Clinical trial NCT02955212
Conditions: Rheumatoid Arthritis (RA)
Keywords: Rheumatoid Arthritis Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) ABT-494
Sponsor: AbbVie
Start date: 2018-01-03; Completion date: 2020-09-03
Enrollment: 338 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study objectives of Period 1 of this study were to compare the efficacy, safety, and tolerability of upadacitinib versus placebo for the treatment of signs and symptoms of subjects from China and selected countries including Brazil and South Korea with moderately to severely active rheumatoid arthritis (RA) who are on a stable dose of csDMARDs and have an inadequate response to csDMARDs.

The study objective of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib in subjects with RA who have completed Period 1.

Detailed description:
This is a Phase 3 multicenter study that includes two periods. Period 1 is a 12-week, randomized, double-blind, parallel-group, placebo-controlled period designed to compare the safety and efficacy of upadacitinib versus placebo for the treatment of signs and symptoms of participants with moderately to severely active RA who are on a stable dose of csDMARDs and have an inadequate response to csDMARDs. Period 2 is an open label 52 week extension period to evaluate the long-term safety, tolerability, and efficacy of upadacitinib in participants with RA who have completed Period 1.

Arms: arm 1: Participants randomized to receive placebo once daily for 12 weeks in Period 1 followed by upadacitinib 15 mg once daily for up to 52 weeks in Period 2. arm 2: Participants randomized to receive upadacitinib 15 mg once daily for 12 weeks in Period 1 and up to an additional 52 weeks in Period 2.
Interventions: intervention 1: Upadacitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets for oral administration intervention 2: Tablets for oral administration

Protocol documents:
Prot_000.pdf: 
Upadacitinib
M15-557 Protocol Amendment 3
1
1.0
Title Page
Clinical Study Protocol M15-557
A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study with Upadacitinib 
(ABT-494) in Subjects from China and Selected 
Countries with Moderately to Severely Active 
Rheumatoid Arthritis Who Have Had an Inadequate 
Response to Conventional Synthetic 
Disease-Modifying Anti-Rheumatic Drugs 
(csDMARDs)
Incorporating Amendments 1, 1.01 (Korea Only), 2 
and 3
AbbVie Investigational
  Product:
Upadacitinib
Date:
17 October 2018
Development Phase:
3
Study Design:
A 12-week randomized, double-blind, parallel-group, placebo-controlled 
period followed by a Week 52 open label extension period
EudraCT Number:
N/A
Investigator(s):
Multicenter trial (Investigator information is on file at AbbVie)
Sponsor:
AbbVie*
1 North Waukegan Road
North Chicago, IL  60064
Sponsor/Emergency 
  Contact:
AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
Office:
Mobile:
Fax:
Email: 
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT02955212


Upadacitinib
M15-557 Protocol Amendment 3
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol 
Date 
Original
24 February 2016
Administrative Change 1
09 June 2016
Amendment 1
07 December 2016
Amendment 1.01 (Korea Only)
28 March 2017
Amendment 2
21 September 2017
The purpose of this amendment is to:
●
Apply administrative changes throughout the protocol
Rationale:  Revised text to improve consistency and readability, and/or 
provide clarity.
●
Update Section 1.2, Synopsis
Rationale:  Revised to be consistent with Amendment 3 revisions.
●
Update Section 1.3, List of Abbreviations
Rationale:  Revised to be consistent with Amendment 3 revisions.
●
Update Section 3.0, Introduction; Section 5.1, Overall Study Design and Plan:  
Description; Section 5.2.1, Inclusion Criteria; Section 5.2.2, Exclusion 
Criteria; Section 5.2.3.2, Prohibited Therapy; Section 5.3.1.1, Subsection 
"Randomization/Treatment Group Assignment;" Section 5.5.3, Method of 
Assigning Subjects to Treatment Groups; Section 8.3, Randomization Methods 
to allow inclusion of subjects with prior exposure to one biologic disease-
modifying anti-rheumatic drug (bDMARD), either with limited exposure 
(< 3 months) or who achieved response but discontinued due to intolerance to 
bDMARD treatment, up to 20% of total number of subjects and after the 
required wash-out period is satisfied as described in this protocol amendment.
Rationale:  Changed to be consistent with the inclusion and exclusion criteria 
of the global Phase 3 Study M13-549 which was also conducted in the same 
study population (i.e., population of csDMARD inadequate responders) and to 
ensure comparability across populations globally. 


Upadacitinib
M15-557 Protocol Amendment 3
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The rationale for allowing inclusion of these subjects is that, in subjects with 
limited exposure < 3 months, inadequate response to treatment with 
bDMARDs cannot be established given the short duration of treatment.  These 
subjects cannot be considered bDMARD-inadequate responders but should 
rather be considered csDMARD-inadequate responders.
Currently, Study M15-557 does not allow these subjects to enter the study 
although they may otherwise satisfy entry criteria for the study and may be in 
need of adequate treatment.  In addition, subjects who show response but 
discontinued bDMARD treatment due to intolerance cannot be considered 
inadequate responders to bDMARDs and should also be considered for 
inclusion in this study.
●
Update Section 5.2.3.1, Permitted Background RA Therapy.
Rationale:  Updated text to provide clarity on csDMARDs that are allowed at 
Week 24 onwards if a subject fails to meet the LDA criterion for adjustment of 
subject's background RA therapies.
●
Update Section 5.2.3.2, Prohibited Therapy.
Rationale:  Updated Subsection "Vaccines" to clarify the wash-out period of 
nasal influenza vaccine.
●
Update Section 5.2.4, Contraception Recommendations.
Rationale:  Revised Subsection "Contraception Recommendation for Females" 
per sponsor guidelines to improve consistency and provide clarity.
Revised Subsection "Contraception Recommendation for Males" per sponsor 
guidelines and to clarify that contraception and sperm donation 
recommendations are specifically intended to prevent pregnancy during 
exposure to the investigational therapy.
●
Revise Table 3, Study Activities (Period 1), Revise Table 4, Study Activities –
Optional Samples for Exploratory Research and Validation Studies (Period 1 
Only) and Revise Table 5, Study Activities (Period 2).
Rationale:  Updated text to provide clarity on hsCRP reporting in Period 1 
and 2, to define that optional sample for Exploratory Research and Validation 
Studies will not be collected for subjects in mainland China, to provide clarity 
and to remain consistent with Amendment 3 changes reflected in the protocol. 


Upadacitinib
M15-557 Protocol Amendment 3
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●
Update Section 5.3.1.1, Study Procedures, Subsection "Informed Consent;" 
Section 5.3.1.2, Collection and Handling of In Vivo Pharmacodynamic 
Biomarker and Optional Samples for Exploratory Research and Validation 
Studies; Section 5.3.6, In Vivo Pharmacodynamic Biomarker Samples and 
Exploratory Research Variables and Validation Studies; Section 8.1.7, 
Statistical Analysis of Biomarker Data; Section 9.3, Subject Information and 
Consent to remove the collection of Pharmacodynamic Biomarkers and 
Optional Samples for Exploratory Research and Validation Studies for 
subjects in mainland China.
Rationale:  Changed as the application for the collection of 
Pharmacodynamic Biomarkers and Optional Samples for Exploratory 
Research and Validation Studies has not been approved by the Human 
Genetics Resources Administration of China (HGRAC).
For consistency, the separate informed consent required to collect Optional 
Samples for Exploratory Research and Validation Studies will be not 
applicable for subjects in mainland China.
●
Update Section 5.3.1.1, Study Procedures, Subsection "TB Testing/TB 
Prophylaxis."
Rationale:  Revised text to prevent unnecessary TB tests in subjects with 
documented prior positive result for QuantiFERON-TB test and/or PPD who 
should be considered positive.  Revised to provide clarity about newly initiated 
TB prophylactic treatment in Period 2.
●
Update Section 5.3.1.1, Study Procedures, Subsection "Clinical Laboratory 
Tests."
Rationale:  Updated footnotes of Table 6 to provide clarity, additional 
instructions and to remain consistent with Amendment 3 changes reflected in 
the protocol.
●
Update Section 5.4.1, Discontinuation of Individual Subjects.
Rationale:  Updated text to clarify that starting at Week 24, at least 20% 
improvement in both swollen joint counts and tender joint counts compared to 
baseline is required to remain in the study.  
Changed text to add the requirement for the Investigator to contact the AbbVie 
TA MD if a subject experiences a study drug interruption > 7 consecutive days 


Upadacitinib
M15-557 Protocol Amendment 3
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during Weeks 1 through 24 or > 30 consecutive days after Week 24 (other than 
for reasons listed in Section 6.1.7) to discuss the management of the subject 
and possible discontinuation from participation in the study.
●
Update Section 5.5.7, Drug Accountability.
Rationale:  Changed text to update the drug accountability requirements 
according to the revised sponsor guidelines and to add the option of on-site 
destruction for sites that meet AbbVie's requirements for on-site destruction.
●
Update Section 6.1.1.3, Adverse Events of Special Interest
Rationale:  Updated the adverse events of special interest that will be 
monitored during the study to align in content and presentation with the 
current version of the Product Safety Statistical Analysis Plan.
●
Update Section 6.2.2, Reporting
Rationale:  Updated text to define Product Complaint reporting timeline as 
1 business day in compliance with sponsor guidelines.
●
Update Section 6.1.7, Toxicity Management.
Rationale:  Changed text to add the requirement for the Investigator to contact 
the AbbVie TA MD if a subject experiences a study drug interruption 
> 7 consecutive days during Weeks 1 through 24 or > 30 consecutive days 
after Week 24 to discuss the management of the subject and possible 
discontinuation from participation in the study.
●
Update Section 7.0, Protocol Deviations.
Rationale:  Updated primary and alternate contact information.
●
Update Section 8.1.5.2.1, Treatment-Emergent Adverse Events (TEAE).
Rationale: Updated search criteria for the AEs of special interest (AESI) 
categories.
●
Update Appendix B, List of Protocol Signatories
Rationale:  Updated based on study personnel and title changes.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix P.


Upadacitinib
M15-557 Protocol Amendment 3
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-557
Name of Study Drug:  Upadacitinib
Phase of Development:  3
Name of Active Ingredient:  Upadacitinib
Date of Protocol Synopsis:  17 October 2018
Protocol Title:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study with Upadacitinib 
(ABT-494) in Subjects from China and Selected Countries with Moderately to Severely Active 
Rheumatoid Arthritis Who Have Had an Inadequate Response to Conventional Synthetic Disease-
Modifying Anti-Rheumatic Drugs (csDMARDs)
Objectives:
Period 1
1.
To compare the efficacy of upadacitinib versus placebo for the treatment of signs and symptoms of 
subjects from China and selected countries including Brazil and South Korea with moderately to 
severely active rheumatoid arthritis (RA) who are on a stable dose of conventional synthetic disease 
modifying anti-rheumatic drugs (csDMARDs) and have an inadequate response to csDMARDs.
2.
To compare the safety and tolerability of upadacitinib versus placebo in subjects from China and 
selected countries including Brazil and South Korea with moderately to severely active RA who are 
on a stable dose of csDMARDs and have an inadequate response to csDMARDs.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib in subjects from China and 
selected countries including Brazil and South Korea with RA who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 50
Study Population:
Adult female and male subjects who are at least 18 years of age with a diagnosis of RA for ≥ 3 months 
who also fulfill the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for 
RA.  Eligible study subjects must have ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints 
(based on 68 joint counts) at Screening and Baseline Visits, and high-sensitivity C-reactive protein 
(hsCRP) ≥ upper limit of normal (central lab) at Screening.  Subjects must have been on a stable dose of 
csDMARD therapy (restricted to methotrexate [MTX], chloroquine, hydroxychloroquine, sulfasalazine, 
or leflunomide) for ≥ 4 weeks prior to the first dose of study drug.  Subjects with inadequate response to 
hydroxychloroquine and/or chloroquine can only be included if they also have failed (lack of efficacy or 
intolerability) MTX, sulfasalazine, or leflunomide.
Number of Subjects to be Enrolled:  Approximately 322


Upadacitinib
M15-557 Protocol Amendment 3
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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 12-week, randomized, 
double-blind, parallel-group, placebo-controlled period designed to compare the safety and efficacy of 
upadacitinib versus placebo for the treatment of signs and symptoms of subjects with moderately to 
severely active RA who are on a stable dose of csDMARDs and have an inadequate response to 
csDMARDs.  Period 2 is an open-label 52 week extension period to evaluate the long-term safety, 
tolerability, and efficacy of upadacitinib in subjects with RA who have completed Period 1.
The study duration will include a 35-day screening period; a 12-week randomized, double-blind, parallel 
group, placebo controlled treatment period (Period 1); an open-label 52 week extension period; and a 
30-day follow-up period.
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of two treatment groups.  
As indicated below, it is expected that approximately 222 subjects will enter the study from China and 
100 subjects from other countries including Brazil and South Korea:
!
Group 1:  Upadacitinib 15 mg QD (N = 161; 111 from China) (Period 1) → Upadacitinib 15 mg 
QD (Period 2)
!
Group 2:  Placebo (N = 161; 111 from China) (Period 1) → Upadacitinib 15 mg QD (Period 2)
Randomization will be stratified by country and the Chinese population will be up to 80% of the total 
study population.
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the first dose of study 
drug and must remain on a stable dose until Week 24; the csDMARD dose may be decreased only for 
safety reasons.  
Subjects with prior exposure to at most one biologic disease-modifying anti-rheumatic drug (bDMARD) 
for RA may be enrolled in the study (up to 20% of total number of subjects) after the required washout 
period is satisfied and if they have limited exposure (< 3 months) OR response to bDMARD but had to 
discontinue that bDMARD due to intolerability (regardless of treatment duration).  Subjects who are 
considered bDMARD inadequate responders (lack of efficacy), as determined by the Investigator, are not 
eligible.
At Week 24, if a subject fails to meet the Low Disease Activity (LDA) criterion (LDA defined as CDAI 
≤ 10), the investigator should adjust the subject's background RA therapies after assessments for Week 24 
have been completed.
Starting at Week 24 (after Week 24 assessments have been performed), initiation of or change in 
corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen/paracetamol, low 
potency analgesics, or csDMARDs (restricted to oral or parenteral MTX, sulfasalazine, 
hydroxychloroquine, chloroquine and leflunomide, and restricted to concomitant use of up to 
2 csDMARDs except the combination of MTX and leflunomide) is allowed as per local label.  For RA 
flare treatment, no more than 3 consecutive days of systemic corticosteroids (maximum dose of 0.5 
mg/kg/day of prednisone or its equivalent) is allowed, after which subject should resume their usual daily 
oral corticosteroid dose.
Subjects taking MTX should take oral folic acid throughout study participation.  Folic acid dosing and 
timing of regimen will be based on the Investigator's discretion.
Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC compared to baseline is required 
to remain on study drug.  Anyone who does not fulfill this criterion at 2 consecutive visits (starting at 
Week 24) (see Section 5.2.3.1) must be discontinued from the study.


Upadacitinib
M15-557 Protocol Amendment 3
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Methodology (Continued):  
Subjects who complete the Week 12 visit (end of Period 1) will enter the 52 week extension portion of 
the study, Period 2.  Subjects who are assigned to upadacitinib treatment in Period 1 will continue to 
receive upadacitinib in an open-label manner.  Subjects who are assigned to placebo in Period 1 will be 
switched to receive upadacitinib from Week 12 onwards.  The primary analysis will be conducted after 
all subjects have completed Period 1 (Week 12) or have prematurely discontinued prior to Week 12.  
Study sites and subjects will remain blinded to the treatment assignment in Period 1 for the duration of 
the study.
Blood samples will be collected for In Vivo Pharmacodynamic biomarker research at designated time 
points throughout the study.  In Vivo Pharmacodynamic biomarker research samples will not be collected 
for subjects in mainland China.
Where not prohibited by local regulations, optional pharmacogenetic samples, epigenetic samples, 
transcriptomic and epigenetic samples, plasma samples for proteomic and targeted protein investigations, 
serum samples for proteomic and targeted protein investigations will be collected for exploratory 
research and validation studies at designated time points throughout the study.
Optional samples for Exploratory Research and Validation Studies will not be collected for subjects in 
mainland China.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who also fulfill the 2010 ACR/EULAR classification criteria for 
RA.
3.
Subjects have been receiving csDMARD therapy ≥ 3 months and on a stable dose for ≥ 4 weeks prior 
to the first dose of study drug.  
!
Subjects must have failed (lack of efficacy) at least one of the following:  MTX, sulfasalazine, 
or leflunomide.
!
Subjects with inadequate response to hydroxychloroquine and/or chloroquine can only be 
included if they have also failed (lack of efficacy or intolerability) MTX, sulfasalazine, or 
leflunomide.
!
The following csDMARDs are allowed (stable dose for ≥ 4 weeks prior to the first dose of study 
drug):  oral or parenteral MTX (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are 
intolerant of MTX at doses ≥ 12.5 mg/week after complete titration; no minimum MTX dose is 
required if MTX is combined with another csDMARD.  For subjects in China and South Korea:  
10 to 25 mg/week; or ≥ 7.5 mg/week in subjects who are intolerant of MTX at doses 
≥10 mg/week after complete titration), sulfasalazine (≤ 3000 mg/day), hydroxychloroquine 
(≤400 mg/day), chloroquine (≤ 250 mg/day), and leflunomide (≤ 20 mg/day).
!
A combination of up to two background csDMARDs is allowed EXCEPT the combination of 
MTX and leflunomide.
4.
Subject meets both of the following disease activity criteria:
a.
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at 
Screening and Baseline Visits; and
b.
hsCRP ≥ upper limit of normal (central lab) at Screening Visit.


Upadacitinib
M15-557 Protocol Amendment 3
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
5.
Subjects with prior exposure to at most one bDMARD may be enrolled (up to 20% of total number 
of subjects) after the required washout period.  Specifically, prior to enrollment:
a.
Subjects with limited exposure to bDMARD (< 3 months) OR
b.
Subjects who are responding to bDMARD therapy but had to discontinue due to intolerability 
(regardless of treatment duration).
Main Exclusion:
1.
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Subjects who are considered inadequate responders (lack of efficacy) to bDMARD therapy as 
determined by the Investigator.
3.
History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint 
disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic 
arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms]).  Current diagnosis of secondary 
Sjogren's Syndrome is permitted.
4.
Laboratory values meeting 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 by simplified 4-variable Modification 
of Diet in Renal Disease formula < 40 mL/min/1.73 m2; total white blood cell count < 2,500/μL; 
absolute neutrophil count < 1,500/μL; platelet count < 100,000/μL; absolute lymphocyte count 
< 800/μL; and hemoglobin < 10 g/dL.
Investigational Product:
Upadacitinib
Dose:
15 mg QD
Mode of Administration:
Oral
Reference Therapy:
Matching placebo for upadacitinib QD
Dose:
N/A
Mode of Administration:
Oral
Duration of Treatment:  Period 1:  12 weeks; Period 2:  up to 52 weeks
Criteria for Evaluation:
Efficacy:
Period 1
The primary endpoint in Period 1 is the proportion of subjects achieving ACR20 response at Week 12.
ACR20 response rate will be determined based on 20% or greater improvement in Tender Joint Count 
(TJC) and Swollen Joint Count (SJC) and ≥ 3 of the 5 measures of Patient's Assessment of Pain (Visual 
Analog Scale [VAS]), Patient's Global Assessment of Disease Activity (VAS), Physician's Global 
Assessment of Disease Activity (VAS), Health Assessment Questionnaire Disability Index (HAQ-DI), or 
hsCRP.


Upadacitinib
M15-557 Protocol Amendment 3
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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 1 (Continued)
Ranked key secondary endpoints (at Week 12) are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
Change from baseline in Short Form-36 (SF-36) Physical Component Score (PCS);
4.
Proportion of subjects achieving low disease activity (LDA) defined as Disease Activity Score 
(DAS)28 (C-reactive protein [CRP]) ≤ 3.2;
5.
Proportion of subjects achieving Clinical remission (CR) based on DAS28 (CRP);
6.
Proportion of subjects achieving LDA based on CDAI ≤ 10;
Other key secondary endpoints (at Week 12, if not specified) are:
!
ACR50 response rate;
!
ACR70 response rate;
!
ACR20 response rate at Week 1.
Additional endpoints at all visits are:
!
Change from baseline in individual components of ACR response; 
!
ACR20/50/70 response rates;
!
Change from baseline in DAS28 (CRP) and DAS28 (erythrocyte sedimentation rate [ESR]); 
!
Change from baseline in CDAI and SDAI;
!
Change from baseline in morning stiffness (severity and duration); 
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.22);
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.3);
!
Proportion of subjects achieving LDA or CR based on DAS28 (CRP), DAS28 (ESR), Simplified 
Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) criteria (see below);
!
ACR/EULAR Boolean remission;
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
  
!
Change from baseline in EQ-5D-5L;
!
Change from baseline in SF-36;
!
Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F);
!
Change from baseline in Work Instability Scale for Rheumatoid Arthritis (RA-WIS).


Upadacitinib
M15-557 Protocol Amendment 3
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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 2
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 16, 20, 24, 36, 48 and 64/PD.
!
ACR20/50/70 response rates;
!
Change from baseline in individual ACR components;
!
Change from baseline in DAS28 (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in CDAI and SDAI;
!
Change from baseline in morning stiffness;
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.22);
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.3);
!
Proportion of subjects achieving LDA and the proportion of subjects achieving CR based on 
DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined for Period 1);
!
ACR/EULAR Boolean remission;
!
Concomitant corticosteroid use (systemic use and intra-articular injections).
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 24 and 48 only:
!
Change from baseline in EQ-5D-5L;
!
Change from baseline in SF-36;
!
Change from baseline in FACIT-F;
!
Change from baseline in RA-WIS.
Pharmacokinetic (Period 1 Only):
Blood samples for assay of upadacitinib and possibly other concomitant medications in plasma will be 
collected at Weeks 1, 2, 4, 8, and 12/Premature Discontinuation.
In Vivo Pharmacodynamic Biomarkers (Periods 1 and 2) (except for subjects in mainland China):
Period 1
Change from baseline in lymphocyte subsets (including but not limited to natural killer cells, natural 
killer T cells, B cells, and T cells) will be evaluated at Weeks 8 and 12/Premature Discontinuation.
Period 2
Change from baseline in lymphocyte subsets (including but not limited to natural killer cells, natural 
killer T cells, B cells, and T cells) will be evaluated at Weeks 16, 24, 36, 48, 64/Premature 
Discontinuation (PD).


Upadacitinib
M15-557 Protocol Amendment 3
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Criteria for Evaluation (Continued):
Exploratory Research Variables and Validation Studies (Optional) (Period 1 Only):
Where not prohibited by local regulations, prognostic, predictive, and pharmacodynamics biomarkers 
signatures may be evaluated.  Samples for pharmacogenetic, epigenetic, transcriptomic, and proteomic 
and targeted protein investigations will be collected at various time points.  Assessments will include but 
may not be limited to nucleic acids, proteins, metabolites, or lipids.
Assessments will not be conducted for subjects in mainland China because optional samples for 
Exploratory Research and Validation Studies will not be collected.
Safety:
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.
Statistical Methods:
Efficacy:
All efficacy analyses will be carried out using the Full Analysis Set population, which includes all 
randomized subjects who receive at least one dose of study drug.
Period 1 Efficacy
Analysis of the Primary and Key Secondary Endpoints:
For binary endpoints, frequencies and percentages will be reported for each treatment group.  
Comparison between upadacitinib group and placebo group will be conducted using the Cochran-Mantel-
Haenszel test adjusting for main stratification factors.  
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Comparison between upadacitinib group and placebo group will be carried out using 
the analysis of covariance model with treatment group as the fixed factor, and the corresponding baseline 
value and the main stratification factors as the covariates.
Non-responder imputation approach will serve as the primary analysis approach for key binary endpoints 
and multiple imputation will serve as the primary analysis approach for key continuous endpoints.  
Sensitivity analyses based on observed cases will also be conducted for key endpoints.  The overall type I 
error rate of the primary and key secondary endpoints will be strongly controlled using sequential testing.
Long-Term Efficacy for Period 1 and Period 2 Combined
Long-term efficacy by time point will be summarized using descriptive statistics.
Pharmacokinetic:
A non-linear mixed-effects modeling approach will be used to estimate the population central values and 
the empirical Bayesian estimates of the individual values of upadacitinib oral clearance (CL/F) and 
volume of distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of 
the data.


Upadacitinib
M15-557 Protocol Amendment 3
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Statistical Methods (Continued):
Safety:
Safety analyses will be carried out using the Safety Analysis Set, which includes all subjects who receive 
at least one dose of study drug.  Analyses will be conducted for Period 1 alone, as well as for Period 1 
and Period 2 combined.  Safety will be assessed by AEs, physical examination, laboratory assessments, 
ECG and vital signs.  Frequency tables and lists of subjects with treatment-emergent AEs by preferred 
term as in the Medical Dictionary for Regulatory Activities dictionary, by system organ class, by 
severity, and by relationship to the study drug as assessed by the Investigator will be provided.  The 
changes from baseline in vital signs, physical examination results, and clinical laboratory values will be 
analyzed in a descriptive manner.  Shift of laboratory values from baseline to defined time points will be 
tabulated.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ACR
American College of Rheumatology
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine transaminase
ANC
absolute neutrophil count
anti-CCP
anti-cyclic citrullinated peptide
AST
aspartate transaminase
AUC
area under the plasma concentration-time curve
BCG
Bacille Calmette-Guérin
bDMARD
biological disease-modifying anti-rheumatic drug
BID
twice daily (Latin:  bis in die)
BUN
blood urea nitrogen
CBC
complete blood count
CD4, CD8
cluster of differentiation
CDAI
clinical disease activity index
CL/F
apparent clearance
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CPK
creatine phosphokinase
CR
clinical remission
CRF
case report form
CRP
C-reactive protein
csDMARD
conventional synthetic disease-modifying anti-rheumatic drug
CSR
clinical study report
CXR
chest x-ray
CYP
cytochrome
DAS
disease activity score
DMARD
disease-modifying anti-rheumatic drug
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
electrocardiogram


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eCRF
electronic case report form
EDC 
electronic data capture
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQoL-5D-5L
ESR
erythrocyte sedimentation rate
EU
European Union
EULAR
European League Against Rheumatism
FACIT-F
Functional Assessment of Chronic Illness Therapy – Fatigue
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HAQ-DI
Health Assessment Questionnaire – Disability Index
HAV-IgM
Hepatitis A virus immunoglobin M
HBc Ab/anti-HBc
Hepatitis B core antibody
HBs Ab/anti-HBs
Hepatitis B surface antibody
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
hsCRP
high-sensitivity C-reactive protein
ICF
informed consent form
ICH
International Conference On Harmonization
IEC
independent ethics committee
IGRA
interferon-gamma release assay
INR
international normalized ratio
IR
immediate release
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JAK
Janus activated kinase


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LDA
low disease activity
LDL-C
low-density lipoprotein cholesterol
MACE
major adverse cardiovascular event
MCID
Minimum clinically important difference
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
MRB
Minimal Residual B-cells
MTX
methotrexate
MTX-IR
methotrexate inadequate responder
NA
no assessment
NK
natural killer
NKT
natural killer-T
NMSC
non-melanoma skin cancer
NONMEM
non-linear mixed-effects modeling
NRI
non-responder imputation
NRS
numerical rating scale
NSAID
non-steroidal anti-inflammatory drug
OC
observed cases
PCR
polymerase chain reaction
PCS
physical component score
PD
premature discontinuation
PhGA
Physician's Global Assessment of Disease Activity
PK
pharmacokinetic
PPD
purified protein derivative
PRN
as needed (Latin:  pro re nata)
PRO
patient-reported outcome
PT
preferred term
PtGA
Patient's Global Assessment of Disease Activity
QD
once daily (Latin:  quaque die)
RA
rheumatoid arthritis
RA-WIS
Work Instability Scale for Rheumatoid Arthritis
RAVE®
EDC system from Medidata
RBC
red blood cell 
RCT
randomized controlled trial


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RNA
Ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SDAI
Simple Disease Activity Index
SF-36
Short Form-36
SJC
swollen joint count
SOC
system organ class
T2T
treat-to-target
TA
Therapeutic Area
TB
tuberculosis
TEAE
treatment-emergent adverse event
TJC
tender joint count
TNF
tumor necrosis factor
TNF-IR
tumor necrosis factor inadequate responder
TRUST
Toluidine Red Unheated Serum Test
Tyk2
Tyrosine kinase 2
ULN
upper limit of normal
V/F
apparent volume of distribution
VAS
visual analog scale
WBC
white blood cell


Upadacitinib
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 6
1.3
List of Abbreviations and Definition of Terms...................................... 14
2.0
Table of Contents ................................................................ 18
3.0
Introduction......................................................................... 24
3.1
Differences Statement .......................................................................... 29
3.2
Benefits and Risks................................................................................ 29
4.0
Study Objectives.................................................................. 30
5.0
Investigational Plan.............................................................30
5.1
Overall Study Design and Plan:  Description ........................................ 30
5.2
Selection of Study Population............................................................... 36
5.2.1
Inclusion Criteria.................................................................................. 36
5.2.2
Exclusion Criteria................................................................................. 38
5.2.3
Prior and Concomitant Therapy............................................................ 42
5.2.3.1
Permitted Background RA Therapy...................................................... 42
5.2.3.2
Prohibited Therapy............................................................................... 45
5.2.4
Contraception Recommendations ......................................................... 49
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, Exploratory 
Research and Validation Studies, and Safety 
Assessments/Variables ......................................................................... 52
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 52
5.3.1.1
Study Procedures.................................................................................. 63
5.3.1.2
Collection and Handling of In Vivo Pharmacodynamic Biomarker 
and Optional Samples for Exploratory Research and Validation 
Studies ................................................................................................. 81
5.3.1.2.1
In Vivo Pharmacodynamic Biomarker Samples.................................... 81
5.3.1.2.2
Optional Samples for Exploratory Research and Validation 
Studies ................................................................................................. 82
5.3.2
Drug Concentration Measurements....................................................... 84
5.3.2.1
Collection of Samples for Analysis....................................................... 84


Upadacitinib
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5.3.2.2
Measurement Methods ......................................................................... 85
5.3.3
Efficacy Variables................................................................................ 85
5.3.3.1
Period 1 Variables ................................................................................ 85
5.3.3.1.1
Primary Variables................................................................................. 85
5.3.3.1.2
Key Secondary Variables ..................................................................... 85
5.3.3.1.3
Additional Variables............................................................................. 86
5.3.3.2
Period 2 Variables ................................................................................ 87
5.3.4
Safety Variables ................................................................................... 88
5.3.5
Pharmacokinetic Variables ................................................................... 88
5.3.6
In Vivo Pharmacodynamic Biomarker Samples and Exploratory
Research Variables and Validation Studies........................................... 89
5.3.6.1
In Vivo Pharmacodynamic Biomarker Samples.................................... 89
5.3.6.2
Exploratory Research Variables and Validation Studies........................ 89
5.4
Removal of Subjects from Therapy or Assessment ............................... 90
5.4.1
Discontinuation of Individual Subjects ................................................. 90
5.4.2
Discontinuation of Entire Study............................................................ 92
5.5
Treatments ........................................................................................... 92
5.5.1
Treatments Administered...................................................................... 92
5.5.2
Identity of Investigational Product........................................................ 92
5.5.2.1
Packaging and Labeling........................................................................ 93
5.5.2.2
Storage and Disposition of Study Drugs ............................................... 93
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 93
5.5.4
Selection and Timing of Dose for Each Subject.................................... 94
5.5.5
Blinding ............................................................................................... 95
5.5.5.1
Blinding of Investigational Product ...................................................... 95
5.5.5.2
Blinding of Data for Data Monitoring Committee................................. 96
5.5.6
Treatment Compliance ......................................................................... 96
5.5.7
Drug Accountability ............................................................................. 96
5.6
Discussion and Justification of Study Design........................................ 97
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 97
5.6.2
Appropriateness of Measurements........................................................ 98
5.6.3
Suitability of Subject Population .......................................................... 98
5.6.4
Selection of Doses in the Study ............................................................ 99


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6.0
Complaints......................................................................... 100
6.1
Medical Complaints ............................................................................100
6.1.1
Definitions ..........................................................................................100
6.1.1.1
Adverse Event.....................................................................................100
6.1.1.2
Serious Adverse Events.......................................................................101
6.1.1.3
Adverse Events of Special Interest.......................................................102
6.1.2
Adverse Event Severity .......................................................................103
6.1.3
Relationship to Study Drug..................................................................103
6.1.4
Adverse Event Collection Period.........................................................104
6.1.5
Serious Adverse Event Reporting ........................................................106
6.1.6
Pregnancy............................................................................................107
6.1.7
Toxicity Management..........................................................................108
6.1.8
Data Monitoring Committee................................................................112
6.1.9
Cardiovascular Adjudication Committee .............................................112
6.2
Product Complaint...............................................................................113
6.2.1
Definition............................................................................................113
6.2.2
Reporting ............................................................................................113
7.0
Protocol Deviations ........................................................... 114
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 115
8.1
Statistical and Analytical Plans............................................................115
8.1.1
Analysis Populations ...........................................................................115
8.1.1.1
Full Analysis Set (FAS).......................................................................115
8.1.1.2
Per Protocol Analysis Set ....................................................................115
8.1.1.3
Safety Analysis Set..............................................................................115
8.1.2
Subject Accountability, Disposition and Study Drug Exposure............116
8.1.2.1
Subject Accountability ........................................................................116
8.1.2.2
Subject Disposition..............................................................................116
8.1.2.3
Study Drug Exposure ..........................................................................116
8.1.3
Analysis of Demographic and Baseline Characteristics........................117
8.1.4
Efficacy Analysis ................................................................................117
8.1.4.1
Efficacy Analysis for Period 1.............................................................117
8.1.4.1.1
Primary Efficacy Variables..................................................................117


Upadacitinib
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8.1.4.1.2
Key Secondary Efficacy Variables ......................................................118
8.1.4.1.3
Other Efficacy Variables .....................................................................118
8.1.4.1.4
Multiplicity Control for the Primary and Ranked Key Secondary 
Endpoints ............................................................................................119
8.1.4.1.5
Imputation Methods ............................................................................119
8.1.4.2
Long-Term Efficacy Analysis for Period 1 and Period 2 
Combined............................................................................................119
8.1.5
Safety Analyses...................................................................................120
8.1.5.1
General Considerations........................................................................120
8.1.5.2
Analysis of Adverse Events.................................................................120
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE) .....................................120
8.1.5.2.2
Serious Adverse Events and Death ......................................................122
8.1.5.3
Analysis of Laboratory, Vital Sign, and ECG Data..............................122
8.1.6
Pharmacokinetic and Exposure-Response Analyses.............................122
8.1.7
Statistical Analysis of Biomarker Data (except for subjects in 
mainland China)..................................................................................124
8.2
Determination of Sample Size .............................................................125
8.3
Randomization Methods......................................................................126
9.0
Ethics.................................................................................. 126
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................126
9.2
Ethical Conduct of the Study...............................................................127
9.3
Subject Information and Consent.........................................................127
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 128
10.1
Source Documents...............................................................................128
10.2
Case Report Forms..............................................................................129
11.0
Data Quality Assurance .................................................... 131
12.0
Use of Information ............................................................ 132
13.0
Completion of the Study ................................................... 133
14.0
Investigator's Agreement.................................................. 134
15.0
Reference List.................................................................... 135


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List of Tables
Table 1.
Summary of Key Efficacy Endpoints at Week 12 from 
Study M13-549 (SELECT-NEXT) ....................................................... 28
Table 2.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers................................................................................................ 47
Table 3.
Study Activities (Period 1) ................................................................... 53
Table 4.
Study Activities – Optional Samples for Exploratory Research 
and Validation Studies (Period 1 Only)................................................. 58
Table 5.
Studies Activities (Period 2)................................................................. 59
Table 6.
Clinical Laboratory Tests ..................................................................... 76
Table 7.
Identity of Investigational Product........................................................ 92
Table 8.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values ...............................................................................110
List of Figures
Figure 1.
Study Design........................................................................................ 33
Figure 2.
Criteria for HBV DNA PCR Qualitative Testing .................................. 79
Figure 3.
Adverse Event Collection....................................................................105
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................138
Appendix B.
List of Protocol Signatories .................................................................140
Appendix C.
Physician's Global Assessment of Disease Activity Example...............141
Appendix D.
Joint Evaluation Worksheet Example ..................................................142
Appendix E.
Latent TB Risk Assessment Form Example.........................................144
Appendix F.
Patient's Global Assessment of Disease Activity Example ...................145
Appendix G.
Patient's Assessment of Pain Example .................................................146
Appendix H.
Health Assessment Questionnaire (HAQ-DI) Example ........................147
Appendix I.
Patient's Assessment of Severity and Duration of Morning 
Stiffness Example................................................................................150
Appendix J.
EuroQoL-5D-5L Example ...................................................................151


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Appendix K.
Short Form-36 (SF-36™) Health Status Survey Questionnaire 
Example ..............................................................................................154
Appendix L.
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F) Scale Example...................................................................160
Appendix M.
RA-WIS Example ...............................................................................161
Appendix N.
Rheumatology Common Toxicity Criteria v.2.0 Example....................162
Appendix O.
Local Requirements.............................................................................174
Appendix P.
Protocol Amendment:  List of Changes ...............................................177


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3.0
Introduction
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown 
etiology.  The hallmark feature of RA is an inflammatory process manifested by persistent 
symmetric polyarthritis of synovial joints which can ultimately lead to bone erosions,
deformity, and disability.  Left untreated, or inadequately treated, progressive functional 
impairment with increasing disability occurs leading to a reduction in quality of life.  The 
prevalence of RA in the general population is approximately 1%, and increases with age 
in both genders, with women being more prone to developing RA than men.  Early 
therapy with disease-modifying anti-rheumatic drugs (DMARDs) is the standard of care, 
including conventional synthetic DMARDs (csDMARDs) (e.g., methotrexate [MTX], 
sulfasalazine, hydroxychloroquine, and leflunomide), and biologic DMARDs 
(bDMARDs) (e.g., anti-tumor necrosis factor [TNF] and non-anti-TNF biologics).
The European League Against Rheumatism (EULAR) recommends a Treat-to-Target 
(T2T) approach to initiate therapy immediately after diagnosis of RA with a goal of 
achieving clinical remission (CR) or low disease activity (LDA), as these are associated 
with improved long-term outcomes.1-3  Also, in line with recent advances in early 
diagnosis, new classification criteria have been developed.  The 2010 American College 
of Rheumatology (ACR)/EULAR classification criteria redefined the paradigm of RA by 
focusing on features at earlier stages of disease that are associated with persistent and/or 
erosive disease, rather than defining the disease by its late-stage features.4
Despite major progress in the treatment of RA, there still remains a large unmet medical 
need, as only a small percentage of RA patients reach or maintain a status of LDA or CR 
over time or need to discontinue due to safety or tolerability issues.5,6  Novel therapies are
therefore needed to complement the available interventions to address the unmet need.5-7


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JAK Inhibitor
Evidence suggests that inhibition of Janus kinase (JAK)-mediated pathways is a 
promising approach for the treatment of patients with this chronic disease.8  AbbVie is 
developing a small molecule inhibitor of JAK, upadacitinib, that may address the current 
needs.
The JAK family is composed of 4 family members:  JAK1, 2, 3, and Tyrosine kinase 2 
(Tyk2).  These cytoplasmic tyrosine kinases are associated with membrane cytokine 
receptors such as common gamma-chain receptors and the glycoprotein 
130 transmembrane proteins.9  Activation of JAK pathways initiates expression of 
survival factors, cytokines, chemokines, and other molecules that facilitate leukocyte 
cellular trafficking and cell proliferation which contribute to inflammatory and 
autoimmune disorders.
Hence, the JAK family has evoked considerable interest in the area of inflammatory 
diseases leading to the development of various JAK inhibitors with different selectivity 
profiles against JAK1, JAK2, JAK3, and Tyk2 which have demonstrated efficacy in 
individuals with RA.10-14  Tofacitinib, the first in this class, has been approved in the 
United States and in other countries for treating moderately to severely active RA 
patients.  Although tofacitinib, a non-selective JAK inhibitor, improves the clinical signs 
and symptoms, and inhibits structural progression in RA patients, questions regarding the 
safety profile remain, including serious infections, herpes zoster reactivation, 
malignancies, and hematologic adverse events (AEs).
The second generation of JAK inhibitors, with different selectivity profiles against JAK1, 
JAK2, JAK3, and Tyk2, are in development.8  Upadacitinib is a novel selective JAK1 
inhibitor being developed for the treatment of adult patients with moderately to severely 
active RA.  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 RA.  
The clinical hypothesis is that upadacitinib should be effective in decreasing joint 


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inflammation and damage associated with RA by interfering with JAK1-mediated 
signaling pathways (i.e., interleukin-6) without causing excessive anemia due to its 
reduced activity against JAK2 (IC50 120 nM), which is essential for erythropoietin 
signaling.  Upadacitinib is also less potent against JAK3 (IC50 2.3 μM), an important 
component of lymphocyte activation and function.  As such, treatment with upadacitinib, 
a selective JAK1 inhibitor with reduced JAK3 inhibition, could result in a decreased risk 
for infection (including viral reactivation) and/or malignancy compared to a pan JAK 
inhibitor or less selective JAK inhibitors.
Phase 2 Studies with Upadacitinib
The Phase 2 program for upadacitinib consisted of 2 randomized controlled trials (RCTs), 
both on stable background MTX therapy, in subjects with moderately to severely active 
RA and one open-label extension (OLE) study (Study M13-538; NCT02049138) for those 
subjects who had completed either one of the RCTs.  Study M13-550 (NCT01960855) 
enrolled subjects who had an inadequate response to anti-TNF therapy and 
Study M13-537 (NCT02066389) enrolled subjects who had shown an inadequate 
response to MTX.  A total of 4 twice daily (BID) and 1 once daily (QD) dose regimens of 
upadacitinib immediate release capsules (3 mg BID, 6 mg BID, 12 mg BID, 18 mg BID, 
and 24 mg QD) were evaluated.
In TNF-inadequate responder (TNF-IR) subjects, who represent the population with the 
greatest unmet need, the primary endpoint of ACR20 response rate at Week 12 was 
significantly greater at all doses of upadacitinib (up to 73%) compared with placebo 
(35%).  In addition, numerically higher proportions of subjects achieved ACR50 and 
ACR70 responses and LDA (based on Disease Activity Score [DAS]28 C-Reactive 
Protein [CRP] and Clinical Disease Activity Index [CDAI]) in the upadacitinib dose 
groups versus placebo.
In MTX-inadequate responder (MTX-IR) subjects, the primary endpoint of ACR20 
response rate at Week 12 was significantly greater (up to 82%) at all but the lowest dose 


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of upadacitinib compared with placebo (50%).  At all doses of upadacitinib compared to 
placebo, significantly higher proportions of subjects achieved LDA and CR at Week 12.
Safety data are available from the two Phase 2 studies (N = 575) which showed that the 
types and frequencies of AEs during upadacitinib treatment were consistent with subjects 
with moderately to severely active RA receiving immunomodulatory therapy.  The 
incidences of AEs were numerically higher in the upadacitinib dose groups, with a trend 
toward higher rates with higher doses of upadacitinib.  The most frequently reported AEs 
(≥ 5%) in the upadacitinib treated subjects were urinary tract infection, headache, upper 
respiratory tract infection, and nausea.  There were 6 subjects (1.3% of total combined 
populations) with herpes zoster reactivation distributed across the upadacitinib dose 
groups, and 2 subjects (1.9%) in the placebo groups.  In these two 12 week studies, a total 
of 2 subjects in the upadacitinib treatment groups reported malignancies.  One subject 
reported non-melanoma skin cancers (NMSC) (basal cell and squamous cell carcinoma) 
and 1 subject was diagnosed with lung cancer after the final scheduled visit, and 
subsequently died 14 weeks after study completion.  These events were reported by the 
Investigators as not possibly related to study drug.  Elevations of liver function tests were 
sporadic with no clear dose-response relationship observed.  As observed with other JAK 
inhibitors, treatment with upadacitinib resulted in an increase in lipids (low-density 
lipoprotein cholesterol [LDL-C] and high density lipoprotein cholesterol [HDL-C]).  
Among subjects with laboratory evidence of systemic inflammation (as evidenced by 
high-sensitivity C-reactive protein [hsCRP] > upper limit of normal [ULN]), treatment 
with lower doses of upadacitinib (3 mg BID and 6 mg BID) was associated with 
improvements in mean hemoglobin relative to placebo.  At higher doses, there was a 
reduction in mean hemoglobin; however, the mean hemoglobin levels remained within 
normal range throughout the treatment period.
Phase 3 Studies with Upadacitinib
Primary results are available from the first RA Phase 3 clinical trial (Study M13-549 
[NCT02675426]) evaluating upadacitinib 15 mg QD and 30 mg QD in subjects with 
moderate to severe RA.  Study M13-549 evaluated upadacitinib compared to placebo in 


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subjects who did not adequately respond to treatment with csDMARDs (same population 
as Study M15-557).  Results show that, after 12 weeks of treatment, both doses of 
upadacitinib (15 mg and 30 mg) met the study's primary endpoints of ACR20 and Low 
Disease Activity (LDA) as well as key secondary endpoints.  At Week 12, 64% and 66% 
of subjects receiving upadacitinib 15 mg (n = 221) or 30 mg QD (n = 219) achieved 
ACR20, respectively, compared to 36% of subjects receiving placebo (n = 221).  Low 
disease activity, based on DAS28 (CRP), was achieved by 48% of subjects receiving 
either dose of upadacitinib, compared to 17% of subjects receiving placebo.24  Overall, 
efficacy data indicate that the higher dose of upadacitinib of 30 mg QD does not provide 
significant incremental efficacy benefit in a csDMARD-IR RA population compared to 
15 mg QD.
Table 1.
Summary of Key Efficacy Endpoints at Week 12 from Study M13-
549 (SELECT-NEXT) 
Dose
ACR20a
ACR50a
ACR70a
LDAb
Clinical 
Remissionc
Upadacitinib 15 mg 
(n = 221)
64
38
21
48
31
Upadacitinib 30 mg 
(n = 219)
66
43
27
48
28
Placebo (n = 221)
36
15
6
17
10
a.
ACR20/50/70 is defined as American College of Rheumatology 20 percent/50 percent/70 percent improvements in 
tender and swollen joint counts, patient assessments of pain, global disease activity and physical function,
physician global assessment of disease activity, and acute phase reactant.
b.
Low Disease Activity (LDA) was defined by a clinical response Disease Activity Score with 28 joint counts 
(C-reactive protein) (DAS-28 [CRP]) ≤ 3.2.
c.
Clinical remission was based on DAS-28 (CRP) response rate < 2.6.
Note:
All primary and key secondary endpoints achieved P values of < 0.001 vs. placebo for both doses.  Not all 
ranked secondary endpoints are shown.
Preliminary safety data from the first Phase 3 trial in RA (Study M13-549) are consistent 
with that observed in the upadacitinib Phase 2 clinical trials in RA. 
Based on efficacy and safety data to date, the 15 mg QD dose of upadacitinib provides the 
optimal balance of efficacy and safety in RA.


