Clinical trial NCT03725202
Conditions: Giant Cell Arteritis (GCA)
Keywords: Giant Cell Arteritis (GCA) ABT-494 Upadacitinib
Sponsor: AbbVie
Start date: 2019-02-06; Completion date: 2025-02-24
Enrollment: 438 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study consists of two periods. The objective of Period 1 is to evaluate the efficacy of upadacitinib in combination with a 26-week corticosteroid (CS) taper regimen compared to placebo in combination with a 52-week CS taper regimen, as measured by the proportion of participants in sustained remission at Week 52, and to assess the safety and tolerability of upadacitinib in participants with giant cell arteritis (GCA). The objective of Period 2 is to evaluate the safety and efficacy of continuing versus withdrawing upadacitinib in maintaining remission in participants who achieved sustained remission in Period 1.

Safety and efficacy data through 06 February 2024 are included in the interim analysis, which was conducted after all participants completed the Week 52 visit or discontinued from the study.

Detailed description:

Arms: arm 1: Participants received placebo tablets for upadacitinib administered orally once daily (QD) for 52 weeks and a 52-week corticosteroid (CS) taper regimen during Period 1. arm 2: Participants received 7.5 mg upadacitinib tablets administered orally once daily (QD) for 52 weeks and a 26-week corticosteroid (CS) taper regimen during Period 1. arm 3: Participants received 15 mg upadacitinib tablets administered orally once daily (QD) for 52 weeks and a 26-week corticosteroid (CS) taper regimen during Period 1. arm 4: Participants who achieved sustained remission for at least 24 weeks prior to the Week 52 visit (at the end of Period 1) OR at remission at the Week 52 visit only who were assigned to placebo tablets for upadacitinib administered orally once daily (QD) in Period 1 continued to receive placebo tablets for upadacitinib administered orally once daily (QD) in Period 2. arm 5: Participants received 7.5 mg upadacitinib tablets administered orally once daily (QD) in Period 2. arm 6: Participants received placebo tablets for upadacitinib administered orally once daily (QD) in Period 2. arm 7: Participants received 15 mg upadacitinib tablets administered orally once daily (QD) in Period 2. arm 8: Participants received placebo tablets for upadacitinib administered orally once daily (QD) in Period 2.
Interventions: intervention 1: Upadacitinib intervention 2: Corticosteroid (CS) intervention 3: Placebo
Intervention descriptions: intervention 1: Administered orally once a day intervention 2: At Baseline, all participants switched to corticosteroids (CS) provided by the sponsor with the oral prednisone or prednisolone dose at 20, 30, 40, 50, or 60 mg QD. The initial dose of prednisone or prednisolone was at the discretion of the investigator, based on disease severity and comorbid medical conditions, at a minimum of 20 mg QD at Baseline. At Baseline, if a participant was on a dose other than 20, 30, 40, 50, or 60 mg QD, the dose was rounded up or down, as clinically indicated per investigator discretion, to the nearest of these doses. Prednisone or prednisolone was tapered according to a predefined schedule over a 26- or 52-week period. Open-label prednisone or prednisolone was provided until the dose was tapered to 20 mg/day. Subsequently, blinded prednisone or prednisolone was provided for the remaining blinded taper regimen through Week 52. intervention 3: Administered orally once a day

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 PATIENTS
11
3
STUDY OBJECTIVES AND ENDPOINTS
12
3.1
OBJECTIVES
12
3.2
PRIMARY ENDPOINT
13
3.3
SECONDARY ENDPOINTS
14
3.4
SAFETY ENDPOINTS
16
3.5
PHARMACOKINETIC ENDPOINTS
16
3.6
PATIENT EXPERIENCE ENDPOINTS
17
3.7
BIOMARKER EXPLORATORY RESEARCH
17
4
INVESTIGATIONAL PLAN
17
4.1
OVERALL STUDY DESIGN AND PLAN
17
4.2
DISCUSSION OF STUDY DESIGN
20
5
STUDY ACTIVITIES
22
5.1
ELIGIBILITY CRITERIA
22
5.2
CONTRACEPTION RECOMMENDATIONS
26
5.3
PROHIBITED MEDICATIONS AND THERAPY
28
5.4
PRIOR AND CONCOMITANT THERAPY
31
5.5
DISCONTINUATION FROM STUDY DRUG OR SUBJECT WITHDRAWAL FROM STUDY
32
5.6
FOLLOW-UP FOR STUDY DRUG DISCONTINUATION OR SUBJECT WITHDRAWAL FROM STUDY
33
5.7
ASSESSMENT OF DISEASE ACTIVITY
35
5.8
STUDY DRUG
35
5.9
RANDOMIZATION/DRUG ASSIGNMENT AND BLINDING
39
5.10 PROTOCOL DEVIATIONS
40
6
SAFETY CONSIDERATIONS
41
6.1
COMPLAINTS AND ADVERSE EVENTS
41
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6.2
TOXICITY MANAGEMENT
45
6.3
DATA MONITORING COMMITTEE
49
6.4
CARDIOVASCULAR ADJUDICATION COMMITTEE
50
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
50
7.1
STATISTICAL AND ANALYTICAL PLANS
50
7.2
DEFINITION FOR ANALYSIS POPULATIONS
50
7.3
STATISTICAL ANALYSES FOR EFFICACY
51
7.4
STATISTICAL ANALYSES FOR SAFETY
52
7.5
INTERIM ANALYSIS
53
8
ETHICS
53
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
53
8.2
ETHICAL CONDUCT OF THE STUDY
53
8.3
SUBJECT CONFIDENTIALITY
53
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
54
10 DATA QUALITY ASSURANCE
54
11 COMPLETION OF THE STUDY
54
12 REFERENCES
55
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
30
TABLE 2.
IDENTITY OF STUDY DRUG
37
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES
47
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
20
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LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
57
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
61
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
62
APPENDIX D.
ACTIVITY SCHEDULE
63
APPENDIX E.
CORTICOSTEROID TAPERING SCHEDULE
69
APPENDIX F.
PROTOCOL SUMMARY OF CHANGES
70
APPENDIX G.
OPERATIONS MANUAL
75
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Giant Cell Arteritis (GCA)
Giant cell arteritis (GCA), also known as temporal arteritis, is a systemic vasculitis of the large vessels 
with a predilection for the cranial branches of the aorta.  GCA affects women to men in a 3:1 ratio and 
almost exclusively those over age 50.  The course of GCA is characterized by a relatively abrupt onset 
followed by chronic vascular and systemic inflammation.  Left untreated, patients with GCA tend to 
manifest persistent systemic and vascular inflammation with resultant pathology related to progressive 
vascular occlusion.
The characteristic symptoms of GCA include those related to vascular occlusion such as headache, jaw 
pain related to use (jaw claudication), as well as ocular symptoms.  Visual symptoms occur in up to 30% 
of GCA patients and can include diplopia or vision loss with 15% of patients manifesting permanent 
unilateral or bilateral loss of vision.  Patients with GCA experience systemic symptoms such as fever, 
fatigue, and weight loss.  There is a significant overlap between GCA and polymyalgia rheumatica (PMR) 
with up to 30% of those with GCA manifesting PMR.
Corticosteroid (CS) therapy is the current mainstay of treatment for GCA.  High doses of CS therapy are 
initially required and most often quickly control inflammation and prevent vision loss and/or other 
irreversible symptoms.  Initial high dose CS therapy is followed by a prolonged period of dose tapering.  
During this tapering phase, between 50% and 80% of GCA patients experience a disease flare.1  In 
addition to symptomatic pathology, prolonged exposure to CS therapy results in approximately 80% of 
GCA patients manifesting steroid-associated pathology within 10 years following diagnosis.2
Though many symptoms such as headache and PMR symptoms resolve rapidly with initiation of high 
dose CS therapy, ischemic complications such as jaw claudication may take considerably longer.  
Additionally, GCA is associated with chronic vascular damage including aortic inflammation with 
subsequent aortic aneurysm formation which may result in spontaneous rupture and/or the need for 
surgical repair.  Notably, there are cases reported of chronic underlying vascular inflammation and 
progression of vascular pathology despite control of clinically apparent disease activity, even while still 
on chronic CS therapy.3  Thus, there remains the potential for improved treatment options which can 
mitigate this subclinical vascular inflammation.
The prevalence of GCA varies by region with reported rates of temporal arteritis/GCA varying widely 
between 1 and 30 per 100,000 individuals and with further enrichment in individuals ≥ 50 years of age.  
The highest rates are observed in populations from Scandinavian countries and of Northern European 
descent.1
The current treatment regimen for GCA consists almost exclusively of CS therapy.  Numerous trials of 
biologic and non-biologic immunosuppressants have attempted to identify steroid-sparing therapies, 
but until recently none have been definitively successful.  Recently, Phase 2 and Phase 3 studies of 
tocilizumab have demonstrated superiority in the achievement of GCA disease remission compared to 
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standard-of-care CS therapy.4,5  In addition to increased rates of remission, these studies demonstrated 
the ability to reduce exposure to CS therapy by nearly half with concomitant tocilizumab treatment.]
Upadacitinib as Potential Treatment for GCA
Targeting the Janus kinase (JAK) signaling pathway for autoimmune diseases such as GCA, rheumatoid 
arthritis (RA), Crohn's disease (CD), psoriatic arthritis (PsA), ulcerative colitis (UC), atopic dermatitis (AD), 
and axial spondyloarthritis (AxSpA), is supported by the involvement of various pro-inflammatory 
cytokines that signal via JAK pathways in the pathogenesis of these immune-related disorders.  The 
activation of JAK signaling initiates expression of survival factors, cytokines, chemokines, and other 
molecules that facilitate leukocyte cellular trafficking and cell proliferation which contribute to multiple 
inflammatory and autoimmune disorders, including the key cytokines driving GCA pathogenesis.6-8
The JAK family is composed of 4 members:  JAK1, 2, 3, and tyrosine kinase 2 (Tyk2).  These cytoplasmic 
tyrosine kinases act in tandem to activate the Signal Transducer and Activator of Transcription (STAT) 
that transduce cytokine-mediated signals, and are associated with multiple membrane cytokine 
receptors such as common gamma chain (CGC) receptors and the glycoprotein 130 transmembrane 
proteins.9  JAK3 and JAK1 are components of the CGC cytokine receptor complexes that are responsible 
for the signaling of the inflammatory cytokines interleukin (IL)-2, -4, -7, -9, -15 and -21; whereas IL-12 
and IL-23 signal through JAK2 and Tyk2.10  Propagation of these signals is important in the amplification 
of inflammatory responses.
Upadacitinib is a novel JAK1 inhibitor currently being developed for the treatment of adult patients with 
inflammatory diseases such as RA, CD, PsA, UC, AD, AxSpA, and Takayasu arteritis.  In an in-vitro setting, 
upadacitinib potently inhibits JAK1 activity, but to a lesser degree, inhibits the other isoforms, JAK2 and 
JAK3.  The enhanced selectivity of upadacitinib against JAK1 may offer an improved benefit/risk profile 
in patients with GCA.  Upadacitinib has reduced activity against JAK2 and JAK3 which may mitigate JAK2 
inhibitory effects on erythropoiesis and myelopoiesis as well as immunosuppressive effect mediated by 
JAK3 inhibition.
By preferentially targeting JAK1, it is anticipated that upadacitinib will demonstrate the ability to 
abrogate signaling of key cytokines involved in the pathogenesis of GCA.  Extensive preclinical, ex vivo, 
and in vivo studies have demonstrated robust inhibition of the JAK1-dependent cytokines IL-6 and 
Interferon gamma (IFN-γ).  These two cytokines have been strongly implicated in the pathogenesis of 
GCA.  IL-6 receptor blockade with tocilizumab has demonstrated efficacy in GCA in Phase 2 and Phase 3 
studies.4,5  However, preclinical and translational human studies have suggested that even in the setting 
of high dose CS with resultant reduction of IL-6 pathway, there persists a level of subclinical 
inflammation driven largely by IFN-γ.11,12  Serial biopsies of patients with GCA treated with high dose 
CS have demonstrated that the IL-6 cytokine pathway is highly responsive to standard CS therapy, 
whereas the IFN-γ pathway is resistant to steroid-mediated immunosuppression.13  Moreover, direct 
IFN-γ blockade abrogates STAT1 activation, reduced expression of ICAM-1, CXCL9, 10, 11 and prevents 
macrophage adhesion/infiltration.
Similarly, treatment with the relatively non-selective JAK inhibitor tofacitinib in a translational model of 
human GCA14 demonstrated abrogation of STAT-1 signaling, reduced blood levels of IFN-γ, and 
prevention of T cell and macrophage accumulation in the vessel wall.
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Clinically, the persistence of smoldering inflammation is supported by studies in which patients with 
GCA, or the closely related large vessel vasculitis Takayasu's arteritis, who were treated with the IL-6 
pathway blocker tocilizumab, demonstrated persistent vasculitis of medium-sized and large vessels on 
autopsy despite apparent clinical response to therapy.15,16  These data suggest that although IL-6 
receptor blockade can provide reduction in flares when used continuously on the background of a 
forced CS taper, ultimately targeting the CS/IL-6 resistant Th1 responses will be necessary to resolve 
chronic smoldering vasculitis.  Among those with a good response to tocilizumab in a 1-year study, over 
half of subjects relapsed (as early as 3 months) after discontinuation of IL-6R blockade.17
Using RA as a model, exposures achieved with upadacitinib 15 mg daily are anticipated to provide a level 
of IL-6 inhibition in range of that achieved with tocilizumab 162 mg weekly (the approved GCA dose).  In 
addition to IL-6 blockade, there is anticipated to be robust inhibition of the IFN-γ signaling with 
upadacitinib.  Thus, upadacitinib treatment has the potential to provide additive efficacy above and 
beyond that observed with IL-6R blockade alone.
Clinical Hypothesis
It is hypothesized that inhibition of cytokine signaling through the IL-6, IFN-γ, and IL-12 signaling 
pathways by upadacitinib, a selective JAK1 inhibitor, will result in improved ability to maintain remission 
with absence of GCA signs and symptoms compared to placebo (PBO), even in the setting of a more 
rapid reduction of CS treatment.
2.2 Benefits and Risks to Patients
Despite the observed benefit of tocilizumab over standard-of-care CS therapy (56% versus 18% rates of 
sustained remission from Week 12 through Week 52 defined as the absence GCA signs and symptoms, 
normalization of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and adherence to 
the CS taper regimen),5 there is still significant room for improvement.  In addition, it is not yet clear if 
the observed benefit translates into a potential for drug-free remission.  Thus, there remains a medical 
need for additional therapeutic options in GCA to further increase rates of sustained remission and 
minimize steroid exposure.
The doses to be evaluated in Study M16-852 (upadacitinib 7.5 and 15 mg once daily [QD]) are expected 
to provide an optimal benefit/risk profile to support chronic administration in this study population; 
refer to the Selection of Doses in the Study section for additional details.
Adverse events (AEs) such as infections including herpes zoster reactivation, major adverse 
cardiovascular events (MACE defined as cardiovascular death, non-fatal myocardial infarctions and non-
fatal strokes), thrombosis, malignancies, and hematologic AEs have been observed with JAK inhibition.  
Upadacitinib is a novel selective JAK1 inhibitor with the ability to decrease inflammation mediated by 
JAK1 signaling while having less inhibitory effect on JAK2 and JAK3.  This could potentially minimize 
some of the reported safety concerns with less selective JAK inhibition which are thought to be 
mediated by inhibition of JAK2 and JAK3 signaling pathways.
An increased risk of infections including opportunistic infections (e.g., mucosal candida infections) and 
herpes zoster, non-melanoma skin cancer (NMSC), and abnormal laboratory changes (e.g., elevations of 
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serum transaminases, lipids, and creatine phosphokinase; and reductions in hemoglobin and white 
blood cells) have been observed with upadacitinib therapy. 
In ORAL Surveillance, a study of a different JAK inhibitor, tofacitinib, in RA patients 50 years of age and 
older with at least one cardiovascular risk factor, higher rates of all-cause mortality, malignancies, MACE 
and thrombosis (overall thrombosis, deep vein thrombosis, and pulmonary embolism) were seen in 
patients treated with tofacitinib versus TNF blockers.7 These higher rates were primarily observed in 
patients 65 years of age and older, patients with a history of atherosclerotic cardiovascular disease, and 
patients with other cardiovascular risk factors (such as current or past long-time smokers). Although 
upadacitinib clinical trial data to date have not indicated a higher risk for MACE, venous 
thromboembolism, malignancies excluding NMSC, or deaths in RA patients treated with upadacitinib 
versus adalimumab, the findings of the ORAL Surveillance study may potentially also apply to other JAK 
inhibitors and an increased risk for these events compared to TNF blockers cannot be completely 
excluded. Therefore, the investigator should consider the benefits and risks of upadacitinib treatment 
and suitable treatment alternatives in determining study participation and the continued use of 
upadacitinib in patients 65 years of age and older, patients with a history of atherosclerotic 
cardiovascular disease or other cardiovascular risk factors, patients who are current or past long-time 
smokers, and/or patients with other malignancy risk factors (e.g., current malignancy or history of 
malignancy).
The results of genetic toxicology testing indicate that upadacitinib is not genotoxic; however, 
upadacitinib is teratogenic based on animal studies, which necessitates avoidance of pregnancy in 
females of childbearing potential.  Based on the calculated safety margins for human fetal exposure with 
seminal fluid transfer, there is judged to be no risk to the pregnancy of female partners of male subjects 
who are treated with upadacitinib.
A detailed discussion of the pre-clinical and clinical toxicology, metabolism, pharmacology, and safety 
experience with upadacitinib can be found in the current Investigator's Brochure.18
Taken together, the safety and efficacy data from upadacitinib studies to date show a favorable 
benefit:risk profile for upadacitinib and support the continued investigation of upadacitinib in patients 
with various autoimmune/inflammatory conditions.
In view of the coronavirus disease 2019 (COVID-19 [coronavirus SARS-CoV-2]) pandemic, the benefit-risk 
profile of various immunomodulatory therapies on COVID-19 is being evaluated.  At this time, the 
effects of upadacitinib on the course of COVID-19 are not well defined.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Period 1
To evaluate the efficacy of upadacitinib 7.5 mg once daily (QD) and 15 mg QD in combination with a 
26-week CS taper regimen compared to PBO in combination with a 52-week CS taper regimen, as 
measured by the proportion of subjects in sustained remission at Week 52, and to assess the safety and 
tolerability of upadacitinib in subjects with GCA.
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Period 2
To evaluate the safety and efficacy of continuing versus withdrawing upadacitinib in maintaining
remission in subjects who achieved remission in Period 1.
3.2 Primary Endpoint
The primary endpoint is the proportion of subjects achieving sustained remission at Week 52.  Sustained 
remission is defined as having achieved both of the following:

Absence of GCA signs and symptoms from Week 12 through Week 52

Adherence to the protocol-defined CS taper regimen.
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volume of distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of 
the data.  Data from this study may be combined with data from other studies for the population 
pharmacokinetic analyses.
3.6 Patient Experience Endpoints
Data on patient experience will be collected by questionnaire at the Baseline visit and answers will be 
recorded in the electronic case report form (eCRF).  The objective of the research is to obtain relevant 
information about patient experiences regarding the burden of GCA disease and treatment.
3.7 Biomarker Exploratory Research
Optional blood samples for exploratory research will be collected as described in the Activity Schedule 
(Appendix D).  Prognostic and predictive biomarker signatures may be evaluated.  Biomarker 
assessments may include nucleic acids, proteins, metabolites, or lipids.  Exploratory research will focus 
on GCA and upadacitinib.  The objective of research is to analyze samples for biomarkers that will help 
to understand the subject's disease and response to upadacitinib.  Genes of interest may include (but 
not limited to) those associated pharmacokinetics (drug metabolizing enzymes, drug transport proteins), 
genes within the target pathway (JAK, Tyk2, tumor necrosis factor [TNF]), or other genes believed to be 
related GCA and other inflammatory diseases (human leukocyte antigens [HLA], IL).  Research may also 
include epigenetic changes in DNA that may associate with the subject's response to treatment or 
disease.  Samples for ribonucleic acid (RNA) and proteomics will be used to research if any genetic 
variants result in changes to gene expression or protein concentrations.
These assessments may be explored in the context of GCA or related conditions and/or upadacitinib or 
drugs of similar classes.  Research on samples collected in Germany will be restricted to GCA and 
upadacitinib.  The results from these analyses are exploratory in nature and may not be included with 
the clinical study report.
The samples may be retained for no longer than 20 years after study completion or per local 
requirements.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
Study M16-852 is a Phase 3, global, multicenter, randomized, double-blind, PBO-controlled study.  
Approximately 420 subjects will be enrolled into this study.
The study population will consist of adult subjects who are at least 50 years of age with a diagnosis of 
active GCA, either new onset or relapsing disease, within 8 weeks of Baseline.  Active GCA is defined by 
the presence of at least one of the following:  unequivocal cranial symptoms of GCA, unequivocal 
symptoms of PMR, or other features judged by the investigator to be consistent with GCA or PMR flares, 
AND an ESR ≥ 30 mm/hr or CRP ≥ 1 mg/dL.
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New onset disease is defined as diagnosis of GCA within 8 weeks of Baseline.  Relapsing disease is 
defined as active GCA in a subject who has failed at least one attempted CS taper.
The study will allow enrollment of a minimum of 30% of subjects with new onset disease and up to 70% 
of subjects with relapsing disease.  The study will also allow enrollment of up to 20% of subjects with 
previous use of an IL-6 inhibitor with discontinuation based on reasons other than disease flare.
The study duration will include a 35-day maximum Screening Period:  a 52-week randomized, 
double-blind, parallel-group treatment period (Period 1); a 52-week blinded extension period in which 
subjects may either be re-randomized or continue their original treatment assignment (Period 2); and a 
30-day follow-up period.
In Period 1, subjects who meet eligibility criteria will be randomized in a 2:1:1 ratio to 1 of 3 treatment 
groups:

Upadacitinib 15 mg administered daily + 26-week CS taper regimen (n = 210)

Upadacitinib 7.5 mg administered daily + 26-week CS taper regimen (n = 105)

