Clinical trial NCT02706873
Conditions: Rheumatoid Arthritis
Keywords: Musculoskeletal disease Arthritis Joint disease Anti-inflammatory agents Antirheumatic agents ABT-494 Upadacitinib
Sponsor: AbbVie
Start date: 2016-02-23; Completion date: 2022-11-10
Enrollment: 1002 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of Period 1 were the following:

* To compare the safety and efficacy of upadacitinib 7.5 mg once daily (QD) monotherapy (for participants in Japan only), 15 mg QD monotherapy, and 30 mg QD monotherapy versus weekly methotrexate monotherapy for the treatment of signs and symptoms of RA in methotrexate-naïve adults with moderately to severely active RA;
* To compare the efficacy of upadacitinib 15 mg QD monotherapy and upadacitinib 30 mg QD monotherapy versus weekly methotrexate monotherapy for prevention of structural progression in methotrexate-naïve adults with moderately to severely active RA.

The objective of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 7.5 mg QD (for participants in Japan only), 15 mg QD, and 30 mg QD in adults with RA who have completed Period 1.

Detailed description:
This study includes 2 periods (a 48-week double-blind treatment period and a long-term extension period) and a Japan substudy. In Period 1 participants will be randomized in a 1:1:1 ratio to treatment Groups 2, 3, and 4 below, except for participants from Japan, who will be randomized in a 2:1:1:1 ratio to Groups 1, 2, 3, and 4:

* Group 1: Upadacitinib 7.5 mg once daily (QD) monotherapy (participants in Japan only)
* Group 2: Upadacitinib 15 mg QD monotherapy
* Group 3: Upadacitinib 30 mg QD monotherapy
* Group 4: Methotrexate monotherapy

Rescue therapy is defined for Weeks 12 through 24, Week 26, and Weeks 36 through 40. Starting at Week 12 through Week 24, participants who do not achieve ≥ 20% improvement in both tender joint count (TJC) and swollen joint count (SJC) compared with baseline at two consecutive visits will continue on their blinded therapy and the Investigator should optimize (initiate or increase) background RA medications: non-steroidal anti-inflammatory drug(s) (NSAIDs), corticosteroids (oral ≤ 10 mg/day prednisone equivalent or prednisone equivalent ≤ 0.5 mg/kg/day for 3 consecutive days) and/or low-potency analgesics.

Rescue therapy for participants who meet the following criteria at Week 26 are as follows:

Participants who do not achieve clinical remission (CR) based on Clinical Disease Activity Index (CDAI) (defined as a CDAI score ≤ 2.8):

* but achieve ≥ 20% improvement in both TJC and SJC compared with baseline will continue on blinded study drug and the Investigator should optimize (initiate or increase) background RA medications: NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 2 local injections), low-potency analgesics and conventional synthetic disease-modifying anti-rheumatic drug(s) (csDMARDs) (only 1 of the following: sulfasalazine, hydroxychloroquine or chloroquine) throughout the remainder of Period 1 and until the study is unblinded.
* and do not achieve ≥ 20% improvement in both TJC and SJC compared with baseline and originally assigned to methotrexate will be re-randomized in a 1:1 ratio to receive blinded upadacitinib 15 mg QD or upadacitinib 30 mg QD (participants in Japan will be randomized 1:1:1 to receive upadacitinib 7.5 mg QD, 15 mg QD, or 30 mg QD) while continuing methotrexate treatment in a blinded manner until the study is unblinded. Participants originally assigned to upadacitinib will add methotrexate 10 mg/week (7.5 mg for Japan) to upadacitinib in a blinded manner and will remain on upadacitinib plus methotrexate 10 mg/week (7.5 mg for Japan) until the study is unblinded.

Starting at Week 36 through Week 40, participants who do not achieve ≥ 20% improvement in both TJC and SJC compared with baseline at two consecutive visits will continue on their blinded therapy and the Investigator should optimize (initiate or increase) background RA medications: NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent or prednisone equivalent ≤ 0.5 mg/kg/day for 3 consecutive days and up to 2 local injections), low-potency analgesics and csDMARDs (only 1 of the following: sulfasalazine, hydroxychloroquine or chloroquine).

Participants who complete the Week 48 visit (end of Period 1) will enter the long-term extension, Period 2 (212 weeks) and continue study treatment per assignment at the end of Period 1 in a blinded fashion. When the last participant completes the last visit of Period 1 (Week 48), study drug assignment in both periods may be unblinded, and participants will be dispensed study drug in an open-label fashion until the completion of Period 2. Starting with Protocol Amendment 6, participants receiving upadacitinib 15 mg and 30 mg QD will receive open-label upadacitinib 15 mg QD, and participants receiving methotrexate will receive open-label methotrexate.

A global analysis will be conducted for the comparisons of the primary and secondary efficacy endpoints between the upadacitinib 15 mg QD and 30 mg QD treatment groups versus the methotrexate treatment group for all participants (excluding the Japan specific upadacitinib 7.5 mg treatment group). Analyses will be conducted separately for United States (US)/Food and Drug Administration (FDA), European Union (EU)/European Medicines Agency (EMA), and Japan/Pharmaceuticals and Medical Devices Agency (PMDA) regulatory purposes, each according to a pre-specified sequence of primary and ranked secondary endpoints.

A separate Japan sub-study analysis will be conducted for the comparisons of the efficacy endpoints between the upadacitinib 7.5 mg QD, 15 mg QD, and 30 mg QD treatment groups versus the methotrexate treatment group for participants enrolled in Japan only.

Arms: arm 1: Period 1: Participants will receive placebo to upadacitinib once daily and methotrexate once weekly for 48 weeks.

Period 2: Participants will continue on placebo to upadacitinib once daily and methotrexate once weekly until the study is unblinded, after which participants will receive open-label methotrexate up to Week 260. arm 2: Period 1: Participants will receive upadacitinib 7.5 mg once daily and placebo to methotrexate once weekly for 48 weeks.

Period 2: Participants will continue on upadacitinib 7.5 mg once daily and placebo to methotrexate once weekly until the study is unblinded, after which participants will receive open-label upadacitinib 7.5 mg up to Week 260. arm 3: Period 1: Participants will receive upadacitinib 15 mg once daily and placebo to methotrexate once weekly for 48 weeks.

Period 2: Participants will continue on upadacitinib 15 mg once daily and placebo to methotrexate once weekly until the study is unblinded, after which participants will receive open-label upadacitinib 15 mg up to Week 260. arm 4: Period 1: Participants will receive upadacitinib 30 mg once daily and placebo to methotrexate once weekly for 48 weeks.

Period 2: Participants will continue on upadacitinib 30 mg once daily and placebo to methotrexate once weekly until the study is unblinded, after which participants will receive open-label upadacitinib 30 mg once daily. After implementation of Protocol Amendment 6 participants will receive upadacitinib 15 mg once daily up to Week 260.
Interventions: intervention 1: Placebo to Upadacitinib intervention 2: Methotrexate intervention 3: Placebo to Methotrexate intervention 4: Upadacitinib
Intervention descriptions: intervention 1: Tablet; Oral intervention 2: Capsule or Tablet; Oral intervention 3: Capsule or Tablet; Oral intervention 4: Tablet; Oral

Protocol documents:
Prot_002.pdf: 


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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
01 October 2015
Amendment 1
15 January 2016
Administrative Change 1
22 January 2016
Amendment 2
29 February 2016
Amendment 2.01 (Japan Only)
07 March 2016
Amendment 3
31 May 2016
Amendment 3.01 (Japan Only)
25 July 2016
Amendment 4
18 August 2016
Amendment 4.01 (Japan Only)
18 October 2016
Administrative Change 2
02 November 2016
Amendment 4.02 (China Only)
21 December 2016
Amendment 5
17 December 2017
Amendment 5.01 (Japan Only)
06 February 2018
Amendment 5.02 (China Only)
07 February 2018
Administrative Change 3
19 March 2018
Administrative Change 4
07 February 2019
Amendment 5.01.01 (Japan Only)
15 July 2019
Amendment 6
16 December 2019
Amendment 6.01 (Japan Only)
03 March 2020
Amendment 6.02 (VHP and Lithuania Only)
06 March 2020
Amendment 7
01 July 2020
Administrative Change 5 (Japan Only)
15 September 2020
The purpose of this amendment is to:
●
Apply administrative changes throughout the protocol.
Rationale:  Revised text to improve consistency and readability, and/or 
provide clarification.
●
Update Section 1.2, Synopsis
 


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Rationale: Revised to be consistent with Amendment 7 revisions.
●
Update Section 1.3, List of Abbreviations
Rationale:  Updated to include new terms, Direct-to Patient (DTP) and 
Coronavirus Disease – 19 (COVID-19)
●
Update Section 3.2, Benefits and Risks
Rationale:  Revised to include the evaluation of the benefit and risk to subjects 
participating in the study relative to COVID-19.
●
Update Section 5.1, Overall Study Design and Plan:  Description
Rationale:  Added provisions for virtual or alternative locations for study 
visits in the event of a pandemic situation like COVID-19 or any state of 
emergency (e.g., natural disaster, conflict/combat) to ensure the safety of 
subjects and site staff, while maintaining the integrity of the study.
●
Update Section 5.2.3.2, Prohibited Therapy.
Rationale:  Revised Table 1 to update the list of examples of commonly used 
strong cytochrome 3A inducers.  
●
Update Section 5.3.1, Efficacy and Safety Measurements Assessed and Flow 
Chart
Rationale: Added clarifications on study activities that can be performed by 
phone/video conference or at local clinic/hospital/laboratory or through the 
optional home healthcare service in the event study visits are impacted by any 
state of emergency or pandemic situation like COVID-19 to ensure subjects'
safety and study continuation, as permitted by IRB/IEC.
●
Update Section 5.3.1.1, Study Procedures
○
Outcomes and Questionnaires
Specified that questionnaires are not eligible for completion by virtual 
interview in the event that an onsite visit cannot be performed due to a 
pandemic or state of emergency and will be completed at the next earliest 
feasible visit.
○
TB (tuberculosis) Testing/TB Prophylaxis and Chest X-rays (CXR)
Specified that chest X-rays can be performed at the next earliest feasible 
visit unless the Investigator has determined that a CXR is required to 
ensure that it is safe to continue study drug administration (e.g., subjects 
 


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with seroconversion on an annual TB test).  In this case, the Investigator 
should contact the AbbVie Therapeutic Area Medical Director (TA MD) to 
determine if the subject may continue on study drug and CXR should be 
performed as soon as restrictions allow at the study site or local 
hospital/facility. 
○
12-Lead Electrocardiogram (ECG)
Specified that the 12-Lead ECG can be performed at the next earliest 
feasible visit unless the Investigator has determined that an ECG is 
required to ensure that it is safe to continue study drug administration. In 
this case, the ECG should be performed as soon as restrictions allow at the 
study site or local hospital/facility.
○
X-Rays of Hands and Feet
Added provision allowing the X-rays of hands and feet to be performed at 
the next earliest feasible visit.
○
Physical Exam
Added provision allowing the complete physical exam to be performed at 
the next earliest feasible visit.
○
Physician Global Assessment of Disease Activity Visual Analog Scale 
(VAS)
Specified that Physician Global Assessment of Disease Activity is not 
eligible for completion by virtual interview in the event that the subject 
cannot perform an onsite visit due to a pandemic or state of emergency and 
will be completed by the physician at the next earliest feasible subject's 
visit.
○
Tender Joint Count (TJC) and Swollen Joint Count (SJC) Assessments
Added provision allowing the TJC and SJC to be performed at the next 
earliest feasible visit by the independent joint assessor, if possible.
○
Pregnancy Test
Added provision allowing the urine pregnancy test to be performed at a 
local laboratory or at home. Updated the reference to contraception 
requirements for male subjects with a partner of childbearing potential for 
consistency with Section 5.2.4 "Contraception Recommendations."
 


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○
Clinical Laboratory Tests
Added provision allowing the laboratory testing at an alternate local 
facility, in the event that a state of emergency or pandemic prevents the 
subject from performing the central laboratory tests and added the 
requirements to allow the study drug dispensation when laboratory tests are 
performed at a local laboratory.
○
Study Drug Dispensing, Dosing and Compliance
Added provision allowing Direct-to-Patient (DTP) shipment of study drug 
and study ancillaries due to state of emergency or pandemic situations.
○
New Section: Optional Home Healthcare Service Due to State of 
Emergency or Pandemic Situation like COVID-19
Added home healthcare visits as an option in case a study visit on site 
cannot be performed due to state of emergency or pandemic-related 
reasons. 
Rationale:  To modify study visits and protocol-specific procedures impacted 
by the COVID-19 or any pandemic/state of emergency as necessary, to ensure 
the safety of subjects/site staff and study continuation including alternative 
locations for data collection, as permitted by IRB/IEC.
●
Update Section 5.4.1, Discontinuation of Individual Subjects
Rationale: Revised to clarify that subjects will have to discontinue study drug 
treatment immediately if they develop a gastrointestinal perforation with the 
exception of appendicitis or mechanical injury to be consistent with the 
Section 6.1.7 "Toxicity Management."
Clarified that the state of emergency and pandemic-related restrictions may 
allow mitigation strategies to ensure subject safety and continuity of care as 
an alternative to study discontinuation/study drug discontinuation and that the 
AbbVie TA MD should be contacted before discontinuing a subject to ensure 
all acceptable mitigation steps have been explored.
●
Update Section 5.5.1, Treatments Administered
Rationale: Added specifications in order to provide the study drug through 
DTP shipment in the event pandemic situation like COVID-19 or state of 
emergency prevent the study drug dispensation to the subject onsite, if 
permitted by local regulations.
 


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●
Update Section 6.1.1.3, Adverse Events of Special Interest
Rationale:  Clarified and updated the list of the adverse events of special 
interest according to the revised sponsor guidelines.
●
Update Section 6.1.4, Adverse Event Collection Period
Rationale: Added supplemental COVID-19 case report forms for missed or 
virtual visits, study drug interruptions or discontinuations, or adverse events
and instructions to collect safety information related to COVID-19 
●
Update Section 6.1.5, Serious Adverse Event Reporting
Rationale: Updated telephone number to contact the Immunology Safety 
Team for safety concerns.
●
Update Section 6.1.6, Pregnancy
Rationale: Updated text to define Pregnancy reporting timeline as 24 hours 
from site staff awareness according to the sponsor requirements.
●
Update Section 6.1.7, Toxicity Management
Rationale:  Added guidance for investigators on the management of subjects
with suspected or confirmed COVID-19 infection during the study.  Clarified 
that the Investigator should also contact the AbbVie TA MD for confirmed ALT 
or AST > 8 × ULN in addition to the immediate study drug interruption. 
●
Update Section 6.2.2, Reporting
Rationale: Updated text to define Product Complaint reporting timeline as 
24 hours from site staff awareness according to the sponsor requirements.
●
Update Section 7.0, Protocol Deviations.
Rationale:  Added language to include provision for modifications due to 
protocol deviations that may be due to pandemic like COVID-19 or state of 
emergency situations in order to guide investigators to notify IRB/EC when 
deviations occur.
●
Update Section 9.2, Ethical Conduct of the Study
Rationale: Inclusion of information regarding COVID-19 or any 
pandemic/state of emergency-related acceptable protocol modifications.
●
Update Section 9.3, Subject Information and Consent
 


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Rationale:  Added provision that in the event of a pandemic situation or state 
of emergency, verbal consent may be obtained in addition to the study 
informed consent in accordance with local regulations.
●
Update Section 10.1 Source Documents
Rationale: Noted that remote monitoring may be employed as needed, due to
COVID-19 or any pandemic/state of emergency.
●
Update Appendix A, Responsibilities of the Clinical Investigator
Rationale: Clarified that clinical research studies sponsored by AbbVie are 
subject to the International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical 
Practices (GCP).
●
Update Appendix B, List of Protocol Signatories.
Rationale:  Updated list of current Protocol Signatories.
 


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M13-545
Name of Study Drug:  Upadacitinib (ABT-494)
Phase of Development:  3
Name of Active Ingredient:  Upadacitinib 
(ABT-494)
Date of Protocol Synopsis:  03 December 2020
Protocol Title:  A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) Once 
Daily Monotherapy to Methotrexate (MTX) Monotherapy in MTX-Naïve Subjects with Moderately to 
Severely Active Rheumatoid Arthritis
Objectives:  
Period 1
1.
To compare the safety and efficacy of upadacitinib 7.5 mg once daily (QD) monotherapy (for 
subjects in Japan only), 15 mg QD monotherapy, and 30 mg QD monotherapy versus weekly 
methotrexate (MTX) monotherapy for the treatment of signs and symptoms of rheumatoid arthritis 
(RA) in MTX-naïve subjects with moderately to severely active RA.
2.
To compare the efficacy of upadacitinib 15 mg QD monotherapy and upadacitinib 30 mg QD 
monotherapy versus weekly MTX monotherapy for prevention of structural progression in 
MTX-naive subjects with moderately to severely active RA.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib 7.5 mg QD (for subjects in 
Japan only), 15 mg QD, and 30 mg QD in subjects with RA who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 330
Study Population:  Adult female and male subjects who are at least 18 years of age with a duration of 
symptoms consistent with RA for ≥ 6 weeks who also fulfill the 2010 ACR/European League Against 
Rheumatism (EULAR) classification criteria for RA and no prior or limited MTX treatment.  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) 
≥5 mg/L (central lab, upper limit of normal [ULN] 2.87 mg/L) at Screening.
Number of Subjects to be Enrolled:  Approximately 975 subjects
Methodology:  
This is a Phase 3 multicenter study that includes two periods and a Japan sub-study.  Period 1 is a 
48-week randomized, double-blind, parallel-group, active comparator controlled treatment period 
designed to compare the safety and efficacy of upadacitinib 7.5 mg QD monotherapy (for subjects in 
Japan only), 15 mg QD monotherapy, and 30 mg QD monotherapy versus MTX monotherapy in adult 
MTX-naïve subjects with moderately to severely active RA.  Period 1 is also designed to compare the 
efficacy of upadacitinib 15 mg QD monotherapy and 30 mg QD monotherapy versus MTX monotherapy 
for the prevention of structural progression.  Period 2 is a long-term extension to evaluate the long-term 
safety, tolerability, and efficacy of upadacitinib (7.5, 15, or 30 mg QD) in subjects with RA who have 
completed Period 1.
 


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Methodology (Continued):
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will receive open-label 
upadacitinib 15 mg QD. Subjects receiving MTX will receive open-label MTX.
The study duration will include a 35-day screening period, a 48-week randomized, double-blind, 
parallel-group, active-comparator controlled treatment period (Period 1); a 212-week extension period 
(blinded until the last subject completes the last visit of Period 1) (Period 2); and a 30-day follow-up (call 
or site visit).
Subjects will be randomized in a 1:1:1 ratio to treatment Groups 2, 3 and 4 below, except for subjects 
from Japan, who will be randomized in a 2:1:1:1 ratio to Groups 1, 2, 3 and 4: 

Group 1:  Upadacitinib 7.5 mg QD monotherapy (subjects in Japan only; N = 75)

Group 2:  Upadacitinib 15 mg QD monotherapy (N = 300) (includes 37 subjects from Japan)

Group 3:  Upadacitinib 30 mg QD monotherapy (N = 300) (includes 37 subjects from Japan)

Group 4:  MTX monotherapy (N = 300) (includes 37 subjects from Japan)
Each subject will be instructed to take 2 capsules once weekly (MTX and/or matching placebo) and 
1 tablet once daily (upadacitinib or matching placebo) to maintain blinding.  MTX and matching placebo 
will be assigned via the Interactive Response Technology (IRT) system, and distributed as identical 
capsules in blister packs, to provide the correct total dose for each individual subject and to maintain 
blinding during and after MTX titration (Period 1 and Period 2).  Detailed dosing instructions can be 
found in the Subject Dosing Diary and Instructions.  Starting with Amendment 6 subjects receiving MTX 
will receive open-label MTX tablets in quantities sufficient to cover their respective dose.
Subjects who are assigned to upadacitinib 7.5 mg QD, 15 mg QD, or 30 mg QD will start on their 
respective upadacitinib dose at Baseline.  Subjects who are assigned to the MTX treatment group will 
start oral MTX treatment at 10 mg/week and will be titrated up to 20 mg/week (increase by 5 mg every 
4 weeks), as tolerated, by Week 8 (minimum 15 mg/week final dose required, with documentation of 
intolerance of > 15 mg/week).  (For subjects in Japan:  start at 7.5 mg/week with titration up to 
10 mg/week at Week 4 and to 15 mg/week, as tolerated, by Week 8; minimum of 7.5 mg/week for final 
dose is required, with documentation of intolerance of > 7.5 mg/week).  After completion of MTX (or 
placebo) titration, a single dose reduction of study drug (by 5 mg of MTX) is allowed for safety reasons, 
up to Week 26, as long as the subject remains on ≥ 15 mg/week of MTX (or matching placebo) weekly 
(for subjects in Japan:  ≥7.5 mg/week).  In addition, all subjects should take a dietary supplement of oral 
folic acid (or equivalent) throughout study participation.  Folic acid dosing and timing of regimen should 
be followed according to Investigator's discretion.  Rescue therapy has been defined for Weeks 12 
through 24, Week 26, and Weeks 36 through 40.  Starting at the Week 48 Visit (after Week 48 
assessments have been performed) and thereafter, initiation of or change in background RA 
medication(s), including corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, and csDMARDs (concomitant use of up to 2 csDMARDs except the 
combination of MTX and leflunomide) is allowed as per local label.
Rescue therapy for those subjects who meet the following criteria from Week 12 through Week 24 are as 
follows:

Those who do not achieve ≥ 20% improvement in both TJC and SJC compared with baseline at 
two consecutive visits starting at Week 12 will continue on their blinded therapy and the 
Investigator should optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent or prednisone equivalent 
≤0.5 mg/kg/day for 3 consecutive days) and/or low-potency analgesics.
 


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Methodology (Continued):
Rescue therapy for those subjects who meet the following criteria at Week 26 are as follows:
1.
Subjects who were originally randomized to MTX:

Those who do not achieve CR by CDAI:
o
but achieve ≥ 20% improvement in both TJC and SJC compared with baseline will continue 
on blinded MTX and the Investigator should optimize (initiate or increase) background RA 
medications:  NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 
2 local injections), low-potency analgesics and csDMARDs (only 1 of the following:  
sulfasalazine, hydroxychloroquine or chloroquine) throughout the remainder of Period 1 and 
until the study is unblinded.
o
and do not achieve ≥ 20% improvement in both TJC and SJC compared with baseline will 
be re-randomized in a 1:1 ratio to receive blinded upadacitinib 15 mg QD or upadacitinib 
30 mg QD (for subjects in Japan:  randomize 1:1:1 to receive upadacitinib 7.5 mg QD, 
15 mg QD, or 30 mg QD) while continuing MTX treatment in a blinded manner and will 
remain on upadacitinib plus MTX throughout the remainder of Period 1 and until the study 
is unblinded.

Those who achieve Clinical Remission (CR) by clinical disease activity index (CDAI) (CDAI 
≤2.8) at Week 26 will continue blinded treatment with MTX throughout the remainder of 
Period 1 and until the study is unblinded (the study is unblinded when all subjects have 
completed Period 1).
2.
Subjects who were originally randomized to upadacitinib:

Those who do not achieve CR by CDAI: 
o
but achieve ≥ 20% improvement in both TJC and SJC compared with baseline will continue 
on blinded upadacitinib and the Investigator should optimize (initiate or increase the dose) 
background RA medications:  NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone 
equivalent and up to 2 local injections), low-potency analgesics and csDMARDs (only 1 of 
the following:  sulfasalazine, hydroxychloroquine or chloroquine) throughout the remainder 
of Period 1 and until the study is unblinded.
o
and do not achieve ≥ 20% improvement in both TJC and SJC compared with baseline will 
add MTX 10 mg/week (7.5 mg for Japan) to upadacitinib in a blinded manner and will 
remain on upadacitinib plus MTX 10 mg/week (7.5 mg for Japan) throughout the remainder 
of Period 1 and until the study is unblinded.

Those who achieve Clinical Remission (CR) by CDAI (CDAI ≤ 2.8) at Week 26 will continue 
blinded treatment with upadacitinib throughout the remainder of Period 1 and until the study is 
unblinded (the study is unblinded when all subjects have completed Period 1). 
 


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Methodology (Continued):
Rescue therapy for those subjects who meet the following criteria from Week 36 through Week 40 are as 
follows:

Starting at Week 36, those who do not achieve ≥ 20% improvement in both TJC and SJC 
compared with baseline at two consecutive visits will continue on their blinded therapy and the 
Investigator should optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent or prednisone equivalent 
≤0.5 mg/kg/day for 3 consecutive days, and up to 2 local injections), low-potency analgesics 
and csDMARDs (only 1 of the following:  sulfasalazine, hydroxychloroquine or chloroquine)
An unblinded analysis will be conducted after all subjects have completed Week 24 for the purpose of 
regulatory submission.  To maintain integrity of the trial and avoid introduction of bias, study sites and 
subjects will remain blinded for the duration of Period 1.  Additional unblinded analyses may be 
conducted after the Week 24 analysis.
Each subject will undergo a maximum of 3 scheduled visits for x-ray examination of bilateral hands and 
feet during Period 1 (unless unscheduled repeat imaging is needed due to failure to meet the quality 
requirements) at Screening, Week 24, and Week 48/Premature Discontinuation.  One additional x-ray 
examination of bilateral hands and feet may be needed depending on the time of premature study drug 
discontinuation for those subjects that continue the study.
Subjects who complete the Week 48 Visit (end of Period 1) will enter the long-term extension, Period 2 
(212 weeks).  Subjects will continue study treatment per assignment at the end of Period 1 in a blinded 
fashion.  When the last subject completes the last visit of Period 1 (Week 48), study drug assignment in 
both periods may be unblinded to the Sponsor and sites, and subjects would then be dispensed study drug 
in an open-label fashion until the completion of Period 2.  All subjects will continue study treatment to 
which they were assigned at the time of study unblinding.  Dose changes of open-label study drugs are 
not permitted during unblinded Period 2.  Background therapies may be adjusted as per the discretion of 
the investigator (refer to Section 5.2.3.1 for additional details on permitted background therapy in 
Period 2).
Each subject will undergo a maximum of 3 scheduled visits for x-ray examination of bilateral hands and 
feet during Period 2 (unless unscheduled repeat imaging is needed due to failure to meet the quality 
requirements) at Week 96, Week 192, and Week 260.  Subjects who prematurely discontinue from 
Period 2 will undergo an x-ray of hands and feet unless the previous x-ray was performed within the 
previous 24 weeks.
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will receive open-label 
upadacitinib 15 mg QD.  Subjects receiving MTX will receive open-label MTX.
Study visits may be impacted by state of emergency or pandemic like COVID-19. If visits cannot be 
conducted onsite due to travel restrictions or other pandemic or state of emergency related reasons, 
virtual visits, visits at alternative locations, or changes in the visit frequency and timing of study 
procedures, among others may be performed. Every effort should be made to ensure the safety of 
subjects and site staff, while maintaining the integrity of the study.
 


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M13-545 Protocol Amendment 8
EudraCT 2015-003334-27
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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Adult male or female, at least 18 years old.
2.
Duration of symptoms consistent with RA for ≥ 6 weeks who also fulfill the 2010 ACR/EULAR 
classification criteria for RA.
3.
Naïve to MTX or, if already on MTX, have received no more than 3 weekly MTX doses with 
requirement to complete a 4-week MTX washout before the first dose of study drug.
4.
Subjects with prior exposure to csDMARDs other than MTX may be enrolled if completed the 
washout period as specified below or should be at least five times the mean terminal elimination 
half-life of a drug:

≥ 4 weeks prior to first dose of study drug for minocycline, penicillamine, sulfasalazine, 
hydroxychloroquine, chloroquine, azathioprine, gold formulations, cyclophosphamide, 
tacrolimus, cyclosporine, mycophenolate;

≥ 8 weeks prior to first dose of study drug for leflunomide if no elimination procedure was 
followed, or adheres to an elimination procedure (i.e., 11 days with colestyramine, or 30 days 
washout with activated charcoal or as per local label).
5.
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 ≥ 5 mg/L (central lab, ULN 2.87 mg/L) at Screening Visit.
6.
≥ 1 bone erosion on x-ray (by local reading) OR in the absence of a documented bone erosion, both 
positive rheumatoid factor and positive anti-cyclic citrullinated peptide autoantibodies are required at 
Screening.
Main Exclusion:  
1.
Intolerant to MTX.
2.
Prior exposure to any JAK inhibitor (including but not limited to tofacitinib, baricitinib, and 
filgotinib).
3.
Prior exposure to any bDMARD(s).
4.
History of any arthritis with onset prior to age 17 years or current diagnosis, 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 SpA, 
reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis, 
fibromyalgia [currently with active symptoms].  Current diagnosis of secondary Sjogren's Syndrome 
is permitted.
5.
Laboratory values meeting the following criteria within the Screening period prior to the first dose of 
study drug:  serum aspartate transaminase > 2 × 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.
 


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M13-545 Protocol Amendment 8
EudraCT 2015-003334-27
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Investigational Product:
Upadacitinib (ABT-494)
Doses:
30 mg QD
15 mg QD
7.5 mg QD (for Japan only)
Mode of Administration:
Oral
Reference Therapy:
MTX, matching placebo for upadacitinib, matching placebo for MTX
Dose:
MTX 10 mg/week titrated up to 20 mg/week given as a single dose 
every week.  For subjects in Japan, MTX 7.5 mg/week titrated up to 
15 mg/week given as a single dose every week.
Mode of Administration:
Oral
Duration of Treatment:  up to 260 weeks (Period 1:  48 weeks; Period 2:  212 weeks)
Criteria for Evaluation:
Efficacy:
Period 1
The primary endpoint in Period 1 is the proportion of subjects achieving ACR50 response at Week 12 
(US/FDA regulatory purposes) or the proportion of subjects achieving Clinical Remission (CR) 
(EU/EMA regulatory purposes) at Week 24.  For Japan/PMDA regulatory purposes, the primary 
endpoints are the proportion of subjects achieving ACR20 response at Week 12 and change from baseline 
in modified Total Sharp Score (mTSS) at Week 24.
ACR20/50 response rate will be determined based on 20%/50% or greater improvement in TJC and 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.
CR is defined as Disease Activity Score (DAS) 28 (C-reactive protein [CRP]) < 2.6.
Modified Total Sharp Score (mTSS) is the van der Heijde mTSS.
 


