Missing Data........................................................................18
9.2.1
Missing Data due to COVID-19 ..............................................................18
9.2.2
Handling of Intercurrent Events and Missing Data in Categorical 
and Continuous Endpoints .......................................................................19
9.3
Primary Efficacy Endpoint(s) and Analyses............................................21
9.3.1
Primary Efficacy Endpoint(s) ..................................................................21
9.3.2
Main Analysis of Primary Efficacy Endpoint(s) .....................................21


ABBV-154
M20-370 – Statistical Analysis Plan
Version 2.0 – 03 August 2022
3
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint(s)...............................................................................................22
9.4
Secondary Efficacy Endpoints and Analyses ..........................................22
9.4.1
Secondary Efficacy Endpoints.................................................................22
9.4.2
Main Analyses of Secondary Efficacy Endpoints....................................23
9.4.3
Sensitivity and Supplementary Analyses for Secondary Efficacy 
Endpoints .................................................................................................25
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses........................25
9.5
Additional Efficacy Analyses ..................................................................25
9.6
Dose-Response Modeling for ABBV-154...............................................26
9.7
Efficacy Subgroup Analyses....................................................................28
10.0
Safety Analyses ......................................................................28
10.1
General Considerations............................................................................28
10.2
Adverse Events ........................................................................................29
10.2.1
Treatment-Emergent Adverse Events ......................................................29
10.2.2
Adverse Event Overview .........................................................................30
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................30
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................31
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................31
10.2.6
Adverse Events of Special Interest ..........................................................31
10.3
Analysis of Laboratory Data....................................................................32
10.4
Analysis of Vital Signs ............................................................................33
10.5
Safety Subgroup Analyses .......................................................................34
10.6
Other Safety Analyses..............................................................................34
11.0
Other Analyses.......................................................................35
12.0
Interim Analyses....................................................................35
12.1
Data Monitoring Committee....................................................................35
13.0
Overall Type-I Error Control ..............................................36
14.0
Version History......................................................................37
15.0
References...............................................................................37


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List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint(s)...............................................................................................22
Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints .................................................................................................24
Table 3.
Summary of the Estimand Attributes of the Additional Efficacy 
Endpoints .................................................................................................25
Table 4.
Candidate Models ....................................................................................27
Table 5.
SAP Version History Summary...............................................................37
List of Figures
Figure 1.
Study Schematic.........................................................................................7
List of Appendices
Appendix A.
Protocol Deviations..................................................................................39
Appendix B.
Potentially Clinically Important Criteria for Safety Endpoints ...............40
Appendix C.
Random Seeds..........................................................................................41


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for ABBV-154 
Study M20-370, "A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-
Ranging Study to Evaluate the Safety and Efficacy of ABBV-154 in Subjects with 
Polymyalgia Rheumatica (PMR) Dependent on Glucocorticoid Treatment."
Study M20-370 examines the efficacy and safety of ABBV-154 in Subjects with PMR
dependent on glucocorticoid treatment.
The analyses of pharmacokinetic endpoints and pharmacodynamic biomarker endpoints 
will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the statistical analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The primary objective is to assess the safety and efficacy of ABBV-154 versus placebo in 
subjects with PMR, who are dependent on treatment with glucocorticoids with doses of at 
least 5 mg/day prednisone equivalent (glucocorticoid-dependent PMR).
●
Primary Efficacy Objective:  The primary efficacy objective of the study is to 
demonstrate that ABBV-154 treatment results in a longer disease-free time 
when compared with placebo treatment in the Intent-to-Treat (ITT) population, 
which consists of all randomized subjects with at least one dose of study drug.
The hypothesis corresponding to the primary efficacy objective is that the time to flare 
with ABBV-154 treatment is longer than that with placebo treatment.  The estimand for 


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the primary endpoint is defined as the median time to flare in the study for each 
ABBV-154 group versus the placebo group in the ITT population.  Subjects will be 
censored at the time of the last available assessment, initiation of immunomodulator, or 
violation of protocol-allowed systemic glucocorticoid use.
●
Secondary Efficacy Objectives:  The secondary efficacy objectives of the study 
are to demonstrate greater efficacy with ABBV-154 treatment when compared 
with placebo treatment with respect to the secondary endpoints specified in 
Section 3.3, in the ITT population.
The estimands corresponding to the secondary efficacy objectives are:
●
For each binary secondary endpoint:  The difference in percentage of subjects 
achieving a response for each ABBV-154 group versus the placebo group in the 
ITT population.
●
For each continuous endpoint:  The mean difference between each ABBV-154 
group versus the placebo group in the ITT population.
2.2
Study Design Overview
Study M20-370 is a randomized, double-blind, placebo-controlled, multicenter, 52-week 
Phase 2 study to assess the safety, tolerability, efficacy, PK, PD, and immunogenicity 
following multiple subcutaneous (SC) injections of ABBV-154 or placebo in 160 subjects 
with glucocorticoid-dependent PMR, as defined in Section 5.0.
The Primary Analysis will be performed after all subjects have either completed the 
Week 24 visit or withdrawn from the study.  Interim analyses may be performed to 
reassess the treatment regimens in this study and to inform development of future studies.
A final analysis will be conducted after all subjects have either withdrawn from the study 
or completed Week 52 and the safety Follow-up Visit.  To maintain integrity of the trial, 
the study sites and subjects will remain blinded until the final analysis is completed.  
Selected AbbVie personnel may be unblinded to treatment assignment to conduct interim 


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analyses or after an interim analysis to support regulatory interaction; details will be 
included in the interim unblinding plan (IUP).
Subjects in select countries and sites where the digital health technology device is 
deployed and available will also participate in a Wearable Device Substudy.  Subjects 
participating in this substudy will wear a watch-like digital device on the wrist that will 
collect data reflecting the subject's UL-ROM and daily activity and sleep parameters.  
Enrollment will be capped at 96 subjects.
There will be optional serial photography for subjects who consent and at sites where 
photography is available.
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
EOW = every other week; PMR = polymyalgia rheumatica; SC = subcutaneous
2.3
Treatment Assignment and Blinding
The Screening Period may be up to 35 days.  At the Baseline Visit, subjects will be 
randomized to one of 4 treatment arms in a 1:1:1:1 ratio, as follows:  placebo 