PBO administered daily + 52-week CS taper regimen (n = 105)
Subjects must have received treatment for active GCA at a dose of ≥ 40 mg prednisone (or equivalent) at 
any time prior to Baseline and must be receiving prednisone (or prednisolone) ≥ 20 mg QD at Baseline.  
Subjects must have GCA that, in the opinion of the investigator, is clinically stable to allow the subject to 
safely initiate the protocol-defined CS taper regimen.
Starting at Baseline, all subjects will switch from CS obtained outside of the study to CS provided by the 
sponsor with the oral prednisone or prednisolone dose at 20, 30, 40, 50, or 60 mg QD.  The initial dose 
of prednisone or prednisolone will be at the discretion of the investigator, based on disease severity and 
comorbid medical conditions, but should be at a minimum of 20 mg QD at Baseline.  At Baseline, if a 
subject is on a dose other than 20, 30, 40, 50, or 60 mg QD, the dose should be rounded up or down, as 
clinically indicated per investigator discretion, to the nearest of these doses.  If a subject has already 
taken the CS dose at home on the day of the Baseline visit, dosing should not be repeated with 
sponsor -provided CS.  Prednisone or prednisolone will be tapered according to a predefined schedule 
over a 26- or 52-week period.  Open-label prednisone or prednisolone will be provided until the dose is 
tapered to 20 mg/day.  Subsequently, blinded prednisone or prednisolone will be provided for the 
remaining blinded taper regimen through Week 52.  See Section 5.8 for additional details regarding CS 
therapy during the study.
Subjects assigned to either dose of upadacitinib who achieve sustained remission for at least 
24 consecutive weeks prior to the Week 52 Visit (at the end of Period 1) will be re-randomized in a 
2:1 ratio to either continue on upadacitinib or switch to PBO in Period 2.  Subjects who achieved 
sustained remission for at least 24 weeks prior to the Week 52 visit (at the end of Period 1) who were 
assigned to PBO in Period 1 will continue to receive PBO in Period 2.  Remission is defined as absence of 
GCA signs and symptoms AND adherence to the protocol-defined CS taper regimen or CS-free.
At Week 52, subjects who have absence of GCA signs and symptoms AND are CS-free at the Week 52 
visit, but do not achieve sustained remission for at least 24 consecutive weeks prior to the Week 52 
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Visit, will continue in Period 2 on their originally randomized treatment assignment.  All other subjects 
will be discontinued from study drug and the study at the end of Period 1.
Subjects who discontinue study drug during Period 1 should receive treatment at the investigator's 
judgment, in accordance with local standard-of-care (which could include tocilizumab), and continue to 
follow the regular visit schedule for the remainder of Period 1 and adhere to the Period 1 study 
procedures as noted in Appendix D.
In Period 2, subjects who experience a flare (defined as an event determined by the investigator to 
represent recurrence of GCA signs or symptoms or an ESR measurement > 30 mm/hr attributable to 
GCA, AND requiring initiation of CS) will start open-label escape therapy with prednisone or 
prednisolone at investigator's discretion.  A flare may be documented at either a scheduled or 
unscheduled visit.  Subjects meeting flare criteria will return within approximately 4 weeks after the visit 
in which flare was determined for reassessment.  The reassessment can occur at either a regularly 
scheduled or unscheduled visit.  If the subject does not have absence of GCA signs and symptoms within 
approximately 4 weeks after the visit in which flare was determined, they will be discontinued from 
study drug.  Subjects who discontinue study drug should receive treatment at the investigator's 
judgment, in accordance with local standard-of-care (which could include tocilizumab), and continue to 
follow the regular visit schedule for Period 2 and adhere to the study procedures as noted in 
Appendix D.
An independent, external data monitoring committee (DMC) will be established for periodic review of 
unblinded safety data and to ensure subject safety.  In addition, a futility analysis will be conducted by 
the DMC to assess lack of efficacy once the first 140 enrolled subjects complete 24 weeks of treatment.  
Study sites and subjects will remain blinded for the duration of the study.  After the last subject 
completes the Week 52 visit the Sponsor will be unblinded to Period 1 study drug assignment to 
facilitate regulatory filings.  See Section 6.3 and Section 7.5 for additional details regarding the DMC and 
the planned futility analysis.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual.
See Section 5 for information regarding eligibility criteria.
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Figure 1.
Study Schematic
R1 = sustained remission for 24 consecutive weeks prior to Week 52; R2 = remission at Week 52 only
4.2 Discussion of Study Design
Choice of Control Group
Placebo control will be used in this study to address potential confounding factors, such as placebo 
effect, potential investigator bias in safety and efficacy assessment or regression to the mean in 
endpoint evaluation.
The control group in this study will be placebo plus a 52-week CS taper regimen and represent a CS 
monotherapy taper regimen.  A 52-week duration for CS taper was chosen for the control group 
because it is consistent with clinical practice standard of care.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with GCA.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
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Suitability of Subject Population
This study will enroll adult female and male subjects who are at least of 50 years of age at the time of 
the Screening visit who have been diagnosed with GCA and who have active disease within 8 weeks of 
Baseline.  The study population selected in this study reflects the standard population for GCA trials with 
new interventions.
Selection of Doses in the Study
This Phase 3 study will evaluate 2 doses of upadacitinib (7.5 or 15 mg QD) using the once-daily tablet 
formulation.  The selection of doses was informed by results from the exposure-response relationships 
characterized in Phase 2 studies in RA (Studies M13-537 and M13-550), the Phase 3 clinical trials in RA 
(Studies M13-549 [SELECT-NEXT] and M13-542 [SELECT-BEYOND]), and the published results for Phase 2 
and Phase 3 studies of the IL-6 inhibitor tocilizumab in GCA.4,5
Exposure-response analyses of the two Phase 2 studies in RA using the immediate-release formulations 
(doses from 3 mg twice daily [BID] to 18 mg BID and 24 mg QD) indicated that the 6 mg BID dose 
(equivalent to the 15-mg QD dose) approaches the plateau of efficacy in RA, and increasing the dose to 
12 mg BID (equivalent to the 30-mg QD dose) appears to result in modest incremental efficacy 
benefit.19,20  A bioavailability study has demonstrated that a 15 mg QD regimen of the once-daily 
formulation provide equivalent daily area under the curve (AUC) and comparable maximum serum 
concentration (Cmax) and minimum serum concentration (Cmin) to 6 mg BID of the immediate-release 
capsule formulation used in Phase 2 studies in RA under fasting conditions.21
Results from the first two RA Phase 3 clinical trials (Study M13-549 [SELECT-NEXT] and Study M13-542 
[SELECT-BEYOND]) evaluating upadacitinib in subjects with moderate to severe RA showed that after 
12 weeks of treatment, both doses of upadacitinib (15 mg and 30 mg QD) met the study's primary 
endpoints of ACR20 and Low Disease Activity (LDA).  Key secondary endpoints were also achieved.  
Study M13-549 evaluated upadacitinib compared to PBO in subjects who did not adequately respond to 
treatment with conventional-synthetic disease-modifying antirheumatic drugs (csDMARD-IR), while 
Study M13-542 evaluated upadacitinib compared to PBO in subjects who did not adequately respond to 
treatment with biologic DMARD antirheumatic drugs (bDMARD-IR).  Results from the Phase 2 and 
Phase 3 RA studies support the use of upadacitinib 15 mg as an efficacious dose in RA, and this dose is 
also expected to be efficacious in GCA.
In addition, a 7.5 mg dose will also be evaluated to ensure the minimal efficacious dose in GCA is 
characterized.  Since GCA affects an older population with co-morbid conditions and requires initiation 
of high dose CS, this population is potentially at greater risk of infections.  As such, a 7.5 mg dose may 
provide an optimal benefit/risk profile to support chronic administration in GCA patients.
The doses to be evaluated in Study M16-852 (upadacitinib 7.5 mg and 15 mg QD) are predicted to 
provide exposures that are lower than the no-observed-adverse-effect level (NOAEL) exposures from 
the preclinical toxicology studies as well as the highest exposures that were previously evaluated and 
found to be safe and well tolerated in healthy volunteers in Phase 1 studies and in subjects with RA or 
CD in Phase 2 studies.  There is now extensive patient exposure to upadacitinib 15 and 30 mg QD in the 
ongoing Phase 3 RA program with a preliminary safety profile consistent with Phase 2 studies of 
upadacitinib as well as the safety profile observed with JAK inhibitors as a class.  Age in adults has no 
impact on upadacitinib pharmacokinetics based on population pharmacokinetic analyses across Phase 1, 
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RA Phase 2, and CD Phase 2 studies.  Results from hepatic and renal impairment studies of upadacitinib 
suggest a limited increase in upadacitinib exposure with hepatic or renal impairment.  Therefore, 
subjects with GCA are not expected to have a clinically relevant difference in upadacitinib plasma 
exposures from previous observations in subjects with RA.
Efficacy in GCA was demonstrated for an IL-6 receptor inhibitor, tocilizumab, using doses that were 
efficacious in RA (162 mg subcutaneous [SC] injection once weekly and 162 mg SC every 2 weeks).4,5
Therefore, the 7.5 mg and 15 mg QD upadacitinib doses selected for Study M16-852, dosed for up to 
104 weeks are expected to provide an acceptable efficacy and safety profile.
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.
Disease Activity
1. Diagnosis of GCA according to the following criteria:

Adult male or female, at least 50 years of age

History of ESR ≥ 50 mm/hour or high sensitivity C-reactive protein (hsCRP)/CRP ≥ 1.0 mg/dL

Presence of at least one of the following:

Unequivocal cranial symptoms of GCA (new-onset localized headache, scalp tenderness, 
temporal artery tenderness or decreased pulsation, ischemia-related vision loss, or 
otherwise unexplained mouth or jaw pain upon mastication), or

Unequivocal symptoms of PMR (shoulder and/or hip girdle pain associated with 
inflammatory morning stiffness).

Presence of at least one of the following:

Temporal artery biopsy revealing features of GCA, or

Evidence of large vessel vasculitis by angiography or cross-sectional imaging (such as 
magnetic resonance imaging [MRI], computed tomography [CT] or positron emission 
tomography [PET]), assessed by a qualified radiologist experienced in evaluating large 
vessel vasculitis, or ultrasound of temporal arteries assessed by a qualified physician 
experienced in evaluating large vessel vasculitis.
2. Active GCA, either new onset or relapsing, within 8 weeks of Baseline.  Active disease is 
defined by the presence of an ESR ≥ 30 mm/hr or hsCRP/CRP ≥ 1 mg/dL AND at least one of the 
following:  unequivocal cranial symptoms of GCA, unequivocal symptoms of PMR, or other 
features judged by the investigator to be consistent with GCA or PMR flares.
3. Subjects must have received treatment with ≥ 40 mg prednisone (or equivalent) at any time 
prior to Baseline and be receiving prednisone (or prednisolone) ≥ 20 mg QD at Baseline.
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4. Subjects must have GCA that, in the opinion of the investigator, is clinically stable to allow the 
subject to safely initiate the protocol-defined CS taper.
Contraception
5. Women of childbearing potential must not have a positive serum pregnancy test at the 
Screening Visit and must have a negative urine pregnancy test at the Baseline Visit prior to study 
drug dosing. 
Note:  subjects with borderline serum pregnancy test at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result.
6. If female, subject must be either postmenopausal, OR permanently surgically sterile OR, for 
women of childbearing potential, practicing at least 1 protocol-specified method of birth control 
(Section 5.2) that is effective from Study Day 1 through at least 30 days after the last dose of 
study drug.  Additional local requirements may apply; country-specific requirements are 
provided in Section 5 of the Operations Manual.
7. Female subjects must not be pregnant, breastfeeding, or considering becoming pregnant 
during the study or within 30 days after the last dose of study drug.
Consent
8. Subjects must be able to understand and adhere to all protocol requirements and must 
voluntarily sign and date an informed consent, approved by an independent ethics committee 
(IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific 
procedures.
9. Are willing and able to comply with procedures required in this protocol.
Laboratory Values
10. Laboratory values must meet the following criteria within the screening period prior to the 
first dose of study drug:  

Serum aspartate transaminase ≤ 2 × upper limit of normal (ULN)

Serum alanine transaminase ≤ 2 × ULN 

Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in 
Renal Disease formula ≥ 30 mL/min/1.73 m2

Total white blood cell (WBC) count ≥ 2,500/µL

Absolute neutrophil count (ANC) ≥ 1,500/µL

Platelet count ≥ 100,000/µL

Absolute lymphocyte count (ALC) ≥ 750/µL

Hemoglobin ≥ 9 g/dL.
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Subject History
11. 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 electrocardiogram (ECG) performed during Screening.
12. Subject must not have a history of clinically significant (per investigator's judgment) drug or 
alcohol abuse within the last 6 months.
13. Subject must have no current or past history of infection including:

No history of two or more episodes of herpes zoster, or one or more episodes of 
disseminated herpes zoster;

No history of one or more episodes of disseminated herpes simplex (including eczema 
herpeticum);

No human immunodeficiency virus (HIV) infection defined as confirmed positive anti-HIV 
antibody (HIV Ab) test;

Subject does not have active tuberculosis (TB) and does not meet TB exclusionary 
parameters (specific requirements for TB testing are provided in the operations manual);

For subjects in Japan:  No positive result of beta-D-glucan or two consecutive indeterminate 
results of beta-D-glucan (screening for Pneumocystis jirovecii infection) during the Screening 
Period;

No active infection(s) requiring treatment with intravenous anti-infectives within 30 days, or 
oral/intramuscular anti-infectives within 14 days prior to the Baseline Visit;

No 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;

No active hepatitis B virus (HBV) or hepatitis C virus (HCV) defined as:

HBV:  hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV 
deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for 
subjects who are hepatitis B core antibody (HBc Ab) positive (+) (and for hepatitis B 
surface antibody (HBs Ab) positive [+] subjects in Japan only);

HCV:  HCV RNA detectable in any subject with anti-HCV antibody (HCV Ab).

Confirmed active COVID-19:  the Baseline Visit must be at least 14 days from the onset of 
signs/symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, 
defined as resolution of fever without use of antipyretics and improvement of symptoms;

Suspected COVID-19:  subjects with signs/symptoms suggestive of COVID-19, known 
exposure, or high-risk behavior should undergo molecular (e.g., PCR) testing to rule out 
SARS-CoV-2 infection or must be asymptomatic for 14 days following potential exposure.
14. Subject must not have any underlying medical disease or problems including but not limited 
to the following:

Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary 
stenting, and aorto-coronary bypass surgery or other ischemic events unrelated to GCA
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
Uncontrolled hypertension defined by a confirmed systolic blood pressure > 160 mmHg or 
diastolic blood pressure > 100 mmHg

Has been a previous recipient of an organ transplant which requires continued 
immunosuppression

History of gastrointestinal perforation (other than due to appendicitis or mechanical injury), 
diverticulitis or have a significantly increased risk for gastrointestinal perforation per the 
investigator's judgment

Conditions that could interfere with drug absorption including but not limited to short 
bowel syndrome

History of any malignancy except for successfully treated non-melanoma skin cancer or 
localized carcinoma in situ of the cervix.
15. Subject must not have undergone any major surgical procedure (except cutaneous 
procedures) within 60 days prior to the Baseline and must not have any planned surgery during 
the trial that would impact study procedures or assessments.
16. Subject must not be permanently wheelchair-bound or bedridden.
17. Subject must not have any clinically significant medical condition or any other reason which, 
in the opinion of the investigator, would make the subject an unsuitable candidate to receive 
study drug or would put the subject at risk by participating in the study.
Concomitant Medications
18. Subject has not been treated with any investigational drug of chemical or biologic nature 
(see Section 5.3 for additional information on biologic therapies) within a minimum of 30 days 
or five half-lives (whichever is longer) prior to the first dose of study drug or is not currently 
enrolled in another interventional clinical study.
19. Subject must have no systemic use of known strong cytochrome P450 3A (CYP3A) inhibitors 
from Screening through the end of the study or strong CYP3A inducers 30 days prior to study 
drug administration through the end of the study (refer to Table 1 in Section 5.3 for examples of 
commonly used strong CYP3A inhibitors and inducers).
20. Subject must not have received any live vaccine within 4 weeks (8 weeks for subjects in 
Japan) prior to the first dose of study drug, or expected to need live vaccination during study 
participation including at least 4 weeks (8 weeks for subjects in Japan) after the last dose of 
study drug.
21. Subject must not have had prior exposure to any JAK inhibitor (including but not limited to 
upadacitinib, tofacitinib, ruxolitinib, baricitinib, and filgotinib).
22. Subject must not have been treated with an interleukin-6 (IL-6) inhibitor (including but not 
limited to tocilizumab, sirukumab, and sarilumab) within 4 weeks of Baseline.  Subjects 
previously treated with an IL-6 inhibitor must not have experienced disease flare during 
treatment.
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23. Subject must not have received a biologic or non-biologic DMARD within at least five times 
the mean terminal elimination half-life of a drug or must follow the washout period specified 
below:

Anakinra within 1 week of Baseline;

Methotrexate, hydroxychloroquine, cyclosporine, azathioprine, or mycophenolate within 
4 weeks of Baseline;

≥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);

Cell-depleting agents (e.g., anti-CD 20) or alkylating agents including cyclophosphamide 
within 6 months of Baseline.
24. Subject must not have chronic use of systemic (oral, intravenous, and/or intramuscular) CS 
for > 4 years or if ≤4 years, an inability, in the opinion of the investigator, to withdraw from CS 
treatment through the protocol-defined taper regimen.
25. Subject must not have used oral CS for conditions other than GCA within 4 weeks of Baseline 
or intravenous CS within 4 weeks of Baseline.  Subjects must not have had > 2 courses of 
systemic CS therapy to treat conditions other than GCA within 1 year prior to baseline.
26. Subject must not have a 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, or to 
corticosteroids.
27. Subject must not have received oral Traditional Chinese Medicines within 4 weeks prior to 
Baseline (refer to Section 5.3).
5.2 Contraception Recommendations
Contraception Requirements for Females
A woman who is permanently surgically sterile or postmenopausal is not considered to be a woman of 
childbearing potential and is not required to follow contraception recommendations.
Surgically sterile is defined as:

Bilateral oophorectomy (surgical removal of both ovaries); or

Bilateral salpingectomy (surgical removal of both fallopian tubes); or

Hysterectomy (surgical removal of uterus).
Postmenopausal is defined as:

Age > 55 years with no menses for 12 or more months without an alternative medical cause; or

Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause 
AND a follicle stimulating hormone (FSH) level > 30 mIU/mL.
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For a woman who is ≤ 55 years of age and is not permanently surgically sterile, as defined above, and 
has had no menses for 12 or more months, FSH should be tested at Screening.

If FSH is not tested, it is assumed that the subject is of childbearing potential and 
protocol -specified contraception is required.

If the FSH is tested and the result is consistent with post-menopausal status, contraception is 
not required.

If the FSH is tested and the result is consistent with pre-menopausal status, contraception is 
required and pregnancy testing requirements for women of childbearing potential must be 
followed as described in the Study Activities Table (Appendix D).
A woman who does not meet the definition of postmenopausal or permanently surgically sterile is 
considered of childbearing potential and is required to practice at least one of the following highly 
effective methods of birth control that is effective from Study Day 1 (or earlier) through at least 30 days 
after the last dose of study drug:

Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, 
transdermal, injectable) associated with the inhibition of ovulation, initiated at least 30 days 
prior to Study Day 1.

Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 30 days prior to Study Day 1.

Bilateral tubal occlusion/ligation (For subjects in Japan:  Bilateral tubal ligation).

Vasectomized partner(s), provided the vasectomized partner has received medical confirmation 
of the surgical success and is the only sexual partner.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

True abstinence (if acceptable per local requirements):  Refraining from heterosexual 
intercourse-when this is in line with the preferred and usual lifestyle of the subject.  Periodic 
abstinence (for example, using calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable.
If required per local guidelines, male or female condom with or without spermicide OR cap, diaphragm 
or sponge with spermicide should be used in addition to one of the highly effective birth control 
methods listed above (excluding true abstinence).
If during the course of the study a woman becomes surgically sterile or post-menopausal (defined 
above) and complete documentation is available, contraceptive measures as defined above are no 
longer required.
It is important to note that contraception requirements described above are specifically intended to 
prevent pregnancy during exposure to the investigational therapy upadacitinib.
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Contraception recommendations related to use of concomitant therapies prescribed per standard of 
care should be based on the local label.
Contraceptive counseling 
At each visit, the study staff should review the pregnancy avoidance recommendations with each female 
of childbearing potential and document this discussion in the subject's source records.
Females for whom the childbearing potential changes during the study due to meeting any of the 
criteria for non-childbearing potential above do not need to continue using birth control during or 
following study drug treatment.
Additional local requirements may apply; refer to Section 5 of the Operations Manual for 
country -specific requirements.  For participating countries having no additional country specific 
requirements, the above-mentioned contraceptive requirements should be followed in full.
5.3 Prohibited Medications and Therapy
Biologic Therapies 
Subjects must have discontinued any biologic therapies with immunosuppressive potential prior to the 
first dose of study drug as specified in the washout procedures (Eligibility Criterion 23, Section 5.1).  For 
all other biologic therapies, contact the AbbVie Therapeutic Area Medical Director (TA MD) for the 
washout period required prior to the first dose of study drug.
Biologic therapies with immunosuppressive potential are prohibited medications through the end of 
study drug administration, and include, but are not limited to, the following:

Abatacept

Adalimumab

Anakinra

Anifrolumab

Belimumab

Certolizumab

Dupilumab

Etanercept

Golimumab

Guselkumab

Infliximab

Ixekizumab

Lebrikizumab

Natalizumab
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
Nemolizumab

Rituximab

Risankizumab

Sarilumab

Secukinumab

Tocilizumab

Tralokinumab

Ustekinumab

Vedolizumab
Immunosuppressants
Introduction of additional systemic immunosuppressants (such as methotrexate, hydroxychloroquine, 
cyclosporine, azathioprine, or mycophenolate) concurrent with study drug is prohibited from 4 weeks 
prior to first dose of study drug through the end of the study.  Subjects who discontinue study drug may 
receive treatment with immunosuppressants in accordance with the investigator's best clinical 
judgment, irrespective of whether or not the subject decides to continue participation in the study.
Parenteral Corticosteroids
Intra-articular, trigger-point/tender point injection, intra-bursa, or epidural administration of CS is not 
permitted during Period 1 of the study.  Section 5.4 describes use of CS for non-GCA-related conditions 
that is allowed during the study.  During Period 2 of the study, one intra-articular, trigger-point/tender 
point injection, intra-bursal injection, epidural, or intra-muscular injection is allowed for 
non-GCA-related conditions if it meets the permitted amount of CS allowed in Period 2 as described in 
Section 5.4.
Strong CYP3A Inhibitors or Inducers 
Systemic use of known strong CYP3A inhibitors is prohibited from Screening through the end of the 
study and strong CYP3A inducers are prohibited from 30 days prior to study drug administration through 
the end of the study.  Commonly used strong CYP3A inhibitors and inducers are listed in Table 1. In 
addition, herbal therapies and other traditional medicines with unknown effects on CYP3A are not 
permitted from Screening through the end of study drug administration.
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Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Strong CYP3A Inhibitors 
Strong CYP3A Inducers 
Boceprevir 
Ceritinib
Cobicistat 
Clarithromycin 
Conivaptan 
Grapefruit (fruit or juice) 
Idelalisib
Itraconazole 
Ketoconazole 
Mibefradil 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir (alone or in combination danoprevir, 
elvitegravir, indinavir, lopinavir, nirmatrelvir, 
paritaprevir, saquinavir, telaprevir, tipranavir, 
ombitasvir and/or dasabuvir)
Telithromycin 
Troleandomycin 
Voriconazole 
Apalutamide
Carbamazepine
Enzalutamide
Ivosidenib
Lumacaftor
Mitotane
Phenytoin
Rifampin (Rifampicin)
Rifapentine
St. John's Wort
Avasimibe
Investigational Drugs
The use of any investigational drug within 30 days or five half-lives of the drug (whichever is longer) is 
prohibited.  Investigational drugs are also prohibited during the study.
Vaccines
If the subject and investigator choose to administer live vaccines with replicating potential, these 
vaccinations must be completed (per local label) at least 4 weeks (8 weeks for subjects in Japan) before 
first dose of study drug.  Live vaccinations with replicating potential are prohibited during the study 
participation including at least 30 days after the last dose of study drug.
Examples of live vaccines with replicating potential include, but are not limited to, the following:

Monovalent live influenza A (H1N1) (intranasal);

Seasonal trivalent live influenza (intranasal);

Herpes zoster (Zostavax®, live attenuated);

Rotavirus;

Varicella (chicken pox);
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
Measles-mumps-rubella or measles-mumps-rubella-varicella;

Oral polio vaccine;

Smallpox/monkeypox vaccine capable of replicating (ACAM2000®);

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), pertussis (Tdap), and SARS-CoV-2 (inactivated, messenger RNA [mRNA], 
RNA).  Whenever possible, subjects should not have received a COVID-19 vaccination in the 7 days prior 
to randomization or plan to receive a COVID-19 vaccination within the first 7 days after initiation of 
study drug. Viral vector vaccines that are not of replicating potential (such as Convidecia and Convidecia 
Air to treat Covid-19) are allowed. 
JAK/TYK2 Inhibitors
JAK Inhibitors are prohibited during the study. Oral and topical JAK/TYK2 inhibitors (e.g., commercial 
upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], ruxolitinib [Jakafi®; Opzelura®], baricitinib [Olumiant®], 
peficitinib [Smyraf®], abrocitinib [PF-04965842], and Cibinqo®], filgotinib) [Jyseleca®], fedratinib [Inrebic 
®], and deucravacitinib [Sotyktu™])
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 within 30 days prior to Screening and/or receives during the 
study must be recorded along with the reason for use, date(s) of administration including start and end 
dates, and dosage information including dose, route and frequency must be recorded in the eCRF.  Also, 
medications taken for GCA since date of diagnosis (based on subject recollection and available medical 
records) should be entered into the appropriate eCRF inclusive of the dates of first and last dose, 
maximum dosage taken, route of administration and reason for discontinuation, if known.
Subjects must be consented for the study prior to discontinuing any prohibited medications for the 
purpose of meeting study eligibility.
Throughout the study, addition of a biologic or non-biologic immunomodulators other than CS while 
taking blinded study drug (upadacitinib or PBO) is not permitted for rescue.
Inhaled and nasal CS for stable medical conditions are allowed during the study but must have been at a 
stable dose for ≥ 4 weeks prior to the Baseline Visit.  Short-term use (≤ 10 days) of CS (oral, inhaled, 
nasal, intravenous, or intramuscular) for non-GCA-related conditions for events such as exacerbation of 
asthma or chronic obstructive pulmonary disease, allergic reactions, or serious infection when additional 
CS may be required to prevent adrenal insufficiency (a total of up to 100 mg of prednisone or equivalent 
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through 52 weeks in Period 1 and a total of up to 100 mg of prednisone or equivalent through 52 weeks 
in Period 2) is allowed during the study.
Subjects should be treated with anti-platelet therapy (aspirin or clopidogrel) at the discretion of the 
investigator and in accordance with local standard-of-care practice.
Subjects should receive oral calcium and 25-hydroxy vitamin D supplementation (calcium
1200 – 1500 mg and vitamin D 800 – 1000 IU daily in divided doses), and/or bisphosphonate therapy 
(e.g., alendronate 70 mg weekly or zolendronate 4 mg annually), unless contraindicated, at the 
discretion of the investigator and in accordance with local standard-of-care practice for the prevention 
of glucocorticoid-induced osteoporosis.  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 [NOF]).
Any questions regarding concomitant or prior therapy should be raised to the AbbVie TA MD or AbbVie 
emergency contact.  Information regarding potential drug interactions with upadacitinib can be located 
in the upadacitinib Investigator's Brochure.
5.5 Discontinuation from Study Drug or Subject Withdrawal from Study
Subjects can request to be discontinued from participating in the study at any time for any reason 
including but not limited to disease progression or lack of response to treatment.  The investigator may 
discontinue any subject's participation at any time for any reason, including but not limited to disease 
progression, lack of response to treatment, an AE, safety concerns, or failure to comply with the 
protocol.
Subjects will have study drug discontinued immediately if any of the following occur:

Abnormal laboratory results or AEs that either meet the criteria of discontinuation of study 
drug, as stated in Section 6.2 or rule out safe continuation of study drug.

Serious infection (e.g., sepsis) that cannot be adequately controlled by anti-infective treatment 
or would put the subject at risk for continued participation in the trial as determined by the 
investigator.

Confirmed diagnosis of deep vein thrombosis, pulmonary embolus or noncardiac, 
non-neurologic arterial thrombosis.

The investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.

Inclusion or exclusion criteria violation was noted after the subject started the study drug, when 
continuation of the study drug would place the subject at risk.

Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk.

Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.

The subject becomes pregnant while on study drug.
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
Any malignancy, except for a localized nonmelanoma skin cancer (NMSC) or a carcinoma in-situ 
of the cervix which can successfully be treated at its localization.

The investigator determines the subject is significantly non-compliant with study procedures.

Subject develops a gastrointestinal perforation (other than due to appendicitis or mechanical 
injury).

The subject experiences a serious hypersensitivity reaction without an alternative etiology.