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M13-545 Protocol Amendment 8
EudraCT 2015-003334-27
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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 1 (Continued)
Ranked key secondary endpoints for US/FDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP) at Week 12;
2.
Change from baseline in HAQ-DI at Week 12;
3.
Change from baseline in modified Total Sharp Score (mTSS) at Week 24;
4.
Proportion of subjects achieving Low Disease Activity (LDA) based on DAS28 (CRP) ≤ 3.2 at 
Week 12;
5.
Proportion of subjects achieving CR based on DAS28 (CRP) < 2.6 at Week 24;
6.
Change from baseline in Short Form-36 (SF-36) Physical Component Score (PCS) at Week 12.
Ranked key secondary endpoints (at Week 24) for EU/EMA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI; 
3.
ACR50 response rate;
4.
Change from baseline in modified Total Sharp Score (mTSS);
5.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2;
6.
Change from baseline in SF-36 PCS; 
7.
Proportion of subjects with no radiographic progression (defined as change from baseline in 
mTSS ≤0) at Weeks 24.
Ranked key secondary endpoints for Japan/PMDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP) at Week 12; 
2.
Change from baseline in HAQ-DI at Week 12; 
3.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12;
4.
Proportion of subjects achieving CR based on DAS28 (CRP) < 2.6 at Week 24;
5.
Change from baseline in SF-36 PCS at Week 12.
Other key secondary endpoints for US/FDA regulatory purposes are:
1.
ACR20 response rate at Week 12;
2.
ACR70 response rate at Week 12;
3.
Proportion of subjects with no radiographic progression at Week 24.
Other key secondary endpoints for EU/EMA regulatory purposes are:
1.
ACR20 response rate at Week 24;
2.
ACR70 response rate at Week 24.
Other key secondary endpoints for Japan/PMDA regulatory purposes are:
1.
ACR50 response rate at Week 12;
2.
ACR70 response rate at Week 12;
3.
Proportion of subjects with no radiographic progression at Week 24.
 


Upadacitinib
M13-545 Protocol Amendment 8
EudraCT 2015-003334-27
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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 1 (Continued)
Additional endpoints are:

ACR20/50/70 response rates at all visits;

Change from baseline in individual components of ACR response at all visits;

Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation rate [ESR]) at all 
visits;

Change from baseline in CDAI and SDAI at all visits;

Proportion of subjects achieving LDA or CR by DAS28(CRP), DAS28(ESR), Simplified 
Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) at all visits;

Change from baseline in morning stiffness (severity and duration) at all visits;

Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22 at all visits;

Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3 at all visits;

ACR/EULAR Boolean remission at all visits;

Change from baseline in EQ-5D-5L at Weeks 12, 24, and 48;

Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
at Weeks 12, 24, and 48;

Change from baseline in Work Productivity and Activity Impairment (WPAI) at Weeks 12, 24, 
and 48;

Change from baseline in SF-36 at Weeks 12, 24, and 48;

Change from baseline in mTSS at Weeks 24 and 48;

Proportion of subjects with no radiographic progression (defined as change from baseline in 
mTSS ≤ 0) at Weeks 24 and 48;

Change from baseline in radiographic joint space narrowing and erosion scores at Weeks 24 and 
48.
DAS28 (CRP) and 
DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
  
 


Upadacitinib
M13-545 Protocol Amendment 8
EudraCT 2015-003334-27
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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 60, 72, 84, 96, every 12 weeks through Week 240, and Week 260/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;

Proportion of subjects achieving LDA and proportion of subjects achieving CR based on DAS28 
(CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined for Period 1);

Change from baseline in morning stiffness (severity and duration);

Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22;

Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3;

ACR/EULAR Boolean remission at all visits

Concomitant corticosteroid use.
Additionally, assessment for the evaluation of radiographic changes in Period 2 will occur at Week 96 
and every 96 weeks thereafter (or Premature Discontinuation Visit):

Change from baseline in mTSS;

Proportion of subjects with no radiographic progression (defined as change from baseline mTSS 
of ≤ 0);

Change from baseline in radiographic joint space narrowing and erosion scores.
Pharmacokinetic (Period 1 Only):
Blood samples for assay of upadacitinib and possibly other medications in plasma will be collected at 
Weeks 2, 4, 12, 16, 20, 24, 32, 36, 40, and 48/Premature Discontinuation.
Exploratory Research Variables and Validation Studies (Optional) (Period 1 Only):
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.
 


Upadacitinib
M13-545 Protocol Amendment 8
EudraCT 2015-003334-27
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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 the global analysis, comparisons of the primary and key secondary efficacy endpoints will be made 
between the upadacitinib 15 mg QD and 30 mg QD groups versus the MTX group for all subjects 
(excluding the Japan specific upadacitinib 7.5 mg treatment arm).  The overall type I error rate of the 
primary and key secondary endpoints for the two doses will be strongly controlled.
For the Japan sub-study, comparisons of the primary and key secondary efficacy endpoints will be made 
between the upadacitinib 7.5 mg QD, 15 mg QD and 30 mg QD groups versus the MTX group for 
subjects enrolled in Japan only.  
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons between each upadacitinib group and the MTX 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.  Pairwise comparisons between each of the upadacitinib treatment groups and the MTX 
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.
For mTSS-based endpoints, both linear extrapolation and as observed analysis will be conducted.  For 
other endpoints, non-responder imputation approach will serve as the primary analysis approach for key 
binary endpoints and multiple imputations will serve as the primary analysis approach for key continuous 
endpoints.  Sensitivity analyses based on observed cases will also be conducted for key endpoints.
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.
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.
 


Upadacitinib
M13-545 Protocol Amendment 8
EudraCT 2015-003334-27
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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
AP
anteroposterior
AST
aspartate transaminase
AUC
Area under the plasma concentration-time curve
BCG
Bacille Calmette-Guérin
bDMARD
biologic 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 Observed Plasma Concentration
CPK
creatine phosphokinase
COVID-19
Coronavirus Disease – 2019
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
CYP3A
cytochrome P450 3A
DAS
disease activity score
DMARD
disease-modifying anti-rheumatic drug
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
 


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M13-545 Protocol Amendment 8
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DTP
Direct-to-Patient
ECG
electrocardiogram
eCRF
electronic case report form
EDC 
electronic data capture
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
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
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
IAG
Imaging Acquisition Guide
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
independent ethics committee
IGRA
interferon-gamma release assay
IMP
investigational medicinal product
INR
international normalized ratio
IR
inadequate responder
IRB
institutional review board
 


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IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JAK
Janus kinase
LDA
low disease activity
LDL-C
low-density lipoprotein cholesterol
MACE
major adverse cardiovascular event
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
mTSS
modified total sharp score
MTX
methotrexate
MTX-IR
methotrexate inadequate responder
NA
no assessment
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
OLE
open-label extension
PA
posterior-anterior
PCR
polymerase chain reaction
PCS
physical component summary
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
RAVE®
EDC system from Medidata
 


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M13-545 Protocol Amendment 8
EudraCT 2015-003334-27
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RBC
red blood cell
RCT
randomized controlled trial
RF
rheumatoid factor
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
SUSAR
suspected unexpected serious adverse reaction
T2T
treat-to-target
TB
tuberculosis
TEAE
treatment-emergent adverse event
TJC
tender joint count
TNF
tumor necrosis factor
TNF-IR
anti-tumor necrosis factor inadequate responder
TSJ
tender and swollen joints
Tyk2
Tyrosine kinase 2
ULN
upper limit of normal
V/F
apparent volume of distribution
VAS
visual analog scale
VTE
venous thromboembolic events
VZV
Varicella zoster virus
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
 


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 .....................................................................................................8
1.3
List of Abbreviations and Definition of Terms........................................18
2.0
Table of Contents...................................................................22
3.0
Introduction ...........................................................................28
3.1
Differences Statement..............................................................................31
3.2
Benefits and Risks....................................................................................32
4.0
Study Objectives....................................................................32
5.0
Investigational Plan...............................................................33
5.1
Overall Study Design and Plan:  Description ..........................................33
5.2
Selection of Study Population..................................................................44
5.2.1
Inclusion Criteria .....................................................................................44
5.2.2
Exclusion Criteria ....................................................................................46
5.2.3
Prior, Concomitant, and Prohibited Therapy ...........................................50
5.2.3.1
Permitted Background RA Therapy.........................................................50
5.2.3.2
Prohibited Therapy...................................................................................52
5.2.3.3
Rescue Therapy........................................................................................56
5.2.4
Contraception Recommendations ............................................................58
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, Exploratory 
Research and Validation Studies, and Safety 
Assessments/Variables.............................................................................62
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................62
5.3.1.1
Study Procedures .....................................................................................64
5.3.1.2
Collection and Handling of Optional Samples for Exploratory 
Research and Validation Studies .............................................................90
5.3.2
Drug Concentration Measurements .........................................................92
5.3.2.1
Collection of Samples for Analysis .........................................................92
5.3.2.2
Measurement Methods.............................................................................93
5.3.3
Efficacy Variables....................................................................................93
5.3.3.1
Period 1 Variables....................................................................................93
 


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5.3.3.1.1
Primary Variables ....................................................................................93
5.3.3.1.2
Key Secondary Variables.........................................................................94
5.3.3.1.3
Additional Variables ................................................................................96
5.3.3.2
Period 2 Variables....................................................................................97
5.3.4
Safety Variables.......................................................................................98
5.3.5
Pharmacokinetic Variables ......................................................................98
5.3.6
Exploratory Research Variables and Validation Studies.........................98
5.4
Removal of Subjects from Therapy or Assessment.................................99
5.4.1
Discontinuation of Individual Subjects....................................................99
5.4.2
Discontinuation of Entire Study.............................................................101
5.5
Treatments..............................................................................................101
5.5.1
Treatments Administered.......................................................................101
5.5.2
Identity of Investigational Product.........................................................103
5.5.2.1
Packaging and Labeling.........................................................................104
5.5.2.2
Storage and Disposition of Study Drugs................................................104
5.5.3
Method of Assigning Subjects to Treatment Groups.............................104
5.5.4
Selection and Timing of Dose for Each Subject....................................105
5.5.5
Blinding..................................................................................................107
5.5.5.1
Blinding of Investigational Product.......................................................107
5.5.5.2
Blinding of Data for Data Monitoring Committee.................................108
5.5.6
Treatment Compliance...........................................................................108
5.5.7
Drug Accountability...............................................................................108
5.6
Discussion and Justification of Study Design........................................109
5.6.1
Discussion of Study Design and Choice of Control Groups..................109
5.6.2
Appropriateness of Measurements.........................................................110
5.6.3
Suitability of Subject Population ...........................................................111
5.6.4
Selection of Doses in the Study .............................................................111
6.0
Complaints ...........................................................................112
6.1
Medical Complaints...............................................................................112
6.1.1
Definitions..............................................................................................113
6.1.1.1
Adverse Event........................................................................................113
6.1.1.2
Serious Adverse Events .........................................................................113
6.1.1.3
Adverse Events of Special Interest ........................................................115
 


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6.1.2
Adverse Event Severity..........................................................................115
6.1.3
Relationship to Study Drug....................................................................115
6.1.4
Adverse Event Collection Period...........................................................116
6.1.5
Serious Adverse Event Reporting..........................................................118
6.1.6
Pregnancy...............................................................................................120
6.1.7
Toxicity Management ............................................................................120
6.1.8
Data Monitoring Committee..................................................................126
6.1.9
Cardiovascular Adjudication Committee...............................................126
6.2
Product Complaint .................................................................................126
6.2.1
Definition ...............................................................................................126
6.2.2
Reporting................................................................................................127
7.0
Protocol Deviations..............................................................127
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................129
8.1
Statistical and Analytical Plans..............................................................129
8.1.1
Analysis Populations..............................................................................129
8.1.1.1
Full Analysis Set....................................................................................129
8.1.1.2
Per Protocol Analysis Set.......................................................................130
8.1.1.3
Safety Analysis Set ................................................................................130
8.1.2
Subject Accountability, Disposition and Study Drug Exposure............130
8.1.2.1
Subject Accountability...........................................................................130
8.1.2.2
Subject Disposition ................................................................................130
8.1.2.3
Study Drug Exposure.............................................................................131
8.1.3
Analysis of Demographic and Baseline Characteristics ........................131
8.1.4
Efficacy Analysis ...................................................................................132
8.1.4.1
Efficacy Analysis for Period 1...............................................................132
8.1.4.1.1
Primary Efficacy Variables....................................................................132
8.1.4.1.2
Key Secondary Efficacy Variables ........................................................132
8.1.4.1.3
Other Efficacy Variables........................................................................133
8.1.4.1.4
Multiplicity Control for the Primary and Ranked Key Secondary 
Endpoints ...............................................................................................133
8.1.4.1.5
Imputation Methods...............................................................................134
8.1.4.2
Long-Term Efficacy for Period 1 and Period 2 Combined....................134
 


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8.1.5
Safety Analysis ......................................................................................135
8.1.5.1
General Considerations..........................................................................135
8.1.5.2
Analysis of Adverse Events...................................................................135
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE) ......................................135
8.1.5.2.2
Serious Adverse Events and Death ........................................................137
8.1.5.3
Analysis of Laboratory, Vital Sign, and ECG Data...............................137
8.1.6
Pharmacokinetic and Exposure-Response Analyses .............................137
8.2
Determination of Sample Size ...............................................................139
8.3
Randomization Methods ........................................................................140
9.0
Ethics.....................................................................................140
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................140
9.2
Ethical Conduct of the Study .................................................................141
9.3
Subject Information and Consent...........................................................142
9.3.1
Informed Consent Form and Explanatory Material ...............................143
9.3.2
Revision of the Consent Form and Explanatory Material .....................143
10.0
Source Documents and Case Report Form 
Completion ...........................................................................143
10.1
Source Documents .................................................................................143
10.2
Case Report Forms.................................................................................144
11.0
Data Quality Assurance ......................................................147
12.0
Use of Information...............................................................147
13.0
Completion of the Study .....................................................148
14.0
Investigator's Agreement....................................................149
15.0
Reference List ......................................................................150
List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers....................................................................................................54
Table 2.
Clinical Laboratory Tests.........................................................................83
Table 3.
Identity of Investigational Product.........................................................103
 


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values..................................................................................123
List of Figures
Figure 1.
Period 1 Study Design .............................................................................39
Figure 2.
Period 2 Study Design .............................................................................40
Figure 3.
Handling of X-Rays of Hands and Feet after Baseline (Period 1)...........76
Figure 4.
Criteria for HBV DNA PCR Qualitative Testing ....................................86
Figure 5.
Adverse Event Collection ......................................................................117
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................153
Appendix B.
List of Protocol Signatories....................................................................155
Appendix C.
Local Requirements ...............................................................................156
Appendix D.
Study Activities (Period 1).....................................................................162
Appendix E.
Study Activities – Optional Samples for Exploratory Research 
and Validation Studies (Period 1 Only).................................................168
Appendix F.
Study Activities (Period 2).....................................................................169
Appendix G.
Physician's Global Assessment of Disease Activity Example...............172
Appendix H.
Joint Evaluation Worksheet Example....................................................173
Appendix I.
Latent TB Risk Assessment Form Example ..........................................175
Appendix J.
Patient's Global Assessment of Disease Activity Example ...................176
Appendix K.
Patient's Assessment of Pain Example...................................................177
Appendix L.
Health Assessment Questionnaire (HAQ-DI) Example.........................178
Appendix M.
Patient's Assessment of Severity and Duration of Morning 
Stiffness Example ..................................................................................181
Appendix N.
EuroQoL-5D Example...........................................................................182
Appendix O.
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F) Scale Example.....................................................................185
Appendix P.
Work Productivity and Activity Impairment Questionnaire:  
Specific Health Problem (WPAI:SHP) Questionnaire Example ...........186
 


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Appendix Q.
Short Form-36 (SF-36™) Health Status Survey Questionnaire 
Example .................................................................................................189
Appendix R.
Rheumatology Common Toxicity Criteria v.2.0 Example ....................195
 


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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 (ABT-494), 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 from these two studies (N = 575) 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.
3.1
Differences Statement
Study M13-545 differs from other upadacitinib studies as it is the first study to evaluate 
the safety and efficacy (clinical and structural) of upadacitinib in subjects diagnosed with 
active RA who are naïve to MTX therapy.
 


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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 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 
support further development of upadacitinib in Phase 3 in subjects with RA.
In view of the COVID-19 pandemic, the benefit:risk profile of various 
immunomodulatory therapies on COVID-19 is being evaluated.  At this time, the effects 
of upadacitinib on the course of COVID-19 are not well defined.
4.0
Study Objectives
Period 1
1.
To compare the safety and efficacy of upadacitinib 7.5 mg QD monotherapy (for 
subjects in Japan only), 15 mg QD monotherapy, and 30 mg QD monotherapy 
versus weekly MTX monotherapy for the treatment of signs and symptoms of RA 
in MTX-naïve subjects with moderately to severely active RA.
2.
To compare the efficacy of upadacitinib 15 mg QD monotherapy and upadacitinib 
30 mg QD monotherapy versus weekly MTX monotherapy for prevention of 
structural progression in MTX-naive subjects with moderately to severely active 
RA.
 


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Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib 7.5 mg QD (for 
subjects in Japan only), 15 mg QD, and 30 mg QD 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 and a Japan sub-study.  
Period 1 is a 48-week randomized, double-blind, parallel-group, active comparator 
controlled treatment period designed to compare the safety and efficacy of upadacitinib 
7.5 mg QD monotherapy (for subjects in Japan only), 15 mg QD monotherapy, and 30 mg 
QD monotherapy versus MTX monotherapy in adult MTX-naïve subjects with 
moderately to severely active RA.  Period 1 is also designed to compare the efficacy of 
upadacitinib 15 mg QD monotherapy and 30 mg QD monotherapy versus MTX 
monotherapy for the prevention of structural progression. Period 2 is a long-term 
extension to evaluate the long-term safety, tolerability, and efficacy of upadacitinib (7.5, 
15, or 30 mg QD) in subjects with RA who have completed Period 1.  Starting with 
Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will receive 
open-label upadacitinib 15 mg QD. Subjects receiving MTX will receive open-label 
MTX.
The study is designed to enroll approximately 975 subjects at approximately 
330 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 may not be enrolled.
The study duration will include a 35-day screening period, a 48-week randomized, 
double-blind, parallel-group, active-comparator controlled treatment period (Period 1); a 
 


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212 week long-term extension period (blinded until the last subject completes the last visit 
of Period 1) (Period 2); and a 30-day follow-up (call or site visit).
Subjects will be randomized in a 1:1:1 ratio to treatment Groups 2, 3 and 4 below, except 
for subjects from Japan, who will be randomized in a 2:1:1:1 ratio to Groups 1, 2, 3 and 4:
●
Group 1:  Upadacitinib 7.5 mg QD monotherapy (subjects in Japan only; 
N = 75)
●
Group 2:  Upadacitinib 15 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 3:  Upadacitinib 30 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 4:  MTX monotherapy (N = 300) (includes 37 subjects from Japan)
Each subject will be instructed to take 2 capsules once weekly (MTX and/or matching 
placebo) and 1 tablet once daily (upadacitinib or matching placebo) to maintain blinding.  
MTX and matching placebo will be assigned via the Interactive Response Technology 
(IRT) system, and distributed as identical capsules in blister packs, to provide the correct 
total dose for each individual subject and to maintain blinding during and after MTX 
titration (Period 1 and Period 2).  Detailed dosing instructions can be found in the Subject 
Dosing Diary and Instructions. Starting with Amendment 6 subjects receiving MTX will 
receive open-label MTX tablets in quantities sufficient to cover their respective dose.
Subjects who are assigned to upadacitinib 7.5 mg QD, 15 mg QD, or 30 mg QD will start 
on their respective upadacitinib dose at Baseline.  Subjects who are assigned to the MTX 
treatment group will start oral MTX treatment at 10 mg/week and will be titrated up to 
20 mg/week (increase by 5 mg every 4 weeks), as tolerated, by Week 8 (minimum 
15 mg/week final dose required, with documentation of intolerance of > 15 mg/week).  
(For subjects in Japan:  start at 7.5 mg/week with titration up to 10 mg/week at Week 4 
and to 15 mg/week, as tolerated, by Week 8; minimum of 7.5 mg/week for final dose is 
required, with documentation of intolerance of > 7.5 mg/week).  After completion of 
MTX (or placebo) titration, a single dose reduction of study drug (by 5 mg of MTX) is 
 


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allowed for safety reasons, up to Week 26, as long as the subject remains on 
≥15 mg/week of MTX (or matching placebo) weekly (for subjects in Japan:  
≥7.5 mg/week).  In addition, all subjects should take a dietary supplement of oral folic 
acid (or equivalent) throughout study participation.  Folic acid dosing and timing of 
regimen should be followed according to Investigator's discretion.  Rescue therapy has 
been defined for Weeks 12 through 24, Week 26, and Weeks 36 through 40.  Starting at 
the Week 48 Visit (after Week 48 assessments have been performed) and thereafter, 
initiation of or change in background RA medication(s), including corticosteroids, non-
steroidal anti-inflammatory drugs (NSAIDs), acetaminophen/paracetamol, and 
csDMARDs (concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide) is allowed as per local label.
Rescue therapy for those subjects who meet the following criteria from Week 12 through 
Week 24 are as follows:
Starting at Week 12 through Week 24, those who do not achieve ≥ 20% improvement in 
both TJC and SJC compared with baseline at two consecutive visits will continue on their 
blinded therapy and the Investigator should optimize (initiate or increase) background RA 
medications:  NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent or 
prednisone equivalent ≤ 0.5 mg/kg/day for 3 consecutive days) and/or low-potency 
analgesics.
Rescue therapy for those subjects who meet the following criteria at Week 26 are as 
follows:
1.
Subjects who were originally randomized to MTX:
●
Those who do not achieve CR by CDAI: 
○
but achieve ≥ 20% improvement in both TJC and SJC compared with 
baseline will continue on blinded MTX and the Investigator should 
optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 2 local 
injections), low-potency analgesics and csDMARDs (only 1 of the 
 


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following:  sulfasalazine, hydroxychloroquine or chloroquine) throughout 
the remainder of Period 1 and until the study is unblinded.
○
and do not achieve ≥ 20% improvement in both TJC and SJC compared 
with baseline will be re-randomized in a 1:1 ratio to receive blinded 
upadacitinib 15 mg QD or upadacitinib 30 mg QD (for subjects in Japan:  
randomize 1:1:1 to receive upadacitinib 7.5 mg QD, 15 mg QD, or 30 mg 
QD) while continuing MTX treatment in a blinded manner and will remain 
on upadacitinib plus MTX throughout the remainder of Period 1 and until 
the study is unblinded.
●
Those who achieve Clinical Remission (CR) by clinical disease activity index 
(CDAI) (CDAI ≤ 2.8) at Week 26 will continue blinded treatment with MTX 
throughout the remainder of Period 1 and until the study is unblinded (the 
study is unblinded when all subjects have completed Period 1).
2.
Subjects who were originally randomized to upadacitinib:
●
Those who do not achieve CR by CDAI:
○
but achieve ≥ 20% improvement in both TJC and SJC compared with 
baseline will continue on blinded upadacitinib and the Investigator should 
optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 2 local 
injections), low potency analgesics and csDMARDs (only 1 of the 
following:  sulfasalazine, hydroxychloroquine or chloroquine) throughout 
the remainder of Period 1 and until the study is unblinded. 
○
and do not achieve ≥ 20% improvement in both TJC and SJC compared 
with baseline will add MTX 10 mg/week (7.5 mg for Japan) to 
upadacitinib in a blinded manner and will remain on upadacitinib plus 
MTX 10 mg/week (7.5 mg for Japan) throughout the remainder of Period 1 
and until the study is unblinded.
●
Those who achieve Clinical Remission (CR) by CDAI (CDAI ≤ 2.8) at 
Week 26 will continue blinded treatment with upadacitinib throughout the 
remainder of Period 1 and until the study is unblinded (the study is unblinded 
when all subjects have completed Period 1).
 


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Rescue therapy for those subjects who meet the following criteria from Week 36 through 
Week 40 are as follows:
●
Starting at Week 36 through Week 40, those who do not achieve ≥ 20% 
improvement in both TJC and SJC compared with baseline at two consecutive 
visits will continue on their blinded therapy and the Investigator should 
optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤10 mg/day prednisone equivalent or prednisone 
equivalent ≤ 0.5 mg/kg/day for 3 consecutive days and up to 2 local injections), 
low-potency analgesics and csDMARDs (only 1 of the following:  
sulfasalazine, hydroxychloroquine or chloroquine).
An unblinded analysis will be conducted after all subjects have completed Week 24 for 
the purpose of regulatory submission.  To maintain integrity of the trial and avoid 
introduction of bias, study sites and subjects will remain blinded for the duration of 
Period 1.  Additional unblinded analyses may be conducted after the first unblinded 
analysis for regulatory purposes.
Each subject will undergo a maximum of 3 scheduled visits for x-ray examination of 
bilateral hands and feet during Period 1 (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Screening, Week 24, and 
Week 48/Premature Discontinuation.  One additional x-ray examination of bilateral hands 
and feet may be needed depending on the time of premature study drug discontinuation 
for those subjects that continue the study (refer to Section 5.3.1.1 for additional details).
Subjects who complete the Week 48 Visit (end of Period 1) will enter the long-term 
extension, Period 2 (212 weeks).  Subjects will continue study treatment per assignment at 
the end of Period 1 in a blinded fashion.  When the last subject completes the last visit of 
Period 1 (Week 48), study drug assignment in both periods may be unblinded to the 
Sponsor and sites, and subjects would then be dispensed study drug in an open-label 
fashion until the completion of Period 2.  All subjects will continue study treatment to 
which they were assigned at the time of study unblinding.  Dose changes of open-label 
 


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study drugs are not permitted during unblinded Period 2.  Background therapies may be 
adjusted as per the discretion of the investigator (refer to Section 5.3.1.1 for additional 
details on permitted background therapy in Period 2).
Each subject will undergo a maximum of 3 scheduled visits for x-ray examination of 
bilateral hands and feet during Period 2 (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Week 96, Week 192, and Week 260.  
Subjects who prematurely discontinue from Period 2 will undergo an x-ray of hands and 
feet unless the previous x-ray was performed within the previous 24 weeks.
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will 
receive open-label upadacitinib 15 mg QD. Subjects receiving MTX will receive open-
label MTX.
Study design schematics of Period 1 and Period 2 are shown in Figure 1 and Figure 2, 
respectively.
 


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Figure 1.
Period 1 Study Design
MTX = methotrexate; n = number; QD = once daily; SJC = swollen joint count; TJC = tender joint count; W = week
*
Evaluation for inadequate responders to determine need for rescue therapy at Week 26; refer to Section 5.2.3.3.
†
Evaluation for inadequate responders to determine need for rescue therapy at Weeks 12 – 24 and Weeks 36 – 40; 
refer to Section 5.2.3.3.
Note:
The follow-up period is only for subjects who do not enter Period 2.
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2.
Period 2 Study Design
csDMARD = conventional synthetic disease modifying anti-rheumatic drug; NSAIDs = non-steroidal anti-inflammatory 
drugs; QD = once daily; RA = rheumatoid arthritis; W = week
Note:
Period 2 will remain blinded until the last subject completes Week 48 (Period 1).  Subjects who prematurely 
discontinue from Period 2 will undergo an x-ray of hands and feet unless the previous x-ray was performed 
within the previous 24 weeks.
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will receive open-label 
upadacitinib 15 mg QD. Subjects receiving MTX will receive open-label MTX.
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 Appendix D.  Lab values can be re-tested once during 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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the screening period.  If the re-tested lab value(s) remain exclusionary, the subject will be 
considered a screen failure with no additional re-screening possible.  Redrawing samples 
if initial samples were unable to be analyzed would not count as a retest since initial result 
was never obtained.
Subjects that initially screen fail for the study are permitted to re-screen once following 
re-consent.  For additional re-screening, AbbVie Therapeutic Area Medical Director 
approval is required.  All screening procedures with the possible exceptions noted below 
will be 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) or a 
purified protein derivative (PPD) test (or equivalent), 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 and no more than 90 days have 
passed.
Period 1 (48-Week Randomized, Double-Blind Treatment Period)
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 48 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 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, and 48.  A ± 3 day 
window is permitted around scheduled study visits until Week 32 and then ± 7 days for 
the remainder of the period.  The last dose of study drug in Period 1 is taken the day prior 
to the Week 48 Visit.  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.  
 


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Period 2 (Long-Term Extension Period [212 Weeks])
Period 2 will begin at Week 48 Visit after all assessments have been completed.  During 
Period 2, subjects will visit the study site at Weeks 60, 72, 84, 96, every 12 weeks through 
Week 240, and Week 260/PD.  A ± 7-day window is permitted around scheduled study 
visits.  Starting at Week 48, subjects who fail to show at least 20% improvement in both 
TJC and SJC compared to baseline at 2 consecutive visits, despite optimization of 
background RA therapies (see Section 5.2.3.1 for permitted background RA therapies), 
will be discontinued from study drug.  Therefore, the earliest discontinuation would be at 
Week 60, after completion of all Week 60 study visit activities.
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will 
receive open-label upadacitinib 15 mg QD. Subjects receiving MTX will receive open-
label MTX.
Discontinuation of Study Drug and Continuation of Study Participation (Period 1 
and Period 2)
Subjects may discontinue study drug treatment, but may choose to continue to participate 
in the study (refer to Section 5.4.1 for additional details).  Subjects who prematurely 
discontinue study drug should complete a Premature Discontinuation visit (PD visit) as 
soon as possible, preferably within 2 weeks, and preferably prior to initiation of another 
therapy.  To minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment should continue to be followed for all 
regularly scheduled visits as outlined in the Activity Schedule (Appendix D and 
Appendix F), unless subjects have decided to discontinue study participation entirely 
(withdrawal of informed consent).  Subjects should be advised on the continued scientific 
importance of their data even if they discontinue treatment with study drug early.  
Following discontinuation of study drug, the subject should be treated in accordance with 
the investigator's best clinical judgment irrespective of whether the subject decides to 
continue participation in the study.  In addition, all future rescue- and efficacy-driven 
discontinuation criteria no longer apply.  This includes 20% TJC/SJC calculations at 
Weeks 12 – 24, Weeks 36 – 40 and Week 48 and thereafter, as well as CDAI calculation 
 


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at Week 26, if applicable.  If at any point a subject no longer wants to provide assessments 
(withdrawal of informed consent) following discontinuation of study drug, a second PD 
visit is not required.
Premature Discontinuation of Study (Withdrawal of Informed Consent) (Period 1 
and Period 2)
Subjects may withdraw from the study completely (withdrawal of informed consent) for 
any reason at any time (refer to Section 5.4.1 for additional details).  If a subject 
prematurely discontinues study drug treatment and study participation (withdrawal of 
informed consent) 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 and preferably prior to initiation of another therapy.  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 Visit
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 Follow-Up Visit when they have either:
●
Completed the last visit of Period 1 (Week 48), but decided not to participate 
in the extension Period 2; OR
●
Completed the last visit of Period 2 (Week 260); OR
●
Prematurely discontinued study drug and/or study participation.  This visit 
may be a telephone call if a site visit is not possible.  Vital signs and laboratory 
test may not be required.  The Follow-Up Visit is not applicable for subjects 
who discontinued study drug and continued study participation and completed 
at least one study visit at least approximately 30 days after last dose.
 