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administered SC in combination with a glucocorticoid taper or ABBV-154 administered 
as 40 mg every other week (EOW), 150 mg EOW, or 340 mg EOW in combination with a 
glucocorticoid taper.  The glucocorticoid taper is identical for placebo and active 
treatment groups.  Starting at Baseline, each subject will switch from oral glucocorticoids 
obtained from independent sources to oral prednisone/prednisolone provided by the 
Sponsor at the equivalent dose that the subject was taking just prior to the Baseline Visit, 
rounded up to the nearest 1 mg to a maximum of 15 mg.  Beginning at Week 3, subjects 
will taper prednisone/prednisolone per the protocol-defined glucocorticoid taper schedule 
to 0 mg by Week 24 and remain off prednisone/prednisolone until the end of the 
Treatment Period, Week 52, unless a PMR flare is confirmed.  A safety follow-up visit 
will be performed approximately 70 days after the last administration of 
ABBV-154/placebo.
If a subject has a suspected PMR flare at any time during the study, the flare should be 
confirmed according to the protocol-defined flare definition as soon as possible, prior to 
initiating glucocorticoid rescue treatment.  Flare may be confirmed at either a scheduled 
visit or unscheduled visit.  PMR must be confirmed as the cause of flare by eliminating 
other causes of the subject's symptoms/signs such as infection or other underlying disease.  
Once flare is confirmed at the visit, glucocorticoid rescue can be administered with the 
dose and subsequent tapering at the discretion of the investigator, taking into 
consideration local standard of care, the subject's preflare and/or baseline dose, and not 
exceeding 15 mg/day.
Addition of immunomodulators other than glucocorticoid rescue, as outlined above, are 
not permitted for rescue.  If the investigator determines it is in the best interest of the 
subject to start an immunomodulator, the subject must discontinue study drug 
(ABBV-154/placebo and Sponsor-supplied prednisone/prednisolone; glucocorticoid will 
then be prescribed by the investigator as necessary, with dosing based on the investigator's 
judgement and in accordance with local standard of care).


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2.4
Sample Size Determination
A total of 37 flares in the highest dose of ABBV-154 group and placebo group would 
provide more than 90% power to detect a hazard ratio of 0.296 at 2-sided significance 
level of 0.1.  The hazard ratio of 0.296 is determined under the assumption that flares
would occur during the tapering and within 12 weeks after the end of tapering (up to 
Week 36), and 70% and 30% of subjects will remain flare-free by Week 36 in the highest 
dose of ABBV-154 group and placebo group, respectively.
Based on an Emax model with ED50 of 150 mg, a total of 74 flares are expected for the 
Primary Analysis.  A sample size of 40 subjects in each of the ABBV-154 and placebo 
arms is planned to ensure appropriate accrual of flares.  A sample size re-estimation may 
be considered at an interim analysis prior to unblinding of the study team.  The sample 
size increase will be capped at approximately 100 subjects.
3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint is the time to flare, where flare is defined as follows:
●
Presence of clinical signs and symptoms of PMR
AND
●
Requirement to increase the glucocorticoid dose per investigator.
Clinical signs and symptoms of PMR are defined as shoulder and/or hip girdle pain with 
inflammatory stiffness, neck pain with inflammatory stiffness, or new or worsened limited 
range of motion of hips and/or shoulders, as outlined in protocol.
3.2
Secondary Endpoint(s)
●
Achievement of flare-free state up to Week 24
●
Cumulative glucocorticoid dose by 24 weeks
●
Change from Baseline in glucocorticoid dose at Week 24


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3.3
Other Efficacy Endpoint(s)
The primary and/or secondary efficacy endpoints are listed in Section 3.1 and/or 
Section 3.2, respectively.  All secondary endpoints will be analyzed at all visits other than 
those listed.  In addition, the following endpoints will be analyzed at all visits assessed
when applicable:
●
Time to disease flare defined as Polymyalgia Rheumatica Activity Score 
(PMR-AS) increased from Baseline by ≥6.6.
○
PMR-AS = high-sensitivity CRP (hsCRP) (mg/dL) + Patient Assessment 
of Pain Severity (numeric rating scale [NRS], 0 – 10) + Physician Global 
Assessment of Disease Activity (NRS, 0 – 10) + (morning stiffness 
duration [MST] in minutes × 0.1) + elevation of upper limbs (EUL) (scale 
of 3 – 0)
●
Time to disease flare defined as PMR-AS ≥9.35
●
Achievement of PMR-AS < 1.5
●
Achievement of PMR-AS < 7
●
Achievement of ESR ≤ 30 mm/h at Week 24
●
Achievement of hsCRP ≤ upper limit of normal (ULN) at Week 24
●
Change from Baseline in hsCRP
●
Change from Baseline in PMR-AS
●
Change from Baseline in MST
●
Change from Baseline in EUL
●
Change from Baseline in Physician Global Assessment of Disease Activity 
NRS
●
Change from Baseline in Patient Assessment of Pain Severity NRS
●
Change from Baseline in Patient Assessment of Stiffness Severity NRS
●
Change from Baseline in Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-Fatigue)
●
Change from Baseline in Health Assessment Questionnaire Disability Index 
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●
Change from Baseline in Patient-Reported Outcomes Measurement Information 
System (PROMIS) Item Bank v 1.0 – Sleep Disturbance
●
Change from Baseline in Patient Assessment of Bruising Severity NRS
●
Change from Baseline in EuroQol 5-dimension questionnaire, 5-level 
(EQ-5D-5L)
●
Change from Baseline in Physician Assessment of Bruising Severity NRS
●
For subjects participating in the Wearable Device Substudy:
○
Change from Baseline in the following sleep parameters: total sleep time, 
wake after sleep onset, sleep efficiency, and sleep onset latency
○
Change from Baseline in upper limbs range of motion (UL-ROM)
3.4
Safety Endpoint(s)
Safety measures monitored in the study include the following:
●
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 
and AEs leading to discontinuation of study drug;
●
Occurrence of potentially glucocorticoid-related AEs; and
●
Potentially clinically significant laboratory, vital signs, and electrocardiogram 
(ECG) variables.
3.5
Additional Endpoint(s)
Pharmacokinetic, immunogenicity, and biomarker research endpoints will be analyzed 
separately, and the corresponding analysis plan is not covered in this SAP.
4.0
Analysis Populations
The following population will be used for the efficacy analysis except for Wearable 
Device Substudy-related endpoints:
●
Intent-to-Treat (ITT) Population:  The ITT Population includes all subjects who 
were randomized and received at least 1 dose of study drug.  The ITT 