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Moreover, response rates (Study M13-549) as measured by ACR20 at Week 12 from 
csDMARD-inadequate responders which included also subjects with prior exposure to 
one bDMARD, showed that, for subjects receiving either placebo or upadacitinib 15 mg 
(treatment arms of Study M15-557), there is no difference between the csDMARD 
failures without prior bDMARD exposure and those with prior exposure as defined in the 
Inclusion Criterion 6.
3.1
Differences Statement
Study M15-557 differs from other upadacitinib studies as it is the first study to evaluate 
the safety and efficacy of upadacitinib in the csDMARD inadequate responder population 
in China and selected countries including Brazil and South Korea.
3.2
Benefits and Risks
Despite the availability of various RA therapies, including csDMARDs and bDMARDs, 
many patients still do not respond adequately to these treatments, or gradually lose 
response over time.  Upadacitinib is a novel selective JAK1 inhibitor with the ability to 
decrease joint inflammation and damage mediated by JAK1 signaling while having 
minimal inhibitory effects on JAK2 and JAK3.  This could potentially minimize some of 
the reported safety concerns with non-selective JAK inhibition which are thought to be 
mediated by inhibition of JAK2 and JAK3 signaling pathways.  The Phase 2 program 
with upadacitinib as well as preliminary data from the first Phase 3 study in RA 
demonstrated efficacy for improvement in signs and symptoms of RA and the safety 
results were consistent with those known to be associated with JAK inhibition.13-21  Taken 
together, the safety and efficacy data from the Phase 2 program and the preliminary safety 
and efficacy data from the first Phase 3 study in RA support further development of 
upadacitinib in Phase 3 in subjects with RA.


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4.0
Study Objectives
Period 1
1.
To compare the efficacy of upadacitinib versus placebo for the treatment of signs 
and symptoms of subjects from China and selected countries including Brazil and 
South Korea with moderately to severely active RA who are on a stable dose of 
csDMARDs and have an inadequate response to csDMARDs.
2.
To compare the safety and tolerability of upadacitinib versus placebo in subjects 
from China and selected countries including Brazil and South Korea with 
moderately to severely active RA who are on a stable dose of csDMARDs and 
have an inadequate response to csDMARDs.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib in subjects with 
RA who have completed Period 1.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 12-week, 
randomized, double-blind, parallel-group, placebo-controlled period designed to compare 
the safety and efficacy of upadacitinib 15 mg QD versus placebo for the treatment of signs 
and symptoms of subjects from China and selected countries including Brazil and South 
Korea with moderately to severely active RA who are on a stable dose of csDMARDs and 
have an inadequate response to csDMARDs.  Period 2 is an open-label 52-week extension 
period to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 15 mg 
QD in subjects from China and selected countries including Brazil and South Korea with 
RA who have completed Period 1.


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The study is designed to enroll approximately 322 subjects at approximately 50 study 
centers worldwide to meet scientific and regulatory objectives without enrolling an undue 
number of subjects in alignment with ethical considerations.  Therefore, if the target 
number of subjects has been enrolled, there is a possibility that additional subjects in 
screening will not be enrolled.
The study duration will include a 35-day screening period; a 12-week randomized, 
double-blind, parallel-group, placebo controlled treatment period (Period 1); an open-label 
52-week extension period (Period 2); and a 30-day follow-up period (call or visit).
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of 
two treatment groups.  As indicated below, it is expected that approximately 222 subjects 
will enter the study from China and 100 subjects from other countries including Brazil 
and South Korea:  
●
Group 1:  Upadacitinib 15 mg QD (N = 161; 111 from China) (Period 1) → 
Upadacitinib 15 mg QD (Period 2)
●
Group 2:  Placebo (N = 161; 111 from China) (Period 1) → Upadacitinib
15 mg QD (Period 2)
Randomization will be stratified by country and the Chinese population will be up to 80% 
of the total study population.
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the 
first dose of study drug and must remain on a stable dose until Week 24; the csDMARD 
dose may be decreased only for safety reasons.  
Subjects with prior exposure to at most one bDMARD for RA may be enrolled in the 
study (up to 20% of total number of subjects) after the required washout period is satisfied 
and if they have limited exposure to bDMARD (< 3 months) OR response to bDMARD 
but had to discontinue that bDMARD due to intolerability (regardless of treatment 
duration) (for washout periods, see Inclusion Criterion 7, Section 5.2.1).  Subjects who are 


Upadacitinib
M15-557 Protocol Amendment 3
32
considered bDMARD inadequate responders (lack of efficacy), as determined by the 
Investigator, are not eligible.
At Week 24, if a subject fails to meet the Low Disease Activity (LDA) criterion (LDA 
defined as CDAI ≤ 10) the investigator should adjust the subject's background RA 
therapies.  Starting at Week 24 (after Week 24 assessments have been performed),
initiation of or change in corticosteroids, non-steroidal anti-inflammatory drugs 
(NSAIDs), acetaminophen, or adding or increasing doses of csDMARDs (concomitant 
use of up to 2 csDMARDs except the combination of MTX and leflunomide) is allowed 
as per local label.  Starting at Week 24, at least 20% improvement in BOTH TJC AND 
SJC compared to baseline is required to remain in the study.  Anyone who does not fulfill 
this criterion at 2 consecutive visits (starting at Week 24) (see Section 5.2.3.1) must be 
discontinued from the study.
Subjects taking MTX should take oral folic acid throughout study participation.  Folic 
acid dosing and timing of regimen will be based on the Investigator's discretion.  
Subjects who complete the Week 12 visit (end of Period 1) will enter the open-label 
52-week extension portion of the study, Period 2.  Subjects who are assigned to 
upadacitinib treatment in Period 1 will continue to receive upadacitinib per original 
randomization assignment in an open-label manner.  Subjects who are assigned to placebo 
in Period 1 will be switched to receive open-label upadacitinib from Week 12 onwards.
The primary analysis will be conducted after all subjects have completed Period 1 
(Week 12) or have prematurely discontinued prior to Week 12.  Study sites and subjects 
will remain blinded to the treatment assignment in Period 1 for the duration of the study.
Schematics of Period 1 and Period 2 are shown in Figure 1.


Upadacitinib
M15-557 Protocol Amendment 3
33
Figure 1.
Study Design
Screening Period
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and undergo the 
screening procedures outlined in Table 3.  Lab values can be re-tested once during the 
screening period.  If the re-tested lab value(s) remain(s) exclusionary, the subject will be 
considered a screen failure with no additional re-screening possible.  Redrawing samples 
if previous samples were unable to be analyzed would not count as a retest since previous 
result was never obtained.
Subjects that initially screen fail for the study are permitted to re-screen once following 
re-consent.  Lab values can be re-tested once during the re-screening period.  For 
additional re-screening, AbbVie Therapeutic Area Medical Director (TA MD) approval is 
required.  All screening procedures with the possible exceptions noted below will be 


Upadacitinib
M15-557 Protocol Amendment 3
34
repeated during re-screening.  The subject must meet all the inclusion and none of the 
exclusion criteria at the time of re-screening in order to qualify for the study.  There is no 
minimum period of time a subject must wait to re-screen for the study.  If the subject had 
a complete initial screening evaluation including the assessment of an Interferon Gamma 
Release Assay (IGRA; QuantiFERON® Tuberculosis [TB] Gold In Tube test) and/or a 
purified protein derivative (PPD) test (or equivalent) (or both if required per local 
guidelines), or chest x-ray and electrocardiogram (ECG), these tests will not be required 
to be repeated for re-screening provided the conditions noted in Section 5.2 are met, there 
are no changes in the subject's medical history that would warrant re-testing, and no more 
than 90 days have passed.
Period 1 (12-Week Randomized, Double-Blind Treatment Period)
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 12 Visit.  At the 
Baseline Visit, subjects who meet all the inclusion criteria and none of the exclusion 
criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the study and 
randomized to double-blind treatment.  During this period of the study, subjects will visit 
the study site at Weeks 1, 2, 4, 8, and 12.  A ± 3 day window is permitted around 
scheduled study visits.  The study drug dose taken the day prior to the Week 12 visit is 
considered the last dose in Period 1.  Subjects who complete Period 1, but decide not to 
continue in Period 2 should complete a 30 day follow-up visit after the last dose of study 
drug.
Period 2 (Open Label 52-Week Extension Period)
Period 2 will begin at the Week 12 visit after all assessments have been completed.  
During Period 2, subjects will have a study visit at Weeks 16, 20, 24, 36, 48 and 64/PD.  
A ± 7 day window is permitted around scheduled study visits.  At Week 24, if a subject 
fails to meet LDA criterion (LDA defined as CDAI ≤ 10) investigator should adjust the 
subject's background RA therapies.  Starting at Week 24, at least 20% improvement in 
BOTH TJC AND SJC compared to baseline is required to remain in the study.  Anyone 


Upadacitinib
M15-557 Protocol Amendment 3
35
who does not fulfill this criterion at 2 consecutive visits (starting at Week 24) (see 
Section 5.2.3.1) must be discontinued from the study.
Premature Discontinuation from Study (Period 1 and Period 2)
Subjects may discontinue from the study (withdrawal of informed consent) for any reason 
at any time during study participation (refer to Section 5.4.1 for additional details).  If a 
subject prematurely discontinues from the study, the procedures outlined for the 
Premature Discontinuation visit (PD visit) should be completed as soon as possible, 
preferably within 2 weeks of study drug discontinuation.  
In addition, if the subject is willing, a 30-day follow-up visit (or phone call if a visit is not 
possible) may occur to determine the status of any ongoing AEs/SAEs or the occurrence 
of any new AEs/SAEs.
Follow-Up Period
A Follow-Up Visit will occur approximately 30 days after the last dose of study drug to 
obtain information on any new or ongoing AE/SAEs, and to collect vital signs and clinical 
laboratory tests.
Subjects will complete the 30 day-Follow-Up Visit when they have either:
●
Completed the last visit of Period 1 (Week 12), but decided not to participate 
in Period 2; OR
●
Completed the last visit of Period 2; OR
●
Prematurely discontinued study drug.  If a PD visit has already occurred, then 
the 30 day Follow-Up visit may be a telephone call if a site visit is not 
possible.


Upadacitinib
M15-557 Protocol Amendment 3
36
5.2
Selection of Study Population
It is anticipated that approximately 322 subjects with moderately to severely active RA 
will be randomized at approximately 50 study centers in China and selected countries 
including Brazil and South Korea. 
A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria specified in Section 5.2.1 and none of the exclusion criteria specified in 
Section 5.2.2 of this protocol.
5.2.1
Inclusion Criteria
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who also fulfill the 2010 ACR/EULAR 
classification criteria for RA.
3.
Subjects have been receiving csDMARD therapy ≥ 3 months and on a stable dose 
for ≥ 4 weeks prior to the first dose of study drug.
●
Subjects must have failed (lack of efficacy) at least one of the following:  
MTX, sulfasalazine, or leflunomide.
●
Subjects with inadequate response to hydroxychloroquine and/or chloroquine 
can only be included if they have also failed (lack of efficacy or intolerability) 
MTX, sulfasalazine, or leflunomide.
●
The following csDMARDs are allowed (stable dose for ≥ 4 weeks prior to the 
first dose of study drug):  oral or parenteral MTX (15 to 25 mg/week; or 
≥10 mg/week in subjects who are intolerant of MTX at doses ≥ 12.5 mg/week 
after complete titration; no minimum MTX dose is required if MTX is 
combined with another csDMARD).  For subjects in China and South Korea:  
10 to 25 mg/week; or ≥7.5 mg/week in subjects who are intolerant of MTX at 
doses ≥ 10 mg/week after complete titration, sulfasalazine (≤ 3000 mg/day), 
hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and 
leflunomide (≤ 20 mg/day).
●
A combination of up to two background csDMARDs is allowed EXCEPT the 
combination of MTX and leflunomide.


Upadacitinib
M15-557 Protocol Amendment 3
37
4.
Subject meets both of the following disease activity criteria:
a.
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 
68 joint counts) at Screening and Baseline Visits; and
b. hsCRP ≥ upper limit of normal (central lab) at Screening Visit.
5.
Stable dose of NSAIDs and acetaminophen/paracetamol must have been at a stable 
dose ≥ 1 week prior to the first dose of study drug; oral corticosteroids (equivalent 
to prednisone ≤ 10 mg/day), or inhaled corticosteroids for stable medical conditions 
are allowed but must have been at a stable dose ≥ 4 weeks prior to the first dose of 
study drug.
6.
Subjects with prior exposure to at most one bDMARD may be enrolled (up to 20% 
of total number of subjects).  Specifically, prior to enrollment:
a.
Subjects with limited exposure to bDMARD (< 3 months) OR
b. Subjects who are responding to a bDMARD therapy but had to discontinue 
due to intolerability (regardless of treatment duration).
7.
Subjects must have discontinued bDMARD therapy prior to the first dose of study 
drug.
The washout period for bDMARDs prior to the first dose of study is specified 
below or at least five times the mean terminal elimination half-life of a drug:
●
≥ 4 weeks for etanercept;
●
≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, 
and tocilizumab;
●
≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pre-treatment 
level or normal reference range if pre-treatment levels are not available.
●
For all other bDMARDs, contact the TA MD for the washout period required 
prior to the first dose of study drug.
8.
Subjects must have discontinued all high-potency opiates at least 1 week and oral 
traditional Chinese medicine for at least 4 weeks prior to the first dose of study 
drug (refer to Section 5.2.3.2 for prohibited medications).


Upadacitinib
M15-557 Protocol Amendment 3
38
9.
If female, subject must be either postmenopausal, OR permanently surgically 
sterile OR for women of childbearing potential practicing at least one protocol 
specified method of birth control (refer to Section 5.2.4), that is effective from 
Study Day 1 through at least 30 days after the last dose of study drug. 
10.
Women of childbearing potential must not have a positive serum pregnancy test 
result at Screening and must have a negative urine pregnancy test at the Baseline 
visit prior to first dose of study drug.  Note:  subjects with borderline serum 
pregnancy tests at Screening must have serum pregnancy test ≥ 3 days later to 
document continued lack of a positive result.
Women of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined above) at Screening do not require pregnancy testing.
11.
If male, and subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 30 days after the last dose of 
study drug, to practice the protocol-specified contraception (refer to Section 5.2.4).
12.
Subjects 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.
Rationale for Inclusion Criteria
1 – 8
To select the appropriate subject population
9 – 11
Upadacitinib is teratogenic in both rats and rabbits.  The effect of upadacitinib 
on pregnancy and reproduction is unknown
12
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Prior exposure to any JAK inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).


Upadacitinib
M15-557 Protocol Amendment 3
39
2.
Subjects who are considered inadequate responders (lack of efficacy) to bDMARD 
therapy as defined by the Investigator.
3.
History of any arthritis with onset prior to age 17 years or current diagnosis of 
inflammatory joint disease other than RA (including but not limited to gout, 
systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis including 
ankylosing spondylitis and non-radiographic axial spondyloarthritis, reactive 
arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms]).  Current 
diagnosis of secondary Sjogren's Syndrome is permitted.
4.
History of chronic pain disorders that may interfere with study assessments.
5.
Has been treated with intra-articular, intramuscular, intravenous, trigger point or 
tender point, intra-bursa, or intra-tendon sheath corticosteroids in the preceding 
8 weeks prior to the first dose of study drug.
6.
Has been treated with any investigational drug within 30 days or five half-lives of 
the drug (whichever is longer) prior to the first dose of study drug or is currently 
enrolled in another clinical study.
7.
Requirement for any excluded medication (see Section 5.2.3) (including receipt of 
Traditional Chinese Medicine within 4 weeks prior to first dose of study drug and 
throughout the study).
8.
Female who is pregnant, breastfeeding, or considering becoming pregnant during 
the study or for approximately 30 days after the last dose of study drug.
9.
Male who is considering fathering a child or donating sperm during the study or for 
approximately 30 days after the last dose of study drug.
10.
Any active, chronic, or recurrent viral infection that, based on the Investigator's 
clinical assessment, makes the subject an unsuitable candidate for the study.
11.
Positive test result for hepatitis A virus immunoglobulin M (HAV-IgM), 
hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the 
HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative 


Upadacitinib
M15-557 Protocol Amendment 3
40
test for hepatitis B core antibody (HBc Ab) positive (+) subjects; (and for 
Hepatitis B surface antibody positive [+] subjects in mainland China only); or HCV 
ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody 
(HCV Ab), syphilis antibody (subjects in mainland China only) or HIV antibody 
(HIV Ab).
12.
History of symptomatic herpes zoster infection (within 12 weeks prior to the 
first dose of study drug), recurrent or disseminated (even a single episode) herpes 
zoster, or disseminated (even a single episode) herpes simplex.
13.
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB testing).
14.
Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong 
CYP3A inducers from Screening through the end of the study (refer to Table 2 for 
examples of commonly used strong CYP3A inhibitors and inducers).
15.
Receipt of any live vaccine < 4 weeks prior to the first dose of study drug, or 
expected need of live vaccination during study participation including at least 
4 weeks after the last dose of study drug.
16.
History of any malignancy except for successfully treated NMSC or localized 
carcinoma in situ of the cervix.
17.
History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months.
18.
History of gastrointestinal perforation (other than appendicitis or penetrating 
injury) diverticulitis or significantly increased risk for GI perforation per 
investigator judgment.
19.
Conditions that could interfere with drug absorption including but not limited to 
short bowel syndrome.
20.
Subject has been a previous recipient of an organ transplant.


Upadacitinib
M15-557 Protocol Amendment 3
41
21.
History of clinically significant medical conditions (including but not limited to 
clinically significant cardiac, hepatic, neurologic, respiratory, hematologic, 
gastrointestinal, renal, or psychiatric disease), or any other reason that in the 
opinion of the Investigator would interfere with the subject's participation in this 
study or would make the subject an unsuitable candidate to receive study drug.
22.
Active infection(s) requiring treatment with parenteral anti-infectives within 
30 days, or oral anti-infectives within 14 days prior to the first dose of study drug.
23.
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.
24.
Laboratory values meeting the following criteria within the Screening period prior 
to the first dose of study drug:
●
Serum aspartate transaminase (AST) > 2 × ULN;
●
Serum alanine transaminase (ALT) > 2 × ULN;
●
Estimated glomerular filtration rate (GFR) by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula 
< 40 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 < 800/μL;
●
Hemoglobin < 10 g/dL.
25.
History of any of the following cardiovascular conditions:
●
Moderate to severe congestive heart failure (New York Heart Association 
class III or IV); 
●
Recent (within past 6 months) cerebrovascular accident, myocardial infarction, 
coronary stenting; 
●
Uncontrolled hypertension as defined by a persistent confirmed systolic blood 
pressure > 160 mmHg or diastolic blood pressure > 100 mmHg;


Upadacitinib
M15-557 Protocol Amendment 3
42
●
Any other condition which, in the opinion of the Investigator, would put the 
subject at risk by participating in the protocol.
26.
Clinically relevant or significant ECG abnormalities, including ECG with QT 
interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) 
> 500 msec.
27.
Subject with any planned (elective) surgery within the first 12 weeks of the study.
Rationale for Exclusion Criteria
1 – 4
To select the appropriate subject population
8, 9
Upadacitinib is teratogenic in both rats and rabbits.  The impact of 
upadacitinib on pregnancies is unknown
5 – 7, 10 – 27
To ensure safety of the subjects throughout the study
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements including folic acid) that the subject is receiving 
within 28 days prior to Screening, 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.  Also, medications including but not 
limited to DMARDs taken for RA since date of RA diagnosis (based on subject 
recollection and available medical records) should be entered into the appropriate eCRF.
The AbbVie Therapeutic Area Medical Director should be contacted if there are any 
questions regarding concomitant or prior therapies.
5.2.3.1
Permitted Background RA Therapy
Subjects should continue on their stable (≥ 4 weeks prior to the first dose of study drug) 
background csDMARD therapy (restricted to oral or parenteral MTX [15 to 25 mg/week; 
or ≥ 10 mg/week in subjects who are intolerant of MTX at doses ≥ 12.5 mg/week after 


Upadacitinib
M15-557 Protocol Amendment 3
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complete titration; no minimum MTX dose is required if MTX is combined with another 
csDMARD.  For subjects in China and South Korea:  10 to 25 mg/week; or 
≥7.5 mg/week in subjects who are intolerant of MTX at doses ≥ 10 mg/week after 
complete titration], sulfasalazine [≤ 3000 mg/day], hydroxychloroquine [≤ 400 mg/day], 
chloroquine [≤250 mg/day], and leflunomide [≤ 20 mg/day]) up to Week 24.  A 
combination of up to two background csDMARDs is allowed EXCEPT the combination 
of MTX and leflunomide.  For subjects that are taking a combination of MTX and 
leflunomide therapy, discontinuation of either MTX or leflunomide should occur prior to 
the first dose of study drug (refer to csDMARD Washout below).  Up to Week 24, the 
csDMARD dose may be decreased only for safety reasons.  Subjects taking MTX should 
take a dietary supplement of oral folic acid (or equivalent, such as folinic acid) throughout 
study participation.  Folic acid dosing and timing of regimen should be followed 
according to Investigator's instructions.  AbbVie will not provide the csDMARDs (or folic 
acid, if taking MTX).  
csDMARD Washout
The following washout period should be met for subjects who are being treated with 
multiple csDMARDs if washout of 1 or more csDMARD is required to meet the protocol 
requirements:  
●
≥ 4 weeks prior to the first dose of study drug for MTX, minocycline, 
penicillamine, sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, 
gold formulations, cyclophosphamide, tacrolimus, cyclosporine, mizoribine, 
mycophenolate;
●
≥ 8 weeks prior to the first dose of study drug for leflunomide if no elimination 
procedure was followed, or adhere to a washout procedure ( i.e., 11 days with 
colestyramine, or 30 days washout with activated charcoal or as per local 
label);
●
≥ five times the mean terminal elimination half-life for any other csDMARDs 
not listed above.


Upadacitinib
M15-557 Protocol Amendment 3
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Subjects should also continue on their stable doses of NSAIDs, 
acetaminophen/paracetamol, oral corticosteroids (equivalent to prednisone ≤ 10 mg/day), 
or inhaled corticosteroids.  
●
If taking any of the above on a scheduled basis, they should continue to take 
them as they did at study entry with no change in dose or frequency, including 
on study visit days (see Inclusion Criterion 5);
●
If not taking any of the above at baseline, these must not be initiated except 
where permitted by protocol (after Week 24 assessments have been 
performed);
●
If taking any of the above, including low potency analgesics, i.e., tramadol, 
codeine, hydrocodone or propoxyphene at baseline on an as-needed basis 
(PRN), they should continue to use them for the same reason and same dose 
each time but they should not be taken within the 24 hours prior to any study 
visit to avoid bias in outcome measurements.
In the event of tolerability (or other safety) issues, the doses of these medications may be 
decreased or discontinued with substitution of another permitted medication from that 
class (see Section 5.2.3.2 for prohibited therapies).  
PRN use of inhaled corticosteroids is permitted at any time.
At Week 24 (after Week 24 assessments have been performed) if a subject fails to meet 
the LDA criterion (LDA defined as CDAI ≤ 10), the investigator should adjust the 
subject's background RA therapies.  Initiation of or change in corticosteroids, NSAIDs, 
acetaminophen/paracetamol, low potency analgesics, or csDMARDs (restricted to oral or 
parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine and leflunomide, and 
restricted to concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide) is allowed as per local label.
Starting at Week 24 (after Week 24 assessments have been performed) and thereafter, 
intra-articular, intramuscular, intravenous, trigger point or tender point, intra bursa, and 
intra-tendon sheath injections of corticosteroids, dosage and frequency per standard of 


Upadacitinib
M15-557 Protocol Amendment 3
45
care, are allowed.  However, joint injections should be avoided within 21 days prior to the 
next scheduled study visit to avoid confounding effects of systemic absorption of intra-
articular corticosteroids.  For the analysis of the TJC and SJC, injected joints will be 
considered "not assessable" for 3 months from the time of the intra-articular injection.  
For RA flare treatment, no more than 3 consecutive days of high-dose systemic 
corticosteroids (maximum dose of 0.5 mg/kg/day of prednisone or its equivalent) is 
allowed, after which subject should resume their usual daily oral corticosteroid dose.
5.2.3.2
Prohibited Therapy
JAK Inhibitor
Prior exposure to JAK inhibitors (including but not limited to tofacitinib [Xeljanz®], 
baricitinib, and filgotinib) is not allowed.
Corticosteroids
Oral corticosteroids (> 10 mg prednisone/day or equivalent), intra-articular, 
intramuscular, intravenous, trigger point or tender point, intra-bursa, and intra-tendon 
sheath corticosteroids are NOT allowed up to Week 24.
Biologic Therapies
All biologic therapies related to RA treatment are prohibited during the study 
(i.e., Periods 1 and 2).
Subjects with prior exposure to at most one bDMARD for RA may be enrolled in the 
study (up to 20% of study total number of subjects) after the required washout period is 
satisfied and if they have:
a.
limited bDMARD exposure (< 3 months), OR
b. response to a bDMARD but had to discontinue that bDMARD due to intolerability 
(regardless of treatment duration).  


Upadacitinib
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Subjects must have discontinued all bDMARDs prior to the first dose of study drug as 
specified in the washout procedures (Inclusion Criterion 7, Section 5.2.1).  For all other 
bDMARDs, contact the Therapeutic Area Medical Director for the washout period 
required prior to the first dose of study drug.
Examples of biologic therapies include but are not limited to the following:
●
Humira® (adalimumab)
●
Enbrel® (etanercept)
●
Remicade® (infliximab)
●
Orencia® (abatacept)
●
Kineret® (anakinra)
●
Rituxan® (rituximab)
●
Cimzia® (certolizumab pegol)
●
Simponi® (golimumab)
●
Actemra® (tocilizumab)
●
Raptiva® (efalizumab)
●
Tysabri® (natalizumab)
●
Stelara® (ustekinumab)
●
Benlysta® (belimumab)
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors or strong CYP3A inducers is excluded 
from the Screening Visit through the end of the study (i.e., end of Period 2).  Examples of 
commonly used strong CYP3A inhibitors and inducers are listed in Table 2.


Upadacitinib
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Table 2.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Carbamazepine
Phenytoin
Rifampin
Rifapentine
St. John's Wort
Opiates
High potency opiates are not permitted during the study (i.e., Periods 1 and 2), and 
subjects must have discontinued high potency opiates at least 1 week prior to the 
first dose of study drug, including (but not limited to):
●
oxycodone
●
oxymorphone
●
fentanyl
●
levorphanol
●
buprenorphine
●
methadone
●
hydromorphone
●
morphine


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●
meperidine
Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 
five half-lives of the drug (whichever is longer) prior to the first dose of study drug are 
excluded from participation in this study.  Investigational drugs are also prohibited during 
the study.
Vaccines
Although not mandated by the protocol, vaccines recommended by local guidelines 
should be considered.  If the subject and investigator choose to administer live vaccines, 
these vaccinations must be completed (per local label) at least 4 weeks before first dose of 
study drug with appropriate precautions.  Live vaccinations are prohibited during the 
study participation including at least 30 days after the last dose of study drug.
Examples of live vaccines include, but are not limited to, the following:
●
Monovalent live influenza A (H1N1) (intranasal);
●
Seasonal trivalent live influenza (intranasal);
●
Herpes zoster;
●
Rotavirus;
●
Varicella (chicken pox);
●
Measles-mumps-rubella or measles mumps rubella varicella;
●
Oral polio vaccine;
●
Smallpox;
●
Yellow fever;
●
Bacille Calmette-Guérin (BCG);
●
Typhoid.


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Examples of common vaccines that are inactivated, toxoid, or biosynthetic, include but 
are not limited to:  injectable influenza vaccine, pneumococcal and pertussis (Tdap) 
vaccines.
If the nasal influenza vaccine is administered, the vaccine must be administered at least 
8 weeks prior to first dose of study drug.
Chinese Traditional Medicine
Oral Chinese traditional medicine is not permitted during the study (i.e., Periods 1 and 2), 
and subjects must have discontinued any oral Chinese traditional medicine at least 
4 weeks prior to the first dose of study drug.
5.2.4
Contraception Recommendations  
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.  
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 an FSH level > 40 mIU/mL.
If the female subject is < 55 years of age AND has had no menses for ≥ 12 months AND 
has no history of permanent surgical sterilization (defined above), 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.


Upadacitinib
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●
If the FSH is tested and the result is consistent with pre-menopausal status, 
contraception is required, and a serum pregnancy test must be performed (see 
Section 5.3.1.1 "Pregnancy test").
For a female subject at any age: 
●
Female subjects with menses within the past 12 months are of childbearing 
potential and FSH is therefore not required but contraception is required.
●
Female subjects who are surgical sterile (defined above) are not of 
childbearing potential and therefore no FSH testing or contraception is 
required.
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.
●
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 [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable).


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If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the highly 
effective birth control methods listed above (excluding true abstinence).
It is important to note that contraception recommendations described above are 
specifically intended to prevent pregnancy during exposure to the investigational therapy 
upadacitinib.  The concomitant csDMARDs (i.e., methotrexate, sulfasalazine, etc.) have 
been prescribed per standard of care prior to study entry and are allowed to be continued 
during the study.  Contraception should continue while the subject is on the concomitant 
csDMARD and that duration of contraception after discontinuation of the csDMARD 
should be based on the local label.
If during the course of the study a woman becomes surgically sterile or postmenopausal 
(defined above) and complete documentation is available, contraceptive measures as 
defined above are no longer required.
Contraception Recommendation for Males
Based on data from animal studies (including a fertility study) there is no effect of 
upadacitinib on male reproduction.
For a male subject who is sexually sterile (vasectomy with medical assessment confirming 
surgical success) OR has a female partner who is postmenopausal or permanently sterile, 
no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of oral study drug to 
practice contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures as defined in the protocol for female study subjects of childbearing 
potential.


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●
True abstinence:  Refraining from heterosexual intercourse-when this is in line 
with the preferred and usual lifestyle of the subject.  (Note:  Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of study drug. 
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.
It is important to note that contraception and sperm donation recommendations described 
above are specifically intended to prevent pregnancy during exposure to the 
investigational therapy with upadacitinib.  The concomitant csDMARDs 
(i.e., methotrexate, sulfasalazine, etc.) have been prescribed per standard of care prior to 
study entry and are allowed to be continued during the study.
Contraception should continue while the subject is on the concomitant csDMARD and 
that duration of contraception after discontinuation of the csDMARD should be based on 
the local label.
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, Exploratory 
Research and Validation Studies, and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Table 3.


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Table 3.
Study Activities (Period 1)
Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12/PDa
30-Day 
F/U Visitc
D –35 to D –1
D 1b
D 8
D 15
D 29
D 57
D 85
Informed Consentd
Xd
Inclusion/Exclusion Criteria
X
X
Medical/Surgical Historye
X
X
Alcohol and Nicotine Use
X
Adverse Event Assessmentf
Only SAEs and protocol-related 
nonserious AEs
X
X
X
X
X
X
X
Prior/Concomitant Therapy
X
X
X
X
X
X
X
X
Patient Questionnairesg
PtGA
Pain (VAS)
HAQ-DI
Morning Stiffness (Severity and 
Duration)
X
X
X
X
X
X
Patient Questionnairesg
EQ-5D-5L
SF-36
FACIT-F
RA-WIS
X
X
X
Latent TB Risk Assessment Formh
X
Xi
Central Lab QuantiFERON-TB Gold 
Testh (and/or Local PPD Skin Test)
X
Xi


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Table 3.
Study Activities (Period 1) (Continued)
Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12/PDa
30-Day 
F/U Visitc
D –35 to D –1
D 1b
D 8
D 15
D 29
D 57
D 85
Chest X-Rayj
X
12-Lead ECGk
X
Xk
Height (Screening Only) and Weight
X
X
X
X
X
X
X
Vital Signsl
X
X
X
X
X
X
X
Physical Examm
X
X
X
Physician Global Assessment (PhGA)
X
X
X
X
X
X
TJC68/SJC66
X
X
X
X
X
X
X
Serum Pregnancy Test at Central Labn
X
Local Urine Pregnancy Testo
X
X
X
X
X
X
Central lab Tests
hsCRPp
Blood Chemistryq
Hematology (CBC)
Urinalysisr
X
X
X
(hsCRP 
only)
X
X
X
X
X
ESR (Local Lab)
X
X
X
X
X
X
X


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Table 3.
Study Activities (Period 1) (Continued)
Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12/PDa
30-Day 
F/U Visitc
D –35 to D –1
D 1b
D 8
D 15
D 29
D 57
D 85
Other Central Lab Tests
Rheumatoid Factor
Anti-CCP Autoantibodies
HBV/HCV Screenings
Syphilis Screening (in mainland 
China only)
hepatitis A Virus Immunoglobulin M 
(HAV-IgM)
X
HIVt
Xt
IgG and IgM (central lab)
X
X
Blood Samples for Upadacitinib PK 
Assay
Xu
Xu
Xv
Xv
Xv
In Vivo Pharmacodynamic Biomarkersw
X
X
X
X
Blood Samples for Exploratory 
Research and Validation Studies 
(Optional – see Table 4)x
X
X
X
X
Randomization/Treatment Group 
Assignment
X
Dispense Study Drug and Subject 
Dosing Diary
X
X
X
Xy
Review and Retain a copy of Subject 
Dosing Diary and Perform Drug 
Reconciliation
X
X
X


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Table 3.
Study Activities (Period 1) (Continued)
BL = Baseline Visit; CBC = complete blood count; CCP = cyclic citrullinated peptide; D = Day; ECG = electrocardiogram; EQ-5D-5L = EuroQoL-5D; ESR = erythrocyte 
sedimentation rate; FACIT-F = Functional Assessment of Chronic Illness Therapy – Fatigue; F/U = Follow-up; HAQ-DI = Health Assessment Questionnaire – Disability Index; 
HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; NRS = numerical rating scale; 
PD = Premature Discontinuation (completely from study [withdrawal of consent]); PhGA = Physician's Global Disease Activity; PK = pharmacokinetics; PPD = purified protein 
derivative; PtGA = Patient's Global Assessment of Disease Activity; SAE = serious adverse event; SJC = Swollen Joint Count; SF-36 = 36-Item Short Form Health Survey; 
TB = tuberculosis; TJC = Tender Joint Count; VAS = visual analog scale; Wk = Week
a.
If a subject prematurely discontinues study participation, the procedures outlined for the Premature Discontinuation visit (PD visit) should be completed as soon as possible, 
preferably within 2 weeks of study drug discontinuation.
b.
The Baseline visit procedures will serve as the reference for all subsequent visits with the exception of the ECG which will be obtained at Screening only and used as the 
baseline reference.
c.
This visit is 30 days after last dose of study drug for those subjects who complete Period 1 and do NOT enter Period 2 or for those subjects who prematurely discontinued 
study drug and study participation.  A 30-day follow-up phone call may be allowed for subjects who have already completed PD visit to determine the status of any ongoing 
AEs/SAEs or the occurrence of any new AEs/SAEs.
d.
Informed consent should be obtained at Screening prior to performing any study related procedures.
e.
Note herpes zoster and hepatitis B vaccination status in medical history.
f.
Collect serious adverse events and protocol-related nonserious AEs that occur after a subject signs the informed consent, prior to the first dose of study drug.
g.
Prior to other procedures.  For morning stiffness, duration will be captured only if NRS rating is > 0.
h.
Refer to Section 5.3.1.1 Study Procedures TB Testing for specific requirements for TB testing and TB Prophylaxis.
i.
This is only applicable to subjects from China at Week 12.
j.
The chest x-ray will not be required if a subject had a previous normal chest-x-ray within 90 days of Screening, provided that all source documentation is available at the site 
(refer to Section 5.3.1.1 Chest X-Ray for specific requirements).
k.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required, provided all source documentation is available.  Refer to 
Section 5.3.1.1 12-Lead ECG for additional details.  For subjects who do not enter Period 2 or Prematurely Discontinue from the study, an ECG will be performed.
l.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.
m.
A full physical exam is required at the visits indicated.  A symptom-directed physical exam may be performed when necessary.


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Table 3.
Study Activities (Period 1) (Continued)
n.
For all women of childbearing potential, collect serum for pregnancy test only at screening.  If serum pregnancy test comes back borderline, a repeat test is necessary 
(pregnancy is an exclusion criterion).  If still borderline ≥ 3 days later, this will be considered documentation of continued lack of a positive result and the subject can be 
enrolled into the study.  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.  If during the course of the study a woman becomes surgically sterile
or post-menopausal and complete documentation is available, urine pregnancy test is no longer required.
o.
For all women of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits except Week 1.  If urine pregnancy test (which is performed at 
the site) is negative, begin or continue dosing. If urine pregnancy test is positive, withhold dosing and perform a serum pregnancy test.  Pregnant subjects must discontinue 
from the study.  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
p.
Central lab hsCRP results will remain blinded to Sponsor, Investigator, study site personnel, and the subject for all visits except Screening.
Local laboratory or site testing for hsCRP or CRP is not allowed after Baseline.  Results of tests such as hsCRP may be blunted in subjects taking a JAK inhibitor, thereby 
limiting the clinical utility of these tests in the setting of a possible safety assessment or adverse event management.  Any local hsCRP or local CRP tests should not be 
reported to the investigator until a subject completes Period 1.  Treatment assignment may be unblinded to Sponsor only when the last subject completes Period 1 (Week 12 
visit) for analysis for regulatory purposes.
q.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-fasting status will be recorded in study source documentation.
r.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A microscopic analysis will be performed in the event the dipstick 
results show leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.
s.
At Screening only.  For mainland China only, subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at screening, HBV DNA PCR test should be performed every 
12 weeks.  HBV DNA PCR testing every 12 weeks is not necessary when the subject has a history of HBV vaccine and HBs Ab+.
t.
Subjects will be tested for antibodies to HIV at Screening.  The results of the HIV Ab testing will be retained by the study site under confidential restriction.
u.
At Week 1 and Week 2 visits, PK samples should be collected prior to dosing and the subjects should take the study drug dose at the clinic after collecting the PK blood 
sample.  However, if the subject normally takes the study drug dose at a time that is after the time of the scheduled study visit, the subject should follow the regular dosing 
schedule and the PK sample should be collected at any time during the visit.
v.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.
w.
In Vivo Pharmacodynamic biomarkers will not be collected for subjects in mainland China.
x.
Samples only collected if subject provides written consent and if not prohibited by local regulations.  Optional samples for Exploratory Research and Validation Studies will 
not be collected for subjects in mainland China.
y.
For subjects entering Period 2.
Note:
Visit window is ± 3 days for Period 1.  Any of the procedures may be performed at an unscheduled visit at the discretion of the Investigator.


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Table 4.
Study Activities – Optional Samples for Exploratory Research and Validation Studies (Period 1 Only)
Activity
Screening
BL
Wk 2
Wk 4
Wk 8
Wk 12/PD
D –35 to D –1
D 1a
D 15
D 29
D 57
D 85
Pharmacogenetic Samplesa,b
--
X
--
--
--
--
Epigenetic Samplesb
--
X
X
X
--
X
Transcriptomic and Epigenetic Samplesb
--
X
X
X
--
X
Plasma Samples for Proteomic and Targeted Protein Investigationsb
--
X
X
X
--
X
Serum Samples for Proteomic and Targeted Protein Investigationsb
--
X
X
X
--
X
BL = Baseline Visit; D = Day; F/U = Follow-Up; PD = Premature Discontinuation; Wk = Week
a.
The sample is preferred to be collected at BL, but can be drawn at any time during the subject's participation.
b.
Based on the value of the different technologies, samples may also be used to assess other biomarker signatures, including but not limited to metabolomics, lipidomics, and 
other approaches.
Notes:
Collections to be performed only if subject provides separate written consent to collect the exploratory research/validation studies samples and if not prohibited by local 
regulations; if the separate consent is not signed, no samples can be collected.  The separate written consent may be part of the main consent form.
Optional samples for Exploratory Research and Validation Studies will not be collected for subjects in mainland China.


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Table 5.
Studies Activities (Period 2)
Activity
Wk 16
Wk 20
Wk 24
Wk 36
Wk 48
Monthly
Wk 64/Final/PD 
Visit
30-Day F/U 
Visita
Adverse Event Assessment
X
X
X
X
X
X
X
Concomitant Therapy
X
X
Xb
X
X
X
X
Patient Questionnairesc
PtGA
Pain (VAS)
HAQ-DI
Morning Stiffness (Severity and Duration)
X
X
X
X
X
X
Patient Questionnairesc
EQ-5D-5L
SF-36
FACIT-F
RA-WIS
X
X
Latent TB Risk Assessment Form
Xd
X
Central Lab QuantiFERON-TB Gold Test  
(and/or Local PPD Skin Test)
Xd
Xe
Chest X-Ray
Xd
X
12-Lead ECGf
X
Vital Signs and Body Weightg
X
X
X
X
X
X
X
Physical Examh
X
X
X
Physician Global Assessment (PhGA)
X
X
X
X
X
X
TJC68/SJC66
X
X
X
X
X
X


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Table 5.
Studies Activities (Period 2) (Continued)
Activity
Wk 16
Wk 20
Wk 24
Wk 36
Wk 48
Monthly
Wk 64/Final/PD 
Visit
30-Day F/U 
Visita
20% Joint Assessment (TJC and SJC)i
X
X
X
Local Urine Pregnancy Testj
X
X
X
X
X
X
X
In-home urine pregnancy testj
X
Central Lab Tests
hsCRPk
Blood Chemistryl
Hematology (CBC)
Urinalysism
HBV Testing (DNA PCR)n
X
X
X
X
X
X
X
CDAI IRT calculationo
X
ESR (Local Lab)
X
X
X
X
X
X
In Vivo Pharmacodynamic Biomarkersp
X
X
X
X
X
Dispense Study Drug and Subject Dosing Diary
X
X
X
X
X
Review and Retain A Copy of Subject Dosing 
Diary and Perform Drug Reconciliation
X
X
X
X
X
X
BL = Baseline Visit; CBC = complete blood count; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ECG = electrocardiogram; F/U = Follow-up; 
HAQ-DI = Health Assessment Questionnaire – Disability Index; hsCRP = high-sensitivity C-reactive protein; NRS = numerical rating scale; PD = Premature Discontinuation; 
PhGA = Physician's Global Disease Activity; PPD = purified protein derivative; PtGA = Patient's Global Assessment of Disease Activity; RCT = randomized controlled trial; 
SAE = serious adverse event; SJC = Swollen Joint Count; TB = tuberculosis; TJC = Tender Joint Count; VAS = visual analog scale; Wk = Week
a.
This visit is 30 days after last dose of study drug for those subjects who complete Period 2 or for those subjects who prematurely discontinued study drug and study 
participation.  A 30-day follow-up phone call may be allowed for subjects who have already completed PD visit to determine the status of any ongoing AEs/SAEs or the 
occurrence of any new AEs/SAEs.


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Table 5.
Studies Activities (Period 2) (Continued)
b.
At Week 24 (after Week 24 assessments have been performed), if a subject fails to meet LDA criterion (LDA defined as CDAI ≤ 10) investigator should adjust the subject's 
background RA therapies.  Initiation of or change in corticosteroids, NSAIDs, acetaminophen, or adding or increasing doses of csDMARDs (concomitant use of up to 
2 csDMARDs except the combination of MTX and leflunomide; see Inclusion Criterion 3) is allowed as per local label.
c.
Prior to other procedures.  For morning stiffness, duration will be captured only if NRS rating is > 0.
d.
This is only applicable to subjects from China at Week 24.
e.
TB testing should be performed in all subjects with previous negative Quantiferon and/or PPD tests.  Subjects with new evidence of latent TB should initiate prophylactic 
treatment immediately per local guidelines. Refer to Section 5.3.1.1 TB Testing/TB prophylaxis for additional details.
f.
An ECG may be performed at any visit if deemed necessary by the Investigator.
g.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.
h.
A full physical exam is required at Week 24, Week 48 and Week 64/PD.  A symptom-directed physical exam may be performed when necessary.
i.
Starting at Week 24 and thereafter, subjects who failed to show at least 20% improvement in TJC and SJC compared to baseline at 2 consecutive visits despite optimization of 
background RA therapies should be discontinued from the study.
j.
For women of childbearing potential, a urine pregnancy test will be performed at all visits and, starting at Week 24, monthly at home between scheduled study visits.  The 
results of the monthly at home tests will be communicated to the site.  If a urine pregnancy test is positive, the subject must stop dosing, come in to the clinic and have blood 
drawn for a serum pregnancy test that will be analyzed at the central laboratory.  Pregnant subjects must discontinue from the study.  Refer to Section 5.3.1.1 Study 
Procedures Pregnancy Test for additional details.  If during the course of the study a woman becomes surgically sterile or post-menopausal and complete documentation is 
available, urine pregnancy test is no longer required.
k.
hsCRP results will remain blinded to Sponsor, Investigator, study site personnel, and the subject.  Local laboratory or site testing for hsCRP or CRP is not allowed after 
Baseline.  Results of tests such as hsCRP may be blunted in subjects taking a JAK inhibitor, thereby limiting the clinical utility of these tests in the setting of a possible safety 
assessment or adverse event management.  Any local hsCRP or local CRP tests should not be reported to the investigator until a subject completes Period 1.  Treatment 
assignment may be unblinded to Sponsor only when the last subject completes Period 1 (Week 12 visit) for analysis for regulatory purposes.  During open label study conduct 
hs-CRP may be reported to the Sponsor, Investigator, study site personnel, and/or the subject.
l.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-fasting status will be recorded in study source documentation.
m.
Dipstick urinalysis will be completed by the central lab at all required visits.  Specified abnormal macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or 
blood greater than negative, or glucose greater than normal will be followed up with a microscopic analysis at the central laboratory.


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Table 5.
Studies Activities (Period 2) (Continued)
n.
For mainland China only, subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at screening, HBV DNA PCR test should be performed every 12 weeks.  HBV 
DNA PCR testing every 12 weeks is not necessary when the subject has a history of HBV vaccine and HBs Ab+.
o.
CDAI calculation requires input of SJC28 + TJC28 + PtGA + PhGA into IRT system.  At Week 24, investigator should optimize background RA therapies in subjects who 
failed to achieve CDAI ≤ 10.
p.
In Vivo Pharmacodynamic biomarker samples will not be collected for subjects in mainland China.
Note:
Visit window is ± 7 days for the study.  Any of the procedures may be performed at an unscheduled visit at the discretion of the Investigator.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 3 and Table 5 are discussed in detail in this 
section, with the exception of in vivo pharmacodynamic biomarkers (discussed in 
Section 5.3.1.2.1), exploratory research and validation studies (discussed in 
Section 5.3.1.2.2), drug concentration measurements (discussed in Section 5.3.2), the 
collection of prior and concomitant medication information (discussed in Section 6.0), and 
the collection of AE information (discussed in Section 6.0).  All study data will be 
recorded in source documents and on the appropriate eCRFs.
Informed Consent
At the Screening visit, the subject will sign and date a study specific, IEC/IRB approved, 
informed consent form for the study (i.e., includes both Periods 1 and 2) before any study 
procedures are performed or any medications are withheld from the subject in order to 
participate in this study.  Separate written consent will be required for each subject in 
order to participate in the optional exploratory research and validation studies, if not 
prohibited by local regulations.  The separate informed consent is not required for subjects 
in mainland China because optional samples for exploratory research and validation 
studies will not be collected.
Subjects can withdraw informed consent at any time.
Details regarding how informed consent will be obtained and documented are provided in 
Section 9.3.  
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at both Screening and Baseline Visits.