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Protocol Modifications due to State of Emergency or Pandemic like COVID-19
Study visits may be impacted by a pandemic situation (including the COVID-19 
pandemic) or any state of emergency.  If visits cannot be conducted onsite due to travel 
restrictions or other pandemic-related reasons, virtual visits, visits at alternative locations, 
or changes in the visit frequency and timing of study procedures, among others may be 
performed.  Additional details are provided in the subsequent sections.  Every effort 
should be made to ensure the safety of subjects and site staff, while maintaining the 
integrity of the study.
5.2
Selection of Study Population
It is anticipated that approximately 975 subjects with moderately to severely active RA 
will be randomized at approximately 330 study centers, globally.
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.
Duration of symptoms consistent with RA for ≥ 6 weeks who also fulfill the 2010 
ACR/EULAR classification criteria for RA.
3.
Naïve to MTX or, if already on MTX, have received no more than 3 weekly MTX 
doses with requirement to complete a 4-week MTX washout before the first dose of 
study drug.
4.
Subjects with prior exposure to csDMARDs other than MTX may be enrolled if 
completed the washout period as specified below or should be at least five times 
the mean terminal elimination half-life of a drug:
 


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●
≥ 4 weeks prior to first dose of study drug for minocycline, penicillamine, 
sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, gold 
formulations, cyclophosphamide, tacrolimus, cyclosporine, mycophenolate;
●
≥ 8 weeks prior to first dose of study drug for leflunomide if no elimination 
procedures was followed, or adhere to an elimination procedure (i.e., 11 days 
with colestyramine, or 30 days washout with activated charcoal or as per local 
label).
5.
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 ≥ 5 mg/L (central lab, ULN 2.87 mg/L) at Screening Visit.
6.
≥ 1 bone erosion on x-ray (by local reading) OR in the absence of documented 
bone erosion, both positive rheumatoid factor (RF) and positive anti-cyclic 
citrullinated peptide (anti-CCP) autoantibodies are required at Screening.
7.
Stable dose of non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, 
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 ≥1 week prior to the first dose of study drug.
8.
Subjects must have discontinued all high-potency opiates prior at least 1 week to 
the first dose of study drug (refer to Section 5.2.3.2 for prohibited medications).
9.
Women of childbearing potential (refer to Section 5.3.1.1), must not have a 
positive pregnancy test at the Screening or Baseline Visits.  Note:  Subjects with 
borderline pregnancy tests at Screening must have a serum pregnancy test ≥ 3 days 
later to document continued lack of a positive result.
10.
If female, subject must be 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 180 days after the last dose of study drug.
 


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●
Additional local requirements may apply.  Refer to Appendix C for local 
requirements.
11.
Male subjects who are sexually active with female partner(s) of childbearing 
potential must agree from Study Day 1 through 180 days after the last dose of study 
drug to practice the protocol-specified contraception (refer to Section 5.2.4).
●
Additional local requirements may apply.  Refer to Appendix C for local 
requirements.
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 human pregnancy and reproduction is unknown.
12
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Intolerant to MTX.
2.
Prior exposure to any JAK inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
3.
Prior exposure to any bDMARD(s).
4.
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, 
 


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dermatomyositis, fibromyalgia [currently with active symptoms]).  Current 
diagnosis of secondary Sjogren's Syndrome is permitted.
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.
Female who is pregnant, breastfeeding or considering becoming pregnant during 
the study or for approximately 180 days after the last dose of study drug.
8.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 180 days after the last dose of study drug.
9.
Any active or recurrent viral infection that, based on the Investigator's clinical 
assessment, makes the subject an unsuitable candidate for the study, including 
hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated 
(even a single episode) herpes zoster, disseminated (even a single episode) herpes 
simplex, or known history of human immunodeficiency virus (HIV).  Active HBV 
and HCV are defined as: 
●
HBV:  hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity 
on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) 
qualitative test for Hepatitis B core antibody (HBc Ab) positive (+) subjects; 
(and for Hepatitis B surface antibody positive [+] subjects in Japan only);
●
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV 
antibody (HCV Ab).
10.
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB testing).
 


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11.
Systemic use of known strong cytochrome P450 3A (CYP3A) inhibitors or strong 
CYP3A inducers from Screening through the end of the study (refer to Table 1 for 
examples of commonly used strong CYP3A inhibitors and inducers).
12.
Receipt of any live vaccine within 4 weeks prior to the first dose of study drug, or 
expected need of live vaccination during study participation including at least 
4 weeks after the last dose of study drug.
13.
History of any malignancy except for successfully treated NMSC or localized 
carcinoma in situ of the cervix.
14.
History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months.
15.
History of gastrointestinal perforation (other than appendicitis or penetrating 
injury), diverticulitis, or significantly increased risk for GI perforation per 
investigator judgment.
16.
Conditions that could interfere with drug absorption including but not limited to 
short bowel syndrome.
17.
Subject has been a previous recipient of an organ transplant.
18.
History of clinically significant medical conditions 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.
19.
Active infection(s) requiring treatment with parenteral anti-infectives within 
30 days, or oral anti-infectives within 14 days prior the first dose of study drug.
20.
History of an allergic reaction or significant sensitivity to constituents of the study 
drug(s) (and their excipients) and/or other products in the same class.
21.
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
 


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●
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 count (WBC) < 2,500/µL
●
Absolute neutrophil count (ANC) < 1,500/µL
●
Platelet count < 100,000/µL
●
Absolute lymphocyte count < 800/µL
●
Hemoglobin < 10 g/dL
22.
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 (BP) > 160 mmHg or diastolic BP > 100 mmHg.  
●
Any other condition which, in the opinion of the Investigator, would put the 
subject at risk by participating in the protocol.
23.
Clinically relevant or significant ECG abnormalities, including ECG with QT 
interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) 
> 500 msec.
24.
For subjects in Japan only:  Positive result of beta-D-glucan (screening for 
pneumocystis jiroveci infection).
Rationale for Exclusion Criteria
1 – 2
To select the appropriate subject population
7 – 8
Upadacitinib is teratogenic in both rats and rabbits.  The effect of 
upadacitinib on human pregnancy and reproduction is unknown.
3 – 6, 9 – 24
To ensure safety of the subjects throughout the study
 


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5.2.3
Prior, Concomitant, and Prohibited 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 on the appropriate electronic case report 
form (eCRF).  Also, medications including but not limited to DMARDs taken for RA 
(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 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.
●
If not taking any of the above at baseline, these must not be initiated except 
where permitted by protocol-defined rescue therapy.
●
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.
 


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In Period 1, starting at Week 26 (after Week 26 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 care, are allowed.  To avoid confounding effects of systemic absorption of 
intra-articular corticosteroids, joint injections should be avoided, if possible, within 
21 days prior to the next scheduled study visit.  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.  Refer to Section 5.2.3.3 for rescue therapy at Week 26.
In Period 2, starting at Week 48 (after Week 48 assessments have been performed) and 
thereafter, initiation of or change in corticosteroids (including:  oral, intra-articular, trigger 
point or tender point, intra-bursa, intra-tendon sheath, intramuscular and intravenous) is 
allowed.  In addition, the initiation of or change in NSAIDs, acetaminophen/paracetamol 
and low potency narcotics is also permitted to optimize concomitant RA medications.  
Adding one of the following, sulfasalazine, hydroxychloroquine, or chloroquine, is also 
permitted, as per local label.  Period 2 may be unblinded after all subjects complete 
Period 1, at which time the Investigator will know if the subject is taking MTX or MTX 
placebo.  If subject is not taking MTX, he/she may add a maximum of 2 csDMARDs, 
including MTX, leflunomide, sulfasalazine, hydroxychloroquine, or chloroquine, but not 
MTX plus leflunomide.  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) are allowed, after which subject should resume his/her usual daily oral 
corticosteroid dose.
Traditional Chinese Medicine
Traditional oral Chinese medicine cannot be initiated or changed during the study as these 
may interfere with upadacitinib metabolism and exposure and may impact efficacy and 
safety of upadacitinib treatment.
 


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5.2.3.2
Prohibited Therapy
Local label recommendations for contraindicated concomitant therapies with MTX 
(i.e., trimethoprim-sulfamethoxazole) should be followed.
JAK Inhibitor
Prior exposure to JAK inhibitors and concurrent use during the study (including but not 
limited to tofacitinib [Xeljanz®], baricitinib, and filgotinib) is not allowed.
Corticosteroids
Oral corticosteroids > 10 mg prednisone/day, or equivalent, are NOT allowed in Period 1.  
Intra-articular, intramuscular, intravenous, trigger point or tender point, intra-bursa, and 
intra-tendon sheath corticosteroids are NOT allowed up to Week 26.  There are exceptions 
if rescue therapy is needed between Weeks 12 and 24.  Refer to Section 5.2.3.3.
Biologic Therapies
All biologic therapies are prohibited during the study (i.e., Periods 1 and 2).
Subjects with prior exposure to bDMARDs are excluded from participation in this study.
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)
 


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●
Raptiva® (efalizumab)
●
Tysabri® (natalizumab)
●
Stelara® (ustekinumab)
●
Benlysta® (belimumab)
●
Dupixent® (dupilumab)
●
Taltz® (ixekizumab)
●
Cosentyx® (secukinumab)
●
Entyvio® (vedolizumab)
csDMARD Therapies
Subjects must be naïve to MTX; however, those who have received not more than 
3 weekly doses of MTX may be enrolled if they complete a 4-week washout of the MTX 
before the first dose of study drug (Inclusion Criterion 3, Section 5.2.1).
Subjects must have discontinued all csDMARDs prior to Baseline Visit as specified in the 
washout procedures (Inclusion Criterion 4, Section 5.2.1).
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., Periods 1 and 2).  The most 
common strong CYP3A inhibitors and inducers are listed in Table 1.
 


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Table 1.
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
Avasimibe
Carbamazepine
Phenytoin
Rifampin
Rifapentine
St. John's Wort
In Period 2, when study drug has been unblinded, systemic use of known strong CYP3A 
inhibitors or strong CYP3A inducers is permitted for subjects not receiving upadacitinib.
Opiates
High potency opiates are not permitted during the study (i.e., Periods 1 and 2), with the 
exception of analgesic care related to AEs or SAEs 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
 


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●
methadone
●
hydromorphone
●
morphine
●
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) 4 weeks before first dose of study 
drug with appropriate precautions.  Live vaccinations are prohibited during Period 1, 
including at least 30 days (or longer if required locally) after last dose of study drug.
Examples of live vaccines include, but are not limited to, the following:
●
Monovalent live influenza A (H1N1) (intranasal);
●
Seasonal trivalent live influenza (intranasal);
●
Zostavax (herpes zoster, live attenuated);
●
Rotavirus;
●
Varicella (chicken pox);
●
Measles-mumps-rubella or measles mumps rubella varicella;
●
Oral polio vaccine;
●
Smallpox;
●
Yellow fever;
●
Bacille Calmette-Guérin (BCG);
 


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●
Typhoid.
In Period 2, if a live vaccine must be administered during study participation, study drug 
must be held for at least 30 days prior to the vaccination and at least 30 days after the 
vaccination (or longer if required locally).
If the live herpes zoster vaccine is to be administered and there is no known history of 
primary varicella (chicken pox), preexisting immunity to varicella should be confirmed 
with antibody testing prior to administration of the herpes zoster vaccine.  If varicella 
antibody testing is negative, the live herpes zoster vaccine should not be administered.
Administration of inactivated (non-live) vaccines is permitted during the study according 
to local practice guidelines.  Examples of common vaccines that are inactivated, toxoid or 
biosynthetic, include but are not limited to:  injectable influenza vaccine, pneumococcal, 
Shingrix (zoster vaccine, recombinant, adjuvanted) and, pertussis (Tdap) vaccines. 
If the nasal Influenza vaccine is administered, the vaccine must be administered at least 
4 weeks prior to first dose of study drug.
5.2.3.3
Rescue Therapy
Rescue therapy for those subjects who meet the following criteria from Week 12 through 
Week 24 are as follows:
●
Those who do not achieve ≥ 20% improvement in both TJC and SJC compared 
with baseline at two consecutive visits starting at Week 12 will continue on 
their blinded therapy and the Investigator should optimize (initiate or increase) 
background RA medications:  NSAIDs, corticosteroids (oral ≤ 10 mg/day 
prednisone equivalent or prednisone equivalent ≤ 0.5 mg/kg/day for 
3 consecutive days) and/or low-potency analgesics.
Rescue therapy for those subjects who meet the following criteria at Week 26 are as 
follows:
 


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1.
Subjects who were originally randomized to MTX:
●
Those who do not achieve CR by CDAI: 
○
but achieve ≥ 20% improvement in both TJC and SJC compared with 
baseline will continue on blinded MTX and the Investigator should 
optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 2 local 
injections), low-potency analgesics and csDMARDs (only 1 of the 
following:  sulfasalazine, hydroxychloroquine or chloroquine) throughout 
the remainder of Period 1 and until the study is unblinded.
○
and do not achieve ≥ 20% improvement in both TJC and SJC compared 
with baseline will be re-randomized in a 1:1 ratio to receive blinded 
upadacitinib 15 mg QD or upadacitinib 30 mg QD (for subjects in Japan:  
randomize 1:1:1 to receive upadacitinib 7.5 mg QD, 15 mg QD, or 30 mg 
QD) while continuing MTX treatment in a blinded manner and will remain 
on upadacitinib plus MTX throughout the remainder of Period 1 and until 
the study is unblinded.  
●
Those who achieve Clinical Remission (CR) by CDAI (CDAI ≤ 2.8) at 
Week 26 will continue blinded treatment with MTX throughout the remainder 
of Period 1 and until the study is unblinded (the study is unblinded when all 
subjects have completed Period 1).
2.
Subjects who were originally randomized to upadacitinib:
●
Those who do not achieve CR by CDAI: 
○
but achieve ≥ 20% improvement in both TJC and SJC compared with 
baseline will continue on blinded upadacitinib and the Investigator should 
optimize (initiate or increase the dose) background RA medications:  
NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up 
to 2 local injections), low potency analgesics and csDMARDs (only 1 of 
the following:  sulfasalazine, hydroxychloroquine or chloroquine) 
throughout the remainder of Period 1 and until the study is unblinded.
○
but do not achieve ≥ 20% improvement in both TJC and SJC compared 
with baseline will add MTX 10 mg/week (7.5 mg for Japan) to 
upadacitinib in a blinded manner and will remain on upadacitinib plus 
 


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MTX 10 mg/week (7.5 mg for Japan) throughout the remainder of Period 1 
and until the study is unblinded.
●
Those who achieve CR by CDAI (CDAI ≤ 2.8) at Week 26 will continue 
blinded treatment with upadacitinib throughout the remainder of Period 1 and 
until the study is unblinded (the study is unblinded when all subjects have 
completed Period 1).
Rescue therapy for those subjects who meet the following criteria from Week 36 through 
Week 40 are as follows:
●
Those who do not achieve ≥ 20% improvement in both TJC and SJC compared 
with baseline at two consecutive visits starting at Week 36 will be rescued 
with optimizing (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent or prednisone 
equivalent ≤ 0.5 mg/kg/day for 3 consecutive days and up to 2 local injections), 
low-potency analgesics and csDMARDs (only 1 of the following:  
sulfasalazine, hydroxychloroquine or chloroquine).
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.
 


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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.
●
Female subjects who are surgically 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 180 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.
 


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●
Vasectomized partner(s), provided the vasectomized partner has received 
medical confirmation of the surgical success and is the sole sexual partner of 
the women of childbearing potential trial participant.
●
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).
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 and after exposure to the investigational 
therapies, upadacitinib and MTX.  In Period 2, starting at Week 48, concomitant 
csDMARDs (i.e., sulfasalazine, hydroxychloroquine, chloroquine and leflunomide) can be 
prescribed, per standard of care.  The duration of contraception after discontinuation of 
these prescribed csDMARDs should be based on the local label.
If during the course of the study a woman becomes surgically sterile or post-menopausal 
and complete documentation is available, contraception measures as defined above are no 
longer required.
Additional local requirements may apply.  Refer to Appendix C for local requirements 
(Canada and Colombia).
Contraception Recommendation for Males
There are no contraception requirements for male subjects receiving upadacitinib only, or 
their female partner(s).  
 


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For a male subject receiving MTX who has a female partner who is postmenopausal or 
permanently sterile, no contraception is required.
A male subject receiving MTX who is sexually active with female partner(s) of 
childbearing potential must agree from Study Day 1 through 180 days after the last dose 
of MTX 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).
●
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 receiving MTX must agree not to donate sperm from Study 
Day 1 through 180 days after the last dose of MTX study drug.
Male subjects receiving MTX are responsible for informing his partner(s) of the risk of 
becoming pregnant and for reporting any pregnancy to the study doctor.  
It is important to note that contraception and sperm donation recommendations described 
above are specifically intended to prevent pregnancy during and after exposure to the 
investigational therapy, MTX.  In Period 2, starting at Week 48, concomitant csDMARDs 
(i.e., sulfasalazine, hydroxychloroquine, chloroquine and leflunomide) can be prescribed, 
per standard of care.  The duration of contraception and requirement not to donate sperm 
after discontinuation of these prescribed csDMARDs should be based on the local label.
Additional local requirements may apply.  Refer to Appendix C for local requirements 
(Canada and Colombia).
 


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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 Appendix D, Appendix E, and Appendix F.
Study visits may be impacted by cases of state of emergency or pandemic situations like 
COVID-19.  This may include changes such as virtual visits, visits at alternative locations, 
or changes in the visit frequency and timing of study procedures, among others.  
Additional details are provided in Section 5.3.1.1.
Every effort should be made to ensure the safety of subjects and site staff, while 
maintaining the integrity of the study.
Supplemental study case report forms should be completed in the event of missed/virtual 
visits, or study drug interruptions or discontinuations related to COVID-19.
Study Visits and/or activities should be performed as scheduled whenever possible.  
During a state of emergency or pandemic situation, if it is not possible for all study 
procedures to be performed as specified due to travel restrictions or other reasons, the 
following modifications are allowed:
●
If permitted by local regulations, the IRB/IEC and the subject, study visits may 
be conducted in a subject's home residence (see Section 5.3.1.1 – Sub-Section 
"Optional Home Healthcare Service Due to State of Emergency or Pandemic 
Situation like COVID-19").
●
The following study activities may be performed virtually by phone/video 
conference:
○
Adverse event assessment
○
Concomitant therapy assessment including compliance to contraception 
requirements, if applicable
 


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○
Latent TB risk assessment 
○
Communication of in-home urine pregnancy test result
○
Dispense study drug and subject dosing diary (see Section 5.3.1.1 - Sub-
Section "Study Drug Dispensing, Dosing, and Compliance" for details 
about the Direct-to-Patient shipment)
○
Review of subject dosing diary, compliance to IP administrations
●
During a virtual visit, the following activities should not be performed:
○
Patient questionnaires
○
X-rays (bilateral hands/feet)
○
Vital signs and body weight
○
Physical exam
○
Physician Global Assessment (PhGA)
○
TJC68/SJC66
●
The following study activities may be performed by a local 
clinic/hospital/laboratory:
○
QuantiFERON-TB Gold test or equivalent (and/or local PPD skin test)
○
Chest x-ray, if the Investigator has determined, based on clinical 
judgement, that a CXR is required to ensure that it is safe to continue study 
drug administration (e.g., subjects with seroconversion on an annual TB 
test).
In this case, CXR should be performed as soon as restrictions allow at the 
study site or local hospital/facility.  Otherwise, the CXR will be performed 
at the next earliest feasible visit.
○
12-lead ECG, if the Investigator has determined, based on clinical 
judgement, that an ECG is required to ensure that it is safe to continue 
study drug administration In this case, ECG should be performed as soon 
as restrictions allow at the study site or local hospital/facility.  Otherwise, 
the ECG will be performed at the next earliest feasible visit.
○
Local urine pregnancy test
○
Lab tests (blood chemistry, hematology, urinalysis)
○
ESR
 


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All procedures performed at local facilities must be performed by 
appropriately qualified personnel.
●
Lab draws should be obtained as close as possible to the scheduled visit.
●
The study site should keep records of all visits/study activities performed 
virtually by phone/video or through the optional Home Healthcare Service or 
by a local clinic/hospital/laboratory.
5.3.1.1
Study Procedures
The study procedures outlined in Appendix D and Appendix F are discussed in detail in 
this section, with the exception of exploratory research and validation studies (discussed 
in Section 5.3.1.2), drug concentration measurements (discussed in Section 5.3.2), the 
collection of prior and concomitant medication information (discussed in Section 5.2.3), 
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.  The 
separate written consent may be part of the main consent form.  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 Appendix D and 
Appendix F; 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 J)
●
Patient's Assessment of Pain VAS (Appendix K)
●
Health Assessment Questionnaire – Disability Index (HAQ-DI) to assess the 
physical function and health-related quality of life of each subject 
(Appendix L)
●
Patient's Assessment of Severity and Duration of Morning Stiffness Numerical 
Rating Scale (NRS) (Appendix M)*
●
EuroQoL-5D-5L (EQ-5D-5L) (Appendix N)
●
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) 
(Appendix O)
 


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●
Work Productivity and Activity Impairment (WPAI) (Appendix P)
●
Short Form-36 (SF-36) (Appendix Q)
Period 2
●
Patient's Global Assessment of Disease Activity VAS (Appendix J)
●
Patient's Assessment of Pain VAS (Appendix K)
●
HAQ-DI to assess the physical function and health-related quality of life of 
each subject (Appendix L)
●
Patient's Assessment of Severity and Duration of Morning Stiffness NRS 
(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.
Due to a state of emergency or pandemic situation like COVID-19, subject visits may be 
conducted via phone or video conference.  In these situations, questionnaires will be 
completed by the subject at the next feasible visit.
TB Testing/TB Prophylaxis
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.
At Screening, all subjects will be assessed for evidence of increased risk for TB by a risk 
assessment form (Appendix I) 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.
 


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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.
For subjects with a negative TB test result at Screening or most recent evaluation, an 
annual TB re-test will be performed.  The TB test(s) to be performed depends on local 
guidelines and whether or not the site has capacity to perform QuantiFERON-TB Gold 
testing (see below).  If an annual TB test is newly positive (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 Investigator's discretion.  Any 
positive TB test result after the patient has started study drug should be reported as an 
adverse event (AE).
TB Test:
●
For regions that require both PPD and QuantiFERON-TB Gold testing, both 
will be performed.  A positive TB test is defined by local guidelines (for 
example, in some countries, both PPD and QuantiFERON-TB Gold are 
performed, and if either one is positive, the TB test is considered positive). 
●
In the absence of local guidelines defining a positive result when both PPD 
and QuantiFERON-TB Gold tests are performed, then the QuantiFERON-TB 
Gold test result will be the TB test result (QuantiFERON supersedes PPD).
●
If a site has the capacity to perform both PPD and QuantiFERON-TB Gold 
tests, and local guidelines require only one test to be performed, then the 
QuantiFERON-TB Gold is the preferred test.  At a site with capacity to 
perform both tests, whatever TB test method (i.e., PPD or QuantiFERON-TB 
Gold or other IGRA) was performed at screening, then the subject should have 
their annual TB test performed with the same test method.
●
If QuantiFERON-TB Gold test is NOT possible (or if both the 
QuantiFERON-TB Gold test and the PPD skin test are required per local 
 


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guidelines):  the PPD skin test (also known as a TB skin test) will be 
performed according to standard clinical practice. The TB skin test 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 for RA subjects is considered a 
positive reaction.  The absence of induration will be recorded as "0 mm" not 
"negative."  Subjects who have had an ulcerating reaction to the TB skin test in 
the past should not be re-exposed and the TB Skin Test should be considered
positive with no requirement for subsequent testing with either PPD or 
QuantiFERON-TB Gold test.
●
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.
●
Interpretation of a positive annual TB test in low risk subjects:  In cases where 
the QuantiFERON-TB Gold test by the central laboratory is positive and the 
Investigator considers the subject at low risk for TB and has no clinical 
suspicion of TB, the Investigator may perform a local QuantiFERON-TB Gold 
test (or repeat testing through the central laboratory if not locally available) to 
confirm the positive test result.  If the repeat testing result is negative, the 
Investigator may consider the test to be negative based on his/her clinical 
judgment; if the repeat testing result is positive or indeterminate, the test is 
considered positive.
●
An equivalent Interferon Gamma Release Assay (IGRA) (such as T-SPOT TB 
test) may be substituted for the QuantiFERON-TB Gold 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 
during the study and should be considered positive.  Annual TB questionnaire 
should be completed for ALL subjects.
 


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Subjects with a negative TB test and 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 may not be enrolled.
TB Prophylaxis:
At Screening, if the subject has evidence of a latent TB infection (positive TB test and the 
subject has a CXR not suggestive of active TB), prophylactic treatment must be initiated 
at least 2 weeks prior to administration of study drug (or per local guidelines, whichever is 
longer).  The 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.  If the Investigator 
deems that it is necessary, consultation with a TB expert could be considered. 
Note:  Rifampicin or Rifapentine is Not Allowed for TB prophylaxis
In Period 2, when study drug has been unblinded, rifampicin or rifapentine are allowed for 
TB prophylaxis for subjects not receiving upadacitinib.
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy 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.
Obtain a CXR annually for subjects with newly identified TB risk factors as determined 
by the TB risk assessment form (Appendix I), or for subjects living in areas endemic for 
TB or for subjects with newly positive PPD or QuantiFERON-TB Gold test.
For subjects with seroconversion on an annual TB test, if a CXR cannot be done due to 
state of emergency or pandemic situation like COVID-19, the Investigator should contact 
 


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the AbbVie TA MD to determine if the subject may continue on study drug.  CXR should 
be performed as soon as restrictions allow at the study site or local hospital/facility.
Subjects with a 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.
During the study, subjects with new evidence of latent TB should initiate prophylactic 
treatment immediately per local guidelines.  Study drug(s) should not be withheld and 
Isoniazid and/or rifampin/rifapentine should be initiated and 2 to 4 weeks later (per local 
guidelines), subject should be re-evaluated (unscheduled visit) for signs and symptoms of 
isoniazid toxicity. 
In Period 2, when study drug has been unblinded, rifampicin or rifapentine are allowed for 
TB prophylaxis for subjects not receiving upadacitinib. 
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, 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.
 


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●
Annually for subjects with newly identified TB risk factors as determined by 
the TB risk assessment form (Appendix I) or for subjects living in areas 
endemic for TB or for subjects with newly positive PPD and/or 
QuantiFERON-TB Gold test.
Due to a state of emergency or pandemic situation like COVID-19, subject visits may be 
conducted via phone or video conference.  In these situations, if a visit requires 
completion of a CXR, the CXR will be performed at the next earliest feasible visit, unless 
the Investigator has determined, based on clinical judgement, that a CXR is required to 
ensure that it is safe to continue study drug administration. In this case, CXR should be 
performed as soon as restrictions allow at the study site or local hospital/facility.
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 his/her 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
For all subjects, a resting 12-lead ECG will be performed at Screening and every 
48 weeks thereafter, as specified in Appendix D and Appendix F.  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 Fridericia'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 
 


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ventricular conduction abnormalities.  In case of QTcF prolongation, 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 
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.
Due to a state of emergency or pandemic situation like COVID-19, subject visits may be 
conducted via phone or video conference.  In these situations, if a visit requires 
completion of an ECG, the ECG will be performed at the next earliest feasible visit, 
unless the Investigator has determined, based on clinical judgement, that an ECG is 
required to ensure that it is safe to continue study drug administration. In this case, the 
ECG should be performed as soon as restrictions allow at the study site or local 
hospital/facility.
X-Rays of Hands and Feet
Detailed instructions for performing and transmitting the study related x-rays of hands and 
feet are provided in a separate Imaging Acquisition Guideline (IAG)/Site Operational 
Manual.
Handling of X-Rays of Hands and Feet at Screening
Screening x-rays of bilateral hands (posterior-anterior view) and bilateral feet 
(anteroposterior view) must be performed within the 35-day screening period.
 


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Once a subject has been deemed eligible to participate and has had screening x-rays 
performed, the x-rays will be sent to the central imaging laboratory designated by the 
Sponsor.  Digitalized images may be acceptable, provided that they meet the 
specifications outlined in the IAG/Site Operations Manual.  X-rays not meeting the 
quality requirements must be repeated within the 35-day screening window.  Subjects can 
receive the first dose of study drug if the x-rays have been determined to be of sufficient 
quality by the central imaging laboratory.
Screening x-rays of hands and feet will serve as baseline x-rays for scoring purposes.
Joint x-rays will be sent to the central imaging vendor designated by the Sponsor.  The x-
rays will only be assessed by the imaging vendor for erosions and joint space narrowing, 
and will not be assessed for any other clinically significant findings that may impact a 
subject's health.
Handling of X-Rays of Hands and Feet after Baseline
Handling of x-rays of hands and feet after baseline in Period 1 is illustrated in Figure 3.  
All subjects (regardless of response) will receive Week 24 x-rays (Figure 3, box A) and 
Week 48 x-rays (Figure 3, box B).
If a subject prematurely discontinues from the study (withdrawal of informed consent), 
depending on the time of discontinuation, new x-rays might be needed.
●
Subjects who prematurely discontinue before Week 12 will not get x-rays 
(Figure 3, box C)
●
Subjects who prematurely discontinue from Week 12 to before Week 24 
(≥Week 12 and < Week 24), will have new x-rays performed (Figure 3, 
box D).
●
Subjects who prematurely discontinue after Week 24 to before Week 36 
(> Week 24 and < Week 36), will not have x-rays performed (Figure 3, box E).
 


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●
Subjects who prematurely discontinue from Week 36 to before Week 48 
(≥Week 36 and < Week 48), will have new x-rays performed (Figure 3, 
box F).
If a subject prematurely discontinues from study drug but continues to participate in the 
study, subject should follow the regular visit schedule as outlined in Appendix D and 
Appendix F, including performance of scheduled x-rays of hands and feet.  However, 
depending on the time of study drug discontinuation in Period 1, new x-rays might be 
needed.
●
Subjects who prematurely discontinue from study drug before Week 12 will 
not get new x-rays.
●
Subjects who prematurely discontinue from study drug from Week 12 to 
Week 16 (≥Week 12 and ≤ Week 16), will have new x-rays performed.
●
Subjects who prematurely discontinue from study drug after Week 16 to 
Week 24 (> Week 16 and ≤Week 24), will have x-rays performed at Week 24 
(standard).
●
Subjects who prematurely discontinue from study drug after Week 24 to 
Week 36 (> Week 24 and < Week 36), will not have new x-rays performed.
●
Subjects who prematurely discontinue from study drug from Week 36 to 
Week 40 (≥Week 36 and ≤Week 40), will have new x-rays performed. 
●
Subjects who prematurely discontinue from study drug after Week 40 to 
Week 48 (> Week 40 and ≤Week 48), will have x-rays performed at Week 48 
(standard).
X-rays will be sent to the central imaging laboratory designated by the Sponsor.  
Digitalized images may be acceptable, provided that they meet the specifications outlined 
in the IAG/Site Operations Manual.  X-rays not meeting the quality requirements must be 
repeated.
Overall in Period 1, each subject will undergo a maximum of 3 scheduled visits for x-ray 
examination of bilateral hands and feet (unless unscheduled repeat imaging is needed due 
 


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to failure to meet the quality requirements) at Screening, Week 24, and Week 48/PD.  
One additional x-ray examination of bilateral hands and feet may be needed depending on 
the time of premature study drug discontinuation for those subjects that continue the 
study.
In Period 2, a follow-up x-ray of hands and feet is planned at Week 96, Week 192, and 
Week 260.  Subjects who prematurely discontinue from Period 2 will undergo an x-ray of 
hands and feet unless the previous x-ray was performed within the previous 24 weeks.  
Images will be sent to the central imaging laboratory designated by the Sponsor.
Due to a state of emergency or pandemic situation like COVID-19, subject visits may be 
conducted via phone or video conference.  In these situations, if a visit by phone or video 
conference occurs at one of the designated study visits specified to complete x-rays of 
hands and feet, it will be performed at the next earliest feasible visit.
 