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Population will be analyzed as randomized (i.e., according to the randomized 
treatment assignment).
The following population will be used for the safety analysis:
●
Safety Population:  The Safety Population includes all subjects who were 
randomized and received at least 1 dose of study drug.  The Safety Population 
will be analyzed as treated (i.e., according to the actual treatment received).
The Per-Protocol Population will include ITT subjects with the exception of those who 
have major protocol deviations that are determined to have a potential impact on the 
primary efficacy endpoint up to Week 24.  The final criteria and the exclusion of subjects 
for the per-protocol population will be finalized before unblinding data for the Primary 
Analysis.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled (randomized), and treated will 
be summarized.  Reasons for exclusion, including screen failure, will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects enrolled (randomized) in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
●
Subjects in each analysis population, as applicable.
For end of study participation, the number and percentage of subjects who completed the 
protocol defined follow-up period (or did not with associated reasons) will be summarized 
overall and by treatment group.


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6.0
Study Drug Duration and Compliance
For the Safety population, duration of treatment will be summarized for each treatment 
group and for all investigational study drug dose groups combined.  Duration of treatment 
is defined for each subject as last dose date minus first dose date plus 14 days.  Duration 
of treatment will be summarized using the number of subjects treated, mean, standard 
deviation, median, minimum and maximum.  In addition, the number and percentage of 
subjects in each treatment duration interval (< 2 weeks [14 days], ≥ 2 weeks [14 days], 
≥4 weeks [28 days], ≥ 8 weeks [56 days], ≥ 12 weeks [84 days], ≥ 24 weeks [168 days],
≥36 weeks [252 days], and ≥ 52 weeks [364 days]) will be summarized.
Treatment compliance will be summarized for the entire treatment period by treatment 
group and total ABBV-154 group for the Safety population. Treatment compliance is 
defined as the number of injection actually taken divided by the number of injection that 
should have been taken.  All placebo injections will be included in the calculation for 
treatment compliance.  Percent compliance will be summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the ITT overall and by treatment group.
Categorical variables will be summarized with the number and percentage of subjects; 
percentages will be calculated based on the number of non-missing observations.
Continuous variables will be summarized with descriptive statistics (number of 
non-missing observations, mean and standard deviation, median, minimum and 
maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, ethnicity, race, age Group 1 
(< 65, or ≥65 years), age Group 2 (< 65, ≥65 and < 75, or ≥75 years), weight Group 1


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(< 60 or ≥ 60 kg), weight Group 2 (< 100 or ≥ 100 kg), BMI Group 1 (< 25 or ≥25 
kg/m2), BMI Group 2 (< 35 or ≥ 35 kg/m2), region (Europe, North America, or rest of 
world), tobacco user (current, former, never, unknown), and alcohol user (current, former, 
never, unknown).
Disease characteristics that will be summarized as continuous and categorical variables 
are listed below:
PMR Medical History and Characteristics
●
Duration of PMR diagnosis in years
●
Duration of PMR diagnosis category (< 1, ≥ 1 and ≤ 2, or > 2 years)
Baseline PMR Disease Characteristics
●
High sensitivity c-reactive protein (hs-CRP) (mg/L)
●
Erythrocyte sedimentation rate (ESR) (mm/h)
●
Patient Assessment of Pain Severity Numeric Rating Scale (NRS)
●
Physician Global Assessment of Disease Activity NRS
●
Morning Stiffness (MST) Duration
●
Elevation of Upper Limbs (EUL)
●
Polymyalgia Rheumatica Activity Score (PMR-AS)
●
Polymyalgia Rheumatica Activity Score (PMR-AS) (< 1.5, ≥ 1.5 and < 7, ≥ 7 
and < 17, or ≥ 17)
●
Patient Assessment of Stiffness Severity NRS
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)
●
Health Assessment Questionnaire Disability Index (HAQ-DI)
●
Patient-Reported Outcomes Measurement Information System (PROMIS) –
Sleep Disturbance
●
Patient Assessment of Bruising Severity NRS
●
EuroQol 5-dimension questionnaire, 5-level (EQ-5D-5L)
●
Physician Assessment of Bruising Severity NRS


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●
Rheumatoid factor (Positive (≥ 14 IU/mL), Negative (< 14 IU/mL))
●
Time since most recent PMR flare prior to Baseline (≤ 12 weeks, > 12 weeks)
Prior and Concomitant Treatment use
●
Length of prior glucocorticoid treatment for PMR* category (≤ 1 or > 1 year)
●
Baseline glucocorticoid dose
●
Baseline glucocorticoid dose categories 1 (< 10 or ≥ 10 mg/day prednisone 
equivalent)
●
Baseline glucocorticoid dose categories 2 (< 7.5, ≥ 7.5 and < 10, ≥ 10 and ≤15, 
or > 15 mg/day prednisone equivalent)
●
Prior biologic DMARD use (yes/no)
●
Prior synthetic DMARD use (yes/no)
○
Prior conventional synthetic DMARD use (yes/no)
○
Prior targeted synthetic DMARD use (yes/no)
●
Length of prior glucocorticoid use for PMR* (years)
●
Prior cumulative glucocorticoid dose (mg) 
●
Prior cumulative glucocorticoid dose (mg) (within one year before 
randomization)
*: Only consider glucocorticoid treatment use on or after confirmed PMR 
diagnosis date
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report. The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group. The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 