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Medical and Surgical History
A complete non-RA-related medical and surgical history, including history of alcohol and 
nicotine use, will be taken from each subject during the Screening Visit.  Additionally, a 
list of each subject's specific RA-related medical and surgical history will be recorded at 
Screening.  History of herpes zoster, herpes zoster vaccination, and hepatitis B 
vaccination status will be recorded as part of the medical history.  An updated medical 
history will be obtained prior to study drug administration at Baseline, to ensure the 
subject is still eligible for enrollment.
A detailed medical history with respect to TB risk factors will be documented in the study 
source documentation.  This information will include BCG vaccination, cohabitation with 
individuals who have had TB, and travel to, residence in, or work in TB endemic 
locations.
Patient Questionnaires
Subjects will complete the following questionnaires as specified in Table 3 and Table 5; a 
validated translation will be provided in their local language, as applicable:
Period 1
●
Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) 
(Appendix F)
●
Patient's Assessment of Pain Visual Analog Scale (VAS) (Appendix G)
●
Health Assessment Questionnaire – Disability Index (HAQ-DI) to assess the 
physical function and health-related quality of life of each subject 
(Appendix H)
●
Patient's Assessment of Severity and Duration of Morning Stiffness Numerical 
Rating Scale (NRS) (Appendix I)*
●
EuroQoL-5D-5L (EQ-5D-5L) (Appendix J)
●
Short Form-36 (SF-36) (Appendix K)
●
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) 
(Appendix L)


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●
Work Instability Scale for RA (RA-WIS) (Appendix M)
Period 2
●
Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) 
(Appendix F)
●
Patient's Assessment of Pain Visual Analog Scale (VAS) (Appendix G)
●
Health Assessment Questionnaire – Disability Index (HAQ-DI) to assess the 
physical function and health-related quality of life of each subject 
(Appendix H)
●
Patient's Assessment of Severity and Duration of Morning Stiffness Numerical 
Rating Scale (NRS) (Appendix I)*
●
EuroQoL-5D-5L (EQ-5D-5L) (Appendix J) 
●
Short Form-36 (SF-36) (Appendix K)
●
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) 
(Appendix L) 
●
Work Instability Scale for RA (RA-WIS) (Appendix M)
*
Paper; all other patient-reported outcomes (PROs) collected electronically.
The subject should complete the questionnaires before site personnel perform any clinical 
assessments and before any interaction with site personnel has occurred to avoid biasing 
the subject's response.
TB Testing/TB Prophylaxis
Period 1
The TB screening tests are diagnostic test results to be interpreted in the context of the 
subject's epidemiology, history, exam findings, etc., and it is the responsibility of the 
Investigator to determine if a subject has previous, active, or latent TB.  Expert 
consultation for the evaluation and/or management of TB may be considered per 
Investigator discretion.


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All subjects will be assessed for evidence of increased risk for TB by a risk assessment 
form (Appendix E) and tested for TB infection by QuantiFERON®-TB Gold test.  The 
PPD Skin Test should be utilized only when a QuantiFERON®-TB Gold Test is not 
possible for any reason (unless both tests are required per local guidelines).  The site staff 
will complete the TB risk assessment form and enter the data into an appropriate eCRF.
If a subject had a negative QuantiFERON®-TB Gold (and/or PPD) test (or IGRA 
equivalent such as T-SPOT TB test) within 90 days prior to Screening and source 
documentation is available, the test does not need to be repeated, provided nothing has 
changed in the subject's medical history to warrant a repeat test.  These cases may be 
discussed with the AbbVie Therapeutic Area Medical Director.  The results of the TB 
test(s) will be retained at the site as the original source documentation.
Subjects with a negative QuantiFERON®-TB Gold test (and/or negative PPD TB skin 
test) and chest x-ray (CXR) not suggestive of active TB or prior TB exposure may be 
enrolled.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent 
TB, including signs and symptoms and CXR.  Subjects with no signs or symptoms and a 
CXR not suggestive of active TB may be enrolled after initiation of TB prophylaxis (see
below).  Subjects with evidence of active TB must not be enrolled.
Subjects with evidence of active TB must not be enrolled.
TB test:
●
Subjects with documentation of prior positive result of QuantiFERON-TB 
Gold Test (or equivalent) and/or PPD are not required to repeat either test at 
Screening or during the study and should be considered positive. 
●
For regions that require both PPD and QuantiFERON-TB Gold testing, both 
will be performed.  If either PPD or QuantiFERON-TB Gold are positive, the 
TB test is considered positive.


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●
The PPD Skin Test (also known as a TB Skin Test or Mantoux Test) should be 
utilized only when a QuantiFERON-TB Gold Test is not possible for any 
reason (unless both tests are required per local guidelines).  
●
If only a PPD is placed at screening, then the TB test to be used for the 
remainder of the study for that subject is the PPD.  Similarly, if a subject 
enters the study with a QuantiFERON-TB Gold test (or equivalent) alone, then 
the subject should have their annual TB test performed with a QuantiFERON-
TB Gold test.
●
If the QuantiFERON-TB Gold Test is NOT possible (or if both the 
QuantiFERON-TB Gold Test and the PPD are required per local guidelines) 
the PPD will be performed.  The PPD should be read by a licensed healthcare 
professional between 48 and 72 hours after administration.  A subject who 
does not return within 72 hours will need to be rescheduled for another skin 
test.  The reaction will be measured in millimeters (mm) of induration and 
induration ≥ 5 mm is considered a positive reaction.  The absence of induration 
will be recorded as "0 mm" not "negative."  Subjects who have an ulcerating 
reaction to the PPD in the past should not be re-exposed and the PPD should 
be considered positive.
●
If the QuantiFERON-TB Gold test is indeterminate, then the investigator 
should perform a local QuantiFERON-TB Gold test (or through the central 
laboratory if not locally available) to rule out a positive test result.  If testing 
remains indeterminate or is positive, then the subject is considered to be 
positive for the purpose of this study.  If the testing result is negative, then the 
patient is considered to be negative.
TB prophylaxis:
At Screening, if the subject has evidence of latent TB infection (QuantiFERON®-TB Gold 
test and/or the PPD test positive and the subject has a CXR not suggestive of active TB), 
prophylactic treatment must be initiated at least 3 weeks prior to administration of study 
drug (or per local guidelines, whichever is longer).  At least 6 months of prophylaxis 
needs to be completed; however, the full course of prophylaxis does not need to be 
completed prior to the first dose of study drug.  


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Of note:  Rifampicin or Rifapentine are not allowed for TB prophylaxis.
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy per local guidelines within 1 year prior to first study drug 
administration will be allowed to enter the study provided nothing has changed in the 
subject's medical history to warrant repeat treatment.
Subjects with documented completion of a full course of anti-TB therapy greater than 
1 year prior to first study drug administration may be allowed to enter the study only after 
consultation with the AbbVie Therapeutic Area Medical Director.
Newly initiated prophylactic treatment should be captured in the eCRF and in the source 
documents.  Prior therapy should be captured in the eCRF.
Period 2
Subjects with documentation of prior positive result of QuantiFERON-TB Gold Test (or 
equivalent) and/or PPD are not required to repeat either TB test during the study and 
should be considered positive.  The TB risk assessment form will be completed annually 
for all subjects, regardless of TB test results.
For subjects with a negative QuantiFERON®-TB Gold (and/or PPD) test at Screening, a 
QuantiFERON®-TB Gold (and/or PPD) re-test will be performed (or both if required by 
local guidelines) at Week 48 as indicated in Table 5.  Subjects from China will have 
additional re-tests at Week 12 and Week 24.  If the QuantiFERON®-TB Gold test is 
indeterminate, then the investigator should perform a local QuantiFERON®-TB Gold test 
(or through the central laboratory if not locally available) to rule out a positive test result.  
If testing remains indeterminate or is positive, then the subject is considered to be positive 
for the purpose of this study.  If the local testing result is negative, then the patient is 
considered to be negative.  If one of these subsequent tests has a positive test result 
(seroconversion), a chest x-ray (CXR) needs to be performed as soon as possible to aid in 
distinguishing active versus latent TB.  Expert consultation can be considered per 


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Investigator's discretion.  Any positive TB screen after the patient has started the study, 
should be reported as an adverse event (AE) of latent or active TB (as applicable).
Obtain a CXR for subjects with TB risk factors as identified by the TB risk assessment 
form (Appendix E) or for subjects living in areas endemic for TB or for subjects with 
newly positive PPD or QuantiFERON®-TB Gold test.
Subjects with new evidence of latent TB should initiate prophylactic treatment 
immediately per local guidelines and complete at least 6 months of prophylaxis.  TB 
prophylaxis should be initiated and study drug(s) should not be withheld.  Two to 4 weeks 
later (per local guidelines), 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 and prior therapy should be captured in the eCRF.
If the subject is experiencing signs or symptoms suspicious for TB or something has 
changed in the subject's medical history to warrant a repeat test before the next scheduled 
annual TB re-test, a repeat test should be performed as soon as possible and the case 
(including the TB test results) must be discussed with the AbbVie Therapeutic Area 
Medical Director.
Chest X-Ray (CXR)
A CXR (posterior-anterior and lateral views) is required:
●
For all subjects at Screening to rule out the presence of TB or other clinically 
relevant findings.  The CXR will not be required if the subject had a previous 
normal CXR (posterior-anterior and lateral views) within 90 days of 
Screening, provided all source documentation is available at the site as 
outlined below and provided nothing has changed in the subject's medical 
history to warrant a repeat test.  
●
For all subjects at Week 48.  Subjects from China will have an additional CXR 
performed at Week 24.


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Subjects can have a repeat CXR at any time during the study as warranted, based on the 
opinion of the Investigator.
A radiologist or pulmonologist must perform an assessment of the CXR.  The Principal 
Investigator will indicate the clinical significance of any findings and will sign and date 
the report.  In the assessment of the CXR, the Principal Investigator or their delegate must 
indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.  If the CXR demonstrates changes 
suggestive of previous TB (e.g., calcified nodule, fibrotic scar, apical or basilar pleural 
thickening) or other findings that are clinically significant, the Principal Investigator 
should contact the AbbVie Therapeutic Area Medical Director before enrolling the 
subject.
12-Lead ECG
A resting 12-lead ECG will be performed at the designated study visits as specified in 
Table 3 and Table 5.  A qualified physician will interpret the clinical significance of any 
abnormal finding, sign, and date each ECG.  ECG with QT interval corrected for heart 
rate using Friedericia's correction formula (QTcF) should be reported (or calculated) and 
documented in the source documents and later transcribed on to the appropriate eCRF if 
QTcF prolongation is observed.  A valid QTcF cannot be calculated in subjects who have 
a pacemaker or supraventricular or ventricular conduction abnormalities.  In these cases, 
the baseline QTcF will need to be entered into the appropriate eCRF for comparison as 
well.  In addition, any clinically significant findings will be documented in the source 
documents and later transcribed on to the appropriate eCRF.  Each signed original ECG 
will be monitored by the responsible site monitor and kept with subject's source 
documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided source documentation is available and provided 
nothing has changed in the subject's medical history to warrant a repeat test.  If there are 


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other findings that are clinically significant, the Investigator must contact the AbbVie 
Therapeutic Area Medical Director before enrolling the subject.
Subjects can have a repeat ECG at any time during the study as warranted based on the 
opinion of the Investigator.
Height and Weight
Height will be measured at the Screening Visit only (with shoes off).  Body weight will be 
measured at all scheduled visits except Week 1 as specified in Table 3 and Table 5.  All 
measurements will be recorded in metric units where applicable.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse
rate, respiratory rate, and body temperature will be obtained at visits specified in Table 3
and Table 5.  Blood pressure, pulse rate, body temperature, and respiratory rate should be 
performed before blood draws are performed.
Physical Examination
A complete physical examination will be performed at the designated study visits as
specified in Table 3 and Table 5.  The physical examination at the Baseline Visit will 
serve as the baseline physical examination for the entire study.  Physical examination 
abnormalities noted by the Investigator at Baseline prior to the first dose of study drug 
will be recorded in the subject's medical history; abnormalities noted after the first dose of 
study drug will be evaluated and documented by the Investigator as to whether or not the 
abnormality is an AE (see Section 6.1.1.1 for AE definition).  All findings, whether 
related to an AE or part of each subject's medical history, will be captured on the 
appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed 
necessary by the Investigator.


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Physician Global Assessment of Disease Activity VAS
At visits specified in Table 3 and Table 5, the Physician will rate global assessment of 
subject's current disease activity ranging from 0 to 100 independent of the subject's 
self-assessment using the VAS, which consists of a horizontal 100 mm line anchored at 
either end by opposite adjectives reflecting the spectrum/severity of the parameters 
assessed (Appendix C).
TJC and SJC Assessment
TJC Assessment
An assessment of 68 joints (Appendix D) will be done for tenderness by pressure 
manipulation on physical examination at visits specified in Table 3 and Table 5.  Joint 
pain/tenderness will be classified as:  present ("1"), absent ("0"), replaced ("9") or no 
assessment ("NA").
SJC Assessment
An assessment of 66 joints (Appendix D) will be done by directed physical examination at 
visits specified in Table 3 and Table 5.  The joints to be examined for swelling are the 
same as those examined for tenderness, except the hip joints are excluded.  Joint swelling 
will be classified as present ("1"), absent ("0"), replaced ("9") or no assessment ("NA").
Any injected joints will be considered as "not assessed" ("NA") for 3 months from the 
time of the intra-articular injection.
If possible, the TJC and SJC should be performed by an independent and blinded joint 
assessor who should not perform any other study related procedures.
In order to minimize variability, the same independent joint assessor should evaluate the 
subject at each visit for the duration of the trial as much as possible.  A back-up 
independent joint assessor should be identified.  The independent joint assessor should be 
a qualified medical professional (e.g., nurse, physician's assistant, physician).  Any other 


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joint assessor must be trained and competent in performing such assessments.  It is the 
responsibility of the Investigator to ensure that all assessors are qualified and trained to 
perform joint assessments.  If the independent assessor is not available, the pre-identified 
back-up assessor should perform such assessments.
CDAI
The CDAI calculation is required to determine if a subject fails to achieve low disease 
activity at the Week 24 visit.  An Interactive Response Technology (IRT) will calculate 
CDAI with input from site personnel on joint counts and the subject's and physician's 
Global Assessment of RA Disease Activity score.  A worksheet will be provided to 
capture the components required for IRT entry to obtain the CDAI calculation.
The calculation used to determine CDAI score at Week 24 is as follows:
CDAI = TJC28 + SJC28 + PtGA (cm) + PhGA (cm)
NOTE:  Investigator should optimize background RA therapies in subjects who failed to 
achieve a CDAI ≤ 10.
Pregnancy Testing
A serum pregnancy test will be performed for all women of childbearing potential at the 
Screening Visit.  The serum pregnancy test will be sent to and performed by the central 
laboratory.  If the serum pregnancy test is positive the subject is considered a screen 
failure.  If the serum pregnancy test is borderline, it should be repeated ≥ 3 days later to 
determine eligibility.  If the repeat serum pregnancy test is:
●
Positive, the subject is considered a screen failure;
●
Negative, the subject can be enrolled into the trial;
●
Still borderline ≥ 3 days later, this will be considered documentation of 
continued lack of a positive result and the subject can be enrolled into the 
study.


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In Period 1, a urine pregnancy test will be performed for all women of childbearing 
potential at the Baseline Visit prior to the first dose of study drug and all subsequent visits 
except Week 1.  More frequent pregnancy tests will be performed throughout the study if 
required per local/country requirements.
●
If the baseline urine pregnancy test performed at the site is negative, then 
dosing with study drug may begin.  
●
If the baseline or post-baseline urine pregnancy test performed at the site is 
positive, dosing with study drug must be withheld and a serum pregnancy test 
is required.  The serum pregnancy test will be sent to and performed by the 
central laboratory.  If the serum pregnancy test is negative, study drug may be 
started or resumed.  If the serum pregnancy test is positive, study drug must be 
permanently discontinued and the subject must be discontinued from the study.  
In the event a serum pregnancy test comes back borderline, a repeat test is 
required (≥ 3 days later) to document continued lack of a positive result.
In Period 2, for women of childbearing potential, a urine pregnancy test will be performed 
at all visits, including the 30 days follow-up visit, and starting at Week 24 a urine 
pregnancy test will be performed monthly at home between scheduled study visits.  The 
results of the monthly at home tests will be communicated to the site.  If a urine 
pregnancy test is positive, the subject must stop dosing, come in to the clinic and have 
blood drawn for a serum pregnancy test that will be analyzed at the central laboratory.
At each visit, the study staff should review the pregnancy avoidance recommendations 
with women of childbearing potential and male subjects with a partner of childbearing 
potential, and document this discussion in the subject's source records.
If during the course of the study a woman becomes surgically sterile or post-menopausal 
and complete documentation as described in Section 5.2.4 is available, pregnancy testing 
is no longer required.
A pregnant or breastfeeding female will not be eligible for participation or continuation in 
this study.


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Clinical Laboratory Tests
Samples will be obtained for the clinical laboratory tests listed in Table 6.  Unscheduled 
clinical labs may be obtained at any time during the study if deemed appropriate per 
Investigator's discretion.  A certified central laboratory will be utilized to process and 
provide results for the clinical laboratory tests.  All abnormal laboratory tests that are 
considered clinically significant by the Investigator will be followed to a satisfactory 
resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing, and shipping of these samples.
Blood samples will be obtained for the laboratory tests at visits specified in Table 3 and 
Table 5.  Blood draws should be performed only after all clinical assessments and 
questionnaires (HAQ-DI, Patient's Assessment of Pain, etc.) and vital sign determinations 
are obtained.
For clinic visits where samples for serum chemistry tests are collected, subjects should be 
fasting (a minimum 8-hour fast) whenever possible.  If a subject is not able to fast when 
necessary, due to unforeseen circumstances, the non-fasting status will be recorded in 
study source documentation.
Urine samples will be obtained for urinalysis testing at visits specified in Table 3 and 
Table 5.  The central laboratory will be responsible for performing a macroscopic 
urinalysis (urine dipstick) on the collected urine specimens.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater 
than negative, or glucose greater than normal will be followed up with a microscopic 
analysis at the central laboratory.
For any laboratory test value outside the reference range that the Investigator considers to 
be clinically significant, the Investigator should apply the standard of care for medical 
evaluation and treatment per local guidelines:


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●
The Investigator will repeat the test to verify the out-of-range value.
●
The Investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
A laboratory test value that requires a subject to be discontinued from the study drug or 
requires a subject to receive treatment will be recorded as an AE.
Table 6.
Clinical Laboratory Tests
Hematology 
(Central Lab)
Clinical Chemistrya
(Central Lab)
Urinalysisb
(Central Lab)
Other Laboratory Tests
Hematocrit
Hemoglobin
RBC count
WBC count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
BUN
Creatinine
Total bilirubin
INR (reflex only)c
ALT
AST
Alkaline phosphatase
CPK 
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Inorganic phosphate
Uric acid
Cholesterol
LDL-C
HDL-C
Total protein
Glucose
Triglycerides
Albumin
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocytes
Nitrites 
Microscopic 
examination, if 
needed
Central Lab Tests:
Serum pregnancy (bHCG) testd
HBs Age
HBs Abe
HBc Abe
HBV DNA PCR reflex onlye
HCV Abe
HCV RNA (reflex only)e
QuantiFERON-TB Goldf
HIV-1e,g
HIV-2e,g
HAV-IgMe
Syphilis antibody (in mainland 
China only)e
Rheumatoid Factore
Anti-CCP autoantibodiese
hs-CRPh
IgG and IgM
FSHi
Local Lab Tests:
Urine pregnancy testj
ESR
MRB Panelk
ALT = alanine aminotransferase; AST = aspartate aminotransferase; bHCG = beta human chorionic gonadotropin; 
BUN = blood urea nitrogen; CCP = cyclic citrullinated peptide; CPK = creatine phosphokinase; 
DNA = deoxyribonucleic acid; ESR = erythrocyte sedimentation rate; HBc Ab = hepatitis B core antibody; HBs 
Ab = hepatitis B surface antibody; HBs Ag = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV Ab = hepatitis C virus antibody; HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency 
virus; hsCRP = high-sensitivity C-reactive protein; IgG = immunoglobulin G; IgM = immunoglobulin M; 
IN = international normalized ratio; LDL C = low density lipoprotein cholesterol; PCR = polymerase chain reaction; 
RBC = red blood cell; RNA = ribonucleic acid; TB = tuberculosis; WBC = white blood cell


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Table 6.
Clinical Laboratory Tests (Continued)
a.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the 
non-fasting status will be recorded in study source documentation.
b.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A 
microscopic analysis will be performed in the event the dipstick results show leukocytes, nitrite, protein, ketones, 
or blood greater than negative or glucose greater than normal.
c.
INR will only be measured with a separate blood sample at repeat testing if ALT and/or AST > 3 × ULN.
d.
A serum pregnancy test will be performed for all women of childbearing potential at the Screening Visit and if 
postbaseline urine pregnancy test turns positive.
e.
At Screening only.  For mainland China only, subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at 
screening, HBV DNA PCR test should be performed every 12 weeks.  HBV DNA PCR testing every 12 weeks is 
not necessary when the subject has a history of HBV vaccine and HBs Ab+.
HBV DNA testing is also required for subjects who meet specific toxicity management criteria (See ALT/AST 
toxicity management criteria in Table 8).
f.
If PPD not performed.
g.
Subjects will be tested for antibodies to HIV at Screening.  The results of the HIV Ab testing will be retained by 
the study site under confidential restriction.  A subject will not be eligible for study participation if test results 
indicate a positive HIV infection.  AbbVie will not receive results from the testing and will not be made aware of 
any positive result.
h.
The hsCRP results starting from baseline (Day 1) will not be reported to the Sponsor, Investigator, study site 
personnel, and the subject.  hsCRP will be performed by the Central Lab.  Local laboratory or site testing for 
hsCRP or CRP is not allowed after Baseline.  Results of tests such as hsCRP may be blunted in subjects taking a 
JAK inhibitor, thereby limiting the clinical utility of these tests in the setting of a possible safety assessment or 
adverse event management.  Any local hsCRP or local CRP tests should not be reported to the investigator until a 
subject completes Period 1.  During open label study conduct hs-CRP may be reported to the Sponsor, Investigator, 
study site personnel, and/or the subject.
i.
For more details, please refer to Section 5.2.4 (Contraception Recommendations).
j.
A urine pregnancy test will be performed for all women of childbearing potential at the Baseline Visit prior to the 
first dose of study drug and all subsequent visits except Week 1.  If the baseline urine pregnancy test performed at 
the site is negative, then dosing with study drug may begin.  If the baseline urine pregnancy test performed at the 
site is positive, dosing with study drug must be withheld and a serum pregnancy test is required.  The serum 
pregnancy test will be sent to and performed by the central laboratory.  If the serum pregnancy test is positive, 
study drug must be withheld and the subject must be discontinued from the study.  In the event a pregnancy test 
comes back borderline, a repeat test is required (≥ 3 days later) to document continued lack of a positive result.  If a 
urine pregnancy test postbaseline is positive, study drug needs to be temporarily discontinued and a serum 
pregnancy test is required.  The serum pregnancy test will be sent to and performed by the central laboratory.  If 
serum pregnancy test is negative, study drug may be restarted.  If the serum pregnancy test is positive, study drug 
must be permanently discontinued.
k.
If needed to assess B cell counts in subjects who have discontinued rituximab, see Inclusion Criteria 7.


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Hepatitis Screen
All subjects will be tested for the presence of HAV, HBV and HCV at Screening.
Hepatitis A:
Blood samples for hepatitis A serology will be obtained at the Screening Visit.  A subject 
will not be eligible for study participation in case of positive test result for hepatitis A 
virus immunoglobulin M (HAV-IgM).
Hepatitis B:
Subjects will be tested for the presence of HBV at screening using the following tests:
●
HBs Ag (Hepatitis B surface antigen)
●
HBc Ab/anti-HBc (Hepatitis B core antibody)
●
HBs Ab/anti-HBs (hepatitis B surface antibody)
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will be tested (automatic reflex testing) for core antibodies 
(HBc Ab) and surface antibodies (HBs Ab).
●
A negative test result for HBc Ab and HBs Ab does not require HBV DNA 
PCR qualitative testing and the subject may be enrolled (Figure 2, Scenarios A 
and B).  
●
For a subject who has had a HBV vaccination (should document in the medical 
history), a positive test result for HBs Ab is expected and the subject may be 
enrolled (Figure 2, Scenario B).*
●
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic 
reflex testing) (Figure 2, Scenarios C and D).
○
A positive result for HBV DNA or a result that exceeds detection 
sensitivity will be exclusionary.
○
A subject with a negative result for HBV DNA may be enrolled.


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●
For subjects in mainland China only: A positive result for HBs Ab/anti-HBs 
requires HBV DNA PCR testing.
○
A positive result for HBV DNA or a result that exceeds detection 
sensitivity will be exclusionary.
○
A subject with a negative result for HBV DNA may be enrolled.
○
For subjects with HBc Ab+ (irrespective of HBs Ab status) and negative 
HBV DNA at screening and a positive result for HBV DNA PCR testing 
during the study who also manifest an ALT > 5 × ULN OR ALT/AST 
> 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR
ALT/AST > 3 × ULN along with clinical signs of possible hepatitis, study 
drug will need to be interrupted immediately and a hepatologist 
consultation should occur within 1 week for recommendation regarding 
subsequent treatment.
Figure 2.
Criteria for HBV DNA PCR Qualitative Testing
*
For subjects who have had a HBV vaccination (should document in the medical history), a positive test result for 
HBs Ab is expected and these subjects may be enrolled.  For subjects without a history of HBV vaccination, a 
positive result for HBs Ab/anti-HBs requires HBV DNA PCR testing.
**
For mainland China only: subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at screening, HBV 
DNA PCR test should be performed every 12 weeks.  HBV DNA PCR testing every 12 weeks is not necessary 
when the subject has a history of HBV vaccine and HBs Ab+.


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Hepatitis C:
Blood samples for hepatitis C serology will be obtained at the Screening Visit.  A subject 
will not be eligible for study participation if test results indicate active hepatitis C (HCV 
RNA detectable in any subject with anti HCV Ab).
HIV Screen
Subjects will have blood tested by a certified laboratory for the presence of HIV Ab at 
Screening.  Only those subjects negative for the presence of antibodies will be allowed to 
enroll in the study.  The results of the HIV Ab testing will be retained by the study site 
under confidential restriction.  AbbVie will not receive results from the testing and will 
not be made aware of any positive result.
Syphilis Screen (For Subjects in Mainland China Only)
A Syphilis Ab test will be performed at Screening utilizing the Toluidine Red Unheated 
Serum Test (TRUST) to test anticardiolipin antibody in serum.  Subjects with a positive 
TRUST result will have a treponema pallidum particle agglutination assay (TPPA) to 
confirm a syphilis infection.  A positive test result for both the TRUST and TPPA tests 
will be exclusionary.  The syphilis tests will be performed by a certified laboratory.
Randomization/Treatment Group Assignment
All Screening laboratory results must be reviewed, signed and dated by the Investigator 
prior to the Baseline Visit.  Subjects will not be enrolled into the study if laboratory or 
other Screening result abnormalities are deemed clinically significant by Investigator.
Subjects will be eligible for randomization if they continue to meet all of the selection 
criteria (Section 5.2) at Baseline and are willing to continue in the study.
Subjects will be randomized in a 1:1 ratio using interactive response technology (IRT) to 
receive double-blind study drug in one of the following treatment groups.  As indicated 


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below, it is expected that approximately 222 subjects will enter the study from China and 
100 subjects from other countries including Brazil and South Korea:  
●
Group 1:  Upadacitinib 15 mg QD (N = 161; 111 from China) (Period 1) → 
Upadacitinib 15 mg QD (Period 2)
●
Group 2:  Placebo (N = 161; 111 from China) (Period 1) → Upadacitinib 
15 mg QD (Period 2)
Randomization will be stratified by country and the Chinese population will be up to 80% 
of the total study population.
See Section 5.5.3 for details.
Study Drug Dispensing, Dosing, and Compliance
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in 
Table 3 and Table 5.  The first dose of study drug will be administered after all other 
Baseline (Day 1) procedures are completed. Subjects will maintain a dosing diary for all 
study drug administered outside of the study visit (i.e., at home) to capture dosing dates 
and times.  At visits specified in Table 3 and Table 5, the site personnel will review and 
retain a copy of the dosing diary, returned study drug kits, and empty study drug 
packaging to verify compliance.
All relevant dosing information will be entered into the eCRF at each visit.
(Refer to Section 5.5 for additional information.)
5.3.1.2
Collection and Handling of In Vivo Pharmacodynamic 
Biomarker and Optional Samples for Exploratory Research 
and Validation Studies
5.3.1.2.1
In Vivo Pharmacodynamic Biomarker Samples
Blood samples will be collected at the visits indicated in Table 3 and Table 5 and will be 
utilized to assess effects of upadacitinib inhibition on certain lymphocyte subsets, 


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including but not limited to T (CD4+ and CD8+) cells, B (CD19+) cells, natural killer 
(NK) cells, and natural killer-T (NKT) cells.
In Vivo Pharmacodynamic biomarker samples will not be collected for subjects in 
mainland China.
The samples should be labeled and shipped as outlined in the study-specific laboratory 
manual.
AbbVie (or people or companies working with AbbVie) will store the samples in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be 
retained while research on upadacitinib (or drugs of this class) or this disease and related 
conditions continues, but for no longer than 5 years after study completion, or per local 
requirement.
5.3.1.2.2
Optional Samples for Exploratory Research and Validation 
Studies
In Period 1, subjects will have the option to provide samples for exploratory research and 
validation studies, where not prohibited by local regulations.  Subjects may still 
participate in the main study even if they decide not to participate in this optional 
exploratory research/validation study.
Optional samples for Exploratory Research and Validation Studies will not be collected 
for subjects in mainland China.
Exploratory research can help to improve our understanding of how individuals respond 
to drugs and our ability to predict which subjects would benefit from receiving specific 
therapies.  In addition, exploratory research may help to improve our understanding of 
how to diagnose and assess/monitor RA by assessing associations between disease 
characteristics, outcomes data, and biomarkers of interest.


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Validation studies, including those related to the development of potential in vitro 
diagnostic tests, may be carried out retrospectively in order to assess associations between 
events of interest (i.e., efficacy and/or safety events) and candidate biomarkers.
AbbVie (or people or companies working with AbbVie) will store the biomarker 
exploratory research/validation studies samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
upadacitinib (or drugs of this class) or RA and related conditions continues, but for no 
longer than 5 years after study completion.  The procedure for obtaining and documenting 
informed consent for exploratory research samples is discussed in Section 9.3.
DNA Samples for Pharmacogenetic or Epigenetic Analyses
Optional whole blood samples for DNA isolation will be collected at the visits indicated 
in Table 4 from each subject who consents to provide samples for exploratory/validation 
research.  The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.
Samples will be shipped frozen to AbbVie or a designated laboratory for DNA extraction 
and/or long-term storage or analyses.  Instructions for the preparation and shipment of the 
pharmacogenetic and/or epigenetic research samples will be provided in a laboratory 
manual.
RNA Samples for Transcriptomic and/or Epigenetic Analyses
Optional whole blood samples for RNA isolation will be collected at the visits indicated 
in Table 4 from each subject who consents to provide samples for exploratory/validation 
research.  The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.
Samples will be shipped to AbbVie or a designated laboratory for RNA extraction and/or 
long-term storage or analyses.  Instructions for the preparation and shipment of the 
samples will be provided in a laboratory manual.


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Serum and Plasma Samples for Systemic Analyses, Including but Not Limited to 
Proteomic and Metabolomic
Serum and plasma samples will be collected at the visits indicated in Table 4 from each 
subject who consents to provide samples for exploratory/validation research.  The 
procedure for obtaining and documenting informed consent is discussed in Section 9.3.
Samples will be shipped to AbbVie or a designated laboratory for long-term storage 
and/or analyses.  Instructions for the preparation and shipment of the samples will be 
provided in a laboratory manual.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for assay of upadacitinib and possibly other concomitant medications will 
be collected as follows:
●
Weeks 1 and 2 prior to dosing; 
●
Weeks 4, 8, and 12/Premature Discontinuation at any time during the visit.
On Week 1 and Week 2 visit days, if possible, subjects should take the study drug dose at 
the clinic after collecting the PK blood sample, except if the subjects regularly take the 
study drug dose at night.  Those subjects who regularly take the study drug dose at night 
should continue to take study drug according to their normal schedule.  For all other 
visits, subjects can take the study drug dose on visit days at their regular schedule and not 
necessarily at the clinic.
The date and accurate time of the PK sample collection will be recorded on the lab 
requisition form.  The date and accurate time of the last two study drug doses will be 
recorded on the eCRF to the nearest minute.
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment.


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5.3.2.2
Measurement Methods
Plasma concentrations of upadacitinib will be determined under the supervision of the 
Drug Analysis Department at AbbVie using a validated liquid chromatography/mass 
spectrometry method.
5.3.3
Efficacy Variables
5.3.3.1
Period 1 Variables
5.3.3.1.1
Primary Variables
The primary endpoint in Period 1 is the proportion of subjects achieving ACR20 response 
at Week 12.
ACR20 response rate will be determined based on 20% or greater improvement in TJC 
and SJC and ≥ 3 of the 5 measures of Patient's Assessment of Pain (VAS), Patient's 
Global Assessment of Disease Activity (VAS), Physician's Global Assessment of Disease 
Activity (VAS), HAQ-DI, or hsCRP.
5.3.3.1.2
Key Secondary Variables
Ranked key secondary endpoints (at Week 12) are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
Change from baseline in SF-36 Physical Component Score (PCS);
4.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2;
5.
Proportion of subjects achieving CR based on DAS28 (CRP);
6.
Proportion of subjects achieving LDA based on CDAI ≤ 10;
Other key secondary endpoints (at Week 12, if not specified) are:


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●
ACR50 response rate;
●
ACR70 response rate;
●
ACR20 response rate at Week 1.
ACR20/50/70 response rates will be determined based on 20%/50%/70% or greater 
improvement in TJC and SJC and ≥ 3 of the 5 measures of Patient's Assessment of Pain 
(VAS), Patient's Global Assessment of Disease Activity (VAS), Physician's Global 
Assessment of Disease Activity (VAS), HAQ-DI, or hsCRP.
LDA is defined as DAS28 (CRP) ≤ 3.2.  DAS28 (CRP) score will be determined based on 
a continuous scale of combined measures of TJC, SJC, Patient's Global Assessment of 
Disease Activity (PtGA) (in mm), and hsCRP (in mg/L) at Week 12.
DAS28 (CRP) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(hsCRP& + 1) 
+ 0.014 × PtGA>> + 0.96
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
&
hsCRP refers to the high-sensitivity c-reactive protein lab value.  hsCRP unit in the DAS28 (CRP) equation 
is expressed as mg/L.
>>
PtGA refers to the Patient's Global Assessment of Disease Activity.
where √is square root and ln is natural log.
5.3.3.1.3
Additional Variables
Additional endpoints at all visits are:
●
Change from baseline in individual components of ACR response;
●
ACR20/50/70 response rates;
●
Change from baseline in DAS28 (CRP) and DAS28 (erythrocyte 
sedimentation rate [ESR]);
●
Change from baseline in CDAI and SDAI;
●
Change from baseline in morning stiffness;
●
Proportion of subjects achieving MCID in change from baseline in HAQ-DI


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(defined as change from baseline in HAQ-DI ≤ –0.22);
●
Proportion of subjects achieving MCID in change from baseline in HAQ-DI 
(defined as change from baseline in HAQ-DI ≤ –0.3);
●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), DAS28 (ESR), Simplified Disease Activity Index 
(SDAI), and CDAI criteria (see below);
●
ACR/EULAR Boolean remission;
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in SF-36.
●
Change from baseline in Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-F);
●
Change from baseline in Work Instability Scale for Rheumatoid Arthritis 
(RA-WIS).
5.3.3.2
Period 2 Variables
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the 
following measures at Weeks 16, 20, 24, 36, 48, and 64/PD:
●
ACR20/50/70 response rates;
●
Change from baseline in individual ACR components;
●
Change from baseline in DAS28 (CRP);
●
Change from baseline in DAS28 (ESR);
●
Change from baseline in CDAI and SDAI;
●
Change from baseline in morning stiffness;
●
Proportion of subjects achieving MCID in change from baseline in HAQ-DI 
(defined as change from baseline in HAQ-DI ≤ –0.22);


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●
Proportion of subjects achieving MCID in change from baseline in HAQ-DI 
(defined as change from baseline in HAQ-DI ≤ –0.3);
●
Proportion of subjects achieving LDA and the proportion of subjects achieving 
CR based on DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as 
defined for Period 1);
●
ACR/EULAR Boolean remission;
●
Concomitant corticosteroid use (systemic use and intra-articular injections).
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the 
following measures at Weeks 24 and 48 only:
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in SF-36;
●
Change from baseline in FACIT-F;
●
Change from baseline in RA-WIS.
5.3.4
Safety Variables
Safety evaluations include AE monitoring, physical examinations, vital sign 
measurements, ECG, and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.
5.3.5
Pharmacokinetic Variables
Plasma upadacitinib concentrations will be obtained at the times indicated in Table 3.  A 
non-linear mixed-effects modeling approach will be used to estimate the population 
central values and the empirical Bayesian estimates of the individual values of 
upadacitinib oral clearance (CL/F) and volume of distribution (V/F).  Additional 
parameters may be estimated if useful in the interpretation of the data.


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5.3.6
In Vivo Pharmacodynamic Biomarker Samples and 
Exploratory Research Variables and Validation Studies
5.3.6.1
In Vivo Pharmacodynamic Biomarker Samples
Blood samples will be collected to assess the effects of upadacitinib inhibition on 
lymphocyte subsets including but not limited to:  T (CD4+ and CD8+) cells, B (CD19+) 
cells, NK cells, and NKT cells.
In Vivo Pharmacodynamic biomarker research samples will not be collected for subjects 
in mainland China.
5.3.6.2
Exploratory Research Variables and Validation Studies
Where not prohibited by local regulations, optional samples may be collected to conduct 
exploratory investigations into known and novel biomarkers.  The types of biomarkers to 
be analyzed may include, but are not limited to nucleic acids, proteins, lipids, or 
metabolites.
Optional samples for Exploratory Research and Validation Studies will not be collected 
for subjects in mainland China.
Biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  Theses assessments may be 
explored in the context of RA or related conditions and/or upadacitinib or drugs of similar 
classes.  The results from these analyses are exploratory in nature and may not be 
included with the clinical study report (CSR).
The samples may also be used to develop new therapies, research methods or 
technologies.  In addition, samples from this study may be stored for future use.  Samples 
may then be used to validate putative biomarker signatures obtained from a prospective 
study, leading to the development of diagnostic tests.


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects can request to be discontinued from participation 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 for any reason, including an 
AE, safety concerns, lack of efficacy, or failure to comply with the protocol.  See 
Section 6.1.7 for toxicity management criteria.
Subjects will be withdrawn from the study immediately if any of the following occur:
●
Clinically significant abnormal laboratory results or AEs, which rule out 
continuation of the study drug, as determined by the Investigator or the 
AbbVie Therapeutic Area Medical Director.
●
Serious infections (e.g., sepsis) which cannot be adequately controlled within 
2 weeks by anti-infective treatment or would put the subject at risk for 
continued participation in the trial as determined by the Investigator.
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion or exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie Therapeutic Area Medical Director.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk, as determined by the AbbVie 
Therapeutic Area Medical Director.
●
Subject is non-compliant with TB prophylaxis (if applicable) or develops 
active TB at any time during the study.
●
The subject becomes pregnant while on study drug.
●
Malignancy, except for localized NMSC or carcinoma in situ of the cervix.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial as determined by the 
Investigator.


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●
Subject develops a gastrointestinal perforation.
●
Starting at Week 24, at least 20% improvement in BOTH TJC and SJC 
compared to baseline is required to remain in the study.  Anyone who does not 
fulfill this criterion at 2 consecutive visits (starting at Week 24) must be 
discontinued from the study.
The Investigator should contact the AbbVie TA MD if a subject experiences a study drug 
interruption > 7 consecutive days during Weeks 1 through 24 or > 30 consecutive days 
after Week 24 (other than for reasons listed in Section 6.1.7) to discuss the management 
of the subject and possible discontinuation from participation in the study.
If a subject prematurely discontinues study participation, the procedures outlined for the 
Premature Discontinuation visit (PD visit) should be completed as soon as possible, 
preferably within 2 weeks.  In addition, if subject is willing, a 30-day follow-up 
visit/phone call after the last dose of study drug may be completed to ensure all treatment 
emergent AEs/SAEs have been resolved.  Subjects who discontinue the study prematurely 
after randomization will not be replaced.
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study participation.  The information will be 
recorded on the appropriate eCRF page.  However, these procedures should not interfere 
with the initiation of any new treatments or therapeutic modalities that the Investigator 
feels are necessary to treat the subject's condition.  Following discontinuation of study 
drug, the subject will be treated in accordance with the Investigator's best clinical 
judgment.
Lost to Follow-Up
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, two phone calls must 
be made and one certified letter must be sent and documented in the subject's source 
documentation.


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5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the Investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Study drug will be taken orally once daily, beginning on Day 1 (Baseline), and should be 
taken at approximately the same time each day.  The study drug can be taken with or 
without food.  Subjects will continue their weekly stable background therapy of 
csDMARD.  AbbVie will not supply csDMARD(s) (nor folic acid or equivalent, such as 
folinic acid, for subjects who are on MTX).
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 7.
Table 7.
Identity of Investigational Product
Investigational Product
Mode of Administration
Formulation
Strength
Manufacturer
Upadacitinib (ABT-494)
Oral
Tablet
15 mg
AbbVie
Upadacitinib (ABT-494) 
matching placebo
Oral
Tablet
NA
AbbVie


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5.5.2.1
Packaging and Labeling
Upadacitinib (ABT-494) and matching placebo will be packaged in bottles with quantities 
sufficient to accommodate study design.  Each kit label will contain a unique kit number.  
This kit number is assigned to a subject via IRT and encodes the appropriate study drug to 
be dispensed at the subject's corresponding study visit.  Each kit will be labeled as 
required per country requirements.  Labels must remain affixed to the kits.  All blank 
spaces on the label will be completed by the site staff prior to dispensing to the subjects.
5.5.2.2
Storage and Disposition of Study Drugs
Upadacitinib (ABT-494) must be stored at controlled room temperature (15° to 25°C/59° 
to 77°F).  The investigational products are for investigational use only and are to be used 
only within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or destroyed on site as appropriate.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be randomized using IRT.  Before the study is initiated, IRT directions 
will be provided to each site.
All subjects will be assigned a unique identification number by the IRT at the Screening 
Visit.  For subjects that re-screen, the Screening number assigned by the IRT at the initial 
Screening visit should be used; a new Screening number should not be requested.
Subjects will be eligible for randomization if they continue to meet all of the selection 
criteria (Section 5.2) at Baseline and are willing to continue in the study.  
Subjects will be randomized in a 1:1 ratio using interactive response technology (IRT) to 
receive double-blind study drug in one of the following treatment groups. As indicated 
below, it is expected that approximately 222 subjects will enter the study from China and 
100 subjects from other countries including Brazil and South Korea:


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●
Group 1:  Upadacitinib 15 mg QD (N = 161; 111 from China) (Period 1) → 
Upadacitinib 15 mg QD (Period 2)
●
Group 2:  Placebo (N = 161; 111 from China) (Period 1) → Upadacitinib 
15 mg QD (Period 2)
Randomization will be stratified by country and the Chinese population will be up to 80% 
of the total study population.
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.
IRT will provide the appropriate study drug kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Section 5.3.1.1.  
Returned study drug should not be re-dispensed to any subject.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.5.1.
On dosing days that occur on study visit days, subjects should follow the regular dosing 
schedule (refer to Section 5.3.2.1 regarding Week 1 and Week 2 visits).
Each subject's dosing schedule should be closely monitored by the site at each study visit 
by careful review of the subject's dosing diary.  This will ensure that all subjects enrolled 
into the study maintain their original dosing schedule beginning with the first dose of 
study drug (Baseline/Day 1).
If a subject should forget to take their upadacitinib (or matching placebo) dose at their 
regularly scheduled dosing time, they should take the forgotten dose as soon as they 
remember the dose was missed as long as it is at least 10 hours before their next scheduled 
dose.  If a subject only remembers the missed dose within 10 hours before next scheduled 
dose, the subject should skip the missed dose and take the next dose at the scheduled time.  


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If the subject experiences a study drug interruption > 7 consecutive days during Weeks 1 
through 24 or > 30 consecutive days after Week 24, they should notify their study site 
physician, and the subject should be discontinued from the study.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
Period 1 will be double blinded.  All AbbVie personnel with direct oversight of the 
conduct and management of the trial (with the exception of AbbVie Drug Supply 
Management Team), the Investigator, study site personnel, and the subject will remain 
blinded to each subject's treatment during this period.
In order to maintain the blind, the upadacitinib tablets and placebo tablets provided for the 
study will be identical in appearance.  The IRT will provide access to unblinded subject 
treatment information in the case of 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 Therapeutic Area Medical Director 
prior to breaking the blind.  However, if an urgent therapeutic intervention is necessary 
which warrants breaking the blind prior to contacting the AbbVie Therapeutic Area 
Medical Director, the Investigator can directly access the IRT system 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 EndPoint technical support via 
either phone (preferred) or email (support@endpointclinical.com).  For country-specific 
phone numbers, please see the following website:  http://www.endpointclinical.com/help-
desk/.  In the event that the blind is broken before notification to the AbbVie Therapeutic 
Area Medical Director, AbbVie requests that the AbbVie Therapeutic Area Medical 
Director 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 the appropriate eCRF.


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The primary analysis will be conducted after all subjects have completed Period 1 
(Week 12) or have prematurely discontinued prior to Week 12.  Study sites and subjects 
will remain blinded to the treatment assignment in Period 1 for the duration of the study.  
5.5.5.2
Blinding of Data for Data Monitoring Committee
An external Data Monitoring Committee (DMC) comprised 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.
A separate DMC charter will be prepared outside of the protocol and will describe the 
roles and responsibilities of the DMC members, frequency of data reviews, and relevant 
safety data to be assessed.
Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.
5.5.6
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subject dosing will be recorded on a subject dosing diary.  Subjects will be instructed to 
return all drug containers (even if empty) to the study site personnel at each clinic visit.  
The study site personnel will document compliance in the study source documents.
5.5.7
Drug Accountability
The Investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt or similar document and by registering the arrival of drug through the 


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IRT.  The original Proof of Receipt Note and the IRT confirmation sheet will be kept in 
the site files as a record of what was received.
In addition, an IRT will be used to document investigational product accountability 
including but not limited to date received, the lot number, kit number(s), date dispensed, 
subject number, and the identification of the person dispensing the drug.
All empty/used study drug packaging will be inventoried by the site.  Empty/used study 
drug packaging should be returned by the subject at each visit for accountability by the 
site and compliance purposes and new packaging issued as necessary.  Site staff will 
complete study drug accountability via IRT, source documents, subject dosing diaries, and 
by visually inspecting the packaging whenever possible.  
After drug accountability has been completed by the site, empty used packaging may be 
discarded with any subject identifiers removed or returned to AbbVie-designated 
destruction depot. 
Unused study drug and used packaging with remaining study drug will be destroyed on 
site according to local procedures or regulations, or returned to the AbbVie-designated 
destruction depot (for those sites that do not meet AbbVie's requirements for on-site 
destruction). 
For sites performing on-site drug destruction or using a third party vendor for drug 
destruction, a copy of the destruction methodology and date of destruction/date prepared 
for destruction should be maintained at the site's facility.  Monitors will reconcile the site's 
processes, source documents, subject's dosing diaries, IRT or site accountability records, 
and destruction records to assure site compliance.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This study includes two periods.  