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Figure 3.
Handling of X-Rays of Hands and Feet after Baseline (Period 1)
MTX = methotrexate; n = number; PD = premature discontinuation; QD = once daily; SJC = swollen joint count; 
TJC = tender joint count; W = week
*
Subjects who prematurely discontinue from the study drug from Week 12 to Week 16 (≥Week 12 and ≤ Week 16) 
or from Week 36 to Week 40 (≥ Week 36 and ≤ Week 40), but continue to participate in the study will have new x-
rays performed.
Height and Weight
Height will be measured at the Screening Visit only (with shoes off).  Body weight will be 
measured at all scheduled visits as specified in Appendix D and Appendix F.  All 
measurements will be recorded in metric units where applicable.
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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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 
Appendix D and Appendix F.  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 Appendix D and Appendix F.  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.
Due to a state of emergency or pandemic situation like COVID-19, subject visits may be 
conducted via phone or video conference.  In these situations, if a visit by phone or video 
conference occurs at one of the designated study visits specified to complete physical 
examination, the complete physical examination will be performed at the next feasible 
visit.
At any time, a symptom-directed physical examination can be performed as deemed 
necessary by the Investigator.
Physician Global Assessment of Disease Activity VAS
At visits specified in Appendix D and Appendix F, 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 
 


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anchored at either end by opposite adjectives reflecting the spectrum/severity of the 
parameters assessed (Appendix G).
Due to a state of emergency or pandemic situation like COVID-19, subject visits may be 
conducted via phone or video conference.  In these situations, the Physician Global 
Assessment of Disease Activity will be completed by the physician at the next feasible 
visit.
TJC and SJC Assessment
TJC Assessment
An assessment of 68 joints (Appendix H) will be done for tenderness by pressure 
manipulation on physical examination at visits specified in Appendix D and Appendix F.  
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 H) will be done by directed physical examination at 
visits specified in Appendix D and Appendix F.  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 
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be a qualified medical professional (e.g., nurse, physician's assistant, physician).  Any 
other 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.
Due to a state of emergency or pandemic situation like COVID-19, subject visits may be 
conducted via phone or video conference.  In these situations, the TJC and SJC will be 
performed at the next feasible visit by the independent joint assessor, if possible.
CDAI
The CDAI calculation is required to determine if a subject fails to achieve Clinical 
Remission at the Week 26 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 26 is as follows:
CDAI = TJC28 + SJC28 + PtGA + PhGA
NOTE:  As described in the section pertaining to Rescue Therapy, the Investigator should 
optimize background RA therapies in subjects who fail to achieve a CDAI ≤ 2.8 at 
Week 26, but achieve at least 20% improvement in both TJC and SJC.
Pregnancy Test
A serum pregnancy test will be performed for all women of child bearing 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:
 


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●
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 trial.
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 at all subsequent 
visits.  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 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 permanently discontinued.  In the event a 
pregnancy test comes back borderline, a repeat test is required.
●
If a urine pregnancy test post baseline 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 the 
serum pregnancy test is negative, study drug may be restarted.  If the serum 
pregnancy test is positive, study drug must be permanently discontinued.
In Period 2, for women of childbearing potential, a urine pregnancy test will be performed 
at all visits and 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, return to the study site and have blood drawn for a 
serum pregnancy test that will be analyzed at the central laboratory.
In the event a urine pregnancy test may not be performed at the protocol specified visits 
due to study modifications related to a state of emergency or pandemic situation like 
COVID-19, it can be performed by subjects at a local laboratory or it is possible for the 
Investigator to arrange a shipment from the study site directly to the subject's home of 
 


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urine pregnancy test kits to have the urine pregnancy test done at home (see 
Section 5.3.1.1 - Sub-Section "Study Drug Dispensing, Dosing, and Compliance" for 
details). Home urine pregnancy test should be performed monthly, regardless of ability to 
obtain other laboratory samples.
At each visit, the study staff should review the pregnancy avoidance recommendations 
with each subject of childbearing potential and male subjects receiving MTX 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 in this study or be 
allowed to continue study drug.
Clinical Laboratory Tests
Samples will be obtained for the clinical laboratory tests listed in Table 2.  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.
If travel restrictions or other changes in local regulations due to state of emergency or 
pandemic situation like COVID-19 prevent the subject from having blood drawn for 
laboratory testing at the study site, it is possible for the Investigator to arrange for subjects 
to have laboratory work done at a local lab, hospital, or other facility to ensure the safety 
 


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assessments are conducted per protocol.  Local lab results should be obtained along with 
reference ranges and kept within the subjects' source documentation.  Local lab results 
should be reviewed by the investigator or designee as soon as possible and documented in 
the eCRF.
If laboratory samples cannot be obtained, study drug administration may be continued 
provided labs have been obtained within the prior 3 months, the investigator has reviewed 
the laboratory results and confirmed and discussed with the subject that there is no safety 
concern for the subject to continue use of the study drug in the absence of current lab 
results.  The subject should be scheduled for laboratory draws as soon as feasible and no 
later than the next scheduled visit in order to continue the study drug administration.
If laboratory results are not available within the prior 3 months/two consecutive 12-week 
intervals, study drug dispensation is not allowed until the required laboratory tests are 
completed to ensure the safety assessments are conducted per protocol.
Blood samples will be obtained for the laboratory tests at visits specified in Appendix D
and Appendix F.  Blood draws should be performed only after all questionnaires 
(HAQ-DI, Patient's Assessment of Pain, etc.), clinical assessments, 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 Appendix D and 
Appendix F.  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.
 


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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:
●
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 study drug or 
requires a subject to receive treatment will be recorded as an AE.
Table 2.
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 
only)e
HCV Abe
HCV RNA reflex onlye
QuantiFERON-TB Goldf
Rheumatoid Factore
Anti-CCP autoantibodiese
hs-CRPg
IgG and IgM
FSHh
VZV specific IgGi
Beta-D-Glucani
Local Lab Tests:
Urine pregnancy testj
ESR
HIV (if required)k
 


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Table 2.
Clinical Laboratory Tests (Continued)
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; FSH = follicle stimulating hormone; 
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; INR = 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; VZV = varicella zoster virus
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 post 
baseline urine pregnancy test turns positive.
e.
HBV DNA testing is required for subjects who meet specific toxicity management criteria (See ALT/AST toxicity 
management criteria in Table 4).
f.
If PPD not performed.
g.
Central lab hsCRP results will remain blinded to the Sponsor, Investigator, study site personnel, and subject for all 
visits except Screening.  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 treatment allocation is 
unblinded.
h.
For more details, please refer to Section 5.2.4 (Contraception Recommendations).
i.
At Screening for subjects in Japan only.
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.  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 permanently discontinued.  In the event a pregnancy test comes back borderline, a repeat test is required.  
If a urine pregnancy test post baseline 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 the 
serum pregnancy test is positive, study drug must be permanently discontinued.
k.
If required by country regulatory authorities to confirm eligibility, subjects will be tested for antibodies to HIV at 
Screening, and it should be documented that the test has been performed.  This testing is to be done at a local lab.  
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.
 


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Hepatitis Screen
All subjects will be tested for the presence of HBV and HCV at Screening.
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 does not require HBV DNA PCR qualitative 
testing and the subject may be enrolled (Figure 4, 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 4, Scenario B).*
●
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic 
reflex testing) (Figure 4, 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.
●
For subjects in Japan 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.
 


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Figure 4.
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.
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
Subjects with a known history of HIV infection are excluded from study participation.  If 
required by country regulatory authorities to confirm eligibility, subjects will be tested for 
antibodies to HIV at Screening.  This testing is to be done at a local lab.  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.
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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VZV (For Subjects in Japan Only)
Tests for varicella-zoster virus (VZV) will be performed at Screening to evaluate 
immunity of a subject to VZV for better understanding of the safety profile of 
upadacitinib.
To assess the cell-mediated immune status to VZV, a skin test using the VZV antigen will 
be performed.  VZV antigen is injected intradermally into the forearm of each subject, and 
the longest diameters of erythema and edema will be measured in millimeters (mm) 
between 24 (recommended) and 48 hours after the injection and recorded on the 
appropriate eCRF page along with date and time of injection and measurement.  The 
absence of erythema or edema will be recorded as "0 mm."
Blood samples will be used for measuring IgG-class antibodies specific to VZV to 
estimate the prior exposure to VZV of the subject.
Randomization/Drug Assignment
All Screening laboratory results must be reviewed, signed, and dated by the Principal 
Investigator or Sub-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 the Principal Investigator or Sub-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 1:1:1 ratio using interactive response technology (IRT)
to treatment Groups 2, 3, and 4, below, except for subjects from Japan, who will be 
randomized in a 2:1:1:1 ratio to Groups 1, 2, 3, and 4:
●
Group 1:  Upadacitinib 7.5 mg QD monotherapy (subjects in Japan only; 
N = 75)
●
Group 2:  Upadacitinib 15 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
 


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●
Group 3:  Upadacitinib 30 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 4:  MTX monotherapy (N = 300) (includes 37 subjects from Japan)
Randomization will be stratified by geographic region.
See Section 5.5.3 for details.
Study Drug Dispensing, Dosing, and Compliance
Study drug(s) will be dispensed to subjects beginning at Baseline (Day 1) and as specified 
in Appendix D and Appendix F.  The first dose of study drug(s) will be administered after 
all other Baseline (Day 1) procedures are completed.  Subjects will maintain a dosing 
diary for all study drug(s) administered outside of the study visit (i.e., at home) to capture 
dosing dates and times.  At visits specified in Appendix D and Appendix F, 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.
To maintain the blind in this study with two blinded investigational study drugs (MTX 
and upadacitinib), each subject will be instructed to take two capsules once weekly (MTX 
and/or matching placebo) and a tablet once daily (upadacitinib or matching placebo).  
MTX and matching placebo will be distributed as identical capsules to maintain blinding 
during the MTX titration and during the rest of the study.  Starting with Amendment 6 
subjects receiving MTX will receive open-label MTX tablets in quantities sufficient to 
cover their respective dose.
Determination of which subjects are assigned to receive MTX-placebo versus 
upadacitinib placebo will be via the IRT (Interactive Response Technology), which will 
randomly assign each subject to the appropriate treatment group in a blinded manner.
All relevant dosing information will be entered into the eCRF at each visit.
(Refer to Section 5.5 for additional information.)
 


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Study drug may be shipped from the study site directly to the study subject's home due to 
study modifications related to a state of emergency or pandemic situation like COVID-19 
if all the following criteria are met:
●
Direct-to-patient (DTP) shipment of study drug is allowed by local regulations 
and the relevant ethics committee
●
Subject agrees to have the study drug shipped directly to their home
●
Shipments may also include other study supplies (e.g., drug dosing diaries, in-
home urine pregnancy test kits).  Instructions will be provided by AbbVie as to 
how a study site can initiate a DTP shipment using Marken, a global vendor 
selected by AbbVie to provide this service when necessary.  Shipments of 
study drugs from the study site to a subject's home will be appropriately 
temperature controlled (qualified shipper or temperature monitoring) within 
the labeled storage conditions.  Signature is required upon delivery; due to 
COVID-19 related social distancing, this may be provided by the courier after 
delivery.  Documentation of the shipment is to be retained by the clinical site.
●
AbbVie will not receive subject identifying information related to these 
shipments, as the site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug, and for obtaining consent to provide delivery information to the 
courier and documenting this consent in source documents.
Optional Home Healthcare Service Due to State of Emergency or Pandemic 
Situation like COVID-19
Subjects may be offered the option of home healthcare visits provided by a study nurse or 
third-party vendor.  Study procedures conducted in the home setting may include vital 
signs and body weight, physical exam, blood and urine samples collection, urine 
pregnancy test, adverse event and concomitant therapy assessment including compliance 
to contraception requirements if applicable, latent TB risk assessment form, review of 
subject dosing diary, TJC and SJC performed by the same independent joint assessor, if 
possible, to minimize variability.
 


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This option can only be offered in countries and sites that comply with local regulatory 
and IRB/IEC requirements for homecare.  Any pre-requisite submissions or notifications 
to the site IRB/IEC and local competent health authority should be made, and approvals 
must be obtained prior to implementation.
The investigator should be available via phone call if a consultation is necessary.
It is recommended that medical personnel entering a subject's home adhere to local health 
regulations during the COVID-19 pandemic, such as the use of Personal Protective 
Equipment (PPE), as required.
If the home visits will not be performed by site personnel, the site may be responsible for 
selecting a vendor, contracting with a vendor, and for ensuring continued compliance with 
the terms of the Clinical Study Agreement.
Individuals performing home visits need to be added to the delegation log.
5.3.1.2
Collection and Handling of 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.  Subjects may still participate in the study even if they decide not to 
participate in this optional exploratory research/validation study.
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.
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.
 


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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 20 years after the completion of Period 1.
DNA Samples for Pharmacogenetic or Epigenetic Analyses
Whole blood samples for DNA isolation will be collected at the visits indicated in 
Appendix E 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
Whole blood samples for RNA isolation will be collected at the visits indicated in 
Appendix E 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.
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 Appendix E from 
each subject who consents to provide samples for exploratory/validation research.  These 
 


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samples may be used for assay of study drugs if needed.  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 medications will be collected 
as follows:
●
At Weeks 2 and 4 prior to dosing; 
●
At Weeks 12, 16, 20, 24, 32, 36, 40, and 48/PD at any time during the visit.
On Week 2 and Week 4 Visit days, if possible, subjects should take the study drug dose at 
the clinic after collecting the pharmacokinetic (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 by 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 ACR50 response 
at Week 12 (US/FDA regulatory purposes) or the proportion of subjects achieving 
Clinical Remission (CR) (EU/EMA regulatory purposes) at Week 24.  For Japan/PMDA 
regulatory purposes, the primary endpoints are the proportion of subjects achieving 
ACR20 response at Week 12 and change from baseline in modified Total Sharp Score 
(mTSS) at Week 24.  Analyses will be conducted separately for US/FDA, EU/EMA and 
Japan/PMDA regulatory purposes; the primary endpoint is specified separately for each 
set of analyses.
ACR20/50 response rate will be determined based on 20%/50% 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.
CR is defined as Disease Activity Score (DAS)28 (C-reactive protein [CRP]) < 2.6.  
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 24.
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.
 


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**
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. 
Modified Total Sharp Score (mTSS) is the van der Heijde mTSS.
5.3.3.1.2
Key Secondary Variables
Ranked key secondary endpoints for US/FDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP) at Week 12;
2.
Change from baseline in HAQ-DI at Week 12;
3.
Change from baseline in modified Total Sharp Score (mTSS) at Week 24;
4.
Proportion of subjects achieving Low Disease Activity (LDA) based on DAS28 
(CRP) ≤ 3.2 at Week 12;
5.
Proportion of subjects achieving CR based on DAS28 (CRP) < 2.6 at Week 24;
6.
Change from baseline in Short Form-36 (SF-36) Physical Component Score (PCS) 
at Week 12.
Ranked key secondary endpoints at Week 24 for EU/EMA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI; 
3.
ACR50 response rate;
4.
Change from baseline in modified Total Sharp Score (mTSS);
5.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2;
6.
Change from baseline in SF-36 PCS; 
 


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7.
Proportion of subjects with no radiographic progression (defined as change from 
baseline in mTSS ≤0) at Weeks 24.
Ranked key secondary endpoints for Japan/PMDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP) at Week 12; 
2.
Change from baseline in HAQ-DI at Week 12; 
3.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12;
4.
Proportion of subjects achieving CR based on DAS28 (CRP) < 2.6 at Week 24;
5.
Change from baseline in SF-36 PCS at Week 12.
Other key secondary endpoints for US/FDA regulatory purposes are:
1.
ACR20 response rate at Week 12;
2.
ACR70 response rate at Week 12;
3.
Proportion of subjects with no radiographic progression at Week 24.
Other key secondary endpoints for EU/EMA regulatory purposes are:
1.
ACR20 response rate at Week 24;
2.
ACR70 response rate at Week 24.
Other key secondary endpoints for Japan/PMDA regulatory purposes are:
1.
ACR50 response rate at Week 12;
2.
ACR70 response rate at Week 12;
3.
Proportion of subjects with no radiographic progression at Week 24.
 


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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, and hsCRP.
5.3.3.1.3
Additional Variables
Additional endpoints at all visits are:
●
ACR20/50/70 response rates at all visits;
●
Change from baseline in individual components of ACR response at all visits;
●
Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation 
rate [ESR]) at all visits;
●
Change from baseline in CDAI and SDAI at all visits;
●
Proportion of subjects achieving LDA or CR by DAS28(CRP), DAS28(ESR), 
Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index 
(CDAI) at all visits (see below);
●
Change from baseline in morning stiffness (severity and duration) at all visits;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22 at all 
visits;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3 at all 
visits;
●
ACR/EULAR Boolean remission at all visits.
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
Additional endpoints (at Weeks 12, 24, and 48) are:
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in FACIT-F;
●
Change from baseline in WPAI;
 


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●
Change from baseline in SF-36.
Additional endpoints (at Weeks 24 and 48) are:
●
Change from baseline in mTSS;
●
Proportion of subjects with no radiographic progression (defined as change
from baseline in mTSS ≤ 0);
●
Change from baseline in radiographic joint space narrowing and erosion scores.
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 60, 72, 84, 96, every 12 weeks through Week 240, and 
Week 260/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;
●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined 
for Period 1);
●
Change from baseline in morning stiffness (severity and duration);
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3;
●
ACR/EULAR Boolean remission at all visits;
●
Concomitant corticosteroid use.
Additionally, assessment for the evaluation of radiographic changes in Period 2 will occur 
at Week 96 and every 96 weeks thereafter (or Premature Discontinuation Visit):
 


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●
Change from baseline in mTSS;
●
Proportion of subjects with no radiographic progression (defined as change 
from baseline mTSS of ≤ 0);
●
Change from baseline in radiographic joint space narrowing and erosion scores.
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 Appendix D.  
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.
5.3.6
Exploratory Research Variables and Validation Studies
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.
Biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  These assessments may be 
explored in the context of RA or related conditions and/or upadacitinib or drugs of similar 
classes.  These 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 
 


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used to validate putative biomarker signatures obtained from a prospective study, leading 
to the development of diagnostic tests.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects can request to be discontinued from participating in the study at any time for any 
reason, including but not limited to disease progression or lack of response to treatment.  
The Investigator may discontinue any subject's participation 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 have study drug discontinued immediately if any of the following occur:
●
Clinically significant abnormal laboratory results or AEs, which rule out 
continuation of the study drug, as determined by the Investigator or the 
AbbVie Therapeutic Area Medical Director.
●
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.
 


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●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation as determined by the Investigator 
or the AbbVie Therapeutic Area Medical Director.
●
Subject develops a gastrointestinal perforation (other than due to appendicitis 
or mechanical injury).
●
Subject with disease progression or not responding to treatment as determined 
by the Investigator.
●
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus or 
non-cardiac, non-neurologic arterial thrombosis.
●
Starting at Week 48, subjects who fail to show at least 20% improvement in 
both TJC and SJC compared to baseline at 2 consecutive visits, despite 
optimization of background RA therapies (see Section 5.2.3.1 for permitted 
background RA therapies), will be discontinued from study drug.  Therefore, 
the earliest discontinuation would be at Week 60, after completion of all Week 
60 study visit activities.
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment or study participation should complete a 
Premature Discontinuation visit (PD visit) as described in Section 5.1.
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study drug or study participation.  The information 
will be recorded on the appropriate eCRF page.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
Investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of study drug, the subject will be treated in accordance with the Investigator's best clinical 
judgment, irrespective of whether the subject decides to continue participation in the study.
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to 
enable the investigator to ensure subject safety and continuity of care.
During a state of emergency or pandemic situation like COVID-19, the investigator 
should contact the sponsor medical contact before discontinuing a subject from the study 
 


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or study drug for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored.
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.
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
There are two active study drugs in this study.  The first is daily upadacitinib and the 
second is weekly MTX.
Upadacitinib (or matching placebo) 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.
 


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MTX (or matching placebo) study drug will be taken orally once weekly, beginning on 
Day 1 (Baseline), and should be taken the same day and approximately the same time 
each week.  The study drug can be taken with or without food.
Each subject will be instructed to take 2 capsules once weekly (MTX and/or matching 
placebo) and 1 tablet once daily (upadacitinib or matching placebo) to maintain blinding.  
MTX and matching placebo will be assigned via the Interactive Response Technology 
(IRT) system, and distributed as identical capsules in blister packs, to provide the correct 
total dose for each individual subject and to maintain blinding during and after MTX 
titration (Period 1 and Period 2).  Detailed dosing instructions can be found in the Subject 
Dosing Diary and Instructions.  Starting with Amendment 6 subjects receiving MTX will 
receive open-label MTX tablets in quantities sufficient to cover their respective dose.
Subjects should take a dietary supplement of oral folic acid beginning on Day 1 (Baseline) 
throughout study participation.  Folic acid dosing and timing of regimen should be 
followed according to the Investigator's instructions.
When the last subject completes the Week 24 Visit of Period 1, the study conduct of 
Period 1 may be unblinded only to the sponsor for analysis.  Subjects and sites will 
remain blinded to treatment assignment throughout Period 1.  When the last subject 
completes the last visit of Period 1 (Week 48), study drug assignment in both periods may 
be unblinded to the Sponsor and sites, and subjects would then be dispensed study drug in 
an open-label fashion until the completion of Period 2.  All subjects will continue study 
treatment to which they were assigned at the time of study unblinding.  Dose changes of 
open-label study drugs are not permitted during unblinded Period 2.  Background 
therapies may be adjusted as per the discretion of the investigator.  Starting with 
Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will receive open-
label upadacitinib 15 mg QD. Starting with Amendment 6 subjects receiving MTX will 
receive open-label MTX.
If a subject is unable to come to the study site to pick up their study drug due to state of 
emergency or any pandemic like COVID-19, a direct-to-patient (DTP) study drug 
 


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shipment can be made from the study site to the subject if allowed by local regulations.  
AbbVie will submit any required notifications to the regulatory authority as applicable.  
Refer to Section 5.3.1.1 for details on DTP shipment of study drug.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 3.
Table 3.
Identity of Investigational Product
Investigational 
Product
Mode of 
Administration
Formulation
Strength
Manufacturer
Upadacitinib 
(ABT-494)
oral
tablet
7.5 mg
15 mg
30 mg
AbbVie
Upadacitinib 
(ABT-494) 
matching placebo
oral
tablet
NA
AbbVie
MTX
oral
2.5 mg tablet 
over-encapsulated 
in hard gelatin 
capsule
7.5 mg 
10 mg
Over-encapsulated MTX 
capsule:  
Fisher Clinical Services for 
AbbVie 
MTX:  
Dava Pharmaceuticals and/or 
Orion and/or Hexal AG and/or 
Goldshield and/or PAR 
Pharmaceuticals
MTX
oral
tablet
2.5 mg
Dava Pharmaceuticals and/or 
Orion and/or Hexal AG and/or 
Goldshield and/or PAR 
Pharmaceuticals and/or SUN 
Pharmaceuticals and/or Mylan 
and/or Hikma Pharmaceuticals
MTX matching 
placebo
oral
capsule
NA
Fisher Clinical Services and/or 
AbbVie
Folic acid will be supplied by the subject, according to Investigator's instructions for 
dosing and timing of administration.
 


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5.5.2.1
Packaging and Labeling
Upadacitinib and matching placebo will be packaged in bottles with quantities sufficient 
to accommodate study design.  MTX and matching placebo will be packaged in blister 
packs and/or bottles and/or cartons 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
Study drugs 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 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 1:1:1 ratio using interactive response technology (IRT) 
to treatment Groups 2, 3, and 4, below, except for subjects from Japan, who will be 
randomized in a 2:1:1:1 ratio to Groups 1, 2, 3, and 4:
 


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●
Group 1:  Upadacitinib 7.5 mg QD monotherapy (subjects in Japan only; 
N = 75)
●
Group 2:  Upadacitinib 15 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 3:  Upadacitinib 30 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 4:  MTX monotherapy (N = 300) (includes 37 subjects from Japan)
Randomization will be stratified by geographic region.
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.
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will 
receive open-label upadacitinib 15 mg QD. Starting with Amendment 6 subjects 
receiving MTX will receive open-label MTX.
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 2 and Week 4 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).
 


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Upadacitinib/Placebo tablets (daily dosing):
●
If a subject should forget to take his/her daily upadacitinib (or matching 
placebo) dose at his/her regularly scheduled dosing time, he/she should take 
the forgotten dose as soon as they remember the dose was missed as long as it 
is at least 10 hours before his/her 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.
●
If the subject experiences a study drug interruption > 14 consecutive days 
during Period 1 or > 30 days during Period 2 (other than for reasons listed in 
Section 6.1.7), he/she should notify the Investigator, and the Investigator will 
determine if study drug should be restarted.  If study drug treatment is 
interrupted or withdrawn in Periods 1 or 2, both daily and weekly study drug 
administration must be stopped.  Period 2 may be unblinded after all subjects 
complete Period 1, at which time daily and weekly study drugs can be 
individually interrupted.
MTX/Placebo capsules or tablets (weekly dosing):
●
Weekly MTX (or matching placebo) should be taken the same day and 
approximately the same time each week.  If the subject should forget to take 
his/her oral MTX (or matching placebo) dose on his/her regularly scheduled 
dosing date, he/she should take the forgotten dose as soon as he/she 
remembers.  If more than 72 hours has elapsed since the missed dose, the 
subject should contact the Investigator for further dosing instructions.  The 
study drug can be taken with or without food.
●
If the subject experiences a study drug interruption ≥ 3 consecutive missed 
doses in Period 1 or 2 (other than for reasons listed in Section 6.1.7), he/she 
should notify the Investigator, and the Investigator will determine if study drug 
should be restarted.  If study drug treatment is interrupted or withdrawn in 
Periods 1 or 2, both daily and weekly study drug administration must be 
stopped.  Period 2 may be unblinded after all subjects complete Period 1, at 
which time daily and weekly study drugs can be individually interrupted.
 


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5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
All AbbVie personnel with direct oversight conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the Investigator, study site 
personnel, and the subject will remain blinded to each subject's treatment throughout 
Period 1.
In order to maintain the blind, the upadacitinib and placebo tablets along with MTX and 
placebo capsules 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, we request 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. 
When the last subject completes the last visit of Period 1 (Week 48), study drug 
assignment in both periods may be unblinded to the Sponsor and sites, and subjects would 
then be dispensed study drug in an open-label fashion until the completion of Period 2.
 


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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.
As of September 2018, with all subjects having reached the end of Period 1, and after 
final review of unblinded safety data, the DMC concluded its oversight of this study.
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 and 
compliance purposes and new packaging issued as necessary.  Site staff will complete 
study drug accountability via IRT by using source documents, subject dosing diaries, and 
by visually inspecting the packaging whenever possible.  After drug accountability and 
monitor reconciliation has been completed, used packaging and unused study drug will be 
destroyed on site according to local procedures or regulations or returned to the 
destruction depot (for those sites that do not meet AbbVie's documentation requirements 
for on-site destruction).  The use of a third-party vendor for drug destruction must be pre-
approved by AbbVie.  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 should be maintained at the site's facility.
Site 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 multicenter study includes two periods.  
Period 1 is a 48-week randomized, double-blind, parallel-group, active 
comparator-controlled treatment period designed to compare the safety and efficacy of 
upadacitinib 7.5 mg QD monotherapy (for subjects in Japan only), 15 mg QD 
 


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monotherapy, and 30 mg QD monotherapy versus MTX monotherapy in adult MTX-
naïve subjects with moderately to severely active RA.  Period 1 is also designed to 
compare the efficacy of upadacitinib 15 mg QD monotherapy and 30 mg QD 
monotherapy versus MTX monotherapy for the prevention of structural progression.  
Period 1 is designed to test superiority of upadacitinib versus MTX for achieving the 
primary endpoint (the proportion of subjects achieving ACR50 response [US/FDA 
regulatory purposes] or the proportion of subjects achieving CR [EU/EMA regulatory 
purposes] or ACR20 and change from baseline in mTSS [Japan/PMDA regulatory 
purposes]) at Week 24, and other secondary efficacy parameters.
The purpose of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of 
upadacitinib (7.5, 15, or 30 mg QD) in subjects with RA who have completed Period 1.  
All subjects will continue treatment to which they were assigned at the end of Period 1 in 
a blinded manner.  This will allow unbiased assessments of long-term safety of 
upadacitinib without compromising the study conduct or results of ongoing Period 1.  
Dose reduction or escalation of upadacitinib during Period 2 is not permitted to allow 
unbiased assessments of long-term safety and efficacy of upadacitinib 30 mg QD versus 
15 mg QD.
When the last subject completes the last visit of Period 1 (Week 48), study drug 
assignment in both periods may be unblinded to the Sponsor and sites, and subjects would 
then be dispensed study drug in an open-label fashion until the completion of Period 2.
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will 
receive open-label upadacitinib 15 mg QD. Starting with Amendment 6 subjects 
receiving MTX will receive open-label MTX.
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 
 


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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 are naïve 
to MTX treatment.  Key entry criteria are to enroll adult female and male subjects who are 
at least 18 years of age with symptoms consistent with RA for ≥ 6 weeks who also fulfill 
the 2010 ACR/EULAR classification criteria for RA and no prior or limited MTX 
treatment.  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 ≥5 mg/L (central lab, ULN 2.87 mg/L) at Screening.
5.6.4
Selection of Doses in the Study
Three doses of the once-daily formulation of upadacitinib will be evaluated:  upadacitinib 
7.5 mg QD (subjects in Japan only), 15 mg QD, and 30 mg QD.  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 M13-545, upadacitinib 7.5 mg QD (for subjects in Japan only), 
15 mg QD, and 30 mg QD, dosed up to 260 weeks, are expected to be efficacious with an 
acceptable safety profile.
Preliminary results from an ongoing relative bioavailability study demonstrated that single 
15 mg and 30 mg doses of the once-daily formulation provide comparable AUC and 
significantly lower Cmax than single doses of 12 mg immediate release formulation (AUC 
equivalent to 6 mg BID dose tested in Phase 2) and 24 mg immediate release formulation 
(AUC equivalent to 12 mg BID dose tested in Phase 2), respectively, under fasting 
conditions.  At steady-state, the once-daily dose of 15 mg QD is predicted to achieve 
comparable daily AUC and Cmax, and non-inferior Ctrough to 6 mg BID immediate release 
formulation.  In the Phase 2 studies, the 6 mg BID dose was shown to achieve near 
 


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maximum efficacy.  The once-daily dose of 30 mg QD is predicted to achieve comparable 
daily AUC and Cmax, and non-inferior Ctrough to 12 mg BID immediate release formulation.  
In the Phase 2 studies, the 12 mg BID dose was clearly shown to achieve the plateau of 
efficacy.
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.
 


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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 
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 
study drug, 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 adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
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.
 


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Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
result 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.
 