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order within each SOC. Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name. A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug. A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the date of the last dose of study drug plus 70 days. The number and percentage of 
subjects taking medications will be summarized by generic drug name based on the World 
Health Organization (WHO) Drug Dictionary for both prior and concomitant medications.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Secondary Endpoints
The primary efficacy endpoint (defined in Section 3.1) will be analyzed based on the ITT 
population and subjects will be censored at the time of the last available assessment, 
initiation of immunomodulator, or violation of protocol-allowed systemic glucocorticoid 
use.
The categorical secondary efficacy endpoint (defined in Section 3.2) will be analyzed 
based on the ITT population and the following methods will be used to address the 
potential intercurrent events:
●
Subjects will be considered as not achieving the response after the initiation of 
rescue medication, immunomodulator or violation of protocol-allowed systemic 
glucocorticoid use.
The continuous secondary efficacy endpoints (defined in Section 3.2) will be analyzed 
based on the ITT population and the following methods will be used to address the 
potential intercurrent events:


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●
No intercurrent event will be considered in the analysis of glucocorticoid dose.
9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted in the ITT Population in each period. In addition, 
Per-protocol analysis for the primary endpoint will be performed. All tests will be 2-sided 
at an alpha level of 0.1.
The Primary Analysis will be performed after all subjects have either completed the Week 
24 visit or withdrawn from the study.  This analysis will be the only and final analysis for 
the primary and secondary efficacy endpoints.
The primary endpoint will be analyzed using logrank test stratified by baseline 
stratification factors [Glucocorticoid use at Baseline (≥10 mg/day; < 10 mg/day 
prednisone equivalent); Length of prior glucocorticoid treatment for PMR (≤ 1 year; 
> 1 year)].  The point and 95% confidence interval (CI) estimate of median time to event 
and event-free rate for each group will be reported based on Kaplan-Meier curves.  
Hazard ratio and its corresponding 95% CI for each ABBV-154 group compared with 
placebo will be estimated using Cox regression analysis adjusting for Baseline 
stratification factors [Glucocorticoid use at Baseline (≥10 mg/day; < 10 mg/day 
prednisone equivalent); Length of prior glucocorticoid treatment for PMR (≤ 1 year; 
> 1 year)].  For all analyses of time-to-event endpoints, 1) subject without an event at the 
time of the analysis will be administratively censored at the time of the last available 
assessment or cutoff, whichever is later; 2) a flare at Baseline will not be counted as an 
event; 3) if a flare event and an intercurrent event happen on the same day, subject will be 
counted as having a flare event.
Unless otherwise specified, the categorical endpoints and continuous endpoints will be 
analyzed by Cochran-Mantel-Haenszel (CMH) and Mixed-Effect Model Repeat 


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Measurement (MMRM), respectively, and the corresponding analyses are specified in 
Section 9.2.
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the actual stratum the subject belongs to.
"Baseline" refers to the last non-missing observation on or before the day of the 
first administration of study drug or randomization if no study drug is given.  Observation
on the same day as the first administration of study drug will be considered for the 
baseline, regardless of whether observation time (if available) was before or after the 
first administration of study drug time.
9.2
Handling of Missing Data
For time-to-event endpoints, event and censoring details will be described in Section 9.3.
9.2.1
Missing Data due to COVID-19
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the study, or missing due to COVID-19 infection or logistic 
restriction.
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis, and the interpretation 
of clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  Impacted visits 
due to COVID-19 will be recorded in the database.  The probability of having missed 
visits and missing data due to COVID-19 infection or logistical restrictions related to the 
COVID-19 pandemic can be reasonably assumed to be unrelated to the unobserved 
values.  Therefore, for the purpose of statistical analysis, it is reasonable to assume that 
these missing data are missing at random (MAR) and the statistical models that require 
MAR assumption are appropriate.  Sensitivity analyses will be performed to assess the 
impact of missing data and the robustness of the conclusion.


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9.2.2
Handling of Intercurrent Events and Missing Data in 
Categorical and Continuous Endpoints
●
Non-Responder Imputation incorporating multiple imputation to handle 
COVID-19 (NRI-MI) will be the primary approach to handle missing data for 
categorical endpoints.  The NRI-MI will categorize any subject who does not 
have an evaluation during a pre-specified visit window (either due to missing 
assessment, due to early withdrawal from the study, or due to intercurrent 
event) as a non-responder for the visit.  The only exceptions are:  1) when the 
subject is a responder both before and after the visit window, the subject will be 
categorized as a responder for the visit.  2) missing data due to COVID-19 
infection or logistical restriction will be handled by Multiple Imputation.  In 
addition, all assessments after the start of intercurrent events will not be 
included in the analyses; as a result, subjects will be counted as non-responders 
thereafter and will not be imputed by MI.
●
Non-Responder Imputation (NRI): In the interim analyses, NRI may be used 
due to subjects being in the study for different durations which makes multiple 
imputation infeasible.
●
Multiple Imputation (MI): Markov Chain Monte Carlo (MCMC) will be first 
applied to augment data into monotonic missing pattern and PROC MI will be 
used to generate 30 datasets using the regression method.  The variables to be 
included in the imputation model are treatment group, stratification factors at 
randomization [Glucocorticoid use at Baseline (≥10 mg/day; < 10 mg/day 
prednisone equivalent); Length of prior glucocorticoid treatment for PMR
(≤1 year; > 1 year)], Baseline, and measurements at each visit. The random 
seed for MCMC and the random seed for PROC MI are specified in 
Appendix C. The imputed post-baseline measurements will be rounded to the 
same precision as the observed data before the determination of responder 
status. Subjects will be characterized as responders or non-responders based on 
MI imputed datasets. Using the Cochran-Mantel-Haenszel (CMH) model 
adjusted by stratification factors [Glucocorticoid use at Baseline (≥10 mg/day; 
< 10 mg/day prednisone equivalent); Length of prior glucocorticoid treatment 
for PMR (≤ 1 year; > 1 year)], the imputed endpoints will be analyzed using 
each of the 30 datasets.  SAS PROC MIANALYZE will be used to generate the 
final inferences of the risk difference between each ABBV-154 group and 