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Period 1 is a 12-week, randomized, double-blind, placebo-controlled period to compare 
safety and efficacy of upadacitinib versus placebo in subjects with moderately to severely
active RA who are on a stable dose of csDMARDs and have an inadequate response to 
csDMARDs.  Period 1 is designed to test superiority of upadacitinib versus placebo for 
achieving the primary endpoint (ACR20) at Week 12, and other secondary efficacy 
parameters, all on a stable background csDMARD therapy.  
The purpose of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of 
upadacitinib 15 mg QD in an open-label fashion in subjects with RA who have completed 
Period 1.  Subjects who are assigned to upadacitinib in Period 1 will continue to receive 
upadacitinib 15 mg QD per original randomization assignment in an open-label manner.  
Subjects who are assigned to placebo in Period 1 will be switched to receive upadacitinib 
15 mg in an open-label fashion.  
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All 
efficacy measurements in this study are standard for assessing disease activity in subjects 
with RA.  All clinical and laboratory procedures in this study are standard and generally 
accepted.
5.6.3
Suitability of Subject Population
The intended study population is moderately to severely active RA patients who have had 
an inadequate response to prior csDMARD treatment.  Key entry criteria are to enroll 
adult female and male subjects who are at least 18 years of age with a diagnosis of RA for 
≥ 3 months who also fulfill the 2010 ACR/EULAR classification criteria for RA.  Eligible 
study subjects must have ≥6 swollen joints (based on 66 joint counts) and ≥ 6 tender 
joints (based on 68 joint counts) at Screening and Baseline Visits, and hsCRP ≥ upper 
limit of normal (central lab) at Screening.  Subjects must have been on a stable dose of 
csDMARD therapy (restricted to MTX, chloroquine, hydroxychloroquine, sulfasalazine, 
or leflunomide) for ≥ 4 weeks prior to the first dose of study drug.  Subjects with 


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inadequate response to hydroxychloroquine and/or chloroquine can only be included if 
they also failed (lack of efficacy) MTX, sulfasalazine, or leflunomide.
5.6.4
Selection of Doses in the Study
This Phase 3 study will evaluate a single dose of upadacitinib 15 mg using the once-daily 
tablet formulation based on the following:
The dose selection in this study is based on extrapolation of pre-clinical efficacy models 
and analyses of PK, pharmacodynamic, safety, and efficacy data from the Phase 1 studies 
in healthy volunteers (single and multiple ascending dose Studies M13-401 and M13-845, 
respectively) and Phase 2 studies in RA subjects (Studies M13-537 and M13-550).  The 
doses selected for Study M15-557, ABT-494 15 mg QD, dosed up to 15 months, are 
expected to be efficacious with an acceptable safety profile.
Doses of 15 mg QD using the once-daily formulation provide equivalent daily AUC and 
comparable Cmax and Cmin to 6 mg BID and 12 mg BID, respectively, of the immediate-
release formulation tested in Phase 2 studies in subjects with RA.  In Phase 2 studies, the 
6 mg BID dose was shown to achieve the near maximum efficacy and the 12 mg BID 
dose was clearly shown to achieve the plateau of efficacy.
Results from the first Phase 3 clinical trial (Study M13-549) evaluating upadacitinib in 
subjects with moderate to severe RA with inadequate response to csDMARD treatment 
(same patient population as Study M15-557) show that, after 12 weeks of treatment, both 
doses of upadacitinib (15 mg and 30 mg) met the study's primary endpoints of ACR20 
and Low Disease Activity (LDA) as well as key secondary endpoints.  A higher dose of 
upadacitinib of 30 mg QD however did not provide significant incremental efficacy 
benefit in a csDMARD-IR RA population compared to 15 mg QD.  The safety profile 
from this trial was consistent with that observed in the upadacitinib Phase 2 clinical trials 
in RA, and no new safety signals were detected.  Results therefore indicate that 
upadacitinib 15 mg QD provides the optimal balance of efficacy and safety in RA.  


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The dose selected for Study M15-557, upadacitinib 15 mg QD, dosed up to 15 months, is 
therefore expected to be efficacious with an acceptable safety profile.
6.0
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 after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For AEs, please refer to Section 6.1.  For product 
complaints, please refer to Section 6.2.
6.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of AEs on 
a routine basis throughout the study.  The Investigator will assess and record any AE in 
detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drug, and 
any action(s) taken.  For SAEs considered as having "no reasonable possibility" of being 
associated with study drug, the Investigator will provide other cause(s) of the event.  For 
AEs to be considered intermittent, the events must be of similar nature and severity.  AEs, 
whether in response to a query, observed by site personnel, or reported spontaneously by 
the subject will be recorded.
All AEs will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 


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causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an AE.  Worsening in 
severity of a reported AE should be reported as a new AE.  Laboratory abnormalities and 
changes in vital signs are considered to be AEs only if they result in discontinuation from 
the study, necessitate therapeutic medical intervention, and/or if the investigator considers 
them to be AEs.
An elective surgery/procedure scheduled to occur during the study will not be considered 
an AE if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre-planned prior to study entry.  However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure 
is being done will be considered an AE.
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as an SAE 
within 24 hours of the site being made aware of the SAE.
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.


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Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for 
any length of time or prolongs the subject's hospital stay.  
This does not include an emergency room visit or 
admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly 
that results in fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences 
of relatively minor medical significance such as 
headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject 
and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of 
subject, life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any 
elective or spontaneous abortion or stillbirth is considered 
an important medical event.  Examples of such events 
include allergic bronchospasm requiring 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
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
6.1.1.3
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study (see detailed 
toxicity management in Section 6.1.7):
●
Serious infections;


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●
Opportunistic infections;
●
Herpes zoster;
●
Tuberculosis;
●
Malignancy (all types);
●
Gastrointestinal perforations;
●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE]);
●
Lipid profile changes;
●
Anemia;
●
Neutropenia;
●
Lymphopenia;
●
Increased serum creatinine and renal dysfunction;
●
Hepatic events and increased hepatic transaminases;
●
Elevated creatine phosphokinase (CPK).
●
Embolic and thrombotic events (non-cardiac, non-CNS).
6.1.2
Adverse Event Severity
The investigator will classify AEs according to the Rheumatology Common Toxicity 
Criteria v.2.0 (Appendix N).22
6.1.3
Relationship to Study Drug
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.


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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 relationship 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, an Other cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All AEs reported from the time of study drug administration until 30 days following 
discontinuation of study drug administration have elapsed 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 signed the study-specific 
informed consent.
Adverse event information will be collected as shown in Figure 3.


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Figure 3.
Adverse Event Collection
Additionally, in order to assist the adjudication process, additional information on any 
potential MACE will be collected, if applicable.
In the case of any of the following reported events, an appropriate supplemental MACE 
eCRF should be completed:
●
Cardiac events;
●
Myocardial infarction or unstable angina;
●
Heart failure;
●
Cerebral vascular accident and transient ischemic attack;
●
Cardiovascular procedures (SAE Supplemental Procedure eCRF).
In the case of any of the following AEs, the corresponding Supplemental AE eCRF 
should be completed:
●
Hepatic;
●
Renal;
●
Herpes Zoster Infection;
●
CPK increases considered by the investigator to be an AE;
●
Embolic and thrombotic events (non-cardiac, non-CNS)
SAEs and
Protocol-Related 
Nonserious AEs
Consent
Signed
Study Drug 
Start
Study Drug 
Stopped
30 Days After 
Study Drug 
Stopped
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported


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6.1.5
Serious Adverse Event Reporting
In the event of an SAE, whether associated with study drug or not, the Investigator will 
notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the 
SAE by entering the SAE data into the electronic data capture (EDC) system.  SAEs that 
occur prior to the site having access to the RAVE® system, or if RAVE is not operable, 
should be documented on the SAE Non-CRF forms and emailed (preferred route) or faxed 
to Clinical Pharmacovigilance within 24 hours of the site being made aware of the SAE.
Email: 
FAX to
For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
1 North Waukegan Road
North Chicago, Illinois  60064
Office:
Email:




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Pregnancy in a study subject is not considered an AE.  The medical outcome for either 
mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, stillbirth, or congenital anomaly is considered a serious adverse event and must 
be reported to AbbVie within 24 hours of the site becoming aware of the event.
In the event of pregnancy occurring in the partner of an enrolled subject, written informed 
consent for release of medical information from the partner must be obtained prior to the 
collection of any pregnancy-specific information and the pregnancy will be followed to 
outcome.
6.1.7
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), interruption of study drug dosing with 
appropriate clinical management if applicable, and discontinuation of the subjects from 
the study.  The management of specific AEs and laboratory parameters is described 
below.
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection or an opportunistic infection.  A 
subject who develops a new infection during treatment with study drug should undergo 
prompt diagnostic testing appropriate for an immunocompromised subject.  As 
appropriate, antimicrobial therapy should be initiated, and the subject should be closely 
monitored.  Re-challenge with study drug may occur once the infection has been 
successfully treated.  Subjects who develop active TB must be discontinued from the 
study.
Serious Gastrointestinal Perforations:  Subjects presenting with the onset of signs or 
symptoms of a gastrointestinal perforation should be evaluated promptly for early 


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diagnosis and treatment of gastrointestinal perforation.  If the diagnosis of gastrointestinal 
perforation is confirmed, the subject must be discontinued.
Cardiovascular Events (MACE):  Subjects presenting with potential cardiovascular 
events should be carefully monitored.  These events will be reviewed and adjudicated by 
an independent Cardiovascular Adjudication Committee in a blinded manner.
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in situ 
of the cervix must be discontinued.  Information including histopathological results 
should be queried for the confirmation of the diagnosis.
ECG Abnormality:  Subjects must be discontinued for an ECG change considered 
clinically significant and with reasonable possibility of relationship to study drug OR a 
confirmed absolute QTcF value > 500 msec.
Management of Select Laboratory Abnormalities:  For any given laboratory 
abnormality, the Investigator should assess the subject and apply the standard of care for 
medical evaluation and treatment following any local guidelines.  Specific toxicity 
management guidelines for abnormal laboratory values are described in Table 8 and may 
require an appropriate supplemental eCRF to be completed.  All abnormal laboratory tests 
that are considered clinically significant by the Investigator will be followed to a 
satisfactory resolution.  If a repeat test is required per Table 8, the repeat testing must 
occur as soon as possible.


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Table 8.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values
Laboratory Parameter
Toxicity Management Guideline
Hemoglobin
!
If hemoglobin < 8 g/dL, interrupt study drug dosing and confirm by repeat testing 
with new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample.
!
If confirmed, continue to withhold study drug until hemoglobin value returns to 
normal reference range or its baseline value.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative etiology is 
known, the subject may remain on study drug at the investigator's discretion.
Absolute neutrophil 
count (ANC)
!
If confirmed < 1000 cells/μL by repeat testing with new sample, interrupt study 
drug dosing until ANC value returns to normal reference range or its baseline 
value.
!
Discontinue study drug if confirmed < 500 cells/μL by repeat testing with new 
sample.
Absolute lymphocyte 
counts (ALC)
!
If confirmed < 500 cells/μL by repeat testing with new sample, interrupt study 
drug dosing until ALC returns to normal reference range or its baseline value.
Total white blood cell 
count
!
If confirmed < 2000 cells/μL by repeat testing with new sample, interrupt study 
drug dosing until white blood cell count returns to normal reference range or its 
baseline value.
Platelet count
!
If confirmed < 50,000 cells/μL by repeat testing with new sample, interrupt study 
drug dosing until platelet count returns to normal reference range or its baseline 
value.
AST or ALT
!
Discontinue study drug if confirmed ALT or AST > 3 × ULN by repeat testing 
with new sample and either a total bilirubin > 2 × ULN or an international 
normalized ratio (INR) > 1.5.
o
INR will only need to be measured in subjects with ALT or AST > 3 × ULN 
by the central lab and confirmation is not needed for consideration in toxicity 
management criteria.
!
Discontinue study drug if confirmed ALT or AST > 3 × ULN by repeat testing 
with new sample along with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
!
Discontinue study drug if confirmed ALT or AST > 8 × ULN by repeat testing 
with new sample.
!
Discontinue study drug if confirmed ALT or AST > 5 × ULN by repeat testing 
with new sample for more than 2 weeks.


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Table 8.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory Parameter
Toxicity Management Guideline
AST or ALT (continued)
!
For subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV 
DNA at screening who manifest an ALT> 5 × ULN OR ALT/AST > 3 × ULN and 
either a total bilirubin > 2 × ULN or INR>1.5 OR ALT/AST > 3 × ULN along with 
clinical signs of possible hepatitis, HBV DNA by PCR testing should be performed 
within 1 week.  A positive result for HBV DNA PCR testing in these subjects will 
require immediate interruption of study drug and a hepatologist consultation should 
occur within 1 week for recommendation regarding subsequent treatment.
For any confirmed ALT or AST elevations > 3 ULN, complete supplemental hepatic 
eCRF.
Serum Creatinine
!
If serum creatinine is > 1.5 × 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 and ≤ ULN.
!
If confirmed serum creatinine ≥ 2 mg/dL, interrupt study drug and re-start study 
drug once serum creatinine returns to normal reference range or its baseline value. 
For the above serum creatinine elevation scenarios, complete supplemental renal eCRF.
Creatine Phosphokinase
!
For confirmed CPK value ≥ 4 × ULN, and there are no symptoms suggestive of 
myositis or rhabdomyolysis, the subjects may continue study drug at the 
investigator's discretion.
!
If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact the AbbVie TA MD.
For the above CPK elevation scenarios, complete supplemental CPK eCRF.
For allowed study drug interruption, the following rules apply:
Period 1
●
Allow study drug interruption up to 7 consecutive days for AEs and 
emergency surgery.  Elective surgery will not be allowed during this 12 week 
period.
●
If the subject must undergo emergency surgery, the study drug should be 
interrupted at the time of the surgery.  After emergency 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.


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Period 2
●
Allow study drug interruption up to 7 consecutive days for AEs and 
emergency surgery during Week 16 to Week 24 in Period 2, and after Week 24 
until Week 64/PD, up to 30 consecutive days of study drug interruption is 
allowed.
●
If the subject undergoes elective surgery, the study drug should be interrupted 
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.
●
If the subject must undergo emergency surgery, the study drug should be 
interrupted at the time of 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.
The Investigator should contact the AbbVie TA MD if a subject experiences a study drug 
interruption > 7 consecutive days during Weeks 1 through 24 or > 30 consecutive days 
after Week 24 to discuss the management of the subject and possible discontinuation from 
participation in the study.
6.1.8
Data Monitoring Committee
An external DMC will review unblinded safety data.  See Section 5.5.5.2 for details.
6.1.9
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.


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6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or 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 (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  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 may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
Investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.


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7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The Principal Investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the Principal Investigator is responsible for notifying 
IEC/IRB regulatory authorities (as applicable), and the following AbbVie Clinical 
Contacts:
Primary Contact:
AbbVie Srl 
Viale dell'Arte, 25
00144 Roma
ITALY
Office:
Fax:
Email:
Alternate Contact:
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
Examples of protocol deviations include the following:
●
Subject entered into the study even though she/he did not satisfy entry criteria;
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn;
●
Subject who received wrong treatment or incorrect dose;
●
Subject who received excluded or prohibited concomitant treatment.


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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The primary analysis will be conducted after all subjects have completed Period 1 
(Week 12).  
Completed and specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 
database lock for the analysis at the end of Period 1.  The statistical analyses will be 
performed using SAS (SAS Institute Inc., Cary, NC, USA).
8.1.1
Analysis Populations
8.1.1.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) includes all randomized subjects who received at least 
one dose of study drug.  The FAS will be used for all efficacy and baseline analyses.
8.1.1.2
Per Protocol Analysis Set
The Per-Protocol Analysis Set represents a subset of the FAS and consists of all FAS 
subjects who did not meet any major protocol violations during the study.  Definitions of 
major protocol violations will be detailed in the SAP.  Additional analysis may be 
conducted on the Per Protocol analysis set, in order to evaluate the impact of major 
protocol violations.
8.1.1.3
Safety Analysis Set
The Safety Analysis Set consists of all subjects who received at least one dose of study 
drug.  For the Safety Analysis Set, subjects are assigned to a treatment group based on the 
treatment actually received, regardless of the treatment randomized.


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8.1.2
Subject Accountability, Disposition and Study Drug 
Exposure
8.1.2.1
Subject Accountability
The following will be summarized by site and by treatment group as well as overall, 
separately for Period 1 and Period 2:  number of subjects randomized, the number of 
subjects who received at least one dose of study drug, the number of subjects who 
completed, and the number of subjects who prematurely discontinued.
8.1.2.2
Subject Disposition
Separately for Period 1 and Period 2, the number and percentage of subjects who are 
randomized, received at least one dose of study drug, prematurely discontinued and 
completed will be summarized by treatment group and overall.  Reasons for premature 
discontinuation will be summarized separately for all randomized subjects by treatment 
group and overall, with frequencies and percentages by reason for discontinuation.
8.1.2.3
Study Drug Exposure
Exposure to study drug will be summarized for the Safety Analysis Set for Period 1 alone 
as well as for Period 1 and Period 2 combined.  The exposure to study drug (days) will be 
summarized with the mean, standard deviation, median, and range for each treatment 
group.  The exposure to study drug is defined as the difference between the dates of the 
first and last doses of the study drug plus 1 day.  
Study drug compliance will be summarized for each treatment group.  The compliance is 
defined as the number of tablets taken (i.e., the difference between the number of tablets 
dispensed and the number of tablets returned) during the subject's participation divided by 
the number of tablets a subject is supposed to take each day times the length of time that 
the subject was in the Treatment Phase.


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8.1.3
Analysis of Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group and 
overall for the FAS.  For the purpose of this analysis, baseline data for each subject will 
be the data collected immediately prior to the first dose of study drug in Period 1.
Summary statistics for continuous variables will include the number of observations, 
mean, standard deviation, median, and range.  For discrete variables, frequencies and 
percentages for each category will be summarized.
Medical history will be presented by counts and percentages of subjects, broken down by 
Body System and Diagnosis.
Prior therapy and medication will be summarized by treatment group.  Prior therapy and 
medication will include all therapies and medications with a start date prior to the date of 
first dose of study drug.
Concomitant medications will also be summarized with frequencies and percentages for 
each treatment group.  All medications administered during study drug exposure will be 
included.
8.1.4
Efficacy Analysis
All efficacy analyses will be carried out using the FAS population, which includes all 
randomized subjects who receive at least one dose of study drug.
8.1.4.1
Efficacy Analysis for Period 1
8.1.4.1.1
Primary Efficacy Variables
The primary endpoint in Period 1 (at Week 12) is the proportion of subjects achieving 
ACR20 response at Week 12.
Analysis of the primary endpoint will be conducted on the FAS based on treatment as 
randomized.  Comparison of the primary endpoint will be made between the upadacitinib 


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group and the placebo group using the Cochran-Mantel-Haenszel test adjusting for main 
stratification factors.  For the primary analysis, Non-Responder Imputation (NRI) will be 
used.  
The analysis will be repeated using Observed Cases (OC).  Supportive analysis will also 
be conducted on the Per Protocol Analysis Set.
The primary efficacy analyses will also be performed in demographic subgroups including 
age, gender, weight, body mass index, race, and country to assess the consistency of the 
treatment effect.  Additional subgroup analyses based on baseline disease characteristics 
and stratification factors will also be conducted.
8.1.4.1.2
Key Secondary Efficacy Variables
Key secondary endpoints are listed in Section 5.3.3.1.2. 
For binary endpoints, frequencies and percentages will be reported for each treatment 
group.  Similar analyses as for the primary endpoint will be conducted.
For continuous endpoints, the mean, standard deviation, median, and range will be
reported for each treatment group.  Comparison for the upadacitinib treatment group and 
the placebo group will be carried out using the analysis of covariance model with 
treatment group as the fixed factor, and the corresponding baseline value and the main 
stratification factors as the covariates.
See Section 8.1.4.1.5 for imputation methods.
8.1.4.1.3
Other Efficacy Variables 
Additional efficacy variables are listed in Section 5.3.3.1.3 and will be summarized for all 
visits.  For binary endpoints, frequencies and percentages will be reported for each 
treatment group. For continuous endpoints, the change from baseline mean, standard 
deviation, median, and range will be reported for each treatment group.


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8.1.4.1.4
Multiplicity Control for the Primary and Ranked Key 
Secondary Endpoints
In order to preserve Type I error, a step-down approach will be used to test the primary 
and ranked key secondary endpoints where statistical significance can be claimed for a 
lower ranked endpoint only if the previous endpoints in the sequence meet the 
requirements of significance.
8.1.4.1.5
Imputation Methods
The following methods will be used for missing data imputation:
Observed Cases (OC):  The OC analysis will not impute values for missing evaluations, 
and thus a subject who does not have an evaluation on a scheduled visit will be excluded 
from the OC analysis for that visit.
Multiple Imputation (MI):  The MI analysis imputes missing data multiple times under 
appropriate random variation and thus generates multiple imputed "pseudo-complete" 
datasets.  Results will be aggregated across the multiple imputed datasets, overcoming 
drawbacks of the single imputation methods.
Non-Responder Imputation (NRI):  NRI applies to binary endpoints only.  In NRI 
analysis, subjects who prematurely discontinue study drug will be considered non 
responders after discontinuation.
The NRI approach will serve as the primary analysis approach for key binary endpoints.  
The MI approach will serve as the primary analysis approach for key continuous 
endpoints.  Sensitivity analyses based on OC will also be conducted for key endpoints.
8.1.4.2
Long-Term Efficacy Analysis for Period 1 and Period 2 
Combined
The efficacy endpoints of long-term efficacy analysis are listed in Section 5.3.3.2 and will 
be summarized for all visits.


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Long-term efficacy by time point will be summarized using descriptive statistics.  For 
binary endpoints, frequencies and percentages will be summarized.  For continuous 
endpoints, the mean and standard deviation will be reported.
8.1.5
Safety Analyses
8.1.5.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set.  Analyses will be 
conducted for Period 1 alone, as well as for Period 1 and Period 2 combined.
Safety analyses are based on treatments actually received.  Safety will be assessed by 
AEs, physical examination, laboratory assessments, ECG, and vital signs.  Frequency 
tables and lists of subjects with treatment-emergent AEs by preferred term as in the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary, by system organ 
class, by severity, and by relationship to the study drug as assessed by the Investigator 
will be provided.  The changes from baseline in vital signs, physical examination results, 
and clinical laboratory values will be analyzed.  Shift of laboratory values from baseline 
to defined time points will be tabulated.
Missing safety data will not be imputed.
8.1.5.2
Analysis of Adverse Events
Unless otherwise specified, the following conventions apply for both the Period 1 safety 
analysis and the combined safety analysis of Period 1 and Period 2.
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE)
AEs will be coded using MedDRA.  A TEAE is defined as AE that began or worsened in 
severity after initiation of study drug.
AEs starting more than 30 days following the last dose of study drug will not be included 
in summaries of TEAEs.  For subjects who continued into Period 2, AEs that are reported 
in Period 2 will be captured in the combined safety analysis of Period 1 and Period 2.


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As a general safety summary, the number and percentage of subjects experiencing TEAEs 
will be summarized for each treatment group for the following AE categories:
●
All AEs;
●
All severe AEs;
●
All reasonably possibly related AEs;
●
All SAEs;
●
Frequent AEs (reported in 2% of subjects or more in any treatment group);
●
Frequent reasonably possibly related AEs (reported in 2% of subjects or more 
in any treatment group);
●
Discontinuations due to AEs;
●
Death.
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
TEAEs will be summarized and presented by system organ classes (SOCs) and preferred 
terms (PTs) using MedDRA.  The SOCs will be presented in alphabetical order, and the 
PTs will be presented in alphabetical order within each SOC.
TEAE will also be summarized by maximum severity and by maximum relationship.
The AEs of special interest (including but not limited to serious infection, opportunistic 
infection, herpes zoster, TB, gastrointestinal perforations, malignancies, adjudicated 
cardiovascular events (e.g., major adverse cardiovascular event [MACE]), lipid profile 
changes, anemia, neutropenia, lymphopenia, increased serum creatinine and renal 
dysfunction, hepatic events and increased hepatic transaminases, elevated CPK and non-
cardiac, non-CNS embolic and thrombotic events) will be summarized.  Event rate (per 
100 patient years) for AEs of special interest will also be summarized for the combined 
safety analysis of Period 1 and Period 2.


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All AEs leading to discontinuation of study drug will be presented in listing format.  A 
listing by treatment group of TEAEs grouped by SOC and MedDRA preferred term with 
subject identification numbers will be generated.
8.1.5.2.2
Serious Adverse Events and Death
All treatment-emergent SAEs and AEs leading to death will also be presented in listing 
format.  In addition, SAEs will be summarized by SOC and MedDRA PT.
8.1.5.3
Analysis of Laboratory, Vital Sign, and ECG Data
Changes from baseline by visit, and changes from baseline to minimum value, maximum 
value, and final values in continuous laboratory data, and vital signs will be summarized 
by treatment group. 
Baseline values are defined as the last non-missing measurements recorded on or before 
the date of the first dose of study drug in Period 1.  
The laboratory data will be categorized as Grade 1, Grade 2, Grade 3 and Grade 4 
according to OMERACT criteria (Rheumatology Common Toxicity Criteria V.2.0).  For 
creatine phosphokinase and serum creatinine, NCI CTC criteria will be used.  The shift 
tables will tabulate the number and percentage of subjects with baseline and post-baseline 
values by grade level.  
Listings will be provided for potentially clinically significant laboratory values and vital 
signs.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Individual upadacitinib plasma concentrations at each study visit will be tabulated and 
summarized with appropriate statistical methods.
Data from this study may be combined with data from other studies for the population PK 
and exposure-response analyses.  Population PK and exposure-response analyses of only 


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data from this study may not be conducted.  The following general methodology will be 
used for the population PK and exposure-response analyses.
Population PK analyses will be performed using the actual sampling time relative to 
dosing.  PK models will be built using a non-linear mixed-effects modeling approach with 
NONMEM software (Version 7, or a higher version).  The structure of the starting PK 
model will be based on the PK analysis of data from previous studies.  The CL/F and V/F 
of upadacitinib will be the PK parameters of major interest in the analyses.  If necessary, 
other parameters, including the parameters describing absorption characteristics, may be 
fixed if useful in the analysis.
The evaluation criteria described below will be used to examine the performance of 
different models.
1.
The objective function of the best model is significantly smaller than the alternative 
model(s).
2.
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept and 
a slope of one) than the alternative model(s).
3.
Visual inspection of model fits, standard errors of model parameters and change in 
inter-subject and intra-subject error.
Once an appropriate base PK model (including inter- and intra-subject error structure) is 
developed, empirical Bayesian estimates of individual model parameters will be 
calculated by the posterior conditional estimation technique using non-linear mixed 
effects modeling.  The relationship between these conditional estimates CL/F and V/F 
values with only potentially physiologically relevant or clinically meaningful covariates 
(such as subject age, sex, body weight, concomitant medications, laboratory markers of 
hepatic of renal function, etc.) will be explored using stepwise forward selection method, 
or another suitable regression/smoothing method at a significance level of 0.05.  After 
identification of all relevant covariates, a stepwise backward elimination of covariates 


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from the full model will be employed to evaluate the significance (at P < 0.005, 
corresponding to a decrease in objective function > 7.88 for one degree of freedom) of 
each covariate in the full model.
Linear or non-linear relationships of primary PK parameters with various covariates will 
be explored.
Relationships between upadacitinib exposure and clinical observations (primary efficacy 
variable) will be explored.  Exposure-response relationships for secondary efficacy 
variables and/or some safety measures of interest may also be explored.  The relationship 
between exposure (e.g., population PK model predicted average concentrations, area 
under the curve, trough concentrations, the individual model-predicted PK profiles, or 
some other appropriate measure of exposure) and drug effect will be explored.  Several 
classes of models (e.g., linear, log-linear, exponential, Emax, sigmoid Emax, etc.) will be 
evaluated to characterize the exposure-response relationship based on observed data.  
Results of the PK and exposure-response analyses may be summarized in a separate report 
prior to regulatory filing of upadacitinib for the treatment of RA, rather than in the CSR.
Additional analyses will be performed if useful and appropriate.
8.1.7
Statistical Analysis of Biomarker Data (except for subjects 
in mainland China)
Summary statistics for the in vivo pharmacodynamic biomarkers (including but not 
limited to NK, NKT, B cells, and T cells) at baseline and post-treatment time points 
(Weeks 8 and 12/PD in Period 1, and Weeks 16, 24, 36, 48 and 64/PD in Period 2), in 
addition to change from baseline at each time will be provided; this will include mean, 
standard deviation, median, quartiles, and range for each group.  The pharmacodynamic 
effect of each biomarker between the placebo and upadacitinib treatment groups will be 
evaluated via a non-linear mixed-effects modeling approach with Change from baseline of 
the biomarker as response variable, Treatment, Time, and Treatment × Time interaction as 
fixed-effects, the corresponding baseline biomarker score as a covariate, and "subjects 
nested within the treatment group" as a random-effect.  Other baseline variables such as 


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age, weight, etc., may be considered as appropriate.  For biomarkers identified to have 
significant overall treatment effect via the non-linear mixed effects modeling analysis, 
dose-response models with the biomarker as a continuous response will be explored.  In 
addition to the above analyses of biomarkers individually, the effect of certain 
combination of biomarkers on the treatment groups may be explored.
If the optional exploratory research variables including an additional panel of prognostic, 
predictive, and pharmacodynamic biomarkers are evaluated, then those data may be 
analyzed as follows.  The association of biomarkers to the efficacy and safety endpoints 
may be explored for each biomarker one at a time, and also for combinations of 
biomarkers via some multivariate predictive modeling algorithms.  Optimal multivariate 
combinations of biomarkers that associate with efficacy endpoints, subject 
response/non-response (with respect to appropriate clinical endpoints), and also with 
safety endpoints may be explored via a variety of statistical predictive modeling 
algorithms.  Also cut-points for individual biomarkers and optimal combinations of 
biomarkers that differentiate the subject response with respect to efficacy/safety endpoints 
may be explored.  The significance of these multivariate combinations of biomarkers may 
be assessed via at least 20 iterations of 5 fold cross-validation.
8.2
Determination of Sample Size
The planned total sample size of 322 for this study provides over 90% power for a 21.7% 
difference in ACR20 response rate (assuming a placebo ACR20 response rate of 36.7%), 
at two-sided significance level of 0.05 and accounting for a 10% dropout rate.  This 
sample size will also provide at least 90% power for most of the key secondary endpoints, 
including change from baseline in DAS28(CRP), ACR50 response rate, LDA and CR 
based on DAS28(CRP), and SF-36 PCS, at two-sided significance level of 0.05 and 
accounting for a 10% dropout rate.


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8.3
Randomization Methods
Subjects will be randomly assigned in a 1:1 ratio to one of the two treatment groups.  As 
indicated below, it is expected that approximately 222 subjects will enter the study from
China and 100 subjects from other countries including Brazil and South Korea:
●
Group 1:  Upadacitinib 15 mg QD (N = 161; 111 from China) (Period 1) → 
Upadacitinib 15 mg QD (Period 2)
●
Group 2:  Placebo (N = 161; 111 from China) (Period 1) → Upadacitinib 
15 mg QD (Period 2)
Randomization will be stratified by country and the Chinese population will be up to 80% 
of the total study population.
See Section 5.5.3 for details.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice requires that the clinical protocol, any protocol amendments, the 
Investigator's Brochure, the informed consent, and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific 
and medical appropriateness of the study before it is conducted.  IEC/IRB approval of the 
protocol, informed consent, and subject information and/or advertising, as relevant, will 
be obtained prior to the authorization of drug shipment to a study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.


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Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies, as required by 
local regulations.  During the conduct of the study, the Investigator should promptly 
provide written reports (e.g., ICH Expedited Reports, and any additional reports required 
by local regulations) to the IEC/IRB of any changes that affect the conduct of the study 
and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (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 clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent will be given to the subject and the original will be placed in the 
subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent.
An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before samples are collected for optional exploratory research, where not prohibited by 


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local regulations.  The nature of the testing should be explained and the subject given an 
opportunity to ask questions.  The informed consent must be signed before the samples 
are collected and any testing is performed.  If the subject does not consent to provide 
samples for the optional exploratory research, it will not impact their participation in the 
study.
The separate informed consent is not required for subjects in mainland China because 
optional samples for exploratory research and validation studies will not be collected.
In the event a subject withdraws consent to participate in the study, stored biomarker 
samples and optional exploratory research samples will continue to be used for research 
and analysis.  In the event that a subject would like to withdraw consent for research using 
these samples, the subject may request that their samples be withdrawn.  Once AbbVie 
receives the request, remaining biomarker samples will be destroyed.  If the subject 
changes his/her consent, and the samples have already been tested, those results will still 
remain as part of the overall research data.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data, and records.  This may include 
joint evaluation, hospital records, clinical and office charts, laboratory data/information, 
subjects' diaries or evaluation checklists, pharmacy dispensing and other records, recorded 
data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
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.


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10.2
Case Report Forms
Case report forms (CRFs) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an EDC system called Rave® provided by the technology vendor Medidata 
Solutions Incorporated, NY, USA.  The EDC system and the study-specific eCRFs will 
comply with Title 21 CFR Part 11.  The documentation related to the validation of the 
EDC system is available through the vendor, Medidata, while the validation of the study 
specific eCRFs will be conducted by AbbVie and will be maintained in the Trial Master 
File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The Investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  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 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 


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Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
Patient and site reported data must be completed for each subject screened/enrolled in this 
study.
●
The following data are being collected with an Electronic Patient-Reported 
Outcome (ePRO) system called Trialmax, provided by the technology vendor 
CRF Health of Plymouth Meeting, PA, USA:
○
Completed by Patient:
●
Patient Global Assessment of Disease Activity VAS
●
Patient's Assessment of Pain VAS
●
HAQ-DI
●
SF-36
●
FACIT-F
●
RA-WIS
●
EQ-5D-5L
○
Completed by Site:
●
Physician Global Assessment of Disease Activity VAS
●
The following data will be completed by the patient on paper and entered into 
the EDC system:
○
Patient's Assessment of Severity and Duration of Morning Stiffness
The ePRO system is in compliance with Title 21 CFR Part 11.  The documentation related 
to the system validation of the ePRO system is available through the vendor, CRF Health, 
while the user acceptance testing of the study-specific PRO design will be conducted and 
maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source and will be maintained and 
managed by CRF Health.


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Internet access to the ePRO data will be provided by CRF Health for the duration of the 
trial.  This access will be available for the duration of the trial to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO 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 ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media.
The ePRO data will be collected by the following method:
Tablet Based
●
The instrument/scale will be collected electronically via a tablet device into 
which the subject will directly enter the required pieces of information.  The 
electronic device will be programmed to allow data entry for only the visits 
specified in the protocol and will not allow for subjects to complete more than 
one of the same assessment at any one visit.  All data entered on the device 
will be immediately stored to the device itself and automatically uploaded to a 
central server administrated by CRF Health.  The Investigator and delegated 
staff will be able to access all uploaded subject entered data via a password 
protected website, up until the generation, receipt and confirmation of the 
study archive.
11.0
Data Quality Assurance
Prior to the initiation of the study, a meeting will be held with AbbVie personnel, the 
investigators and appropriate site personnel.  This meeting will include a detailed 
discussion of the protocol, performance of study procedures, CRF, subject dosing diary, 
and specimen collection methods.  
The AbbVie monitor will monitor each site throughout the study.  Source document 
review will be performed against entries on the CRF and a quality assurance check will be 
performed to ensure that the investigator is complying with the protocol and regulations.


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All data hand entered in the database will be verified at AbbVie.  Any discrepancies will 
be reviewed against the CRF and corrected on-line.  After completion of the entry 
process, computer logic and manual checks will be created by AbbVie to identify items 
such as inconsistent study dates.  Any necessary corrections will be made by the site to the 
eCRF.
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
Routine hematology, serum chemistry and serology, and urinalysis, and other tests such as 
rheumatoid factor, anti-CCP, and HBV/HCV testing, will be conducted using a central 
laboratory (refer to Table 2 and Table 4).  The data from these analyses will be 
electronically transferred from the central laboratory to the study database.
Laboratory tests including, but not limited to, urine pregnancy testing and ESR, will be 
conducted locally by each study site (refer to Table 3 and Table 5).  Sites will provide 
AbbVie with laboratory certifications and normal ranges for each local laboratory used.  
The full name, address, phone number and fax number for each local laboratory will also 
be included.
12.0
Use of Information
Any research that may be done using exploratory research/validation studies samples from 
this study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from exploratory research/validation 
studies may be provided to investigators and used in scientific publications or presented at 
medical conventions.  Optional exploratory research/validation studies information will be 
published or presented only in a way that does not identify any individual subject.


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13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the Investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The Investigator must retain any records related to the study according to local 
requirements.  If the Investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory Investigator from the Investigators who participate in the 
study.  Selection criteria for this Investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug, and study protocol.  
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products Guidance 
on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for Upadacitinib 
(ABT-494).
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
with Upadacitinib (ABT-494) in Subjects from China and Selected 
Countries with Moderately to Severely Active Rheumatoid Arthritis 
Who Have Had an Inadequate Response to Conventional Synthetic 
Disease-Modifying Anti-Rheumatic Drugs (csDMARDs)
Protocol Date:
17 October 2018
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
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Vermeer M, Kuper HH, Bernelot Moens HJ, et al.  Adherence to a treat-to-target 
strategy in early rheumatoid arthritis:  results of the DREAM remission induction 
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Verstappen SM, Jacobs JW, van der Veen MJ, et al.  Intensive treatment with 
methotrexate in early rheumatoid arthritis:  aiming for remission.  Computer 
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Aletaha D, Neogi T, Silman AJ, et al.  2010 rheumatoid arthritis classification 
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Burmester GR, Feist E, Dorner T.  Emerging cells and cytokine targets in 
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Lawendy N, Krishnaswami S, Wang R, et al.  Effect of CP-690,550, an orally 
active janus kinase inhibitor, on renal function in healthy adult volunteers.  J Clin 
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Greenwald MK, Fidelus-Gort R, Levy R, et al.  A randomized dose-ranging, 
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subjects with active rheumatoid arthritis [abstract].  Arthritis Rheum.  
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Dougados M, van der Heijde D, Chen YC, et al.  Baricitinib, an oral janus kinase 
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inadequate response to CDMARD therapy:  results of the phase 3 RA-build study.  
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Genovese MC, Kremer J, Zamani O, et al.  Baricitinib, an oral janus kinase 
(JAK)1/JAK2 inhibitor, in patients with active rheumatoid arthritis (RA) and an 
inadequate response to TNF inhibitors:  results of the phase 3 RA-beacon study.  
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Fleischmann R, Kremer J, Cush J, et al.  Placebo-controlled trial of tofacitinib 
monotherapy in rheumatoid arthritis.  N Engl J Med.  2012;367(6):495-507.
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van Vollenhoven RF, Fleischmann R, Cohen S, et al.  Tofacitinib or adalimumab 
versus placebo in rheumatoid arthritis.  N Engl J Med.  2012;367(6):508-19.
17.
Burmester GR, Blanco R, Charles-Schoeman C, et al.  Tofacitinib (CP-690,550) in 
combination with methotrexate in patients with active rheumatoid arthritis with an 
inadequate response to tumour necrosis factor inhibitors:  a randomized phase 3 
trial.  Lancet.  2013;381(9865):451-60.
18.
Kremer J, Li ZG, Hall S, et al.  Tofacitinib in combination with nonbiologic 
disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis:  
a randomized trial.  Ann Intern Med.  2013;159(4):253-61.


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19.
van der Heijde D, Tanaka Y, Fleischmann R, et al.  Tofacitinib (CP-690,550) in 
patients with rheumatoid arthritis receiving methotrexate:  twelve month data from 
a twenty-four-month phase III randomized radiographic study.  Arthritis Rheum.  
2013;65(3):559-70.
20.
Galapagos.  Press release.  14 April 2015.  Available from:  
http://www.glpg.com/files/1314/2904/2940/PR_Darwin1_April_14_2015_FINAL.
pdf.  Accessed on:  02 September 2015.
21.
Galapagos.  Press release.  27 April 2015.  Available from:  
http://www.glpg.com/files/3514/3016/6234/PR_Darwin2_FINAL.pdf.  Accessed 
on:  02 September 2015.
22.
Woodworth T, Furst DE, Alten R, et al.  Standardizing assessment and reporting of 
adverse effects in rheumatology clinical trials II:  the Rheumatology Common 
Toxicity Criteria v.2.0.  J Rheumatol.  2007;34(6):1401-14.
23.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
24.
AbbVie.com.  AbbVie's Upadacitinib (ABT-494) Meets All Primary and Ranked 
Secondary Endpoints in Phase 3 Study in Rheumatoid Arthritis.  Available from:  
https://news.abbvie.com/news/abbvies-upadacitinib-abt-494-meets-all-primary-
and-ranked-secondary-endpoints-in-phase-3-study-in-rheumatoid-arthritis.htm.  
Accessed on:  16 August 2017.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
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., independent ethics committee [IEC] or
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
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 investigation and all amendments.