At Week 52, subject does not meet criteria for continuation into Period 2.
When the study drug upadacitinib or PBO are discontinued, the study drug CS dispensed by the Sponsor 
must also be discontinued.  After discontinuation of study drug (upadacitinib or PBO and CS dispensed 
by Sponsor), CS will be prescribed by the investigator and dosing will be based on the investigator's 
judgment and in accordance with local standard of care.  Medications prescribed by the investigator 
should be documented on the concomitant medication eCRF.
Unless subjects request to discontinue from participating in the study (withdrawal of informed consent), 
subjects who prematurely discontinue study drug should continue to be followed for all regularly 
scheduled visits for the period from which they discontinued (refer to Section 5.6).
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  At a minimum, 2 telephone calls must be made and 
1 certified letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The 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 risk/benefit 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.
5.6 Follow-Up for Study Drug Discontinuation or Subject Withdrawal 
from Study
Discontinuation of Study Drug and Continuation of Study Participation
Following discontinuation of study drug, the subject should be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.
If a subject prematurely discontinues study drug, the procedures outlined for the Premature 
Discontinuation Visit (PD 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 Visit after the last dose 
of study drug is required to ensure all treatment-emergent AEs/serious adverse events (SAEs) have been 
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resolved.  The Follow-Up Visit is not applicable for subjects who discontinued study drug and continued 
study participation and completed at least 1 study visit at least 30 days after last dose of study drug.
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits for the period 
from which they discontinue as outlined in the Activity Schedule (Appendix D), unless subjects have 
decided to discontinue the study participation entirely (withdrawal of informed consent).  That is, 
subjects who discontinue study drug during Period 1 should continue to follow the visit schedule for the 
remainder of Period 1, but not continue into Period 2.  Subjects who discontinue study drug during 
Period 2, should follow the visit schedule for the remainder of Period 2.  As noted in the Activity 
Schedule (Appendix D), at the visits after study drug discontinuation, subjects should adhere to all study 
procedures except for dispensing study drug or reviewing returns and accountability, 
dispensing/reviewing study drug instructions, dosing diaries, pharmacokinetic sample collection, and 
sample collection for exploratory research.  Subjects should be advised on the continued scientific 
importance of their data even if they discontinue treatment with study drug early.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
Subjects may withdraw from the study completely (discontinuation of study drug treatment and study 
participation; withdrawal of informed consent) for any reason at any time.  If a subject prematurely 
discontinues study drug treatment and study participation (withdrawal of informed consent) 
simultaneously, the procedures outlined for the PD Visit should be completed as soon as possible, 
preferably within 2 weeks, and preferably prior to initiation of another therapy.
If a subject discontinues from study (withdrawal of informed consent) following a previous 
discontinuation of study drug that resulted in an initial PD Visit, a second PD Visit is not required.
If a subject is discontinuing at Week 52 because they do not meet the criteria to enter Period 2, a 
separate PD Visit is not needed; instead, the Week 52 Visit should be performed.  In addition, a 30-day 
Follow-Up Visit after the last dose of study drug should occur to ensure all treatment emergent
AEs/SAEs have been resolved.  This visit may be a telephone call if a site visit is not possible.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status, including the date of the last study drug dose and the primary 
reason for discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  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.
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5.7 Assessment of Disease Activity
Assessment of GCA Signs and Symptoms
Clinical signs and symptoms of GCA will be evaluated at every study visit according to the schedule of 
assessment and entered into the eCRF.  GCA signs and symptoms include the following:

Fever (> 38°C or 100.4°F)

Symptoms of PMR (morning stiffness and/or pain, in the shoulder and/or hip girdles)

Localized headache, temporal artery or scalp tenderness

Visual signs or symptoms such as acute or subacute vision loss due to arteritic anterior ischemic 
optic neuropathy, transient blurry vision (generally monocular or at least affecting one eye at a 
time, but potentially affecting both eyes)

Jaw or mouth pain

New or worsened extremity claudication

Other features judged by the Clinical Assessor to be consistent with a GCA or PMR flare.
Acute Phase Reactants:  High Sensitivity C-Reactive Protein (hsCRP) and Erythrocyte 
Sedimentation Rate (ESR)
Knowledge of the laboratory results for hsCRP may result in inadvertent unblinding of a subject's 
treatment.  Therefore, after the Baseline Visit, hsCRP results (analyzed and reported by the central 
laboratory) will not be made available to the Sponsor, the investigator, study site personnel, or the 
subject through the duration of the study. The Sponsor will be blinded to the hsCRP results until the 
time of the primary analysis.  
After the Screening visit, ESR results (analyzed and reported by the local laboratory) will not be made 
available to the Sponsor, the investigator, the subject, and study site personnel, with the exception of 
the local Laboratory Assessor to prevent biased efficacy assessment.  A local Laboratory Assessor will be 
assigned at each study site to review ESR results.  Only the Laboratory Assessor is permitted to review 
ESR results and will advise the investigator of any ESR measurement > 30 mm/hr.
5.8 Study Drug
Study drug includes the investigational product (IP) of upadacitinib and matching upadacitinib PBO as 
well as CS therapy (open label or blinded prednisone/prednisolone and matching CS PBO) included as 
part of the protocol-defined CS taper.
Study drug will be taken orally once daily beginning on Day 1 (Baseline) and should be taken at 
approximately the same time each day, with or without food.  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.
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AbbVie will supply upadacitinib, matching upadacitinib PBO, as well as open-label and blinded CS 
therapy (prednisone or prednisolone) and matching CS PBO included as part of the protocol-defined CS 
taper.
All study drug (IP and CS) must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  US 
sourced prednisone 20 mg will need to be stored protected from light and moisture.  Study drug will be 
packaged in quantities sufficient to accommodate study design.
In cases of state of emergency or pandemic situations, study drug shipment can be made from the study 
site to the subject if allowed by local regulations.  Refer to the Operations Manual in Appendix G for 
details on direct-to-patient (DTP) shipment of study drug.  
Each kit will be labeled per local requirements and this label must remain affixed to the kit.  Upon 
receipt, study drug should be stored as specified on the label and kept in a secure location.  Each kit will 
contain a unique kit number.  This kit number is assigned to a subject via interactive response 
technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  All blank spaces on the label will be completed by the site staff prior to dispensing to 
subjects.  Study drug will only be used for the conduct of this study.
Upon completion of or discontinuation from study treatment, all original study drug units (containing 
unused study drugs) will be returned to the sponsor (or designee) or destroyed on site.  All return or 
destruction procedures will be according to instructions from the sponsor and according to local 
regulations following completion of drug accountability procedures.
Individual study drug information is presented in Table 2.
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Table 2.
Identity of Study Drug
Investigational 
Product (IP)
IP
IP Placebo 
(PBO)
Corticosteroid 
(CS)
CS
CS PBO
Name
upadacitinib
upadacitinib
Matching 
upadacitinib 
PBO
Prednisone/ 
Prednisolone
Prednisone/ 
Prednisolone
Matching 
CS PBO
Blinded or 
Open Label
Blinded
Blinded
Blinded
Open Label 
(doses 
≥20 mg)
Blinded 
(doses 
< 20 mg)
Blinded
Mode of 
Administration
Oral
Oral
Oral
Oral
Oral
Oral
Strength
15 mg
7.5 mg
N/A
1,a 5, 10 and 
20 mg
1, 2, 5 and 
10 mg
N/A
Dosing 
Regimen
1 upadacitinib 
15 mg tablet
1 upadacitinib 
7.5 mg tablet
1 upadacitinib 
matching PBO 
tablet
Per Tapering 
Scheduleb
Per Tapering Schedulea
Dosage Form
Tablet
Tablet
Tablet
Tablets/ 
Capsules
Capsules
Frequency of 
administration
QD
QD
QD
QD
QD
a.
The 1-mg prednisone/prednisolone open-label dose is not needed for protocol-defined open-label taper, but may be used 
for escape therapy, if needed (Corticosteroid Escape Therapy during the Study).
b.
The CS tapering schedule is provided in Appendix E.
Corticosteroid Therapy as Study Drug
There are two phases to the CS (prednisone or prednisolone) taper regimen:

Open-label taper, for CS dosages from 60 mg/day to 20 mg/day

Blinded taper, for CS dosages < 20 mg/day.
Starting at Baseline, all subjects will switch from CS obtained outside of the study to open-label oral 
prednisone or prednisolone provided by the Sponsor at a dose of 20, 30, 40, 50, or 60 mg QD.  The initial 
dose of prednisone or prednisolone will be at the discretion of the investigator, based on disease 
severity and comorbid medical conditions, but should be at a minimum of 20 mg QD at Baseline.  At 
Baseline, if a subject is on a dose other than 20, 30, 40, 50, or 60 mg QD, the dose should be rounded up 
or down, as clinically indicated per investigator discretion, to the nearest of these doses.  Subjects will 
follow the CS Tapering Schedule as per Appendix E, completing the open-label phase and transitioning 
to the blinded phase of tapering depending on the CS dose at baseline (i.e., subjects starting on 
20 mg/day will transition to the double-blind phase of tapering more quickly than patients starting on 
60 mg/day).
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Open-label prednisone or prednisolone will be provided until the dose is tapered to less than 
20 mg/day.  Subsequently, blinded CS therapy and/or matching CS PBO will be provided for the 
remaining blinded taper regimen.  While receiving blinded CS therapy, subjects will receive 1 carton 
containing 3 bottles of CS study drug per week and will be instructed to take 1 capsule per bottle per 
day; the 3 capsules combined will be equivalent to the weekly dose according to the CS Tapering 
Schedule (Appendix E).
Corticosteroid Escape Therapy during the Study
Subjects who require CS escape therapy for their GCA disease will be deemed non-responders in the 
primary analysis.  Any use of CS for escape therapy throughout the study will be documented in the 
eCRF.
Period 1:
At every visit, an assessment of subject's disease will be made to assess if the subject can adhere to the 
CS tapering schedule.  If subject has no flare of GCA and is able to follow the CS tapering schedule, the 
subject will continue receiving protocol-defined blinded or open label CS therapy in the study.
In Period 1, disease flare is defined as an event determined by the investigator to represent recurrence 
of GCA signs or symptoms or an ESR measurement ≥30 mm/hr (attributable to GCA), AND requiring an 
increase in CS dose.
Subjects who experience disease flare or are unable to adhere to the protocol-defined CS tapering 
regimen during open-label tapering of prednisone (at doses of 60 mg/day to 20 mg/day) should stop the 
protocol-defined CS taper and receive open-label escape therapy with prednisone or prednisolone at 
the discretion of the investigator.  Ongoing CS use and subsequent tapering will be at the discretion of 
the investigator.  While on open-label CS escape therapy, the subject should continue in the study for 
the full 52 weeks and receive blinded study drug (upadacitinib or PBO).  If, after 2 weeks of open-label 
CS escape therapy, the investigator believes it is medically necessary to treat the subject with other 
available treatments, blinded study drug (upadacitinib or PBO) and CS should be discontinued and the 
subject should be managed based on standard-of-care therapies, which may include tocilizumab.  After 
discontinuation of study drug (upadacitinib or PBO and CS dispensed by Sponsor), CS will be prescribed 
by the investigator and dosing will be based on the investigator's judgment and in accordance with local 
standard of care.  Medications prescribed by the investigator should be documented on the 
concomitant medication eCRF.  Subjects who are discontinued from study drug during Period 1 should 
continue to follow the visit schedule for the remainder of Period 1 (Section 5.6).
Subjects who experience disease flare or are unable to adhere to the protocol-defined CS tapering 
regimen during the blinded protocol-defined CS taper should stop the protocol-defined CS taper and 
receive open-label escape therapy with prednisone or prednisolone starting with at least 20 mg/day at 
the discretion of the investigator.  Ongoing CS use and subsequent tapering will be at the discretion of 
the investigator.  While on open-label CS escape therapy, the subject should continue in the study for 
the full 52 weeks and receive blinded study drug (upadacitinib or PBO).  If, after 2 weeks of open-label 
CS escape therapy, the investigator believes it is medically necessary to treat the subject with other 
available treatments, blinded study drug (upadacitinib or PBO) and CS should be discontinued and the 
subject should be managed based on standard-of-care therapies, which may include tocilizumab.  After 
discontinuation of study drug (upadacitinib or PBO and CS dispensed by Sponsor), CS will be prescribed 
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by the investigator and dosing will be based on the investigator's judgment and in accordance with local 
standard of care.  Medications prescribed by the investigator should be documented on the 
concomitant medication eCRF.  Subjects who are discontinued from study drug during Period 1 should 
continue to follow the visit schedule for the remainder of Period 1 (Section 5.6).
Subjects who receive CS escape therapy will be eligible to continue in Period 2 if meeting criteria for 
study continuation outlined in Section 4.1.
Period 2
In Period 2, disease flare is defined as an event determined by the investigator to represent recurrence 
of GCA signs or symptoms or an ESR measurement ≥30 mm/hr, AND requiring initiation of CS.  Subjects 
who experience disease flare in Period 2 (blinded extension phase) should receive an escape regimen of 
open-label prednisone or prednisolone at investigator's discretion.  Thereafter, open-label escape CS 
taper will be based on the investigator's judgment and in accordance with local standard-of-care.  At the 
investigator's discretion, these subjects may also discontinue study drug (upadacitinib or PBO and CS 
dispensed by Sponsor) and receive treatment in accordance with local standard-of-care, which may 
include tocilizumab, and should continue to follow the visit schedule for the remainder of Period 2 
(Section 5.6).  After discontinuation of study drug (upadacitinib or PBO and CS dispensed by Sponsor), CS 
will be prescribed by the investigator and dosing will be based on the investigator's judgment and in 
accordance with local standard of care.  Medications prescribed by the investigator should be 
documented on the concomitant medication eCRF.
5.9 Randomization/Drug Assignment and Blinding
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.  Subjects may only be rescreened one time without prior AbbVie approval.  For additional 
re-screening, AbbVie TA MD approval is required.
All screening activities must be completed and reviewed prior to enrollment.  Subjects who meet the 
eligibility criteria will proceed to enrollment via the IRT system on Day 1 (Baseline Visit of Treatment 
Period 1).  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule generated by the statistics department at AbbVie.  
A subject number is assigned at screening via IRT.  Enrolled subjects will keep their screening number as 
their subject number throughout the study.
This study is designed to enroll 420 subjects to meet scientific and regulatory objectives without 
enrolling an undue number of subjects in alignment with ethical considerations.  Subjects in screening 
will be permitted to enroll even if the target number of subjects has been enrolled.
Randomization of all subjects, except for those in Japan, will be stratified by baseline CS dose 
(prednisone or prednisolone > 30 mg or ≤ 30 mg), prior use of an IL-6 inhibitor, and whether entering 
the study with new onset or relapsing disease.  In Japan, the study will attempt to include a minimum of 
8 subjects; no stratification will be utilized for randomization, however, data on all 3 stratification 
factors will be collected.  In Period 1, subjects will be randomized in a 2:1:1 ratio (upadacitinib 15 mg + 
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26-week CS taper regimen, upadacitinib 7.5 mg + 26-week CS taper regimen, or PBO + 52-week CS taper 
regimen).
In Period 2, subjects from the Period 1 upadacitinib group who achieve remission for at least 24 weeks 
prior to the Week 52 visit (at the end of Period 1) will be re-randomized to either continue on 
upadacitinib or switch to PBO (Section 4.1); re-randomization will be stratified by baseline disease status 
(new onset or relapsing disease).  Subjects from the Period 1 Placebo group who achieve remission for 
at least 24 weeks prior to the Week 52 visit (at the end of Period 1) will continue to receive PBO.  In 
Period 2, subjects previously on upadacitinib will be re-randomized in a 2:1 ratio (upadacitinib [same 
dose as Period 1] or PBO).  Subjects who were assigned to PBO in Period 1 will continue to receive PBO.  
At Week 52, subjects who have absence of GCA signs and symptoms AND are CS-free, but do not meet 
the above remission criteria will continue in Period 2 on their originally randomized treatment 
assignment.  All other subjects will be discontinued from study drug at the end of Period 1.
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team) will remain blinded to each subject's treatment 
until the last subject completes the Week 52 visit.  After the last subject completes the Week 52 visit the 
Sponsor will be unblinded to Period 1 and Period 2 study drug assignments to facilitate regulatory filings.  
The investigator, study site personnel, and the subject will remain blinded to each subject's treatment 
throughout the study.  To maintain the blind, upadacitinib tablets and matching PBO tablets as well as 
CS capsules and matching PBO capsules 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 situation 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 Unblind Subject 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 
(support@endpointclinical.com).  For country-specific phone numbers, please see the following website:  
(http://www.endpointclinical.com/help-desk/).
In the event that the blind is broken before notification to the AbbVie TA MD, we request that the 
AbbVie TA MD 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.  Protocol 
deviations are prohibited except when necessary to eliminate an immediate hazard to study subjects.  If 
a protocol deviation occurs (or is identified, including those that may be due to the COVID-19 
pandemic), the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable) 
and AbbVie.  In Japan, the investigator will record all protocol deviations in the appropriate medical 
records at the site.
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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 drug component of the product.
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, or packaging issues.
Product complaints concerning the investigational product must be reported to AbbVie within 
1 business day of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
Reporting will be done via electronic data capture (EDC). The date the product complaint details are 
entered into EDC and the form is saved represents the date reported to AbbVie. A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue. If a back-up paper form is used, the date the form is emailed to RD_PQC_QA@abbvie.com 
represents the date reported to AbbVie.
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor. Product complaints associated with adverse events 
will be reported in the study summary. All other complaints will be monitored on an ongoing basis. 
Product complaints occurring during the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
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pre planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If an adverse event, whether associated with study drug or not, meets any of the following criteria, it is 
to be reported to AbbVie clinical pharmacovigilance as a serious adverse event within 24 hours of the 
site being made aware of the serious adverse event (refer to Section 4.3 of the Operations Manual for 
reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, SAEs and protocol-related nonserious AEs will be collected from the time the subject signs the 
study-specific informed consent.
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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 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 Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local guidelines.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study:

Serious infections

Opportunistic infections

Herpes Zoster

Active TB

Malignancy (all types)

Adjudicated Gastrointestinal Perforations

Adjudicated MACE

Anemia

Neutropenia

Lymphopenia

Renal dysfunction

Hepatic disorder

Elevated CPK

Adjudicated Embolic and thrombotic events (non-cardiac, non-central nervous system [CNS])
In addition to the AESIs listed above, the following adverse events will also be monitored during the 
study: Bone Fracture; Retinal detachment.
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Adverse Event Severity and Relationship to Study Drug
Investigators will rate the severity of each AE according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0, which can be accessed at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc.
If no grading criteria are provided for the reported event, then the event should be graded follows: 
Mild (Grade 1)
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Moderate (Grade 2)
Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)
Severe (Grade 3 – 5)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL (self-care ADL refer to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden)
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
The investigator will assess the relationship of the AE to the study drugs upadacitinib (or matching 
placebo) and prednisone/prednisolone (or matching placebo).  Summary of CS-related AEs will be based 
on this assessment.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being related to the 
study drug will be considered "associated."  Events assessed as having no reasonable possibility of being 
related to study drug will be considered "not associated."  In addition, when the investigator has not 
reported a causality or deemed it not assessable, AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is given, another 
cause of event must be provided by the investigator for the SAE.
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Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day of the 
site becoming aware of the pregnancy. If a pregnancy occurs in a study subject information regarding 
the pregnancy and the outcome will be collected.  
Subjects should avoid pregnancy throughout the course of the study, starting with the Screening Visit 
through 30 days after the last study drug administration for female subjects.  Results of a positive 
pregnancy test or confirmation of a pregnancy will be assessed starting with the Screening Visit through 
the final study visit.  
Subjects who become pregnant during the study must be discontinued (Section 5.5).
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 of the site becoming aware of the 
event.
6.2 Toxicity Management
The toxicity management of the AEs including AEs of special interest consists of safety monitoring 
(review of AEs on an ongoing basis, and periodical/ad hoc review of safety issues by a safety data 
monitoring committee), and if applicable, interruption of study drug dosing with appropriate clinical 
management and/or discontinuation of the subjects from study drug.  The management of specific AEs 
and laboratory parameters is described below. 
For subjects who discontinue study drug but continue study participation and are on standard of care 
therapies, these toxicity management requirements do not apply (including alerts from the central lab) 
and any intolerability to standard of care therapies should be managed by the prescribing physician. 
Serious Infections:  Subjects should be closely monitored for the development of signs and symptoms of 
infection during and after treatment with study drug.  Study drug should be interrupted if a subject 
develops a serious infection.  A subject who develops a new infection during treatment with study drug 
should undergo prompt diagnostic testing appropriate for an immunocompromised subject.  As 
appropriate, antimicrobial therapy should be initiated, and the subject should be closely monitored.  
Study drug may be restarted once the infection has been successfully treated.  Subjects who develop 
active TB must be permanently discontinued from study drug. 
Herpes Zoster:  If a subject develops herpes zoster, consider temporarily interrupting study drug until 
the episode resolves.
Gastrointestinal Perforation:  Subjects presenting with the onset of signs or symptoms of a 
gastrointestinal perforation should be evaluated promptly for early diagnosis and treatment.  If the 
diagnosis of gastrointestinal perforation (other than due to appendicitis or mechanical injury) is 
confirmed, the subject must be permanently discontinued from study drug.
Major Cardiovascular Event:  For subjects who develop a major cardiovascular event (MACE:  acute 
myocardial infarction, cerebrovascular accident [stroke]) while on study drug, the investigator should 
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evaluate the benefit/risk of, and discuss with the TA MD whether it is appropriate to continue study 
drug.
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in situ of the cervix must 
be permanently discontinued from study drug.  Information including histopathological results should be 
queried for the confirmation of the diagnosis.  Periodic skin examination is recommended for subjects 
who are at an increased risk for skin cancer.  Subjects who develop malignancies should be referred to 
appropriate specialists and managed as per standard of care.
Muscle-related symptoms:  If a subject experiences symptoms suggestive of myositis or 
rhabdomyolysis, consider checking CPK and aldolase with clinical management and/or study drug 
interruption as deemed appropriate by the investigator.
Thrombosis Events: Subjects who develop symptoms of thrombosis should be promptly evaluated and 
treated appropriately.  If the diagnosis of deep vein thrombosis, pulmonary embolus or noncardiac, 
non-neurologic arterial thrombosis is confirmed, the subject must be discontinued from study drug.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change considered 
clinically significant and with reasonable possibility of relationship to study drug, OR a confirmed 
absolute QT interval corrected for heart rate using Fridericia's formula (QTcF) value > 500 msec. 
COVID-19:  Study drug should be interrupted in subjects with a confirmed diagnosis of COVID-19.  
Consider interrupting study drug in subjects who show signs and/or symptoms with suspicion of COVID-
19.  Study drug may be restarted once the infection has resolved, or 5 days have passed since the 
COVID-19 positive test result (whichever comes last).  The COVID-19 eCRF must be completed.
Management of Select Laboratory Abnormalities:  For any given laboratory abnormality, the 
Investigator should assess the subject, apply the standard of care for medical evaluation and treatment 
following any local guidelines.  Specific toxicity management guidelines for abnormal laboratory values 
are described in Table 3, and may require a supplemental eCRF to be completed.  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 per Table 3, the 
repeat testing must occur as soon as possible. 
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Table 3.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory Parameter
Toxicity Management Guideline for Upadacitinib and Matching Placebo
Hemoglobin 

If hemoglobin < 8 g/dL, interrupt study drug dosing and confirm by repeat testing 
with a new sample.  If confirmed, continue to withhold study drug until 
hemoglobin value returns to ≥ 8 g/dL.
OR

If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample.  

If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative etiology 
is known or the hemoglobin value remains in the normal reference range, the 
subject may remain on study drug at the investigator's discretion.  

If confirmed, continue to withhold study drug until hemoglobin value returns 
to within 3.0 g/dL from baseline.
Absolute neutrophil 
count (ANC)

If confirmed < 1000/μL by repeat testing with new sample, interrupt study drug 
dosing until ANC value returns to ≥ 1000/μL.

For confirmed < 500/μL, if value returns to ≥ 1000/μL, restarting study drug is 
allowed if there is an alternative etiology identified; documentation should 
include reason rechallenge is expected to be safe for the subject.  Study drug 
should be discontinued if no alternative etiology can be found.
Absolute lymphocyte 
counts (ALC) 
If confirmed < 500/μL by repeat testing with new sample, interrupt study drug dosing 
until ALC returns to ≥ 500/μL.
Total white blood cell 
count 
If confirmed < 2000/μL by repeat testing with new sample, interrupt study drug dosing 
until white blood cell count returns to ≥ 2000/μL.
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 baseline value. 
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Laboratory Parameter
Toxicity Management Guideline for Upadacitinib and Matching Placebo
Aspartate 
aminotransferase 
(AST) or alanine 
aminotransferase 
(ALT) 
Interrupt study drug if any of the following scenarios are confirmed by repeat testing 
of AST/ALT:

ALT or AST > 3 × ULN 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.

If a creatine phosphokinase (CPK) value is not available, a CPK should be 
drawn to exclude AST/ALT elevations related to muscle injury 

ALT or AST > 3 × ULN along with new appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or new-onset 
eosinophilia.

ALT or AST > 5 × ULN for more than 2 weeks.
If ALT or AST > 8 × ULN, interrupt study drug immediately, repeat testing with a new 
sample, and if repeat test confirms result contact the TA MD. 

Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA at 
screening who develop the following should have HBV DNA by PCR testing 
performed within 1 week (based on initial elevated value): 

ALT > 5 × ULN OR

ALT or AST > 3 × ULN if an alternative cause is not readily identified.

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).  Within 1 week of the first episode of a 
positive HBV DNA PCR test, a hepatologist consultation should occur 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.  The 
investigator should contact the AbbVie TA MD to discuss the management of a subject 
when an alternative etiology has been determined.  The alternative etiology should be 
documented appropriately in the eCRF.  If ALT or AST values return to the normal 
reference range or its Baseline value, study drug may be restarted.  If restarting study 
drug, documentation should include reason rechallenge is expected to be safe.  Study 
drug should be discontinued if no alternative etiology can be found and ALT or AST 
elevations persist. 
For any confirmed ALT or AST elevations > 3 ULN, complete the appropriate 
supplemental hepatic eCRF(s). 
Serum Creatinine 

If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the test for 
serum creatinine (with subject in an euvolemic state) to confirm the results. If the 
results of the repeat testing still meet this criterion, then interrupt study drug and 
re-start study drug once serum creatinine returns to ≤ 1.5 × baseline value.
For the above serum creatinine elevation scenarios, complete the appropriate 
supplemental renal eCRF(s).
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Laboratory Parameter
Toxicity Management Guideline for Upadacitinib and Matching Placebo
Creatine 
Phosphokinase 
Investigators should complete the supplemental elevated CPK eCRF for the below CPK 
elevation scenarios or if CPK increase is considered to be an AE by the investigator.

If a subject experiences any symptoms suggestive of myositis or rhabdomyolysis, 
blood for measuring CPK and aldolase levels should be drawn with clinical 
management as deemed appropriate by the investigator.

If confirmed CPK value ≥ 4 × ULN and there are no symptoms suggestive of 
myositis or rhabdomyolysis, the subject may continue study drug at the 
investigator's discretion after evaluation. 

If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact AbbVie medical monitor.
Urgent and Emergency Surgeries
For urgent and emergency surgeries the following rules will apply:

If the subject must undergo an urgent or emergency surgery, the study drug should be 
interrupted at least 1 week prior to a planned urgent surgery if possible, or at the time of an 
emergency 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.