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placebo. Note that measurements will be considered as missing after the start
of confounding medication before MI.  Regardless of MI imputed values, 
subjects after receiving confounding medication will be counted as non-
responders.
Efficacy assessments after the initiation of rescue medication, immunomodulator or 
violation of protocol-allowed systemic glucocorticoid use will not be included in the 
analyses. As a result, the subjects will be considered as non-responders in the NRI-MI 
approach.
●
Mixed-Effect Model Repeat Measurement (MMRM):  MMRM will be the 
primary approach to the analysis of continuous variables except for 
glucocorticoid dose.  The repeated measures analysis will be conducted using a 
mixed model including observed measurements at all visits.  Subject's 
observations after intercurrent events will not be used in the MMRM.  The 
mixed model includes the categorical fixed effects of treatment, visit and 
treatment-by-visit interaction, stratification factors at randomization 
[Glucocorticoid use at Baseline (≥10 mg/day; < 10 mg/day prednisone 
equivalent); Length of prior glucocorticoid treatment for PMR (≤ 1 year; 
> 1 year)], and the continuous fixed covariates of baseline measurement.  An 
unstructured variance-covariance matrix (UN) will be used.  If the model does 
not converge, an alternative variance-covariance structure matrix (e.g., 
autoregressive (1) or compound symmetry) will be used.  Parameter estimation 
is based on the assumption of data being missing at random and the method of 
restricted maximum likelihood (REML) will be used.
●
Analysis of covariance (ANCOVA):  ANCOVA will be the primary approach 
for the analysis of glucocorticoid dose. No intercurrent event will be 
considered in the analysis of glucocorticoid dose. The ANCOVA model 
includes the categorical fixed effects of treatment and stratification factors at 
randomization [Glucocorticoid use at Baseline (≥ 10 mg/day; < 10 mg/day 
prednisone equivalent); Length of prior glucocorticoid treatment for PMR 
(≤1 year; > 1 year)], and baseline glucocorticoid dose as a covariate.
●
As Observed (AO):  The AO analysis will not impute values for missing 
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visit will be excluded from the AO analysis for that visit.  AO will include all 
values collected in the study.
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint(s)
The primary endpoint is the time to flare, where flare is defined as follows:
●
Presence of clinical signs and symptoms of PMR 
AND
●
Requirement to increase the glucocorticoid dose per investigator.
Clinical signs and symptoms of PMR are defined as shoulder and/or hip girdle pain with 
inflammatory stiffness, neck pain with inflammatory stiffness, or new or worsened limited 
range of motion of hips and/or shoulders, as outlined in protocol.
9.3.2
Main Analysis of Primary Efficacy Endpoint(s)
The statistical null hypothesis corresponding to the primary endpoint is that there is no 
difference between an ABBV-154 group and the placebo group in time to flare.
Analysis of the primary endpoint will be conducted in the ITT Population based on 
treatment as randomized.  Comparison of the primary endpoint will be made between 
each ABBV-154 group and the placebo group using logrank test stratified by baseline 
stratification factors [Glucocorticoid use at Baseline (≥10 mg/day; < 10 mg/day 
prednisone equivalent); Length of prior glucocorticoid treatment for PMR (≤ 1 year; 
> 1 year)].
The attributes of the estimands corresponding to the primary efficacy endpoint are 
summarized in Table 1.


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Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint(s)
Estimand Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events 
(IE)
Statistical 
Summary
Primary:
Time to flare 
(Composite)
ABBV-154 
vs. Placebo
Time to 
flare
ITT
IE1: at the time of 
immunomodulator 
initiation
IE2: at the time of 
violation of protocol-
allowed systemic 
glucocorticoid use
Subjects will be 
censored at the time 
of intercurrent event.
Between 
ABBV-154 
and placebo: 
difference in 
number of 
events, 
difference in 
median time 
to event, 
event-free 
rate
difference, 
hazard ratio 
and its 
corresponding 
CI
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint(s)
Not applicable.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Secondary Efficacy Endpoints
The categorical secondary endpoint is
●
Achievement of flare-free state up to Week 24
The continuous secondary endpoints are
●
Cumulative glucocorticoid dose by 24 weeks


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●
Change from Baseline in glucocorticoid dose at Week 24
For the analysis of glucocorticoid dose, all systemic glucocorticoid use will be included 
regardless of the indication.
9.4.2
Main Analyses of Secondary Efficacy Endpoints
The statistical null hypothesis corresponding to the secondary endpoint is that there is no 
difference between an ABBV-154 group and the placebo group.
Analysis of the secondary endpoint will be conducted in the ITT Population based on 
treatment as randomized.  Comparison of the secondary endpoint will be made between 
each ABBV-154 group and the placebo group using:
●
For categorical variable: CMH test adjusted by baseline randomization 
stratification factor [Glucocorticoid use at Baseline (≥10 mg/day; < 10 mg/day 
prednisone equivalent); Length of prior glucocorticoid treatment for PMR (≤ 1 
year; > 1 year)].
●
For analyses of glucocorticoid dose: ANCOVA mentioned in Section 9.2.
The attributes of the estimands corresponding to the secondary efficacy endpoints are 
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Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints
For binary endpoint:
Estimand
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of
Intercurrent Events
Statistical 
Summary
Binary 
Secondary 
Variable 
(Composite)
ABBV-154 
vs. Placebo
Achievement 
of flare-free 
state up to 
Week 24
ITT
IE1: Initiation of rescue 
medication
IE2: Initiation of 
immunomodulator
IE3: Initiation of 
violation of protocol-
allowed systemic 
glucocorticoid use
Subjects will be 
considered as non-
responders for visits after 
ICEs.
Difference 
in 
proportion 
of subjects 
achieving 
flare-free 
state up to 
Week 24
For analyses of glucocorticoid dose:
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Analyses of 
glucocorticoid 
dose
(Treatment 
Policy)
ABBV-154 
vs Placebo
Change from 
Baseline at 
Week 24 or 
cumulative 
assessment 
by Week 24
ITT
No IE.
Difference 
in the mean 
change 
from 
Baseline at 
Week 24 or 
cumulative 
assessment 
by Week 24 