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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.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Pharmacovigilance and Patient 
Safety
Statistics
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical Program Development
Bioanalysis


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Appendix C.
Physician's Global Assessment of Disease Activity Example
Visual Analog Scale (VAS)
VAS will be used to assess the physician's global assessment of disease activity and the 
subject's assessment of pain.  The VAS consists of a horizontal 100 mm line anchored at 
either end by opposite adjectives reflecting the spectrum/severity of the parameters 
assessed:
●
Physician's global assessment of disease activity (current status)
The Physician will rate global assessment of subject's current disease activity 
ranging from 0 to 100 (see example below)
Mark the line below to indicate the subject's rheumatoid arthritis disease activity 
(independent of the subject's self-assessment).
0
100
Very Low
Very High






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Appendix E.
Latent TB Risk Assessment Form Example
1.
Have you or an immediate family member or other close contact ever been 
diagnosed or treated for tuberculosis?
2.
Have you lived in or had prolonged travels to countries in the following regions:
●
Africa
●
Eastern Europe
●
Asia
●
Latin America
●
Russia
●
Caribbean Islands
3.
Have you lived or worked in a prison, homeless shelter/refugee camp, immigration 
center, hospital or nursing home?
4.
Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:
●
Chronic Cough
●
Chest pain, or pain with breathing or coughing
●
Blood-Streaked Sputum (coughing up blood)
●
Unexplained Weight Loss
●
Fever
●
Fatigue/Tiredness
●
Night Sweats
●
Shortness of Breath
From:
http://www mayoclinic.org/diseases-conditions/tuberculosis/symptoms-causes/dxc-20188557
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf


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Appendix F.
Patient's Global Assessment of Disease Activity Example
Visual Analog Scale (VAS)
VAS will be used to assess the subject's global assessment of disease activity.  Each VAS 
consists of a horizontal 100 mm line anchored at either end by opposite adjectives 
reflecting the spectrum/severity of the parameters assessed:
●
Subject's global assessment of disease activity (within last 24 hours)
The subject will rate the severity of the RA symptoms and how he/she is doing 
from 0 to 100.  This assessment will be used for the DAS28 (CRP) calculation 
in this study (see example below):
Please place a vertical mark on the line below to indicate how well your rheumatoid 
arthritis has been doing during THE LAST 24 HOURS:
0
100
Very Well
Very Poorly


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Appendix G.
Patient's Assessment of Pain Example
Visual Analog Scale (VAS)
VAS will be used to assess the subject's assessment of pain.  Each VAS consists of a 
horizontal 100 mm line anchored at either end by opposite adjectives reflecting the 
spectrum/severity of the parameters assessed:
How much pain have you had because of your condition within the previous week?
Place a mark on the line below to indicate how severe your pain has been.
NO 
PAIN
WORST 
POSSIBLE 
PAIN


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Appendix H.
Health Assessment Questionnaire (HAQ-DI) Example
HEALTH ASSESSMENT QUESTIONNAIRE
In this section we are interested in learning how your illness affects your ability to 
function in daily life.
Please check the response which best describes your usual abilities OVER THE PAST WEEK:
WITHOUT ANY
DIFFICULTY
WITH SOME
DIFFICULTY
WITH MUCH
DIFFICULTY
UNABLE
TO DO
DRESSING AND GROOMING
Are you able to:
Dress yourself, including tying 
shoelaces and doing buttons?
Shampoo your hair?
ARISING
Are you able to:
Stand up from a straight chair?
Get in and out of bed?
EATING
Are you able to:
Cut your own meat?
Lift a full cup or glass to your 
mouth?
Open a new milk carton?
WALKING
Are you able to:
Walk outdoors on flat ground?
Climb up five steps?
Please check any AIDS OR DEVICES that you usually use for any of these activities:
  Cane
  Devices used for dressing (button hook, zipper pull, long 
handled shoe horn, etc.)
  Walker
  Built up or special utensils
  Crutches
  Special or built up chair
  Wheelchair
  Other (Specify:  __________________)


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Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
  Dressing and Grooming
  Eating
  Arising
  Walking
Please check the response which best describes your usual abilities OVER THE PAST WEEK:
WITHOUT ANY
DIFFICULTY
WITH SOME
DIFFICULTY
WITH MUCH
DIFFICULTY
UNABLE
TO DO
HYGIENE
Are you able to:
Wash and dry your body?
Take a tub bath?
Get on and off the toilet?
REACH
Are you able to:
Reach and get down a 5-pound 
object (such as a bag of sugar) 
from just above your head?
Bend down to pick up clothing 
from the floor?
GRIP
Are you able to:
Open car doors?
Open jars which have been 
previously opened?
Turn faucets on and off?
ACTIVITIES
Are you able to:
Run errands and shop?
Get in and out of a car?
Do chores such as vacuuming 
or yard work?
Please check any AIDS OR DEVICES that you usually use for any of these activities:
  Raised toilet seat
  Bathtub bar
  Bathtub seat
  Long-handled appliances for reach
  Jar opener (for jars previously opened)
  Long-handled appliances in bathroom
  Other (Specify: ___________________)


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Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
  Hygiene
  Gripping and opening things
  Reach
  Errands and chores
HAQ – United States/English
HAQ-DI_AU1.0-eng-USori.doc
© Stanford University


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Appendix I.
Patient's Assessment of Severity and Duration of Morning Stiffness 
Example
Instructions: 
Please clearly mark an 'x' in the box (☒) that best describes your experience with 
morning stiffness on awakening in the past 7 days.
No morning
stiffness
Worst possible morning 
stiffness
▼
▼
0
1
2
3
4
5
6
7
8
9
10
When you experience morning stiffness, how long does it take to get as limber as 
possible:  ___hours ____ minutes


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Appendix J.
EuroQoL-5D-5L Example
Under each heading, please check the ONE box that best describes your health TODAY:
Mobility
I have no problems walking
☐
I have slight problems walking
☐
I have moderate problems walking
☐
I have severe problems walking
☐
I am unable to walk 
☐
Self-Care
I have no problems washing or dressing myself
☐
I have slight problems washing or dressing myself 
☐
I have moderate problems washing or dressing myself
☐
I have severe problems washing or dressing myself
☐
I am unable to wash or dress myself 
☐
Usual Activities (e.g., work, study, housework, family or leisure activities)
I have no problems with doing my usual activities 
☐
I have slight problems with doing my usual activities 
☐
I have moderate problems with doing my usual activities
☐
I have severe problems with doing my usual activities
☐
I am unable to do my usual activities 
☐


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Pain/Discomfort
I have no pain or discomfort 
☐
I have slight pain or discomfort 
☐
I have moderate pain or discomfort
☐
I have severe pain or discomfort
☐
I have extreme pain or discomfort 
☐
Anxiety/Depression
I am not anxious or depressed 
☐
I am slightly anxious or depressed 
☐
I am moderately anxious or depressed
☐
I am severely anxious or depressed
☐
I am extremely anxious or depressed 
☐


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!
We would like to know how good or bad your health is 
TODAY.
!
This scale is numbered from 0 to 100.
!
100 means the best health you can imagine.
0 means the worst health you can imagine.
!
Mark an X on the scale to indicate how your health is 
TODAY.
!
Now, please write the number you marked on the scale in 
the box below. 
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health    
you can imagine
The worst health  
you can imagine


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Appendix K.
Short Form-36 (SF-36™) Health Status Survey Questionnaire 
Example
Your Health and Well-Being
This survey asks for your views about your health.  This information will help keep 
track of how you feel and how well you are able to do your usual activities.  Thank 
you for completing this survey!
For each of the following questions, please mark an ☒in the box that best describes 
your answer.
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor
1
2
3
4
5
2.
Compared to 1 year ago, how would you rate your health in general now?
Much better now 
than one year ago
Somewhat better 
now than one year 
ago
About the same as 
one year ago
Somewhat worse 
now than one year 
ago
Much worse now 
than one year ago
1
2
3
4
5


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3.
The following questions are about activities you might do during a typical day.  
Does your health now limit you in these activities?  If so, how much?
Yes,
limited
a lot
Yes,
limited
a little
No, not
limited
at all
a
Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous 
sports
1
2
3
b
Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or playing golf
1
2
3
c
Lifting or carrying groceries
1
2
3
d
Climbing several flights of stairs
1
2
3
e
Climbing one flight of stairs
1
2
3
f
Bending, kneeling, or stooping
1
2
3
g
Walking more than a mile
1
2
3
h.
Walking several hundred yards
1
2
3
i
Walking one hundred yards
1
2
3
j
Bathing or dressing yourself
1
2
3


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4.
During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of your 
physical health?
All of the 
time
Most of 
the time
Some 
of the 
time
A little 
of the 
time
None of the 
time
a
Cut down on the amount of time you 
spent on work or other activities
1
2
3
4
5
b
Accomplished less than you would like
1
2
3
4
5
c
Were limited in the kind of work or 
other activities
1
2
3
4
5
d
Had difficulty performing the work or 
other activities (for example, it took extra
effort) 
1
2
3
4
5


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5.
During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of any 
emotional problems (such as feeling depressed or anxious)?
All of 
the 
time
Most of 
the 
time
Some 
of the 
time
A little 
of the 
time
None 
of the 
time
a
Cut down on the amount of time you spent 
on work or other activities
1
2
3
4
5
b
Accomplished less than you would like
1
2
3
4
5
c
Did work or other activities less carefully 
than usual
1
2
3
4
5
6.
During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, 
neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
1
2
3
4
5
7.
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very Severe
1
2
3
4
5
6


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8.
During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
1
2
3
4
5
9.
These questions are about how you feel and how things have been with you during 
the past 4 weeks.  For each question, please give the one answer that comes closest 
to the way you have been feeling.  How much of the time during the past 4 weeks:
All of the 
time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
a
Did you feel full of life?
1
2
3
4
5
b
Have you been very nervous?
1
2
3
4
5
c
Have you felt so down in the dumps 
that nothing could cheer you up?
1
2
3
4
5
d
Have you felt calm and peaceful?
1
2
3
4
5
e
Did you have a lot of energy?
1
2
3
4
5
f
Have you felt downhearted and 
depressed?
1
2
3
4
5
g
Did you feel worn out?
1
2
3
4
5
h
Have you been happy?
1
2
3
4
5
i
Did you feel tired?
1
2
3
4
5


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10.
During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting friends, 
relatives, etc.)?
All of the
time
Most of the
time
Some of the
time
A little of the 
time
None of the
time
1
2
3
4
5
11.
How TRUE or FALSE is each of the following statements for you?
Definitely 
true
Mostly 
true
Don't 
know
Mostly 
false
Definitely 
false
a
I seem to get sick a little easier 
than other people
1
2
3
4
5
b
I am as healthy as anybody I know
1
2
3
4
5
c
I expect my health to get worse
1
2
3
4
5
d
My health is excellent
1
2
3
4
5
THANK YOU FOR COMPLETING THESE QUESTIONS
SF-36v2™ Health Survey© 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.
SF-36® is a registered trademark of Medical Outcomes Trust
(SF-36v2 Standard, US Version 2.0)


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Appendix L.
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F) Scale Example
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
Not 
at all
A little 
bit
Some-
what
Quite 
a bit
Very 
much
HI7
I feel fatigued .........................................................
0
1
2
3
4
HI12
I feel weak all over ................................................
0
1
2
3
4
An1
I feel listless ("washed out") ..................................
0
1
2
3
4
An2
I feel tired ...............................................................
0
1
2
3
4
An3
I have trouble starting things because I am tired 
0
1
2
3
4
An4
I have trouble finishing things because I am tired
0
1
2
3
4
An5
I have energy ..........................................................
0
1
2
3
4
An7
I am able to do my usual activities ........................
0
1
2
3
4
An8
I need to sleep during the day ................................
0
1
2
3
4
An12
I am too tired to eat ................................................
0
1
2
3
4
An14
I need help doing my usual activities ....................
0
1
2
3
4
An15
I am frustrated by being too tired to do the things 
I want to .................................................................
0
1
2
3
4
An16
I have to limit my social activity because I am 
tired ........................................................................
0
1
2
3
4
English (Universal)
16 November 2007
Copyright 1987, 1997
Page 1 of 1




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Appendix N.
Rheumatology Common Toxicity Criteria v.2.0 Example
For designation of adverse event terms not shown in the Rheumatology Common Toxicity 
Criteria v.2.0 table, the approach described in Row 1 should be used.


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Rheumatology Common Toxicity Criteria v.2.0
Based on Woodworth TG, et al.  Standardizing assessment of adverse effects in rheumatology clinical trials II.  Status of OMERACT Drug Safety Working Group 
May 2006:  OMERACT 8.  Standardizing Assessment and Reporting of Adverse Effects in Rheumatology Clinical Trials:  Enabling Description of Comparative 
Safety Profiles for Anti-Rheumatic Therapies
1 – Mild
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
No medication or OCT
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve.  (may be 
prescription)
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation, or/and dose reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent.
Multiple meds
Hospitalised > 24 hr
Study drug discontinued
A.  Allergic/Immunologic
A1.  Allergic 
reaction/ 
hypersensitivity 
(includes drug fever)
Transient rash:  drug fever 
< 38°C:  transient, asymptomatic 
bronchospasm
Generalised urticaria responsive to 
meds; or drug fever > 38°C, or 
reversible bronchospasm
Symptomatic bronchospasm 
requiring meds; symptomatic 
urticaria persisting with meds, 
allergy related oedema/angioedema
Anaphylaxis, laryngeal/pharyngeal 
oedema, requiring resuscitation
A2.  Autoimmune 
reaction
Seriologic or other evidence of 
autoimmune reaction, but patient 
asymptomatic:  all organ function 
normal and no treatment is 
required (e.g., vitiligo)
Evidence of autoimmune reaction 
involving a non-essential organ or 
functions, requiring treatment 
other than immunosuppressive 
drugs (e.g., hypothyroidism)
Reversible autoimmune reaction 
involving function of a major organ 
or toxicity requiring short term 
immunosuppressive treatment 
(e.g., transient colitis or anaemia)
Causes major organ dysfunction, or 
progressive, not reversible, or 
requires long term administration 
of high dose immunosuppressive 
therapy
A3.  Rhinitis 
(includes sneezing, 
nasal stuffiness, post 
nasal discharge)
Transient, non-prescription meds 
relieve
Prescription med. required, slow
Corticosteroids or other prescription 
med. with persistent disabling 
symptoms such as impaired exercise 
tolerance
NA
A4.  Serum sickness
Transient, non-prescription meds 
relieve
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Prolonged; symptoms only partially 
relieved by meds; parenteral 
corticosteroids required
Major organ dysfunction, requires 
long-term high-dose 
immunosuppressive therapy


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A.  Allergic/Immunologic (continued)
A5.  Vasculitis
Localised, not requiring 
treatment; or rapid response to 
meds; cutaneous
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Generalised, parenteral 
corticosteroids required or/and short 
duration hospitalisation
Prolonged, hospitalisation, 
ischemic changes, amputation
B.  Cardiac
B1.  Arrhythmia
Transient, asymptomatic
Transient, but symptomatic or 
recurrent, responds to meds
Recurrent/persistent; maintenance 
prescription
Unstable, hospitalisation required, 
parenteral meds
B2.  Cardiac function 
decreased
Asymptomatic decline in resting 
ejection fraction by > 10%, but 
< 20% of baseline value
Asymptomatic decline of resting 
ejection fraction ≥ 20% of baseline 
value
CHF responsive to treatment
Severe or refractory CHF
B3.  Edema
Asymptomatic
(e.g., 1 + feet/calves), self-limited, 
no therapy required
Symptomatic
(e.g., 2 + feet/calves), requires 
therapy
Symptoms limiting function 
(e.g., 3 + feet/calves, 2 + thighs), 
partial relief with treatment 
prolonged
Anasarca; no response to treatment
B4.  Hypertension 
(new onset or 
worsening)
Asymptomatic, transient increase 
by > 20 mmHg (diastolic) or to 
> 150/100 if previously normal, 
no therapy required
Recurrent or persistent increase 
> 150/100 or by > 10 mmHg 
(diastolic), requiring and 
responding readily to treatment
Symptomatic increase > 150/100, 
> 20 mmHg, persistent, requiring 
multi agency therapy, difficult to 
control
Hypertensive crisis
B5.  Hypotension 
(without underlying 
diagnosis)
Transient, intermittent, 
asymptomatic, orthostatic 
decrease in blood pressure 
> 20 mmHg
Symptomatic, without interference 
with function, recurrent or 
persistent > 20 mmHg decrease, 
responds to treatment
Syncope or symptomatic, interferes 
with function, requiring therapy and 
sustained medical attention, dose 
adjustment or drug discontinuation
Shock
B6.  Myocardial 
ischaemia
Transient chest pain/ECG 
changes; rapid relief with nitro
Recurring chest pain, transient 
ECG ST-T changes; treatment 
relieves
Angina with infarction, no or 
minimal functional compromise, 
reduce dose or discontinue study 
drug
Acute myocardial infarction, 
arrthymia or/and CHF


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B.  Cardiac (continued)
B7.  Pericarditis/ 
pericardial effusion
Rub heard, asymptomatic
Detectable effusion by 
echocardiogram, symptomatic 
NSAID required
Detectable on chest x-ray, 
dyspnoea; or pericardiocentesis; 
requires corticosteroids
Pulsus alternates with low cardiac 
output; requires surgery
B8.  
Phlebitis/thrombosis/ 
Embolism (excludes 
injection sites)
Asymptomatic, superficial, 
transient, local, or no treatment 
required
Symptomatic, recurrent, deep vein 
thrombosis, no anticoagulant 
therapy required
Deep vein thrombosis requiring 
anticoagulant therapy
Pulmonary embolism
C.  General (Constitutional)
C1.  Fatigue/malaise 
(asthenia)
Increase over baseline; most usual 
daily functions maintained, short 
term
Limits daily function intermittently 
over time
Interferes with basic ADL, 
persistent
Unable to care for self, bed or 
wheelchair bound > 50% of day 
debilitating, hospitalisation
C2.  Fever (pyrexia) 
(note:  fever due to 
drug allergy should 
be coded as allergy)
Transient, few symptoms
37.7 – 38.5°C
Symptomatic, recurrent
38.6 – 39.9°C.  Relieved by meds
≥ 40°C; ≤ 24 h, persistent 
symptoms; partial response to meds.
≥ 40°C, debilitating, > 24 h, 
hospitalisation; no relief with meds
C3.  Headache
Transient or intermittent, no meds 
or relieved with OTC
Persistent, recurring, non-narcotic 
analgesics relieve
Prolonged with limited response to 
narcotic medicine
Intractable, debilitating, requires 
parenteral meds.
C4.  Insomnia
Difficulty sleeping, short term, no 
interfering with function
Difficulty sleeping interfering with 
function, use of prescription med.
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C5.  Rigors, chills
Asymptomatic, transient, no 
meds, or non-narcotic meds 
relieve
Symptomatic, narcotic meds 
relieve.
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C6.  Sweating 
(diaphoresis)
Episodic, transient
Frequent, short term
Frequent, drenching, disabling
Dehydration, requiring IV 
fluids/hospitalization > 24 hrs
C7.  Weight gain
5% – 9.9%
10% – 19.9%
20% – 30%
NA
C8.  Weight loss
5% – 9.9%
10% – 19.9%
20% – 30%
NA


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D.  Dermatologic
D1.  Alopecia
Subjective, transient
Objective, fully reversible
Patchy, wig used, partly reversible
Complete, or irreversible even if 
patchy
D2.  Bullous eruption
Localised, asymptomatic
Localised, symptomatic, requiring 
treatment
Generalised, responsive to 
treatment; reversible
Prolonged, generalised, or 
requiring hospitalisation for 
treatment
D3.  Dry skin
Asymptomatic, controlled with 
emollients
Symptoms eventually (1 – 2 wks) 
controlled with emollients
Generalised, interfering with ADL 
> 2 wks, persistent pruritis, partially 
responsive to treatment
Disabling for extended period, 
unresponsive to ancillary therapy 
and requiring study drug 
discontinuation for relief
D4.  Injection site 
reaction
Local erythema, pain, pruritis, 
< few days
Erythema, pain, oedema, may 
include superficial phlebitis,
1 – 2 wks
Prolonged induration, superficial 
ulceration; includes thrombosis
Major ulceration necrosis requiring 
surgery
D5.  Petechiae 
(without vasculitis)
Few, transient asymptomatic
Dependent areas, persistent up to 
2 wks
Generalised, responsive to 
treatment; reversible
Prolonged, irreversible, disabling
D6.  Photosensitivity
Transient erythema
Painful erythema and oedema 
requiring topical treatment
Blistering or desquamation, requires 
systematic corticosteroids
Generalised exfoliation or 
hospitalisation
D7. Pruritis
Localised, asymptomatic, 
transient, local treatment
Intense, or generalised, relieved by 
systematic medication
Intense or generalised; poorly 
controlled despite treatment
Disabling, irreversible
D8.  Rash (not 
bullous)
Erythema, scattered 
macular/popular eruption; pruritis 
transient; TOC or no meds
Diffuse macular/popular eruption 
or erythema with pruritus; dry 
desquamation; treatment required
Generalised, moist desquamation, 
requires systemic corticosteroids; 
responsive to treatment; reversible
Exfoliative or ulcerating; or 
requires hospitalisation; or 
parenteral corticosteroids
D9.  Indurartion/ 
fibrosis/Thickening 
(not sclerodermal)
Localized, high density on 
palpation, reversible, no effect on 
ADL and not disfiguring
Local areas < 50% body surface, 
not disfiguring, transient 
interference with ADL, reversible
Generalized, disfiguring, interferes 
with ADL, reversible
Disabling, irreversible, systemic 
symptoms
E.  Ear/Nose/Throat
E1.  Hearing loss
Transient, intermittent, no 
interference with function
Symptomatic, treatment required, 
reversible
Interferes with function; incomplete 
response to treatment
Irreversible deafness
E2.  Sense of smell
Slightly altered
Markedly altered
Complete loss, reversible
Complete loss, without recovery


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E.  Ear/Nose/Throat (continued)
E3.  Stomatitis
Asymptomatic
Painful, multiple, can eat
Interferes with nutrition, slowly 
reversible
Requires enteral support; residual 
dysfunction
E4.  Taste 
disturbance 
(dysgeusia)
Transiently altered; metallic
Persistently altered; limited effect 
on eating
Disabling, effect on nutrition
NA
E5.  Tinnitus
Intermittent, transient, no 
interference with function
Requires treatment, reversible
Disabling, or associated with 
hearing loss
Irreversible deafness
E6.  Voice changes 
(includes hoarseness, 
loss of voice, 
laryngitis)
Intermittent hoarseness, able to 
vocalize
Persistent hoarseness, able to 
vocalize
Whispered speech, slow return of 
ability to vocalize
Unable to vocalize for extended
E7.  Xerostomia (dry 
mouth)
Transient dryness
Relief with meds
Interferes with nutrition, slowly 
reversible
Extended duration interference 
with nutrition, requires parenteral 
nutrition
F.  Eye/Ophthalmologic
F1.  Cataract
Asymptomatic, no change in 
vision, non-progressive
Symptomatic, partial visual loss, 
progressive
Symptoms impairing function, 
vision loss requiring treatment, 
including surgery
NA
F2.  Conjunctivitis
Asymptomatic, transient, rapid 
response to treatment
Symptomatic, responds to 
treatment, changes not interfering 
with function
Symptoms prolonged, partial 
response to treatment, interferes 
with function
NA
F3.  Lacrimation 
increased (tearing, 
watery eyes)
Symptoms not requiring 
treatment, transient
Symptomatic, treatment required, 
reversible
Unresponsive to treatment with 
major effect on function
NA
F4.  Retinopathy
Asymptomatic, non-progressive, 
no treatment
Reversible change in vision; 
readily responsive to treatment
Disabling change in vision 
ophthalmological findings 
reversible, sight improves over time
Loss of sight


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F.  Eye/Ophthalmologic (continued)
F5.  Vision changes 
(e.g., blurred, 
photophobia, night 
blindness, vitreous 
floaters)
Asymptomatic, transient, no 
treatment required
Symptomatic, vision changes not 
interfering with function, 
reversible
Symptomatic, vision changes 
interfering with function
Loss of sight
F6.  Xerophtalmia 
(dry eyes)
Mild scratchiness
Symptomatic without interfering 
with function, requires artificial 
tears
Interferes with vision/function, 
corneal ulceration
Loss of sight
G.  Gastrointestinal
G1.  Anorexia
Adequate food intake, minimal 
weight loss
Symptoms requiring oral 
nutritional supplementation
Prolonged, requiring iv support
Requires hospitalization for 
nutritional support
G2.  Constipation
Asymptomatic, transient, 
responds to stool softener, OTC 
laxatives
Symptomatic, requiring 
prescription laxatives, reversible
Obstipation requiring medical 
intervention
Bowel obstruction.  Surgery 
required.
G3.  Diarrhea
Transient, increase of
2 – 3 stools/day over 
pre-treatment (no blood or 
mucus), OTC agents relieve
Symptomatic, increase
4 – 6 stools/day, nocturnal stools, 
cramping, requires treatment with 
prescription meds.
Increase > 6 stools/day, associated 
with disabling symptoms, 
e.g., incontinence, severe cramping, 
partial response to treatment.
Prolonged, dehydration, 
unresponsive to treatment, requires 
hospitalization.
G4.  Dyspepsia 
(heartburn)
Transient, intermittent, responds 
to OTC antacids, H-2 blockers
Prolonged, recurrent, requires 
prescription meds, relieved by 
meds
Persistent despite treatment, 
interferes with function, associated 
with GI bleeding
NA
G5.  GI bleed 
(gastritis, gastric or 
duodenal ulcer 
diagnosed-define 
aetiology)
Asymptomatic, endoscopic 
finding, haemocult + stools, no 
transfusion, responds rapidly to 
treatment
Symptomatic, transfusion ≤ 2 units 
needed; responds to treatment
Haematemesis, transfusion
3 – 4 units, prolonged interference 
with function
Recurrent, transfusion > 4 units, 
perforation, requiring surgery, 
hospitalisation
G6.  Haematochezia 
(rectal bleeding)
Haemorrhodial, asymptomatic, no 
transfusion
Symptomatic, transfusion
≤ 2 units, reversible
Recurrent, transfusion > 3 – 4 units
> 4 units, hypotension, requiring 
hospitalization


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G.  Gastrointestinal (continued)
G7.  Hepatitis
Laboratory abnormalities, 
asymptomatic, reversible
Symptomatic laboratory 
abnormalities, not interfering with 
function, slowly reversible
Laboratory abnormalities persistent 
> 2 wks, symptoms interfere with 
function
Progressive, hepato-renal, anasarca, 
pre-coma or coma
G8.  Nausea, or 
nausea/vomiting (use 
diagnostic term)
Transient, intermittent, minimal 
interference with intake, rapid 
response to meds.
Persistent, recurrent, requires 
prescription meds, intake 
maintained
Prolonged, interferes with daily 
function and nutritional intake, 
periodic iv fluids
Hypotensive, hospitalization, 
parenteral nutrition, unresponsive 
to out-patient management
G9.  Pancreatitis
Anylase elevation, intermittent 
nausea/vomiting, transient, 
responds rapidly to treatment
Amylase elevation with abdominal 
pain, nausea, occasional vomiting, 
responsive to treatment
Severe, persistent abdominal pain 
with pancreatitic enzyme elevation, 
incomplete or slow response to 
treatment
Complicated by shock, 
haemorrhage (acute circulatory 
failure)
G10.  Proctitis
Perianal pruritus, haemorrhoids 
(new onset), transient, or 
intermittent, relieved by OTC 
meds
Tenesmus or ulcerations, anal 
fissure, responsive to treatment, 
minimal interference with function
Unresponsive to treatment, marked 
interference with function
Mucosal necrosis with 
haemorrhage, infection, surgery 
required.
H.  Musculoskeletal
H1.  Avascular 
necrosis
Asymptomatic MRI changes, 
non-progressive
MRI changes and symptoms 
responsive to rest and analgesia
MRI changes, symptoms requiring 
surgical intervention
Wheelchair bound; surgical repair 
not possible
H2.  Arthralgia
Intermittent transient symptoms, 
no meds or relieved by OTC meds
Persistent or recurrent symptoms, 
resolve with meds, little effect on 
function
Severe symptoms despite meds 
impairs function
Debilitating, hospitalisation 
required for treatment
H3.  Leg cramps
Transient, intermittent, does not 
interfere with function
Recurrent symptoms, minimally 
interferes with function or sleep, 
responds to meds
Persistent, prolonged interference 
with function or sleep, partial or no 
response to meds
NA
H4.  Myalgia
Occasional; does not interfere 
with function
Frequent, requires meds 
(non-narcotic); minor effects on 
function
Major change in function/lifestyle, 
narcotic pain meds
Debilitating, profound weakness, 
requires wheelchair, unresponsive 
to meds


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I.  Neuropsychiatric
I1.  Anxiety or 
Depression (mood 
alteration)
Symptomatic, does not interfere 
with function; no meds
Frequent symptoms, responds to 
meds; interferes with ADL at times
Persistent, prolonged symptoms, 
partial or no response to meds, 
limits daily function
Suicidal ideation or danger to self
I2.  Cerebrovascular 
ischaemia
NA
Single transient ischaemic event, 
responsive to treatment
Recurrent transient ischaemic events
Cerebrovascular vascular accident 
with permanent disability
I3.  Cognitive 
disturbance
Subjective symptoms, transient, 
intermittent, not interfering with 
function
Objective symptoms, persisting, 
interferes with daily function 
occasionally
Persistent, or worsening objective 
symptoms; interferes with routine 
daily routine
Debilitating/disabling and 
permanent; toxic psychosis
I4.  Depressed 
consciousness 
(somnolence)
Observed, transient, intermittent, 
not interfering with function
Somnolence or sedation, 
interfering with function
Persistent, progressive, obtundation, 
stupor
Coma
I5.  Inability to 
concentrate
Subjective symptoms, does not 
interfere with function
Objective findings, interferes with 
function
Persistent, prolonged objective 
findings or organic cause
NA
I6.  Insomnia (in 
absence of pain)
Occasional difficulty sleeping, 
transient intermittent, not 
interfering with function
Recurrent difficulty sleeping; 
requires meds for relief; occasional 
interference with function
Persistent or worsening difficulty 
sleeping; severely interferes with 
routine daily function
NA
I7.  Libido decreased
Decrease in interest
Loss of interest; influences 
relationship
Persistent, prolonged interfering 
with relationship
NA
I8.  Peripheral motor 
neuropathy
Subjective or transient loss of 
deep tendon reflexes; function 
maintained
Objective weakness, persistent, no 
significant impairment of daily 
function
Objective weakness with substantial 
impairment of function
Paralysis
I9.  Peripheral 
sensory neuropathy 
(sensory disturbance)
Subjective symptoms without 
objective findings, transient, not 
interfering with function
Objective sensory loss, persistent, 
not interfering with function
Prolonged sensory loss or 
paraethesias interfering with 
function
NA
I10.  Seizure
NA
Recurrence of old seizures, 
controlled with adjustment of 
medication
Recurrence/exacerbation with 
partial response to medication
Recurrence not controlled, 
requiring hospitalization; new 
seizures


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I.  Neuropsychiatric (continued)
I11.  Vertigo 
(dizziness)
Subjective symptoms, transient, 
intermittent, no treatment
Objective findings, recurrent, meds 
relieve, occasionally interfering 
with function
Persistent, prolonged, interfering 
with daily function; partial response 
to medication
Debilitating without response to 
medication, hospitalization
J.  Pulmonary
J1.  Asthma
Occasional wheeze, no 
interference with activities
Wheezing, requires oral meds, 
occasional interference with 
function
Debilitating, requires nasal O2
Requires ventilator assistance
J2.  Cough
Transient, intermittent, occasional 
OTC meds relieve
Persistent, requires narcotic or 
other prescription meds for relief
Recurrent, persistent coughing 
spasms without consistent relief by 
meds, interferes with function
Interferes with oxygenation; 
debilitating
J3.  Dyspnea
Subjective, transient, no 
interference with function
Symptomatic, intermittent or 
recurring, interferes with 
exertional activities
Symptomatic during daily routine 
activities, interferes with function, 
treatment with intermittent nasal O2
relieves
Symptomatic at rest, debilitating, 
requires constant nasal O2
J4.  Pleuritic pain 
(pleurisy)
Transient, intermittent symptoms, 
no treatment or OTC meds relieve
Persistent symptoms, requires 
prescription meds for relief
Prolonged symptoms, interferes 
with function, requires frequent 
narcotic pain relief
Debilitation, requiring 
hospitalisation
J5.  Pneumonitis 
(pulmonary 
infiltrates)
Asymptomatic radiographic 
changes, transient, no treatment 
required
Symptomatic, persistent, requiring 
corticosteroids
Symptomatic, requiring treatment 
including O2
Debilitating, not reversible; or 
requiring assisted ventilation
J6.  Pulmonary 
function decreased 
(FVC or carbon 
monoxide diffusion 
capacity – DLCO)
76% – 90% of pre-treatment value
51% – 75% of pre-treatment value
26% – 50% of pre-treatment value
≤ 25% of pre-treatment value


Upadacitinib
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Laboratory Data
K.  Haematology
K1.  Hgb (g/dl) 
decrease from 
pre-treatment
1.0 – 1.4
1.5 – 2.0
2.1 – 2.9, or Hgb < 8.0, > 7.0
≥ 3.0; or Hgb < 7.0
K2.  Leukopenia 
(total WBC) × 1000
3.0 – 3.9
2.0 – 2.9
1.0 – 1.9
< 1.0
K3.  Neutropenia 
(× 1000)
1.5 – 1.9
1.0 – 1.4
0.5 – 0.9
< 0.5
K4.  Lymphopenia 
(× 1000)
1.5 – 1.9
1.0 – 1.4
0.5 – 0.9
< 0.5
K5.  Platelets 
(× 1000)
75 – LLN
50 – 74.9
20 – 49.9; platelet transfusion 
required
< 20; recurrent platelet transfusions
L.  Chemistry
L1.  Hypercalcaemia 
(mg/dl)
1.1 × ULN – 11.5
11.6 – 12.5
12.6 – 13.5; or symptoms present
> 13.5; or associated coma
L2.  Hyperglycemia 
(mg/dl) Fasting
140 – 160
161 – 250
251 – 500
> 500, or associated with
ketoacidosis
L3.  Hyperkalaemia 
(mg/dl)
5.5 – 5.9
6.0 – 6.4
6.5 – 7.0 or any ECG change
> 7.0 or any arrhythmia
L5.  Hypocalcaemia 
(mg/dl)
0.9 × LLN – 7.8
7.7 – 7.0
6.9 – 6.5; or associated with 
symptoms
< 6.5 or occurrence of tetany
L6.  Hypoglycemia 
(mg/dl)
55 – 64 (no symptoms)
40 – 54 (or symptoms present)
30 – 39 (symptoms impair function)
< 30 or coma
L7.  Hyponatraemia 
(mg/dl)
--
125 – 129
120 – 124
< 120
L8.  Hypokalaemia 
(mg/dl)
--
3.0 – 3.4
2.5 – 2.9
< 2.5


Upadacitinib
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L.  Chemistry (continued)
L9.  CPK (also if 
polymyositis-
disease)*
1.2 – 1.9 × ULN
2.0 – 4.0 × ULN
4.0 × ULN with weakness but 
without life-threatening signs or 
symptoms
> 4.0 × ULN with signs or 
symptoms of rhabdomyolysis or 
life-threatening
L10.  Serum uric acid
1.2 – 1.6 × ULN
1.7 – 2.9 × ULN
3.0 – 5.0 × ULN or gout
NA
L11.  Creatinine 
(mg/dL)*
1.1 – 1.3 × ULN
1.3 – 1.8 × ULN
1.9 – 3.0 × ULN
> 3.0 × ULN
L12.  SGOT (AST)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.1 – 8.0 × ULN
> 8.0 × ULN
L13.  SGPT (ALT)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.0 – 8.0 × ULN
> 8.0 × ULN
L14.  Alkaline 
phosphatase
1.1 – 2.0 × ULN
1.6 – 3.0 × ULN
3.0 – 5.0 × ULN
> 5.0 × ULN
L15.  T. bilirubin
1.1 – 1.4 × ULN
1.5 – 1.9 × ULN
2.0 – 3.0 × ULN
> 3.0 × ULN
L16.  LDH
1.3 – 2.4 × ULN
2.5 – 5.0 × ULN
5.1 – 10 × ULN
> 10 × ULN
M.  Urinalysis
M1.  Haematuria
Micro only
Gross, no clots
Clots, transfusion < 2 units 
Transfusion required
M2.  Proteinuria (per 
24 h)
300 – 500 mg (tr/1+)
501 – 1999 mg (2+)
2 – 5.0 g (3+) nephrotic syndrome
5.0 g (4+) anasarca
M3.  WBC in urine
NA
NA
Indicating acute interstitial nephritis
Associated with acute renal failure
M4.  Uric acid 
crystals
Present without symptoms
NA
With stones or symptoms of stones 
(e.g., renal colic)
Causing renal outflow obstruction 
and hospitalization
OTC = over-the-counter medication; ADL = activities of daily living; IV = intravenous; ECG = electrocardiogram; CHF = congestive heart failure; MRI = magnetic resonance 
imaging; Hb = haemoglobin; LLN = lower limit of normal; ULN = upper limit of normal; WBC = white blood cells; SLE = systemic lupus erythematosus; ANA = antinuclear 
antibodies; H-2 blockers = histamine-2 blockers; FVC = forced vital capacity
*
For CPK and Creatinine NCI CTC grading will be used.  For CPK the following gradings apply:  Grade 1:  > ULN – 2.5 × ULN, Grade 2:  > 2.5 – 5.0 × ULN; Grade 3:  
> 5.0 – 10.0 × ULN; Grade 4:  > 10.0 × ULN; For Creatinine the following gradings apply:  Grade 1:  > 1 – 1.5 × Baseline; > ULN – 1.5 × ULN; Grade 2:  > 1.5 –
3.0 × Baseline; > 1.5 – 3.0 × ULN; Grade 3:  > 3.0 × Baseline; > 3.0 – 6.0 × ULN; Grade 4:  > 6.0 × ULN.


Upadacitinib
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Appendix O.
Local Requirements
Korea
Section 5.2.4 Contraception Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.  
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 an FSH level > 40 mIU/mL.
If the female subject is < 55 years of age AND has had no menses for ≥ 12 months AND 
has no history of permanent surgical sterilization (defined above), 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 a serum pregnancy test must be performed (see 
Section 5.3.1.1 "Pregnancy test").
For a female subject at any age: 
●
Female subjects with menses within the past 12 months are of childbearing 
potential and FSH is therefore not required but contraception is required.


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●
Female subjects who are surgical sterile (defined above) are not of 
childbearing potential and therefore no FSH testing or contraception is 
required.
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) 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 4 weeks prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the highly 
effective birth control methods listed above.
It is important to note that contraception recommendations described above are 
specifically intended to prevent pregnancy during exposure to the investigational therapy 
upadacitinib.  The concomitant csDMARDs (i.e., methotrexate, sulfasalazine, etc.) have 
been prescribed per standard of care prior to study entry and are allowed to be continued 
during the study.  Contraception should continue while the subject is on the concomitant 


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csDMARD and that duration of contraception after discontinuation of the csDMARD 
should be based on the local label.
Contraception Recommendation for Males
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of study drug to practice 
contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures as defined in the protocol for female study subjects of childbearing 
potential.
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of study drug. 
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.
As described above, contraception should continue while the subject is on the concomitant 
csDMARD and that duration of contraception after discontinuation of the csDMARD 
should be based on the local label.


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Appendix P.
Protocol Amendment:  List of Changes
Refer to Section 1.1 for a summary of changes for Amendment 2.
Specific Protocol Changes
Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M15-557
Name of Study Drug:  Upadacitinib
Phase of Development:  3
Name of Active Ingredient:  Upadacitinib
Date of Protocol Synopsis:  21 September 2017
Protocol Title:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study with Upadacitinib 
(ABT-494) in Subjects from China and Selected Countries with Moderately to Severely Active 
Rheumatoid Arthritis Who Have Had an Inadequate Response to Conventional Synthetic Disease-
Modifying Anti-Rheumatic Drugs (csDMARDs)
Objectives:
Period 1
1.
To compare the efficacy of upadacitinib versus placebo for the treatment of signs and symptoms of 
subjects from China and selected countries including Brazil and South Korea with moderately to 
severely active rheumatoid arthritis (RA) who are on a stable dose of conventional synthetic disease 
modifying anti-rheumatic drugs (csDMARDs) and have an inadequate response to csDMARDs.
2.
To compare the safety and tolerability of upadacitinib versus placebo in subjects from China and 
selected countries including Brazil and South Korea with moderately to severely active RA who are 
on a stable dose of csDMARDs and have an inadequate response to csDMARDs.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib in subjects from China and 
selected countries including Brazil and South Korea with RA who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 50
Study Population:
Adult female and male subjects who are at least 18 years of age with a diagnosis of RA for ≥ 3 months 
who also fulfill the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for 
RA.  Eligible study subjects must have ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints 
(based on 68 joint counts) at Screening and Baseline Visits, and high-sensitivity C-reactive protein 
(hsCRP) ≥ upper limit of normal (central lab) at Screening.  Subjects must have been on a stable dose of 
csDMARD therapy (restricted to methotrexate [MTX], chloroquine, hydroxychloroquine, sulfasalazine, 
or leflunomide) for ≥ 4 weeks prior to the first dose of study drug.  Subjects with inadequate response to 
hydroxychloroquine and/or chloroquine can only be included if they also have failed (lack of efficacy or 
intolerability) MTX, sulfasalazine, or leflunomide.
Number of Subjects to be Enrolled:  Approximately 322


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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 12-week, randomized, 
double-blind, parallel-group, placebo-controlled period designed to compare the safety and efficacy of 
upadacitinib versus placebo for the treatment of signs and symptoms of subjects with moderately to 
severely active RA who are on a stable dose of csDMARDs and have an inadequate response to 
csDMARDs.  Period 2 is an open-label 52 week extension period to evaluate the long-term safety, 
tolerability, and efficacy of upadacitinib in subjects with RA who have completed Period 1.
The study duration will include a 35-day screening period; a 12-week randomized, double-blind, parallel 
group, placebo controlled treatment period (Period 1); an open-label 52 week extension period; and a 
30-day follow-up period.
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of two treatment groups.  
As indicated below, it is expected that approximately 222 subjects will enter the study from China and 
100 subjects from other countries including Brazil and South Korea:
!
Group 1:  Upadacitinib 15 mg QD (N = 161; 111 from China) (Period 1) → Upadacitinib 15 mg 
QD (Period 2)
!
Group 2:  Placebo (N = 161; 111 from China) (Period 1) → Upadacitinib 15 mg QD (Period 2)
Randomization will be stratified by country and the Chinese population will be up to 80% of the total 
study population.
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the first dose of study 
drug and must remain on a stable dose until Week 24; the csDMARD dose may be decreased only for 
safety reasons.  At Week 24, if a subject fails to meet the Low Disease Activity (LDA) criterion (LDA 
defined as CDAI ≤ 10), the investigator should adjust the subject's background RA therapies after 
assessments for Week 24 have been completed.
Starting at Week 24 (after Week 24 assessments have been performed), initiation of or change in 
corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or csDMARDs 
(restricted to oral or parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine and leflunomide, 
and restricted to concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide) is allowed as per local label.  For RA flare treatment, no more than 3 consecutive days of 
systemic corticosteroids (maximum dose of 0.5 mg/kg/day of prednisone or its equivalent) is allowed, 
after which subject should resume their usual daily oral corticosteroid dose.
Subjects taking MTX should take oral folic acid throughout study participation.  Folic acid dosing and 
timing of regimen will be based on the Investigator's discretion.
Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC is required to remain on study 
drug.  Anyone who does not fulfill this criterion at 2 consecutive visits (starting at Week 24) (see 
Section 5.2.3.1) must be discontinued from study drug treatment.
Subjects who complete the Week 12 visit (end of Period 1) will enter the 52 week extension portion of 
the study, Period 2.  Subjects who are assigned to upadacitinib treatment in Period 1 will continue to 
receive upadacitinib in an open-label manner.  Subjects who are assigned to placebo in Period 1 will be 
switched to receive upadacitinib from Week 12 onwards.  The primary analysis will be conducted after 
all subjects have completed Period 1 (Week 12) or have prematurely discontinued prior to Week 12.  
Study sites and subjects will remain blinded to the treatment assignment in Period 1 for the duration of 
the study.


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Methodology (Continued):  
Blood samples will be collected for In Vivo Pharmacodynamic biomarker research at designated time 
points throughout the study.
Where not prohibited by local regulations, optional pharmacogenetic samples, epigenetic samples, 
transcriptomic and epigenetic samples, plasma samples for proteomic and targeted protein investigations, 
serum samples for proteomic and targeted protein investigations will be collected for exploratory 
research and validation studies at designated time points throughout the study.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who also fulfill the 2010 ACR/EULAR classification criteria for 
RA.
3.
Subjects have been receiving csDMARD therapy ≥ 3 months and on a stable dose for ≥ 4 weeks prior 
to the first dose of study drug.  
!
Subjects must have failed (lack of efficacy) at least one of the following:  MTX, sulfasalazine, 
or leflunomide.
!
Subjects with inadequate response to hydroxychloroquine and/or chloroquine can only be 
included if they have also failed (lack of efficacy or intolerability) MTX, sulfasalazine, or 
leflunomide.
!
The following csDMARDs are allowed (stable dose for ≥ 4 weeks prior to the first dose of study 
drug):  oral or parenteral MTX (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are 
intolerant of MTX at doses ≥ 12.5 mg/week after complete titration; no minimum MTX dose is 
required if MTX is combined with another csDMARD.  For subjects in China and South Korea:  
10 to 25 mg/week; or ≥ 7.5 mg/week in subjects who are intolerant of MTX at doses 
≥10 mg/week after complete titration), sulfasalazine (≤ 3000 mg/day), hydroxychloroquine 
(≤400 mg/day), chloroquine (≤ 250 mg/day), and leflunomide (≤ 20 mg/day).
!
A combination of up to two background csDMARDs is allowed EXCEPT the combination of 
MTX and leflunomide.
4.
Subject meets both of the following disease activity criteria:
c.
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at 
Screening and Baseline Visits; and
d.
hsCRP ≥ upper limit of normal (central lab) at Screening Visit.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
1.
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Subjects with prior exposure to bDMARD therapy.
3.
History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint 
disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic 
arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms]).  Current diagnosis of secondary 
Sjogren's Syndrome is permitted.
4.
Laboratory values meeting 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 by simplified 4-variable Modification 
of Diet in Renal Disease formula < 40 mL/min/1.73 m2; total white blood cell count < 2,500/μL; 
absolute neutrophil count < 1,500/μL; platelet count < 100,000/μL; absolute lymphocyte count 
< 800/μL; and hemoglobin < 10 g/dL.
Investigational Product:
Upadacitinib
Dose:
15 mg QD
Mode of Administration:
Oral
Reference Therapy:
Matching placebo for upadacitinib QD
Dose:
N/A
Mode of Administration:
Oral
Duration of Treatment:  Period 1:  12 weeks; Period 2:  up to 52 weeks
Criteria for Evaluation:
Efficacy:
Period 1
The primary endpoint in Period 1 is the proportion of subjects achieving ACR20 response at Week 12.
ACR20 response rate will be determined based on 20% or greater improvement in Tender Joint Count 
(TJC) and Swollen Joint Count (SJC) and ≥ 3 of the 5 measures of Patient's Assessment of Pain (Visual 
Analog Scale [VAS]), Patient's Global Assessment of Disease Activity (VAS), Physician's Global 
Assessment of Disease Activity (VAS), Health Assessment Questionnaire Disability Index (HAQ-DI), or 
hsCRP.


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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 1 (Continued)
Ranked key secondary endpoints (at Week 12) are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
Change from baseline in Short Form-36 (SF-36) Physical Component Score (PCS);
4.
Proportion of subjects achieving low disease activity (LDA) defined as Disease Activity Score 
(DAS)28 (C-reactive protein [CRP]) ≤ 3.2;
5.
Proportion of subjects achieving Clinical remission (CR) based on DAS28 (CRP);
6.
Proportion of subjects achieving LDA based on CDAI ≤ 10;
Other key secondary endpoints (at Week 12, if not specified) are:
!
ACR50 response rate;
!
ACR70 response rate;
!
ACR20 response rate at Week 1.
Additional endpoints at all visits are:
!
Change from baseline in individual components of ACR response; 
!
ACR20/50/70 response rates;
!
Change from baseline in DAS28 (CRP) and DAS28 (erythrocyte sedimentation rate [ESR]); 
!
Change from baseline in CDAI and SDAI;
!
Change from baseline in morning stiffness (severity and duration); 
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.22);
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.3);
!
Proportion of subjects achieving LDA or CR based on DAS28 (CRP), DAS28 (ESR), Simplified 
Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) criteria (see below);
!
ACR/EULAR Boolean remission;
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
  
!
Change from baseline in EQ-5D-5L;
!
Change from baseline in SF-36;
!
Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F);
!
Change from baseline in Work Instability Scale for Rheumatoid Arthritis (RA-WIS).


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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 2
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 16, 20, 24, 36, 48 and 64/PD.
!
ACR20/50/70 response rates;
!
Change from baseline in individual ACR components;
!
Change from baseline in DAS28 (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in CDAI and SDAI;
!
Change from baseline in morning stiffness;
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.22);
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.3);
!
Proportion of subjects achieving LDA and the proportion of subjects achieving CR based on 
DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined for Period 1);
!
ACR/EULAR Boolean remission;
!
Concomitant corticosteroid use (systemic use and intra-articular injections).
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 24 and 48 only:
!
Change from baseline in EQ-5D-5L;
!
Change from baseline in SF-36;
!
Change from baseline in FACIT-F;
!
Change from baseline in RA-WIS.
Pharmacokinetic (Period 1 Only):
Blood samples for assay of upadacitinib and possibly other concomitant medications in plasma will be 
collected at Weeks 1, 2, 4, 8, and 12/Premature Discontinuation.
In Vivo Pharmacodynamic Biomarkers (Periods 1 and 2):
Period 1
Change from baseline in lymphocyte subsets (including but not limited to natural killer cells, natural 
killer T cells, B cells, and T cells) will be evaluated at Weeks 8 and 12/Premature Discontinuation.
Period 2
Change from baseline in lymphocyte subsets (including but not limited to natural killer cells, natural 
killer T cells, B cells, and T cells) will be evaluated at Weeks 16, 24, 36, 48, 64/Premature 
Discontinuation (PD).


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Criteria for Evaluation (Continued):
Exploratory Research Variables and Validation Studies (Optional) (Period 1 Only):
Where not prohibited by local regulations, prognostic, predictive, and pharmacodynamics biomarkers 
signatures may be evaluated.  Samples for pharmacogenetic, epigenetic, transcriptomic, and proteomic 
and targeted protein investigations will be collected at various time points.  Assessments will include but 
may not be limited to nucleic acids, proteins, metabolites, or lipids.
Safety:
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.
Statistical Methods:
Efficacy:
All efficacy analyses will be carried out using the Full Analysis Set population, which includes all 
randomized subjects who receive at least one dose of study drug.
Period 1 Efficacy
Analysis of the Primary and Key Secondary Endpoints:
For binary endpoints, frequencies and percentages will be reported for each treatment group.  
Comparison between upadacitinib group and placebo group will be conducted using the Cochran-Mantel-
Haenszel test adjusting for main stratification factors.  
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Comparison between upadacitinib group and placebo group will be carried out using 
the analysis of covariance model with treatment group as the fixed factor, and the corresponding baseline 
value and the main stratification factors as the covariates.
Non-responder imputation approach will serve as the primary analysis approach for key binary endpoints 
and multiple imputation will serve as the primary analysis approach for key continuous endpoints.  
Sensitivity analyses based on observed cases will also be conducted for key endpoints.  The overall type I 
error rate of the primary and key secondary endpoints will be strongly controlled using sequential testing.
Long-Term Efficacy for Period 1 and Period 2 Combined
Long-term efficacy by time point will be summarized using descriptive statistics.
Pharmacokinetic:
A non-linear mixed-effects modeling approach will be used to estimate the population central values and 
the empirical Bayesian estimates of the individual values of upadacitinib oral clearance (CL/F) and 
volume of distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of 
the data.