Elective surgery, and interruption of study drug for such a surgery, should be avoided until after 
the Week 52 visit has been completed.  If elective surgery is considered prior to the primary 
endpoint visit, it must be discussed with the TA MD and performed with TA MD approval. If the 
subject undergoes elective surgery, the study drug should be interrupted at least 1 week prior to 
the planned 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.
6.3 Data Monitoring Committee
An independent, external DMC will be established for periodic review of unblinded safety data and to 
alert AbbVie to possible safety concerns related to the conduct of the study to ensure subject safety.  
The DMC will review safety data of the first 80 enrolled subjects through 8 weeks of treatment to 
determine if there are any significant safety concerns that would warrant any study action.  Thereafter, 
the DMC will review safety data on a regular basis and as needed based on the accumulating safety data 
and will provide recommendations to AbbVie. 
The DMC Charter will describe the roles and responsibilities of the DMC members, frequency of data 
reviews, and relevant data to be assessed.  Communications from the DMC to the Study Team will not 
contain information that could potentially unblind the team to subject treatment assignments.
In addition, the DMC will conduct a futility analysis as described in Section 7.5.
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6.4 Cardiovascular Adjudication Committee
An independent committee of physician experts in cardiovascular adjudication will be utilized to assess 
potential cardiovascular AEs in a blinded manner as defined by the Cardiovascular Adjudication 
Committee charter.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
An unblinded analysis for Period 1 will be conducted after all subjects have completed Week 52 or have 
prematurely discontinued the study prior to Week 52.  An unblinded analysis for Period 2 will be 
conducted after all subjects have completed Week 104 or have prematurely discontinued the study 
prior to Week 104.  Additional unblinded analysis in Period 2 may be conducted for regulatory purposes.  
To maintain integrity of the trial and avoid introduction of bias, study sites and subjects will remain 
blinded until all subjects have completed Period 2 (Week 104). 
Statistical analyses will be described and fully documented in the Statistical Analysis Plan (SAP).  The 
statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) will be defined for Period 1 and Period 2.  The FAS population in Period 1
(FAS1) includes all randomized subjects who received at least 1 dose of study drug in Period 1.  The FAS 
population in Period 2 (FAS2) is defined as all subjects who achieved remission for at least 24 
consecutive weeks prior to the Week 52 Visit (at the end of Period 1) and received at least 1 dose of 
study drug in Period 2.  In addition, an exploratory analysis set will be defined for Period 2 to include all 
subjects who did not meet these remission criteria (i.e., achieve remission for at least 24 weeks prior to 
the Week 52 Visit) but continued in Period 2 on their originally randomized treatment assignment.  
Primary efficacy analysis for primary and key secondary endpoints will be carried out on the FAS1
population in Period 1 and on the FAS2 population in Period 2.  Exploratory efficacy analyses for Period 2 
will be conducted for selected variables for the exploratory analysis set.  Subjects will be grouped 
according to treatment as randomized.  
The Per-Protocol Analysis Set will be defined to represent a subset of the FAS1 subjects without any 
major protocol violations during the study which are expected to impact the primary endpoint.  Subjects 
to be excluded from the Per-Protocol Population will be identified before the Week 52 database lock.  
The Per-Protocol Population will be used to analyze the primary efficacy endpoint in a sensitivity 
analysis.  Additional analyses may be conducted on the Per-Protocol Analysis Set in order to evaluate the 
impact of major protocol violations.
The Safety Analysis Set will be defined for Period 1 and Period 2.  The Safety Analysis Set in Period 1 will 
consist of all subjects who received at least 1 dose of study drug in Period 1.  The Safety Analysis Set in 
Period 2 will consist of all subjects who received at least 1 dose of study drug in Period 2.  For the Safety 
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Analysis Set, subjects are assigned to a treatment group based on the treatment actually received, 
regardless of the randomized treatment.
7.3 Statistical Analyses for Efficacy
Analysis of Primary and Key Secondary Endpoints in Period 1
For the global analysis, the overall type I error rate of the primary and ranked key secondary endpoints 
for the 2 upadacitinib doses will be strongly controlled using a graphical multiple testing procedure. 
Specifically, the testing will utilize the endpoint sequence of primary endpoint followed by key 
secondary endpoints in the order as specified in Section 3.2 and Section 3.3. The testing will start with 
the primary endpoint of 15 mg QD with α = 0.05.  Continued testing will follow a pre-specified α transfer 
path, which includes downstream transfer along the endpoint sequence within each dose as well as 
cross-dose transfer.  The testing of 7.5 mg QD dose will start with transferred α if endpoint 7 in 
Section 3.3 of the 15 mg QD dose is significant.  The group of endpoints labeled as 8 in Section 3.3 will 
be tested using the Hochberg procedure, conditional on significance of higher ranked endpoints.  More 
details of the graphical procedure will be specified in the SAP.  An alternative testing procedure will be 
done for the regulatory purposes in Japan.  More details of the graphical procedure will be specified in 
the SAP.  Unless otherwise specified, all statistical tests will be performed at a 2-sided significance level 
of 0.05.
The primary analysis will be conducted after all subjects have completed the Week 52 visit or have 
prematurely discontinued from the study prior to Week 52.  For the primary efficacy endpoint, the 
upadacitinib groups will be compared with the PBO group using the Cochran-Mantel-Haenszel method 
adjusting for stratification factors.  The primary approach for handling missing data will be Non-
Responder Imputation incorporating multiple imputation (NRI-MI). Subjects with missing data will be 
counted as non-responders, except when missing at random can be reasonably assumed, which will be 
handled by multiple imputation. For example, missing due to COVID-19 logistical restriction or due to 
political conflict will be handled by multiple imputation. A sensitivity analysis will be performed based on 
As Observed analysis in which subjects with missing components of sustained remission at Week 52 will 
be excluded from analysis.  Other key binary endpoints will be analyzed similarly.  
For continuous change from baseline endpoints such as change from baseline in SF-36, PGA, EQ-5D-5L 
and FACIT-Fatigue, comparisons between the upadacitinib treatment groups and the PBO group will be 
carried out using the Mixed-Effect Model Repeat Measurement (MMRM) model with treatment group, 
visit, treatment-by-visit interaction, and stratification factors as the fixed factors and the corresponding 
baseline values as the covariates.  TSQM, PGIC value will be analyzed using an MMRM model with 
treatment group, visit, treatment-by-visit interaction and stratification factors as the fixed factors.  For 
cumulative CS dose, comparisons between the upadacitinib treatment group and the PBO group will be 
analyzed using a van Elteren test stratified by stratification factors.  The median total cumulative 
prednisone dose over the 52 weeks for each treatment group and the corresponding 95% CI for the 
median will be presented.
For time-to-event endpoints, median time-to-event will be reported for each treatment group.  
Comparisons between the upadacitinib group and the PBO group will be conducted using stratified log 
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rank test; additional analyses may be conducted using Cox's regression to include baseline values and 
stratification factors as covariates.
For count endpoints, comparisons between the upadacitinib treatment group and the PBO group will be 
carried out using Poisson regression model with treatment group and stratification factors as covariates, 
adjusting for exposure duration. 
Other Efficacy Variables
Additional efficacy variables are listed in Section 3.3 and will be summarized for Period 1 and 2.  For all 
the additional efficacy variables in Period 1, the summary statistics and the statistical method will be the 
same as the corresponding variables described in the primary and key secondary analyses.  For all the 
additional efficacy variables in Period 2, descriptive statistics will be provided for each treatment group 
sequence.  For binary endpoints, frequencies and percentage with 95% CI using normal approximation 
will be reported for each treatment group and 95% CI will be reported for treatment difference.  For 
continuous endpoints, the mean, standard deviation, 95% CI, median, and range will be reported for 
each treatment group and 95% CI will be reported for treatment difference.  For time-to-event 
endpoints, median time-to-event will be reported for each treatment group.  For count endpoints, the 
exposure duration adjusted event rates will be reported for each treatment group.
Sample Size Estimation
The planned total sample size of 420 subjects with a 2:1:1 ratio (upadacitinib 15 mg QD: upadacitinib 
7.5 mg QD: PBO QD) was determined to have at least 90% power to detect a 20% difference in sustained 
remission rate at Week 52 between the upadacitinib 15 mg arm and the PBO arm (assuming a response 
rate of 40% in the PBO arm), using Fisher's exact test, with an overall two-sided alpha = 0.05.
7.4 Statistical Analyses for Safety
Safety analyses for Period 1 and Period 2 alone and long-term safety analyses for Period 1 and Period 2 
combined will be carried out using the Safety Analysis Set in Period 1 (for safety analyses for Period 1 
alone and Periods 1 and 2 combined) as well as the Safety Analysis Set in Period 2 (for safety analyses 
for Period 2 alone) respectively, and will be based on treatments actually received regardless of the 
randomly assigned treatment.  
Safety will be assessed by treatment-emergent adverse events (TEAEs), physical examination, laboratory 
assessments, ECG, and vital sign results.  The number and percentage of subjects experiencing TEAEs by 
treatment group will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class (SOC) and preferred term (PT).  In addition, summaries of SAEs and TEAEs by severity and 
relationship to study drug as assessed by the investigator will be provided.  SAEs, severe TEAEs, and 
TEAEs that lead to premature study discontinuation will be listed. Changes in vital signs, physical 
examination results, and clinical laboratory variables at each visit as compared to baseline will be 
summarized.  Shift of laboratory values from baseline to defined time points will be tabulated.
Missing safety data will not be imputed.
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7.5 Interim Analysis
In addition to periodic review of safety data (Section 6.3), the DMC will conduct a futility analysis to 
assess lack of efficacy once the first 140 enrolled subjects complete 24 weeks of treatment 
(approximately 70 subjects in the 15-mg active treatment arm; 35 subjects in the 7.5-mg active 
treatment arm and 35 in the PBO arm).  A futility recommendation will be made when the futility 
criterion is met.  Further details will be provided in the DMC Charter.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all participant 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 participant 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, 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 cases of state of emergency or pandemic situations leading to difficulties in performing 
protocol -specified procedures, AbbVie will 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.  Refer to the Operations Manual for additional details.  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 subjects 
against any 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.
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9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection(s), providing direct access to source data documents.  
Electronic case report forms (eCRFs) must be completed for each subject screened and/or enrolled in 
this study.  These forms will be used to transmit information collected during the study to AbbVie and 
regulatory authorities, as applicable.  The eCRF data for this study are being collected with an electronic 
data capture (EDC) system called Rave®.  All data entered into the eCRF will be recorded by investigative 
site personnel in the EDC system and will be supported by source documentation.  
The eCRFs will be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed access to all 
source documents pertinent to the study in order to verify eCRF entries.  The investigator will review the 
eCRFs for completeness and accuracy and provide his or her electronic signature and date to eCRFs as 
evidence thereof.   
Data from the EDC system will be archived on appropriate data media (CD-ROM, etc.) and provided to 
the investigator at that time as a durable record of the site's eCRF data.  
In cases of state of emergency or pandemic situations, remote data review and verification 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.
Individual results will not be reported to anyone not directly involved in this research other than for 
regulatory purposes.  
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit.
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12
REFERENCES
1.
Alba MA, Garcia-Martinez A, Prieto-Gonzalez S, et al.  Relapses in patients with giant cell 
arteritis:  prevalence, characteristics, and associated clinical findings in a longitudinally followed 
cohort of 106 patients.  Medicine (Baltimore).  2014;93(5):194-201.
2.
Proven A, Gabriel SE, Orces C, et al.  Glucocorticoid therapy in giant cell arteritis:  duration and 
adverse outcomes.  Arthritis Rheum.  2003;49(5):703-8.
3.
Unizony S, Arias-Urdaneta L, Miloslavsky E, et al.  Tocilizumab for the treatment of large-vessel 
vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica.  Arthritis Care Res 
(Hoboken).  2012;64(11):1720-9.
4.
Villiger PM, Adler S, Kuchen S, et al.  Tocilizumab for induction and maintenance of remission in 
giant cell arteritis:  a phase 2, randomised, double-blind, PBO-controlled trial.  Lancet.  
2016;387(10031):1921-7.
5.
Stone JH, Tuckwell K, Dimonaco S, et al.  Efficacy and safety of tocilizumab in patients with giant 
cell arteritis:  primary and secondary outcomes from a phase 3, randomized, double-blind, 
placebo-controlled trial [abstract].  Arthritis Rheumatol.  2016;68 (Suppl 10). 
6.
O'Shea JJ, Holland SM, Staudt LM.  JAKs and STATs in immunity, immunodeficiency, and cancer.  
N Engl J Med.  2013;368(2):161-70. 
7.
Rawlings JS, Rosler KM, Harrison DA.  The JAK/STAT signaling pathway.  J Cell Sci.  
2004;117 (Pt 8):1281-3.
8.
Borchers AT, Gershwin ME.  Giant cell arteritis:  a review of classification, pathophysiology, 
geoepidemiology, and treatment. Autoimmun Rev.  2012;11(6-7):A544-54.
9.
Murray PJ.  The JAK-STAT signaling pathway:  input and output integration.  J Immunol.  
2007;178(5):2623-9.
10. Ghoreschi K, Laurence A, O'Shea JJ.  Janus kinases in immune cell signaling.  Immunol Rev.  
2009;228(1):273-87.
11. Deng J, Younge BR, Olshen RA, et al.  Th17 and Th1 T-cell responses in giant cell arteritis.  
Circulation.  2010;121(7):906-15.
12. Weyand CM, Younge BR, Goronzy JJ.  IFN-gamma and IL-17:  the two faces of T-cell pathology in 
giant cell arteritis.  Curr Opin Rheumatol.  2011;23(1):43-9.
13. Weyand CM, Goronzy JJ.  Immune mechanisms in medium and large-vessel vasculitis.  Nat Rev 
Rheumatol.  2013;9(12):731-40.
14. Zhang H, Watanabe R, Berry GJ, et al.  Inhibition of JAK-STAT signaling suppresses pathogenic 
immune responses in medium and large vessel vasculitis.  Circulation.  2017.  [Epub ahead of 
print].
15. Unizony S, Arias-Urdaneta L, Miloslavsky E, et al.  Tocilizumab for the treatment of large-vessel 
vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica.  Arthritis Care Res.  
2012;64(11):1720-9.
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16. Xenitidis T, Horger M, Zeh G, et al.  Sustained inflammation of the aortic wall despite tocilizumab 
treatment in two cases of Takayasu arteritis.  Rheumatology (Oxford).  2013;52(9):1729-31.
17. Adler S, Reichenbach S, Kuchen S, et al.  Termination of tocilizumab treatment in giant cell 
arteritis:  follow-up of patients after the RCT.  Arthritis Rheumatol.  2016;68 (Suppl 10). 
18. AbbVie.  Upadacitinib Investigator's Brochure Edition 12.  16 August 2021.
19. Kremer JM, Emery P, Camp HS, et al.  A phase IIb study of ABT-494, a selective JAK-1 inhibitor, in 
patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor 
therapy.  Arthritis Rheumatol.  2016;68(12):2867-77.
20. Genovese MC, Smolen JS, Weinblatt ME, et al.  Efficacy and safety of ABT-494, a selective JAK-1 
inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response 
to methotrexate.  Arthritis Rheumatol.  2016;68(12):2857-66.
21. Mohamed ME, Zeng J, Song IH, et al.  Pharmacokinetics of ABT-494 with the once-daily 
extended-release tablet formulation being utilized in the ongoing rheumatoid arthritis phase 3 
trials [abstract].  Arthritis Rheumatol.  2016;68 (Suppl 10).
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
Ab
antibody
AD
atopic dermatitis
ADL
activities of daily living
AE
adverse event
ALC
absolute lymphocyte counts
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the curve
AxSpA
axial spondyloarthritis
bDMARD
biologic disease modifying antirheumatic drugs
BID
twice daily
CD
Crohn's disease
CGC
common gamma chain
Cmax
maximum serum concentration
Cmin
minimum serum concentration
CL/F
oral clearance
CNS
central nervous system
COVID-19
coronavirus disease – 2019 (coronavirus SARS-CoV-2)
CPK
creatine phosphokinase 
CRP
C-reactive protein
CS
corticosteroid(s) 
csDMARD-IR
conventional-synthetic disease modifying antirheumatic drugs
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CXR
chest x-ray
CYP3A
cytochrome P450 3A
DMARD
disease modifying antirheumatic drugs
DMC
data monitoring committee
DTP
direct-to-patient
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ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ESR
erythrocyte sedimentation rate
EQ-5D-5L
EuroQol Five Dimensions Five Levels Questionnaire
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS
Full Analysis Set
FSH
Follicle-stimulating hormone
GCA
giant cell arteritis
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBc Ab
hepatitis B core antibody
HBs Ab
hepatitis B surface antibody
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
hepatitis C virus antibody
HIV
human immunodeficiency virus
HLA
human leukocyte antigens
hsCRP
high sensitivity C-reactive protein 
ICH
International Council for Harmonisation
IEC
independent ethics committee
IFN-γ
interferon-gamma
IL
interleukin
IL-6
interleukin-6
IMP
Investigational Medicinal Product
INR
international normalized ratio
IP
investigational product
IR
inadequate response
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JAK
Janus kinase 
JAK1
Janus kinase 1
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LDA
low disease activity
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MMRM
mixed-effect model repeat measurement
NK
natural killer (cells)
NMSC
non-melanoma skin cancer
NOAEL
no-observed-adverse-effect level
NOF
National Osteoporosis Foundation
NRI
non-responder imputation
PBO
placebo
PCR
polymerase chain reaction
PCS
Physical Component Score
PD
Premature Discontinuation
PD Visit
Premature Discontinuation Visit
PET
positron emission tomography
PGA
Patient Global Assessment
PGIC
Patients' Global Impression of Change
PK
pharmacokinetic(s)
PMR
polymyalgia rheumatica
PPD
purified protein derivative
PsA
psoriatic arthritis
PT
preferred term
QD
once daily
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia's formula
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SF-36
Short Form 36
SOC
system organ class
STAT
Signal Transducer and Activator of Transcription
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SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
tuberculosis
TA MD
Therapeutic Area Medical Director
TEAE
Treatment-emergent adverse event
TNF
tumor necrosis factor
TSQM
Treatment Satisfaction Questionnaire for Medication 
Tyk2
tyrosine kinase 2
UC
ulcerative colitis
ULN
upper limit of normal
V/F
apparent volume of distribution
WBC
white blood cell
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-852:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety and Efficacy of Upadacitinib in Subjects with Giant Cell Arteritis:  SELECT-GCA
Protocol Date:  31 May 2023
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Immunology Development
Statistics
Statistics
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across Period 1 and Period 2; the individual activities 
are described in detail in the Operations Manual.  Allowed modifications due to a state of emergency or 
pandemic situation are detailed within the Operations Manual.
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h.
Subjects with a negative TB test result at Screening (or the most recent evaluation) will have an annual TB follow-up test performed, with the same type of TB test used at 
Screening (e.g., QuantiFERON-TB Gold Test or Local PPD Skin Test), if the subject is still taking the study drug.  If an annual TB test is newly positive (seroconversion), a CXR 
needs to be performed as soon as possible to aid in distinguishing active versus latent TB.  During the study, subjects with new evidence of latent TB should initiate prophylactic 
treatment immediately per local guidelines and complete at least 6 months of prophylaxis (or per local guidelines, whichever is longer).  TB prophylaxis should be initiated, and 
study drug should not be withheld.  Two to 4 weeks later, the subject should be re-evaluated (unscheduled visit) for signs and symptoms, as well as laboratory assessment of 
toxicity to TB prophylaxis.  Newly initiated prophylactic treatment should be captured in the eCRF and in the source documents.
i.
Women of childbearing potential are required to have monthly pregnancy testing.  At Weeks 32, 40, 48, 64, 72, 76, 84, 88, 96, and 100, women of childbearing potential may 
have an unscheduled office visit for required monthly pregnancy testing or elect to perform the required monthly testing at home with test kits provided by the site.  Additional 
testing may be required per local requirements.
j.
Serum pregnancy testing is required at Baseline only if urine pregnancy testing is positive, or if serum pregnancy testing is required at Baseline per local practices.
k.
FSH should be tested at Screening if the female subject is ≤ 55 years of age AND has had no menses ≥ 12 months AND has no history of permanent surgical sterilization (Refer to 
Section 5.2 for further details regarding definition of postmenopausal).
l.
For subjects in Japan with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at screening, HBV DNA PCR test should be performed every 12 weeks (as necessary, unscheduled 
visits may be needed).  HBV DNA PCR testing every 12 weeks is not necessary when the subject has a history of HBV vaccine and HBs Ab+, HBc Ab–.
m.
After the Baseline Visit, results of hsCRP (central laboratory) will be blinded to the Sponsor, the investigator, the subject, and study site personnel.  After the Screening Visit, 
results of ESR (local laboratory) will be blinded to the Sponsor, the investigator, the subject, and study site personnel with the exception of the local Laboratory Assessor 
assigned at each study site (see Section 5.7 for additional information).
n.
Applies to Period 1 only.
o.
Subjects who achieved remission for at least 24 consecutive weeks prior to the Week 52 Visit (at the end of Period 1) will be re-randomized into Period 2.  Remission is defined 
as absence of GCA signs and symptoms AND adherence to the protocol-defined CS taper regimen or corticosteroid-free.  At Week 52, subjects who have absence of GCA signs 
and symptoms AND are CS-free at the Week 52 visit, but do not meet remission criteria (i.e., achieve remission for at least 24 consecutive weeks prior to the Week 52 Visit) will 
continue in Period 2 on their originally randomized treatment assignment.  All other subjects will be discontinued from study drug and the study at the end of Period 1.
p.
Dosing instructions will be provided at the Baseline Visit and replaced if lost or damaged.
q.
Approximately 2 days prior to each visit with scheduled pharmacokinetic (PK) sample collection, site personnel will contact subjects as reminder to document dosing 
information on dosing diary and to bring completed dosing diary to the visit.  Additional details are provided in the Operations Manual.
Note 1.
Visit window is ± 2 days for Period 1 (Week 2 through Week 52 Visit) and ± 2 days for Period 2 (Week 56 through Week 104 Visit).  Any of the procedures may be 
performed at an unscheduled visit at the discretion of the investigator.  
Note 2.
Subjects who choose to discontinue study drug treatment, but continue to participate in the study, should complete a Premature Discontinuation Visit (PD Visit) as 
soon as possible, preferably within 2 weeks.  Afterwards, subjects should follow the regular visit schedule for the period from which they discontinue and adhere to all 
study procedures except for dispensing study drug, or reviewing returns and accountability, dispensing/reviewing study drug instructions, dosing diaries, PK sample 
collection, and sample collection for exploratory research.  That is, subjects who discontinue study drug in Period 1 should complete the visits in Period 1, but not 
continue to Period 2.  Subjects who discontinue study drug in Period 2, should complete the visits in Period 2.  In addition, all future CS escape therapy and 
efficacy-driven discontinuation criteria no longer apply. 
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APPENDIX E. CORTICOSTEROID TAPERING SCHEDULE
Baseline
20
30
40
50
60
Baseline
20
30
40
50
60
Wk 1
17
25
35
40
50
Wk 1
15
25
35
40
50
Wk 2
17
20
30
35
40
Wk 2
12
20
30
35
40
Wk 3
15
17
25
30
35
Wk 3
12
15
25
30
35
Wk 4
15
17
20
25
30
Wk 4
10
12
20
25
30
Wk 5
12
15
17
20
25
Wk 5
9
12
15
20
25
Wk 6
10
15
17
17
20
Wk 6
8
10
12
15
20
Wk 7
10
12
15
17
17
Wk 7
7
9
12
12
15
Wk 8
10
10
15
15
17
Wk 8
6
8
10
12
12
Wk 9
10
10
12
15
15
Wk 9
6
7
9
10
12
Wk 10
9
10
10
12
15
Wk 10
5
6
8
9
10
Wk 11
9
10
10
10
12
Wk 11
5
6
7
8
9
Wk 12
9
9
10
10
10
Wk 12
4
5
6
7
8
Wk 13
9
9
10
10
10
Wk 13
4
5
6
6
7
Wk 14
8
9
9
10
10
Wk 14
3
4
5
6
6
Wk 15
8
9
9
9
10
Wk 15
3
4
5
5
6
Wk 16
8
8
9
9
9
Wk 16
2
3
4
5
5
Wk 17
8
8
9
9
9
Wk 17
2
3
4
4
5
Wk 18
7
8
8
9
9
Wk 18
1
2
3
4
4
Wk 19
7
8
8
8
9
Wk 19
1
2
3
3
4
Wk 20
7
7
8
8
8
Wk 20
0
1
2
3
3
Wk 21
7
7
8
8
8
Wk 21
0
1
2
2
3
Wk 22
6
7
7
8
8
Wk 22
0
0
1
2
2
Wk 23
6
7
7
7
8
Wk 23
0
0
1
1
2
Wk 24
6
6
7
7
7
Wk 24
0
0
0
1
1
Wk 25
6
6
7
7
7
Wk 25
0
0
0
0
1
Wk 26
5
6
6
7
7
Wk 26
0
0
0
0
0
Wk 27
5
6
6
6
7
Wk 27
0
0
0
0
0
Wk 28
5
5
6
6
6
Wk 28
0
0
0
0
0
Wk 29
5
5
6
6
6
Wk 29
0
0
0
0
0
Wk 30
4
5
5
6
6
Wk 30
0
0
0
0
0
Wk 31
4
5
5
5
6
Wk 31
0
0
0
0
0
Wk 32
4
4
5
5
5
Wk 32
0
0
0
0
0
Wk 33
4
4
5
5
5
Wk 33
0
0
0
0
0
Wk 34
3
4
4
5
5
Wk 34
0
0
0
0
0
Wk 35
3
4
4
4
5
Wk 35
0
0
0
0
0
Wk 36
3
3
4
4
4
Wk 36
0
0
0
0
0
Wk 37
3
3
4
4
4
Wk 37
0
0
0
0
0
Wk 38
2
3
3
4
4
Wk 38
0
0
0
0
0
Wk 39
2
3
3
3
4
Wk 39
0
0
0
0
0
Wk 40
2
2
3
3
3
Wk 40
0
0
0
0
0
Wk 41
2
2
3
3
3
Wk 41
0
0
0
0
0
Wk 42
1
2
2
3
3
Wk 42
0
0
0
0
0
Wk 43
1
2
2
2
3
Wk 43
0
0
0
0
0
Wk 44
1
1
2
2
2
Wk 44
0
0
0
0
0
Wk 45
1
1
2
2
2
Wk 45
0
0
0
0
0
Wk 46
0
1
1
2
2
Wk 46
0
0
0
0
0
Wk 47
0
1
1
1
2
Wk 47
0
0
0
0
0
Wk 48
0
0
1
1
1
Wk 48
0
0
0
0
0
Wk 49
0
0
1
1
1
Wk 49
0
0
0
0
0
Wk 50
0
0
0
1
1
Wk 50
0
0
0
0
0
Wk 51
0
0
0
0
1
Wk 51
0
0
0
0
0
Wk 52
0
0
0
0
0
Wk 52
0
0
0
0
0
Open-label taper until 20 mg 
*Prednisone or Prednisolone
Blinded 52-Wk Costicosteroid* Taper (Dose in mg)
Blinded 26-Wk Corticosteroid* Taper (Dose in mg)
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions 
Protocol 
Date
Version 1.0
27 March 2018
Version 2.0
05 September 2018
Version 2.1 (VHP)
15 February 2019
Version 3.0
28 March 2019
Version 4.0
27 March 2020
Version 5.0
09 December 2020
Administrative Change 1
13 October 2021
Version 6.0
29 March 2022
Administrative Change 2 (Japan Only)
08 August 2022
Summary of Protocol Changes:
The following changes were made in Version 7.0 of this protocol:
Protocol

Title page, Footer: Added EU CT number.
Rationale: To provide EU CT number. 