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9.4.3
Sensitivity and Supplementary Analyses for Secondary 
Efficacy Endpoints
Not applicable.
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses
Not applicable.
9.5
Additional Efficacy Analyses
Additional efficacy endpoints described in Section 3.3 will be analyzed at all visits 
assessed using the same methods listed in above and Section 9.2. The attributes of the 
estimands corresponding to the additional efficacy endpoints are summarized in Table 3.
Table 3.
Summary of the Estimand Attributes of the Additional Efficacy 
Endpoints
For binary endpoint:
Estimand
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of
Intercurrent Events
Statistical 
Summary
Binary 
Additional
Variable 
(Composite)
ABBV-154 
vs. Placebo
Achievement 
of each 
binary 
additional
endpoint 
respectively
ITT
IE1: Initiation of rescue 
medication
IE2: Initiation of 
immunomodulator
IE3: Initiation of 
violation of protocol-
allowed systemic 
glucocorticoid use
Subjects will be 
considered as non-
responders for visits after 
ICEs.
Difference 
in 
proportion 
of subjects 
achieving 
each binary 
additional
endpoint


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For continuous endpoint: 
Estimand
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of
Intercurrent Events
Statistical 
Summary
Continuous
Additional
Variable 
(Composite)
ABBV-154 
vs. Placebo
Change from 
Baseline in 
each 
respective 
continuous 
additional
endpoint
ITT
IE1: Initiation of rescue 
medication
IE2: Initiation of 
immunomodulator
IE3: Initiation of 
violation of protocol-
allowed systemic 
glucocorticoid use
Efficacy assessments 
after the start of IE will 
not be included in the 
analyses, and visits after 
IE will be handled by 
MMRM.
Difference 
in the mean 
change 
from 
Baseline in 
each 
continuous
additional
endpoint
9.6
Dose-Response Modeling for ABBV-154
The dose-response relationship among ABBV-154 dose groups and the placebo group 
will be characterized for the primary endpoint using the Multiple Comparison Procedure –
Modeling (MCP-Mod) method [Pinheiro 2006, Bretz 2005].  The summary level response 
rates based on the primary analysis approach above will be used, and ADDPLAN DF 
software will be used to perform the MCP-Mod analyses.
A set of 6 pre-specified standardized candidate dose-response models, as described in 
Table 4 will be utilized to examine the dose-response relationship.  A statistically 
significant dose-response relationship will be declared if at least one model is identified 
by the MCP-Mod method to be statistically significant at two-sided α = 0.1.  The fitted 
dose-response curves will be presented graphically for all statistically significant models 
along with 95% confidence bands.  The minimum effective dose (MED) will be identified 
for each statistically significant model based on the pre-specified clinical meaningful 


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target of 22%.  The weighted MED across all significant models will be calculated, with 
weight being the inverse of each candidate dose-response model AIC.
Table 4.
Candidate Models
Model
𝒇(𝒅, 𝜽)
d = dose,
θ = Model Parameters
𝒇𝟎(𝒅, 𝜽)
Standardized Model
Initial Value(s)
for Parameter(s)*
Linear
E0 + δd
d
NA
Exponential
𝐸0 + 𝐸1 [𝑒𝑥𝑝(𝑑
𝛿) −1]
𝑒𝑥𝑝(𝑑
𝛿) −1
δ = 680
Logistic
𝐸0 +
𝐸𝑚𝑎𝑥
1 + 𝑒𝑥𝑝(𝐸𝐷50 −𝑑
𝛿
)
1
1 + 𝑒𝑥𝑝(𝐸𝐷50 −𝑑
𝛿
)
ED50 = 150, δ = 64.5
Emax
𝐸0 +
𝐸𝑚𝑎𝑥𝑑
𝐸𝐷50 + 𝑑
𝑑
𝐸𝐷50 + 𝑑
ED50 = 83.9
sigEMax
𝐸0 +
𝐸𝑚𝑎𝑥𝑑ℎ
𝐸𝐷50
ℎ+ 𝑑ℎ
𝑑ℎ
𝐸𝐷50
ℎ+ 𝑑ℎ
ED50 = 150, h = 3.6
Quadratic
𝐸0 + 𝛽1𝑑+ 𝛽2𝑑2
𝑑+ 𝛽2
|𝛽1| 𝑑2
δ = –0.001
*
For Exponential model, the initial value was determined based on the assumption that ABBV-154 340 mg EOW 
will achieve 95% of the maximum efficacy of ABBV-154. For Logistic, Emax, sigEMax, and Quadratic model, 
the initial values were determined based on the assumption that ABBV-154 340 mg EOW and ABBV-154 150 mg 
EOW will achieve 95% and 50% of the maximum efficacy of ABBV-154, respectively.
Steps of MCP-Mod:
1.
Choose a candidate set of models as in Table 4.
2.
Compute the optimum contrast for each model.
3.
Use contrast test to find all significant models while preserving family-wise error 
rate (FWER).


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4.
Use all significant models to make inference about the weighted target dose of 
interest.
9.7
Efficacy Subgroup Analyses
Subgroup analysis for the primary endpoint will be conducted by the subgroups specified 
below.  The difference in the primary efficacy endpoint between the treatment groups in 
each subgroup will be assessed using the same approach for primary endpoint.
●
Baseline glucocorticoid use (≥10 mg/day; < 10 mg/day prednisone equivalent)
●
Length of prior glucocorticoid treatment for PMR (≤ 1 year; > 1 year)
●
Age (≤median; > median)
●
Sex (female; male)
●
Race (white; nonwhite)
●
Time since most recent PMR flare prior to Baseline (≤ 12 weeks; > 12 weeks)
In addition, change from Baseline in glucocorticoid dose at Week 24 will be analyzed by 
the following subgroup.  The difference in this endpoint between the treatment groups in 
each subgroup will be assessed using ANCOVA approach.  Treatment difference and 
corresponding confidence interval will be used to summarize the result.
●
Glucocorticoid status at Week 24 (glucocorticoid free; not glucocorticoid free)
If any subgroup has fewer than 10% of the total subjects, then the analysis for this 
subgroup will not be performed.
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Population. Safety summaries will be 
presented by treatment group, including a total group for all subjects on active study drug.