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Statistical Methods (Continued):
Safety:
Safety analyses will be carried out using the Safety Analysis Set, which includes all subjects who receive 
at least one dose of study drug.  Analyses will be conducted for Period 1 alone, as well as for Period 1 
and Period 2 combined. Safety will be assessed by AEs, physical examination, laboratory assessments, 
ECG and vital signs.  Frequency tables and lists of subjects with treatment-emergent AEs by preferred 
term as in the Medical Dictionary for Regulatory Activities dictionary, by system organ class, by 
severity, and by relationship to the study drug as assessed by the Investigator will be provided.  The 
changes from baseline in vital signs, physical examination results, and clinical laboratory values will be 
analyzed in a descriptive manner.  Shift of laboratory values from baseline to defined time points will be 
tabulated.
Has been changed to read:
AbbVie Inc.
Protocol Number:  M15-557
Name of Study Drug:  Upadacitinib
Phase of Development:  3
Name of Active Ingredient:  Upadacitinib
Date of Protocol Synopsis:  17 October 2018
Protocol Title:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study with Upadacitinib 
(ABT-494) in Subjects from China and Selected Countries with Moderately to Severely Active 
Rheumatoid Arthritis Who Have Had an Inadequate Response to Conventional Synthetic Disease-
Modifying Anti-Rheumatic Drugs (csDMARDs)
Objectives:
Period 1
1.
To compare the efficacy of upadacitinib versus placebo for the treatment of signs and symptoms of 
subjects from China and selected countries including Brazil and South Korea with moderately to 
severely active rheumatoid arthritis (RA) who are on a stable dose of conventional synthetic disease 
modifying anti-rheumatic drugs (csDMARDs) and have an inadequate response to csDMARDs.
2.
To compare the safety and tolerability of upadacitinib versus placebo in subjects from China and 
selected countries including Brazil and South Korea with moderately to severely active RA who are 
on a stable dose of csDMARDs and have an inadequate response to csDMARDs.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib in subjects from China and 
selected countries including Brazil and South Korea with RA who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 50


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Study Population:
Adult female and male subjects who are at least 18 years of age with a diagnosis of RA for ≥ 3 months 
who also fulfill the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for 
RA.  Eligible study subjects must have ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints 
(based on 68 joint counts) at Screening and Baseline Visits, and high-sensitivity C-reactive protein 
(hsCRP) ≥ upper limit of normal (central lab) at Screening.  Subjects must have been on a stable dose of 
csDMARD therapy (restricted to methotrexate [MTX], chloroquine, hydroxychloroquine, sulfasalazine, 
or leflunomide) for ≥ 4 weeks prior to the first dose of study drug.  Subjects with inadequate response to 
hydroxychloroquine and/or chloroquine can only be included if they also have failed (lack of efficacy or 
intolerability) MTX, sulfasalazine, or leflunomide.
Number of Subjects to be Enrolled:  Approximately 322


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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 12-week, randomized, 
double-blind, parallel-group, placebo-controlled period designed to compare the safety and efficacy of 
upadacitinib versus placebo for the treatment of signs and symptoms of subjects with moderately to 
severely active RA who are on a stable dose of csDMARDs and have an inadequate response to 
csDMARDs.  Period 2 is an open-label 52 week extension period to evaluate the long-term safety, 
tolerability, and efficacy of upadacitinib in subjects with RA who have completed Period 1.
The study duration will include a 35-day screening period; a 12-week randomized, double-blind, parallel 
group, placebo controlled treatment period (Period 1); an open-label 52 week extension period; and a 
30-day follow-up period.
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of two treatment groups.  
As indicated below, it is expected that approximately 222 subjects will enter the study from China and 
100 subjects from other countries including Brazil and South Korea:
!
Group 1:  Upadacitinib 15 mg QD (N = 161; 111 from China) (Period 1) → Upadacitinib 15 mg 
QD (Period 2)
!
Group 2:  Placebo (N = 161; 111 from China) (Period 1) → Upadacitinib 15 mg QD (Period 2)
Randomization will be stratified by country and the Chinese population will be up to 80% of the total 
study population.
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the first dose of study 
drug and must remain on a stable dose until Week 24; the csDMARD dose may be decreased only for 
safety reasons.  
Subjects with prior exposure to at most one biologic disease-modifying anti-rheumatic drug (bDMARD) 
for RA may be enrolled in the study (up to 20% of total number of subjects) after the required washout 
period is satisfied and if they have limited exposure (< 3 months) OR response to bDMARD but had to 
discontinue that bDMARD due to intolerability (regardless of treatment duration).  Subjects who are 
considered bDMARD inadequate responders (lack of efficacy), as determined by the Investigator, are not 
eligible.
At Week 24, if a subject fails to meet the Low Disease Activity (LDA) criterion (LDA defined as CDAI 
≤ 10), the investigator should adjust the subject's background RA therapies after assessments for Week 24 
have been completed.
Starting at Week 24 (after Week 24 assessments have been performed), initiation of or change in 
corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen/paracetamol, low 
potency analgesics, or csDMARDs (restricted to oral or parenteral MTX, sulfasalazine, 
hydroxychloroquine, chloroquine and leflunomide, and restricted to concomitant use of up to 
2 csDMARDs except the combination of MTX and leflunomide) is allowed as per local label.  For RA 
flare treatment, no more than 3 consecutive days of systemic corticosteroids (maximum dose of 
0.5 mg/kg/day of prednisone or its equivalent) is allowed, after which subject should resume their usual 
daily oral corticosteroid dose.
Subjects taking MTX should take oral folic acid throughout study participation.  Folic acid dosing and 
timing of regimen will be based on the Investigator's discretion.
Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC compared to baseline is required 
to remain on study drug.  Anyone who does not fulfill this criterion at 2 consecutive visits (starting at 
Week 24) (see Section 5.2.3.1) must be discontinued from the study.


Upadacitinib
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Methodology (Continued):  
Subjects who complete the Week 12 visit (end of Period 1) will enter the 52 week extension portion of 
the study, Period 2.  Subjects who are assigned to upadacitinib treatment in Period 1 will continue to 
receive upadacitinib in an open-label manner.  Subjects who are assigned to placebo in Period 1 will be 
switched to receive upadacitinib from Week 12 onwards.  The primary analysis will be conducted after 
all subjects have completed Period 1 (Week 12) or have prematurely discontinued prior to Week 12.  
Study sites and subjects will remain blinded to the treatment assignment in Period 1 for the duration of 
the study.
Blood samples will be collected for In Vivo Pharmacodynamic biomarker research at designated time 
points throughout the study.  In Vivo Pharmacodynamic biomarker research samples will not be collected 
for subjects in mainland China.
Where not prohibited by local regulations, optional pharmacogenetic samples, epigenetic samples, 
transcriptomic and epigenetic samples, plasma samples for proteomic and targeted protein investigations, 
serum samples for proteomic and targeted protein investigations will be collected for exploratory 
research and validation studies at designated time points throughout the study.
Optional samples for Exploratory Research and Validation Studies will not be collected for subjects in 
mainland China.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who also fulfill the 2010 ACR/EULAR classification criteria for 
RA.
3.
Subjects have been receiving csDMARD therapy ≥ 3 months and on a stable dose for ≥ 4 weeks prior 
to the first dose of study drug.  
!
Subjects must have failed (lack of efficacy) at least one of the following:  MTX, sulfasalazine, 
or leflunomide.
!
Subjects with inadequate response to hydroxychloroquine and/or chloroquine can only be 
included if they have also failed (lack of efficacy or intolerability) MTX, sulfasalazine, or 
leflunomide.
!
The following csDMARDs are allowed (stable dose for ≥ 4 weeks prior to the first dose of study 
drug):  oral or parenteral MTX (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are 
intolerant of MTX at doses ≥ 12.5 mg/week after complete titration; no minimum MTX dose is 
required if MTX is combined with another csDMARD.  For subjects in China and South Korea:  
10 to 25 mg/week; or ≥ 7.5 mg/week in subjects who are intolerant of MTX at doses 
≥10 mg/week after complete titration), sulfasalazine (≤ 3000 mg/day), hydroxychloroquine 
(≤400 mg/day), chloroquine (≤ 250 mg/day), and leflunomide (≤ 20 mg/day).
!
A combination of up to two background csDMARDs is allowed EXCEPT the combination of 
MTX and leflunomide.
4.
Subject meets both of the following disease activity criteria:
e.
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at 
Screening and Baseline Visits; and
f.
hsCRP ≥ upper limit of normal (central lab) at Screening Visit.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
5.
Subjects with prior exposure to at most one bDMARD may be enrolled (up to 20% of total number 
of subjects) after the required washout period.  Specifically, prior to enrollment:
a.
Subjects with limited exposure to bDMARD (< 3 months) OR
b.
Subjects who are responding to bDMARD therapy but had to discontinue due to intolerability 
(regardless of treatment duration).
Main Exclusion:
1.
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Subjects who are considered inadequate responders (lack of efficacy) to bDMARD therapy as 
determined by the Investigator.
3.
History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint 
disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic 
arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms]).  Current diagnosis of secondary 
Sjogren's Syndrome is permitted.
4.
Laboratory values meeting 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 by simplified 4-variable Modification 
of Diet in Renal Disease formula < 40 mL/min/1.73 m2; total white blood cell count < 2,500/μL; 
absolute neutrophil count < 1,500/μL; platelet count < 100,000/μL; absolute lymphocyte count 
< 800/μL; and hemoglobin < 10 g/dL.
Investigational Product:
Upadacitinib
Dose:
15 mg QD
Mode of Administration:
Oral
Reference Therapy:
Matching placebo for upadacitinib QD
Dose:
N/A
Mode of Administration:
Oral
Duration of Treatment:  Period 1:  12 weeks; Period 2:  up to 52 weeks
Criteria for Evaluation:
Efficacy:
Period 1
The primary endpoint in Period 1 is the proportion of subjects achieving ACR20 response at Week 12.
ACR20 response rate will be determined based on 20% or greater improvement in Tender Joint Count 
(TJC) and Swollen Joint Count (SJC) and ≥ 3 of the 5 measures of Patient's Assessment of Pain (Visual 
Analog Scale [VAS]), Patient's Global Assessment of Disease Activity (VAS), Physician's Global 
Assessment of Disease Activity (VAS), Health Assessment Questionnaire Disability Index (HAQ-DI), or 
hsCRP.


Upadacitinib
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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 1 (Continued)
Ranked key secondary endpoints (at Week 12) are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
Change from baseline in Short Form-36 (SF-36) Physical Component Score (PCS);
4.
Proportion of subjects achieving low disease activity (LDA) defined as Disease Activity Score 
(DAS)28 (C-reactive protein [CRP]) ≤3.2;
5.
Proportion of subjects achieving Clinical remission (CR) based on DAS28 (CRP);
6.
Proportion of subjects achieving LDA based on CDAI ≤ 10;
Other key secondary endpoints (at Week 12, if not specified) are:
!
ACR50 response rate;
!
ACR70 response rate;
!
ACR20 response rate at Week 1.
Additional endpoints at all visits are:
!
Change from baseline in individual components of ACR response; 
!
ACR20/50/70 response rates;
!
Change from baseline in DAS28 (CRP) and DAS28 (erythrocyte sedimentation rate [ESR]); 
!
Change from baseline in CDAI and SDAI;
!
Change from baseline in morning stiffness (severity and duration); 
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.22);
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.3);
!
Proportion of subjects achieving LDA or CR based on DAS28 (CRP), DAS28 (ESR), Simplified 
Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) criteria (see below);
!
ACR/EULAR Boolean remission;
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
  
!
Change from baseline in EQ-5D-5L;
!
Change from baseline in SF-36;
!
Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F);
!
Change from baseline in Work Instability Scale for Rheumatoid Arthritis (RA-WIS).


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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 2
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 16, 20, 24, 36, 48 and 64/PD.
!
ACR20/50/70 response rates;
!
Change from baseline in individual ACR components;
!
Change from baseline in DAS28 (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in CDAI and SDAI;
!
Change from baseline in morning stiffness;
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.22);
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.3);
!
Proportion of subjects achieving LDA and the proportion of subjects achieving CR based on 
DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined for Period 1);
!
ACR/EULAR Boolean remission;
!
Concomitant corticosteroid use (systemic use and intra-articular injections).
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 24 and 48 only:
!
Change from baseline in EQ-5D-5L;
!
Change from baseline in SF-36;
!
Change from baseline in FACIT-F;
!
Change from baseline in RA-WIS.
Pharmacokinetic (Period 1 Only):
Blood samples for assay of upadacitinib and possibly other concomitant medications in plasma will be 
collected at Weeks 1, 2, 4, 8, and 12/Premature Discontinuation.
In Vivo Pharmacodynamic Biomarkers (Periods 1 and 2) (except for subjects in mainland China):
Period 1
Change from baseline in lymphocyte subsets (including but not limited to natural killer cells, natural 
killer T cells, B cells, and T cells) will be evaluated at Weeks 8 and 12/Premature Discontinuation.
Period 2
Change from baseline in lymphocyte subsets (including but not limited to natural killer cells, natural 
killer T cells, B cells, and T cells) will be evaluated at Weeks 16, 24, 36, 48, 64/Premature 
Discontinuation (PD).


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Criteria for Evaluation (Continued):
Exploratory Research Variables and Validation Studies (Optional) (Period 1 Only):
Where not prohibited by local regulations, prognostic, predictive, and pharmacodynamics biomarkers 
signatures may be evaluated.  Samples for pharmacogenetic, epigenetic, transcriptomic, and proteomic 
and targeted protein investigations will be collected at various time points.  Assessments will include but 
may not be limited to nucleic acids, proteins, metabolites, or lipids.
Assessments will not be conducted for subjects in mainland China because optional samples for 
Exploratory Research and Validation Studies will not be collected.
Safety:
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.
Statistical Methods:
Efficacy:
All efficacy analyses will be carried out using the Full Analysis Set population, which includes all 
randomized subjects who receive at least one dose of study drug.
Period 1 Efficacy
Analysis of the Primary and Key Secondary Endpoints:
For binary endpoints, frequencies and percentages will be reported for each treatment group.  
Comparison between upadacitinib group and placebo group will be conducted using the Cochran-Mantel-
Haenszel test adjusting for main stratification factors.  
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Comparison between upadacitinib group and placebo group will be carried out using 
the analysis of covariance model with treatment group as the fixed factor, and the corresponding baseline 
value and the main stratification factors as the covariates.
Non-responder imputation approach will serve as the primary analysis approach for key binary endpoints 
and multiple imputation will serve as the primary analysis approach for key continuous endpoints.  
Sensitivity analyses based on observed cases will also be conducted for key endpoints.  The overall type I 
error rate of the primary and key secondary endpoints will be strongly controlled using sequential testing.
Long-Term Efficacy for Period 1 and Period 2 Combined
Long-term efficacy by time point will be summarized using descriptive statistics.
Pharmacokinetic:
A non-linear mixed-effects modeling approach will be used to estimate the population central values and 
the empirical Bayesian estimates of the individual values of upadacitinib oral clearance (CL/F) and 
volume of distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of 
the data.


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Statistical Methods (Continued):
Safety:
Safety analyses will be carried out using the Safety Analysis Set, which includes all subjects who receive 
at least one dose of study drug.  Analyses will be conducted for Period 1 alone, as well as for Period 1 
and Period 2 combined.  Safety will be assessed by AEs, physical examination, laboratory assessments, 
ECG and vital signs.  Frequency tables and lists of subjects with treatment-emergent AEs by preferred 
term as in the Medical Dictionary for Regulatory Activities dictionary, by system organ class, by 
severity, and by relationship to the study drug as assessed by the Investigator will be provided.  The 
changes from baseline in vital signs, physical examination results, and clinical laboratory values will be 
analyzed in a descriptive manner.  Shift of laboratory values from baseline to defined time points will be 
tabulated.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:  
MCID
Minimum clinically important difference
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Delete:  
WOCBP
women of childbearing potential
Section 3.0  Introduction
Subsection Phase 3 Studies with Upadacitinib
Add:  new last paragraph
Moreover, response rates (Study M13-549) as measured by ACR20 at Week 12 from 
csDMARD-inadequate responders which included also subjects with prior exposure to 
one bDMARD, showed that, for subjects receiving either placebo or upadacitinib 15 mg 
(treatment arms of Study M15-557), there is no difference between the csDMARD 
failures without prior bDMARD exposure and those with prior exposure as defined in the 
Inclusion Criterion 6.


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Section 5.1  Overall Study Design and Plan:  Description
Sixth paragraph previously read:
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the 
first dose of study drug and must remain on a stable dose until Week 24; the csDMARD 
dose may be decreased only for safety reasons.  At Week 24, if a subject fails to meet the 
Low Disease Activity (LDA) criterion (LDA defined as CDAI ≤ 10) the investigator 
should adjust the subject's background RA therapies.  Starting at Week 24 (after Week 24 
assessments have been performed), initiation of or change in corticosteroids, non-steroidal 
anti-inflammatory drugs (NSAIDs), acetaminophen, or adding or increasing doses of 
csDMARDs (concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide) is allowed as per local label.  Starting at Week 24, at least 20% improvement 
in BOTH TJC AND SJC compared to baseline is required to remain in the study.  Anyone 
who does not fulfill this criterion at 2 consecutive visits (starting at Week 24) (see 
Section 5.2.3.1) must be discontinued from the study.
Has been changed to read:
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the 
first dose of study drug and must remain on a stable dose until Week 24; the csDMARD 
dose may be decreased only for safety reasons.  
Subjects with prior exposure to at most one bDMARD for RA may be enrolled in the 
study (up to 20% of total number of subjects) after the required washout period is satisfied 
and if they have limited exposure to bDMARD (< 3 months) OR response to bDMARD 
but had to discontinue that bDMARD due to intolerability (regardless of treatment 
duration) (for washout periods, see Inclusion Criterion 7, Section 5.2.1).  Subjects who are 
considered bDMARD inadequate responders (lack of efficacy), as determined by the 
Investigator, are not eligible.
At Week 24, if a subject fails to meet the Low Disease Activity (LDA) criterion (LDA 
defined as CDAI ≤ 10) the investigator should adjust the subject's background RA 
therapies.  Starting at Week 24 (after Week 24 assessments have been performed), 


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initiation of or change in corticosteroids, non-steroidal anti-inflammatory drugs 
(NSAIDs), acetaminophen, or adding or increasing doses of csDMARDs (concomitant 
use of up to 2 csDMARDs except the combination of MTX and leflunomide) is allowed 
as per local label.  Starting at Week 24, at least 20% improvement in BOTH TJC AND 
SJC compared to baseline is required to remain in the study.  Anyone who does not fulfill 
this criterion at 2 consecutive visits (starting at Week 24) (see Section 5.2.3.1) must be 
discontinued from the study.
Section 5.1  Overall Study Design and Plan:  Description
Seventh paragraph, third and fourth sentence previously read:
Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC is required to 
remain on study drug.  Anyone who does not fulfill this criterion at 2 consecutive visits 
(starting at Week 24) (see Section 5.2.3.1) must be discontinued from study drug 
treatment.
Has been changed to read:
Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC compared to 
baseline is required to remain in the study.  Anyone who does not fulfill this criterion at 2 
consecutive visits (starting at Week 24) (see Section 5.2.3.1) must be discontinued from 
the study.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Period 2 (Open Label 52-Week Extension Period)
Fourth and fifth sentence previously read:
Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC is required to 
remain on study drug.  Anyone who does not fulfill this criterion at 2 consecutive visits 
(starting at Week 24) (see Section 5.2.3.1) must be discontinued from study drug 
treatment.


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Has been changed to read:
Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC compared to 
baseline is required to remain in the study.  Anyone who does not fulfill this criterion at 2 
consecutive visits (starting at Week 24) (see Section 5.2.3.1) must be discontinued from 
the study.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Premature Discontinuation from Study (Period 1 and Period 2)
Last paragraph previously read:
In addition, if the subject is willing, a 30-day follow-up phone call may occur to 
determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.
Has been changed to read:
In addition, if the subject is willing, a 30-day follow-up visit (or phone call if a visit is not 
possible) may occur to determine the status of any ongoing AEs/SAEs or the occurrence 
of any new AEs/SAEs.
Section 5.2.1  Inclusion Criteria
Add:  new Criterion 6 and 7
6.
Subjects with prior exposure to at most one bDMARD may be enrolled (up to 20% 
of total number of subjects).  Specifically, prior to enrollment:
a.
Subjects with limited exposure to bDMARD (< 3 months) OR
b. Subjects who are responding to a bDMARD therapy but had to discontinue 
due to intolerability (regardless of treatment duration).
7.
Subjects must have discontinued bDMARD therapy prior to the first dose of study 
drug.
The washout period for bDMARDs prior to the first dose of study is specified 
below or at least five times the mean terminal elimination half-life of a drug:
●
≥ 4 weeks for etanercept;


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●
≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, 
and tocilizumab;
●
≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pre-treatment 
level or normal reference range if pre-treatment levels are not available.
●
For all other bDMARDs, contact the TA MD for the washout period required 
prior to the first dose of study drug.
Section 5.2.1  Inclusion Criteria
Subsection Rationale for Inclusion Criteria
Previously read:
1 – 6
To select the appropriate subject population
7 – 9
Upadacitinib is teratogenic in both rats and rabbits.  The effect of upadacitinib 
on pregnancy and reproduction is unknown
10
In accordance with harmonized Good Clinical Practice (GCP)
Has been changed to read:
1 – 8
To select the appropriate subject population
9 – 11
Upadacitinib is teratogenic in both rats and rabbits.  The effect of upadacitinib 
on pregnancy and reproduction is unknown
12
In accordance with harmonized Good Clinical Practice (GCP)
Section 5.2.2  Exclusion Criteria
Criterion 2 previously read:
Subjects with prior exposure to bDMARD therapy
Has been changed to read:
Subjects who are considered inadequate responders (lack of efficacy) to bDMARD 
therapy as defined by the Investigator.


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Section 5.2.3.1  Permitted Background RA Therapy
Subsection csDMARD Washout
Second paragraph, first bullet previously read:
If taking any of the above on a scheduled basis, they should continue to take them as they 
did at study entry with no change in dose or frequency, including on study visit days;
Has been changed to read:
If taking any of the above on a scheduled basis, they should continue to take them as they 
did at study entry with no change in dose or frequency, including on study visit days (see 
Inclusion Criterion 5);
Section 5.2.3.1  Permitted Background RA Therapy
Subsection csDMARD Washout
Fifth paragraph, last sentence previously read:
Initiation of or change in corticosteroids, NSAIDs, acetaminophen, or csDMARDs 
(restricted to oral or parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine and 
leflunomide, and restricted to concomitant use of up to 2 csDMARDs except the 
combination of MTX and leflunomide) is allowed as per local label.
Has been changed to read:
Initiation of or change in corticosteroids, NSAIDs, acetaminophen/paracetamol, low 
potency analgesics, or csDMARDs (restricted to oral or parenteral MTX, sulfasalazine, 
hydroxychloroquine, chloroquine and leflunomide, and restricted to concomitant use of up 
to 2 csDMARDs except the combination of MTX and leflunomide) is allowed as per local 
label.
Section 5.2.3.2  Prohibited Therapy
Subsection Biologic Therapies
Second paragraph previously read:
Subjects with prior exposure to bDMARDs are excluded from participation in this study.


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Has been changed to read:
Subjects with prior exposure to at most one bDMARD for RA may be enrolled in the 
study (up to 20% of study total number of subjects) after the required washout period is 
satisfied and if they have:
a.
limited bDMARD exposure (< 3 months), OR
b. response to a bDMARD but had to discontinue that bDMARD due to intolerability 
(regardless of treatment duration).  
Subjects must have discontinued all bDMARDs prior to the first dose of study drug as 
specified in the washout procedures (Inclusion Criterion 7, Section 5.2.1).  For all other 
bDMARDs, contact the Therapeutic Area Medical Director for the washout period 
required prior to the first dose of study drug.
Section 5.2.3.2  Prohibited Therapy
Subsection Vaccines
Add:  new last paragraph
If the nasal influenza vaccine is administered, the vaccine must be administered at least 
8 weeks prior to first dose of study drug.
Section 5.2.4  Contraception Recommendations  
Subsection Contraception Recommendation for Females
Fourth paragraph, second bullet previously read:
Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 4 weeks prior to Study Day 1.
Has been changed to read:
Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 30 days prior to Study Day 1.


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Section 5.2.4  Contraception Recommendations  
Subsection Contraception Recommendation for Females
Fourth paragraph, fourth bullet previously read:
Vasectomized partner(s), provided the vasectomized partner verbally confirms receipt of 
the medical assessment of the surgical success and is the only sexual partner.
Has been changed to read:
Vasectomized partner(s), provided the vasectomized partner has received medical 
confirmation of the surgical success and is the only sexual partner.
Section 5.2.4  Contraception Recommendations  
Subsection Contraception Recommendation for Females
Fourth paragraph, last bullet previously read:
True abstinence (if acceptable per local requirements):  Applies to women of childbearing 
potential who do not have male partners and are not engaging in heterosexual intercourse 
as their preferred and usual lifestyle (periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable).
Has been changed to read:
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 [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
Section 5.2.4  Contraception Recommendations  
Subsection Contraception Recommendation for Males
Third paragraph previously read:
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of study drug to practice 
contraception with:


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Has been changed to read:
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of oral study drug to 
practice contraception with:
Section 5.2.4  Contraception Recommendations  
Subsection Contraception Recommendation for Males
Last paragraph previously read:
As described above, contraception should continue while the subject is on the concomitant 
csDMARD and that duration of contraception after discontinuation of the csDMARD 
should be based on the local label.
Has been changed to read:
It is important to note that contraception and sperm donation recommendations described 
above are specifically intended to prevent pregnancy during exposure to the 
investigational therapy with upadacitinib.  The concomitant csDMARDs 
(i.e., methotrexate, sulfasalazine, etc.) have been prescribed per standard of care prior to 
study entry and are allowed to be continued during the study.
Contraception should continue while the subject is on the concomitant csDMARD and 
that duration of contraception after discontinuation of the csDMARD should be based on 
the local label.


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Table 3.  Study Activities (Period 1)
Activity "In Vivo Pharmacodynamic Biomarkers," "Blood Samples for Exploratory Research and Validation Studies 
(Optional – see Table 4)w," and "Dispense Study Drug and Subject Dosing diary" previously read:
Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12/PDa
30-Day 
F/U Visitc
D –35 to D –1
D 1b
D 8
D 15
D 29
D 57
D 85
In Vivo Pharmacodynamic Biomarker
X
X
X
X
Blood Samples for Exploratory 
Research and Validation Studies 
(Optional – see Table 4)w
X
X
X
X
Dispense Study Drug and Subject 
Dosing Diary
X
X
X
Xx
Has been changed to read:
Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12/PDa
30-Day 
F/U Visitc
D –35 to D –1
D 1b
D 8
D 15
D 29
D 57
D 85
In Vivo Pharmacodynamic 
Biomarkersw
X
X
X
X
Blood Samples for Exploratory 
Research and Validation Studies 
(Optional – see Table 4) x
X
X
X
X
Dispense Study Drug and Subject 
Dosing Diary
X
X
X
Xy


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Table 3.  Study Activities (Period 1)
Table note "n.," "p.," and "w." previously read:
n.
For all women of childbearing potential, collect serum for pregnancy test only at screening.  If serum pregnancy 
test comes back borderline, a repeat test is necessary (pregnancy is an exclusion criterion).  If still borderline ≥ 3 
days later, this will be considered documentation of continued lack of a positive result and the subject can be 
enrolled into the study.  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
p.
hsCRP results will remain blinded to Sponsor, Investigator, study site personnel, and the subject for all visits 
except Screening.
w.
Samples only collected if subject provides written consent and if not prohibited by local regulations.  
Has been changed to read:
n.
For all women of childbearing potential, collect serum for pregnancy test only at screening.  If serum pregnancy 
test comes back borderline, a repeat test is necessary (pregnancy is an exclusion criterion).  If still borderline ≥ 3 
days later, this will be considered documentation of continued lack of a positive result and the subject can be 
enrolled into the study.  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.  If during 
the course of the study a woman becomes surgically sterile or post-menopausal and complete documentation is 
available, urine pregnancy test is no longer required.
p.
Central lab hsCRP results will remain blinded to Sponsor, Investigator, study site personnel, and the subject for all 
visits except Screening.
Local laboratory or site testing for hsCRP or CRP is not allowed after Baseline.  Results of tests such as hsCRP 
may be blunted in subjects taking a JAK inhibitor, thereby limiting the clinical utility of these tests in the setting of 
a possible safety assessment or adverse event management.  Any local hsCRP or local CRP tests should not be 
reported to the investigator until a subject completes Period 1.  Treatment assignment may be unblinded to Sponsor 
only when the last subject completes Period 1 (Week 12 visit) for analysis for regulatory purposes.
x.
Samples only collected if subject provides written consent and if not prohibited by local regulations.  Optional 
samples for Exploratory Research and Validation Studies will not be collected for subjects in mainland China.
Table 3.  Study Activities (Period 1)
Add:  new table note "w."
In Vivo Pharmacodynamic biomarkers will not be collected for subjects in mainland 
China.
Table 4.  Study Activities – Optional Samples for Exploratory Research and 
Validation Studies (Period 1 Only)
Table note "Notes:"
Add:  new last sentence
Optional samples for Exploratory Research and Validation Studies will not be collected 
for subjects in mainland China.


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Table 5.  Studies Activities (Period 2)
Activity "In Vivo Pharmacodynamic Biomarkers" previously read:
In Vivo Pharmacodynamic Biomarkers
Has been changed to read:
In Vivo Pharmacodynamic Biomarkersp
Table 5.  Studies Activities (Period 2)
Add:  new last sentence
If during the course of the study a woman becomes surgically sterile or post-menopausal 
and complete documentation is available, urine pregnancy test is no longer required.
Table 5.  Studies Activities (Period 2)
Table note "j." 
Add:  new table note "p."
In Vivo Pharmacodynamic biomarker samples will not be collected for subjects in 
mainland China.
Section 5.3.1.1  Study Procedures
Subsection Informed Consent
First paragraph
Add:  new third sentence
The separate informed consent is not required for subjects in mainland China because 
optional samples for exploratory research and validation studies will not be collected.
Section 5.3.1.1  Study Procedures
Subsection TB Testing/TB Prophylaxis
Heading "Period 2"
Add:  new first paragraph
Subjects with documentation of prior positive result of QuantiFERON-TB Gold Test (or
equivalent) and/or PPD are not required to repeat either TB test during the study and 


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should be considered positive.  The TB risk assessment form will be completed annually 
for all subjects, regardless of TB test results.
Section 5.3.1.1  Study Procedures
Subsection TB Testing/TB Prophylaxis
Heading "Period 2"
Third paragraph, last sentence previously read:
Study drug(s) should not be withheld and Isoniazid should be initiated, and 2 to 4 weeks 
later (per local guidelines), the subject should be re-evaluated (unscheduled visit) for signs 
and symptoms as well as laboratory assessment of isoniazid toxicity.  
Has been changed to read:
TB prophylaxis should be initiated and study drug(s) should not be withheld.  Two to 4 
weeks later (per local guidelines), 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 and prior therapy should be captured in the eCRF.
Table 6.  Clinical Laboratory Tests
Subsection Other Laboratory Tests
Heading "Local Lab Tests"
Add:  
MRB Panelk
Table 6.  Clinical Laboratory Tests
Table note "e."
Add:  new last sentence
HBV DNA testing is also required for subjects who meet specific toxicity management 
criteria (See ALT/AST toxicity management criteria in Table 8).


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Table 6.  Clinical Laboratory Tests
Table note "j."
Sixth sentence previously read:
In the event a pregnancy test comes back borderline, a repeat test is required.
Has been changed to read:
In the event a pregnancy test comes back borderline, a repeat test is required (≥ 3 days 
later) to document continued lack of a positive result.  
Table 6.  Clinical Laboratory Tests
Add:  new last table note "k."
If needed to assess B cell counts in subjects who have discontinued rituximab, see 
Inclusion Criteria 7.
Section 5.3.1.2.1  In Vivo Pharmacodynamic Biomarker Samples
Add:  new second paragraph
In Vivo Pharmacodynamic biomarker samples will not be collected for subjects in 
mainland China.
Section 5.3.1.2.2  Optional Samples for Exploratory Research and Validation Studies
Add:  new second paragraph
Optional samples for Exploratory Research and Validation Studies will not be collected 
for subjects in mainland China.
Section 5.3.6.1  In Vivo Pharmacodynamic Biomarker Samples
Add:  new last paragraph
In Vivo Pharmacodynamic biomarker research samples will not be collected for subjects 
in mainland China.


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Section 5.3.6.2  Exploratory Research Variables and Validation Studies
Add:  new second paragraph
Optional samples for Exploratory Research and Validation Studies will not be collected 
for subjects in mainland China.
Section 5.4.1  Discontinuation of Individual Subjects
Twelfth and thirteenth bullet previously read:
●
Starting at Week 24 and thereafter, subjects who failed to show at least 20% 
improvement in TJC and SJC compared to baseline at 2 consecutive visits 
despite optimization of background RA therapies should be discontinued from 
the study.
●
If the subject experiences a study drug interruption > 7 consecutive days 
during Weeks 1 through 24 or > 30 consecutive days after Week 24 (other than 
for reasons listed in Section 6.1.7).
Has been changed to read:
●
Starting at Week 24, at least 20% improvement in BOTH TJC and SJC 
compared to baseline is required to remain in the study.  Anyone who does not 
fulfill this criterion at 2 consecutive visits (starting at Week 24) must be 
discontinued from the study.
The Investigator should contact the AbbVie TA MD if a subject experiences a study drug 
interruption > 7 consecutive days during Weeks 1 through 24 or > 30 consecutive days 
after Week 24 (other than for reasons listed in Section 6.1.7) to discuss the management 
of the subject and possible discontinuation from participation in the study.
Section 5.4.1  Discontinuation of Individual Subjects
Third paragraph, second sentence previously read:
In addition, if subject is willing, a 30-day follow-up phone call after the last dose of study 
drug may be completed to ensure all treatment emergent AEs/SAEs have been resolved.  


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Has been changed to read:
In addition, if subject is willing, a 30-day follow-up visit/phone call after the last dose of 
study drug may be completed to ensure all treatment emergent AEs/SAEs have been 
resolved.  
Section 5.5.7  Drug Accountability
Last paragraph previously read:
All empty/used study drug packaging will be inventoried by the site and verified by the 
site monitor.  Empty/used study drug packaging should be returned by the subject at each 
visit for accountability and compliance purposes and new packaging issued as necessary.  
Empty/used packaging will be retained (unless prohibited by local law) until the site 
monitor is on site to confirm the returned study drug.  Site monitor(s) and site staff will 
complete study drug accountability via IRT, source documents, subject dosing diaries, and 
by visually inspecting the packaging whenever possible.  After drug accountability has 
been completed, used packaging and unused study drug will be returned to the Abbvie-
designated destruction depot by the site monitor.
Has been changed to read:
All empty/used study drug packaging will be inventoried by the site.  Empty/used study 
drug packaging should be returned by the subject at each visit for accountability by the 
site and compliance purposes and new packaging issued as necessary.  Site staff will 
complete study drug accountability via IRT, source documents, subject dosing diaries, and 
by visually inspecting the packaging whenever possible.  
After drug accountability has been completed by the site, empty used packaging may be 
discarded with any subject identifiers removed or returned to AbbVie-designated 
destruction depot. 
Unused study drug and used packaging with remaining study drug will be destroyed on 
site according to local procedures or regulations, or returned to the AbbVie-designated 


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M15-557 Protocol Amendment 3
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destruction depot (for those sites that do not meet AbbVie's requirements for on-site 
destruction). 
For sites performing on-site drug destruction or using a third party vendor for drug 
destruction, a copy of the destruction methodology and date of destruction/date prepared 
for destruction should be maintained at the site's facility.  Monitors will reconcile the site's 
processes, source documents, subject's dosing diaries, IRT or site accountability records, 
and destruction records to assure site compliance.
Section 6.1.1.3  Adverse Events of Special Interest
Bullet list previously read:
●
Serious infections, opportunistic infections, herpes zoster, and TB;
●
Malignancy and lymphoproliferative disorders;
●
Gastrointestinal perforations;
●
Cardiovascular events (e.g., major adverse cardiovascular event [MACE]);
●
Lipid profile changes;
●
Anemia and hemoglobin effects;
●
Decreased neutrophil counts;
●
Decreased lymphocyte counts;
●
Increased serum creatinine and renal dysfunction;
●
Hepatic events and increased hepatic transaminases;
●
Increased creatine phosphokinase (CPK).
●
Embolic and thrombotic events (non-cardiac, non-CNS).
Has been changed to read:
●
Serious infections;
●
Opportunistic infections;
●
Herpes zoster;
●
Tuberculosis;
●
Malignancy (all types);


Upadacitinib
M15-557 Protocol Amendment 3
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●
Gastrointestinal perforations;
●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE]);
●
Lipid profile changes;
●
Anemia;
●
Neutropenia;
●
Lymphopenia;
●
Increased serum creatinine and renal dysfunction;
●
Hepatic events and increased hepatic transaminases;
●
Elevated creatine phosphokinase (CPK).
●
Embolic and thrombotic events (non-cardiac, non-CNS).
Section 6.1.7  Toxicity Management
Add:  new last paragraph
The Investigator should contact the AbbVie TA MD if a subject experiences a study drug 
interruption > 7 consecutive days during Weeks 1 through 24 or > 30 consecutive days 
after Week 24 to discuss the management of the subject and possible discontinuation from 
participation in the study.
Section 6.2.2  Reporting
First paragraph, first sentence previously read:
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  
Has been changed to read:
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.  


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Section 7.0  Protocol Deviations
Contact information previously read:
Primary Contact:
United States
Office:
Fax:
Email:
Alternate Contact:
AbbVie Srl 
Viale dell'Arte, 25
00144 Roma
ITALY
Office:
Fax:
Email:
Has been changed to read:
Primary Contact:
AbbVie Srl 
Viale dell'Arte, 25
00144 Roma
ITALY
Office:
Fax:
Email:
Alternate Contact:
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:
Section 8.1.5.2.1  Treatment-Emergent Adverse Events (TEAE)
Seventh paragraph previously read:
The AEs of special interest (including but not limited to serious infection, opportunistic 
infection, herpes zoster, TB, gastrointestinal perforations, malignancies, MACE, renal 
dysfunction, anemia, increased CPK, and drug-related hepatic disorders) will be 


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summarized.  Event rate (per 100 patient years) for AEs of special interest will also be 
summarized for the combined safety analysis of Period 1 and Period 2.
Has been changed to read:
The AEs of special interest (including but not limited to serious infection, opportunistic 
infection, herpes zoster, TB, gastrointestinal perforations, malignancies, adjudicated 
cardiovascular events (e.g., major adverse cardiovascular event [MACE]), lipid profile 
changes, anemia, neutropenia, lymphopenia, increased serum creatinine and renal 
dysfunction, hepatic events and increased hepatic transaminases, elevated CPK and non-
cardiac, non-CNS embolic and thrombotic events) will be summarized.  Event rate (per 
100 patient years) for AEs of special interest will also be summarized for the combined 
safety analysis of Period 1 and Period 2.
Section 8.1.7  Statistical Analysis of Biomarker Data
Section title previously read:
Statistical Analysis of Biomarker Data
Has been changed to read:
Statistical Analysis of Biomarker Data (except for subjects in mainland China)
Section 9.3  Subject Information and Consent
Add:  new fourth paragraph
The separate informed consent is not required for subjects in mainland China because 
optional samples for exploratory research and validation studies will not be collected.


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Pharmacovigilance and Patient 
Safety
Statistics
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical Project Development
Bioanalysis
Has been changed to read:
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Pharmacovigilance and Patient 
Safety
Statistics
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical Program Development
Bioanalysis

SAP_001.pdf: 
Upadacitinib
M15-557 – Statistical Analysis Plan
Version 1.0 – 30 May 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M15-557
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study with Upadacitinib (ABT-494) in 
Subjects from China and Selected Countries with 
Moderately to Severely Active Rheumatoid Arthritis 
Who Have Had an Inadequate Response to 
Conventional Synthetic Disease-Modifying Anti-
Rheumatic Drugs (csDMARDs) 
Date:  30 May 2019
Version 1.0
NCT02955212


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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................7
4.0
Study Objectives, Design and Procedures.............................7
4.1
Study Objectives ........................................................................................7
4.2
Overall Study Design and Plan..................................................................7
4.3
Sample Size..............................................................................................10
4.4
Interim Analysis and Data Base Lock......................................................11
4.5
Data Monitoring Committee (DMC) Activities.......................................11
5.0
Analysis Populations and Analysis Windows .....................11
5.1
Analysis Populations................................................................................11
5.2
Analysis Windows ...................................................................................12
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............15
6.1
Demographics and Baseline Characteristics............................................15
6.2
Medical History .......................................................................................18
6.3
Prior Treatment and Concomitant Medications.......................................18
6.4
Protocol Deviations..................................................................................19
7.0
Patient Disposition.................................................................19
8.0
Study Drug Exposure and Compliance...............................21
8.1
Study Drug Exposure...............................................................................21
8.2
Compliance ..............................................................................................22
9.0
Efficacy Analysis....................................................................22
9.1
General Considerations............................................................................22
9.1.1
Efficacy Analysis at Different Phases of the Study.................................22
9.1.2
Definition of Missing Data Imputation....................................................23
9.2
Efficacy Analysis for Period 1.................................................................25
9.2.1
Primary Efficacy Analysis .......................................................................25
9.2.2
Sensitivity Analysis of Primary Efficacy Variables ................................25
9.2.3
Key Secondary Efficacy Analyses...........................................................25
9.2.4
Additional Efficacy Analyses ..................................................................26


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9.2.5
Handling of Multiplicity ..........................................................................27
9.2.6
Efficacy Subgroup Analysis ....................................................................28
9.2.7
Summary of Efficacy Analysis for Period 1 ............................................28
9.3
Long-Term Efficacy Analysis..................................................................31
9.4
Efficacy Variables Definitions and Conventions.....................................33
9.4.1
ACR Criteria ............................................................................................33
9.4.2
Joint Evaluation .......................................................................................36
9.4.3
Patient's Global Assessment of Disease Activity Visual Analog 
Scale (VAS) .............................................................................................37
9.4.4
Physician's Global Assessment of Disease Activity Visual Analog 
Scale (VAS) .............................................................................................38
9.4.5
Patient's Global Assessment of Pain........................................................38
9.4.6
Disease Activity Score (DAS28) .............................................................38
9.4.7
Simplified Disease Activity Index (SDAI) ..............................................39
9.4.8
Clinical Disease Activity Index (CDAI)..................................................39
9.4.9
Clinical Remission (CR) and Low Disease Activity (LDA)....................40
9.4.10
ACR/EULAR Boolean Remission...........................................................40
9.4.11
Disability Index of Health Assessment Questionnaire (HAQ-DI)...........40
9.4.12
EuroQoL-5D (EQ-5D-5L) .......................................................................41
9.4.13
Form SF-36v2 ..........................................................................................41
9.4.14
Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F)................................................................................................42
9.4.15
Work Instability Scale for Rheumatoid Arthritis (RA-WIS)...................42
10.0
Safety Analysis.......................................................................43
10.1
General Considerations............................................................................43
10.2
Analysis of Adverse Events.....................................................................44
10.2.1
Analysis of Adverse Events for Period 1.................................................45
10.2.1.1
Adverse Events Overview........................................................................45
10.2.1.2
Adverse Events by System Organ Class and Preferred Term..................45
10.2.1.3
TEAEs by Maximum Severity.................................................................46
10.2.1.4
TEAEs by Relationship............................................................................46


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10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and Preferred 
Term.........................................................................................................47
10.2.1.6
Adverse Events of Special Interest ..........................................................47
10.2.2
Analysis of Long-Term Adverse Event Rates .........................................49
10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................50
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT ........................................................................50
10.2.2.3
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................51
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation ........................51
10.3
Analysis of Laboratory Data....................................................................51
10.3.1
Variables and Units..................................................................................51
10.3.2
Analysis of Laboratory Data for Period 1................................................53
10.3.2.1
Assessment of Mean Change from Baseline and Percent Change 
from Baseline in Clinical Laboratory Variables ......................................54
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................54
10.3.2.3
Assessment of Potentially Clinically Significant Laboratory 
Variables ..................................................................................................55
10.3.2.4
Assessment of Liver Elevations...............................................................55
10.3.3
Analysis of Long-Term Laboratory Data.................................................56
10.3.3.1
Assessment of Mean Change from Baseline and Percent Change 
from Baseline in Clinical Laboratory Variables ......................................56
10.3.3.2
Assessment of Potentially Clinically Significant Laboratory 
Values ......................................................................................................56
10.3.3.3
Assessment of Liver Elevations...............................................................57
10.4
Analysis of Vital Signs ............................................................................57
10.4.1
Variables and Criteria Defining Abnormality..........................................57
10.4.2
Analysis of Vital Sign for Period 1..........................................................58
10.4.3
Analysis of Long-Term Vital Sign...........................................................58
11.0
References...............................................................................59


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12.0
Appendix.................................................................................60
List of Tables
Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ACR 
Components and Morning Stiffness) .......................................................13
Table 2.
Analysis Windows for Safety Analysis of Labs and Vital Signs 
for Period 1 ..............................................................................................13
Table 3.
Analysis Windows for Efficacy Analysis for Period 1 (for 
EQ-5D-5L, SF-36, FACIT-F and RA-WIS)............................................14
Table 4.
Analysis Windows for Safety Analysis of Lab Parameters IgG and 
IgM for Period 1.......................................................................................14
Table 5.
Analysis Windows for Safety Analysis of Lymphocyte subsets 
Lab Parameters for Period 1.....................................................................14
Table 6.
Subgroups for Efficacy Analysis .............................................................28
Table 7.
Summary of Efficacy Variables and Corresponding Analyses for 
Efficacy Analysis in Period 1 ..................................................................29
Table 8.
Summary of Efficacy Variables and Corresponding Analyses for 
Long-Term Efficacy Analysis..................................................................33
Table 9.
Anatomical Joints Assessed for Calculation of Tender and 
Swollen Joint Counts (TJC68 and SJC66)...............................................37
Table 10.
Anatomical Joints for DAS28(CRP) Calculation ....................................39
Table 11.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................48
Table 12.
List of Laboratory Variables....................................................................52
Table 13.
Criteria for Potentially Clinically Significant Vital Sign Findings..........58
List of Figures
Figure 1.
Study Design............................................................................................10


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List of Appendices
Appendix A.
OMERACT Criteria.................................................................................61
Appendix B.
Analysis of Binary Endpoints ..................................................................72
Appendix C.
Analysis of Continuous Endpoints using Mixed Effect Model 
Repeat Measurement (MMRM)...............................................................74


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the Data and Statistical Science Department for upadacitinib Study M15-557.  It provides 
details to further elaborate statistical methods as outlined in the protocol.  
Pharmacokinetic and biomarker analyses will be performed separately, and the 
corresponding analysis plan is documented separately.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Study Objectives
Period 1
1.
To compare the efficacy of upadacitinib 15 mg QD versus placebo for the 
treatment of signs and symptoms of subjects with moderately to severely active RA 
who are on a stable dose of csDMARDs and have an inadequate response to 
csDMARDs.
2.
To compare the safety and tolerability of upadacitinib 15 mg QD versus placebo in 
subjects with moderately to severely active RA who are on a stable dose of 
csDMARDs and have an inadequate response to csDMARDs.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib 15 mg QD in 
subjects with RA who have completed Period 1.
4.2
Overall Study Design and Plan
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 12-week, 
randomized, double-blind, parallel-group, placebo-controlled period designed to compare 


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the safety and efficacy of upadacitinib 15 mg QD versus placebo for the treatment of signs 
and symptoms of subjects with moderately to severely active RA from China, Brazil, and 
South Korea who are on a stable dose of csDMARDs and have an inadequate response to 
csDMARDs.  Period 2 is an open-label 52-week extension period to evaluate the long-
term safety, tolerability, and efficacy of upadacitinib 15 mg QD in subjects from China, 
Brazil, and South Korea who have completed Period 1.
The study is designed to enroll approximately 322 subjects at approximately 50 study 
centers in China, Brazil and South Korea to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
Therefore, if the target number of subjects has been enrolled, there is a possibility that 
additional subjects in screening will not be enrolled.
The study duration will include a 35-day screening period; a 12-week randomized, 
double-blind, parallel-group, placebo-controlled treatment period (Period 1); an open-
label 52-week extension period (Period 2); and a 30-day follow-up period (visit or call).
Subjects who meet eligibility criteria will be randomized in a 1:1 ratio to one of 
two treatment groups.  It is expected that approximately 222 subjects will enter the study 
from China and 100 subjects from other countries including Brazil and South Korea:
●
Group 1:  upadacitinib 15 mg QD (Period 1) → upadacitinib 15 mg QD 
(Period 2)
●
Group 2:  Placebo (Period 1) → upadacitinib 15 mg QD (Period 2)
Randomization will be stratified by country.
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the 
first dose of study drug and must remain on a stable dose until Week 24; the csDMARD 
dose may be decreased only for safety reasons.  At Week 24, if a subject fails to meet the 
Low Disease Activity (LDA) criterion (LDA defined as CDAI ≤ 10) the investigator 
should adjust the subject's background RA therapies.  Starting at Week 24 (after Week 24 


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9
assessments have been performed), initiation of or change in corticosteroids, non-steroidal 
anti-inflammatory drugs (NSAIDs), acetaminophen, low potency analgesics, or 
csDMARDs (restricted to oral or parenteral MTX, sulfasalazine, hydroxychloroquine, 
chloroquine and leflunomide, and restricted to concomitant use of up to 2 csDMARDs 
except the combination of MTX and leflunomide) is allowed as per local label.  Starting at 
Week 24, at least 20% improvement in BOTH TJC AND SJC is required to remain in the 
study.  Anyone who does not fulfill this criterion at 2 consecutive visits (starting at 
Week 24) must be discontinued from the study.
Subjects taking MTX should take oral folic acid throughout study participation.  Folic 
acid dosing and timing of regimen will be based on the Investigator's discretion.  
Subjects who complete the Week 12 visit (end of Period 1) will enter the open-label 
52-week extension portion of the study, Period 2.  Subjects who are assigned to 
upadacitinib treatment in Period 1 will continue to receive upadacitinib per original 
randomization assignment in an open-label manner.  Subjects who are assigned to placebo 
in Period 1 will be switched to receive open-label upadacitinib from Week 12 onwards.
The primary analysis will be conducted after all subjects have completed Period 1 
(Week 12) or have prematurely discontinued prior to Week 12.  
Schematics of Period 1 and Period 2 are shown in Figure 1.