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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, opportunistic infections, herpes zoster, and TB;
●
Malignancy (all types);
●
Adjudicated gastrointestinal perforations;
●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE]);
●
Anemia;
●
Decreased neutrophil counts;
●
Decreased lymphocyte counts;
●
Increased serum creatinine and renal dysfunction;
●
Hepatic events and increased hepatic transaminases;
●
Increased creatine phosphokinase (CPK);
●
Adjudicated embolic and thrombotic events (non-cardiac, non-CNS).
6.1.2
Adverse Event Severity
The Investigator will classify adverse events according to the Rheumatology Common 
Toxicity Criteria v.2.0 (Appendix R).22
6.1.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
 


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Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the Investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, 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.  Subjects who discontinue study drug 
treatment but continue to participate in the study will have SAEs and nonserious AEs 
collected for the remainder of study participation.  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 5.
 


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Figure 5.
Adverse Event Collection
Additionally, in order to assist the adjudication process, additional information on any 
potential cardiovascular events including thromboembolic events will be collected, if 
applicable.
In case of any of the following reported events, an appropriate supplemental 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);
●
Embolic and thrombotic events (non-cardiac, non-CNS);
●
Hepatic;
●
Renal;
●
Herpes Zoster Infection;
●
CPK increase considered by the investigator to be an AE.
●
COVID-19.
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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events (including documentation of specific signs/symptoms of infection and testing 
results).
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above. 
The following COVID-19 related supplemental eCRFs should be completed (for both 
serious and non-serious events):
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form
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 (RAVE®).  
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:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660
For safety concerns, contact the Immunology Safety Team at:
 




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for upadacitinib and/or the Summary of Product Characteristics (SmPC) for MTX, as 
applicable.
In Japan, the Principal Investigator will provide documentation of all SAEs to the Director 
of the investigative site and the Sponsor.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued from study drug (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  Pregnancies in study subjects will be collected from the date 
of the first dose through 180 days following the last dose of study drug.
Pregnancy in a study subject is not considered an AE.  However, the medical outcome of 
an elective or spontaneous abortion, stillbirth, or congenital anomaly is considered an 
SAE and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
Subjects and partners of subjects receiving MTX should avoid pregnancy throughout the 
course of the study, starting with the Screening Visit through 180 days after the last study 
drug administration for female subjects and male subjects receiving MTX.  Male subjects 
receiving MTX should also refrain from donating sperm for up to 180 days post last dose 
of study drug.  Results of a positive pregnancy test or confirmation of a pregnancy will be 
assessed starting with the Screening Visit through the final study visit.  
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 
 


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the study drug.  The management of specific AEs and laboratory parameters is described 
below.
For subjects who discontinued study drug, but continued study participation and are 
instead on standard of care therapies, these toxicity management requirements do not 
apply (including alerts from the central lab) and any intolerability to standard of care 
therapies should be managed by the prescribing physician.
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection 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 study 
drug.
COVID-19:  Interrupt study drug in subjects with a confirmed diagnosis of COVID-19.  
Consider interrupting study drug in subjects with signs and/or symptoms and suspicion of 
COVID-19.  The COVID-19 eCRF must be completed.
Herpes zoster:  If a subject develops herpes zoster, consider temporarily interrupting 
study drug until the episode resolves.
Gastrointestinal Perforation:  If a diagnosis of gastrointestinal perforation is confirmed 
(other than appendicitis or penetrating injury), the subject must be permanently 
discontinued from study drug.
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.
 


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Thrombosis Events: Subjects who develop symptoms of thrombosis should be promptly 
evaluated and treated appropriately.  If the diagnosis of deep vein thrombosis, pulmonary 
embolus or non-cardiac, non-neurologic arterial thrombosis is confirmed, the subject must
be discontinued from study drug.
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in situ 
of the cervix must be discontinued from study drug.  Information including 
histopathological results should be queried for the confirmation of the diagnosis.  Periodic 
skin examination is recommended for subjects who are at increased risk for skin cancer.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change 
considered clinically significant and with reasonable possibility of relationship to study 
drug OR a confirmed absolute QTcF value > 500 msec.
Management of Select Laboratory Abnormalities:  For any given laboratory 
abnormality, the Investigator should assess the subject, apply the standard of care for 
medical evaluation and treatment following any local guidelines.  Specific toxicity 
management guidelines for abnormal laboratory values are described in Table 4, 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 4, the repeat testing must 
occur as soon as possible.
 


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Table 4.
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 dosing and confirm by repeat testing with new sample.

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. 

If confirmed, continue to withhold study drug until hemoglobin value returns to 
normal reference range or its baseline value.
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.
 


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory Parameter
Toxicity Management Guideline
AST or ALT

Interrupt study drug immediately 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 > 1.5.
o
A separate blood sample for INR testing will be needed to measure INR at the 
time of repeat testing for ALT or AST.  A repeat test of INR is not needed for 
determination if above toxicity management criteria are met. 

Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat 
testing with new sample along with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).

Interrupt study drug immediately if confirmed ALT or AST > 5 × ULN by repeat 
testing with new sample for more than 2 weeks. 

If ALT or AST > 8 × ULN, interrupt study drug immediately, confirm by repeat 
testing with new sample, and contact the TA MD.
Subjects who meet any of the above criteria should be evaluated for an alternative 
etiology of the ALT or AST elevation and managed as medically appropriate.  If 
applicable, the alternative etiology should be documented in the eCRF.  If ALT or AST 
values return to the normal reference range or its Baseline value, study drug may be 
restarted.  If restarting study drug, documentation should include reason that rechallenge 
is expected to be safe.  If after clinically appropriate evaluation, no alternative etiology 
for ALT or AST elevation is found or the ALT or AST elevation has not resolved or is 
not trending down toward normal, the subject should be discontinued from study drug.
For any confirmed ALT or AST elevations > 3 ULN, complete supplemental hepatic 
eCRF.

Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA at 
screening who develop the following should have HBV DNA by PCR testing 
performed within 1 week:
o
ALT > 5 × ULN OR
o
ALT or AST > 3 × ULN if an alternative cause is not readily identified
o
A separate blood sample for HBV DNA PCR testing will be needed at the 
time of repeat testing for ALT or AST.
A positive result for HBV DNA PCR testing in these subjects will require 
immediate interruption of study drug and a hepatologist consultation should occur 
within 1 week for recommendation regarding subsequent treatment.
Serum Creatinine

If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the test for 
serum creatinine (with subject in an euvolemic state) to confirm the results.  If the 
results of the repeat testing still meet this criterion, then interrupt study drug and re-
start study drug once serum creatinine returns to ≤ 1.5 × baseline value 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.
 


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory Parameter
Toxicity Management Guideline
Creatine Phosphokinase

If confirmed CPK value ≥ 4 × ULN and there are no symptoms suggestive of 
myositis or rhabdomyolysis, the subject may continue study drug at the 
investigator's discretion.

If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact AbbVie TA MD.
For the above CPK elevation scenarios, complete supplemental CPK eCRF.
For allowed study drug interruption, the following rules apply:
Period 1
●
Upadacitinib/Placebo tablet (daily dosing):
○
Allow study drug interruption ≤ 14 consecutive days for AEs and 
emergency surgery during the first 24 weeks;
○
After Week 24, study drug interruption due to AEs/ surgery is allowed 
≤21 days.
●
MTX/Placebo capsules (weekly dosing):
○
Allow study drug interruption ≤ 2 consecutive missed doses for AEs and 
emergency surgery during the first 24 weeks;
○
After Week 24, study drug interruption due to AEs/surgery is allowed 
≤3 consecutive doses.
●
If the subject must undergo emergency surgery, the study drug should be 
interrupted at the time of the surgery.
●
Elective surgery during the first 24 weeks is discouraged and needs to be 
discussed with the AbbVie Therapeutic Area Medical Director.  If the subject 
undergoes elective surgery, the study drugs should be interrupted one week 
prior to the planned surgery.
●
After surgery, allow reintroduction of study drugs 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
●
Upadacitinib/Placebo tablet (daily dosing):
○
Up to 30 consecutive days of oral study drug interruption is allowed.  The 
Investigator will make determination if study drug should be restarted for 
interruptions > 30 days.
●
MTX/Placebo capsules or tablets (weekly dosing):
○
Study drug interruption due to AEs/surgery is allowed for ≤ 3 consecutive 
doses.  The Investigator will make determination if study drug should be 
restarted for interruptions > 30 days.
●
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.
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.
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.
 


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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 24 hours 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 AEs 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.
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, 
including those that may be due to the COVID-19 or any pandemic or any state of 
 




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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
A global analysis will be conducted for the comparisons of upadacitinib 15 mg QD and 
30 mg QD treatment groups versus the MTX treatment group for all subjects (excluding 
the Japan specific upadacitinib 7.5 mg treatment group).  A separate Japan sub-study 
analysis will be conducted for the comparisons of upadacitinib 7.5 mg QD, 15 mg QD, 
and 30 mg QD treatment groups versus the MTX treatment group for subjects enrolled in 
Japan only.
An unblinded analysis will be conducted after all subjects have completed Week 24 for 
the purpose of regulatory submission.  To maintain integrity of the trial and avoid 
introduction of bias, study sites and subjects will remain blinded for the duration of 
Period 1.  Additional unblinded analyses may be conducted after the Week 24 analysis.
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 primary analysis at Week 24.  The statistical analyses will be 
performed using SAS (SAS Institute Inc., Cary, NC, USA).
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will 
receive open-label upadacitinib 15 mg QD. Starting with Amendment 6 subjects 
receiving MTX will receive open-label MTX. The details for handling the change in dose 
in analysis will be described in the Statistical Analysis Plan (SAP) for final reporting.
8.1.1
Analysis Populations
8.1.1.1
Full Analysis Set
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.
 


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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.
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, the number of subjects who prematurely discontinued study drug, and the 
number of subjects who prematurely discontinued study participation.
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 study drug, 
prematurely discontinued study participation, and completed will be summarized by 
treatment group and overall.  Reasons for premature discontinuation of study drug and 
study participation will be summarized separately for all randomized subjects by 
treatment group and overall, with frequencies and percentages by reason for 
discontinuation.
 


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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.  
Study drug compliance will be summarized for each treatment group for Period 1.  The 
compliance is defined as the number of tablets/capsules taken (i.e., the difference between 
the number of tablets/capsules dispensed and the number of tablets/capsules returned) 
during the subject's participation in Period 1 divided by the number of tablets/capsules a 
subject is supposed to take each day/week times the length of time that the subject was in 
the Treatment Phase of Period 1.
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.
 


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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 endpoints for US/FDA, EU/EMA, and Japan/PMDA regulatory purposes are 
listed in Section 5.3.3.1.1.  Analyses will be conducted separately for US/FDA, EU/EMA 
and Japan/PMDA regulatory purposes; for each set of analyses, only the specified primary 
endpoint is applicable.
The analysis of the primary efficacy endpoint will be conducted on the FAS based on 
treatment as randomized.  Supportive analysis will also be conducted on the Per Protocol 
Analysis Set.  For the analysis of ACR20, ACR50 and CR, the comparisons will be made 
between each upadacitinib dose and the MTX group using the Cochran-Mantel-Haenszel 
test adjusting for main stratification factors.  Non-Responder Imputation (NRI) will be 
used as the primary analysis.  For the analysis of change from baseline in mTSS, between-
group comparisons for each upadacitinib treatment group and the MTX treatment group 
will be performed 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.  Both linear extrapolation analysis and as observed analysis will be conducted.
The primary efficacy analyses will be performed in demographic subgroups including age, 
gender, weight, body mass index, race, and geographical region 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 for US/FDA, EU/EMA, and Japan/PMDA regulatory purposes 
regulatory purposes are listed in Section 5.3.3.1.2.
 


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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.  Between-group comparisons for each upadacitinib 
treatment group and the MTX treatment group will be performed using the analysis of 
covariance model with treatment groups 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, including visits beyond Week 24.  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.
8.1.4.1.4
Multiplicity Control for the Primary and Ranked Key 
Secondary Endpoints
For the global analysis of upadacitinib 15 mg QD and 30 mg QD compared to MTX 
(excluding the Japan specific upadacitinib 7.5 mg treatment group), the overall type I 
error rate of the primary and ranked key secondary endpoints for the two doses will be 
strongly controlled using a graphical multiple testing procedure.23  Specifically, the testing 
will utilize the endpoint sequence of primary endpoint(s) followed by the ranked key 
secondary endpoints in the order as specified in Section 5.3.3.1.2, and will begin with 
testing the primary endpoint using α of 0.025 for each dose.  Continued testing will follow 
a pre-specified α transfer path which includes downstream transfer along the endpoint 
sequence within each dose as well as cross-dose transfer.  More details of the graphical 
procedure will be specified in the SAP.
 


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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 generate 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.
Linear Extrapolation for Radiographic Data:  For radiographic data (i.e., mTSS-based 
endpoints), if a subject receives rescue therapy or prematurely discontinued, the 
radiographic data at time points after rescue or discontinuation will be imputed assuming 
a linear relationship between baseline and previous time point when X-ray should be 
collected. 
For non-radiographic data, 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 analysis based on OC will also be conducted for 
key endpoints.  For radiographic data, analysis based on both linear extrapolation and an 
as-observed analysis (where the as-observed Week 24/48 assessments for all subjects are 
used) will be conducted.
8.1.4.2
Long-Term Efficacy 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 Analysis
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 in a descriptive manner.  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 summarized 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 5% 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, MACE, renal 
dysfunction, anemia, increased CPK, drug-related hepatic disorders, and embolic and 
thrombotic events (non-cardiac, non-CNS)) 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.
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.
 


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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 
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 
 


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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 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.
 


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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.
8.2
Determination of Sample Size
The planned sample size of 900 (not including the Japan specific upadacitinib 7.5 mg QD 
treatment group) provides at least 90% power for a 20% difference in ACR50 response 
rate (assuming a Week 12 MTX ACR50 rate of 20%).  This sample size also provides at 
least 90% power for a 16% difference in DAS28 CR response rate (assuming a Week 24 
MTX CR rate of 24%), and for a 20% difference in ACR20 response rate (assuming a 
Week 12 MTX ACR20 rate of 50%).  With this sample size, there is approximately 80% 
power to detect a difference of 0.58 in change from baseline in mTSS (assuming a 
standard deviation of 2.2).  This sample size will also provide at least 90% power for 
other ranked key secondary endpoints including change from baseline in DAS28 (CRP), 
change from baseline in HAQ-DI, ACR70, and SF-36.  The above power calculations are 
all based on a two-sided significance level of 0.025 and accounting for a 10% dropout rate.  
An additional 75 Japanese subjects will be enrolled into the Japan specific upadacitinib 
7.5 mg QD treatment arm for Japan/PMDA regulatory purposes.
 


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8.3
Randomization Methods
Subjects will be randomly assigned in a 1:1:1 ratio to treatment Groups 2, 3, and 4, below, 
except for subjects from Japan, who will be randomized in a 2:1:1:1 ratio to Groups 1, 2, 
3, and 4:
●
Group 1:  Upadacitinib 7.5 mg QD monotherapy (subjects in Japan only; 
N = 75)
●
Group 2:  Upadacitinib 15 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 3:  Upadacitinib 30 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 4:  MTX monotherapy (N = 300) (includes 37 subjects from Japan)
Randomization will be stratified by geographic region.
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, 
 


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maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
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, 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.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, 
conflict/combat) occurs leading to difficulties in performing protocol-specified procedures, 
AbbVie may engage with study site personnel in efforts to ensure the safety of subjects, 
maintain protocol compliance, and minimize risks to the integrity of the study while 
trying to best manage subject continuity of care.  This may include alternative methods for 
assessments (e.g., virtual site visits), alternative locations for data collection (e.g., use of a 
local lab instead of a central lab), and shipping investigational product and/or supplies 
direct to subjects to ensure continuity of treatment where allowed.  In all cases, these 
alternative measures must be allowed by local regulations and permitted by IRB/IEC.  
Investigators should notify AbbVie if any urgent safety measures are taken to protect the 
subjects against any immediate hazard.
 


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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.
Samples for exploratory research/validation studies will only be collected if the subject 
has voluntarily signed and dated the separate written consent for exploratory 
research/validation studies, approved by an IRB/IEC, after the nature of the testing has 
been explained and the subject has had an opportunity to ask questions.  The separate 
written consent must be signed before the exploratory research/validation studies samples 
are collected and testing is performed.  The separate written consent may be part of the 
main consent form.  If the subject does not consent to the exploratory research/validation 
studies, it will not impact the subject's participation in the study.
In the event a subject withdraws from the main study, optional exploratory research 
samples will continue to be stored and analyzed unless the subject specifically withdraws 
consent for the optional samples.  If consent is withdrawn for the optional sampling, the 
subject must inform their study doctor, and once AbbVie is informed, the optional 
samples will be destroyed.  However, if the subject withdraws his/her consent and the 
samples have already been tested, those results will still remain as part of the overall 
research data.
 


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Due to a pandemic situation like COVID-19 or state of emergency, it is possible that 
additional protocol modifications not outlined in this protocol may become necessary.  If 
this situation arises, in addition to the study informed consent, additional verbal consent 
may be obtained prior to these adaptations or substantial changes in study conduct in 
accordance with local regulations.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the Principal Investigator will prepare the informed consent and explanatory 
material required to obtain subject's consent to participate in the study with the 
cooperation of the sponsor and will revise these documents as required.  The prepared or 
revised consent forms and explanatory material will be submitted to the sponsor. 
Approval of the IRB will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the Principal Investigator will revise the informed consent and explanatory 
material based on the information without delay and will obtain the approval of the IRB 
prior to use in the study.  The Investigator will provide the information, without delay, to 
each subject already participating in the study, and will confirm the intention of each 
subject to continue the study or not.  The Investigator shall also provide a further 
explanation using the revised form and explanatory material and shall obtain written 
consent from each subject of their own free will to continue participating in the study.
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 form, 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, 
 


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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.
During the COVID-19 pandemic or any pandemic/state of emergency, remote monitoring 
of data may be employed if allowed by the local regulatory authority, IRB/IEC, and the 
study site.
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 
 


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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 study 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 
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
●
WPAI
●
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
 


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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.
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.
 


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11.0
Data Quality Assurance
Prior to the initiation of the study, a meeting may be held with AbbVie personnel, the 
investigators and appropriate site personnel.  This meeting may include a detailed 
discussion of the protocol, performance of study procedures, CRF, subject dosing diary, 
and specimen collection methods.  Another alternative of site training may include 
module training via a study portal.  
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.
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.
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 Appendix D and Appendix F).  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 Appendix D and Appendix F).  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 
 


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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.  Exploratory research/validation studies information will be 
published or presented only in a way that does not identify any individual subject.
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 (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the Investigator (Director of the Site in Japan) 
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 (Director of the Site in Japan) must retain any records related to the study 
according to local requirements.  If the Investigator (Director of the Site in Japan) 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.
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 Study Comparing 
Upadacitinib (ABT-494) Once Daily Monotherapy to MTX 
Monotherapy in MTX-Naïve Subjects with Moderately to Severely 
Active Rheumatoid Arthritis
Protocol Date:
03 December 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
1.
Grigor C, Capell H, Stirling A, et al.  Effect of treatment strategy of tight control 
for rheumatoid arthritis (the TICORA study):  a single-blind randomised controlled 
trial.  Lancet.  2004;364(9430):263-9.
2.
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 
cohort.  Arthritis Res Ther.  2012;14(6):R254.
3.
Verstappen SM, Jacobs JW, van der Veen MJ, et al.  Intensive treatment with 
methotrexate in early rheumatoid arthritis:  aiming for remission.  Computer 
Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label 
strategy trial).  Ann Rheum Dis.  2007;66:1143-9.
4.
Aletaha D, Neogi T, Silman AJ, et al.  2010 rheumatoid arthritis classification 
criteria:  an American College of Rheumatology/European League Against 
Rheumatism collaborative initiative.  Ann Rheum Dis.  2010;69(9):1580-8.
5.
Burmester GR, Feist E, and Dorner T.  Emerging cells and cytokine targets in 
rheumatoid arthritis.  Nat Rev Rheumatol.  2014;10(2):77-88.
6.
Emery P.  Why is there persistent disease despite biological therapy?  Importance 
and early intervention.  Arthritis Res Ther.  2014;16(3):115.
7.
Meier FM, McInnes IB.  Small-molecule therapeutics in rheumatoid arthritis:  
scientific rationale, efficacy and safety.  Best Pract Res Clin Rheumatol.  
2014;28(4):605-24.
8.
Vaddi K, Luchi M.  JAK inhibition for the treatment of rheumatoid arthritis:  a new 
era in oral DMARD therapy.  Expert Opin Investig Drugs.  2012;21(7):961-73.
9.
Murray PJ.  The Jak-STAT signaling pathway:  input and output integration.  J 
Immunol.  2007;178(5):2623-9.
10.
Xeljanz® (tofacitinib) [package insert] New York, NY; Pfizer Labs, 2015.
 


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11.
Nawendy N, Krishnaswai 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 
Pharmacol. 2009;49(4):423-9.
12.
Greenwald MK, Fidelus-Gort R, Levy R, et al.  A randomized dose-ranging, 
placebo-controlled study of INCB028050, a selective JAK1 and JAK2 inhibitor in 
subjects with active rheumatoid arthritis [abstract].  Arthritis Rheum.  
2010;62 (Suppl 10):2172.
13.
Dougados M, van der Heijde D, Chen YC, et al.  Baricitinib, an oral janus kinase 
(JAK)1/JAK2 inhibitor, in patients with active rheumatoid arthritis (RA) and an 
inadequate response to CDMARD therapy:  results of the phase 3 RA-build study.  
Ann Rheum Dis.  2015;74 (Suppl 2):79.
14.
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.  
Ann Rheum Dis.  2015;74 (Suppl 2):75.
15.
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.
16.
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 Z-G, Hall S, et al.  Tofacitinib in combination with nonbiologic 
disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis.  
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.
 


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
Good Clinical Practices (GCP) and local regulations and guidelines governing the study at 
the site location.  In signing the Investigator Agreement 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.
 


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8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
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
Executive Medical Director
Immunology Clinical Development
Medical Director
Therapeutic Area
Senior Medical Director
Pharmacovigilance and Patient Safety
Director, Statistics
Statistics
Senior Director, Immunology 
Therapeutic Area Head
Statistics
 
Assistant Director, Clinical 
Pharmacology
Clinical Pharmacokinetics and 
Pharmacodynamics
Study Project Manager
Clinical Program Development 
 


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Appendix C.
Local Requirements
Canada
Section 5.2.1 Inclusion Criteria
10.
If female of childbearing potential, subject must be practicing two forms of 
contraception (one highly effective method combined with one effective method, 
refer to Contraception Recommendations for Females below) that are effective 
from Study Day 1 through at least 180 days after the last dose of study drug.
11.
Male subjects who are sexually active with female partner(s) of childbearing 
potential must agree from Study Day 1 through 180 days after the last dose of study 
drug to practice the protocol-specified contraception (refer to Contraception 
Recommendations for Males below).
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.  
 


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●
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.
●
Female subjects who are surgically 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 use two forms of 
contraception.  This includes one form of highly effective contraception and one effective 
method of contraception that are effective from Study Day 1 (or earlier) through at least 
180 days after the last dose of study drug.
●
Highly effective methods:
○
Hormonal contraceptives started at least 2 months prior to randomization 
(e.g., combined [estrogen and progestogen containing] oral contraceptives, 
patch, vaginal ring, injectables, and implants);
○
Intrauterine device (IUD) or intrauterine system (IUS);
○
Vasectomy and tubal ligation.
●
Effective methods: 
○
Barrier methods of contraception (e.g., male condom, female condom, 
cervical cap, diaphragm, contraceptive sponge).
 


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○
Note:  The proper use of diaphragm or cervical cap includes use of 
spermicide and is considered one barrier method.  The cervical cap and 
contraceptive sponge are less effective in parous women.  The use of 
spermicide alone is not considered a suitable barrier method for 
contraception.  When used consistently and correctly, "double barrier"
methods of contraception (e.g., male condom with diaphragm, male 
condom with cervical cap) can be used as an effective alternative to the 
highly effective contraception methods described above.  Male and female 
condoms should not be used together as they can tear of become damaged.
Contraception Recommendation for Males
There are no contraception requirements for male subjects receiving upadacitinib only, or 
their female partner(s).  
For a male subject receiving MTX who has a female partner who is postmenopausal or 
permanently sterile, no contraception is required.
A male subject receiving MTX who is sexually active with female partner(s) of 
childbearing potential must agree from Study Day 1 through 180 days after the last dose 
of MTX study drug to practice contraception with:
●
Condom use and female partner(s) using at least one of the highly effective 
contraceptive methods as defined in the protocol for female study subjects of 
childbearing potential.
Additionally, male subjects receiving MTX must agree not to donate sperm from Study 
Day 1 through 180 days after the last dose of MTX study drug. 
Male subjects receiving MTX are responsible for informing his partner(s) of the risk of 
becoming pregnant and for reporting any pregnancy to the study doctor.  
Colombia
Section 5.2.1 Inclusion Criteria
 


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10.
If female of childbearing potential, subject must be practicing two forms of 
contraception (one highly effective method combined with one effective method, 
refer to Contraception Recommendations for Females below) that are effective 
from Study Day 1 through at least 180 days after the last dose of study drug.
11.
Male subjects who are sexually active with female partner(s) of childbearing 
potential must agree from Study Day 1 through 180 days after the last dose of 
study drug to practice the protocol-specified contraception (refer to Contraception 
Recommendations for Males below).
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.
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 180 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.
 


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●
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 sole sexual partner of 
the women of childbearing potential trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
A second form of contraception (barrier) such as a 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.
Contraception Recommendation for Males
There are no contraception requirements for male subjects receiving upadacitinib only, or 
their female partner(s).  
For a male subject receiving MTX who has a female partner who is postmenopausal or 
permanently sterile, no contraception is required.
A male subject receiving MTX who is sexually active with female partner(s) of 
childbearing potential must agree from Study Day 1 through 180 days after the last dose 
of MTX 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 receiving MTX must agree not to donate sperm from Study 
Day 1 through 180 days after the last dose of MTX study drug.
 


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Male subjects receiving MTX are responsible for informing his partner(s) of the risk of 
becoming pregnant and for reporting any pregnancy to the study doctor.  
 


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Appendix D.
Study Activities (Period 1)
Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
26
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 48/
PDa
30-Day 
F/U 
Visitc
D –35 to 
D –1
D1b
D15
D29
D57
D85
D113
D141
D169
D183
D197
D225
D253
D281
D337
Informed consentd
X
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
X
X
X
X
X
X
X
X
Prior/concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xg
X
Patient questionnairesh
PtGA
Pain (VAS) 
HAQ-DI 
Morning Stiffness 
(severity and duration)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient questionnairesh
EQ-5D-5L 
FACIT-F 
WPAI 
SF-36
X
X
X
X
 


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Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
26
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 48/
PDa
30-Day 
F/U 
Visitc
D –35 to 
D –1
D1b
D15
D29
D57
D85
D113
D141
D169
D183
D197
D225
D253
D281
D337
Latent TB risk assessment 
formi
X
X
Central lab 
QuantiFERON-TB Gold 
testi (and/or local PPD skin 
test)
X
Xi
Chest x-rayj
X
Xj
12-lead ECGk
X
Xk
X-rays (bilateral hands/feet)
Xl
Xm
Xm
Height (screening only) and 
weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examo
X
X
X
Physician Global 
Assessment (PhGA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TJC68/SJC66
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test at 
central labp
X
Local urine pregnancy testq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central Lab Tests 
hsCRPr
Blood chemistrys
Hematology (CBC) 
Urinalysist
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
26
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 48/
PDa
30-Day 
F/U 
Visitc
D –35 to 
D –1
D1b
D15
D29
D57
D85
D113
D141
D169
D183
D197
D225
D253
D281
D337
ESR (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Central Lab Tests 
Rheumatoid factor 
Anti-CCP 
autoantibodies 
HBV/HCV screening
X
HIV local lab (if required)u
Xu
VZV skin testv and VZV 
specific IgGw
X
IgG and IgM (central lab)
X
X
X
X
Blood samples for 
upadacitinib PK assay
Xx
Xx
Xy
Xy
Xy
Xy
Xy
Xy
Xy
Xy
Blood samples for 
exploratory research and 
validation studies (optional 
– see Appendix E)z
X
X
X
X
X
Randomization/Drug 
assignment
X
Calculation for rescue based 
on TJC/SJC
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Calculation for drug 
assignment based on 
TJC/SJC and CDAI
Xbb
Dispense study drug and 
subject dosing diary
X
X
X
X
X
X
X
X
X
X
X
X
Xcc
 


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Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
26
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 48/
PDa
30-Day 
F/U 
Visitc
D –35 to 
D –1
D1b
D15
D29
D57
D85
D113
D141
D169
D183
D197
D225
D253
D281
D337
Review and copy subject 
dosing diary and perform 
drug reconciliation
X
X
X
X
X
X
X
X
X
X
X
X
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; SF-36 = 36-Item Short Form Health Survey; SJC = Swollen Joint Count; 
TB = tuberculosis; TJC = Tender Joint Count; VAS = visual analog scale; VZV = varicella zoster virus; Wk = Week; WPAI = Work Productivity and Activity Impairment
a.
Subjects may withdraw from the study completely (withdrawal of informed consent) or may discontinue study drug treatment, but may choose to continue to participate in the 
study (refer to Section 5.4.1 for additional details).  If a subject is prematurely discontinued from study drug, 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 and x-rays of hands and feet, which will be obtained at 
Screening only and used as the baseline reference (see also footnote l regarding x-rays of the hands and feet at Screening).
c.
This visit is 30 days after last dose of study drug for those subjects who prematurely discontinue from study drug and study participation.  A 30-day follow-up phone call may 
occur for subjects who prematurely discontinued from study drug and study participation 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.
Also 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.
At Week 48 (after Week 48 assessments have been performed), per Investigator judgment, may add csDMARDs (concomitant use of up to 2 csDMARDs, except the 
combination of MTX and leflunomide), or increasing csDMARD dose.
h.
Prior to other procedures.  For morning stiffness, duration will be captured only if NRS rating is > 0.
i.
Refer to Section 5.3.1.1 Study Procedures TB Testing for specific requirements for TB testing and TB prophylaxis.  QuantiFERON-TB Gold test (and/or PPD skin test) is not 
required at the PD visit.
 


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j.
The screening 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).  At Week 48, obtain chest x-ray for subjects with TB risk factors as identified by the TB risk 
assessment form or for subjects living in areas endemic for TB or for subjects with a newly positive QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.  A 
chest x-ray is not required at the PD visit.
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.  All subjects will have an ECG at Week 48 and PD visit as applicable.
l.
X-rays of hands and feet must be performed during the screening process.  Subjects are eligible for the study if the locally read screening x-rays confirms the presence of 
≥1 bone erosion OR in the absence of the documented bone erosion, both positive RF and positive anti-CCP autoantibodies are required.  Screening x-rays will serve as 
baseline x-rays for scoring purposes.  Refer to Section 5.3.1.1 Study Procedures X-Rays of Hands and Feet for additional details.
m.
For handling of x-rays during the study, please refer to Section 5.3.1.1.
n.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.
o.
A full physical exam is required at the visits indicated.  A symptom-directed physical exam may be performed when necessary.
p.
For all women of childbearing potential, collect serum for pregnancy test at screening.  If serum pregnancy test comes back borderline, a repeat test is necessary (pregnancy is 
an exclusion criterion).  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
q.
For all women of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits.  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 permanently discontinue 
study drug.  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
r.
Central lab hsCRP results will remain blinded to the Sponsor, Investigator, study site personnel, and subject for all visits except Screening.  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 treatment allocation is unblinded.
s.
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.
t.
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.
u.
If required by country regulatory authorities to confirm eligibility, subjects will be tested for antibodies to HIV at Screening, and it should be documented that the test has 
been performed.  This testing is to be done at a local lab.  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.
v.
For subjects in Japan only, VZV skin test will be performed locally at Screening.
w.
For subjects in Japan only, VZV specific IgG will be measured centrally at Screening.
 