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For the safety analysis, subjects are assigned to a treatment group based on the treatment 
actually received, regardless of the treatment randomized.
A subject's actual treatment will be determined by the most frequent dose regimen 
received.
"Baseline" refers to the last non-missing observation on or before the day of the 
first administration of study drug or randomization if no study drug is given. Observation 
on the same day as the first administration of study drug will be considered for the 
baseline, regardless if observation time (if available) was after the first administration of 
study drug time.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock. The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with the onset that is after the first dose 
of study drug and with an onset date no more than 5 half-lives of the study drug (i.e., 70 
days). Events where the onset date is the same as the study drug start date are assumed to 
be treatment-emergent, unless the study drug start time and the AE start time are collected 
and the AE start time is prior to the study drug start time. All treatment-emergent AEs 
will be summarized overall, as well as by primary MedDRA SOC and Preferred Term.
The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.


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The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
Adverse events of special interest (AESI, formerly known as safety topics of 
interest)
●
All deaths
●
Deaths occurring ≤ 70 days after last dose of study drug
●
Deaths occurring > 70 days after last dose of study drug.
An overview of treatment-emergent AEs per 100 patient-years of exposure will be 
presented by treatment group for the same AE categories listed above.
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by
subject number and SOC and PT. Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise. In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to investigational product will be reported.


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In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the total active group.
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
exposure in 100 patient-years. The study drug exposure is defined as the last dose date 
plus 5 × half-life (70 days), minus the first dose date.
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
In addition, the event rate per 100 patient-years of exposure will also be provided by SOC 
and PT for each treatment-emergent SAE and TEAE leading to study drug 
discontinuation.
10.2.6
Adverse Events of Special Interest
AESI will be summarized by SOC and PT and will be based on standardized or company 
MedDRA queries (SMQs or CMQs), or based on adjudication results. AESI to be 
summarized will follow those indicated in the latest version of the Product Safety 
Statistical Analysis Plan (PSSAP) for ABBV-154 in the AESI section.  Detailed 
information about search criteria for the AESI are also provided in a table in the same 
section.
Tabular listings of AESI will be provided.
In addition, the event rate per 100 patient-years of exposure will also be provided by SOC 
and PT for each AESI.


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10.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded. The 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum. Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean. The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between treatment groups (ABBV-154 vs. 
placebo).
Changes in laboratory parameters will be tabulated using shift tables either by NCI CTC 
criteria or categorized as low, normal, or high based on the normal ranges of the 
laboratory used for each sample. A shift table from baseline either to the worse value 
(based on NCI CTC criteria) during treatment or to minimum and maximum value (based 
on normal range), will be created. A similar shift table will be provided to summarize 
shifts from baseline to the final post-baseline value.
Laboratory abnormalities meeting CTC criteria grade 3 and 4 will be summarized.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (criteria in PSSAP will be used first, if the criteria are not available in 
PSSAP, then criteria in NCI CTC will be used). For each laboratory PCI criterion, the 
number and percentage of subjects who have a laboratory value meeting the criteria will 
be summarized. Listings will be provided to summarize subject-level laboratory data for 
subjects meeting PCI criteria.


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For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by "as treated" treatment group:
●
ALT > 3 × ULN
●
ALT > 5 × ULN
●
ALT > 10 × ULN
●
ALT > 20 × ULN
●
AST > 3 × ULN
●
AST > 5 × ULN
●
AST > 10 × ULN
●
AST > 20 × ULN
●
TBL > 2 × ULN
●
Alkaline phosphatase > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and concurrent INR > 1.5
●
ALT and/or AST > 3 × ULN and concurrent TBL > 2 × ULN
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions simultaneously, will be provided: ALT > 3 × ULN or AST > 3 × ULN that is 
associated with an increase in bilirubin > 2 × ULN.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, respiratory 
rate, and body temperature will be summarized.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum. Mean change from baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
baseline mean, and visit mean.  The change from baseline mean, standard error, and 95% 


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confidence interval will be presented for the mean change from baseline within each 
treatment group and difference between treatment groups (ABBV-154 vs. Placebo).
Vital sign variables will be evaluated based on PCI criteria.  Pulse rate, body temperature, 
and respiratory rate will follow the criteria in Appendix B.  All other vital sign 
measurements will follow criteria in PSSAP. For each vital sign PCI criterion, the 
number and percentage of subjects who have a vital sign value meeting the criteria will be 
summarized. Listings will be provided to summarize subject-level vital sign data for 
subjects meeting PCI criteria.
10.5
Safety Subgroup Analyses
The AE Overview and AE by SOC and PT summaries will be provided for the following 
subgroups:
●
Baseline Glucocorticoid dose Categories Group 1 (< 7.5, ≥ 7.5 and < 10, ≥ 10 
and ≤ 15, or > 15 mg/day prednisone equivalent)
●
Baseline Glucocorticoid dose Categories Group 2 (< 10 and ≥ 10 mg/day 
prednisone equivalent)
●
Duration of PMR Diagnosis Categories (< 1, ≥ 1 and ≤2, or > 2 years)
●
Length of prior glucocorticoid treatment for PMR (≤ 1 and > 1 year)
If any subgroup has fewer than 10% of the total subjects, then the analysis for this 
subgroup will not be performed.
10.6
Other Safety Analyses
ECG is collected at screening, Week 24, and Week 52.  ECG findings will be summarized 
by treatment group for each parameter and visit.
Dual-energy X-ray absorptiometry (DXA) is collected at screening and Week 52.  DXA 
measurements, including bone mineral density and the corresponding T-scores and 
Z-scores, will be summarized by treatment group for each visit and also in the following 
subgroups:


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●
Vitamin D status at baseline (< 30 and ≥ 30 nmol/L)
●
Female patients' post-menopausal status at baseline (Yes and No)
●
Bone protective agent status at baseline (Yes and No)
If available, body composition should be collected at screening and Week 52.  Body 
composition measurements, including body fat mass (grams), lean body mass (grams), 
total body mass (grams), fat (%), and lean (%) will be summarized by treatment group for 
each visit.
11.0
Other Analyses
Not applicable.
12.0
Interim Analyses
An interim analysis will be conducted for this study approximately 3 weeks before the 
Primary Analysis for M20-466 (ABBV-154 Rheumatoid Arthritis [RA] Phase 2b study).  
Additional interim analyses may be performed to reassess the treatment regimens in this 
study and to inform development of future studies.  The interim analysis result will not be 
reviewed by the Data Monitoring Committee (DMC).
A separate interim unblinding plan will be developed to describe the detailed interim 
analysis plan, including the interim unblinding team, decision rules, execution logistics, 
and data chain of custody to protect the integrity of the clinical study.  The interim 
analysis result will not be reviewed by the Data Monitoring Committee (DMC) and the 
interim analysis plan will not be documented in the DMC charter.
These interim analyses will not impact the study conduct.
12.1
Data Monitoring Committee
An external data monitoring committee (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.


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A separate DMC charter will be prepared to describe the roles and responsibilities of the 
DMC members, frequency and scope of the data reviews, and expectations for blinded 
communications.
An internal independent glucocorticoid adjudication committee will be established to 
adjudicate potentially glucocorticoid-related AEs.  A separate charter describes the roles 
and responsibilities of the adjudication committee members, frequency of data reviews, 
and expectations for blinded communications.
13.0
Overall Type-I Error Control
Overall Type I error control is not planned in this Phase 2 study.
Since there are no efficacy analyses for early stopping planned for the DMC or IERC
review, no alpha spending is needed due to the DMC or IERC review.


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14.0
Version History
Table 5.
SAP Version History Summary
Version
Date
Summary
1.0
29 November 2021
Original version
2.0
03 August 2022
•
Section 2.2, Section 2.3, Section 2.4, and Section 
12.0:  update the sample size, interim analysis 
language, sample size for Wearable Device 
Substudy, study schematics, randomization ratio, to 
align with protocol version 3.0.
•
Section 7.1:  update/add details for the age Group 1, 
Rheumatoid factor, and length of prior 
glucocorticoid use for PMR, add summarization for 
time since most recent PMR flare prior Baseline (≤ 
12 weeks, > 12 weeks).
•
Section 9.1:  add details for time-to-event (censoring, 
event at the Baseline, event and flare happen on the 
same day) and efficacy Baseline definition.
•
Section 9.2:  add statements for NRI instead of NRI-
MI will be used in the interim analysis.
•
Section 9.5:  clarify the intercurrent event for the 
additional efficacy endpoint.
•
Section 9.7:  add efficacy subgroup time since most 
recent PMR flare prior Baseline (≤ 12 weeks, > 12 
weeks)
•
Section 10.1:  add details for safety Baseline 
definition
•
Section 10.2:  clarify the definition of Treatment-
emergent AEs; use AESI instead of STI for 
terminology 
•
Section 10.5:  add new safety subgroup
•
Section 10.6:  add details for BMD analysis
•
Appendix B:  add PCI criteria for selected laboratory 
variables.
15.0
References
1.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data:  a case 
study using agriculture industry codes.  J Am Stat Assoc.  1987;81:366-74.


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2.
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-
19 Pandemic - Guidance for Industry, Investigators, and Institutional Review 
Boards.  FDA.  2020.
3.
Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency - Guidance for Industry.  FDA.  2020.
4.
Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials.  EMA.  2020.
5.
Graham JW, Olchowski AE, Gilreath TD.  How many imputations are really 
needed?  Some practical clarifications of multiple imputation theory.  Prev Sci.  
2007;8(3):206-13.
6.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data:  a case 
study using agriculture industry codes.  J Am Stat Assoc.  1987;81:366-74.
7.
White IR, Royston P, Wood AM.  Multiple imputation using chained equations:  
Issues and guidance for practice.  Stat Med.  2011;30(4):377-99.
8.
Pinheiro J, Bornkamp B, Bretz F.  Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures.  J Biopharm Stat.  
2006;16(5):639-56.
9.
Bretz F, Pinheiro JC, Branson M.  Combining multiple comparisons and modeling 
techniques in dose-response studies.  Biometrics.  2005;61(3):738-48.


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


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Version 2.0 – 03 August 2022
40
Appendix B.
Potentially Clinically Important Criteria for Safety Endpoints
The PCI criteria for selected laboratory variables are described in Table B1 instead of 
using NCI CTC.
Table B1.
Potentially Clinically Important Criteria for Selected Laboratory
Variables
Laboratory Variables
Definition of Potentially Clinically 
Important
HbA1c
< 6.5%
>= 6.5% to < 8%
>= 8%
HDL
< 1.03 mmol/L
>= 1.03 mmol/L
LDL
< 3.36 mmol/L
>= 3.36 to <4.14 mmol/L
>= 4.14 mmol/L
The PCI criteria for selected vital sign variables are described in Table B2.
Table B2.
Potentially Clinically Important Criteria for Selected Vital Sign 
Variables
Vital Signs Variables
Criterion
Definition of Potentially Clinically Important
Pulse rate
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Body temperature
High
> 39.0 degrees C (102.3 degrees F)
Respiratory rate
Low
< 10 breaths/min
High
> 24 breaths/min


ABBV-154
M20-370 – Statistical Analysis Plan
Version 2.0 – 03 August 2022
41
Appendix C.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 10000 at each 
attempt until convergence of model happens.
Random Seeds for NRI-MI
Endpoints
Random Seed
MCMC procedure
PROC MI
PMR-AS related binary endpoints
10001
20001
ESR
10002
20002
hsCRP
10003
20003