Section 1, Synopsis: Updated Objectives and Endpoints, Study Drug and Duration of Treatment, 
date.
Rationale: To align with protocol updates.

Section 2.2, Benefits and Risks to Patients: Updated AEs observed in patients receiving JAK 
inhibitors, added results of ORAL Surveillance study, a study of a different JAK inhibitor.
Rationale: To align with known AEs and to provide additional detail based on the ORAL 
Surveillance study to support the current research. 

Section 3.3, Secondary Endpoints: Updated title to Multiplicity-Controlled Secondary Endpoints 
and Additional Endpoints.
Rationale: To clarify that the secondary endpoints will be multiplicity-controlled.

Section 3.3, Secondary Endpoints:  Updated language of several of the endpoints.
Rationale: For correction, clarification, and/or alignment without actual change to the 
definitions of the existing endpoints.

Section 3.3, Secondary Endpoints; Section 7.3, Statistical Analyses for Efficacy; Appendix D, 
Activity Schedule: Updated FACIT-F to FACIT-Fatigue.
Rationale: To clarify FACIT-Fatigue (13 item) is the PRO being used in this trial.  
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Section 5.2, Contraception Recommendations

Updated criteria for FSH levels for postmenopausal females.
Rationale: To align with criteria for postmenopausal females.

Added language for contraceptive counseling.
Rationale: To clarify contraception requirements in subjects whose childbearing potential 
changes during the study. 

Section 5.3, Prohibited Medications and Therapy: 

Updated lists of prohibited biologic therapies, prohibited JAK inhibitors, examples of live 
vaccines, and examples of commonly used strong CYP3A inhibitors and inducers. Indicated 
that viral vaccines that cannot replicate are not prohibited and that herbal therapies and 
other traditional medicines with unknown effects on CYP3A are prohibited.
Rationale:  To update the lists of prohibited biologic therapies and JAK inhibitors to align 
with currently approved medications, to align with current knowledge of CYP3A inhibitors 
and inducers, and to clarify that live vaccines without replicating potential are permitted 
during the study.  

Section 5.5, Discontinuation from Study Drug or Subject Withdrawal from Study:

Updated malignancy language.
Rationale:  To clarify that subjects with non-melanoma skin cancer and carcinoma in situ of 
the cervix may only remain in the study if the cancer can be successfully removed at its 
localization.  

Removed language that the AbbVie TA MD may mandate individual subject discontinuation.
Rationale: To minimize the introduction of bias if discontinuation is requested without clear 
safety criteria for discontinuation.  

Updated language for study termination.
Rationale: For clarification that advanced notice is not required for study termination.

Section 5.6, Follow-Up for Study Drug Discontinuation or Subject Withdrawal from Study: 
updated description of 30-day follow-up visit to indicate treatment-emergent AEs/SAEs.
Rationale: For clarification that only treatment-emergent AEs will be reviewed during the follow-
up visit.

Section 5.7, Assessment of Disease Activity: Indicated that hsCRP will remain masked until the 
end of the study for the investigators, site staff and subjects, and that the Sponsor will be 
unmasked to the hsCRP results at the time of primary analysis.
Rationale: To clarify the current language to ensure we maintain the integrity of the blind.

Section 5.8, Study Drug: Updated disease flare definition ESR measurement to ≥30 mm.
Rationale: To correct inconsistencies throughout protocol and operations manual documents. 

Section 6.1, Complaints and Adverse Events: 

Added language to describe electronic data capture (EDC) reporting.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Rationale: To align with electronic data capture procedures.

Updated language for SAE reporting.
Rationale: To align with SAE reporting to AbbVie clinical pharmacovigilance.

Added language for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting.
Rationale: To align with SUSAR reporting procedures.

Added retinal detachment and bone fracture as AEs that will be monitored during the study.
Rationale: To align with updates to the AEs monitored per regulatory request.

Section 6.2, Toxicity Management: Added language for muscle-related symptoms, Updated 
language for COVID-19, Updated guidelines for AST or ALT, Updated guidelines for creatine 
phosphokinase, indicated that the medical monitor and not the TA MD should be contacted if 
CPK ≥ 4 × ULN is accompanied by symptoms suggestive of myositis or rhabdomyolysis.
Rationale: To provide clarification of study drug management for respective
events

Updated language for urgent and emergency surgeries.
Rationale: To clarify the circumstances under which elective surgeries may be considered.

Section 7.2, Definition for Analysis Populations: Clarified that the FAS in Period 2 is defined as all 
subjects who achieved sustained remission for at least 24 consecutive weeks prior to Week 52 
visit.
Rationale: For clarification. 

Section 7.3, Statistical Analyses for Efficacy: Added language for NRI-MI.
Rationale: To align with statistical approaches to handling missing data.

Appendix D, Activity Schedule: Indicated that for subjects with a negative TB test at Screening or 
most recent evaluation, an annual TB re-test will be performed if subject is still taking study 
drug.
Rationale: For clarification that re-test is only performed if subject is still taking study drug.
Operations Manual

Section 2.1, Individual Treatment Period Visit Activities: Updated 30-day Follow-Up visit to 
include phone call, updated description of 30-day follow-up visit to indicate treatment-
emergent AEs/SAEs, indicated that for subjects with a negative TB test at Screening or most 
recent evaluation, an annual TB re-test will be performed if subject is still taking study drug.
Rationale: To allow more flexibility if there are no safety issues necessitating an in-person visit, 
and for clarification that only treatment-emergent AEs will be reviewed during the follow-up 
visit.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Section 2.1, Individual Treatment Period Visit Activities; Section 3.6, Quality of Life and Patient-
Reported Outcomes; Appendix C, Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-Fatigue) Scale Example: Updated FACIT-F to FACIT-Fatigue.
Rationale: To clarify FACIT-Fatigue (13 item) is the PRO being used in this trial. 

Section 3.10, Vital Signs: indicated that blood pressure, pulse rate, body temperature, and 
respiratory rate should preferably be performed before blood draws are performed.
Rationale: For clarification on timing of procedures related to collecting vital signs.

Section 3.12, Chest X-Ray (CXR): Clarified language for assessment of CXR to rule out active TB.
Rationale: To clarify CXR procedures associated with TB assessment.

Section 3.18, Clinical Laboratory Tests:

Updated standard of care to be applied by the investigator for laboratory test values outside 
of the reference range related to AE reporting.
Rationale: To clarify when an abnormal laboratory test should be considered an AE.
•
Updated disease flare definition from > 30 mm/hr to ≥30 mm/hr, indicated where the 
investigator and the independent ESR assessor should document the ESR result, and 
clarified that the ESR results will be entered by a person who is not doing the clinical 
assessment.
Rationale: Clarification about where to document communications between the laboratory 
assessor and the investigator regarding ESR ≥30 or < 30, clarification about who should 
enter the actual ESR values and when they should be entered (to reduce the risk of 
investigator bias).
•
Updated pregnancy testing.
Rationale: For clarification on procedures related to pregnancy testing.

Indicated that for TB testing, the investigator has the responsibility to follow local guidelines 
in the detection and treatment of active or latent TB, Updated language for positive TB 
assessment.
Rationale: For clarification on procedures related to TB laboratory testing.

Indicated that for subjects with a negative TB test at Screening or most recent evaluation, an 
annual TB re-test will be performed if subject is still taking study drug.
Rationale: For clarification that re-test is only performed if subject is still taking study drug.

Section 4.1, Methods of Timing and Safety Assessment: added eCRFs for Bone Fracture and 
Retinal Detachment.
Rationale: To comply with health authority request.

Section 4.3, Reporting Adverse Events and Intercurrent Illnesses: Added contact for safety 
concerns.
Rationale: To align with appropriate safety contact information.

Section 5.1, Additional Contraception-Related Eligibility Criteria and Requirements for Canada: 
updated criteria to indicate that a female subject of childbearing potential must be practicing 2 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
forms of contraception from Baseline through at least 30 days after the last dose of study drug, 
updated ages for postmenopausal definitions.
Rationale: For correction and internal consistency within the document. 

Updated description of "double barrier" methods of contraception to clarify that the double 
marrier method is not considered a highly effective method of contraception  
Rationale: To align with CTFG guidance. 

Added Section 5.3, Japan-Specific Requirements, added reference to Section 5.3 in Section 5.4.
Rationale: To align with requirements for study drugs for which safety information is reported in 
Japan.

Section 6.4, Selection and Timing of Dose for Each Subject: Updated language regarding how to 
handle an interruption of upadacitinib/matching PBO dosing > 14 consecutive days during the 
first 24 weeks or > 21 consecutive days after Week 24.
Rationale: To advise discussion with TA MD before discontinuation.
In addition to the above modifications, this Amendment contains minor text edits as needed for 
consistency and clarity.
Page 74 of 155
 

SAP_001.pdf: 
Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
1
Statistical Analysis Plan for Study M16-852
A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Safety and Efficacy 
of Upadacitinib in Subjects with Giant Cell Arteritis: 
SELECT-GCA
Date: 14 February 2024
Version 2.0
NCT03725202


Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
2
Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Objectives and Design ................................................5
2.1
Study Objectives .................................................................................... 5
2.2
Study Design Overview.......................................................................... 8
2.3
Treatment Assignment and Blinding..................................................... 10
2.4
Sample Size Determination .................................................................. 12
3.0
Endpoints.............................................................................12
3.1
Primary Endpoint ................................................................................. 12
3.2
Multiplicity-Controlled Secondary Endpoints....................................... 13
3.3
Additional Efficacy Endpoints.............................................................. 14
3.4
Safety Endpoints .................................................................................. 15
4.0
Analysis Populations ...........................................................16
5.0
Subject Disposition..............................................................17
6.0
Study Treatment Duration and Compliance .....................18
7.0
Subject Characteristics .......................................................19
7.1
Demographics and Baseline Characteristics.......................................... 19
7.2
Medical History and Prior and Concomitant Medications ..................... 21
7.3
Protocol Deviations .............................................................................. 21
8.0
Handling of Potential Intercurrent Events for the 
Primary and Multiplicity-Controlled Secondary 
Endpoints.............................................................................22
9.0
Efficacy Analyses.................................................................24
9.1
General Considerations......................................................................... 24
9.2
Handling of Missing Data..................................................................... 24
9.3
Primary Efficacy Endpoint and Analyses.............................................. 26
9.3.1
Primary Efficacy Endpoint ................................................................... 26
9.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 26
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint............................................................................................... 27
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 28
9.4.1
Multiplicity-Controlled Secondary Efficacy Endpoints......................... 28


Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
3
9.4.2
Main Analyses of Multiplicity-Controlled Secondary Endpoints........... 30
9.4.3
Sensitivity and Supplementary Analyses for Multiplicity-
Controlled Secondary Efficacy Endpoints............................................. 34
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses....................... 34
9.5
Additional Efficacy Endpoints and Analyses ........................................ 35
9.6
Efficacy Subgroup Analyses................................................................. 36
10.0
Safety Analyses....................................................................37
10.1
General Considerations......................................................................... 37
10.2
Adverse Events..................................................................................... 38
10.2.1
Treatment-Emergent Adverse Events.................................................... 38
10.2.2
Adverse Event Overview...................................................................... 38
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT ...................... 39
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 40
10.2.5
Deaths, Serious Adverse Events, and Adverse Events Leading to 
Study Treatment Discontinuation.......................................................... 40
10.2.6
Adverse Events of Special Interest........................................................ 40
10.3
Analysis of Laboratory Data................................................................. 42
10.4
Analysis of Vital Signs......................................................................... 44
10.5
Other Safety Analyses .......................................................................... 44
10.6
Safety Subgroup Analyses.................................................................... 45
11.0
Interim Analyses..................................................................45
11.1
Data Monitoring Committee................................................................. 46
12.0
Overall Type-I Error Control.............................................46
13.0
Version History ...................................................................51
14.0
References............................................................................52
List of Tables
Table 1.
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Endpoint ................................................................... 27
Table 2.
Summary of the Estimand Attributes Corresponding to the 
Multiplicity-Controlled Secondary Efficacy Endpoints......................... 32


Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
4
Table 3.
List of Primary and Secondary Endpoints for Regulatory Purpose 
(FAS1) ................................................................................................. 48
Table 4.
SAP Version History Summary ............................................................ 51
List of Figures
Figure 1.
Study Schematic................................................................................... 10
Figure 2.
Graphical Multiple Testing Procedure for Regulatory Purpose 
(FAS1) ................................................................................................. 49
Figure 3.
Graphical Multiple Testing Procedure for PMDA Regulatory 
Purpose (FAS1).................................................................................... 50
List of Appendices
Appendix A.
List of SAP Signatories ........................................................................ 54
Appendix B.
Definition of Adverse Events of Special Interest................................... 55
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 57
Appendix D.
National Cholesterol Education Program (NCEP) Adult 
Treatment Panel III (ATP III) for Selected Lipid Parameters ................ 59
Appendix E.
Interim Futility Analysis Based on the Conditional Power.................... 60
Appendix F.
Tipping Point Analysis for Secondary Continuous Endpoints 
(except for cumulative CS exposure) .................................................... 62
Appendix G.
Non-Responder Imputation Incorporating Multiple Imputation............. 65
Appendix H.
Random Seeds...................................................................................... 70


Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for upadacitinib 
Study M16-852, a multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the safety and efficacy of upadacitinib in subjects with giant cell arteritis (GCA): 
SELECT-GCA.
The analyses of pharmacokinetic endpoints, patient experience endpoints and biomarker 
exploratory research 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 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 Objectives and Design
2.1
Study Objectives
The objective of Period 1 is to evaluate the efficacy of upadacitinib 7.5 mg once daily 
(QD) and 15 mg QD in combination with a 26-week corticosteroid (CS) taper regimen 
compared to placebo in combination with a 52-week CS taper regimen, as measured by 
the proportion of subjects achieving sustained remission at Week 52, and to assess the 
safety and tolerability of upadacitinib in subjects with GCA.
The hypothesis corresponding to the efficacy objective of Period 1 is that the proportion 
of subjects achieving sustained remission at Week 52 is higher in either upadacitinib 
15 mg QD or 7.5 mg QD in combination with a 26-week CS taper regimen when 
compared to placebo in combination with a 52-week CS taper regimen in subjects with 
GCA.


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M16-852 – Statistical Analysis Plan
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The estimand corresponding to the primary endpoint (defined in Section 3.1) is as 
follows:
●
The estimand for the primary endpoint is defined as the difference in the 
proportion of subjects achieving sustained remission at Week 52 between 
either upadacitinib 15 mg QD or 7.5 mg QD in combination with a 26-week 
CS taper regimen group and placebo in combination with a 52-week CS taper 
regimen group in subjects with GCA, without premature discontinuation from 
study drug, and assuming not receiving more than 100 mg prednisone (or 
equivalent) systemic CS for a non-GCA indication.
The estimands corresponding to the multiplicity-controlled secondary endpoints (defined 
in Section 3.2) are as follows:
●
The estimands corresponding to the multiplicity-controlled remission-related 
secondary binary endpoints (which includes proportion of subjects achieving 
sustained complete remission from Week 12 through Week 52, proportion of 
subjects in complete remission at Week 52, and proportion of subjects in 
complete remission at Week 24) are defined as the difference in the proportion 
of subjects achieving each endpoint between either upadacitinib 15 mg QD or 
7.5 mg QD in combination with a 26-week CS taper regimen group and 
placebo in combination with a 52-week CS taper regimen group in subjects 
with GCA, without premature discontinuation from study drug, and assuming 
not receiving more than 100 mg prednisone (or equivalent) systemic CS for a 
non-GCA indication.
●
The estimand corresponding to the multiplicity-controlled secondary binary 
endpoint of proportion of subjects who experience at least 1 disease flare 
through Week 52 is defined as the difference in the proportion of subjects who 
experience at least 1 disease flare through Week 52 between either 
upadacitinib 15 mg QD or 7.5 mg QD in combination with a 26-week CS taper 
regimen group and placebo in combination with a 52-week CS taper regimen 
group in subjects with GCA, regardless of premature discontinuation from
study drug, or receiving more than 100 mg prednisone (or equivalent) systemic 
CS for a non-GCA indication.


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M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
7
●
The estimand corresponding to the multiplicity-controlled secondary endpoint 
of the rate of CS-related AEs through Week 52 is defined as the difference in 
the exposure adjusted treatment-emergent CS-related AE rate in either 
upadacitinib 15 mg QD or 7.5 mg QD in combination with a 26-week CS taper 
regimen group and placebo in combination with a 52-week CS taper regimen 
group in subjects with GCA, regardless of premature discontinuation from
study drug, initiation of CS escape therapy, or receiving more than 100 mg 
prednisone (or equivalent) systemic CS for a non-GCA indication.
●
The estimands corresponding to each multiplicity-controlled secondary 
continuous endpoint (except for cumulative CS exposure) are defined as the 
difference in the mean change from Baseline (or difference in the mean TSQM 
patient global satisfaction subscale) between either upadacitinib 15 mg QD or 
7.5 mg QD in combination with a 26-week CS taper regimen group and 
placebo in combination with a 52-week CS taper regimen group in subjects 
with GCA, regardless of premature discontinuation from study drug, or 
receiving more than 100 mg prednisone (or equivalent) systemic CS for a non-
GCA indication, and without initiation of CS escape therapy.
●
The estimand corresponding to the multiplicity-controlled secondary endpoint 
of cumulative CS exposure through Week 52 is defined as the difference in 
cumulative CS exposure between either upadacitinib 15 mg QD or 7.5 mg QD 
in combination with a 26-week CS taper regimen group and placebo in 
combination with a 52-week CS taper regimen group in subjects with GCA, 
regardless of premature discontinuation from study drug, initiation of CS 
escape therapy, or receiving more than 100 mg prednisone (or equivalent) 
systemic CS for a non-GCA indication.
●
The estimand corresponding to the multiplicity-controlled secondary endpoint 
of time to first disease flare is defined as the difference in the time to first 
disease flare in either upadacitinib 15 mg QD or 7.5 mg QD in combination 
with a 26-week CS taper regimen group and placebo in combination with a 
52-week CS taper regimen group in subjects with GCA, regardless of 
premature discontinuation from study drug, or receiving more than 100 mg 
prednisone (or equivalent) systemic CS for a non-GCA indication.
●
The estimand corresponding to the multiplicity-controlled secondary endpoint 
of number of disease flare per subject is defined as the difference in the 


Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
8
exposure-adjusted number of disease flare per subject between either 
upadacitinib 15 mg QD or 7.5 mg QD in combination with a 26-week CS taper 
regimen group and placebo in combination with a 52-week CS taper regimen 
group in subjects with GCA, regardless of premature discontinuation from
study drug, or receiving more than 100 mg prednisone (or equivalent) systemic 
CS for a non-GCA indication.
The objective of Period 2 is to evaluate the safety and efficacy of continuing versus 
withdrawing upadacitinib in maintaining remission in subjects who achieved remission in 
Period 1.
2.2
Study Design Overview
Study M16-852 is a Phase 3, global, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the safety and efficacy of upadacitinib in subjects with GCA.
The study is designed to enroll approximately 420 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations. Subjects in screening will be permitted to enroll even if the target 
number of subjects has been enrolled. The study population will consist of adult subjects 
who are at least 50 years of age with a diagnosis of active GCA, either new onset or 
relapsing disease, within 8 weeks of Baseline.
The study will allow enrollment of a minimum of 30% of subjects with new onset disease 
and up to 70% of subjects with relapsing disease. The study will also allow enrollment of 
up to 20% of subjects with previous use of an IL-6 inhibitor with discontinuation based on 
reasons other than disease flare.
The Primary Analysis will be conducted after all subjects have completed the Week 52 
visit or have prematurely discontinued from the study prior to the Week 52 visit. The 
Primary Analysis will include efficacy and safety data in Period 1 and safety data in 
Period 2 up to the data cut-off date for the Primary Analysis. The final analysis will be 


Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
9
conducted after all subjects have completed the Week 104 visit and the safety Follow-up 
Visit or have prematurely discontinued from the study.
An independent, external data monitoring committee (DMC) will be established for 
periodic review of unblinded safety data and to ensure subject safety. In addition, a futility 
analysis will be conducted by the DMC to assess lack of efficacy once the first 
140 enrolled subjects complete 24 weeks of treatment. Study sites and subjects will 
remain blinded for the duration of the study.
After all subjects have either completed the Week 52 visit or have prematurely 
discontinued from the study prior to the Week 52, the Sponsor will be unblinded to 
Period 1 and Period 2 study drug assignment to perform the Primary Analysis and 
facilitate potential regulatory filings. The investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment throughout the study.
A schematic of the study is shown in Figure 1.


Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
10
Figure 1.
Study Schematic
R1  sustained remission for 24 consecutive weeks prior to Week 52; R2  remission at Week 52 but not achieving 
sustained remission for at least 24 consecutive weeks prior to the Week 52 Visit
2.3
Treatment Assignment and Blinding
The study duration includes a 35-day maximum screening period; a 52-week randomized, 
double-blind, parallel-group treatment period (Period 1); a 52-week blinded extension 
period in which subjects who qualify are either re-randomized or continue on their 
original assignment (Period 2); and a 30-day follow-up period.
In Period 1, subjects who meet eligibility criteria are randomized in a 2:1:1 ratio to 1 of 
3 treatment groups:
●
Upadacitinib 15 mg administered daily + 26-week CS taper regimen 
●
Upadacitinib 7.5 mg administered daily + 26-week CS taper regimen


Upadacitinib
M16-852 – Statistical Analysis Plan
Version 2.0 – 14 February 2024
11
●
Placebo administered daily + 52-week CS taper regimen
Randomization of all subjects, except for those in Japan, will be stratified by Baseline CS 
dose (prednisone or prednisolone > 30 mg, prednisone or prednisolone ≤ 30 mg), prior use 
of an IL-6 inhibitor (yes, no), and Baseline disease status (new onset disease, relapsing 
disease). In Japan, the study will attempt to include a minimum of 8 subjects. No 
stratification will be utilized for randomization, however, data on all three stratification 
factors will be collected for all Japanese patients.
Starting at Baseline, all subjects will switch from CS obtained outside of the study to 
open-label oral prednisone or prednisolone provided by the Sponsor at a dose of 20, 30, 
40, 50, or 60 mg QD. The initial dose of prednisone or prednisolone will be at the 
discretion of the investigator, based on disease severity and comorbid medical conditions. 
Prednisone or prednisolone will be tapered according to a predefined schedule over a 
26- or 52-week period. Open-label prednisone or prednisolone will be provided until the 
dose is tapered to 20 mg/day. Subsequently, blinded prednisone or prednisolone will be 
provided for the remaining blinded taper regimen through Week 52. Additional details 
regarding CS therapy during the study can be found in Section 5.8 of the protocol.
Subjects assigned to either dose of upadacitinib who achieve sustained remission for at 
least 24 consecutive weeks prior to the Week 52 Visit (at the end of Period 1) will be re-
randomized in a 2:1 ratio to either continue on upadacitinib or switch to placebo in 
Period 2. Re-randomization will be stratified by Baseline disease status (new onset 
disease, relapsing disease). Subjects who achieved sustained remission for at least 
24 consecutive weeks prior to the Week 52 visit (at the end of Period 1) who were
assigned to placebo in Period 1 will continue to receive placebo in Period 2.
At Week 52, subjects who have absence of GCA signs and symptoms AND are CS-free, 
but do not achieve sustained remission for at least 24 consecutive weeks prior to the 
Week 52 Visit will continue in Period 2 on their originally randomized treatment 
assignment. All other subjects will be discontinued from study drug and the study at the 
end of Period 1.