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Figure 1.
Study Design
4.3
Sample Size
The planned total sample size of 322 for this study provides over 90% power for a 21.7% 
difference in ACR20 response rate at Week 12 (assuming a placebo ACR20 response rate 
of 36.7%), at two-sided significance level of 0.05 and accounting for a 10% dropout rate.  
This sample size will also provide at least 90% power for most of the key secondary 
endpoints, including change from baseline in DAS28 (CRP), ACR50 response rate, LDA 
and CR based on DAS28 (CRP), and SF-36 PCS, at two-sided significance level of 0.05 
and accounting for a 10% dropout rate.


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4.4
Interim Analysis and Data Base Lock
An unblinded analysis will be conducted after all subjects have completed Period 1 
(Week 12) or have prematurely discontinued prior to Week 12 for the purpose of 
regulatory submission.  
4.5
Data Monitoring Committee (DMC) Activities
An independent external Data Monitoring Committee (DMC) is used to review unblinded 
safety data at regular intervals during the conduct of the study.  The DMC will provide 
recommendation to an AbbVie Point of Contact on whether to continue, modify, or 
terminate studies after each review.  When needed, high level unblinded efficacy data may 
also be requested by the DMC and be reviewed so that the DMC can assess the 
benefit:risk of any emerging safety differences.
5.0
Analysis Populations and Analysis Windows
5.1
Analysis Populations
Full Analysis Set (FAS)
The Full Analysis Set (FAS) includes all randomized subjects who received at least 
one dose of study drug.  The FAS will be used for all efficacy and baseline analyses.
Per Protocol Analysis Set
The Per Protocol Analysis Set represents a subset of the FAS and consists of all FAS 
subjects who did not meet any major protocol deviations during Period 1 of the study.  
Additional analysis of the primary efficacy endpoint will be conducted on the Per Protocol 
analysis set, in order to evaluate the impact of major protocol deviations.
Major protocol deviations (ICH deviations and other clinically significant non-ICH 
deviations) will be identified prior to database lock.


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Safety Analysis Set
The Safety Analysis Set consists of all subjects who received at least one dose of study 
drug.  For the Safety Analysis Set, subjects are assigned to a treatment group based on the 
"as treated" treatment group, regardless of the treatment randomized.  The "as treated" is 
determined by the treatment the subject received during the majority of the subject's drug 
exposure time in the analysis period.
5.2
Analysis Windows
Definition of Study Days (Days Relative to the First Dose of Study Drug)
Study Days are calculated for each collection date relative to the date of the first dose of 
study drug.  It is defined as the number of days between the date of the first dose of study 
drug and the collection date.  Study days are negative values when the collection date of 
interest is prior to the first study drug dose date.  Study days are positive values when the 
collection date of interest is on or after the first study drug dose date.  The day of the 
first dose of study drug is defined as Study Day 1, while the day prior to the first study 
drug dose is defined as Study Day –1 (there is no Study Day 0).  Study days are used to 
map actual study visits to the protocol-specified study visits.
Definition of Analysis Windows
The following rules will be applied to assign actual subject visits to protocol-specified 
visits.  For each protocol-specified study visit, a target study day will be identified to 
represent the corresponding visit along with a window around the target day.  Windows 
will be selected in a non-overlapping fashion so that a collection date does not fall into 
multiple visit windows.  If a subject has two or more actual visits in one visit window, the 
visit closest to the target day will be used for analysis.  If two visits are equidistant from 
the target day, then the later visit will be used for analysis. 
The visit window and the target study day for each protocol-specified visit in Period 1 are 
displayed in Table 1, Table 2, Table 3, Table 4, and Table 5 (depending on the different 


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visit schedules of different endpoints).  Visit windows for protocol-specified visits in 
Period 2 are defined similarly.
Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ACR 
Components and Morning Stiffness)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
1
2
8
11
2
12
15
22
4
23
29
43
8
44
57
71
12
72
85
min (99, first dose date 
of Period 2)
a.
Day of first dose of study drug.
Table 2.
Analysis Windows for Safety Analysis of Labs and Vital Signs for 
Period 1
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
2
2
15
22
4
23
29
43
8
44
57
71
12
72
85
min (99, first dose date 
of Period 2)
a.
Day of first dose of study drug.


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Table 3.
Analysis Windows for Efficacy Analysis for Period 1 (for 
EQ-5D-5L, SF-36, FACIT-F and RA-WIS)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
4
2
29
57
12
58
85
min (127, first dose 
date of Period 2)
a.
Day of first dose of study drug.
Table 4.
Analysis Windows for Safety Analysis of Lab Parameters IgG and 
IgM for Period 1
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
8
2
57
Min (99, first dose date 
of Period 2)
a.
Day of first dose of study drug.
Table 5.
Analysis Windows for Safety Analysis of Lymphocyte subsets Lab 
Parameters for Period 1
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
8
2
57
71
12
72
85
min (99, first dose date 
of Period 2)
a.
Day of first dose of study drug.


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6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
6.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics information will be collected at the Baseline 
visit of the study and will be summarized for the FAS.  The number of observations, 
mean, standard deviation, median, minimum and maximum will be summarized for 
continuous variables.  Categorical or discrete variables will be summarized via 
frequencies and percentages.  Summary statistics will be computed for each treatment 
group and overall.
Main Demographic and Baseline Characteristics
●
Sex (male/female)
●
Age (years)
●
Age Categories (< 40, [40, 65], ≥ 65 years)
●
Race (White, Black or African American, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Asian, Other)
●
Country (China, South Korea, Brazil)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
●
Weight (kg)
●
Weight Categories (< 60 kg, ≥ 60 kg)
●
Height (cm)
●
Body Mass Index (BMI) (kg/m2)
●
Body Mass Index (BMI) Category (kg/m2) (BMI < 25 vs BMI ≥ 25)
RA Medical History and Characteristics
●
Duration of RA Symptoms in years
●
Duration of RA Diagnosis in years
●
Duration of RA Symptoms Categories (< 5 year or ≥ 5 year)


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●
Duration of RA Diagnosis Categories (< 5 year or ≥ 5 year)
●
Prior exposure to bDMARDs (Yes or No)
ACR and/or DAS Components at Baseline
●
Tender joint count (TJC68) defined as the number of tender joints out of 
68 assessed joints
●
Swollen joint count (SJC66) defined as the number of swollen joints out of 
66 assessed joints
●
Tender joint count (TJC28) defined as the number of tender joints out of 
28 assessed joints used for DAS28 calculation
●
Swollen joint count (SJC28) defined as the number of swollen joints out of 
28 assessed joints used for DAS28 calculation
●
Physician's global assessment of disease activity (mm on a 100-mm horizontal 
visual analogue scale [VAS])
●
Patient's assessment of pain within last week (mm on a 100-mm horizontal 
(VAS)
●
Patient's global assessment of disease activity within last 24 hours (mm on a 
100-mm horizontal VAS)
●
Health Assessment Questionnaire Disability Index of the (HAQ – DI) 
(range:  0 to 3)
●
High sensitivity C-reactive protein (hsCRP) (mg/L)
●
Erythrocyte sedimentation rate (ESR) (mm/hr)
Other Baseline RA Disease Characteristics
●
Anti-cyclic citrullinated peptide (Anti-CCP) (units)
●
Anti-CCP status:  Positive or Negative
●
Rheumatoid Factor (RF) (units)
●
Rheumatoid Factor (RF) status:  Positive or Negative
●
RF and Anti-CCP both positive vs. at least one negative
●
RF and Anti-CCP both negative vs. at least one positive


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Percentage of subjects on oral steroid at baseline
●
Oral steroid dose (prednisone equivalent) at baseline
●
MTX dose at baseline
●
Concomitant csDMARD at baseline (MTX alone, MTX and other csDMARD, 
csDMARD other than MTX)
●
DAS28 [hsCRP]
●
DAS28 [ESR]
●
DAS28 Categories:
○
DAS28 > 5.1 (High Disease Activity)
○
DAS28 ≤5.1
●
Clinical Disease Activity Index (CDAI)
●
CDAI categories:
○
CDAI > 22 (High Disease Activity)
○
CDAI ≤ 22
●
Simplified Disease Activity Index (SDAI)
●
SDAI categories:
○
SDAI > 26 (High Disease Activity)
○
SDAI ≤ 26
Patient Report Outcomes at Baseline
●
Morning stiffness (severity and duration)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
Work Instability Scale for Rheumatoid Arthritis (RA-WIS)
●
36-Item Short Form Health Survey (SF-36) Version 2:  physical component 
summary, mental component summary and the 8 sub-domain scores
●
EQ-5D-5L
Clinical Tests at Screening
●
Chest x-ray


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ECG
●
Tuberculin PPD skin test, QuantiFERON TB Gold test
●
Hepatitis Testing
●
Serum pregnancy test
Immunization History
●
BCG immunization
●
Herpes Zoster immunization
●
Hepatitis B immunization
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [user, ex-user, non-user, unknown]
●
Alcohol Use [drinker, ex-drinker, non-drinker, unknown]
6.2
Medical History
Medical history data will be summarized and presented for FAS population using body 
systems and conditions/diagnoses as captured on the CRF.  The body systems will be 
presented in alphabetical order and the conditions/diagnoses will be presented in 
alphabetical order within each body system.  The number and percentage of subjects with 
a particular condition/diagnosis will be summarized for each randomized treatment group 
as well as overall.  Subjects reporting more than one condition/diagnosis within a body 
system will be counted only once for that body system.  No statistical comparison will be 
performed for medical history reporting.
6.3
Prior Treatment and Concomitant Medications
Prior and concomitant medications will be summarized by each randomized treatment 
group as well as overall for FAS.  Prior medications are those medications taken prior to 
the first dose of study drug.  This includes medications with a start date before the 
first study drug administration date, regardless of the end date of these medications.  


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Medications taken on the day of the first dose of study drug are not counted as prior 
medications.  Concomitant medications are those medications, other than study drug, 
taken after the first dose of study drug and within 1 day of the last dose of study drug.  
This includes medications with a start date between first study drug administration and 
last study drug administration + 1 day, as well as, medications with a start date prior to 
first dose of study drug and which are ongoing after first dose of study drug.  Medications 
taken on the day of the first dose of study drug are counted as concomitant medications.
The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
6.4
Protocol Deviations
Protocol deviations are categorized as follows based on ICH deviation criteria:
●
Those who entered the study even though they did not satisfy the entry criteria
●
Those who developed withdrawal criteria during the study and were not 
withdrawn
●
Those who received the wrong treatment or incorrect dose, and
●
Those who received an excluded or prohibited concomitant medication.
The protocol deviations listed above will be summarized and listed by treatment group.
7.0
Patient Disposition
The following will be summarized by randomized treatment group as well as overall:
●
number of subjects randomized,
●
number of subjects included in key analysis populations (Full Analysis Set and 
Per Protocol Analysis Set for primary efficacy analysis, Safety Analysis Set
for Period 1),
●
number of subjects who completed Period 1 study participation,


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number of subjects who entered Period 2,
●
number of subjects on-going in Period 2 (if applicable),
●
number of subjects who completed overall study (Period 1 and Period 2) 
participation.
This summary will be repeated by site.
Premature discontinuation details will be further summarized separately for Period 1 and 
Period 2 as follows.
Period 1
The number and percentage of subjects completed Period 1 and prematurely discontinued 
in Period 1 will be summarized by randomized treatment group, by study drug 
completion/discontinuation, with the primary reason for discontinuation collected from 
CRF by the following categories:
●
Adverse event (AE)
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy 
●
Other.
Subjects may have more than one reason for discontinuing, but only the primary reason 
will be summarized.
In addition, the number and percentage of subjects enrolled in Period 2 will also be 
summarized by randomized treatment group.
Period 2
Period 2 patient dispositions and reason for discontinuation will be summarized for 
upadacitinib 15 mg QD group.


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Among the subjects who entered Period 2, the number and percentage of subjects 
completed, on-going (if applicable), and prematurely discontinued study drug in Period 2 
will be summarized.  
For subjects who prematurely discontinued study drug, the primary reason for 
discontinuation will be summarized with the same categories as given above for Period 1.
Subjects may have more than one reason for discontinuing, but only the primary reason 
will be summarized.
8.0
Study Drug Exposure and Compliance
8.1
Study Drug Exposure
The duration of exposure to study drug will be summarized for the safety analysis set by 
the following groups.
1.
Upadacitinib 15 mg QD
This includes upadacitinib 15 mg QD exposure from subjects starting on 
upadacitinib 15 mg QD and subjects switching from placebo to upadacitinib 15 mg 
QD.
2.
Placebo
The duration of exposure to study drug will be summarized for each group as specified 
above, with the number of subjects, mean, standard deviation, median, minimum and 
maximum values.  In addition, the number and percentage of subjects exposed to study 
drug will be summarized for the following cumulative duration intervals.
●
≥ 2 weeks
●
≥ 1 month
●
≥ 3 months
●
≥ 6 months


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≥ 9 months
●
≥ 12 months
8.2
Compliance
Study drug compliance will be summarized for each treatment group for Period 1.  The 
compliance is defined as the number of tablets taken (i.e., the difference between the 
number of tablets dispensed and the number of tablets returned) during the subject's 
participation in Period 1 divided by the number of days that the subject was in the 
Treatment Phase of Period 1.
9.0
Efficacy Analysis
9.1
General Considerations
There are two sets of planned efficacy analysis:  efficacy analysis for Period 1 and 
long-term efficacy analysis.  All efficacy analyses will be carried out using the FAS 
population.
9.1.1
Efficacy Analysis at Different Phases of the Study
Efficacy Analysis for Period 1
Standard efficacy analysis by randomized treatment groups (upadacitinib 15 mg QD and 
the placebo group) will be performed on efficacy data for Period 1 (up to Week 12).  No 
protocol-defined treatment switching will occur prior to the time point.  Formal statistical 
inference will be generated, and results from this set of analysis will be used as the key 
efficacy findings of this study.
Long-Term Efficacy Analysis
Long-term efficacy analysis will be performed on As Observed data (defined in 
Section 9.1.2) by randomized treatment group sequence as described below:


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1.
Upadacitinib 15 mg QD
2.
Placebo Ѝ upadacitinib 15 mg QD.
There will be no statistical testing; only descriptive statistics and confidence intervals will 
be provided.
9.1.2
Definition of Missing Data Imputation
Non-Responder Imputation (NRI) Approach
The NRI approach will categorize any subject who has missing value for categorical 
variables at a specific visit as non-responder for that visit. In addition, subjects who 
prematurely discontinue from study drug will be considered as non-responders for all 
subsequent visits after discontinuation.
Observed Cases (OC)
The OC analysis will not impute values for missing evaluations, and thus a subject who 
does not have an evaluation on a scheduled visit will be excluded from the OC analysis 
for that visit.  In addition, the OC will not use values after premature discontinuation of 
study drug.  This sensitivity analysis will only be applied to the analysis in Period 1.
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.  Regardless of treatment switching or premature discontinuation of study 
drug, all observed data will be used in the analysis.  The AO analysis will be applied to 
long-term efficacy analysis.


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Mixed Effect Model Repeat Measurement (MMRM)
The repeated measure 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, main stratification factors at 
randomization, and the continuous fixed covariates of baseline measurement.  An 
unstructured variance covariance matrix will be used.  The parameter estimations are 
based on the assumption of data being missing at random and using the method of 
restrictive maximum likelihood (REML).  The missing at random assumption is 
considered reasonable given the high placebo response rate typically seen in RA trials.  
Additionally, in RA trials, the proportion of discontinuation is relatively small (10 – 15% 
only) and the rate of discontinuation due to lack of efficacy is generally low (< 5%).
Multiple Imputation (MI)
The MI analysis will impute missing data multiple times under appropriate random 
variation and thus generate multiple imputed "pseudo-complete" datasets.  Results will be 
aggregated across the multiple imputed datasets, overcoming drawbacks of the 
single imputation methods.  PROC MI will be used to generate 5 datasets using the fully 
conditional specification (FCS) method.  Specifically, treatment group is included in the 
FCS imputation model to enable sampling stratified by treatment groups. Additionally,
the imputation model includes demographics variables and baseline disease 
characteristics, as well as longitudinal response observed at any other visits.  An 
ANCOVA model will first be performed on each of the multiple imputed datasets 
adjusting for treatment, stratification factor and baseline value. PROC MIANALYZE will 
then be used to aggregate the results for the final statistical inference using Rubin's 
method.  The imputation is based on assumption of data being missing at random.  The 
missing at random assumption is considered reasonable given the high placebo response 
rate typically seen in RA trials.  Additionally, in RA trials, the proportion of 
discontinuation is relatively small (10 – 15% only) and the rate of discontinuation due to 
lack of efficacy is generally low (< 5%).


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9.2
Efficacy Analysis for Period 1
9.2.1
Primary Efficacy Analysis
The primary endpoint is ACR20 response at Week 12.  Analysis of the primary endpoint 
will be conducted on the FAS based on randomized treatment groups (upadacitinib 15 mg 
QD and the placebo group).  Point estimate and 95% CI using normal approximation will 
be provided for the response rate for each randomized treatment group.  Comparison of 
the primary endpoint will be made between the upadacitinib group and placebo group 
using the Cochran-Mantel-Haenszel test adjusting for stratification factor country.  Point 
estimate, 95% CI using normal approximation and p-value for the treatment comparison 
will be presented.  P-value is constructed using the Cochran-Mantel-Haenszel test.  For 
the primary analysis, non-responder imputation (NRI) will be used.
9.2.2
Sensitivity Analysis of Primary Efficacy Variables
The primary analysis for point estimate and CI will be repeated using Observed Cases 
without any imputation as a sensitivity analysis.  This will be conducted on the FAS based 
on randomized treatment groups.
Supportive NRI analysis will also be conducted on the Per Protocol Analysis Set.
9.2.3
Key Secondary Efficacy Analyses
Ranked key secondary endpoints (at Week 12) are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
Change from baseline in Short Form-36 (SF-36) Physical Component Score (PCS);
4.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2;
5.
Proportion of subjects achieving Clinical remission (CR) based on DAS28 (CRP);
6.
Proportion of subjects achieving LDA based on CDAI ≤ 10;


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Other key secondary endpoints (at Week 12) are:
1.
ACR50 response rate;
2.
ACR70 response rate;
3.
ACR20 response rate at Week 1.
For binary endpoints, frequencies and percentages will be reported for each randomized 
treatment group.  Similar analyses as for the primary endpoint will be conducted.
For the major RA continuous endpoints DAS28 and HAQ-DI change from baseline, 
statistical inference will be conducted using analysis of covariance (ANCOVA) coupled 
with MI for missing data handling.  Specifically, the ANCOVA model will include 
treatment as the fixed factor, and the corresponding baseline value and the stratification 
factor country as the covariates.  For other continuous endpoints, statistical inference will 
be conducted using the MMRM model as described in Section 9.1.2, with the main 
stratification factor being country.  From both the MI and MMRM analyses, the LS mean 
and 95% CI will be reported for each randomized treatment group; the LS mean treatment 
difference and associated 95% CI and p-value will be reported comparing upadacitinib 
group with the placebo group.  
9.2.4
Additional Efficacy Analyses
Additional efficacy analysis includes the following endpoints at all visits in Period 1:
●
Change from baseline in individual components of ACR response;
●
ACR20/50/70 response rates;
●
Change from baseline in DAS28 (CRP) and DAS28 (erythrocyte 
sedimentation rate [ESR]);
●
Change from baseline in CDAI and SDAI;
●
Change from baseline in morning stiffness (severity and duration);
●
Proportion of subjects achieving change from baseline in HAQ-DI ≤ –0.22 for 
the subjects with baseline HAQ-DI ≥ 0.22;


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Proportion of subjects achieving change from baseline in HAQ-DI ≤ –0.3 for 
the subjects with baseline HAQ-DI ≥ 0.3;
●
Proportion of subjects achieving LDA or CR based on DAS28 (CRP), DAS28 
(ESR), Simplified Disease Activity Index (SDAI), and Clinical Disease 
Activity Index (CDAI) criteria;
●
ACR/EULAR Boolean remission;
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in SF-36;
●
Change from baseline in Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-F); 
●
Change from baseline in Work Instability Scale for Rheumatoid Arthritis (RA-
WIS).
For binary endpoints, point estimate and 95% CI using normal approximation will be 
provided for the response rate for each randomized treatment group.  Point estimate, 95% 
CI and p-value will be provided for the treatment comparison between upadacitinib group 
and the placebo group using the Cochran-Mantel-Haenszel test adjusting for stratification 
factor country.  The 95% CI will be based on normal approximation.  NRI will be used as 
primary analysis and OC will be used as sensitivity analysis.
For continuous endpoints, the LS mean and 95% CI will be reported for each randomized 
treatment group. The LS mean treatment difference and associated 95% CI and p-values 
between upadacitinib group and the placebo group will be provided using MMRM model 
with fixed effects of treatment, visit and treatment-by-visit interaction, country and 
baseline value as covariates.  
9.2.5
Handling of Multiplicity
In order to preserve Type I error, a step-down approach will be used to test the primary 
and ranked key secondary endpoints where statistical significance can be claimed for a 
lower ranked endpoint only if the previous endpoint in the sequence meets the 
requirements of significance.  Specifically, the testing will utilize the endpoint sequence 


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of primary endpoint followed by ranked key secondary endpoints in the order as specified 
in Section 9.2.3, using α of 0.05.
9.2.6
Efficacy Subgroup Analysis
The primary efficacy endpoint will be examined in the subgroups listed in Table 6 below.  
Treatment difference between upadacitinib and the placebo group will be presented with 
point estimate and 95% confidence interval using normal approximation.  No p-value will 
be provided for subgroup analysis.  If any of the resulting subgroups (except for country 
subgroup) has fewer than 20% of the planned study size (i.e., < 64 subjects), the subgroup 
analyses for that variable will not be presented.
Table 6.
Subgroups for Efficacy Analysis
Subgroup Factor
Categories
Age
< 40, [40, 65), ≥ 65
Sex
Male or Female
Weight
< 60 kg or ≥ 60 kg
BMI
< 25 or ≥ 25
Country
China, South Korea and Brazil
Race 
Asian, non-Asian
Duration of RA diagnosis
< 5 year or ≥ 5 year
Baseline Rheumatoid Factor Status
Positive or Negative
Baseline Anti-CCP Antibody Status
Positive or Negative
Baseline both RF positive and Anti-CCP positive
Both positive vs at least one negative
Baseline both RF negative and Anti-CCP negative
Both negative vs at least one positive
Baseline DAS28 (hsCRP)
≤ 5.1 or > 5.1
Concomitant csDMARD at baseline
MTX alone, MTX and other csDMARD, 
csDMARD other than MTX 
9.2.7
Summary of Efficacy Analysis for Period 1
Table 7 below provides the overview of the efficacy analyses for Period 1 to be performed 
on different endpoints.


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Table 7.
Summary of Efficacy Variables and Corresponding Analyses for 
Efficacy Analysis in Period 1
Efficacy Variables
Analysis Method
Primary Variables
•
ACR20 response at Week 12
•
Point estimate and 95% CI of the response rate for 
upadacitinib group and placebo group.  The 95% CI 
will be based on normal approximation.
•
Point estimate, 95% CI and p-value for the treatment 
comparison between upadacitinib group and placebo 
group, where the p-value is constructed using the 
Cochran-Mantel-Haenszel test adjusting for 
stratification factor country.  The 95% CI will be based 
on normal approximation.
•
Subgroup analysis.
•
Imputation:  NRI for primary analysis and OC for 
sensitivity analysis
•
Analysis Set:  FAS and Per Protocol Analysis Set as 
supportive analysis (NRI only).
Key Secondary Variables
Binary Endpoints:
•
Proportion of subjects achieving 
LDA based on DAS28 (CRP) ≤3.2
at Week 12
•
Proportion of subjects achieving 
Clinical remission (CR) based on 
DAS28 (CRP) at Week 12
•
Proportion of subjects achieving
LDA based on CDAI ≤ 10 at 
Week 12
•
ACR50/70 response at Week 12
•
ACR20 response at Week 1
•
Point estimate and 95% CI of the response rate for each 
treatment group.  The 95% CI will be based on normal 
approximation.
•
Point estimate, 95% CI and p-value for the treatment 
comparison between upadacitinib group and placebo 
group using the Cochran-Mantel-Haenszel test 
adjusting for stratification factor country.  The 95% CI 
will be based on normal approximation.
•
Imputation:  NRI for primary analysis and OC for 
sensitivity analysis
•
Analysis Set:  FAS


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Table 7.
Summary of Efficacy Variables and Corresponding Analyses for 
Efficacy Analysis in Period 1 (Continued)
Efficacy Variables
Analysis Method
Key Secondary Variables (continued)
Continuous Endpoints:
•
Change from baseline in 
DAS28(CRP) at Week 12
•
Change from baseline in HAQ-DI at 
Week 12
•
LS mean, and 95% CI within each treatment group and 
LS mean, 95% CI and p-values between upadacitinib
group and the placebo group using ANCOVA model 
with treatment, country and baseline value as 
covariates.  
•
Imputation:  MI
•
Analysis Set:  FAS
•
Change from baseline in SF-36 
Physical Component Score (PCS) at 
Week 12
•
LS mean and 95% CI within each treatment group and 
LS mean, 95% CI and p-values between upadacitinib 
group and the placebo group using MMRM model with 
fixed effects of treatment, visit and treatment-by-visit 
interaction, country and baseline value as covariate.  
Analysis Set:  FAS
Additional Variables (Summarized at all Visits up to Week 12)
Binary Endpoints:
•
ACR20/50/70 response rate
•
Proportion of subjects achieving 
change from baseline in HAQ-DI 
≤- 0.22 for subjects with baseline 
HAQ-DI ≥0.22
•
Proportion of subjects achieving 
change from baseline in HAQ-DI 
≤- 0.3 for subjects with baseline 
HAQ-DI ≥0.3
•
Proportion of subjects achieving 
LDA and CR based on 
DAS28(CRP), DAS28 (ESR), SDAI, 
and CDAI criteria
•
Boolean remission
•
Point estimate and 95% CI of the response rate for each 
treatment group.  The 95% CI will be based on normal 
approximation.
•
Point estimate, 95% CI and p-value for the treatment 
comparison between upadacitinib group and the 
placebo group using the Cochran-Mantel-Haenszel test 
adjusting for stratification factor country.  Only 
nominal p-value will be provided, and the 95% CI will 
be based on normal approximation.
•
Imputation:  NRI for primary analysis and OC for 
sensitivity analysis
•
Analysis Set:  FAS


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Table 7.
Summary of Efficacy Variables and Corresponding Analyses for 
Efficacy Analysis in Period 1 (Continued)
Efficacy Variables
Analysis Method
Additional Variables (Summarized at all Visits up to Week 12) (continued)
Continuous Endpoints:
•
Change from baseline in individual 
ACR components
•
Change from baseline in DAS28 
(CRP) and DAS28 (ESR)
•
Change from baseline in CDAI and 
SDAI
•
Change from baseline in morning 
stiffness 
•
Change from baseline in EQ-5D-5L
•
Change from baseline in SF-36
•
Change from baseline in FACIT-F
•
Change from baseline in RA-WIS
•
LS mean and 95% CI within each treatment group and 
LS mean, 95% CI and p-values between upadacitinib 
group and the placebo group using MMRM model with 
fixed effects of treatment, visit and treatment-by-visit 
interaction, country and baseline value as covariate.  
•
Analysis Set:  FAS
9.3
Long-Term Efficacy Analysis
Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Weeks 1, 2, 4, 8, 12, 16, 20, 24, 36, 48, and 64/PD:
●
ACR20/50/70 response rates;
●
Change from baseline in individual ACR components;
●
Change from baseline in DAS28 (CRP);
●
Change from baseline in DAS28 (ESR);
●
Change from baseline in CDAI and SDAI;
●
Change from baseline in morning stiffness;
●
Proportion of subjects achieving change from baseline in HAQ-DI ≤ –0.22 for 
subjects with baseline HAQ-DI ≥0.22;
●
Proportion of subjects achieving change from baseline in HAQ-DI ≤ –0.3 for 
subjects with baseline HAQ-DI ≥0.3;


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●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria;
●
Boolean remission;
●
Proportion of subjects with no concomitant corticosteroid use (among subjects 
with corticosteroid use at baseline).
Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Weeks 4, 12, 24, 48:
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in SF-36;
●
Change from baseline in FACIT-F;
●
Change from baseline in RA-WIS.
Descriptive statistics will be provided for each randomized treatment group sequence as 
defined in Section 9.1.1.  These include the number of observations, mean, standard 
deviation, 95% CI, median, minimum, Q1, Q3 and maximum for continuous endpoints; 
and frequencies and percentages with 95% CI using normal approximation for binary 
endpoints.  Plot for each randomized treatment group sequence over time will be provided 
up to Week 64.
No missing data imputation will be applied.  All efficacy analyses will be based on As 
Observed (AO) analysis.
Table 8 below provides the overview of the long-term efficacy analyses to be performed 
on different endpoints.


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Table 8.
Summary of Efficacy Variables and Corresponding Analyses for 
Long-Term Efficacy Analysis
Efficacy Variables
Analysis Method
Binary Endpoints:
•
ACR20/50/70 response by visit
•
Proportion of subjects achieving change from 
baseline in HAQ-DI ≤ –0.22 for subjects with 
baseline HAQ-DI ≥0.22
•
Proportion of subjects achieving change from 
baseline in HAQ-DI ≤ –0.3 for subjects with 
baseline HAQ-DI ≥0.3
•
LDA and CR based on DAS28(CRP), DAS28 
(ESR), SDAI, and CDAI criteria by visit
•
Proportion of subjects with no concomitant 
corticosteroid use (among subjects with 
corticosteroid use at baseline)
•
Boolean remission
•
Point estimate and 95% CI of the response 
rate for each randomized treatment group 
sequence
•
Plot for each randomized treatment group 
sequence over time
•
Imputation:  AO
•
Analysis Set:  FAS
Continuous Endpoints:
•
Change from baseline in individual ACR 
components by visit
•
Change from baseline in DAS28 (CRP) by visit
•
Change from baseline in DAS28 (ESR) by visit
•
Change from baseline CDAI and SDAI by visit
•
Change from baseline in morning stiffness 
(severity and duration) by visit
•
Change from baseline in EQ-5D-5L by visit
•
Change from baseline in FACIT-F
•
Change from baseline in RA-WIS
•
Change from baseline in SF-36 by visit
•
Point estimate, 95% CI of mean change 
from baseline together with SD, Min, Q1, 
Median, Q3 and Max for each randomized 
treatment group sequence
•
Plot for each randomized treatment group 
sequence over time
•
Imputation:  AO
•
Analysis Set:  FAS
9.4
Efficacy Variables Definitions and Conventions
9.4.1
ACR Criteria
ACR criteria are a commonly used standard criteria set mentioned in the guidance of 
American College of Rheumatology to evaluate the effectiveness of investigation drug in 
RA clinical trials.  It is a composite measurement calculated based on the improvement 
over a set of core measurements.


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ACR20 is defined as at least 20% improvement (compared to baseline values) in tender 
and swollen joint counts and at least 20% improvement in 3 of the remaining 5 core set 
measures (subject global assessment of pain, subject global assessment of disease activity, 
physician global assessment of disease activity, subject assessment of physical function 
and acute phase reactant hsCRP).
ACR50 and ACR70 are similarly defined with at least 50% and 70% improvement, 
respectively.
A subject will be classified as an ACR20 (ACR50, ACR70) responder, if the following 
conditions are met:
1.
≥ 20% (50%, 70%) improvement from baseline in tender joint count (TJC68) and
2.
≥ 20% (50%, 70%) improvement from baseline in swollen joint count (SJC66) and
3.
≥ 20% (50%, 70%) improvement from baseline in at least 3 of the following 5:
●
patient's assessment of pain
●
patient's global assessment of disease activity (PGA)
●
physician's global assessment of disease activity (PhGA)
●
patient's self-assessment of physical function (i.e., measured by Health 
Assessment Questionnaire (HAQ-DI score)
●
Acute-phase reactant value CRP
There are seven components to be evaluated to define an ACR response.  Missing values 
for each component can occur due to a missed visit or due to dropout from the study.  
Depending on the pattern of the missing components, ACR responses may be or may not 
be determined using observed values only.
To maximize the utilization of observed information at certain visits and be scientifically 
as robust as possible, the principle to calculate ACR response is to minimize imputation 
whenever possible.  Observed ACR response will be calculated first based on a derived 


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visit window instead of the nominal visit identifier (e.g., Week 6 visit) collected from the 
CRF.
To calculate observed ACR responses:
●
Identify the observed component xx% improvement indicator (0/1/missing), 
1 means achieving ≥ xx% improvement from baseline and 0 means < xx% 
improvement from baseline (e.g., xx% representing 20%/50%/70%).
●
ACRxx = 0 if TJC indicator = 0 OR SJC indicator = 0 OR at least 3 out of 
5 components improvement indicators = 0.
●
ACRxx = 1 if TJC indicator = 1 AND SJC indicator = 1 AND at least 3 out of 
5 components improvement indicators = 1.
●
For all other cases, ACRxx = missing since ACRxx cannot be determined.
The following table illustrates examples for ACR calculations.
Example
TJC 
68
SJC 
66
Component 
1
Component 
2
Component 
3
Component 
4
Component 
5
ACR20-
Response?
A
1
1
1
1
1
.
.
Yes
B
1
0
1
1
1
1
1
No
C
.
0
.
.
.
.
.
No
D
1
.
1
1
1
1
1
.
E
1
1
0
0
0
1
1
No
F
.
.
0
0
0
.
.
No
G
1
1
1
1
0
0
.
.
Legend:  1 = ≥ 20% improved compared to baseline; 0 = < 20% improved compared to baseline; "." missing.
Windowing Rule for ACR Response Calculation:
●
ACR component values will first be determined at each date within a visit 
window.
●
ACR component values at each date will be combined to determine the 
observed ACR composite score at each date in each window.
●
After this calculation, if multiple non-missing ACR composite scores are 
available within a given visit window, the non-missing ACR composite score 


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closest to the target day will be used.  If two composite scores have the same 
distance from the target day, the later one will be used.  The corresponding 
date will be used as the observed ACR response date in the derived efficacy 
dataset.
●
If a non-missing ACR composite score is not available for any day within a 
given visit window, the windowed component values for that visit will be used 
to calculate the ACR composite score for that visit window (component value 
windowing follow the same rules as in steps described above).  The date of 
observed ACR composite score will be determined by the first available ACR 
component date, in the order of TJC, SJC, Pain, PGA, PhGA, HAQ-DI, 
CRP/ESR, in the derived efficacy dataset.
When observed ACR xx response for a given visit is missing, imputation methods will be 
used to calculate "imputed" ACRxx response.
Non-Responder Imputation (NRI) for ACR response:
●
Step 1:  all missing components will be imputed using LOCF, and then the 
ACR composite score can be calculated.
●
Step 2:  if the ACR composite score cannot be determined by Step 1, the ACR 
composite score will be imputed as 0.  In addition, subjects who prematurely 
discontinue from the study drug will be considered as non-responders 
(ACR = 0) for all subsequent visits after the discontinuation date.
9.4.2
Joint Evaluation
Anatomical joints are evaluated for swelling and tenderness at every study visit.  The 
34 anatomical joints in Table 9 are assessed in this study for both the left and right side of 
the body.


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Table 9.
Anatomical Joints Assessed for Calculation of Tender and Swollen 
Joint Counts (TJC68 and SJC66)
Temporomandibular
Sternoclavicular
Acromio-Clavicular
Shoulder
Elbow
Wrist
Metacarpophalangeal I
Metacarpophalangeal II
Metacarpophalangeal 
III
Metacarpophalangeal 
IV
Metacarpophalangeal V
Thumb Interphalangeal
Proximal 
Interphalangeal II
Proximal 
Interphalangeal III
Proximal 
Interphalangeal IV
Proximal 
Interphalangeal V
Distal Interphalangeal 
II
Distal Interphalangeal 
III
Distal Interphalangeal 
IV
Distal Interphalangeal 
V
Hipa
Knee
Ankle
Tarsus
Metatarsophalangeal I
Metatarsophalangeal II
Metatarsophalangeal III
Metatarsophalangeal IV
Metatarsophalangeal V
Great Toe/Hallux
Interphalangeal II
Interphalangeal III
Interphalangeal IV
Interphalangeal V
a.
Hip joints are not assessed for swelling.
At each study visit, a joint evaluator assessed whether a particular joint was "tender or 
painful" where presence of tenderness was scored as "1" and the absence of tenderness 
was scored as "0," provided the joint was not replaced ("9") or could not be assessed 
("NA") due to other reasons (e.g., post-corticosteroid joint injection).  The total tender 
joint count (TJC68), which is based on 68 joints, will be derived as the sum of all "1s" and 
proportional extrapolation will be used to impute joint counts for the joints that are 
replaced or not assessed.  A similar method will be followed for the derivation of total 
swollen joint count (SJC66), which is based on 66 joints as the hip joints are excluded.  
Thus, the range for TJC68 will be 0 to 68 and 0 to 66 for SJC66.
9.4.3
Patient's Global Assessment of Disease Activity Visual 
Analog Scale (VAS)
The subject will assess his/her disease activity for the past 24 hours using a Patient's 
Global Assessment of Disease VAS.  The range is 0 to 100 mm with no activity being 
indicated by 0 and severe activity by 100.


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9.4.4
Physician's Global Assessment of Disease Activity Visual 
Analog Scale (VAS)
The physician will assess Patient's disease activity at the time of visit using a Physician's 
Global Assessment of Disease VAS.  The range is 0 to 100 mm with no activity being 
indicated by 0 and severe activity by 100.
9.4.5
Patient's Global Assessment of Pain
The subject will assess his/her pain in the previous week using a Patient's Global 
Assessment Pain VAS.  The range is 0 to 100 mm with no pain being indicated by 0 and 
severe pain by 100.
9.4.6
Disease Activity Score (DAS28)
DAS28 (CRP) and DAS28 (ESR) are composite indices to assess disease activity in RA 
patients using hsCRP or ESR measurement respectively.  The DAS provides a score 
between 0 and 10, indicating how active the rheumatoid arthritis is at the time of 
measurement.
DAS28 (CRP) and DAS28 (ESR) can be calculated based on Tender Joint Count, Swollen 
Joint Count, Patient's Global Assessment of Disease Activity (PtGA) (in mm), and hsCRP 
(in mg/L) or ESR (mm/hr).
DAS28 (CRP) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(hsCRP& + 1) + 
0.014 × PtGA» + 0.96
DAS28 (ESR) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.70 × ln(ESR#) + 0.014 ×
PtGA»
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
&
hsCRP refers to the high-sensitivity c-reactive protein lab value.  hsCRP unit in the DAS28 (CRP) equation is 
expressed as mg/L.
#
ESR refers to the Erythrocyte sedimentation rate.  ESR unit in the DAS28 (ESR) equation is expressed as mm/hr.
»
PtGA refers to the Patient's Global Assessment of Disease Activity.
where √is square root and ln is natural log.


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Table 10.
Anatomical Joints for DAS28(CRP) Calculation
Shoulder
Elbow
Wrist
Thumb Interphalangeal
Metacarpophalangeal I
Metacarpophalangeal II
Metacarpophalangeal 
III
Metacarpophalangeal 
IV
Metacarpophalangeal V
Proximal 
Interphalangeal II
Proximal 
Interphalangeal III
Proximal 
Interphalangeal IV
Proximal 
Interphalangeal V 
Knee
To calculate observed DAS28 scores, the observed component value will be calculated 
first.  Then the components will be included in the calculation per the DAS formula 
selected.  If any observed component is missing in a window, then the observed DAS28 
score will be missing.
9.4.7
Simplified Disease Activity Index (SDAI)
SDAI is a composite continuous index to assess disease activity based on TJC28, SJC28, 
Patient's Global Assessment of Disease Activity (PtGA) (in cm, 0 – 10), Physician's 
Global Assessment of Disease Activity (PhGA) (in cm, 0 – 10) and hsCRP (mg/dL).  It 
can be derived as follows:
SDAI = TJC28 + SJC28 + PtGA (cm) + PhGA (cm) + hsCRP (mg/dL).
To calculate observed SDAI scores, the observed component value will be calculated first.  
Then the components will be included in the calculation per the SDAI formula selected.  
If any observed component is missing in a window, then the observed SDAI score will be 
missing.
9.4.8
Clinical Disease Activity Index (CDAI)
CDAI is a composite continuous index to assess disease activity without using hsCRP 
measurement.  It can be calculated based on TJC28, SJC28, Patient's Global Assessment 
of Disease Activity (PtGA) (in cm, 0 – 10) and Physician's Global Assessment of Disease 
Activity (PhGA) (in cm, 0 – 10).  It can be derived as follows:


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CDAI = TJC28 + SJC28 + PtGA (cm) + PhGA (cm).
To calculate observed CDAI scores, the observed component value will be calculated 
first.  Then the components will be included in the calculation per the CDAI formula 
selected.  If any observed component is missing in a window, then the observed CDAI 
score will be missing.
9.4.9
Clinical Remission (CR) and Low Disease Activity (LDA)
Clinical remission (CR) and low disease activity (LDA) based on DAS28 (CRP), 
DAS28(ESR), SDAI and CDAI are defined as follows:
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
9.4.10
ACR/EULAR Boolean Remission
ACR/EULAR Boolean remission is defined based on the following four criteria:
●
Tender joint count ≤ 1 (based on 28 joints)
●
Swollen joint count ≤ 1 (based on 28 joints)
●
CRP ≤ 1 mg/dL
●
Patient global assessment of disease activity ≤ 10 (mm)
All four criteria must be satisfied at a visit for a subject to be classified as achieving 
ACR/EULAR Boolean remission.
9.4.11
Disability Index of Health Assessment Questionnaire
(HAQ-DI)
HAQ-DI is a self-reported patient outcome measurement.  It is calculated as the mean of 
the scores from 8 following categories with a range 0 – 3:  Dressing and Grooming, 


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Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities.  The higher the score, the 
more likely to associate with morbidity and mortality for the RA patient.
The maximum score for all the questions in each category is considered as the score for 
the category.  The Standard disability index (HAQ-DI) takes into account the subject's use 
of aids or devices or assistance in the scoring algorithm for a disability category.  For each 
of the eight disability categories there is an AIDS OR DEVICES companion variable(s) 
that is used to record the type of assistance, if any, a subject uses for his/her usual 
activities.  If aids or devices and/or assistance from another person are checked for a 
disability category, the score for this category is set to 2 (much difficulty), if the original 
score is 0 (no difficulty) or 1 (some difficulty).  The HAQ-DI is then calculated by 
summing the adjusted categories scores and dividing by the number of categories 
answered.  The HAQ-DI cannot be calculated if the patient does not have scores for at 
least 6 categories.
9.4.12
EuroQoL-5D (EQ-5D-5L)
EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal.  
The EQ-5D consists of 2 pages.  The first page measures 5 dimensions of the health status 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with 
5 levels per dimension (no problems, slight problems, moderate problems, severe 
problems, and extreme problems corresponding to Level 1 to Level 5 respectively).  The 
second page is an EQ Visual Analogue Scale (EQ VAS).  EQ-5D health states, defined by 
the EQ-5D-5L descriptive system on the first page, may be converted into a single index 
value.  The change from baseline of the index value and EQ VAS will be analyzed and 
reported.  UK scoring algorithm will be used.
9.4.13
Form SF-36v2 
The 36-Item Short Form, Version 2 (SF-36v2) Questionnaire with 4-week recall will be 
completed by the subject at Baseline, Weeks 4 and at study completion (Week 12 or at 
PD).  The SF-36v2 health survey consists of 36 general health questions and this study is 


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using the form for 4 weeks recall period (standard form).  It has 2 components:  physical 
and mental.  For each component, a transformed summary score is calculated using 
8 sub-domains:  physical functioning, role-physical, bodily pain, general health, vitality, 
social functioning, role-emotional, and mental health.
The coding and scoring for the SF-36 will use the software provided by Quality Metrics.
9.4.14
Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F)
Fatigue is one of the most frequent complaints of the elderly and is strongly associated 
with loss of independence and decreased physical activity and functional decline.  
One validated tool to measure fatigue is FACIT Fatigue Scale v4.  The FACIT Fatigue 
Scale is a short, 13-item, easy to administer tool that measures an individual's level of 
fatigue during their usual daily activities over the past week.  Each of the fatigue and 
impact of fatigue items are measured on a four-point Likert scale.  The FACIT Fatigue 
Scale is ranged from 0 to 52 and the higher the score, the better the quality of life.
Score for each item is calculated by either subtracted from 4 or adding 0 depending on 
whether it is a reversal item or not.  FACIT Fatigue Scale is then calculated by adding up 
all item scores, multiplied by 13 and divided by the number of items answered.  It is 
essentially a prorated subscale if there are missing values for some items.  If less than or 
equal to 50% of the items are answered (e.g., 6 out of 13), the proration is not acceptable, 
and the scale will not be computed.
9.4.15
Work Instability Scale for Rheumatoid Arthritis (RA-WIS)
The 23-item RA-WIS is a simple validated tool, applicable only to patients who are 
employed, to evaluate work instability (the consequence of a mismatch between an 
individual's functional ability and their work tasks).  It can be self-administered by the 
patients.  To calculate the RA-WIS scale, one can simply add up the number of "true" 
responses.  If the scale is < 10, it means low risk and no action is needed.  If the scale is 


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between 10 and 17, it means medium risk and appropriate advice and information should 
be given.  If the scale is > 17, it means high risk and it could warrant referral.
10.0
Safety Analysis
10.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set.  There are two sets of 
planned safety analysis:  safety analysis for Period 1 and long-term safety analysis.
Safety Analysis for Period 1
Standard safety analysis by the "as treated" treatment groups of upadacitinib 15 mg QD 
and the placebo groups will be performed on safety data in Period 1.  No protocol-defined 
treatment switching will occur prior to the end of Period 1.
The standard safety analyses will include reporting of adverse events (AEs), laboratory, 
and vital signs measurements.  Frequency tables of subjects with treatment-emergent 
adverse events (TEAEs) by system organ class (SOC) and by preferred term (PT) as in the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be provided by 
treatment group.  Mean changes from baseline in all continuous laboratory parameters and 
vital signs variables at each visit will be summarized by "as treated" treatment group.  
Frequency tables of subjects meeting criteria for potentially clinically significant vital sign 
values and for potentially clinically significant laboratory values will be provided by 
treatment group.  Missing safety data will not be imputed.
Long-Term Safety Analysis
Long-term safety analyses for upadacitinib 15 mg QD include reporting of AE rate 
adjusted by cumulative exposure, mean change from baseline in laboratory parameters 
and vital sign variables, and frequency of potentially clinically significant laboratory and 
vital signs values.  The treatment-emergent adverse event (TEAE) rate per 100 patient-
years of exposure will be presented by actual treatment received at the time of AE (as 
described in Section 10.2.2).  Listing of subjects with TEAEs by SOC and PT will be 


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provided.  Mean changes from baseline in all continuous laboratory parameters and vital 
signs variables at each visit will be summarized by "as treated" treatment group sequences 
defined as follows (as described in Section 10.3.3 and Section 10.4.3).  Frequency tables 
and listings of subjects meeting criteria for potentially clinically significant vital sign 
values and for potentially clinically significant laboratory values will be provided by 
actual treatment received at the time of event.  Missing safety data will not be imputed.
"As treated" treatment group sequences:
1.
upadacitinib 15 mg QD
2.
Placebo Ѝ upadacitinib 15 mg QD
10.2
Analysis of Adverse Events
A treatment-emergent Adverse Event (TEAE) is defined as an adverse event with an onset 
date that is after the first dose of study drug, and no more than 30 days of the drug after 
the last dose of study drug.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent, unless the study drug start time and the adverse event start time are 
collected and the adverse event start time is prior to the study drug start time.  If an 
incomplete onset date was collected for an adverse event, the event will be assumed to be 
treatment-emergent unless there is other evidence that confirms that the event was not 
treatment-emergent (e.g., the event end date was prior to the study drug start date).
Adverse event data will be presented by SOCs and PTs using MedDRA version 21.1 or 
most up to date version.  All adverse event tables will be sorted in alphabetical order by 
SOC and PT.