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x.
At Week 2 and Week 4 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.
y.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.
z.
Samples only collected if subject provides written consent.
aa.
Rescue therapy is clearly outlined for subjects who meet the criteria described in Section 5.2.3.3.
bb. Rescue therapy for those subjects who meet the following criteria at Week 26 is described in Section 5.2.3.3.
cc.
For subjects entering Period 2.
Note:
Visit window is ± 3 days for the first 32 weeks and ± 7 days for the remainder of Period 1.  Any of the procedures may be performed at an unscheduled visit at 
the discretion of the Investigator.  Subjects who choose to discontinue study drug treatment, but continue to participate in the study, should complete a 
Premature Discontinuation Visit (PD Visit) as soon as possible, preferably within 2 weeks.  Refer to Section 5.1 Discontinuation of Study Drug and 
Continuation of Study Participation (Period 1 and Period 2) for additional details.
 


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Appendix E.
Study Activities – Optional Samples for Exploratory Research and Validation Studies (Period 1 Only)
Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
26
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
48/PD
D –35 to 
D –1
D1
D15
D29
D57
D85
D113
D141
D169
D183
D197
D225
D253 
D281
D337
Pharmacogenetic samplesa,b
--
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Epigenetic samplesb
--
X
X
--
X
--
--
--
X
--
--
--
--
--
X
Transcriptomic and epigenetic samplesb
--
X
X
--
X
--
--
--
X
--
--
--
--
--
X
Plasma samples for proteomic and 
targeted protein investigationsb
--
X
X
--
X
--
--
--
X
--
--
--
--
--
X
Serum samples for proteomic and targeted 
protein investigationsb
--
X
X
--
X
--
--
--
X
--
--
--
--
--
X
BL = Baseline Visit; D = Day; 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.  Samples may be used for assay of study drugs if needed.
Note:
Collections to be performed only if subject provides separate written consent to collect the exploratory research/validation studies samples; if the separate 
consent is not signed, no samples can be collected.  The separate written consent may be part of the main consent form.
 


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Appendix F.
Study Activities (Period 2)
Activity
Wk 
60
Wk 
72
Wk 
84
Wk 
96
Every 
12 Weeksa
Monthly
Every 
24 Weeksa
Every 
48 Weeksa
Wk 
192
Final 
(Wk 260)/
PD Visito
30-Day 
F/U 
Visitb
Adverse event assessment
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
Patient questionnairesc
PtGA
Pain (VAS)
HAQ-DI
Morning stiffness (severity 
and duration)
X
X
X
X
X
X
Latent TB risk assessment formd
Xd
Xd
Central lab QuantiFERON-TB 
Gold testd (and/or local PPD skin 
test)
Xd
Xd
Chest x-raye
Xe
Xe
12-lead ECGf
Xf
Xf
X
X-rays (bilateral hands/feet)
X
X
Xg
Vital signs and body weighth
X
X
X
X
X
X
X
Physical exami
X
X
Xi
X
Physician Global Assessment 
(PhGA)
X
X
X
X
X
X
TJC68/SJC66
X
X
X
X
X
X
Local urine pregnancy testj
X
X
X
X
X
X
X
 


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Activity
Wk 
60
Wk 
72
Wk 
84
Wk 
96
Every 
12 Weeksa
Monthly
Every 
24 Weeksa
Every 
48 Weeksa
Wk 
192
Final 
(Wk 260)/
PD Visito
30-Day 
F/U 
Visitb
At-home urine pregnancy testj
X
Central lab tests
hsCRPk
Blood chemistryl
Hematology (CBC)
Urinalysism
X
X
X
X
X
X
X
ESR (local lab)
X
X
X
X
X
X
Calculation for drug assignment 
based on TJC/SJC and CDAI
Xn
Xn
Xn
Xn
Xn
Dispense study drug and subject 
dosing diary
X
X
X
X
X
Review and copy subject dosing 
diary and perform drug 
reconciliation
X
X
X
X
X
X
CBC = complete blood count; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; F/U = Follow-up; HAQ-DI = Health Assessment Questionnaire – Disability Index; 
hsCRP = high-sensitivity C-reactive protein; PD = Premature Discontinuation; PhGA = Physician's Global Disease Activity; PPD = purified protein derivative; PtGA = Patient's 
Global Assessment of Disease Activity; SJC = Swollen Joint Count; TB = tuberculosis; TJC = Tender Joint Count; VAS = visual analog scale; Wk = Week
a.
Every 12, 24, or 48 weeks, from the Week 96 Visit through Week 240.
b.
This visit is 30 days after last dose of study drug for those subjects who complete Period 2.  A 30-day follow-up phone call may occur for subjects who prematurely 
discontinue from study drug and study participation to determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.
c.
Prior to other procedures.  For morning stiffness, duration will be captured only if NRS rating is > 0.
d.
TB testing should be performed every 48 weeks after Week 96 in subjects with previous negative QuantiFERON-TB Gold 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.  Study drug(s) 
should not be withheld at the time of the first positive TB test.
 


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e.
Obtain chest x-ray every 48 weeks after Week 96 for subjects with TB risk factors as identified by the TB risk assessment form, or for subjects living in areas endemic for TB, 
or for subjects with a newly positive QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.
f.
ECGs will be performed every 48 weeks after Week 96.  An ECG may be performed at any visit if deemed necessary by the Investigator.
g.
Subjects who prematurely discontinue from Period 2 will undergo an x-ray of hands and feet unless the previous x-ray was performed within the previous 24 weeks.
h.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.
i.
A full physical exam is required every 24 weeks after Week 96.  A symptom-directed physical exam may be performed when necessary.
j.
For women of childbearing potential, a urine pregnancy test will be performed at all visits and 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 study drug treatment.  Refer to Section 5.3.1.1 Study Procedures 
Pregnancy Test for additional details.
k.
hsCRP results will remain blinded to Sponsor, Investigator, study site personnel, and the subject for all visits until the last subject reaches the end of Period 1.
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.
n.
Starting at Week 48, subjects who fail to show at least 20% improvement in both TJC and SJC compared to baseline at 2 consecutive visits, despite optimization of 
background RA therapies, will be discontinued from study drug.  Refer to Section 5.1.
o.
Subjects may withdraw from the study completely (withdrawal of informed consent) or may discontinue study drug treatment, but may choose to continue to participate in the 
study (refer to Section 5.4.1 for additional details).  
Note:
Visit window is ± 7 days for Period 2.  Any of the procedures may be performed at an unscheduled visit at the discretion of the Investigator.  Subjects who 
choose to discontinue study drug treatment, but continue to participate in the study, should complete a Premature Discontinuation Visit (PD Visit) as soon as 
possible, preferably within 2 weeks.  Refer to Section 5.1 Discontinuation of Study Drug and Continuation of Study Participation (Period 1 and Period 2) for 
additional details.
 


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Appendix G.
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.  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 I.
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:
●
Sub-Saharan Africa
●
India
●
China
●
Mexico
●
Southeast Asia or Micronesia
●
The former Soviet Union
3.
Have you lived or worked in a prison, homeless shelter, immigration center, 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
●
Production of Sputum
●
Blood-Streaked Sputum
●
Unexplained Weight Loss
●
Fever
●
Fatigue/Tiredness
●
Night Sweats
●
Shortness of Breath
From:  http://www mayoclinic.com/health/tuberculosis/DS00372/DSECTION=risk-factors
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf
 


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Appendix J.
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 K.
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 L.
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 M.
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 N.
EuroQoL-5D 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 O.
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.
 
 
 
 
 
 
 
 
 
 
 
 
                  
 
 
 
  
 
 
 
 
 
 
 
 
                         
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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Appendix P.
Work Productivity and Activity Impairment Questionnaire:  
Specific Health Problem (WPAI:SHP) Questionnaire Example
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem V2.0 (WPAI:SHP)
The following questions ask about the effect of your PROBLEM on your ability to work 
and perform regular activities.  Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? _____ NO ___ YES
If NO, check "NO" and skip to question 6.
The next questions are about the past 7 days, not including today.
2.
During the past 7 days, how many hours did you miss from work because of 
problems associated with your PROBLEM?  Include hours you missed on sick days, 
times you went in late, left early, etc., because of your PROBLEM.  Do not include 
time you missed to participate in this study.
_____ HOURS
3.
During the past 7 days, how many hours did you miss from work because of any 
other reason, such as vacation, holidays, time off to participate in this study?
_____ HOURS
4.
During the past 7 days, how many hours did you actually work?
_____ HOURS (If "0," skip to question 6.)
 


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5.
During the past seven days, how much did your PROBLEM affect your 
productivity while you were working?  
Think about days you were limited in the amount or kind of work you could do, 
days you accomplished less than you would like, or days you could not do your 
work as carefully as usual.  If PROBLEM affected your work only a little, choose a 
low number.  Choose a high number if PROBLEM affected your work a great deal.  
Consider only how much PROBLEM affected productivity while you were working.
PROBLEM 
had no 
effect on 
my work
PROBLEM 
completely 
prevented 
me from 
working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
6.
During the past 7 days, how much did your PROBLEM affect your ability to do 
your regular daily activities, other than work at a job?  
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If PROBLEM affected your activities only a little, choose 
a low number.  Choose a high number if PROBLEM affected your activities a great 
deal.  
Consider only how much PROBLEM affected your ability to do your regular daily 
activities, other than work at a job.
 


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PROBLEM 
had no 
effect on 
my daily 
activities
PROBLEM 
completely 
prevented 
me from 
doing my 
daily 
activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER
WPAI:SHP V2.0 (US English) 
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment 
measure.  PharmacoEconomics 1993; 4(5):353-365.
 


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Appendix Q.
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 R.
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 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
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, 
arrhythmia 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 
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
 


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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, 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
 


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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
 


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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
 


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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 = haemglobin; 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.
 

SAP_003.pdf: 
Upadacitinib
M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
1
1.0
Title Page
Statistical Analysis Plan
Study M13-545
A Phase 3, Randomized, Double-Blind Study 
Comparing Upadacitinib Once Daily Monotherapy to 
Methotrexate (MTX) Monotherapy in MTX-Naïve 
Subjects with Moderately to Severely Active 
Rheumatoid Arthritis
Date:  11 September 2020
Version 3.0
NCT02706873


Upadacitinib
M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
2
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..................................................................8
4.3
Sample Size..............................................................................................17
4.4
Interim Analysis and Date Base Lock......................................................18
4.5
Data Monitoring Committee (DMC) Activities.......................................18
5.0
Analysis Populations and Analysis Windows .....................19
5.1
Analysis Populations................................................................................19
5.2
Analysis Windows ...................................................................................20
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............22
6.1
Demographics and Baseline Characteristics............................................22
6.2
Medical History .......................................................................................26
6.3
Prior Treatment and Concomitant Medications.......................................26
6.4
Protocol Deviations..................................................................................27
7.0
Patient Disposition.................................................................27
8.0
Study Drug Exposure and Compliance...............................30
8.1
Study Drug Exposure...............................................................................30
8.2
Compliance ..............................................................................................33
9.0
Efficacy Analysis....................................................................33
9.1
General Considerations............................................................................33
9.1.1
Definition of Missing Data Imputation....................................................36
9.2
Efficacy Analysis for the Primary and Key Secondary Endpoints..........38
9.2.1
Primary Efficacy Analysis .......................................................................38
9.2.1.1
Analysis for ACR20, ACR50 and CR .....................................................38
9.2.1.2
Analysis for Change from Baseline in mTSS at Week 24.......................39
9.2.2
Sensitivity Analysis of Primary Efficacy Variables ................................40
9.2.3
Key Secondary Efficacy Analyses...........................................................40


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M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
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9.2.4
Handling of Multiplicity ..........................................................................43
9.2.5
Efficacy Subgroup Analysis ....................................................................46
9.2.6
Summary of Efficacy Analysis for the Primary and Key 
Secondary Endpoints ...............................................................................47
9.3
Additional Efficacy Analyses for Period 1 ..............................................52
9.3.1
Analysis of non-mTSS-Related Endpoints for Period 1..........................52
9.3.2
Analysis of Additional mTSS-Related Endpoints for Period 1 ...............53
9.3.3
Summary of Additional Efficacy Analysis for Period 1..........................55
9.4
Long Term Efficacy Analysis..................................................................57
9.5
Efficacy Variables Definitions and Conventions.....................................60
9.5.1
ACR Criteria ............................................................................................60
9.5.2
Joint Evaluation .......................................................................................63
9.5.3
Patient's Global Assessment of Disease Activity Visual Analog 
Scale (VAS) .............................................................................................64
9.5.4
Physician's Global Assessment of Disease Activity Visual Analog 
Scale (VAS) .............................................................................................64
9.5.5
Patient's Global Assessment of Pain........................................................64
9.5.6
Disease Activity Score (DAS28) .............................................................64
9.5.7
Simplified Disease Activity Index (SDAI) ..............................................65
9.5.8
Clinical Disease Activity Index (CDAI)..................................................66
9.5.9
Clinical Remission (CR) and Low Disease Activity (LDA)....................66
9.5.10
ACR/EULAR Boolean Remission...........................................................67
9.5.11
Disability Index of Health Assessment Questionnaire (HAQ-DI)...........67
9.5.12
Modified Total Sharp Score (mTSS) .......................................................68
9.5.13
Form SF-36v2 ..........................................................................................71
9.5.14
EuroQoL-5D (EQ-5D-5L) .......................................................................71
9.5.15
Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F)................................................................................................72
9.5.16
Work Productivity and Activity Impairment (WPAI) .............................72
10.0
Safety Analysis.......................................................................73
10.1
General Considerations............................................................................73
10.1.1
Safety Analysis Prior to Protocol-Defined Treatment Switching at 
Week 26 ...................................................................................................73


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M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
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10.1.2
Long Term Safety Analysis .....................................................................73
10.2
Analysis of Adverse Events.....................................................................75
10.2.1
Analysis of Adverse Events Prior to Protocol-Defined Treatment 
Switching at Week 26 ..............................................................................75
10.2.1.1
Adverse Events Overview........................................................................75
10.2.1.2
Adverse Events by System Organ Class and Preferred Term..................76
10.2.1.3
TEAEs by Maximum Severity.................................................................77
10.2.1.4
TEAEs by Maximum Relationship..........................................................77
10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and Preferred 
Term.........................................................................................................78
10.2.1.6
Adverse Events of Special Interest ..........................................................78
10.2.2
Analysis of Long Term Adverse Event Rates..........................................80
10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................81
10.2.2.2
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................82
10.2.2.3
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................83
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation ........................84
10.3
Analysis of Laboratory Data....................................................................84
10.3.1
Variables and Units..................................................................................84
10.3.2
Analysis of Laboratory Data Prior to Protocol-Defined Treatment 
Switching at Week 26 ..............................................................................86
10.3.2.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables................................................................................86
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................86
10.3.2.3
Assessment of Potentially Clinical Significant Laboratory 
Variables ..................................................................................................87
10.3.2.4
Assessment of Liver Elevations...............................................................87
10.3.3
Analysis of Long Term Laboratory Data.................................................88
10.3.3.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables................................................................................88


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10.3.3.2
Assessment of Potentially Clinical Significant Laboratory Values .........89
10.3.3.3
Assessment of Liver Elevations...............................................................90
10.4
Analysis of Vital Signs ............................................................................91
10.4.1
Variables and Criteria Defining Abnormality..........................................91
10.4.2
Analysis of Vital Sign Prior to Protocol-Defined Treatment 
Switching at Week 26 ..............................................................................91
10.4.3
Analysis of Long Term Vital Sign...........................................................91
11.0
Summary of Changes ............................................................93
11.1
Summary of Changes between the Previous Version and the 
Current Version........................................................................................93
12.0
Version History......................................................................94
13.0
Appendices .............................................................................94
14.0
Reference..............................................................................108
List of Tables
Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ACR 
Components and Morning Stiffness) and Safety Analysis for 
Period 1 (for Labs and Vital Signs) .........................................................21
Table 2.
Analysis Windows for Efficacy Analysis for Period 1 (for 
EQ-5D-5L, FACIT-F, WPAI and SF-36)................................................21
Table 3.
Analysis Windows for Efficacy Analysis for Period 1 (for mTSS 
Endpoints)................................................................................................22
Table 4.
Analysis Windows for Efficacy Analysis for Period 1 (for IgG 
and IgM)...................................................................................................22
Table 5.
Subgroups for Efficacy Analysis .............................................................47
Table 6.
Summary of Efficacy Analyses for the Primary and Key 
Secondary Endpoints at Week 12 ............................................................48
Table 7.
Summary of Efficacy Analyses for the Primary and Key 
Secondary Endpoints at Week 24 ............................................................50
Table 8.
Summary of Efficacy Variables and Corresponding Analyses for 
Additional Efficacy Analysis for Period 1 (By Randomized 
Treatment Group).....................................................................................56
Table 9.
Summary of Efficacy Variables and Corresponding Analyses for 
Long Term Efficacy Analysis (By Treatment Group Sequence).............59


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M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
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Table 10.
Anatomical Joints Assessed for Calculation of Tender and 
Swollen Joint Counts (TJC68 and SJC66)...............................................63
Table 11.
Anatomical Joints for DAS28(CRP) Calculation ....................................65
Table 12.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................79
Table 13.
List of Laboratory Variables....................................................................84
Table 14.
Criteria for Potentially Clinically Significant Vital Sign Findings..........91
Table 15.
SAP Version History Summary...............................................................94
List of Figures
Figure 1.
Period 1 Study Design .............................................................................13
Figure 2.
Period 2 Study Design .............................................................................14
Figure 3.
Graphical Multiple Testing Procedure for US/FDA Regulatory 
Purposes ...................................................................................................44
Figure 4.
Graphical Multiple Testing Procedure for EU/EMA Regulatory 
Purposes ...................................................................................................45
Figure 5.
Graphical Multiple Testing Procedure for Japan/PMDA 
Regulatory Purposes ................................................................................46
List of Appendices
Appendix A.
OMERACT Criteria.................................................................................95
Appendix B.
Statistical Analysis to Account for Impact of COVID-19 
Pandemic................................................................................................106


Upadacitinib
M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
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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 M13-545.  It provides 
details to further elaborate statistical methods as outlined in the protocol. 
This SAP will describe the global analysis for US/FDA, EU/EMA and Japan/PMDA 
submission purposes, and also includes the analysis for the Japan sub-study which 
includes Upadacitinib 7.5 mg treatment group and Japan specific endpoints. 
Pharmacokinetic and exploratory 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
To compare the safety and efficacy of Upadacitinib 7.5 mg once daily (QD) monotherapy 
(for subjects in Japan only), 15 mg QD monotherapy, and 30 mg QD monotherapy versus 
weekly methotrexate (MTX) monotherapy for the treatment of signs and symptoms of 
rheumatoid arthritis (RA) in MTX-naïve subjects with moderately to severely active RA.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of Upadacitinib 7.5 mg QD 
(for subjects in Japan only), 15 mg QD, and 30 mg QD in subjects with RA who have 
completed Period 1.


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M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
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4.2
Overall Study Design and Plan
This is a Phase 3 multicenter study that includes two periods and a Japan sub-study.  
Period 1 is a 48-week randomized, double-blind, parallel-group, active comparator 
controlled treatment period designed to compare the safety and efficacy of Upadacitinib 
7.5 mg QD monotherapy (for subjects in Japan only), 15 mg QD monotherapy, and 30 mg 
QD monotherapy versus MTX monotherapy in adult MTX-naïve subjects with 
moderately to severely active RA.  Period 1 is also designed to compare the efficacy of 
Upadacitinib 15 mg QD monotherapy and 30 mg QD monotherapy versus MTX 
monotherapy for the prevention of structural progression.  Period 2 is a long-term 
extension to evaluate the long-term safety, tolerability, and efficacy of Upadacitinib (7.5, 
15, or 30 mg QD) in subjects with RA who have completed Period 1. Starting with 
Amendment 5.01.01, subjects in Japan receiving upadacitinib 30 mg QD will be switched 
to upadacitinib 15 mg QD. For other countries, starting with Amendment 6, subjects 
receiving upadacitinib 15 mg and 30 mg QD will receive open label upadacitinib 15 mg 
QD and subjects receiving MTX will receive open label MTX.
The study is designed to enroll approximately 975 subjects at approximately 330 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 may not be enrolled.
The study duration includes a 35-day screening period, a 48-week randomized, double-
blind, parallel-group, active-comparator controlled treatment period (Period 1); a 
212 week long-term extension period (blinded until the last subject completes the last visit 
of Period 1) (Period 2); and a 30-day follow-up (call or site visit).
Subjects will be randomized in a 1:1:1 ratio to treatment Groups 2, 3 and 4 below, except 
for subjects from Japan, who will be randomized in a 2:1:1:1 ratio to Groups 1, 2, 3 and 4:
●
Group 1:  Upadacitinib 7.5 mg QD monotherapy (subjects in Japan only; 
N = 75)


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M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
9
●
Group 2:  Upadacitinib 15 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 3:  Upadacitinib 30 mg QD monotherapy (N = 300) (includes 
37 subjects from Japan)
●
Group 4:  MTX monotherapy (N = 300) (includes 37 subjects from Japan)
Randomization is stratified by geographic region.
Subjects who are assigned to upadacitinib 7.5 mg QD, 15 mg QD, or 30 mg QD will start 
on their respective upadacitinib dose at Baseline.  Subjects who are assigned to the MTX 
treatment group will start oral MTX treatment at 10 mg/week and will be titrated up to 
20 mg/week (increase by 5 mg every 4 weeks), as tolerated, by Week 8 (minimum 
15 mg/week final dose required, with documentation of intolerance of > 15 mg/week).  
(For subjects in China and Japan:  start at 7.5 mg/week with titration up to 10 mg/week at 
Week 4 and to 15 mg/week, as tolerated, by Week 8; minimum of 7.5 mg/week for final 
dose is required, with documentation of intolerance of > 7.5 mg/week).  After completion 
of MTX (or placebo) titration, a single dose reduction of study drug (by 5 mg of MTX) is 
allowed for safety reasons, up to Week 26, as long as the subject remains on 
≥15 mg/week of MTX (or matching placebo) weekly (for subjects in China and Japan:  
≥7.5 mg/week).  In addition, all subjects should take a dietary supplement of oral folic 
acid (or equivalent) throughout study participation.  Folic acid dosing and timing of 
regimen should be followed according to Investigator's discretion.  Rescue therapy has 
been defined for Weeks 12 through 24, Week 26, and Weeks 36 through 40.  Starting at 
the Week 48 Visit (after Week 48 assessments have been performed) and thereafter, 
initiation of or change in background RA medication(s), including corticosteroids, non-
steroidal anti-inflammatory drugs (NSAIDs), acetaminophen/paracetamol, and 
csDMARDs (concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide) is allowed as per local label.
Rescue therapy for those subjects who meet the following criteria from Week 12 through 
Week 24 are as follows:


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M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
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Starting at Week 12 through Week 24, those who do not achieve ≥ 20% improvement in 
both TJC and SJC compared with baseline at two consecutive visits will continue on their 
blinded therapy and the Investigator should optimize (initiate or increase) background RA 
medications:  NSAIDs, corticosteroids (oral ≤ 10 mg/day prednisone equivalent or 
prednisone equivalent ≤ 0.5 mg/kg/day for 3 consecutive days) and/or low-potency 
analgesics. 
Rescue therapy for those subjects who meet the following criteria at Week 26 are as 
follows:
1.
Subjects who were originally randomized to MTX:
●
Those who do not achieve CR by CDAI: 
○
but achieve ≥ 20% improvement in both TJC and SJC compared with 
baseline will continue on blinded MTX and the Investigator should 
optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 2 local 
injections), low-potency analgesics and csDMARDs (only 1 of the 
following:  sulfasalazine, hydroxychloroquine or chloroquine) throughout 
the remainder of Period 1 and until the study is unblinded.
○
and do not achieve ≥ 20% improvement in both TJC and SJC compared 
with baseline will be re-randomized in a 1:1 ratio to receive blinded 
upadacitinib 15 mg QD or upadacitinib 30 mg QD (for subjects in Japan:  
randomize 1:1:1 to receive upadacitinib 7.5 mg QD, 15 mg QD, or 30 mg 
QD) while continuing MTX treatment in a blinded manner and will remain 
on upadacitinib plus MTX throughout the remainder of Period 1 and until 
the study is unblinded.
●
Those who achieve Clinical Remission (CR) by clinical disease activity index 
(CDAI) (CDAI ≤ 2.8) at Week 26 will continue blinded treatment with MTX 
throughout the remainder of Period 1 and until the study is unblinded (the 
study is unblinded when all subjects have completed Period 1).
2.
Subjects who were originally randomized to Upadacitinib:
●
Those who do not achieve CR by CDAI:


Upadacitinib
M13-545 – Statistical Analysis Plan
Version 3.0 – 11 September 2020
11
○
but achieve ≥ 20% improvement in both TJC and SJC compared with 
baseline will continue on blinded upadacitinib and the Investigator should 
optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent and up to 2 local 
injections), low potency analgesics and csDMARDs (only 1 of the 
following:  sulfasalazine, hydroxychloroquine or chloroquine) throughout 
the remainder of Period 1 and until the study is unblinded. 
○
and do not achieve ≥ 20% improvement in both TJC and SJC compared 
with baseline will add MTX 10 mg/week (7.5 mg for China and Japan) to 
upadacitinib in a blinded manner and will remain on upadacitinib plus 
MTX 10 mg/week (7.5 mg for China and Japan) throughout the remainder 
of Period 1 and until the study is unblinded.
●
Those who achieve Clinical Remission (CR) by CDAI (CDAI ≤ 2.8) at 
Week 26 will continue blinded treatment with upadacitinib throughout the 
remainder of Period 1 and until the study is unblinded (the study is unblinded 
when all subjects have completed Period 1).
Rescue therapy for those subjects who meet the following criteria from Week 36 through 
Week 40 are as follows:
●
Starting at Week 36 through Week 40, those who do not achieve ≥ 20% 
improvement in both TJC and SJC compared with baseline at two consecutive 
visits will continue on their blinded therapy and the Investigator should 
optimize (initiate or increase) background RA medications:  NSAIDs, 
corticosteroids (oral ≤ 10 mg/day prednisone equivalent or prednisone 
equivalent ≤ 0.5 mg/kg/day for 3 consecutive days and up to 2 local 
injections), low-potency analgesics and csDMARDs (only 1 of the following:  
sulfasalazine, hydroxychloroquine or chloroquine).
An unblinded analysis will be conducted after all subjects have completed Week 24 for 
the purpose of regulatory submission.  To maintain integrity of the trial and avoid 
introduction of bias, study sites and subjects will remain blinded for the duration of 


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Period 1.  Additional unblinded analyses may be conducted after the first unblended 
analysis.
Each subject will undergo a maximum of 3 scheduled visits for x-ray examination of 
bilateral hands and feet during Period 1 (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Screening, Week 24, and 
Week 48/Premature Discontinuation.  One additional x-ray examination of bilateral hands 
and feet may be needed depending on the time of premature study drug discontinuation 
for those subjects that continue the study.
Subjects who complete the Week 48 Visit (end of Period 1) will enter the long-term 
extension, Period 2 (212 weeks).  Subjects will continue study treatment per assignment at 
the end of Period 1 in a blinded fashion.  When the last subject completes the last visit of 
Period 1 (Week 48), study drug assignment in both periods may be unblinded to the 
Sponsor and sites, and subjects would then be dispensed study drug in an open-label 
fashion until the completion of Period 2.  All subjects will continue study treatment to 
which they were assigned at the time of study unblinding.  Dose changes of open-label 
study drugs are not permitted during unblinded Period 2.  Background therapies may be 
adjusted as per the discretion of the investigator.
Each subject will undergo a maximum of 3 scheduled visits for x-ray examination of 
bilateral hands and feet during Period 2 (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Week 96, Week 192, and Week 260.  
Subjects who prematurely discontinue from Period 2 will undergo an x-ray of hands and 
feet unless the previous x-ray was performed within the previous 24 weeks.
Study design schematics of Period 1 and Period 2 are shown in Figure 1 and Figure 2, 
respectively.


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Figure 1.
Period 1 Study Design
MTX = methotrexate; n = number; QD = once daily; SJC = swollen joint count; TJC = tender joint count; W = week
*
Evaluation for inadequate responders to determine need for rescue therapy at Week 26.
†
Evaluation for inadequate responders to determine need for rescue therapy at Weeks 12 – 24 and Weeks 36 – 40.
Note:
The follow-up period is only for subjects who do not enter Period 2.


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Figure 2.
Period 2 Study Design
csDMARD = conventional synthetic disease modifying anti-rheumatic drug; NSAIDs = non-steroidal anti-inflammatory 
drugs; QD = once daily; RA = rheumatoid arthritis; W = week
Note:
Period 2 will remain blinded until the last subject completes Week 48 (Period 1).  Subjects who prematurely 
discontinue from Period 2 will undergo an x-ray of hands and feet unless the previous x-ray was performed 
within the previous 24 weeks.
Starting with Amendment 6, subjects receiving upadacitinib 15 mg and 30 mg QD will receive upadacitinib 
15 mg QD.  Subjects receiving MTX will receive MTX.
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 the protocol.  Lab values can be re-tested once during the 


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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-screenings, AbbVie Therapeutic Area Medical Director approval is required.  
All screening procedures with the possible exceptions noted below will be 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 the protocol 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 (48-Week Randomized, Double-Blind Treatment Period)
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 48 Visit.  At the 
Baseline Visit, subjects who meet all the inclusion criteria and none of the exclusion 
criteria described in the protocol 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 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, and 48.  A ± 3 day window is permitted 
around scheduled study visits until Week 32 and then ± 7 days for the remainder of the 
period.  The last dose of study drug in Period 1 is taken the day prior to the Week 48 
Visit.  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.  


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Period 2 (Blinded Long-Term Extension Period [212 Weeks])
Period 2 will begin at the Week 48 Visit after all assessments have been completed.  
During Period 2, subjects will have a study visit at Weeks 60, 72, 84, 96, every 12 weeks
through Week 240, and Week 260/PD.  A ± 7 day window is permitted around scheduled 
study visits.  Starting at Week 48, subjects who fail to show at least 20% improvement in 
both TJC and SJC compared to baseline at 2 consecutive visits, despite optimization of 
background RA therapies, will be discontinued from study drug.  Therefore, the earliest 
discontinuation would be at Week 60, after completion of all Week 60 study visit 
activities.
Discontinuation of Study Drug and Continuation of Study Participation (Period 1 
and Period 2)
Subjects may discontinue study drug treatment, but may choose to continue to participate 
in the study.  Subjects who prematurely discontinue study drug should complete a 
Premature Discontinuation visit (PD visit) as soon as possible, preferably within 2 weeks.  
To minimize missing data for efficacy and safety assessments, subjects who prematurely 
discontinue study drug treatment should continue to be followed for all regularly 
scheduled visits as outlined in the protocol, unless subjects have decided to discontinue 
study participation entirely (withdrawal of informed consent). Subjects should be advised 
on the continued scientific importance of their data even if they discontinue treatment 
with study drug early. Following discontinuation of study drug, the subject should be 
treated in accordance with the investigator's best clinical judgment irrespective of whether 
the subject decides to continue participation in the study. In addition, all future rescue-
and efficacy-driven discontinuation criteria no longer apply for these subjects.  This 
includes 20% TJC/SJC calculations at Weeks 12 – 24, Weeks 36 – 40 and Week 48 and 
thereafter, as well as CDAI calculation at Week 26, if applicable.  If at any point a subject 
no longer wants to provide assessments (withdrawal of informed consent) following 
discontinuation of study drug, a second PD visit is not required.