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In Period 2, subjects who experience a flare will start open-label CS escape therapy with 
prednisone or prednisolone at investigator's discretion. Subjects meeting flare criteria will 
return within approximately 4 weeks after the visit in which flare was determined for 
reassessment (either at a regularly scheduled or unscheduled visit). If the subject does not 
have absence of GCA signs and symptoms within approximately 4 weeks after the visit in 
which flare was determined, they will be discontinued from study drug. Subjects who 
discontinue study drug should receive treatment at the investigator's judgment, in 
accordance with local standard-of-care (which could include tocilizumab) and continue to 
follow the regular visit schedule for Period 2 and adhere to the study procedures.
2.4
Sample Size Determination
The planned total sample size of 420 subjects with 2:1:1 ratio (upadacitinib 15 mg QD: 
upadacitinib 7.5 mg QD: Placebo QD) was determined to have at least 90% power to
detect a 20% difference in sustained remission rate at Week 52 between the upadacitinib
15 mg arm and placebo arm (assuming a response rate of 40% in the placebo arm), using
Fisher's exact test, with an overall two-sided alpha of 0.05.
3.0
Endpoints
3.1
Primary Endpoint
The primary endpoint is the proportion of subjects achieving sustained remission at 
Week 52. Sustained remission is defined as having achieved both of the following:
●
Absence of GCA signs and symptoms from Week 12 through Week 52
●
Adherence to the protocol-defined CS taper regimen


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3.2
Multiplicity-Controlled Secondary Endpoints
Multiplicity-controlled secondary endpoints include:
1.
Proportion of subjects achieving sustained complete remission from Week 12 through Week 52.
Sustained complete remission is defined as having achieved all of the following:
•
Absence of GCA signs and symptoms from Week 12 through Week 52;
•
Normalization of ESR (to ≤30 mm/hr; if ESR > 30 mm/hr and elevation is not attributable 
to GCA, this criterion can still be met) from Week 12 through Week 52;
•
Normalization of hsCRP (to < 1 mg/dL without elevation [on 2 consecutive visits] to 
≥1 mg/dL) from Week 12 through Week 52; and 
•
Adherence to the protocol-defined CS taper regimen.
2.
Cumulative CS exposure through Week 52.
3.
Time to first disease flare through Week 52. Disease flare is defined as an event determined by 
the investigator to represent recurrence of GCA signs or symptoms or an ESR measurement 
> 30 mm/hr (attributable to GCA) AND requiring an increase in CS dose.
4.
Proportion of subjects who experience at least 1 disease flare through Week 52.
5.
Proportion of subjects in complete remission at Week 52. Complete remission is defined as 
having achieved all of the following:
•
Absence of GCA signs and symptoms; 
•
Normalization of ESR (to ≤30 mm/hr); if ESR > 30 mm/hr and elevation is not attributable 
to GCA, this criterion can still be met;
•
Normalization of hsCRP to < 1 mg/dL; and 
•
Adherence to the protocol-defined CS taper regimen.
6.
Proportion of subjects in complete remission at Week 24.
7.
Change from Baseline in the 36-item Short Form Quality of Life Questionnaire (SF-36) Physical 
Component Score (PCS) at Week 52.
8.
A group of four endpoints:
•
Number of disease flares per subject through Week 52;
•
Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-Fatigue) at Week 52;
•
Assessment of Treatment Satisfaction Questionnaire for Medication (TSQM) patient global 
satisfaction subscale at Week 52;
•
Rate of CS-related AEs through Week 52


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3.3
Additional Efficacy Endpoints
The additional endpoints for Period 1 are as follows:
•
Proportion of subjects in complete remission at Week 12
•
Change from Baseline in SF-36 by visit
•
Change from Baseline in FACIT-Fatigue by visit
•
Assessment of TSQM patient global satisfaction subscale by visit
•
Change from Baseline in EuroQoL Five Dimensions Five Levels Questionnaire (EQ-5D-5L) by 
visit
•
Assessment of Patients' Global Impression of Change (PGIC) by visit
•
Change from Baseline in Patient Global Assessment (PGA) by visit
•
Proportion of subjects with GCA-related Health Resource Utilization by visit
•
Proportion of subjects in remission at each visit through Week 52. Defined as:
o
Absence of GCA signs and symptoms
o
Adherence to the protocol-defined CS taper regimen


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The additional endpoints for Period 2 are as follows:
•
Time to first disease flare from onset of Period 2 through Week 104. Disease flare is defined as an 
event determined by the investigator to represent recurrence of GCA signs or symptoms or an ESR 
measurement > 30 mm/hr attributable to GCA AND requiring initiation of CS.
•
Proportion of subjects maintaining remission from onset of Period 2 through Week 104. Remission 
is defined as absence of GCA signs and symptoms and CS-free.
•
Cumulative CS exposure (Period 2 and inclusive of Periods 1 and 2) through Week 104
•
Proportion of subjects in complete remission at Week 104. Complete remission is defined as having 
achieved all of the following:
o
Absence of GCA signs and symptoms;
o
Normalization of ESR (to ≤30 mm/hr); if ESR > 30 mm/hr and elevation is not attributable to 
GCA, this criterion can still be met;
o
Normalization of hsCRP (to < 1 mg/dL); and
o
CS-free.
•
Proportion of subjects who experience at least 1 disease flare from onset of Period 2 through 
Week 104
•
Number of disease flares per subject from onset of Period 2 through Week 104
•
Change in SF-36 from onset of Period 2 through Week 104
•
Change in FACIT-Fatigue from onset of Period 2 through Week 104
•
Assessment of TSQM patient global satisfaction subscale from onset of Period 2 through Week 104
•
Change in EQ-5D-5L from onset of Period 2 by visit through Week 104
•
Assessment of PGIC from onset of Period 2 through Week 104
•
Proportion of subjects with GCA-related Health Resource Utilization at Week 104
3.4
Safety Endpoints
Safety will be assessed by AE monitoring, physical examination, vital signs, 
electrocardiogram and clinical laboratory testing during the entire study. Laboratory 
assessments will include hematologic parameters, chemistry, liver function tests, and lipid 
parameters.


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4.0
Analysis Populations
The following population sets will be used for the analyses.
●
The Full Analysis Set (FAS) will be defined for Period 1 and Period 2.
○
The FAS in Period 1 (FAS1) consists of all randomized subjects who 
received at least 1 dose of study drug in Period 1.
○
The FAS in Period 2 (FAS2) consists of all subjects who achieved
remission for at least 24 consecutive weeks prior to the Week 52 Visit (at 
the end of Period 1) and received at least 1 dose of study drug in Period 2.
●
An exploratory analysis set (FAS2 E) is defined for Period 2 to include all 
subjects who had absence of GCA signs and symptoms AND were CS-free at 
the Week 52 visit, but did not achieve remission for at least 24 consecutive 
weeks prior to the Week 52 Visit, and continued and received at least 1 dose of 
study drug in Period 2 on their originally randomized treatment assignment.
●
The Per-Protocol Analysis Set is defined to represent a subset of the FAS1
subjects without any major protocol violations during the study which are 
expected to impact the primary endpoint. The final criteria and the exclusion of 
subjects for the Per-Protocol Analysis Set will be finalized before the database 
lock for Primary Analysis. The Per-Protocol Analysis Set will be used to 
analyze the primary efficacy endpoint as a supplementary analysis.
●
The Safety Analysis Set in Period 1 (SS1) consists of all subjects who received 
at least 1 dose of study drug in Period 1.
●
The Safety Analysis Set in Period 2 (SS2) consists of all subjects who received 
at least 1 dose of study drug in Period 2.
●
The Long-Term Safety Analysis Set (SS LT) consists of all subjects who 
received at least one dose of study drug in Period 1 and received the same 
study drug in Period 2.
Primary efficacy analysis for primary and multiplicity-controlled secondary endpoints will 
be carried out on FAS1 and SS1 (for the endpoint of rate of CS-related AEs) in Period 1. 
Efficacy analysis for additional endpoints in Period 1 will be carried out on FAS1, and 
efficacy analysis for additional endpoints in Period 2 will be carried out on FAS2. 


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Exploratory efficacy analyses for Period 2 will be conducted for additional endpoints in 
Period 2 on FAS2 E. For all efficacy analyses, subjects will be grouped according to 
treatment (or treatment sequence) as randomized.
For Safety Analysis Sets, subjects are assigned to a treatment group based on the 
treatment actually received, regardless of the treatment randomized.
5.0
Subject Disposition
Enrollment failure subjects and the associated reasons for failure to randomize will be 
tabulated for all screened subjects.
Separately for Period 1 and Period 2, the number and percentage of subjects for each of 
the following categories will be summarized, for overall and for each treatment group (or 
treatment sequence) on FAS1 and FAS2: 
●
Subjects randomized in the study
●
Subjects who took at least one dose of study treatment
●
Subjects who completed study treatment
●
Subjects who prematurely discontinued study treatment
●
Subjects who completed study participation
●
Subjects who prematurely discontinued study participation
Primary reason and all reasons for premature discontinuation of study drug and study 
participation will be summarized separately by treatment group and overall, with 
frequencies and percentages by reason for discontinuation.
The subject disposition for Period 1 will be summarized overall and by randomized 
treatment group in Period 1.
The subject disposition for Period 2 will be summarized overall and by each treatment 
sequence on FAS2 and FAS2 E.


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In addition, a summary of subject accountability by investigator will be provided for 
Period 1, where the number of subjects in each of the above categories will be tabulated 
for each treatment group on FAS1.
6.0
Study Treatment Duration and Compliance
Duration of treatment will be summarized for each treatment group on SS1 for Period 1, 
SS2 for Period 2 and SS LT across Period 1 and Period 2.
Duration of treatment will be summarized using the number of subjects treated, mean, 
standard deviation, median, minimum and maximum.
Study Drug Duration (in Days) in Period 1:
●
Date of last dose of study drug in Period 1 Date of first dose of study drug in 
Period 1 + 1
Study Drug Duration (in Days) in Period 2:
●
Date of last dose of study drug in Period 2 Date of first dose of study drug in 
Period 2 + 1
Study Drug Duration (in Days) for SS LT:
●
Date of last dose of study drug - Date of first dose of study drug + 1
In addition, the number and percentage of subjects exposed to study drug will be 
summarized for the following cumulative duration intervals for SS1 and SS LT.
●
≥ 1 day
●
≥ 2 weeks
●
≥ 4 weeks
●
≥ 12 weeks
●
≥ 24 weeks


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●
≥ 36 weeks
●
≥ 48 weeks
●
≥ 60 weeks
●
≥ 72 weeks
●
≥ 84 weeks
●
≥ 96 weeks
Treatment compliance will be summarized for each treatment group on SS1 for Period 1, 
SS2 for Period 2, and SS LT across Period 1 and Period 2. Treatment compliance is 
defined as the number of tablets actually taken divided by the number of tablets that 
should have been taken. Percent compliance will be summarized.
7.0
Subject Characteristics
Categorical variables will be summarized with the number and percentage of subjects.
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
Demographics and selected Baseline characteristics will be summarized descriptively, 
overall and by treatment group (or treatment sequence) for FAS1 and FAS2. Unless 
otherwise specified, "Baseline" is defined as the last non-missing value on or before the 
day of the first administration of study drug or randomization if no study drug is given.
Categorical demographic variables include:
●
Sex (Male, Female)
●
Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, Multiple)
●
Race Group (White, Non-White)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Age Group 1 (< 65 years, ≥65 years)


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Age Group 2 (< 65 years, ≥65 and < 75 years, ≥75 years)
●
Body Mass Index (BMI) Group (< 25 kg/m2, ≥ 25 kg/m2 and < 30 kg/m2, 
≥30 kg/m2)
●
Geographic Region Group (North America, Western Europe, Eastern Europe, 
Asia, Oceania)
●
Nicotine User (Current, Former, Never, Unknown)
●
Alcohol User (Current, Former, Never, Unknown)
Continuous demographic variables include:
●
Age (years)
●
Weight (kg)
●
Height (cm)
●
BMI (kg/m2)
Selected Baseline characteristics include:
●
Prior Use of IL-6 Inhibitor (Yes, No)
●
New Onset of GCA (Yes, No)
●
Baseline CS Dose (mg)
●
Baseline CS Dose Group (> 30 mg, ≤ 30 mg)
●
Disease Duration since Diagnosis (years)
●
Baseline C-Reactive Protein (mg/dL)
●
Baseline Erythrocyte Sedimentation Rate (mm/hr)
●
Ischemia-Related Vision Loss (Yes, No)
●
History of Unequivocal Symptoms of PMR Symptom without Cranial 
Symptoms of GCA (Yes, No)
●
Baseline FACIT-Fatigue Score
●
Baseline SF-36 Score (PCS, Mental Component Summary (MCS), the 
8-Sub-domain Scores)
●
Baseline EQ-5D-5L


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●
Baseline PGA
7.2
Medical History and Prior and Concomitant Medications
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 (SOC) and preferred term) will 
be summarized overall and by treatment group for FAS1. The SOC will be presented in 
alphabetical order, and the preferred terms will be presented in alphabetical order within 
each SOC. Subjects reporting more than one condition/diagnosis will be counted only 
once in each row (SOC or preferred term).
Prior medication will be summarized for FAS1. Concomitant medications will be 
summarized separately for FAS1 and FAS2. 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 + 1 day. The number and percentage of subjects taking prior and 
concomitant medications will be summarized by generic drug name, based on the World 
Health Organization (WHO) Drug Dictionary. The actual version of the WHO Drug 
Dictionary will be noted in the statistical tables and clinical study report.
7.3
Protocol Deviations
Protocol deviations include eligibility criteria violations, receipt of wrong treatment or 
incorrect dose of study treatment, development of withdrawal criteria without being 
withdrawn, and use of prohibited concomitant medications.


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For each of the following protocol deviation categories and across all categories, the 
number and percentage of randomized subjects with at least one protocol deviation will be 
summarized overall and by treatment group:
●
Subject entered into the study even though did not satisfy entry criteria;
●
Subject developed withdrawal criteria during the study but was not withdrawn;
●
Subject received wrong treatment or incorrect dose of study treatment;
●
Subject took prohibited concomitant medication.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Multiplicity-Controlled Secondary 
Endpoints
The primary endpoint and multiplicity-controlled secondary endpoints (defined in 
Section 3.1 and Section 3.2) will be analyzed based on FAS1, except for the endpoint of 
the rate of CS-related AEs which will be analyzed based on SS1.
Intercurrent Events (ICEs):
●
ICE1: Premature discontinuation from study treatment
●
ICE2: Investigator-initiated CS escape therapy
●
ICE3: Received more than 100 mg prednisone (or equivalent) systemic CS for 
a non-GCA indication 
The following method will be used to address potential intercurrent events above:
For the primary analysis of the primary efficacy endpoint, estimand with composite and 
hypothetical strategy will be used. For ICE1: subjects will be considered as non-
responders after ICE1. ICE2 is not applicable for the primary endpoint. For ICE3: data 
after ICE3 will be handled by multiple imputation (MI).
For the primary analysis of the multiplicity-controlled secondary binary remission related 
efficacy endpoints, estimands with composite and hypothetical strategy will be used. For 


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ICE1: subjects will be considered as non-responders after ICE1. ICE2 is not applicable for 
remission related endpoints. For ICE3: data after ICE3 will be handled by MI.
For the primary analysis of the secondary binary efficacy endpoint of proportion of 
subjects who experience at least 1 disease flare through Week 52, estimand with treatment 
policy strategy to handle ICEs will be used: data collected will be used regardless of ICE1 
or ICE3. ICE2 is not applicable for the endpoint of proportion of subjects who experience 
at least 1 disease flare.
For the primary analysis of the secondary continuous efficacy endpoints (except for 
cumulative CS exposure), estimands with treatment policy and hypothetical strategy to 
handle ICEs will be used: data collected will be used regardless of ICE1or ICE3. Data 
collected after ICE2 will be excluded and missing data will be handled by mixed effect 
model repeat measurement (MMRM).
For the primary analysis of secondary endpoint of cumulative CS exposure, estimand with 
treatment policy strategy to handle ICEs will be used: data collected will be used 
regardless of ICE1, ICE2, or ICE3.
For the primary analysis of secondary time-to-event endpoint (i.e., time-to-first disease 
flare), estimand with treatment policy strategy to handle ICEs will be used: data will be 
used regardless of ICE1 or ICE3. ICE2 is not applicable for the endpoint of time-to-first 
disease flare.
For the primary analysis of secondary count endpoint (i.e., number of disease flares per 
subject), estimand with treatment policy strategy to handle ICEs will be used: data will be 
used regardless of ICE1 or ICE3. ICE2 is not applicable for the endpoint of number of 
disease flares per subject.
For the primary analysis of the secondary efficacy endpoint of rate of CS-related AEs, 
estimand with treatment policy strategy to handle ICEs will be used: data collected will be 
used regardless of ICE1, ICE2, or ICE3.


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9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted on the FAS in each period. All Period 1 efficacy 
analyses will be conducted using FAS1. All Period 2 efficacy analyses will be conducted 
using FAS2. In addition, per-protocol analysis for the primary endpoint will be performed 
in the Per-Protocol Analysis Set.
The Primary Analysis will be performed after all subjects have completed Period 1 and 
the database has been locked. This will be the final analysis for all primary and 
multiplicity-controlled secondary endpoints as well as all additional efficacy endpoints in 
Period 1.
The primary and multiplicity-controlled secondary endpoints as specified in Section 3.0
will be tested with graphical multiplicity adjustment1,2 to ensure a strong control of 
family-wise type I error rate at 2-sided α  0.05.
The final analysis will be performed after all subjects have either withdrawn from the 
study or completed Period 2 and safety follow-up.
For analyses with stratification factors used for randomization, any subject who is 
randomized within an incorrect stratum will be analyzed according to the actual stratum to 
which the subject belongs, unless otherwise indicated. The stratification factor of prior use 
of an IL-6 inhibitor (yes, no) will be removed from the models for all analyses due to the 
small number (17 [approximately 4.0%] out of 428 total) of prior IL-6 inhibitor users 
enrolled.
9.2
Handling of Missing Data
Non-Responder Imputation incorporating multiple imputation (NRI-MI)
The NRI-MI will be the primary approach to handle missing data for binary primary and 
secondary endpoints (except for the endpoints of proportion of subjects who experience at 


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least 1 disease flare). The NRI-MI will categorize any subject who does not have an 
evaluation during a pre-specified visit window (either due to missing assessment, early 
withdrawal from the study, or due to intercurrent event) as a non-responder for the visit. 
The only exceptions are: 1) when a 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 logistical restriction will be handled by MI. The MI assumes data are missing 
at random (MAR). In total, 30 datasets will be imputed, and results from the 30 datasets 
will be synthesized following Rubin's formula.1 All assessments after an intercurrent 
event occurs will be handled as specified in Section 8.0. For example, for the primary 
endpoint, all assessments after the visit date of ICE1 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.
As Observed (AO)
The AO analysis will not impute values for missing evaluations, and thus a subject who 
does not have an evaluation on a scheduled visit will be excluded from the AO analysis 
for that visit. All observed data will be used in the analysis. AO analysis will be the 
primary approach to analyze disease flare endpoints (including proportion of subjects who 
experience at least 1 disease flare through Week 52, time to first disease flare through 
Week 52, and number of disease flares per subject through Week 52), cumulative CS 
exposure, and rate of CS-related AEs.
Mixed Effect Model Repeat Measurement (MMRM)
MMRM will be the primary approach for the analysis of continuous variables with more 
than one post Baseline assessment, except for the endpoint of cumulative CS exposure.
MMRM analysis will be conducted using mixed model including observed measurements 
at all visits. The mixed model includes the categorical fixed effects of treatment, visit and 
treatment-by-visit interaction, stratification factors at randomization (Baseline CS dose 
[prednisone or prednisolone >30 mg, prednisone or prednisolone ≤ 30 mg], and Baseline 
disease status [new onset disease, relapsing disease]), and the continuous fixed covariates 


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of Baseline measurement (when applicable). An unstructured variance covariance matrix 
will be used. If the model cannot converge, an appropriate alternative covariance structure 
(e.g., autoregressive (1) or compound symmetry) will be used. The parameter estimations 
will be based on the assumption of data being missing at random and the method of 
restrictive maximum likelihood (REML) will be used.
9.3
Primary Efficacy Endpoint and Analyses
9.3.1
Primary Efficacy Endpoint
The primary endpoint is the proportion of subjects achieving sustained remission at 
Week 52. Sustained remission is defined as having achieved both of the following:
●
Absence of GCA signs and symptoms from Week 12 through Week 52
●
Adherence to the protocol-defined CS taper regimen.
Subject who belongs to any one of following categories will be considered as not adhering 
to the protocol-defined taper regimen:
●
Investigator-initiated escape therapy in any time in Period 1
●
Received more than 100 mg (prednisone-equivalent dose) additional systemic 
CS for GCA indication during Period 1 of the study, without being identified 
as escape therapy. Additional systemic CS is defined as any systemic CS 
captured as concomitant medication other than IRT dispensed CS for taper.
9.3.2
Main Analysis of Primary Efficacy Endpoint
The statistical null hypothesis corresponding to the primary endpoint is that there is no 
difference between either upadacitinib 15mg QD or 7.5mg QD in combination with a 
26-week CS taper regimen group and the placebo in combination with a 52-week CS taper 
regimen group in terms of the proportion of subjects achieving sustained remission at 
Week 52 in Period 1.


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Analysis of the primary endpoint will be conducted on the FAS1 based on treatment as 
randomized. Comparison will be made between each upadacitinib group and placebo 
group using the Cochran-Mantel-Haenszel (CMH) test for common risk difference 
estimated by a weighted average of risk difference across strata using the Mantel-
Haenszel weights. The strata include stratification factors (Baseline CS dose [prednisone 
or prednisolone > 30 mg, prednisone or prednisolone ≤ 30 mg], and Baseline disease 
status [new onset disease, relapsing disease]). NRI-MI will be the primary approach in 
handling missing values. Point estimate, p-value, and 95% CIs for the difference in 
proportions between each upadacitinib group and placebo group will be provided.
The attributes of the estimand corresponding to the primary efficacy endpoint are 
summarized in Table 1.
Table 1.
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Primary
Upadacitinib 
vs. Placebo
Achievement 
of sustained 
remission at 
Week 52
Subjects with 
GCA
•
ICE1: composite
Subjects will be 
considered as non-
responders after ICE1.
•
ICE3: hypothetical
Data after ICE3 will be 
imputed by MI.
Difference in 
proportion of 
subjects 
achieving 
sustained 
remission at 
Week 52
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint
The same primary efficacy analysis will also be performed on Per-Protocol Analysis Set 
as a supplementary analysis for the primary efficacy endpoint.


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9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Multiplicity-Controlled Secondary Efficacy Endpoints
The multiplicity-controlled secondary endpoints are:
1.
Proportion of subjects achieving sustained complete remission from Week 12 through Week 52. 
Sustained complete remission is defined as having achieved all of the following:
•
Absence of GCA signs and symptoms from Week 12 through Week 52; 
•
Normalization of ESR (to ≤30 mm/hr; if ESR > 30 mm/hr and elevation is not attributable 
to GCA, this criterion can still be met) from Week 12 through Week 52;
•
Normalization of hsCRP (to < 1 mg/dL without elevation [on 2 consecutive visits] to 
≥1 mg/dL) from Week 12 through Week 52; and 
•
Adherence to the protocol-defined CS taper regimen.
2.
Cumulative CS exposure through Week 52.
3.
Time to first disease flare through Week 52. Disease flare is defined as an event determined by 
the investigator to represent recurrence of GCA signs or symptoms or an ESR measurement 
> 30 mm/hr (attributable to GCA) AND requiring an increase in CS dose.
4.
Proportion of subjects who experience at least 1 disease flare through Week 52.
5.
Proportion of subjects in complete remission at Week 52. Complete remission is defined as 
having achieved all of the following:
•
Absence of GCA signs and symptoms;
•
Normalization of ESR (to ≤30 mm/hr); if ESR >30 mm/hr and elevation is not attributable 
to GCA, this criterion can still be met.
•
Normalization of hsCRP to < 1 mg/dL; and
•
Adherence to the protocol-defined CS taper regimen.
6.
Proportion of subjects in complete remission at Week 24.
7.
Change from Baseline in the 36-item Short Form Quality of Life Questionnaire (SF-36) Physical 
Component Score (PCS) at Week 52.
8.
A group of four endpoints:
•
Number of disease flares per subject through Week 52;
•
Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-Fatigue) at Week 52;
•
Assessment of Treatment Satisfaction Questionnaire for Medication (TSQM) patient global 
satisfaction subscale at Week 52;
•
Rate of CS-related AEs* through Week 52
*
CS related AE is defined as treatment emergent adverse events related to prednisone/prednisolone (or matching 
placebo) according to the investigator.


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For remission-related secondary endpoints (except for the endpoint of complete remission 
at Week 24), a subject who belongs to any one of following categories will be considered 
as not adhering to the protocol-defined CS taper regimen:
●
Investigator-initiated escape therapy at any time in Period 1
●
Received more than 100 mg (prednisone-equivalent dose) additional systemic 
CS for GCA indication during Period 1 of the study, without being identified 
as escape therapy. Any additional systemic CS is defined as any systemic CS 
administered as a concomitant medication other than the IRT dispensed CS for 
taper.
For the endpoint of complete remission at Week 24, a subject who belongs to any one of 
following categories will be considered as not adhering to the protocol-defined CS taper 
regimen:
●
Investigator-initiated escape therapy up to Week 24
●
Received more than 100 mg (prednisone-equivalent dose) of additional 
systemic CS for GCA indication up to Week 24.
Disease flare is considered only after an assessment meets all the 3 following criteria:
●
Absence of recurrence of GCA signs and symptoms
●
Normalization of ESR
●
No CS dose increase
For the endpoints of disease flare, an increase in CS dose is defined as:
●
Investigator-initiated escape therapy in Period 1
●
Received additional GCA-related systemic CS dose(s) in Period 1
For the endpoint of number of disease flares per subject through Week 52, all flares 
occurred through Week 52 will be counted.


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9.4.2
Main Analyses of Multiplicity-Controlled Secondary 
Endpoints
The statistical null hypothesis corresponding to the multiplicity-controlled secondary 
endpoints is that there is no difference between either upadacitinib 15 mg QD or 7.5 mg 
QD in combination with a 26-week CS taper regimen groups and the placebo in 
combination with a 52-week CS taper regimen group in terms of each multiplicity-
controlled secondary endpoint.
Similar as the primary endpoint, for secondary binary endpoints, comparison will be made 
between each upadacitinib group and placebo group using CMH test for common risk 
difference estimated by a weighted average of risk differences across strata using the 
Mantel-Haenszel weights. Strata include stratification factors (Baseline CS dose 
[prednisone or prednisolone > 30 mg, prednisone or prednisolone ≤ 30 mg], and Baseline 
disease status [new onset disease, relapsing disease]). NRI-MI will be used as the primary 
approach to handle missing data except for the endpoint of proportion of subjects who 
experience at least 1 disease flare through Week 52. Point estimate, p-value, and 95% CI 
for the difference in proportions between each upadacitinib group and placebo will be 
provided.
For the endpoint of proportion of subjects who experience at least 1 disease flare through 
Week 52, the point estimate of flare rate at Week 52 from the Kaplan-Meier estimate for 
each stratum will be used to derive the stratified disease flare rate according to 
Sun R et al.2 Point estimate, p-value, and 95% CI for the odds ratio between each 
upadacitinib group and placebo will be provided.
For continuous endpoints except for cumulative CS exposure, MMRM model will be used 
to compare each upadacitinib group and placebo. The Baseline and visit means will be 
presented for each treatment group who have both Baseline and post-baseline visit values. 
Point estimate, standard error (SE), and 95% CIs of LS mean change from Baseline within 
treatment groups along with p-value between each upadacitinib treatment group and 
placebo will be provided.