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10.2.1
Analysis of Adverse Events for Period 1
10.2.1.1
Adverse Events Overview
The number and percentage of subjects experiencing TEAEs will be summarized by "as 
treated" treatment group for the following AE categories.
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs of special interest
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
For TEAEs of special interest, the point estimate and 95% CI (using normal 
approximation and separate group variance) will be provided for the treatment difference 
in AE percentage between upadacitinib group and the placebo group.
10.2.1.2
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing adverse events will be tabulated by 
SOC and MedDRA PT by "as treated" treatment group.  The SOCs will be presented in 
alphabetical order, and the PTs will be presented in alphabetical order within each SOC.
The following summaries of adverse events will be generated:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug


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●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
●
Frequent AEs (reported in 2% of subjects or more in any treatment group)
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term (most severe incident for the severity tables and most 
related incident for the relationship tables).  Subjects reporting more than one type of 
adverse event within a SOC will be counted only once for that SOC.  Subjects reporting 
more than one type of adverse event will be counted only once in the overall total.
10.2.1.3
TEAEs by Maximum Severity
TEAEs will also be summarized by maximum severity by "as treated" treatment group.  If 
a subject has an AE with an unknown severity, then the subject will be counted in the 
severity category of unknown, even if the subject has another occurrence of the same 
event with a severity present.  The only exception is that if the subject has another 
occurrence of the same AE with the most extreme severity – severe.  In this case, the 
subject will be counted under the severe category.
10.2.1.4
TEAEs by Relationship
TEAEs will also be summarized by relationship to study drug, as assessed by the 
investigator, by "as treated" treatment group.  If a subject has a TEAE with an unknown 
relationship, then the subject will be counted in the relationship category of "unknown," 
even if the subject has another occurrence of the same event with a relationship present.  
The only exception is if the subject has another occurrence of the same TEAE with a 
relationship assessment of "reasonable possibility."  In this case, the subject will be 
counted under the "reasonable possibility" category.


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10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and 
Preferred Term
TEAEs and reasonably possibly related AEs occurring for more than 2% of the subjects in 
any of the "as treated" treatment groups will be summarized by MedDRA PT in 
decreasing frequency separately.
10.2.1.6
Adverse Events of Special Interest
The Adverse Events of Special Interest (AESI) categories will be summarized and 
presented by "as treated" treatment group using SOC and MedDRA PT.  The AESI 
categories will be identified per Standard MedDRA Queries (SMQs)/Company MedDRA 
Queries (CMQs) in Table 11 below.  Adjudicated cardiovascular events will be 
summarized and presented by treatment group using the CAC adjudicated categories.


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Table 11.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection
CMQ
"Opportunistic Infection"
Possible Malignancy
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
"Malignant tumours"
Non-Melanoma Skin Cancer (NMSC)
SMQ
Narrow
Skin Malignant tumours (Narrow 
SMQ) removing Melanoma CMQ
Malignancy excluding NMSC
"Malignant tumours" Narrow SMQ 
removing NMSC output
Lymphoma
SMQ
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders"
Gastrointestinal Perforations
SMQ
Narrow
"Gastrointestinal Perforation"
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
Anemias"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia (Veliparib Product 
Specific)"
Herpes Zoster
CMQ
"Herpes Zoster"
Creatine Phosphokinase (CPK) 
Elevation
PT
Search only for the PT of "Blood 
creatine phosphokinase increased"
Renal Dysfunction
SMQ
Narrow
"Acute Renal, Failure"
Tuberculosis
CMQ
"Tuberculosis"


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Table 11.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches 
(Continued)
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Adjudicated Cardiovascular Events
Output 
from CAC
MACE* 
Undetermined/Unknown Cause of 
Death 
Other Cardiovascular events
Venous Thromboembolic 
Events**
Other Venous Thrombosis 
Arterial Thromboembolic Events 
(non-cardiac, non-neurologic)
*
MACE; Major Adverse Cardiovascular Events, defined as cardiovascular death, non-fatal myocardial infarction 
and non-fatal stroke.
**
Venous thromboembolic events (VTE) include deep vein thrombosis (DVT) and pulmonary embolism (PE).
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
10.2.2
Analysis of Long-Term Adverse Event Rates
Long-term adverse event rates for upadacitinib 15 mg QD will be analyzed using event 
rates adjusted by cumulative exposure.  This includes TEAEs occurred under upadacitinib 
15 mg QD exposure from subjects starting on upadacitinib 15 mg QD and subjects 
switching from placebo to upadacitinib 15 mg QD. 
For this event rate calculation, 1 year will be considered to be 365.25 days.  For each 
treatment group, the numerator of the overall rate will be the total number of TEAEs 
reported for the event; that is, a subject can contribute more than one event to the 
numerator.  The denominator of the rates will be the total number of days exposed to 
upadacitinib 15 mg QD summed across all treated subjects divided by 365.25.  The TEAE 


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rate per 100 patient-years of exposure will be calculated as 
([numerator/denominator])*100.  The number of TEAEs reported (numerator), the total 
number of years of study drug exposure (denominator), and the TEAE rate per 
100 patient-years will be presented for each treatment group.
10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure
An overview of AEs per 100 patient-years of study exposure will be presented for 
upadacitinib 15 mg QD for the following AE categories.
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs of special interest
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT
For upadacitinib 15 mg QD treatment group, the TEAE rate per 100 patient-years of 
exposure as outlined in Section 10.2.2 will be calculated overall, for each SOC and each 
PT, for each of the following events:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug


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●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
10.2.2.3
Adverse Events of Special Interest Rates per 
100 Patient-Years of Study Drug Exposure
The Adverse Events of Special Interest (AESI) rate per 100 patient-years of exposure as 
outlined in Section 10.2.2 will be calculated overall, for each SOC and each PT, for each 
of the AESI listed in Section 10.2.1.6.
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation
All serious adverse events (SAEs), deaths, and adverse events leading to discontinuation 
of study drug will be listed.
10.3
Analysis of Laboratory Data
10.3.1
Variables and Units
All laboratory parameters to be collected in this study are listed below.  Laboratory 
parameters will be reported using the standard international (SI) units.


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Table 12.
List of Laboratory Variables
Laboratory Variables
Hematology
White Blood Cell (WBC) Count
Red Blood Cell (RBC) Count
Hemoglobin
Hematocrit
Platelets count
Neutrophils
Basophils
Eosinophils
Lymphocytes
Monocytes
Bands
Chemistry
Total Bilirubin
Alkaline Phosphatase (ALP)
Serum glutamic oxaloacetic transaminase (SGOT/AST)
Serum glutamic pyruvic transaminase (SGPT/ALT)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Uric acid
Sodium
Potassium
Calcium
Inorganic Phosphorus
Creatine Phosphokinase (CPK)
Chloride


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Table 12.
List of Laboratory Variables (Continued)
Laboratory Variables
Chemistry (continued)
Bicarbonate
Cholesterol
LDL cholesterol
HDL cholesterol
International Normalized Ratio (INR) reflex only
Urinalysis
Specific Gravity
pH
Protein
Glucose
Ketones
Blood
Microscopic Examination (if needed)
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Other
hs-CRP
QuantiFERON-TB Golda
IgG and IgM
ESR
a.
For annual follow-up, QFT is captured only for those with negative QFT at Screening.
10.3.2
Analysis of Laboratory Data for Period 1
The laboratory data will be summarized by the "as treated" treatment groups 
(upadacitinib 15 mg QD and the placebo group).


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10.3.2.1
Assessment of Mean Change from Baseline and Percent 
Change from Baseline in Clinical Laboratory Variables
Analyses of mean change from baseline in continuous hematology, chemistry, and 
urinalysis variables which are measured longitudinally will be performed by visits and by 
"as treated" treatment group.  For each change from baseline analysis, the following 
summary statistics will be presented for each treatment group:  sample size, baseline 
mean, visit mean, and the mean, standard deviation, and median of the changes from 
baseline.  An ANOVA model with treatment as a factor will be used to test statistical 
significance for the change from baseline mean among different treatment groups.
In addition, similar analyses will be conducted for percentage change from baseline in 
hemoglobin, LDL-C, HDL-C, triglycerides, total cholesterol (TC), TC/HDL and 
LDL/HDL.
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables
The baseline and post-baseline laboratory observations will be categorized as Grade 1, 
Grade 2, Grade 3, and Grade 4 according to OMERACT criteria (Rheumatology Common 
Toxicity Criteria v.2.0).  For creatine phosphokinase and creatinine NCI CTC criteria will 
be used.
For each laboratory variable, shift tables will be generated that cross tabulate the subjects 
as deemed appropriate by "as treated" treatment group:
●
Category of the baseline value versus category of the final value.
●
Category of the baseline value versus maximum category.
●
Category of the baseline value versus minimum category.
Note that the minimum/maximum category is used, rather than the category of the 
minimum/maximum value.  The two may be different due to variation in the reference 
range.


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No statistical tests will be performed for this analysis.
10.3.2.3
Assessment of Potentially Clinically Significant Laboratory 
Variables 
The criteria for potentially clinically significant laboratory values will be determined by 
OMERACT criteria of Grade 3 or 4.  For creatine phosphokinase and creatinine, NCI 
CTC criteria will be used.
The number and percentage of subjects meeting the criteria for potentially clinically 
significant laboratory values will be summarized by "as treated" treatment group. Only 
subjects with worsening in grade compared to baseline grade will be captured.
10.3.2.4
Assessment of Liver Elevations
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by "as treated" treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN


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●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
10.3.3
Analysis of Long-Term Laboratory Data
10.3.3.1
Assessment of Mean Change from Baseline and Percent 
Change from Baseline in Clinical Laboratory Variables
Analyses of mean change from baseline in continuous hematology, chemistry, and 
urinalysis variables which are measured longitudinally will be performed by visits and by 
"as treated" treatment group sequences as described in Section 10.1.  For each change 
from baseline analysis, the following summary statistics will be presented for each 
treatment group:  sample size, baseline mean, visit mean, and the mean, standard 
deviation, and median of the changes from baseline.
In addition, similar analyses will be performed for percentage change from baseline in 
hemoglobin, LDL-C, HDL-C, triglycerides, total cholesterol (TC), TC/HDL and 
LDL/HDL.
10.3.3.2
Assessment of Potentially Clinically Significant Laboratory 
Values
Long-term laboratory data will be summarized based on the number and percentage of 
subjects meeting the criteria for potentially clinically significant laboratory values for 
upadacitinib 15 mg QD group.  
In the evaluation of potentially clinically significant laboratory values, the baseline value 
will be determined by the last non-missing measurement recorded on or before the date of 
the first dose of upadacitinib 15 mg QD (which may be different than the first dose of 


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study drug in the study).  For example, for a subject who started on placebo and switched 
to upadacitinib 15 mg QD, lab values under upadacitinib 15 mg QD exposure would be 
evaluated against the baseline value defined as the last non-missing measurement 
recorded on or before the date of the first dose of upadacitinib 15 mg QD.
A listing of all subjects with any laboratory determination meeting OMERACT criteria of 
Grade 3 or 4 will be provided.  For creatine phosphokinase and creatinine, NCI CTC 
criteria will be used.  Only subjects with worsening in grade compared to baseline grade 
will be captured.  For each of these subjects, the whole course of the respective parameter 
will be listed.
10.3.3.3
Assessment of Liver Elevations
The frequencies and percentages of subjects with post baseline liver-specific function test 
values that meet the following criteria of potential clinical interest will be summarized for 
upadacitinib 15 mg QD group, the categories are similarly described as in 
Section 10.3.2.4.
A listing of potentially clinically significant liver elevations based on criteria specified 
above will be provided.  For each of these subjects, the whole course of the respective 
parameter will be listed.
10.4
Analysis of Vital Signs 
10.4.1
Variables and Criteria Defining Abnormality
Vital sign variables include sitting systolic blood pressure, sitting diastolic blood pressure, 
pulse rate, respiratory rate, body temperature, and weight.  The criteria for potentially 
clinically significant vital sign findings are presented in Table 13.


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Table 13.
Criteria for Potentially Clinically Significant Vital Sign Findings
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 15 mmHg from Baseline
High
Value ≥ 105 mmHg and increase ≥ 15 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Respiratory Rate
Low
< 10 rpm
High
> 24 rpm
Body temperature
High
> 39.0°C (102.3°F)
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
10.4.2
Analysis of Vital Sign for Period 1
Analyses of mean change from baseline in continuous vital sign variables which are 
measured longitudinally will be performed by visits and by the "as treated" treatment 
groups of upadacitinib 15 mg QD and placebo.  For each change from baseline analysis, 
the following summary statistics will be presented for each treatment group:  sample size, 
baseline mean, visit mean, and the mean, standard deviation, and median of the changes 
from baseline.  The number and percentage of subjects meeting the criteria for potentially 
clinically significant vital sign values will be summarized by "as treated" treatment group. 
10.4.3
Analysis of Long-Term Vital Sign
Analyses of mean change from baseline in continuous vital signs variables which are 
measured longitudinally will be performed by visits and by "as treated" treatment group 
sequences as described in Section 10.1.  For each change from baseline analysis, the 
following summary statistics will be presented for each treatment group sequence:  
sample size, baseline mean, visit mean, and the mean, standard deviation, and median of 
the changes from baseline.


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Long-Term Vital Sign will also be summarized based on the number and percentage of 
subjects meeting the criteria for potentially clinically significant vital sign values for 
upadacitinib 15 mg QD group. Similar baseline definition as described in 
Section 10.3.3.2 will be applied.
A listing of all subjects with any vital sign values meeting the criteria for potentially 
clinically significant vital signs will be provided.  For each of these subjects, the whole 
course of the respective parameter will be listed.
11.0
References
1.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
2.
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance.  
Biometrika.  1988;75(4):800-2.
3.
Greenland S, Rothman KJ, Lash TL.  Introduction to stratified analysis.  In:  
Rothman KJ, Greeland S, Lash TL, editors.  Modern Epidemiology.  3rd Ed.  
Philaphdelphia:  Lippincott Williams & Wilkins; 2008.
4.
Koch GG.  Comments on 'current issues in non-inferiority trials'.  Stat Med.  
2008;27(3):333-42.
5.
Liu GF, Wang J, Liu K, et al.  Confidence intervals for an exposure adjusted 
incidence rate difference with application to clinical trials.  Stat Med.  
2006;25(8):1275-86.


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12.0
Appendix
Appendix A
OMERACT Criteria
Appendix B
Analysis of Binary Endpoints
Appendix C
Analysis of Continuous Endpoints using Mixed Effect Model Repeat 
Measurement (MMRM)


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Appendix A.
OMERACT Criteria
Rheumatology Common Toxicity Criteria v.2.0
Based on Woodworth TG, et al.  Standardizing assessment of adverse effects in rheumatology clinical trials II.  Status of OMERACT Drug Safety Working Group 
May 2006:  OMERACT 8.  Standardizing Assessment and Reporting of Adverse Effects in Rheumatology Clinical Trials:  Enabling Description of Comparative 
Safety Profiles for Antirheumatic Therapies
(Note that for L9.  CPK and L11.  Creatinine, the criteria in this table is replaced by the NCI CTC grade, as the NCI CTC grade is used for analysis for these two parameters.)
1 – Mild
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
No medication or OTC
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve. (may be 
prescription),
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation, or/and dose reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent.
Multiple meds
Hospitalised > 24 hr
Study drug discontinued
A.  Allergic/Immunologic
A1.  Allergic 
reaction/ 
hypersensitivity 
(includes drug fever)
Transient rash:  drug fever 
< 38°C:  transient, asymptomatic 
bronchospasm
Generalised urticaria responsive to 
meds; or drug fever > 38°C, or 
reversible bronchospasm
Symptomatic bronchospasm 
requiring meds; symptomatic 
urticaria persisting with meds, 
allergy related oedema/angioedema
Anaphylaxis, laryngeal/pharyngeal 
oedema, requiring resuscitation
A2.  Autoimmune 
reaction
Seriologic or other evidence of 
autoimmune reaction, but patient 
asymptomatic:  all organ function 
normal and no treatment is 
required (e.g., vitiligo)
Evidence of autoimmune reaction 
involving a non-essential organ or 
functions, requiring treatment 
other than immunosuppressive 
drugs (e.g., hypothyroidism)
Reversible autoimmune reaction 
involving function of a major organ 
or toxicity requiring short term 
immunosuppressive treatment 
(e.g., transient colitis or anaemia)
Causes major organ dysfunction, or 
progressive, not reversible, or 
requires long-term administration 
of high dose immunosuppressive 
therapy
A3.  Rhinitis 
(includes sneezing, 
nasal stuffiness, 
post-nasal discharge)
Transient, non-prescription meds 
relieve
Prescription med. required, slow
Corticosteroids or other prescription 
med. with persistent disabling 
symptoms such as impaired exercise 
tolerance
NA


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A4.  Serum sickness
Transient, non-prescription meds 
relieve
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Prolonged; symptoms only partially 
relieved by meds; parenteral 
corticosteroids required
Major organ dysfunction, requires 
long-term high-dose 
immunosuppressive therapy
A5.  Vasculitis
Localised, not requiring 
treatment; or rapid response to 
meds; cutaneous
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Generalised, parenteral 
corticosteroids required or/and short 
duration hospitalisation
Prolonged, hospitalisation, 
ischemic changes, amputation
B.  Cardiac
B1.  Arrhythmia
Transient, asymptomatic
Transient, but symptomatic or 
recurrent, responds to meds
Recurrent/persistent; maintenance 
prescription
Unstable, hospitalisation required, 
parenteral meds
B2.  Cardiac function 
decreased
Asymptomatic decline in resting 
ejection fraction by > 10%, but 
< 20% of baseline value
Asymptomatic decline of resting 
ejection fraction ≥ 20% of baseline 
value
CHF responsive to treatment
Severe or refractory CHF
B3.  Edema
Asymptomatic
(e.g., 1 + feet/calves), self-limited, 
no therapy required
Symptomatic
(e.g., 2 + feet/calves), requires 
therapy
Symptoms limiting function 
(e.g., 3 + feet/calves, 2 + thighs), 
partial relief with treatment 
prolonged
Anasarca; no response to treatment
B4.  Hypertension 
(new onset or 
worsening)
Asymptomatic, transient increase 
by > 20 mmHg (diastolic) or to 
> 150/100 if previously normal, 
no therapy required
Recurrent or persistent increase 
> 150/100 or by > 10 mmHg 
(diastolic), requiring and 
responding readily to treatment
Symptomatic increase > 150/100, 
> 20 mmHg, persistent, requiring 
multi agency therapy, difficult to 
control
Hypertensive crisis
B5.  Hypotension 
(without underlying 
diagnosis)
Transient, intermittent, 
asymptomatic, orthostatic 
decrease in blood pressure 
> 20 mmHg
Symptomatic, without interference 
with function, recurrent or 
persistent > 20 mmHg decrease, 
responds to treatment
Syncope or symptomatic, interferes 
with function, requiring therapy and 
sustained medical attention, dose 
adjustment or drug discontinuation
Shock
B6.  Myocardial 
ischaemia
Transient chest pain/ECG 
changes; rapid relief with nitro
Recurring chest pain, transient 
ECG ST-T changes; treatment 
relieves
Angina with infarction, no or 
minimal functional compromise, 
reduce dose or discontinue study 
drug
Acute myocardial infarction, 
arrthymia or/and CHF


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B7.  Pericarditis/ 
pericardial effusion
Rub heard, asymptomatic
Detectable effusion by 
echocardiogram, symptomatic 
NSAID required
Detectable on chest x-ray, 
dyspnoea; or pericardiocentesis; 
requires corticosteroids
Pulsus alternates with low cardiac 
output; requires surgery
B8.  
Phlebitis/thrombosis/ 
Embolism (excludes 
injection sites)
Asymptomatic, superficial, 
transient, local, or no treatment 
required
Symptomatic, recurrent, deep vein 
thrombosis, no anticoagulant 
therapy required
Deep vein thrombosis requiring 
anticoagulant therapy
Pulmonary embolism
C.  General (constitutional)
C1.  Fatigue/malaise 
(asthenia)
Increase over baseline; most usual 
daily functions maintained, short 
term
Limits daily function intermittently 
over time
Interferes with basic ADL, 
persistent
Unable to care for self, bed or 
wheelchair bound > 50% of day 
debilitating, hospitalisation
C2.  Fever (pyrexia) 
(note:  fever due to 
drug allergy should 
be coded as allergy)
Transient, few symptoms 37.7 –
38.5°C
Symptomatic, recurrent 38.6 –
39.9°C.  Relieved by meds
≥ 40°C; ≤ 24 h, persistent 
symptoms; partial response to meds
≥ 40°C, debilitating, > 24 h, 
hospitalisation; no relief with meds
C3.  Headache
Transient or intermittent, no meds 
or relieved with OTC
Persistent, recurring, non-narcotic 
analgesics relieve
Prolonged with limited response to 
narcotic medicine
Intractable, debilitating, requires 
parenteral meds
C4.  Insomnia
Difficulty sleeping, short term, no 
interfering with function
Difficulty sleeping interfering with 
function, use of prescription med
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C5.  Rigors, chills
Asymptomatic, transient, no 
meds, or non-narcotic meds 
relieve
Symptomatic, narcotic meds 
relieve
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C6.  Sweating 
(diaphoresis)
Episodic, transient
Frequent, short term
Frequent, drenching, disabling
Dehydration, requiring IV 
fluids/hospitalization > 24 hrs
C7.  Weight gain
5% – 9.9%
10% – 19.9%
20% – 30%
NA
C8.  Weight loss
5% – 9.9%
10% – 19.9%
20% – 30%
NA
D.  Dermatologic
D1.  Alopecia
Subjective, transient
Objective, fully reversible
Patchy, wig used, partly reversible
Complete, or irreversible even if 
patchy


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D2.  Bullous eruption
Localised, asymptomatic
Localised, symptomatic, requiring 
treatment
Generalised, responsive to 
treatment; reversible
Prolonged, generalised, or 
requiring hospitalisation for 
treatment
D3.  Dry skin
Asymptomatic, controlled with 
emollients
Symptoms eventually (1 – 2 wks) 
controlled with emollients
Generalised, interfering with ADL 
> 2 wks, persistent pruritis, partially 
responsive to treatment
Disabling for extended period, 
unresponsive to ancillary therapy 
and requiring study drug 
discontinuation for relief
D4.  Injection site 
reaction
Local erythema, pain, pruritis, 
< few days
Erythema, pain, oedema, may 
include superficial phlebitis,
1 – 2 wks
Prolonged induration, superficial 
ulceration; includes thrombosis
Major ulceration necrosis requiring 
surgery
D5.  Petechiae 
(without vasculitis)
Few, transient asymptomatic
Dependent areas, persistent up to 
2 wks
Generalised, responsive to 
treatment; reversible
Prolonged, irreversible, disabling
D6.  Photosensitivity
Transient erythema
Painful erythema and oedema 
requiring topical treatment
Blistering or desquamation, requires 
systematic corticosteroids
Generalised exfoliation or 
hospitalisation
D7.  Pruritis
Localised, asymptomatic, 
transient, local treatment
Intense, or generalised, relieved by 
systematic medication
Intense or generalised; poorly 
controlled despite treatment
Disabling, irreversible
D8.  Rash (not 
bullous)
Erythema, scattered 
macular/popular eruption; pruritis 
transient; TOC or no meds
Diffuse macular/popular eruption 
or erythema with pruritus; dry 
desquamation; treatment required
Generalised, moist desquamation, 
requires systemic corticosteroids; 
responsive to treatment; reversible
Exfoliative or ulcerating; or 
requires hospitalisation; or 
parenteral corticosteroids
D9.  
Induration/fibrosis/ 
Thickening (not 
sclerodermal)
Localized, high density on 
palpation, reversible, no effect on 
ADL and not disfiguring
Local areas < 50% body surface, 
not disfiguring, transient 
interference with ADL, reversible
Generalized, disfiguring, interferes 
with ADL, reversible
Disabling, irreversible, systemic 
symptoms
E.  Ear/Nose/Throat
E1.  Hearing loss
Transient, intermittent, no 
interference with function
Symptomatic, treatment required, 
reversible
Interferes with function; incomplete 
response to treatment
Irreversible deafness
E2.  Sense of smell
Slightly altered
Markedly altered
Complete loss, reversible
Complete loss, without recovery
E3.  Stomatitis
Asymptomatic
Painful, multiple, can eat
Interferes with nutrition, slowly 
reversible
Requires enteral support; residual 
dysfunction


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E4.  Taste 
disturbance 
(dysgeusia)
Transiently altered; metallic
Persistently altered; limited effect 
on eating
Disabling, effect on nutrition
NA
E5.  Tinnitus
Intermittent, transient, no 
interference with function
Requires treatment, reversible
Disabling, or associated with 
hearing loss
Irreversible deafness
E6.  Voice changes 
(includes hoarseness, 
loss of voice,
laryngitis)
Intermittent hoarseness, able to 
vocalise
Persistent hoarseness, able to 
vocalise
Whispered speech, slow return of 
ability to vocalise
Unable to vocalize for extended
E7.  Xerostomia (dry 
mouth)
Transient dryness
Relief with meds
Interferes with nutrition, slowly 
reversible
Extended duration interference 
with nutrition, requires parenteral 
nutrition
F.  Eye/Ophthalmologic
F1.  Cataract
Asymptomatic, no change in 
vision, non-progressive
Symptomatic, partial visual loss, 
progressive
Symptoms impairing function, 
vision loss requiring treatment, 
including surgery
NA
F2.  Conjunctivitis
Asymptomatic, transient, rapid 
response to treatment
Symptomatic, responds to 
treatment, changes not interfering 
with function
Symptoms prolonged, partial 
response to treatment, interferes 
with function
NA
F3.  Lacrimation 
increased (tearing, 
watery eyes)
Symptoms not requiring 
treatment, transient
Symptomatic, treatment required, 
reversible
Unresponsive to treatment with 
major effect on function
NA
F4.  Retinopathy
Asymptomatic, non-progressive, 
no treatment
Reversible change in vision; 
readily responsive to treatment
Disabling change in vision 
ophthalmological findings 
reversible, sight improves over time
Loss of sight
F5.  Vision changes 
(e.g., blurred,
photophobia, night 
blindness, vitreous 
floaters)
Asymptomatic, transient, no 
treatment required
Symptomatic, vision changes not 
interfering with function, 
reversible
Symptomatic, vision changes 
interfering with function
Loss of sight


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F6.  Xerophtalmia 
(dry eyes)
Mild scratchiness
Symptomatic without interfering 
with function, requires artificial 
tears
Interferes with vision/function, 
corneal ulceration
Loss of sight
G.  Gastrointestinal
G1.  Anorexia
Adequate food intake, minimal 
weight loss
Symptoms requiring oral 
nutritional supplementation
Prolonged, requiring iv support
Requires hospitalization for 
nutritional support
G2.  Constipation
Asymptomatic, transient, 
responds to stool softener, OTC 
laxatives
Symptomatic, requiring 
prescription laxatives, reversible
Obstipation requiring medical 
intervention
Bowel obstruction.  Surgery 
required
G3.  Diarrhea
Transient, increase of 2 –
3 stools/day over pre-treatment 
(no blood or mucus), OTC agents 
relieve
Symptomatic, increase 4 –
6 stools/day, nocturnal stools, 
cramping, requires treatment with 
prescription meds
Increase > 6 stools/day, associated 
with disabling symptoms, 
e.g., incontinence, severe cramping, 
partial response to treatment
Prolonged, dehydration, 
unresponsive to treatment, requires 
hospitalization
G4.  Dyspepsia 
(heartburn)
Transient, intermittent, responds 
to OTC antacids, H-2 blockers
Prolonged, recurrent, requires 
prescription meds, relieved by 
meds
Persistent despite treatment, 
interferes with function, associated 
with GI bleeding
NA
G5.  GI bleed 
(gastritis, gastric or 
duodenal ulcer 
diagnosed-define 
aetiology)
Asymptomatic, endoscopic 
finding, haemocult + stools, no 
transfusion, responds rapidly to 
treatment
Symptomatic, transfusion ≤ 2 units 
needed; responds to treatment
Haematemesis, transfusion 3 –
4 units, prolonged interference with 
function
Recurrent, transfusion > 4 units, 
perforation, requiring surgery, 
hospitalisation
G6.  Haematochezia 
(rectal bleeding)
Haemorrhodial, asymptomatic, no 
transfusion
Symptomatic, transfusion
≤ 2 units, reversible
Recurrent, transfusion > 3 – 4 units
> 4 units, hypotension, requiring 
hospitalization
G7.  Hepatitis
Laboratory abnormalities, 
asymptomatic, reversible
Symptomatic laboratory 
abnormalities, not interfering with 
function, slowly reversible
Laboratory abnormalities persistent 
> 2 wks, symptoms interfere with 
function
Progressive, hepato-renal, anasarca, 
pre-coma or coma
G8.  Nausea, or 
nausea/vomiting (use 
diagnostic term)
Transient, intermittent, minimal 
interference with intake, rapid 
response to meds
Persistent, recurrent, requires 
prescription meds, intake 
maintained
Prolonged, interferes with daily 
function and nutritional intake, 
periodic iv fluids
Hypotensive, hospitalization, 
parenteral nutrition, unresponsive 
to out-patient management


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G9.  Pancreatitis
Anylase elevation, intermittent 
nausea/vomiting, transient, 
responds rapidly to treatment
Amylase elevation with abdominal 
pain, nausea, occasional vomiting, 
responsive to treatment
Severe, persistent abdominal pain 
with pancreatitic enzyme elevation, 
incomplete or slow response to 
treatment
Complicated by shock, 
haemorrhage (acute circulatory 
failure)
G10.  Proctitis
Perianal pruritus, haemorrhoids 
(new onset), transient, or 
intermittent, relieved by OTC 
meds
Tenesmus or ulcerations, anal 
fissure, responsive to treatment, 
minimal interference with function
Unresponsive to treatment, marked 
interference with function
Mucosal necrosis with 
haemorrhage, infection, surgery 
required
H.  Musculoskeletal
H1.  Avascular 
necrosis
Asymptomatic MRI changes, 
non-progressive
MRI changes and symptoms 
responsive to rest and analgesia
MRI changes, symptoms requiring 
surgical intervention
Wheelchair bound; surgical repair 
not possible
H2.  Arthralgia
Intermittent transient symptoms, 
no meds or relieved by OTC meds
Persistent or recurrent symptoms, 
resolve with meds, little effect on 
function
Severe symptoms despite meds 
impairs function
Debilitating, hospitalisation 
required for treatment
H3.  Leg cramps
Transient, intermittent, does not 
interfere with function
Recurrent symptoms, minimally 
interferes with function or sleep, 
responds to meds
Persistent, prolonged interference 
with function or sleep, partial or no 
response to meds
NA
H4.  Myalgia
Occasional; does not interfere 
with function
Frequent, requires meds 
(non-narcotic); minor effects on 
function
Major change in function/lifestyle, 
narcotic pain meds
Debilitating, profound weakness, 
requires wheelchair, unresponsive 
to meds
I.  Neuropsychiatric
I1.  Anxiety or 
Depression (mood 
alteration)
Symptomatic, does not interfere 
with function; no meds
Frequent symptoms, responds to 
meds; interferes with ADL at times
Persistent, prolonged symptoms, 
partial or no response to meds, 
limits daily function
Suicidal ideation or danger to self
I2.  Cerebrovascular 
ischaemia
NA
Single transient ischaemic event, 
responsive to treatment
Recurrent transient ischaemic events
Cerebrovascular vascular accident 
with permanent disability
I3.  Cognitive 
disturbance
Subjective symptoms, transient, 
intermittent, not interfering with 
function
Objective symptoms, persisting, 
interferes with daily function 
occasionally
Persistent, or worsening objective 
symptoms; interferes with routine 
daily routine
Debilitating/disabling and 
permanent; toxic psychosis


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I4.  Depressed 
consciousness 
(somnolence)
Observed, transient, intermittent, 
not interfering with function
Somnolence or sedation, 
interfering with function
Persistent, progressive, obundation, 
stupor
Coma
I5.  Inability to 
concentrate
Subjective symptoms, does not 
interfere with function
Objective findings, interferes with 
function
Persistent, prolonged objective 
findings or organic cause
NA
I6.  Insomnia (in 
absence of pain)
Occasional difficulty sleeping, 
transient intermittent, not 
interfering with function
Recurrent difficulty sleeping; 
requires meds for relief; occasional 
interference with function
Persistent or worsening difficulty 
sleeping; severely interferes with 
routine daily function
NA
I7.  Libido decreased
Decrease in interest
Loss of interest; influences 
relationship
Persistent, prolonged interfering 
with relationship
NA
I8.  Peripheral motor 
neuropathy
Subjective or transient loss of 
deep tendon reflexes; function 
maintained
Objective weakness, persistent, no 
significant impairment of daily 
function
Objective weakness with substantial 
impairment of function
Paralysis
I9.  Peripheral 
sensory neuropathy 
(sensory disturbance)
Subjective symptoms without 
objective findings, transient, not 
interfering with function
Objective sensory loss, persistent, 
not interfering with function
Prolonged sensory loss or 
paraethesias interfering with 
function
NA
I10.  Seizure
NA
Recurrence of old seizures, 
controlled with adjustment of 
medication
Recurrence/exacerbation with 
partial response to medication
Recurrence not controlled, 
requiring hospitalization; new 
seizures
I11.  Vertigo 
(dizziness)
Subjective symptoms, transient, 
intermittent, no treatment
Objective findings, recurrent, meds 
relieve, occasionally interfering
with function
Persistent, prolonged, interfering 
with daily function; partial response 
to medication
Debilitating without response to 
medication, hospitalization
J.  Pulmonary
J1.  Asthma
Occasional wheeze, no 
interference with activities
Wheezing, requires oral meds, 
occasional interference with 
function
Debilitating, requires nasal O2
Requires ventilator assistance
J2.  Cough
Transient, intermittent, occasional 
OTC meds relieve
Persistent, requires narcotic or 
other prescription meds for relief
Recurrent, persistent coughing 
spasms without consistent relief by 
meds, interferes with function
Interferes with oxygenation; 
debilitating


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J3.  Dyspnea
Subjective, transient, no 
interference with function
Symptomatic, intermittent or 
recurring, interferes with 
exertional activities
Symptomatic during daily routine 
activities, interferes with function, 
treatment with intermittent nasal O2
relieves
Symptomatic at rest, debilitating, 
requires constant nasal O2
J4.  Pleuritic pain 
(pleurisy)
Transient, intermittent symptoms, 
no treatment or OTC meds relieve
Persistent symptoms, requires 
prescription meds for relief
Prolonged symptoms, interferes 
with function, requires frequent 
narcotic pain relief
Debilitation, requiring 
hospitalisation
J5.  Pneumonitis 
(pulmonary 
infiltrates)
Asymptomatic radiographic 
changes, transient, no treatment 
required
Symptomatic, persistent, requiring 
corticosteroids
Symptomatic, requiring treatment 
including O2
Debilitating, not reversible; or 
requiring assisted ventilation
J6.  Pulmonary 
function decreased 
(FVC or carbon 
monoxide diffusion 
capacity – DLCO)
76% – 90% of pre-treatment value
51% – 75% of pre-treatment value
26% – 50% of pre-treatment value
≤ 25% of pre-treatment value
Laboratory Data
K.  Haematology
K1.  Hgb (g/dl) 
decrease from 
pre-treatment
1.0 – 1.4
1.5 – 2.0
2.1 – 2.9, or Hgb < 8.0, > 7.0
≥ 3.0; or Hgb < 7.0
K2.  Leukopenia 
(total WBC) × 1000
3.0 – 3.9
2.0 – 2.9
1.0 – 1.9
< 1.0
K3.  Neutropenia 
(× 1000)
1.5 – 1.9
1.0 – 1.4
0.5 – 0.9
< 0.5
K4.  Lymphopenia 
(× 1000)
1.5 – 1.9
1.0 –1.4
0.5 – 0.9
< 0.5
K5.  Platelets 
(× 1000)
75 – LLN
50 – 74.9
20 – 49.9; platelet transfusion 
required
< 20; recurrent platelet transfusions


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L.  Chemistry
L1.  Hypercalcaemia 
(mg/dl)
1.1 × ULN – 11.5
11.6 – 12.5
12.6 – 13.5; or symptoms present
> 13.5; or associated coma
L2.  Hyperglycemia 
(mg/dl) Fasting
140 – 160
161 – 250
251 – 500
> 500, or associated with 
ketoacidosis
L3.  Hyperkalaemia 
(mmol/l)***
5.5 – 5.9
6.0 – 6.4
6.5 – 7.0 or any ECG change
> 7.0 or any arrhythmia
L5.  Hypocalcaemia 
(mg/dl)
0.9 × LLN – 7.8
7.7 – 7.0
6.9 – 6.5; or associated with 
symptoms
< 6.5 or occurrence of tetany
L6.  Hypoglycemia 
(mg/dl)
55 – 64 (no symptoms)
40 – 54 (or symptoms present)
30 – 39 (symptoms impair function)
< 30 or coma
L7.  Hyponatraemia 
(mmol/l)***
-
125 – 129
120 – 124
< 120
L8.  Hypokalaemia 
(mg/dl)***
-
3.0 – 3.4
2.5 – 2.9
< 2.5
L9.  CPK (also if 
polymyositis-
disease)****
> ULN – 1.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 10.0 × ULN
> 10.0 × ULN
L10.  Serum uric acid
1.2 – 1.6 × ULN
1.7 – 2.9 × ULN
3.0 – 5.0 × ULN or gout
NA
L11.  Creatinine 
(mg/dl)****
> 1 – 1.5 × Baseline; > ULN –
1.5 × ULN
> 1.5 – 3.0 × Baseline; > 1.5 –
3.0 × ULN 
> 3.0 baseline; > 3.0 – 6.0 × ULN
> 6.0 × ULN
L12.  SGOT (AST)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.1 – 8.0 × ULN
> 8.0 × ULN
L13.  SGPT (ALT)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.0 – 8.0 × ULN
> 8.0 × ULN
L14.  Alkaline 
phosphatase
1.1 – 1.5** × ULN
1.6 – 3.0 × ULN
3.0 – 5.0 × ULN
> 5.0 × ULN
L15.  T. bilirubin
1.1 – 1.4 × ULN
1.5 – 1.9 × ULN
2.0 – 3.0 × ULN
> 3.0 × ULN
L16.  LDH
1.3 – 2.4 × ULN
2.5 – 5.0 × ULN
5.1 – 10 × ULN
> 10 × ULN


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M.  Urinalysis
M1.  Haematuria
Micro only
Gross, no clots
Clots, transfusion < 2 units 
Transfusion required
M2.  Proteinuria (per 
24 h)
300 – 500 mg (tr/1+)
501 – 1999 mg (2+)
2 – 5.0 g (3+) nephrotic syndrome
5.0 g (4+) anasarca
M3.  WBC in urine
NA
NA
Indicating acute interstitial nephritis
Associated with acute renal failure
M4.  Uric acid 
crystals
Present without symptoms
NA
With stones or symptoms of stones 
(e.g., renal colic)
Causing renal outflow obstruction 
and hospitalization
*:
in L11, 1.5 – 1.8 × ULN is changed to 1.4 – 1.8 × ULN.
**:
in L14, 1.1 – 2.0 × ULN is changed to 1.1 – 1.5 × ULN.
***:
in L3, L7 and L8, mg/dl is changed to mmol/l.
****: NCI CTC grade.


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Appendix B.
Analysis of Binary Endpoints
The point estimate of the response rate for each treatment group is calculated as ݌̂ ൌ
௞
ேwhere k denotes the number of responders in 
the treatment group and N denotes the total number of subjects in the treatment group.  The corresponding 95% CI is based on normal 
approximation, that is ݌̂ േܼ଴.ଽ଻ହට
ଵ
ே݌̂ሺ1 െ݌̂ሻ, where ܼ଴.ଽ଻ହdenotes the 97.5% quantile of the standard normal distribution.  This is 
implemented by obtaining the Wald asymptotic confidence limits using the SAS procedure PROC FREQ with the BINOMIAL option.  
The SAS code example is as follows:
proc freq data=TESTData1;
  by TRTP;
  tables RESP / binomial(level="1") alpha=0.05;
  weight COUNT/zero;
  output out=CI(keep= L_BIN U_BIN) binomial;
run;
Note:
The input dataset is cell count data, with variable RESP denoting response status ("1" as responder and "0" as non-responder) and variable COUNT denoting the number 
of subjects with the corresponding response status.
The treatment difference is calculated as ݌̂ଵെ݌̂ଶand the corresponding 95% CI for the treatment difference is based on normal 
approximation, that is ݌̂ଵെ݌̂ଶേܼ଴.ଽ଻ହට
ଵ
ேభ݌̂ଵሺ1 െ݌̂ଵሻ൅
ଵ
ேమ݌̂ଶሺ1 െ݌̂ଶሻThis is implemented by obtaining the Wald asymptotic 
confidence limits using the SAS procedure PROC FREQ with the RISKDIFF option. The SAS code example is as follows:
proc freq data=TESTData1;
  tables TRTP*RESP / riskdiff alpha=0.05;
  weight COUNT/zeros;


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  where TRTP in ('PLACEBO','UPA 15MG');
  output out=diff(keep= _RDIF1_ L_RDIF1 U_RDIF1) riskdiff1;
run;
Note:
The input dataset is cell count data, with variable RESP denoting response status ("1" as responder and "0" as non-responder) and variable COUNT denoting the number 
of subjects with the corresponding response status. TRTP denotes the treatment group.
The p-value for the treatment comparison is based on the Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factor. 
This is implemented using the SAS procedure PROC FREQ with the CMH option. The p-value from the "general association 
statistic" is used. The SAS code example is as follows:
proc freq data=TESTData3;
  tables STRATA*TRTP*RESP_VALUE / cmh;
run;
Note:
The input dataset is subject-level data, with variable RESP_VALUE denoting the subject's response status ("1" as responder and "0" as non-responder). TRTP denotes 
the treatment group and STRATA denotes the strata for a given subject.


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Appendix C.
Analysis of Continuous Endpoints using Mixed Effect Model Repeat Measurement (MMRM)
The repeated measure analysis will be conducted using mixed model including observed data at all visits.  For the MMRM analysis, 
data collected after premature discontinuation of study drug will be excluded.  The mixed model includes the categorical fixed effects 
of treatment, visit and treatment-by-visit interaction, main stratification factors at randomization and the continuous fixed covariates of 
baseline measurement.  An unstructured variance covariance matrix will be used.  The parameter estimations are based on the 
assumption of data being missing at random and using the method of restricted maximum likelihood (REML).
The MMRM is implemented using the SAS procedure PROC MIXED.  The LSMEANS statement provides the least-squares means 
and corresponding 95% CIs for each treatment group at each visit, as well as the least-squares means, corresponding 95% CIs and 
p-values for treatment comparisons at each visit.  The SAS code example is as follows:
proc mixed data=CData;
    class TRTP AVISIT STRATA USUBJID;
    model CHG = TRTP AVISIT BASE STRATA TRTP*AVISIT / DDFM=kr htype = 3;
    repeated AVISIT / subject = USUBJID type=un;
    lsmeans TRTP*AVISIT/ cl diff;
    ods output lsmeans=lsmean_output;
run;
Note:
The input dataset is per subject per visit. USUBJID is the unique subject number, TRTP denotes the treatment group, STRATA denotes the strata, and AVISIT denotes 
the visit. CHG denotes the change from baseline value and BASE denotes the baseline value.