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Premature Discontinuation of Study (Withdrawal of Informed Consent) (Period 1 
and Period 2)
Subjects may withdraw from the study completely (withdrawal of informed consent) for 
any reason at any time.  If a subject prematurely discontinues study drug treatment and 
study participation (withdrawal of informed consent) 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 Visit
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 Follow-Up Visit when they have either
●
Completed the last visit of Period 1 (Week 48), but decided not to participate 
in the extension Period 2; OR
●
Completed the last visit of Period 2 (Week 260); OR
●
Prematurely discontinued study drug and/or study participation.  This visit 
may be a telephone call if a site visit is not possible.  Vital signs and laboratory 
test may not be required.  The Follow-Up Visit is not applicable for subjects 
who discontinued study drug and continued study participation and completed 
at least one study visit at least approximately 30 days after last dose.
4.3
Sample Size
The planned sample size of 900 (not including the Japan-specific upadacitinib 7.5 mg QD 
treatment group) provides at least 90% power for a 20% difference in ACR50 response 
rate (assuming a Week 12 MTX ACR50 response rate of 20%).  This sample size also 


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provides at least 90% power for a 16% difference in DAS28 CR response rate (assuming a 
Week 24 MTX CR response rate of 24%), and for a 20% difference in ACR20 response 
rate (assuming a Week 12 MTX ACR20 response rate of 50%).  With this sample size, 
there is approximately 80% power to detect a difference of 0.58 in change from baseline 
in mTSS (assuming a standard deviation of 2.2).  This sample size will also provide at 
least 90% power for other ranked key secondary endpoints including change from 
baseline in DAS28 (CRP), change from baseline in HAQ-DI, ACR70, and SF-36.  The 
above power calculations are all based on a two-sided significance level of 0.025 and 
accounting for a 10% dropout rate.  An additional 75 Japanese subjects will be enrolled 
into the Japan-specific upadacitinib 7.5 mg QD treatment arm for Japan/PMDA regulatory 
purposes.
4.4
Interim Analysis and Date Base Lock
An unblinded analysis will be conducted after all subjects have completed Week 24 for 
the purpose of regulatory submission.  Study sites and subjects will remain blinded for the 
duration of Period 1.  Additional unblinded analysis may be conducted after the Week 24 
unblinded analysis.
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 benefit:
risk of any emerging safety differences.


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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 prior to Week 24 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.
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. 
For all analysis sets, global analyses are performed on the treatment groups of MTX, 
Upadacitinib 15 mg QD, Upadacitinib 30 mg QD, including all subjects enrolled under 
these three treatment groups.  Japan sub-study analyses are performed on the treatment 
groups of MTX, Upadacitinib 7.5 mg QD, Upadacitinib 15 mg QD, Upadacitinib 30 mg 
QD, including only subjects enrolled in Japan.


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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 and Table 3 (depending on the different visit schedules of 
different endpoints).  Visit windows for protocol-specified visits in Period 2 are defined 
similarly. 


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Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ACR 
Components and Morning Stiffness) and Safety Analysis for
Period 1 (for Labs and Vital Signs)
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
99
16
100
113
127
20
128
141
155
24
156
169
176
26
177
183
190
28
191
197
211
32
212
225
239
36
240
253
267
40
268
281
309
48
310
337
379
a.
Day of first dose of study drug.
Table 2.
Analysis Windows for Efficacy Analysis for Period 1 (for
EQ-5D-5L, FACIT-F, WPAI and SF-36)
Protocol Specified Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
12
2
85
127
24
128
169
253
48
254
337
421
a.
Day of first dose of study drug.


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Table 3.
Analysis Windows for Efficacy Analysis for Period 1 (for mTSS 
Endpoints)
Protocol Specified Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
12*
2
85
127
24
128
169
197
36*
198
253
295
48
296
337
379
a.
Day of first dose of study drug.
*
Week 12 and 36 are not protocol specified visits for Xray assessments, but will be used to capture unscheduled or 
PD x-rays.
Table 4.
Analysis Windows for Efficacy Analysis for Period 1 (for IgG and 
IgM)
Protocol Specified Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
8
2
57
113
24
114
169
253
48
254
337
421
a.
Day of first dose of study drug.
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.  


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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)
●
Geographic Region (North America, South/Central America, Western Europe, 
Eastern Europe, Asia-Japan, Asia-Other, Other)
●
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 
●
Duration of RA Diagnosis  
●
Duration of RA Symptoms Categories (< 2 years or ≥ 2 years)
●
Duration of RA Diagnosis Categories (< 6 months or ≥6 months)
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 


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●
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
●
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)


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●
SDAI categories:
○
SDAI > 26 (High Disease Activity)
○
SDAI ≤ 26 
●
Modified Total Sharp Score (mTSS) 
○
Modified Total Sharp Score (mTSS)
○
Erosion score
○
Joint space narrowing score
Patient Reported Outcomes at Baseline
●
Morning stiffness (severity and duration)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
Work Productivity and Activity Impairment Questionnaire (WPAI)
●
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
●
ECG
●
Tuberculin PPD skin test, QuantiFERON TB Gold test
●
Serum pregnancy test
Immunization History
●
BCG immunization
●
Herpes Zoster immunization
●
Hepatitis B immunization


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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.  
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 7 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 + 7 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 or concomitant medication will be tabulated 


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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: 
●
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 and other significant protocol deviations 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), 
●
number of subjects on-going in Period 1 (if applicable)  
●
number of subjects who completed Period 1 study participation, 
●
number of subjects who entered Period 2, 
●
number of subjects who completed overall study (Period 1 and Period 2)  
participation (if applicable).
This summary will be repeated by site.
Premature discontinuation details will be further summarized separately for Period 1 and 
Period 2 as follows. 


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Period 1
The number and percentage of subjects completed Period 1 and prematurely discontinued 
in Period 1 will be summarized separately by study drug and study participation 
completion/discontinuation, with the reasons for discontinuation collected from CRF by 
the following categories:
●
Adverse event (AE)
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy
●
Other.
Study participation completion/discontinuation will be summarized for Period 1 by 
randomized treatment group and by treatment sequence, respectively. 
Study drug completion/discontinuation will be summarized as follows: 
●
By randomized treatment group:  number and percentage of completion by 
Week 26 and by Period 1, number/percentage and primary reason for 
discontinuation by Week 26 and between Week 26 to end of Period 1; 
●
By treatment sequence:  number/percentage and primary reason for 
discontinuation between Week 26 to end of Period 1. Refer to Section 9.1 for 
the definition of treatment sequences.
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. 
For Week 24 reporting, study drug completion/discontinuation will only be summarized 
by randomized treatment group based on the number and percentage of completion by 


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Week 24 and based on the number/percentage and primary reason for discontinuation by 
Week 24.
Period 2
Period 2 patient dispositions and reason for discontinuation will be summarized for 
overall, by treatment group sequences (as defined in Section 9.1), and by treatment 
regimens when entering Period 2 defined as follows: 
1.
MTX 
2.
Upadacitinib 15 mg QD 
3.
Upadacitinib 30 mg QD 
4.
Upadacitinib 15 mg QD + MTX
5.
Upadacitinib 30 mg QD + MTX
For Japan sub-study, there are two additional treatment regimens:  
6.
Upadacitinib 7.5 mg QD 
7.
Upadacitinib 7.5 mg QD + MTX
Among the subjects who entered Period 2 participation (regardless of whether subject 
prematurely discontinued study drug in Period 1), the number and percentage of subjects 
who completed, and who prematurely discontinued study participation in Period 2 will be 
summarized.  Among the subjects who entered Period 2 upon completion of study drug in 
Period 1, the number and percentage of subjects completed, and who prematurely 
discontinued study drug in Period 2 will be summarized.
For subjects who prematurely discontinued study drug or study participation, the primary 
reasons as well as all reasons for discontinuation will be summarized by the following 
categories (as collected in CRF):


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●
Adverse event (AE)
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy
●
Other
Summary of Dose Switch from Upadacitinib 30 mg QD to 15 mg QD
Starting with Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects 
receiving upadacitinib 30 mg QD will be switched to upadacitinib 15 mg QD. The visit at 
which dose switch occurs could be different for each subject. For subjects on upadacitinib 
30 mg QD in Period 2, the number and percentage of subjects switching to upadacitinib 
15 mg QD at each visit 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.
MTX monotherapy
This includes MTX exposure as monotherapy from subjects starting on MTX 
monotherapy censored at time of rescue to upadacitinib + MTX.
2.
Any Upadacitinib 15 mg QD 
This includes Upadacitinib 15 mg QD exposure from subjects starting on 
Upadacitinib 15 mg QD and subjects rescued from MTX to Upadacitinib 15 mg 
QD + MTX.


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3.
Upadacitinib 15 mg QD mono
This includes Upadacitinib 15 mg QD monotherapy exposure from subjects 
starting on Upadacitinib 15 mg QD monotherapy and censored at time of rescue to 
upadacitinib 15 mg QD + MTX or with addition of background csDMARD.
4.
Any Upadacitinib 30 mg QD 
This includes Upadacitinib 30 mg QD exposure from subjects starting on 
Upadacitinib 30 mg QD and subjects rescued from MTX to Upadacitinib 30 mg 
QD + MTX. Exposure is censored at time of dose switch from Upadacitinib 30 mg 
QD to Upadacitinib 15 mg QD.
5.
Upadacitinib 30 mg QD mono
This includes Upadacitinib 30 mg QD monotherapy exposure from subjects 
starting on Upadacitinib 30 mg QD monotherapy and censored at time of rescue to 
upadacitinib 30 mg QD + MTX or with addition of background csDMARD. In 
addition, exposure is censored at time of dose switch from Upadacitinib 30 mg QD 
to Upadacitinib 15 mg QD.
6.
Any Upadacitinib 15 mg QD switched from any Upadacitinib 30mg QD
This includes Upadacitinib 15 mg QD exposure from subjects who switched dose 
from Upadacitinib 30 mg QD to Upadacitinib 15 mg QD.
7.
Upadacitinib 15 mg QD mono switched from Upadacitinib 30mg QD mono
This includes Upadacitinib 15 mg QD monotherapy exposure from subjects who 
started and remained on Upadacitinib 30 mg QD monotherapy (without rescue or 
addition of background csDMARD) and switched dose from Upadacitinib 30 mg 
QD to Upadacitinib 15 mg QD. Exposure is censored at time of addition of 
background csDMARD.
In addition to the groups above, the Japan sub-study has the additional groups of Any 
Upadacitinib 7.5 mg QD and Upadacitinib 7.5 mg QD monotherapy.


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Subjects could be blindly switched from Upadacitinib monotherapy to the combination of 
upadacitinib + MTX at Week 26, or could have background csDMARD added/initiated 
after Week 26, depending upon the CDAI response and joint counts.  For subjects rescued 
with blinded study drug MTX at Week 26, the exposure under upadacitinib monotherapy 
is censored prior to the day when blinded study drug MTX is initiated.  For subjects not 
rescued with blinded study drug MTX at Week 26 but added/initiated csDMARD as a
background therapy, the exposure under the monotherapy of upadacitinib is censored 
prior to the day when the first dose of csDMARD is initiated. 
Starting with Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects 
receiving upadacitinib 30 mg QD will be switched to receiving upadacitinib 15 mg QD. 
Exposure to upadacitinib 30 mg QD (Groups 4 and 5) will be censored prior to the day 
subject received the first dose of upadacitinib 15 mg QD, and subsequent exposure to 
upadacitinib 15 mg QD will be summarized under separate groups (Groups 6 and 7).
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 
●
≥ 9 months 
●
≥ 12 months 
●
≥ 18 months 
●
≥ 2 years
●
≥ 2.5 years
●
≥ 3 years
●
≥ 4 years


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8.2
Compliance
Study drug compliance for Upadacitinib/PBO and for MTX/PBO will be summarized 
separately for each treatment group up to Week 24.  Upadacitinib/PBO compliance is 
defined as the number of Upadacitinib/PBO tablets taken (i.e., the difference between the 
number of tablets dispensed and the number of tablets returned) during the subject's 
participation up to Week 24 divided by the number of days that the subject was in the 
Treatment Phase up to Week 24.  MTX/PBO compliance is defined as the number of 
MTX doses taken during the subject's participation up to Week 24 divided by the number 
of weeks that the subject was in the Treatment Phase up to Week 24.
9.0
Efficacy Analysis
9.1
General Considerations
There are three sets of planned efficacy analysis:  analysis for the primary and key 
secondary endpoints (at Week 12 or Week 24), additional efficacy analysis for Period 1, 
and long-term efficacy analysis (Period 1 and Period 2 combined).  All efficacy analyses 
will be carried out using the FAS population.  For the Japan sub-study, efficacy analyses 
will be conducted for selected variables.
Period 1 Efficacy Analysis 
This includes analysis for the primary and key secondary endpoints (at Week 12 or 
Week 24), and additional efficacy analysis for Period 1. 
Standard efficacy analysis by randomized treatment groups (MTX, Upadacitinib 15 mg 
QD monotherapy, Upadacitinib 30 mg QD monotherapy, and additionally Upadacitinib 
7.5 mg QD monotherapy for Japan sub-study only) will be performed on efficacy data up 
to Week 12.  No protocol-defined background rescue medication or rescue switching will 
occur prior to the time point.  
For visits at Weeks 16, 20, 24 subjects may have initiated background rescue medication 
due to lack of efficacy as evaluated by joint count criteria (i.e., not achieving 20% 


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improvement in both TJC and SJC compared with baseline at two consecutive visits).  In 
addition, at Week 26 subjects may have switched to Upadacitinib + MTX combo 
treatment (rescue switching) that is different from their originally randomized treatment 
due to lack of efficacy as evaluated by CDAI and joint count criteria, jointly.  For 
treatment group comparisons beyond Week 12 to the end of Period 1, appropriate 
approaches will be applied to assessments that occur after the time of such background 
rescue or rescue switching.  For Week 24 reporting, this set of analyses will be presented 
up to Week 24.
Long Term Efficacy Analysis
Long term efficacy analysis (Period 1 and Period 2 combined) will be performed on As 
Observed data (defined in Section 9.1.1) by the treatment group sequences as described 
below. The treatment group sequences are grouped into "non-switchers" and "switchers"
based on the protocol defined rescue at Week 26 (from MTX or upadacitinib to 
upadacitinib plus MTX).
"Non-switcher" sequences:
1.
MTX 
2.
Upadacitinib 15 mg QD 
3.
Upadacitinib 30 mg QD
"Switcher" sequences:
4.
MTX → Upadacitinib 15 mg QD + MTX
5.
MTX → Upadacitinib 30 mg QD + MTX
6.
Upadacitinib 15 mg QD → Upadacitinib 15 mg QD + MTX
7.
Upadacitinib 30 mg QD → Upadacitinib 30 mg QD + MTX


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For Japan sub-study, there are three additional treatment sequences:
8.
Upadacitinib 7.5 mg QD 
9.
MTX → Upadacitinib 7.5 mg QD + MTX
10.
Upadacitinib 7.5 mg QD → Upadacitinib 7.5 mg QD + MTX
There will be no statistical testing; only descriptive statistics and confidence intervals will 
be provided.  For Week 24 reporting, this set of analyses will be presented up to Week 48.
Starting with Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects 
receiving upadacitinib 30 mg QD will be switched to upadacitinib 15 mg QD.  For long 
term efficacy analysis, subjects will continue to be summarized under the treatment 
sequences as described above, regardless of dose switch – i.e., for treatment sequences 3, 
5 and 7, data collected after dose switch will continue to be summarized under the same 
treatment sequences. The visit at which dose switch occurs could be different for each 
subject. The first and last visits at which dose switch occurs will be noted in the 
summary.
Global Analysis versus Japan Sub-Study
The primary and key secondary endpoints and the subsequent multiplicity control are only 
applicable for global analysis for subjects randomized to MTX, Upadacitinib 15 mg QD 
and Upadacitinib 30 mg QD - they do not apply to Japan sub-study. 
For Japan sub-study, no multiplicity adjustments will be applied and only nominal p-
values will be provided for all efficacy analyses.  In addition, model adjustment for region 
will not be applicable for Japan sub-study.  The nominal p-values for the mTSS-related 
endpoints in Japan sub-study should be interpreted with caution due to limited sample 
size.
Subgroup analysis for the primary endpoints is only applicable for global analysis as well.  
No subgroup analysis is planned for Japan sub-study due to limited sample size.


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9.1.1
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 the 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.  In addition, OC will not 
use values after premature discontinuation of study drug.  OC sensitivity analysis will be 
applied to reporting prior to Week 12 where no background rescue medication or rescue 
switching will occur prior to the time point. 
As Observed (AO)
The AO analysis will not impute values for missing evaluations.  Regardless of rescue or 
premature discontinuation of study drug, all observed data will be used in the analysis.
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.  LOCF will be first applied to augment data into monotonic missing 
pattern.  PROC MI will be used to generate 5 datasets using the regression method.  
Specifically, visits will be imputed in order, where later visits are imputed by regressing 
upon all previous visits, baseline, treatment group, demographics and other key baseline 
characteristics.  Analysis will first be performed on each of the multiple imputed datasets, 
and PROC MIANALYZE will then be used to aggregate the results for the final statistical 
inference.  The imputation is based on assumption of data being missing at random.  The 


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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%).
Linear Extrapolation for Radiographic Data 
For radiographic data (i.e., mTSS-based endpoints), linear extrapolation will be applied to 
subjects who prematurely discontinued study drug or switched to a different study drug at 
Week 26, where the x-ray at the time point of interest after rescue switching or PD will be 
imputed assuming a linear relationship between baseline, the x-ray collected at rescue or 
PD, and the time point of interest.  See Section 9.2.1.2 and Section 9.3.2 for details.
Missing Data Imputation Methods
To summarize the use of different missing data handling approaches in the analysis:
●
For non-radiographic data:  The NRI approach will serve as the primary 
analysis approach for binary endpoints in Period 1, while OC will be repeated 
as a sensitivity analysis for Week 12 key binary endpoints and AO will be 
repeated as a sensitivity analysis for Week 24 key binary endpoints.  The MI 
approach will serve as the primary analysis approach for key continuous 
endpoints at Week 12 and 24.  
●
For radiographic data:  Analysis based on both linear extrapolation and AO 
analysis will be conducted, and linear extrapolation results will be used for the 
purpose of multiplicity control.
●
A missing not at random (MNAR) model that varies assumptions for the 
missing data in active treatment groups and MTX group may be used as a 
sensitivity analysis for key continuous endpoints to account for potential 
deviation from the MAR assumption.


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Mixed Effect Model Repeat Measurement (MMRM) and Generalized Linear Mixed 
Model (GLMM) for Long-Term Analysis
The repeated measure analysis will be conducted using mixed model including As 
Observed measurements at all visits.  MMRM will be used for continuous endpoints and 
GLMM will be used for binary endpoints. The mixed models will include the categorical 
fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factor 
geographic region. For the MMRM analysis of change from baseline in continuous 
endpoints, the baseline measurement will be included as a continuous fixed covariate. 
The categorical fixed effect of subject's discontinuation status and other baseline 
covariates may also be included in the model as appropriate. Unstructured, Toeplitz, 
compound symmetry, or other covariance structures may be considered.
9.2
Efficacy Analysis for the Primary and Key Secondary 
Endpoints
9.2.1
Primary Efficacy Analysis
The primary endpoint for US/FDA regulatory purposes is the proportion of subjects 
achieving ACR50 response at Week 12.  The primary endpoint for EU/EMA regulatory 
purposes is the proportion of subjects achieving Clinical Remission (CR) (defined by 
DAS28(CRP) < 2.6) at Week 24.  For Japan/PMDA regulatory purposes, the primary 
endpoints are the proportion of subjects achieving ACR20 response at Week 12 and 
change from baseline in modified Total Sharp Score (mTSS) at Week 24.  Analyses will 
be conducted separately for US/FDA, EU/EMA and Japan/PMDA regulatory purposes. 
9.2.1.1
Analysis for ACR20, ACR50 and CR
For ACR20, ACR50 and CR, point estimate and 95% CI of the response rate for each 
randomized treatment group will be provided.  Comparisons of the primary endpoint will 
be made between each Upadacitinib dose group and the MTX group using the Cochran-
Mantel-Haenszel test adjusting for geographic region.  Point estimate, 95% CI and p-
value for the treatment comparison will be presented.  Both nominal p-value constructed 


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using the Cochran-Mantel-Haenszel test and adjusted p-value through the graphical 
multiplicity procedure described in Section 9.2.5 will be provided.  For the primary 
analysis, non-responder imputation (NRI) will be used.  Subjects who meet the joint count 
rescue criteria at Week 16 or 20 will be treated as non-responders at Week 24 for the 
primary analysis. 
9.2.1.2
Analysis for Change from Baseline in mTSS at Week 24
For mean change from baseline in mTSS at Week 24, both linear extrapolation and As 
Observed (AO) analyses will be conducted.  Linear extrapolation results will be used for 
the purpose of multiplicity control.
According to protocol, subjects who prematurely discontinue study drug between 
≥Week 12 and ≤ Week 16 will have x-ray collected at the PD visit.  All subjects who 
discontinued study drug but remained in the study through Week 24 will have another x-
ray collected at the Week 24 visit.  Available x-ray data will be assigned to the following 
analysis time points based on the analysis windows defined in Table 3:  Baseline, 
Week 12, and Week 24. 
In the linear extrapolation analysis, the Week 24 data will be imputed via linear 
extrapolation using baseline data and Week 12 data for subjects who prematurely 
discontinued study drug between Weeks 12 and 16, and for subjects with otherwise 
(i.e., not prematurely discontinued study drug prior to Week 16) missing observed x-ray at 
Week 24 window but have available x-ray in the Week 12 window. 
In AO analysis, the observed Week 24 measurements will be used and attributed to the 
original randomized treatment groups regardless of study drug discontinuation.
To analyze the mean change from baseline in mTSS at Week 24, the point estimate and 
95% CI will be reported for each randomized treatment group.  Between-group 
comparisons for each Upadacitinib treatment group and the MTX group will be performed 
using ANCOVA model with treatment and geographic region as the fixed factors and the 
corresponding baseline value as the covariate.  In the event that data severely deviates 


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from the normal distribution, non-parametric analyses such as the Wilcoxon rank sum test 
may be considered for treatment comparison. 
Both nominal p-value and adjusted p-value through the graphical multiplicity procedure 
described in Section 9.2.5 will be provided.
9.2.2
Sensitivity Analysis of Primary Efficacy Variables
The analysis of ACR20 and ACR50 at Week 12 will be repeated using Observed Cases 
and the analysis of CR at Week 24 will be repeated using As Observed as a sensitivity 
analysis without any imputation.  These analyses will be conducted on the FAS based on 
randomized treatment groups.
Supportive NRI analysis for ACR20, ACR50 and CR and supportive linear extrapolation 
and AO analysis for change from baseline in mTSS will also be conducted on the Per 
Protocol Analysis Set.
9.2.3
Key Secondary Efficacy Analyses
Ranked key secondary endpoints for US/FDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP) at Week 12;
2.
Change from baseline in HAQ-DI at Week 12;
3.
Change from baseline in modified Total Sharp Score (mTSS) at Week 24;
4.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12;
5.
Proportion of subjects achieving CR based on DAS28 (CRP) < 2.6 at Week 24;
6.
Change from baseline in SF-36 PCS at Week 12;
Other key secondary endpoints for US/FDA regulatory purposes are:
1.
ACR20 response rate at Week 12;
2.
ACR70 response rate at Week 12;


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3.
Proportion of subjects with no radiographic progression (defined as change from 
baseline mTSS ≤ 0) at Week 24
Ranked key secondary endpoints at Week 24 for EU/EMA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
ACR50 response rate;
4.
Change from baseline in modified Total Sharp Score (mTSS);
5.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2;
6.
Change from baseline in SF-36 PCS;
7.
Proportion of subjects with no radiographic progression at Week 24.
Other key secondary endpoints for EU/EMA purposes are:
1.
ACR20 response rate at Week 24
2.
ACR70 response rate at Week 24
Ranked key secondary endpoints for Japan/PMDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP) at Week 12; 
2.
Change from baseline in HAQ-DI at Week 12; 
3.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12;
4.
Proportion of subjects achieving CR based on DAS28 (CRP) < 2.6 at Week 24;
5.
Change from baseline in SF-36 PCS at Week 12.
Other key secondary endpoints for Japan/PMDA regulatory purposes are:


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1.
CR50 response rate at Week 12;
2.
ACR70 response rate at Week 12
3.
Proportion of subjects with no radiographic progression at Week 24
For Week 12 binary endpoints, similar NRI and OC analyses as for the primary endpoint 
of ACR20 and ACR50 at Week 12 will be conducted.  For non-mTSS Week 24 binary 
endpoints, similar NRI and AO analyses as for the primary endpoint of CR at Week 24 
will be conducted. 
For the analysis of the proportion of subjects with no radiographic progression at 
Week 24, both linear extrapolation and AO analyses will be conducted (linear 
extrapolated and AO Week 24 mTSS data derived as described in Section 9.2.1.2).  Linear 
extrapolation results will be used for the purpose of multiplicity control.  Point estimate 
and 95% CI of the response rate for each randomized treatment group will be provided.  
Comparisons will be made between each Upadacitinib dose group and the MTX group 
using the Cochran-Mantel-Haenszel test adjusting for geographic region.  Point estimate, 
95% CI and p-value for the treatment comparison will be presented.
For all continuous key secondary endpoints other than mTSS, statistical inference will be 
conducted using analysis of covariance (ANCOVA) coupled with MI for missing data 
handling.  Specifically, the ANCOVA model will include treatment and geographic region 
as the fixed factors and the corresponding baseline value as the covariates.  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 each 
Upadacitinib dose group with the MTX group.  For subjects who meet the rescue criteria 
at Week 16 or 20, data after rescue will be overwritten by last observation carried forward 
(LOCF). 
Both nominal p-value and adjusted p-value through the graphical multiplicity procedure 
described in Section 9.2.5 will be provided.


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9.2.4
Handling of Multiplicity
The overall type I error rate of the primary and ranked key secondary endpoints for the 
two doses in global analysis will be strongly controlled using a graphical multiple testing 
procedure [1].  Specifically, the testing will utilize the endpoint sequence of primary 
endpoint followed by the ranked key secondary endpoints in the order as specified in
Section 9.2.3, and will begin with testing the primary endpoint using α of 0.025 for each 
dose.  Continued testing will follow a pre-specified α transfer path which includes 
downstream transfer along the endpoint sequence within each dose as well as cross-dose 
transfer.  Adjusted p-values for the primary and ranked key secondary endpoints will be 
provided based on the testing procedure. 
The graphs for the testing procedures are provided in Figure 3 (for US/FDA regulatory 
purposes), Figure 4 (for EU/EMA regulatory purposes) and Figure 5 (for Japan/PMDA 
regulatory purposes).  In the graphs, the arrows specify the α transfer paths.  Once an 
endpoint is rejected (i.e., deemed significant) at its assigned significance level, its 
significance level will be transferred to subsequent endpoint(s) following the arrow(s).  
The numbers on the arrows denote the weights for transferring and (possibly) splitting 
significance levels.  Specifically, the weight 1 denotes 100% transfer of significance level.


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Figure 3.
Graphical Multiple Testing Procedure for US/FDA Regulatory 
Purposes


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Figure 4.
Graphical Multiple Testing Procedure for EU/EMA Regulatory 
Purposes


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Figure 5.
Graphical Multiple Testing Procedure for Japan/PMDA 
Regulatory Purposes
9.2.5
Efficacy Subgroup Analysis
Non-mTSS primary efficacy endpoints will be examined in the subgroups listed in 
Table 5 below.  Treatment difference between each Upadacitinib dose and the MTX 
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 has fewer than 10% of the planned study size (i.e., < 90 subjects), the subgroup 
analyses for that variable will not be presented.


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Table 5.
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
Race
White, Black or African American, American 
Indian or Alaska Native, Native Hawaiian or 
Other Pacific Islander, Asian, Other
Geographic Region
North America, South/Central America, Western 
Europe, Eastern Europe, Asia/Other
RA disease duration from diagnosis 
< 6 months or ≥ 6 months
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
9.2.6
Summary of Efficacy Analysis for the Primary and Key 
Secondary Endpoints
Table 6 and Table 7 below provides the overview of the efficacy analyses for the primary 
and key secondary endpoints


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Table 6.
Summary of Efficacy Analyses for the Primary and Key Secondary 
Endpoints at Week 12 
Efficacy Variables
Analysis Method
Primary Variables

ACR50 response at Week 12a

ACR20 response at Week 12c

Point estimate and 95% CI of the response rate for each 
Upadacitinib dose group and the MTX group.  The 95% CI 
will be based on normal approximation. 

Point estimate, 95% CI and p-value for the treatment 
comparison between each Upadacitinib dose group and the 
MTX group, where the p-value is constructed using the 
Cochran-Mantel-Haenszel test adjusting for geographic 
region.  Both nominal p-value and adjusted p-value through 
the graphical multiplicity procedure described in Section 9.2.5
will be provided.  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: 

ACR20 response rate at 
Week 12a

ACR50 response rate at 
Week 12c

ACR70 response rate at 
Week 12a,c;

Proportion of subjects 
achieving LDA based on 
DAS28 (CRP) ≤ 3.2 at 
Week 12a,c

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 each Upadacitinib dose group and the 
MTX group using the Cochran-Mantel-Haenszel test 
adjusting for geographic region.  Both nominal p-value and 
adjusted p-value (applicable for ranked key secondary 
endpoints) through the graphical multiplicity procedure 
described in Section 9.2.5 will be provided.  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 6.
Summary of Efficacy Analyses for the Primary and Key Secondary 
Endpoints at Week 12 (Continued)
Efficacy Variables
Analysis Method
Continuous Endpoints:

Change from baseline in 
DAS28(CRP) at Week 12a,c

Change from baseline in 
HAQ-DI at Week 12a,c

Change from baseline in 
SF-36 Physical Component 
Score (PCS) at Week 12a,c

LS mean and 95% CI within each treatment group and LS 
mean, 95% CI and p-values between each Upadacitinib dose 
group and the MTX group using ANCOVA model with 
treatment and geographic region as fixed factors and baseline 
value as covariate.  Both nominal p-value and adjusted 
p-value through the graphical multiplicity procedure 
described in Section 9.2.5 will be provided.

Imputation:  MI

Analysis Set:  FAS
a.
US/FDA regulatory purposes.
b.
EU/EMA regulatory purposes.
c.
Japan/PMDA regulatory purposes.