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For cumulative CS exposure, which is likely non-normally distributed, van Elteren test 
stratified by stratification factors will be used. The median total cumulative CS exposure 
over the 52 weeks for each treatment group, p-value and the corresponding 95% CI (based 
on order statistics) for the median will be presented.
For the time to event endpoint (i.e., time to first disease flare), median time-to-event will 
be reported for each treatment group. Treatment comparisons in the distribution of time-
to-event between each upadacitinib group and the placebo will be conducted using 
stratified log-rank test stratified by stratification factors. Median time for each treatment 
group will be provided based on Kaplan-Meier estimate. Subjects who never achieve the 
three criteria required before disease flare is considered (Section 9.4.1) during the 
treatment period will be censored at Baseline. Subjects who achieve the three criteria 
required before disease flare but never experience disease flare will be censored at the last 
assessment in Period 1. Analyses using Cox proportional hazards model with stratification 
factors as covariates will also be performed. Corresponding p-values, hazard ratios and 
95% CIs will be reported.
For count endpoints (i.e., number of disease flare per subject and CS-related AEs), 
comparisons between each upadacitinib treatment group and the placebo group will be 
carried out using Poisson regression model with stratification factors as covariates, 
adjusted by the duration of study participation (or duration of study drug exposure for 
CS-related AEs). Log-transformation and robust standard error will be used in the Poisson 
regression model.
For all secondary binary endpoints (except for sustained complete remission and 
proportion of subjects who experience at least 1 disease flare), summary statistics will be 
provided for each treatment group using AO data. For all secondary continuous endpoints 
(except for cumulative CS exposure), an ANCOVA model will be applied based on AO 
data, with categorical fixed effects of treatment, stratification factors at randomization 
(Baseline CS dose [prednisone or prednisolone > 30 mg, prednisone or prednisolone 
≤30 mg], and Baseline disease status [new onset disease, relapsing disease]), and the 
continuous fixed covariates of Baseline measurement (where applicable) in the model. 


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The attributes of the estimands corresponding to the multiplicity-controlled secondary 
efficacy objectives are summarized in Table 2.
Table 2.
Summary of the Estimand Attributes Corresponding to the 
Multiplicity-Controlled Secondary Efficacy Endpoints
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 
binary 
endpoint 
(remission-
related 
endpoints)
Upadacitinib 
vs. Placebo
Achievement 
of each 
binary 
endpoint 
at/by the 
defined 
timepoint
Subjects 
with GCA
•
ICE1: composite
Subjects will be 
considered as non-
responders after ICE1.
•
ICE3: hypothetical
Data after ICE3 will be 
imputed by MI.
Difference in 
proportion of 
subjects 
achieving 
each endpoint
Secondary 
binary 
endpoint 
(proportion of 
subjects who 
experience at 
least 1 disease 
flare through 
Week 52)
Upadacitinib 
vs. Placebo
Proportion 
of subjects 
with at least 
1 disease 
flare through 
Week 52
Subjects 
with GCA
•
ICE1: treatment 
policy
•
ICE3: treatment 
policy
Data will be used 
regardless of ICE1 or 
ICE3.
Difference in
proportion of 
subjects with 
at least 1 
disease flare 
through 
Week 52
Secondary 
endpoint (rate 
of CS-related 
AEs)
Upadacitinib 
vs. Placebo
Rate of CS-
related AEs 
by Week 52
Subjects 
with GCA
•
ICE1: treatment 
policy
•
ICE2: treatment 
policy
•
ICE3: treatment 
policy
Data will be used 
regardless of ICE1 or
ICE2 or ICE3.
Difference in 
the exposure 
adjusted
treatment-
emergent CS-
related AE
rate


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Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
Secondary 
continuous 
endpoints 
(except for 
cumulative CS 
dose)
Upadacitinib 
vs. Placebo
Change from 
Baseline at 
Week 52
Subjects 
with GCA
•
ICE1: treatment 
policy
Data will be used 
regardless of ICE1.
•
ICE2: hypothetical
Data after ICE2 will be 
excluded and handled 
by MMRM
•
ICE3: treatment 
policy
Data will be used 
regardless of ICE3.
Difference in 
the mean 
change from 
Baseline (or 
difference in 
the mean 
TSQM 
patient global 
satisfaction 
subscale) at 
Week 52
Secondary 
continuous 
endpoint 
(cumulative CS 
dose) 
Upadacitinib 
vs. Placebo
Cumulative 
assessment 
by Week 52
Subjects 
with GCA
•
ICE1: treatment 
policy
•
ICE2: treatment 
policy
•
ICE3: treatment 
policy
Data will be used 
regardless of ICE1 or 
ICE2 or ICE3.
Difference in 
cumulative 
assessment 
by Week 52
Secondary 
count endpoint
Upadacitinib 
vs. Placebo
Number of 
disease 
flares per 
subject by 
Week 52
Subjects 
with GCA
•
ICE1: treatment
policy
•
ICE3: treatment 
policy
Data will be used 
regardless of ICE1 or 
ICE3
Difference in 
the exposure-
adjusted 
number of 
disease per 
subject flares 
by Week 52
Secondary 
time-to-event 
endpoint
Upadacitinib 
vs. Placebo
Time to first 
disease flare 
by Week 52
Subjects 
with GCA
•
ICE1: treatment 
policy
•
ICE3: treatment 
policy
Data will be used 
regardless of ICE1 or 
ICE3.
Difference in 
the median 
time to first 
disease flare 
by Week 52


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9.4.3
Sensitivity and Supplementary Analyses for Multiplicity-
Controlled Secondary Efficacy Endpoints
For multiplicity-controlled secondary continuous endpoints (except for the endpoint of 
cumulative CS exposure), to assess deviations from MAR, tipping point analysis will also 
be conducted as additional sensitivity analysis. Details of the tipping point analysis are 
outlined in Appendix F. To assess the robustness of the main analyses, tipping point 
analyses will be conducted for cumulative CS exposure and proportion of subjects having 
at least one disease flare to handle missing data after premature discontinuation of study. 
For the comparison of cumulative CS exposure between each of the upadacitinib doses vs. 
placebo, the value at each visit after premature discontinuation from study will be imputed 
using a value within a range from the mean cumulative CS exposure of the same treatment 
group to the mean cumulative CS exposure of the other treatment group, with an 
increment of 10% difference between the two means. Van Elteren test will be conducted 
for each increment combination and the p-values will be summarized. For the comparison 
of proportion of subject having at least one disease flare between each of the upadacitinib 
doses vs. placebo, a proportion of the subjects who have prematurely discontinued from 
study and never had a disease flare will be imputed to have a disease flare. The proportion 
will start from 0% (AO) to 100% (NRI) with an increment of 10%. Given a set of 
increment combination, the subjects with missing response will be randomly assigned as 
responders or non-responders using binomial distribution to generate 30 imputed datasets, 
and CMH method will be performed on each of the imputed datasets to obtain the results 
for each comparison between the upadacitinib group versus the placebo group. SAS 
PROC MIANALYZE will be used to generate the final inferences using Rubin's rule.1
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses
No supportive secondary endpoints and analysis are planned.


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9.5
Additional Efficacy Endpoints and Analyses
The additional endpoints for Period 1 are as follows:
•
Proportion of subjects in complete remission at Week 12
•
Change from Baseline in SF-36 by visit#
•
Change from Baseline in FACIT-Fatigue by visit
•
Assessment of TSQM patient global satisfaction subscale by visit
•
Change from Baseline in EuroQoL Five Dimensions Five Levels Questionnaire (EQ-5D-5L) by 
visit
•
Assessment of Patients' Global Impression of Change (PGIC) by visit*
•
Change from Baseline in Patient Global Assessment (PGA) by visit
•
Proportion of subjects with GCA-related Health Resource Utilization by visit
•
Proportion of subjects in remission at each visit through Week 52. Defined as:
o
Absence of GCA signs and symptoms
o
Adherence to the protocol-defined CS taper regimen
#
SF 36 includes PCS, MCS and the 8 sub domains.
*
The assessment of PGIC is defined as achievement of "Very much improved" or "Much improved" on PGIC.
The additional endpoints for Period 2 are as follows:
•
Time to first disease flare from onset of Period 2 through Week 104. Disease flare is defined as an 
event determined by the investigator to represent recurrence of GCA signs or symptoms or an ESR 
measurement > 30 mm/hr attributable to GCA AND requiring initiation of CS.
•
Proportion of subjects maintaining remission from onset of Period 2 through Week 104. Remission 
is defined as absence of GCA signs and symptoms and CS-free.
•
Cumulative CS exposure (Period 2 and inclusive of Periods 1 and 2) through Week 104
•
Proportion of subjects in complete remission at Week 104. Complete remission is defined as having 
achieved all of the following:
o
Absence of GCA signs and symptoms; 
o
Normalization of ESR (to ≤30 mm/hr); if ESR > 30 mm/hr and elevation is not attributable to 
GCA, this criterion can still be met;
o
Normalization of hsCRP (to < 1 mg/dL); and 
o
CS-free.
•
Proportion of subjects who experience at least 1 disease flare from onset of Period 2 through 
Week 104
•
Number of disease flares per subject from onset of Period 2 through Week 104 


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•
Change in SF-36 from onset of Period 2 through Week 104#
•
Change in FACIT-Fatigue from onset of Period 2 through Week 104
•
Assessment of TSQM patient global satisfaction subscale from onset of Period 2 through Week 104
•
Change in EQ-5D-5L from onset of Period 2 by visit through Week 104
•
Assessment of PGIC from onset of Period 2 through Week 104*
•
Proportion of subjects with GCA-related Health Resource Utilization at Week 104
#
SF 36 includes PCS, MCS and the 8 sub domains.
*
The assessment of PGIC is defined as achievement of "Very much improved" or "Much improved" on PGIC.
For the additional endpoints for Period 1, comparison between upadacitinib and placebo 
treatment groups will be performed on FAS1. Similar analysis methods and intercurrent 
events handling approaches as primary and secondary endpoints will be used for each type 
of endpoint as applicable.
Descriptive summaries based on the AO data will be provided for each of the two 
components of remission at each visit through Week 52, as well as each GCA sign or 
symptom.
For the additional endpoints for Period 2, comparisons will be performed for the 
following treatment sequences on FAS2 using similar analysis methods and intercurrent 
events handling approaches as were used for the primary and secondary endpoints.
●
Upadacitinib 15 mg QD + 26 weeks CS taper/Upadacitinib 15 mg QD
vs.
Upadacitinib 15 mg QD + 26 weeks CS taper/Placebo
●
Upadacitinib 7.5 mg QD + 26 weeks CS taper/Upadacitinib 7.5 mg QD
vs.
Upadacitinib 7.5 mg QD+ 26 weeks CS taper/Placebo
9.6
Efficacy Subgroup Analyses
Subgroup analyses of the primary endpoint will include:


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●
Sex (Male, Female)
●
Age Group 1 (< 65 years, ≥65 years)
●
Age Group 2 (< 65 years, ≥65 and < 75 years, ≥75 years)
●
Race Group (White, Non-White)
●
Baseline BMI Group (< 25 kg/m2, ≥ 25 kg/m2 and < 30 kg/m2, ≥ 30 kg/m2)
●
Geographic Region Group (North America, Western Europe, Eastern Europe, 
Asia, Oceania)
●
Nicotine User (Current, Former, Never)
●
Prior Use of IL-6 Inhibitor (Yes, No)
●
New Onset of GCA (Yes, No)
●
Baseline CS Dose (> 30 mg, ≤ 30 mg)
●
Ischemia-Related Vision Loss within 8 Weeks Prior to Baseline (Yes, No)
●
History of Unequivocal Symptoms of PMR Symptom without Cranial 
Symptoms of GCA (Yes, No)
For any subgroup, if there are zero subjects within a stratum in any treatment group, the 
CMH model will not be adjusted by the stratification factors.
Additional subgroup analyses may be conducted as appropriate.
10.0
Safety Analyses
10.1
General Considerations
Unless otherwise specified, safety data will be summarized on SS1 for Period 1, SS2 for 
Period 2 and SS LT across Period 1 and Period 2. Safety analysis will include adverse 
events, laboratory, and vital signs measurements. Safety summaries will be presented by 
treatment group in each safety analysis set, including a total group for all subjects on 
active study treatment.
For the safety analysis, subjects are assigned to a treatment group based on the treatment 
actually received, regardless of the treatment randomized.


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Missing safety data will not be imputed.
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
Unless noted otherwise, all summaries included treatment-emergent AEs (TEAEs) only. 
TEAEs are defined as any event that begins or worsens in severity after initiation of study 
drug through 30 days post-study drug dosing. Events where the onset date is the same as 
the study treatment start date are assumed to be treatment-emergent. All treatment-
emergent AEs will be summarized overall, as well as by primary MedDRA SOC and 
Preferred Term. The SOCs will be presented in alphabetical order, and the PTs will be 
presented in alphabetical order within each SOC.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.
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. 
Treatment differences between each upadacitinib dose group versus the placebo group 
together with 95% CI for each AE category below will also be provided on SS1 for 
Period 1.


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●
Any treatment-emergent AE
●
Any treatment-emergent AE related to upadacitinib (or matching placebo) 
according to the investigator
●
Any treatment-emergent AE related to prednisone/prednisolone (or matching 
placebo) according to the investigator
●
Any treatment-emergent AE with CTCAE grade ≥ 3
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study treatment
(upadacitinib or matching placebo)
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent AE related to COVID-19
●
Any treatment-emergent AEs of Special Interest (AESIs)
●
Any treatment-emergent AEs of bone fracture and retinal detachment
●
All deaths
○
Deaths occurring ≤ 30 days after last dose of study treatment
○
Deaths occurring > 30 days after last dose of study treatment
○
COVID-19 related deaths
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 upadacitinib (or matching placebo) as assessed by the investigator 
(e.g., reasonable possibility or no reasonable possibility) and SOC and PT; by maximum 
relationship to prednisone/prednisolone (or matching placebo) and SOC and PT, by 
maximum toxicity 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 TEAEs per 100 patient-years will be provided, where TEAEs per 
100 patient-years of exposure are defined as the number of TEAEs divided by the total 
exposure in 100 patient-years. The study drug exposure is defined as the last dose date 
minus the first dose date plus 30 days. Exposure-adjusted TEAEs will be summarized on 
SS1 for Period 1 and SS LT for long-term. Treatment differences between each 
upadacitinib dose group versus the placebo group together with 95% CI may also be
provided on SS1 for Period 1 and SS LT for the long-term.
The exposure-adjusted incidence rate (EAIR) (censored at the time of first event) may be 
conducted for selected AESI endpoints as appropriate on SS LT for long-term.
10.2.5
Deaths, Serious Adverse Events, and Adverse Events 
Leading to Study Treatment Discontinuation
Treatment-emergent serious adverse events (SAEs), TEAEs leading to premature 
discontinuation of study treatment, and TEAEs leading to death will be summarized by 
SOC and PT.
Tabular listings will be provided for all deaths, all SAEs, Treatment Emergent SAEs, 
TEAEs leading to death, TEAEs leading to premature discontinuation of study treatment.
10.2.6
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) will be summarized by SOC and PT and will 
be based on standardized or AbbVie-defined company MedDRA queries (SMQs or 
CMQs), PTs, or based on adjudication results. Adjudicated cardiovascular events will be 
summarized and presented by treatment group using the CAC adjudicated categories.
Adverse events of special interest are categorized as follows:


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●
Serious Infections
●
Opportunistic Infection excluding Tuberculosis and Herpes Zoster
●
Herpes Zoster
●
Active Tuberculosis
●
Malignancy
●
Non-Melanoma Skin Cancer (NMSC)
●
Malignancy excluding NMSC
●
Lymphoma
●
Adjudicated Gastrointestinal Perforations
●
Anemia
●
Neutropenia
●
Lymphopenia
●
Renal Dysfunction
●
Hepatic Disorder
●
Creatine Phosphokinase (CPK) Elevation
●Adjudicated MACE
●Adjudicated Embolic and thrombotic events (non-cardiac, non-central nervous 
system [CNS])
○
Adjudicated Venous Thromboembolic Events
○
Adjudicated Arterial Thromboembolic Events
In addition to AESIs, the following adverse events will also be summarized.
●
Bone fracture
●
Retinal detachment
Detailed information about the search criteria is provided in Appendix B.
A Forest Plot will be utilized to visualize the overview of all AESIs along with risk 
differences and 95% CI. A similar Forest Plot will be provided for bone fracture and 
retinal detachment.


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Exposure adjusted event rate (per 100 patient-years) for AESIs as well as bone fracture 
and retinal detachment will also be summarized on SS1 for Period 1 and SS LT for long 
term.
Time to the first occurrence of event will also be analyzed using Kaplan-Meier estimates 
in SS1 and SS LT for each AESI, and displayed as cumulative incidence plots. Similar 
plots will be provided for the adverse events of bone fracture and retinal detachment.
Tabular listings of AESIs and adverse events of bone fracture and retinal detachment will 
be provided.
10.3
Analysis of Laboratory Data
Selected clinical laboratory tests defined in the protocol operations manual (e.g., 
hematology, clinical chemistry) will be summarized on SS1 for Period 1 and SS LT for 
long term.
Baseline is defined as the last non-missing measurements recorded on or before the date 
of the first dose of study drug. For the analysis of laboratory data, values observed within 
30 days of the last dose of study drug will be included.
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. In Period 1, mean change from Baseline will 
be compared between treatment groups using a one-way Analysis of Variance (ANOVA), 
with treatment as a fixed factor. 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.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (Appendix C). For each laboratory PCI criterion, the number and percentage 


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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.
Changes in laboratory parameters will be tabulated using shift tables by National Cancer 
Institute (NCI) Common Terminology Criteria (CTC) (version 4.03). Selected lipid 
parameters will be summarized using National Cholesterol Education Program (NCEP) 
Adult Treatment Panel III (ATPIII) guidelines (Appendix D). A shift table from Baseline 
to the worse value during treatment will be created. A similar shift table will be provided 
to summarize shifts from Baseline to the final post-baseline value.
In addition, ALT/SGPT, AST/SGOT, alkaline phosphatase, and total bilirubin will be 
categorized as follows:
●
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 (ALP) > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 2 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 2 × ULN and alkaline phosphatase 
< 2 × ULN


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A listing of ALT, AST, total bilirubin (and direct and indirect bilirubin, if available), and 
alkaline phosphatase values for subjects meeting the laboratory criteria specified above 
will be provided.
In addition, eDISH plots will be created displaying post-baseline total bilirubin versus 
post-baseline ALT, in terms of the maximum ratio relative to the ULN (not necessarily 
concurrent) for both SS1 and SS LT.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, respiratory 
rate, body temperature and weight will be summarized.
For the analysis of vital signs data, values observed within 30 days of the last dose of 
study drug will be included.
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. In Period 1, mean change from Baseline will be compared 
between treatment groups using a one-way ANOVA, with treatment as a fixed factor. 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.
Vital sign variables will be evaluated based on PCI criteria (Appendix C). 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
Other Safety Analyses
No other safety analyses will be provided.


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10.6
Safety Subgroup Analyses
TEAEs will be assessed by subgroups for SS1 and SS LT as follows:
●
TEAEs Overview
●
TEAEs by SOC and PT
●
AESI Overview and Adverse Events of Bone Fracture and Retinal Detachment
The following subgroups will be assessed:
●
Age Group 1 (< 65 years, ≥65 years)
●
Age Group 2 (< 65 years, ≥65 and < 75 years, ≥75 years)
●
Sex (male, female)
●
Race Group (White, Non-White)
●
Nicotine User (Current, Past, Never)
●
Baseline BMI Group (< 25 kg/m2, ≥ 25 kg/m2 and < 30 kg/m2, ≥ 30 kg/m2)
●
Geographic Region (North America, Western Europe, Eastern Europe, Asia, 
Oceania)
●
Baseline CS Dose (> 30 mg, ≤ 30 mg)
●
Prior Use of IL-6 Inhibitor (Yes, No)
For the events of herpes zoster, additional sub-group analyses will be conducted for SS1 
and SS LT for the following subgroups:
●
Prior History of Herpes Zoster (Yes, No)
●
Prior History of Herpes Zoster Vaccination (Yes, No)
11.0
Interim Analyses
An interim futility analysis will be conducted to assess the lack of efficacy. The interim 
analysis will occur once the first 140 subjects complete 24 weeks of treatment 


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(approximately 70 subjects in the 15 mg active treatment arm; 35 subjects in the 7.5 mg 
active treatment arm and 35 subjects in the placebo arm).
The interim futility analysis is based on the conditional power (with details given in 
Appendix E) of 15 mg dose group compared to placebo for proportion of subjects 
achieving sustained remission at Week 24 (defined as absence of GCA signs and 
symptoms from Week 12 through Week 24 and adherence to the protocol-defined CS 
taper regimen through Week 24). If the conditional power is below the pre-specified 
threshold of 15%, the entire study will stop; otherwise, the entire study will move forward 
without modification. Since the entire study will be either continued without modification 
or terminated based on the futility analysis results, there will be no alpha spending due to 
the futility analysis.
11.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study. The primary responsibility of the DMC will be to protect the safety of 
the subjects participating in this study.
The DMC will review safety data of the first 80 enrolled subjects through 8 weeks of 
treatment to determine if there are any significant safety concerns that would warrant any 
study action. Thereafter, the DMC will review safety data on a regular basis and as needed 
based on the accumulating safety data and will provide recommendations to AbbVie.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no alpha adjustment is needed.
12.0
Overall Type-I Error Control
The overall Type I error rate of the primary and the multiplicity-controlled secondary 
endpoints will be strongly controlled using a graphical multiplicity adjustment method.3.4


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Specifically, the primary and multiplicity-controlled secondary endpoints as specified in 
Section 3.1 and Section 3.2 will be tested in the order as specified below and will begin 
with testing the primary endpoint for upadacitinib 15 mg dose using α of 0.05. Continued 
testing will follow a pre-specified α transfer path which includes downstream transfer 
along the endpoint sequence within each dose as well as cross-dose transfer. Adjusted 
P values for the primary and multiplicity-controlled secondary endpoints will be provided 
based on the testing procedure.
The testing procedures are provided below in Figure 2 (for US/FDA regulatory purpose) 
and Figure 3 (for PMDA regulatory purpose). The arrows specify the α transfer paths. 
Once a null hypothesis of an endpoint is rejected (i.e., deemed significant) at its assigned 
significance level, its significance level will be transferred to subsequent endpoint(s) 
following the arrow(s). The numbers on the arrows denote the weights for transferring and 
(possibly) splitting significance levels. Specifically, the weight 1 and 1/2 denotes 100% 
and 50% transfer of significance level, respectively. The primary and multiplicity-
controlled secondary endpoints (V1-V7 in Table 3) will be tested sequentially. The 
remaining multiplicity-controlled secondary endpoints will be grouped together (V8-H in 
Table 3) and tested using Hochberg procedure.


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Table 3.
List of Primary and Secondary Endpoints for Regulatory Purpose 
(FAS1)
Name
Variable
V0
Proportion of subjects achieving sustained remission at Week 52
V1
Proportion of subjects achieving sustained complete remission from Week 12 
through Week 52
V2
Cumulative CS exposure through Week 52
V3
Time to first disease flare through Week 52
V4
Proportion of subjects who experience at least 1 disease flare through Week 52
V5
Proportion of subjects in complete remission at Week 52
V6
Proportion of subjects in complete remission at Week 24
V7
Change from Baseline in the 36-item Short Form Quality of Life Questionnaire 
(SF-36) Physical Component Score (PCS) at Week 52
V8-H
•
Number of disease flares per subject through Week 52
•
Change from Baseline in Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-Fatigue) at Week 52
•
Assessment of Treatment Satisfaction Questionnaire for Medication 
(TSQM) patient global satisfaction subscale at Week 52
•
Rate of CS-related AEs through Week 52


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Figure 2.
Graphical Multiple Testing Procedure for Regulatory Purpose
(FAS1)


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Figure 3.
Graphical Multiple Testing Procedure for PMDA Regulatory 
Purpose (FAS1)


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13.0
Version History
Table 4.
SAP Version History Summary
Version
Date
Summary
1.0
27 Mar 2018
Initial version
2.0 - Draft
07 Aug 2023
•
Adopted the latest SAP template.
•
Added language for estimands in Section 2.1 and intercurrent 
events handling in Section 8.0 for primary and multiplicity-
controlled secondary endpoints.
•
Updated analysis details according to the current study design and 
agency's responses since SAP v1.0, including:
o
Updated Missing data handling approaches, with details of 
NRI-MI including seed, number of datasets, and how results 
will be combined in Section 9.2.
Added details of multiplicity testing procedure for primary 
and secondary endpoints in Section 12.0.
o
Updated key statistical analysis for primary and secondary 
endpoints in Section 9.0, including stratification factors used 
in all models, with MMRM replacing ANOVA/ANCOVA for 
secondary continuous endpoints, using van Elteren test for 
analyzing cumulative CS exposure, and including details 
about analysis of count and time-to-event endpoints. 
o
Included analysis plan for Period 2 endpoints in Section 9.5.
o
Added tipping point analysis for the secondary continuous 
endpoints in Section 9.4.3 and Appendix F.
o
Added additional as observed analysis for secondary 
endpoints including primary endpoint components in 
Section 9.2 and Section 9.4.3.
•
Updated safety analysis including:
o
Added SS LT in Section 4.0.
o
Including treatment as a fixed factor in ANOVA for safety 
variables in Section 10.3 and Section 10.4.
o
Included analysis for adverse event difference between each 
upadacitinib dose group and placebo group and corresponding 
forest plots for selected AESI in Section 10.2.
o
Included exposure-adjusted incidence rate for selected AESIs 
in Section 10.2.6.
o
Included cumulative incidence plots for AESIs in 
Section 10.2.6.


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Version
Date
Summary
2.0
14 Feb 2024
•
Updated estimands in Section 2.1.
•
Added Race to Baseline disease characteristics in Section 7.1
•
Updated intercurrent events and intercurrent events handling in 
Section 8.0 and Section 9.4.
•
Updated missing data handling in Section 9.2.
•
Updated analysis for the endpoint of proportion of subjects who 
experience at least one disease flare through Week 52.
•
Add ANCOVA analysis as additional analysis for continuous 
endpoint except for cumulative CS exposure
•
Add tipping point analyses as sensitivity analysis for the endpoint 
of cumulative CS exposure and proportion of subjects who 
experience at least one disease flare in Section 9.4.3.
•
Add summary for GCA signs and symptoms in Section 9.5.
•
Update list of AESI to align with the protocol and product safety 
statistical analysis plan in Section 10.2.6 and Appendix B.
•
Add analysis for treatment-emergent bone fracture and retinal 
detachment in Section 10.2 and Section 10.6.
•
Added sample code for NRI-MI in Appendix G and updated 
sample code for tipping point analysis in Appendix F.
•
Updated seeds in Appendix H.
14.0
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.
2.
Sun R, McCaw Z, Tian L, et al. Moving beyond conventional stratified analysis to 
assess the treatment effect in a comparative oncology study. J Immunother Cancer.
2021;9:e003323.
3.
Bretz F, Maurer W, Brannath W. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604.
4.
Hochberg Y. A sharper Bonferroni Procedure for multiple tests of significance. 
Biometrika. 1988;75(4):800-2.


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5.
Sui Y, Bu X, Duan Y, et al. Application of tipping point analysis in clinical trials 
using the multiple imputation procedure in SAS. PharmaSUG. 2023; Paper 
SD-069.


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Appendix A.
List of SAP Signatories
Name
Title
Role/Functional Area
Author
Clinical Statistics
Clinical Statistics
Statistical Programming
Medical/Scientific Monitor


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Appendix B.
Definition of Adverse Events of Special Interest
Adverse Events of Special Interest (AESIs) will be identified using the following search 
criteria:
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection excluding 
Tuberculosis and Herpes Zoster
CMQ
"Opportunistic infection excl. TB 
and Herpes Zoster"
Herpes Zoster
CMQ
"Herpes Zoster"
Active Tuberculosis
CMQ
"Active Tuberculosis"
Malignancy
SMQ
Narrow
"Malignant tumours"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ
Narrow
Skin Malignant tumours (Narrow 
SMQ) removing Melanoma CMQ
Malignancy excluding NMSC
"Malignant tumours" SMQ 
(Narrow SMQ) removing NMSC 
output
Lymphoma
SMQ
Broad
"Malignant Lymphomas"
Adjudicated Gastrointestinal 
Perforations
"Gastrointestinal Perforation"
Events will be based on medical 
review and adjudication (the 
identification of events to be 
adjudicated are described in the 
GI Perforation charter)
Anemia
CMQ
"Non-Hemolytic and Non-
Aplastic Anemias"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia (Upadacitinib 
Product Specific)"
Renal Dysfunction
SMQ
Narrow
"Acute Renal Failure"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders
– Comprehensive Search SMQ"
Creatine Phosphokinase (CPK) 
Elevation 
PT
PT of "Blood creatine 
phosphokinase increased" 


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AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
Search Criteria
Adjudicated MACE*
Output 
from CAC
Based on adjudicated results (the 
identification of events to be 
adjudicated are described in the 
CAC Charter)
Adjudicated Venous 
Thromboembolic Events**
Output 
from CAC
Based on adjudicated results (the 
identification of events to be 
adjudicated are described in the 
CAC Charter)
Adjudicated Arterial 
Thromboembolic Events
Output 
from CAC
Based on adjudicated results (the 
identification of events to be 
adjudicated are described in the 
CAC Charter)
*
MACE; Major Adverse Cardiovascular Events, defined as cardiovascular death, non fatal myocardial infarction 
and non fatal stroke. In addition, undetermined/unknown cause of deaths and other cardiovascular events from 
CAC will be summarized.
**
Venous thromboembolic events (VTE) include deep vein thrombosis (DVT) and pulmonary embolism (PE), and 
PE/DVT (fatal and non fatal).
In addition to AESIs listed above, adverse events of bone fracture and retinal detachment 
will be identified using the following search criteria:
Adverse Events
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
Search Criteria
Bone Fracture
CMQ
"Bone fractures"
Retinal Detachment
CMQ
"Retinal Detachment 
(Upadacitinib Product Specific)"


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCI) laboratory findings are described in 
Table C-1 and Table C-2, and the PCI criteria for vital sign findings are described in 
Table C-3.
Table C-1.
Criteria for Potentially Clinically Important Hematology Values
Hematology Variables
Units
Definition of Potentially 
Clinically Important
Very Low
Hemoglobin
G/L
< 80
Leukocytes
109/L
< 2.0
Lymphocytes
109/L
< 0.5
Neutrophils
109/L
< 1.0
Platelets
109/L
< 50
Note:
A post baseline grade must be more extreme than the baseline grade to be considered a potentially clinically 
important finding.


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Table C-2.
Criteria for Potentially Clinically Important Chemistry Values
Chemistry Variables
Units
Definition of Potentially Clinically Important
Very Low
Very High
ALP
U/L
> 5.0 × ULN
SGOT/AST
U/L
> 5.0 × ULN
SGPT/ALT
U/L
> 5.0 × ULN
Total Bilirubin
umol/L
> 3.0 × ULN
Albumin
g/L
< 20
Glucose (fasting)
mmol/L
< 2.2
> 13.9
Creatinine
mcmol/L
> 3.0 × ULN
Potassium
mmol/L
< 3.0
> 6.0
Corrected Calcium
mmol/L
< 1.75
> 3.1
Sodium
mmol/L
< 130
> 155
Phosphate
mmol/L
< 0.6
Creatine Kinase (CPK)
U/L
> 5.0 × ULN
Total Cholesterol
mmol/L
> 10.34
Triglycerides
mmol/L
> 5.7
Urate
umol/L
> 590
Note:
A post baseline grade must be more extreme than the baseline grade to be considered a potentially clinically 
important finding.
Table C-3.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Signs Variables
Criterion
Definition of Potentially Clinically Important
Systolic Blood Pressure 
(mmHg)
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic Blood Pressure 
(mmHg)
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Pulse (bpm)
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight
Low
> 7% decrease from Baseline
High
> 7% increase from Baseline


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Appendix D.
National Cholesterol Education Program (NCEP) Adult Treatment 
Panel III (ATP III) for Selected Lipid Parameters
●
LDL cholesterol (< 3.36, ≥3.36 and < 4.14, ≥4.14 mmol/L)
●
HDL cholesterol (< 1.03, ≥1.03 mmol/L)
●
Total cholesterol (< 5.17, ≥5.17 and < 6.21, ≥6.21 mmol/L)
●
Triglycerides (< 1.69, ≥1.69 and < 2.26, ≥2.26 mmol/L)


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Appendix E.
Interim Futility Analysis Based on the Conditional Power 
Let parameters 𝑃1 and 𝑃0 represent the sustained remission response rates at Week 24 for 
upadacitinib 15mg dose group and the placebo group respectively and let 𝑛𝑎𝑛𝑑𝑛/2 be 
the sample size in each group. Let 𝛼denote the type 1 error rate and 𝛽denote the type 2 
error rate (so 1 −𝛽is the test power). The null and alternative hypotheses have the form:
𝐻0: 𝑃1 −𝑃0 = 0 𝑣𝑠. 𝐻1: 𝑃1 −𝑃0 > 0.
The test statistic has the following form:
𝑍=
𝑃̂1−𝑃̂0
√𝑃̂1(1 −𝑃̂1)
𝑛
+ 𝑃̂0(1−𝑃̂0)
𝑛/2
,
where 𝑃̂1 and 𝑃̂0 are the sample response rates for the 15mg dose group and the placebo 
group respectively. The null hypothesis is rejected at a two-sided 𝛼level if 𝑍> 𝑍𝛼/2 , 
where 𝑍𝛼/2 is the upper 𝛼/2 percentile of the standard normal distribution.
Let 𝑚= 70 and 𝑚/2 = 35 denote the sample size in upadacitinib 15 mg group and 
placebo group at the interim futility analysis. Let 𝑍(𝑚) denote the test statistic at the 
interim futility analysis (for the comparison of 15 mg dose group vs. placebo), and let 
𝑍(𝑛) denote the corresponding test statistic at the final analysis. Let 𝑡=
𝑚
𝑛denote the 
information fraction at the interim futility analysis (t 1/3). Given that we observe at the 
interim 
𝑍(𝑚) = 𝑧=
𝑃̂1,𝑚−𝑃̂0,𝑚/2
√𝑃̂1,𝑚(1 −𝑃̂1,𝑚)
𝑚
+ 𝑃̂0,𝑚/2(1−𝑃̂0,𝑚/2)
𝑚/2
,


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where 𝑃̂1,𝑚and 𝑃̂0,𝑚/2 are the sample response rates at the interim analysis for 15 mg and 
placebo groups respectively. The conditional power under the current trend is calculated 
as:
𝐶𝑃(𝑡, 𝑧) = 𝑃𝑟𝑜𝑏(𝑍(𝑛) > 𝑍𝛼/2|𝑍(𝑚) = 𝑧) = Φ (
𝑧
√𝑡(1 −𝑡)
−𝑍𝛼/2
√1 −𝑡),
where 𝑍𝛼/2 is the upper 𝛼/2 percentile of the standard normal distribution. The 
conditional power will be compared with the futility boundary 0.15. The whole trial is to 
be terminated if 𝐶𝑃(𝑡, 𝑧) < 0.15.


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Appendix F.
Tipping Point Analysis for Secondary Continuous Endpoints
(except for cumulative CS exposure)
To assess the impact of potential departures from the missing at random assumption, 
tipping point analyses are conducted as a sensitivity check for change from Baseline in the 
multiplicity-controlled secondary continuous endpoints at Week 52.
The tipping point analyses are two-dimensional, i.e., assumptions about the missing 
outcomes on the upadacitinib treatment groups and the placebo group can vary 
independently. In addition, the focus is on scenarios where missing outcomes on 
upadacitinib are worse than the imputed values on upadacitinib, while missing outcomes 
on placebo are better than the imputed values on placebo, for the visit of interest. Missing 
values are first imputed via MI under MAR assumption using data before ICEs at all 
visits, and then a shift parameter is applied to the imputed values of the visit of interest (a 
different shift parameter may be specified for each treatment group). This is implemented 
by PROC MI using the MNAR statement. The number of imputed datasets is 30.
More specifically, PROC MI using the sequential fully conditional specification (FCS) 
method5 will be performed to impute any missing value and does not rely on a monotone 
missing pattern. It also can achieve the exact shifted values for tipping point analysis. 
Treatment is included in the FCS imputation model to enable sampling conditional on 
treatment groups. Additionally, the imputation model includes the same stratification 
factors that are used in the primary analysis and the Baseline value of the endpoints of 
interest, as well as longitudinal response observed at any other prior visits.
For a given pair of shift parameters, the SAS code example is as follows. Prior to the code 
below, any missing Baseline categorical variables are singly imputed with the most 
common level of each variable. Any missing baseline continuous variables are handled 
with FCS based on other baseline variables. Assessment at Baseline was not collected for 
TSQM. Thus, consideration for Baseline in the model is not applicable for TSQM.


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PROC MI DATA=DATA_WIDE OUT=DATA_WIDE_BOUNDED NIMPUTE=30 
SEED=12345;  
CLASS TRTP &COVCAT;    
VAR trtp &COVCON &COVCAT WEEK_8 WEEK_12 WEEK_24 WEEK_52; 
/* FCS for baseline continuous variables */
FCS reg(base = trtp &COVCAT);
/* Sequential FCS for endpoint at different visits */
FCS reg(WEEK 8 = trtp &COVCAT &COVCON);
FCS reg(WEEK 12 = trtp &COVCAT &COVCON WEEK 8);     
FCS reg(WEEK_24 = trtp &COVCAT &COVCON WEEK_8 WEEK_12);
FCS reg(WEEK_52 = trtp &COVCAT &COVCON WEEK_8 WEEK_12 
WEEK_24);
MNAR ADJUST (WEEK 52 / SHIFT=&SJ1 
ADJUSTOBS=(TRTP='PLACEBO'));
MNAR ADJUST (WEEK_52 / SHIFT=&SJ2 ADJUSTOBS=(TRTP='UPA 
7.5MG’));
MNAR ADJUST (WEEK_52 / SHIFT=&SJ2 ADJUSTOBS=(TRTP='UPA 
15MG'));
RUN; 
Note:
The input dataset is in wide format. TRTP denotes the treatment group. &COVCON denotes baseline 
continuous covariates including baseline value of the endpoint of interest. &COVCAT denotes categorical 
covariates including the stratification factors (baseline CS dose [prednisone or prednisolone > 30 mg or 
≤30 mg], and entering study with new onset or relapsing disease). WEEK 8, WEEK 12, WEEK 24, 
WEEK 52 denote the observed values at each visit. &SJ1and &SJ2 denote the shift parameters for the 
placebo group and upadacitinib groups respectively.
In cases where the shifted values are smaller than the minimum or larger than the 
maximum value of the endpoint, (i.e., out of range), the minimum or maximum value of 
the endpoint is used in further analysis steps.
For each pair of shift parameters, the SAS procedure PROC MIXED is used for the 
ANCOVA model which includes the fixed effects of treatment, stratification factors 
(Baseline CS dose [prednisone or prednisolone > 30 mg, prednisone or prednisolone 
≤30 mg], and Baseline disease status [new onset disease, relapsing disease]), and the 
continuous fixed covariate of Baseline measurement on each of the imputed datasets to 
obtain the results for each upadacitinib treatment group versus the placebo group 
comparison. These results will be aggregated using Rubin's method to get p-values.


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If one pair of shift parameters are found to just reverse the study conclusion, in terms of 
p-value larger than 0.05, then the shift parameters are identified as the tipping point. The 
results for a grid of shift parameter combinations are provided in tabular format.
The SAS code example of the data imputation step for tipping point analysis using MI is 
provided above. The SAS code example for the analysis and results combination step 
using PROC MIXED and PROC MIANALYZE at Week 52 is as follows, resulting in a 
treatment effect vs placebo for each upadacitinib group:
PROC MIXED DATA=ALL EMPIRICAL;      
    ODS OUTPUT LSMEANS=MIXEDLSMEANS DIFFS=DIFF;      
    BY Shift1 Shift2 _IMPUTATION;      
    CLASS TRTP AVISITN STRATA USUBJID;    
    MODEL CHG = BASELINE TRTP AVISITN TRTP*AVISITN STRATA / SOLUTION;      
LSMEANS TRTP*AVISITN / CL PDIFF DIFF; 
REPEATED / subject = USUBJID;
RUN;
DATA DIFF1; 
    SET DIFF; 
    IF _TRTP = ‘PLACEBO’ and avisitn = 52 and _avisitn = 52;     
    KEEP _imputation_ shift1 shift2 trtp estimate stderr; 
RUN; 
PROC SORT DATA=DIFF1; BY Shift1 Shift2 trtp _IMPUTATION_; RUN;
PROC MIANALYZE DATA=DIFF1;      
    ODS OUTPUT PARAMETERESTIMATES=GROUP_OUTPUT;      
    BY shift1 shift2 trtp;      
    MODELEFFECTS ESTIMATE;      
    STDERR STDERR; 
RUN; 
Note:
The input dataset ALL includes all (# of shift1 parameters) * (# of shift2 parameters) * (# of imputations in 
MI) imputed datasets. TRTP denotes the treatment group and STRATA denotes the stratification factors used 
in analysis. CHG denotes the change from baseline value and BASELINE denotes the baseline value.


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Appendix G.
Non-Responder Imputation Incorporating Multiple Imputation
G.1 Sample SAS Code for Binary Variable
PROC MI DATA=REMI 2 OUT=REMI FULL NIMPUTE = 30 SEED = XXXXX 
/*RANDOM SEED PRE DEFINED IN SAP*/
DECIMAL*/;
MINMAXITER = 1000;
CLASS TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 WK4 WK8 WK12 
WK16 WK20 WK24 WK28 WK36 WK44 WK52; /*SPECIFIES THE 
CLASSIFICATION VARIABLES IN THE VAR STATEMENT*/
VAR TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 WK4 WK8 WK12 WK16 
WK20 WK24 WK28 WK36 WK44 WK52;
FCS LOGISTIC(BASE= TRT01PN STRATA1N STRATA2N STRATA3N);
FCS LOGISTIC(WK2= TRT01PN STRATA1N STRATA2N STRATA3N BASE);
FCS LOGISTIC(WK4= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2);
FCS LOGISTIC(WK8= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4);
FCS LOGISTIC(WK12= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4 WK8);
FCS LOGISTIC(WK16= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4 WK8 WK12);
FCS LOGISTIC(WK20= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4 WK8 WK12 WK16);
FCS LOGISTIC(WK24= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4 WK8 WK12 WK16 WK20);
FCS LOGISTIC(WK28= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4 WK8 WK12 WK16 WK20 WK24);
FCS LOGISTIC(WK36= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4 WK8 WK12 WK16 WK20 WK24 WK28);
FCS LOGISTIC(WK44= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4 WK8 WK12 WK16 WK20 WK24 WK28 WK36);
FCS LOGISTIC(WK52= TRT01PN STRATA1N STRATA2N STRATA3N BASE WK2 
WK4 WK8 WK12 WK16 WK20 WK24 WK28 WK36 WK44);
RUN;
G.2 Sample SAS Code for Dichotomized Outcome Variable
/**********************/
/*IMPUTATION ALGORITHM*/
/**********************/


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/*NOTE: THIS APPROACH REQUIRES NO MISSING IN CATEGORICAL 
COVARIATES AND REQUIRES AT LEAST ONE OBSERVATION IN BASELIBE OR 
ONE OF THE POSTBASELINE VISIT*/
/*PRE AUGMENTATION CREATE DUMMY FOR CATEGORICAL VARIABLES*/
/********************************************/
DATA PGIC 2; SET PGIC;
/*THE MCMC STATMENT BELOW ASSUMES MULTI VARIATE NORMAL*/
/*IF TREATMENT OR ANY COVARIATES ARE CATEGORICAL WITH L>2 
LEVELS*/
/*NEED TO CREATE L 1 DUMMY VARIABLES*/
/*HERE, TREATMENT (TRT01PN) HAS 3 LEVELS, SO WE NEED 2 DUMMY
VARIABLES*/
IF TRT01PN=1 THEN TRT1=1; ELSE TRT1=0;
IF TRT01PN=2 THEN TRT2=1; ELSE TRT2=0;
IF STRATA1N=1 THEN STRATA1N1=1; ELSE STRATA1N1=0;
IF STRATA2N=1 THEN STRATA2N1=1; ELSE STRATA2N1=0;
IF STRATA3N=1 THEN STRATA3N1=1; ELSE STRATA3N1=0;
/*THIS IS TO TRANSFER STRATIFICATION FACTORS INTO NUMERICAL FORM 
FOR GETTING PGIC MONO STEP BELOW*/
RUN;
/*AUGMENTATION STEP
TO HAVE 30 MONOTONE MISSING DATASETS*/
PROC MI DATA=PGIC 2 OUT=PGIC MONO NIMPUTE=30 SEED= XXXXX /*RANDOM 
SEED PRE DEFINED IN SAP*/
ROUND=. . . . . 0.1 0.1 0.1 0.1 /*VALUE ROUND TO 1ST DECIMAL*/
MIN=. . . . . 1 1 1 1/*MINIMUM VALUE OF PGIC IS 1*/
MAX=. . . . . 7 7 7 7; /*MAXIMUM VALUE OF PGIC IS 7*/
MCMC IMPUTE=MONOTONE ;
/*NOTE: CATEGORICAL VARIABLES SUCH AS TRT1 TRT2 ARE DUMMY, 
CREATED ABOVE*/
/*NOTE: ALL OTHER NON DUMMIED COVARIATES MUST BE CONTINUOUS*/
/*SUPPOSE STRATA2N (NUMERIC VARIABLE FOR STRATA) HAS ONLY 2 
LEVELS, NO NEED TO CREATE DUMMY*/
VAR TRT1 TRT2 STRATA1N1 STRATA2N1 STRATA3N1 WK8 WK12 WK24 WK52;
/*CAUTION TO USE THE "BY" STATEMENT IN MCMC: */
/*MVN MODEL IS FITTED WITHIN EACH 'BY' GROUP, INSTEAD OF ACROSS 
ALL GROUPS*/
RUN;
/*IMPUTATION STEP DETERMINE IMPUTATION DISTRIBUTION AND RANDOMLY
IMPUTE MISSING VALUE TO GENERATE 'COMPLETE' DATASETS*/
/***************************************************/
PROC MI DATA= PGIC MONO OUT= PGIC FULL NIMPUTE=1 SEED=XXXXX 
/*RANDOM SEED PRE DEFINED IN SAP*/
ROUND=. . . . . 0.1 0.1 0.1 0.1 /*VALUE ROUND TO 1ST DECIMAL*/
MIN=. . . . . 1 1 1 1/*MINIMUM VALUE OF PGIC IS 1*/


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MAX=. . . . . 7 7 7 7; /*MAXIMUM VALUE OF PGIC IS 7*/
MINMAXITER=1000;
CLASS TRT01PN STRATA1N STRATA2N STRATA3N;
VAR TRT01PN STRATA1N STRATA2N STRATA3N WK8 WK12 WK24 WK52;
MONOTONE REG (WK12 = TRT01PN STRATA1N STRATA2N STRATA3N WK8);
MONOTONE REG (WK24 = TRT01PN STRATA1N STRATA2N STRATA3N WK8 
WK12);
MONOTONE REG (WK52 = TRT01PN STRATA1N STRATA2N STRATA3N WK8 WK12 
WK24);
/* IMPUTED SEQUENTIALLY, FROM WK 12 TO 52, WITH COVARIATES 
CONSTRUCTED FROM THE CORRESPONDING PRECEDING
VARIABLES*/
BY
IMPUTATION ; /*FOR EACH OF THE 30 MONOTONE MISSING DATASETS, 
IMPUTE A 'COMPLETE' DATASET*/
RUN;
/*DETERMINE DICHOTOMOUS RESPONSE STATUS FOR PGIC*/
DATA ALL; SET PGIC FULL;
IF . <WK8<=2 THEN PGIC 8=1;
ELSE PGIC 8=0;
IF . <WK12<=2 THEN PGIC 12=1;
ELSE PGIC 12=0;
IF . <WK24<=2 THEN PGIC 24=1;
ELSE PGIC 24=0;
IF . <WK52<=2 THEN PGIC 52=1;
ELSE PGIC 52=0;
RUN;
/****************************************************************
*******
*/
/* DATA HANDLING STEPS TO MERGE COVID 19 STATUS OMITTED
*/
/* PLACE TO ADD DATA HANDLING AND MERGING STEPS
*/
/****************************************************************
*******
*/
/*OVERRIDE MISSING VALUES NOT DUE TO COVID 19 WITH TRADITIONAL 
NRI*/
DATA ALLF; SET ALL;
/*COVID19 XX='Y' IF MISSING AT WEEK XX IS DUE TO COVID 19; IF 
NOT,
OVERRIDE WITH TRADITIONAL NRI*/
IF COVID19 8 NE 'Y' THEN PGIC 8=PGICNRI 8;


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/*VARIABLE IBDQ NRI XX: TRADITIONAL NRI DATA AT WEEK XX, WHICH 
COVERS
THE SPECIAL HANDLING SUCH AS THE BEFORE AND AFTER EXCEPTION*/
IF COVID19 12 NE 'Y' THEN PGIC 12=PGICNRI 12;
IF COVID19 24 NE 'Y' THEN PGIC 24=PGICNRI 24;
IF COVID19 52 NE 'Y' THEN PGIC 52=PGICNRI 52;
RUN;
PROC SORT DATA=ALLF; BY
IMPUTATION  SUBJID; RUN;
/****************/
/*ANALYSIS MODEL*/
/****************/
/*KEY CODE: ANALYZING EACH 'COMPLETE' DATASET*/
/***********************************/
/*INDIVIDUAL LEVEL DATA 
> # OF RESPONDERS & # OF SUBJECTS, TO 
BE READIN
TO PROC STDRATE*/
PROC FREQ DATA=ALLF;
BY
IMPUTATION ;
TABLES TRT01PN*STRATAN*PGIC 52/LIST NOCUM NOPRINT
OUT=COUNT TABLE;
/*WEEK 52 RESULTS AS AN EXAMPLE*/
RUN;
DATA COUNT TABLE; SET COUNT TABLE;
DROP PERCENT;
RUN;
PROC TRANSPOSE DATA=COUNT TABLE OUT=FREQ TABLE PREFIX=RESP;
ID PGIC 52;
BY
IMPUTATION  TRT01PN STRATAN;
VAR COUNT;
RUN;
DATA FREQ TABLE1; SET FREQ TABLE;
CASE=RESP1;
SIZE=SUM(RESP0, RESP1);
KEEP
IMPUTATION  TRT01PN STRATAN CASE SIZE;
RUN;
/*RE ORDER TO SET 1 (PLACEBO) AS THE REFERENCE GROUP*/
DATA FREQ TABLE2; SET FREQ TABLE1;
IF TRT01PN=2 THEN TRT01PN=0;
RUN;
/*CALCULATE THE COMMON RISK DIFF FOR EACH COMPLETE DATASET*/
PROC STDRATE DATA=FREQ TABLE2
METHOD=MH STAT=RISK EFFECT=DIFF;
BY
IMPUTATION ;
POPULATION GROUP=TRT01PN EVENT=CASE TOTAL=SIZE;


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STRATA STRATAN / ORDER=DATA STATS(CL=NONE) EFFECT;
ODS OUTPUT EFFECT=EFFECT;
RUN;
/*COMBINING RESULTS USING PROC MIANALYZE*/
/****************************************/
PROC MIANALYZE DATA=EFFECT;
ODS OUTPUT PARAMETERESTIMATES=RISK;
MODELEFFECTS RiskDiff;
STDERR StdErr;
RUN;


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Appendix H.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 10000 at each 
attempt in order to avoid the non-convergence issue that is caused by specific random 
seeds.
A. Random Seeds for NRI-MI for Binary Endpoints
Endpoint
Random Seed
Remission related endpoints
21586*
GCA-related health resource utilization
21587
*
This is SAS numerical form of Feb 06, 2019, which is the first subject randomized in the study.
B. Random Seeds for NRI-MI for Dichotomized Endpoints
Endpoint
Random Seed
MCMC Procedure
PROC MI
PGIC
21588
21589
C. Random Seeds for Tipping Point Analysis for Continuous Endpoints
Endpoint
Random Seed for x% Shift towards the Worse 
Direction for UPA group and y% Shift towards the 
Better Direction for PBO group
SF-36 PCS
(1+(x/200 + y/10)%)*30000
FACIT-Fatigue
(1+(x/200 + y/10)%)*50000
TSQM patient global satisfaction subscore
(1+(x/200 + y/10)%)*70000
D. Random Seeds for Tipping Point Analysis for Binary Endpoint
Endpoint
Random Seed for x% Shift towards the Worse 
Direction for UPA group and y% Shift towards the 
Better Direction for PBO group in z replicate
Disease flare
(1+(x/200 + y/10)%)*90000 + z