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Table 7.
Summary of Efficacy Analyses for the Primary and Key Secondary 
Endpoints at Week 24 
Efficacy Variables
Analysis Method
Primary Variables

CR as measured by 
DAS28(CRP) at Week 24b

Point estimate and 95% CI of the response rate for each 
Upadacitinib dose group and the MTX group.  The 95% CI 
will be based on normal approximation.

Point estimate, 95% CI and p-value for the treatment 
comparison between each Upadacitinib dose group and the 
MTX group, where the p-value is constructed using the 
Cochran-Mantel-Haenszel test adjusting for geographic 
region.  Both nominal p-value and adjusted p-value through 
the graphical multiplicity procedure described in 
Section 9.2.5 will be provided.  The 95% CI will be based on 
normal approximation.

Subgroup analysis.

Imputation and rescue handling:  NRI for primary analysis 
and AO for sensitivity analysis

Analysis Set:  FAS and Per Protocol Analysis Set as 
supportive analysis (NRI only).

Change from baseline in 
modified Total Sharp Score 
(mTSS) at Week 24c

LS mean and 95% CI within each treatment group and LS 
mean, 95% CI and p-values between each Upadacitinib dose 
group and the MTX group using ANCOVA model with 
treatment and geographic region as fixed factors and baseline 
value as covariate.  Both nominal p-value and adjusted 
p-value through the graphical multiplicity procedure 
described in Section 9.2.5 will be provided. 

Imputation:  Linear extrapolation and AO.

Analysis Set:  FAS and Per Protocol Analysis Set as 
supportive analysis.


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Table 7.
Summary of Efficacy Analyses for the Primary and Key Secondary 
Endpoints at Week 24 (Continued)
Efficacy Variables
Analysis Method
Key Secondary Variables
Binary Endpoints: 

Proportion of subjects 
achieving CR based on 
DAS28 (CRP) < 2.6 at 
Week 24a,c;

ACR20/50/70 response rate 
at Week 24b;

Proportion of subjects 
achieving LDA based on 
DAS28 (CRP) ≤ 3.2 at 
Week 24b;

Proportion of subjects with 
no radiographic progression 
(defined as change from 
baseline in mTSS ≤ 0) at 
Weeks 24a,b,c.

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 each Upadacitinib dose group and the 
MTX group using the Cochran-Mantel-Haenszel test 
adjusting for geographic region.  Both nominal p-value and 
adjusted p-value (applicable for ranked key secondary 
endpoints) through the graphical multiplicity procedure 
described in Section 9.2.5 will be provided.  The 95% CI will 
be based on normal approximation.

Imputation and rescue handling for non-mTSS endpoints:  
NRI for primary analysis and AO for sensitivity analysis.

Imputation for mTSS endpoints:  Linear extrapolation and 
AO.  Analysis Set:  FAS
Continuous Endpoints:

Change from baseline in 
DAS28(CRP) at Week 24b

Change from baseline in 
HAQ-DI at Week 24b

Change from baseline in 
modified Total Sharp Score 
(mTSS) at Week 24a,b

Change from baseline in 
SF-36 Physical Component 
Score (PCS) at Week 24b

LS mean and 95% CI within each treatment group and LS 
mean, 95% CI and p-values between each Upadacitinib dose 
group and the MTX group using ANCOVA model with 
treatment and geographic region as fixed factors and baseline 
value as covariate.  Both nominal p-value and adjusted 
p-value through the graphical multiplicity procedure 
described in Section 9.2.5 will be provided.

Imputation for non-mTSS endpoints:  MI

Rescue handling for non-mTSS endpoints:  LOCF after 
rescue and AO for sensitivity analysis

Imputation for mTSS endpoints:  Linear extrapolation and 
AO.

Analysis Set:  FAS
a.
US/FDA regulatory purposes.
b.
EU/EMA regulatory purposes.
c.
Japan/PMDA regulatory purposes.


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9.3
Additional Efficacy Analyses for Period 1
Additional efficacy endpoints are listed below and will be summarized for all visits (that 
measurements are collected) in Period 1 by randomized treatment groups:
●
ACR20/50/70 response rates;
●
Change from baseline in individual components of ACR response;
●
Change from baseline in DAS28(CRP) and DAS28 (ESR);
●
Change from baseline in CDAI and SDAI;
●
Proportion of subjects achieving LDA or CR by DAS28(CRP), DAS28(ESR), 
Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index 
(CDAI);
●
Change from baseline in morning stiffness (severity and duration);
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3 and
≤ –0.22 respectively;
●
ACR/EULAR Boolean remission;
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in FACIT-F;
●
Change from baseline in WPAI;
●
Change from baseline in SF-36;
●
Change from baseline in mTSS at Week 24 and Week 48;
●
Proportion of subjects with no radiographic progression (defined as change 
from baseline in mTSS ≤ 0) at Week 24 and Week 48;
●
Change from baseline in radiographic joint space narrowing and erosion scores 
at Week 24 and Week 48.
9.3.1
Analysis of non-mTSS-Related Endpoints for Period 1
For continuous variables, statistical inference at each visit will be conducted using 
analysis of covariance (ANCOVA) with treatment and geographic region as the fixed 
factors and the corresponding baseline value as the covariate.  Only nominal p-values will 
be provided.  For subjects who meet the rescue criteria defined by not achieving 20% 


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improvement in TJC/SJC (for Week 12 through Week 24), or subjects who meet the 
rescue switching criteria at Week 26 defined by not reaching CDAI CR and not achieving 
20% improvement in TJC/SJC), data after rescue will be overwritten by LOCF for 
primary analysis.  As observed (AO) data regardless of rescue will also be summarized 
using descriptive statistics.
For binary endpoints, frequencies and percentages will be reported for each randomized 
treatment group.  Similar CMH analyses as for the primary endpoint will be conducted 
and only nominal p-values will be provided.  For the primary analysis, non-responder 
imputation will be used.  In addition, subjects who meet the rescue criteria of not 
achieving 20% improvement in TJC/SJC (for Week 12 through Week 24) or subjects who 
meet the rescue switching criteria at Week 26 defined by not reaching CDAI CR and not 
achieving 20% improvement in TJC/SJC will be treated as non-responders at visits after 
rescue.  As observed (AO) data regardless of rescue will also be summarized using 
frequencies and percentages.
Plots by randomized treatment group over time will be provided for selected efficacy 
parameters including ACR20/50/70, LDA and CR by DAS28(CRP) and CDAI, and 
change from baseline in DAS28(CRP), HAQ-DI and pain.  
For Week 24 reporting, this set of analyses will be presented up to Week 24.
9.3.2
Analysis of Additional mTSS-Related Endpoints for Period 1
For other mTSS-related endpoints at Week 24 and 48, analyses based on linear 
extrapolation and the AO analyses will be conducted on the FAS population.  For 
Week 24 reporting, analysis of mTSS-related endpoints will be presented up to Week 24. 
For change from baseline in joint space narrowing score and joint erosion score at 
Week 24, linear extrapolation analysis and AO analysis will be performed similarly as 
described in Section 9.2.1.2. 


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According to protocol, subjects who prematurely discontinue study drug between 
≥Week 12 and ≤ Week 16 or between ≥ Week 36 and ≤ Week 40 will have x-ray 
collected at the PD visit.  All subjects who remain in the study at Week 24 will have x-ray 
collected at Week 24 visit, and all subjects who remain in the study at Week 48 will have 
x-ray collected at Week 48 visit.  Available x-ray data will be assigned to the following 
analysis time points based on the analysis windows defined in Table 3:  Baseline, 
Week 12, Week 24, Week 36, and Week 48.
In the linear extrapolation analysis for Week 48 x-ray endpoints, the Week 48 data will be 
imputed via linear extrapolation for the following subjects:  subjects who meet the rescue 
switching criteria at Week 26, subjects who prematurely discontinued study drug prior to 
Week 40, and subjects otherwise (i.e., not switched to a different study drug at Week 26, 
not discontinued study drug prior to Week 40) missing observed x-ray in the Week 48 
window but have available x-ray at an earlier time point.  For those subjects who have 
switched study drug and/or prematurely discontinued study drug, the most recent x-ray 
data collected at treatment switching or at discontinuation of study drug will be used for 
extrapolation.  For subjects otherwise missing observed x-ray in Week 48 window, 
available x-ray in the most recent analysis window (prior to the Week 48 window) will be 
used for extrapolation. 
In the AO approach, the observed Week 48 measurements will be used and attributed to 
the original randomized treatment groups regardless of treatment switching or study drug 
discontinuation.
Similar statistical inference approach as described in Section 9.2.1.2 and Section 9.2.3
will be used for Week 48 mTSS-related endpoints.  Only nominal p-values will be 
provided. 


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9.3.3
Summary of Additional Efficacy Analysis for Period 1
Table 8 below provides the overview of the additional efficacy analyses for Period 1 to be 
performed on different endpoints by randomized treatment group.  For Week 24 reporting, 
this set of analysis will be presented up to Week 24.


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Table 8.
Summary of Efficacy Variables and Corresponding Analyses for 
Additional Efficacy Analysis for Period 1 (By Randomized 
Treatment Group)
Efficacy Variables
Analysis Method
Additional Variables (Summarized at All Visits in Period 1)
Binary Endpoints: 

ACR20/50/70 response rate

Proportion of subjects achieving 
LDA and CR based on 
DAS28(CRP), DAS28 (ESR), 
SDAI, and CDAI criteria

Proportion of subjects with change 
from baseline in HAQ-DI ≤ –0.3 
and ≤ –0.22, respectively;

Boolean remission;

Proportion of subjects with no 
radiographic progression (defined as 
change from baseline in mTSS ≤ 0) 
at Week 24 and Week 48.

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 each Upadacitinib dose group 
and the MTX group using the Cochran-Mantel-
Haenszel test adjusting for geographic region.  Only 
nominal p-values will be provided, and the 95% CI 
will be based on normal approximation.

Plots by randomized treatment group over time for 
selected endpoints

Imputation and rescue handling for non-mTSS 
endpoints:  NRI; AO for descriptive statistics

Imputation and rescue-switching handling for mTSS 
endpoints:  linear extrapolation and AO.

Analysis Set:  FAS
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 (severity and duration)

Change from baseline in EQ-5D-5L

Change from baseline in FACIT-F

Change from baseline in WPAI

Change from baseline in SF-36

Change from baseline in modified 
Total Sharp Score (mTSS) at 
Week 48

Change from baseline in JSN and 
Erosion at Week 24 and Week 48

LS mean and 95% CI within each treatment group and 
LS mean, 95% CI and p-values between each 
Upadacitinib dose group and the MTX group using 
ANCOVA model with treatment and geographic 
region as fixed factors and baseline value as covariate.  
Only nominal p-values will be provided.

Plots by randomized treatment group over time for 
selected endpoints

Rescue handling for non-mTSS endpoints:  LOCF 
after rescue; AO for descriptive statistics.

Imputation and treatment-switching handling for 
mTSS endpoints:  linear extrapolation and AO.

Analysis Set:  FAS


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9.4
Long Term Efficacy Analysis 
Assessments to evaluate long term efficacy (Period 1 and Period 2 combined) will be 
analyzed for the following measures at Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 
48, every 12 weeks through Week 240, and Week 260/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
●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria;
●
Change from baseline in morning stiffness (severity and duration);
●
Proportion of subjects with change from baseline in HAQ-DI ≤ -0.22;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ -0.3;
●
ACR/EULAR Boolean remission at all visits
●
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 12, 24 and 48:  
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in FACIT-F;
●
Change from baseline in WPAI. 
●
Change from baseline in SF-36.
Assessments for the evaluation of radiographic changes in Period 2 will occur at Week 96, 
Week 192 and Week 260 (or Premature Discontinuation visit):
●
Change from baseline in modified Total Sharp Score mTSS;


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●
Proportion of subjects with no radiographic progression (defined as change 
from baseline mTSS of ≤ 0);
●
Change from baseline in radiographic joint space narrowing and erosion 
scores.
Analyses will be based on As Observed (AO) data. Descriptive statistics will be provided 
for each treatment group sequence as defined in Section 9.1.  These include the number of 
observations, mean, standard deviation, and 95% CI for continuous endpoints; and 
frequencies and percentages with 95% CI using normal approximation for binary 
endpoints.  In addition, longitudinal analysis will be performed using MMRM or GLMM 
as described in Section 9.1.1 for the "non-switcher" sequences (as defined in Section 9.1)
for all endpoints except radiographic endpoints and proportion of subjects with no 
concomitant corticosteroid use. Point estimates and 95% CI from the model will be 
provided for each treatment group sequence. 
Plot for each treatment group sequence over time up to Week 48 will be provided.
For Week 24 reporting, long-term efficacy analysis will be presented up to Week 48.
Table 9 below provides the overview of the long-term efficacy analyses to be performed 
on different endpoints.


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Table 9.
Summary of Efficacy Variables and Corresponding Analyses for 
Long Term Efficacy Analysis (By Treatment Group Sequence)
Efficacy Variables
Analysis Method
Binary Endpoints:

ACR20/50/70 response by visit

LDA and CR based on 
DAS28(CRP), DAS28 (ESR), 
SDAI, and CDAI criteria by visit

Boolean remission;

Proportion of subjects with no 
concomitant corticosteroid use 
(among subjects with corticosteroid 
use at baseline)*

Proportion of subjects with no 
radiographic progression (defined as 
change from baseline mTSS of ≤ 0) 
by visit*

Point estimate and 95% CI of the response rate for 
each treatment group sequence

Plot for each treatment group sequence over time up to 
Week 48

Point estimate and 95% CI of the response rate using 
GLMM model for each "non-switcher" treatment 
group sequence  (*endpoints excluded from this 
analysis)

Plot for each non-switcher treatment group sequence 
over time for key endpoints#

Imputation:  AO 

Analysis Set:  FAS
Continuous Endpoints:

Change from baseline in individual 
ACR components by visit

Change from baseline in DAS28 
(CRP) and DAS28 (ESR) by visit

Change from baseline in CDAI and 
SDAI

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 
by visit

Change from baseline in WPAI by 
visit

Change from baseline in SF-36 by 
visit

Change from baseline in mTSS by 
visit*

Change from baseline in 
radiographic joint space narrowing 
and erosion scores by visit*

Point estimate, and 95% CI of mean change from 
baseline together with SD for each treatment group 
sequence

Plot for each treatment group sequence over time up to 
Week 48

Point estimate and 95% CI of change from baseline 
using MMRM model for each "non-switcher" 
treatment group sequence (*endpoints excluded from 
this analysis)

Plot for each non-switcher treatment group sequence 
over time for key endpoints#

Imputation:  AO

Analysis Set:  FAS
#
Key endpoints for figures include: ACR20/50/70, LDA and CR based on DAS28(CRP) and CDAI criteria, Boolean 
remission, change from baseline in DAS28(CRP) and CDAI.


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9.5
Efficacy Variables Definitions and Conventions
9.5.1
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. 
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


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Of note: 
*
TJC68/SJC66 is typically used.
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 
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. 


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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 
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.


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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.
9.5.2
Joint Evaluation
Anatomical joints are evaluated for swelling and tenderness at every study visit.  The 
34 anatomical joints in Table 10 are assessed in this study for both the left and right side 
of the body.
Table 10.
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 


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("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.
9.5.3
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.
9.5.4
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.
9.5.5
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.
9.5.6
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.


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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.
Table 11.
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.
9.5.7
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 


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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. 
9.5.8
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:
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. 
9.5.9
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


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9.5.10
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. 
9.5.11
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, 
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.


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9.5.12
Modified Total Sharp Score (mTSS)
The radiographic outcome will be assessed and scored according to Sharp's method (Van 
der Heijde modification) centrally by two qualified physicians/radiologists who will be 
blinded to the site number, subject number, treatment allocation, time sequence and 
clinical response.
Calculation of the Modified Total Sharp Score
To obtain the total mTSS score, scores for erosions and JSN in both the hands and feet 
will be added together.  
The range of scores is summarized below. 
Hands
Feet
Total
(Hands and Feet)
Erosion Score Range
0-160
0-120
0-280
Joint Space Narrowing 
Range
0-120
0-48
0-168
mTSS Range for 
Erosion and JSN
0-280
0-168
0-448
The following joints will be examined for assessing Erosions:
Foota
Handb
1st IP
1st IP
4th PIP
Navicular
1st MTP
1st MCP
4th MCP
Lunate
2nd MTP
2nd PIP
5th PIP
Radius
3rd MTP
2nd MCP
5th MCP
Ulnar
4th MTP
3rd PIP
1st MC
5th MTP
3rd MCP
Multangularc
a.
IP:  Inter-Phalangeal, MTP:  Metatarso-Phalangeal.
b.
IP:  Inter-Phalangeal, PIP:  Proximal Inter-Phalangeal, MCP:  Metacarpophalangeal, MC:  Metacarpal.
c.
Trapezium/Trapezoid as read as one unit-Multangular.
The following joints will be examined for assessing Joint Space Narrowing:


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Foota
Handb
1st IP
1st MCP
4th MCP
MN
1st MTP
2nd PIP
5th PIP
CNL
2nd MTP
2nd MCP
5th MCP
RC
3rd MTP
3rd PIP
3rd CMC
4th MTP
3rd MCP
4th CMC
5th MTP
4th PIP
5th CMC
a.
IP:  Inter-Phalangeal, MTP:  Metatarso-Phalangeal.
b.
PIP:  Proximal Inter-Phalangeal, MCP:  Metacarpo-Phalangeal, CMC:  Carpo-Metcarpal, MN:  Multangular-
Navicular, CNL:  Capitate-Navicular Lunate, RC:  Radio-Carpal.
For each Joint and Bone assessed scores range as follows:
●
Erosions:  0 – 5 (hands/wrists) or 0 – 10 (feet) to characterize the extent of 
erosions (where 0 denotes no erosion).
●
Joint Space Narrowing: 0 – 4 to characterize the extent of Joint Space 
Narrowing (JSN) (where 0 denotes no narrowing).
Erosion and JSN scores for each reader are calculated by taking the sum of the left and 
right joints as shown below.
Right
Left
i
Reader 
Erosion
Erosion
Erosion


Right
Left
i
Reader 
JSN
JSN
JSN


for i = 1, 2.
Thus, the maximum erosion score for all 32 joints in hands/wrists is 160.  The maximum 
erosion score for all 12 joints in feet is 120.  Thus, the total erosion score for hands/wrists 
and feet is 280.
The maximum score for JSN in all 30 hand/wrist joints is 120.  The maximum score for 
JSN in all 12 feet joints is 48.  Thus, the total JSN score for hand/wrist and feet is 168.
Since two independent readers evaluate each film, the mean score will be calculated for 
the two readers from the individual erosion and JSN scores as shown below:


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2
Erosion
Erosion
Erosion
Reader2
Reader1 

2
JSN
JSN
JSN
Reader2
Reader1 

The mTSS for each reader is defined as the sum of the erosion and JSN scores:
TSSReader i = ErosionReader i + JSNReader i for i = 1, 2.
The average modified TSS from the two readers will be used for all x-ray endpoint 
calculations.
2
Reader2
Reader1
TSS
TSS
TSS


Handling of Missing Joints in the mTSS Derivation
If a score at any location/joint is missing, the method described below will be used for 
deriving mTSS.
●
If the score for a location/joint is missing at Baseline, this joint will not 
contribute to the calculation of mTSS for this subject at any visit within the 
reading session (even if the score for this location/joint is available at post-
baseline visits).
●
If the score for a location/joint is missing at all post-baseline visits within a 
reading session, this joint will not contribute to the calculation of mTSS for 
this subject at any visit within the reading session (even if the score for this 
location/joint is available at Baseline).
●
If the score for a location/joint is available at Baseline and at least one post-
baseline visit, missing scores for this joint at any other post-baseline visit will 
be imputed assuming no progression from the previous time point with 
available score. 


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Sensitivity analysis may be performed as needed.
Adjudication Process
Two reviewers will independently review the images.  Adjudication will occur for all 
subjects with a discrepancy 
 between the two reviewers' mTSS change scores, in 
which case another reviewer, different from the reviewers who performed primary 
assessments, will make a third, independent assessment.
For the calculation of mTSS, the score of two closest reads (out of the two primary 
reviewers and the adjudicator) will be used.  In the case of equal distance, the average of 
the three reads will be used.
9.5.13
Form SF-36v2 
The 36-Item Short Form, Version 2 (SF-36v2) Questionnaire with 4 week recall consists 
of 36 general health questions and this study is 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 QualityMetrics.
9.5.14
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 


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value.  The change from baseline of the index value and EQ VAS will be analyzed and 
reported.  UK scoring algorithm will be used. 
9.5.15
Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F)
Fatigue is one of the most frequent complaints of individuals with RA 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 (4 = not at all 
fatigued to 0 = very much fatigued).  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.
9.5.16
Work Productivity and Activity Impairment (WPAI)
The Work Productivity and Activity Impairment (WPAI) questionnaire is a validated,
self-administered tool used to assess the impact of disease on productivity.  It measures 
time missed from work and impairment of work and activities due to a specific health 
problem.  The questionnaire consists of 6 questions concerning a patient's ability to work 
and perform regular activities.  Unemployed patients only answer select WPAI questions 
relating to their employment status and ability to perform daily activities other than work.  
WPAI scores are expressed as percent impairment based on six items.  The four main 
impairment measures or scores are absenteeism, presenteeism, percent overall work 
impairment and percent activity impairment. 


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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 prior to Week 26 (will present up to Week 24 for 
Week 24 reporting), and long-term safety analysis.  Selected safety analyses will be 
conducted for the Japan sub-study.  Missing safety data will not be imputed.
10.1.1
Safety Analysis Prior to Protocol-Defined Treatment 
Switching at Week 26
Standard safety analysis by the "as treated" treatment groups of Upadacitinib 15 mg QD, 
Upadacitinib 30 mg QD (for Japan sub-study there will be an additional Upadacitinib 
7.5 mg QD), and MTX will be performed on safety data up to Week 26.  No protocol-
defined rescue switching of study drug will occur prior to this time point. 
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. 
For Week 24 reporting, this set of analyses will be presented up to Week 24.
10.1.2
Long Term Safety Analysis
Long-term safety analyses 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 


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treatment-emergent adverse event (TEAE) rate per 100 patient-years of exposure will be 
presented by actual treatment received (i.e., exposed to) at the time of AE (as described in 
Section 10.2.2), where treatment exposure groups are described in Section 8.1.  Listing of 
subjects with TEAEs by SOC and PT will be provided.  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.  Mean changes from baseline in all continuous laboratory 
parameters and vital signs variables at each visit will be summarized by "as treated" 
exposure sequences defined as follows:
1.
MTX 
2.
Upadacitinib 15 mg QD 
3.
Upadacitinib 30 mg QD 
4.
MTX → Upadacitinib 15 mg QD + MTX
5.
MTX → Upadacitinib 30 mg QD + MTX
6.
Upadacitinib 15 mg QD → Upadacitinib 15 mg QD + MTX/csDMARD
7.
Upadacitinib 30 mg QD → Upadacitinib 30 mg QD + MTX/csDMARD
For Japan sub-study, there are three additional exposure sequences:
8.
Upadacitinib 7.5 mg QD 
9.
MTX → Upadacitinib 7.5 mg QD + MTX
10.
Upadacitinib 7.5 mg QD → Upadacitinib 7.5 mg QD + MTX/csDMARD
Starting with Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects 
receiving upadacitinib 30 mg QD will be switched to upadacitinib 15 mg QD. For these 
subjects, adverse events and exposure to upadacitinib 30 mg QD will be censored at the 
time of dose switch; subsequent adverse events and exposure starting the day of first dose 


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of upadacitinib 15 mg QD will be summarized under separate groups, as described in 
Section 8.1.  Assessment of potentially clinical significant laboratory and vital sign values 
will be based on the same treatment exposure groups as for adverse events, as described 
above.  For summary of mean change from baseline in laboratory values and vital signs, 
exposure sequences 3, 5 and 7 (i.e., subjects who switched from upadacitinib 30 mg QD 
to 15 mg QD) will be censored at the time of dose switch. Mean change from baseline for 
laboratory values and vital signs collected after dose switch will be summarized 
separately by visits post switch.
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 19.0 or 
most up to date version.  All adverse event tables will be sorted in alphabetical order by 
SOC and PT and descending percentages for each treatment group.
10.2.1
Analysis of Adverse Events Prior to Protocol-Defined 
Treatment Switching at Week 26
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. 


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●
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
In the AE overview summary, any event with an unknown severity will be considered as 
severe and any AE with an unknown relationship will be considered as having 
"reasonable possibility" of being related to study drug.
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) will be provided for the treatment difference in AE percentage between 
each Upadacitinib dose group and the MTX group.
As a sensitivity analysis, the AE overview summary will be repeated by randomized 
treatment groups.  In this summary, all AEs with an onset date after the first dose of study 
drug will be included, regardless of whether the AE occurred more than 30 days after the 
last dose of study drug.
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 


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●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events 
●
TEAEs reasonably possibly related to study drug
●
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.
As a sensitivity analysis, the AE summary by SOC and PT will be repeated by 
randomized treatment groups.  In this summary, all AEs with an onset date after the 
first dose of study drug will be included, regardless of whether the AE occurred more than 
30 days after the last dose of study drug.
10.2.1.3
TEAEs by Maximum Severity
TEAEs will also be summarized by maximum severity by "as treated" treatment group 
and overall.  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 Maximum Relationship
TEAEs will also be summarized by maximum relationship to Upadacitinib and Placebo, 
as assessed by the investigator, by "as treated" treatment group and overall.  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 


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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.
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 and overall using SOC and MedDRA PT.  The 
AESI categories will be identified per Standard MedDRA Queries (SMQs)/Company 
MedDRA Queries (CMQs) in Table 12 below.  Adjudicated cardiovascular events will be 
summarized and presented by treatment group using the CAC adjudicated categories.


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Table 12.
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
excluding Tuberculosis and 
Herpes Zoster
CMQ
"Opportunistic Infection excluding 
Tuberculosis and Herpes Zoster"
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" SMQ removing 
NMSC output
Lymphoma
SMQ
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders"
Adjudicated Gastrointestinal 
Perforations
Output from 
adjudication
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
Anemias"
Neutropenia
CMQ
"Hematological Toxicity – Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity – Lymphopenia"
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"
Active Tuberculosis
CMQ
"Active Tuberculosis"
Adjudicated Cardiovascular 
Events
Output from 
CAC
MACE*
Cardiovascular Death
Non-fatal Myocardial 
Infarction
Non-fatal Stroke


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Table 12.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches 
(Continued)
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Undetermined/Unknown 
Cause of Deaths
Other Cardiovascular events
Adjudicated Thrombotic Events
Output From 
CAC
Venous Thromboembolic 
Events**
Deep Vein Thrombosis
Pulmonary Embolism
Other Venous Thrombosis
Arterial Thromboembolic 
Events (non-cardiac, non-
neurologic)
CAC = Cardiovascular Adjudication Committee; CMQ = company MedDRA query; PT = preferred term; 
SMQ = standard MedDRA query
*
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) (fatal 
and non-fatal).
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 will be analyzed using event rates adjusted by cumulative 
exposure and will be based on the actual treatment received at the time of AE occurrence. 
Starting with Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects 
receiving upadacitinib 30 mg QD will be switched to upadacitinib 15 mg QD. For these 
subjects, adverse events and exposure to upadacitinib 30 mg QD will be censored at the 
time of dose switch; subsequent adverse events and exposure starting the day of first dose 


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of upadacitinib 15 mg QD will be summarized under separate groups. The detailed 
treatment exposure groups, including the handling of dose switch, are described in 
Section 8.1.
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 by 
treatment group and overall 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
For this calculation, one 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.  For each 
treatment group, the denominator of the rates will be the total number of days exposed to 
study drug summed across all treated subjects divided by 365.25.  The TEAE 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 and overall.
In the AE overview summary, any event with an unknown severity will be considered as 
severe and any AE with an unknown relationship will be considered as having 
"reasonable possibility" of being related to study drug.  Additional TEAEs may be 


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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) will be provided for the treatment difference in the TEAE rate per 
100 patient years between each Upadacitinib dose group and the MTX group.
As a sensitivity analysis, the AE overview summary per 100 patient-years of study 
exposure will be repeated by exposure groups.  In this summary, all AEs with an onset 
date after the first dose of study drug will be included, regardless of whether the AE 
occurred more than 30 days after the last dose of study drug.  This sensitivity analysis will 
only be performed in final CSR.
10.2.2.2
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure
For each treatment group, the TEAE rate per 100 patient-years of exposure 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
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
For this calculation, one year will be considered to be 365.25 days.  For each treatment 
group, the numerator of the overall rate, the SOC rate, or the PT rate, will be the total 
number of TEAEs reported overall, for the SOC, or for the PT, respectively; that is a 
subject can be counted more than once overall, for a SOC, and for a PT.  For each 
treatment group, the denominator of the rates will be the total number of days exposed to 
study drug summed across all treated subjects divided by 365.25.  The TEAE rate per 
100 patient-years of exposure will be calculated as [(numerator/denominator)]*100.  The 


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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 overall, for each 
SOC, and for each PT for each treatment group.  
As a sensitivity analysis, the AE summary per 100 patient-years of study exposure by 
SOC and PT will be repeated by exposure groups.  In this summary, all AEs with an onset 
date after the first dose of study drug will be included, regardless of whether the AE 
occurred more than 30 days after the last dose of study drug.  This sensitivity analysis will 
only be performed in final CSR.
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) categories will be summarized and 
presented for each treatment group and overall using SOC and MedDRA PT (for 
adjudicated cardiovascular events, the CAC adjudicated categories will be used).  The 
AESI categories will be identified per Standard MedDRA Queries (SMQs)/Company 
MedDRA Queries (CMQs).
For each treatment group, the treatment-emergent Adverse Events of Special Interest 
(AESI) rate per 100 patient-years of exposure will be calculated overall, for each SOC and 
each PT, for each of the AESI listed in Section 10.2.1.6. 
For this calculation, one year will be considered to be 365.25 days.  For each treatment 
group, the numerator of the overall rate, the SOC rate, or the PT rate, will be the total 
number of TEAEs reported overall, for the SOC, or for the PT, respectively; that is a 
subject can be counted more than once overall, for a SOC, and for a PT.  
For each treatment group, the denominator of the rates will be the total number of days 
exposed to study drug summed across all treated subjects divided by 365.25.  Please refer 
to Section 8.1 for the calculation of study drug exposure.  The TEAE 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 


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(denominator), and the TEAE rate per 100 patient-years will be presented overall, for each 
SOC, and for each PT for each treatment group.  
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.
Table 13.
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)


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Table 13.
List of Laboratory Variables (Continued)
Laboratory Variables
Chemistry (continued)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Uric acid
Sodium
Potassium
Calcium
Inorganic Phosphorus
Creatine Phosphokinase (CPK)
Chloride
Bicarbonate
Cholesterol
LDL cholesterol
HDL cholesterol
LDL/HDL ratio
Cholesterol/HDL ratio
International Normalized Ratio (INR) reflux only
Urinalysis
Specific Gravity
pH
Protein
Glucose  
Ketones
Blood
Microscopic Examination (if needed)
Urobilinogen
Bilirubin
Leukocytes


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Table 13.
List of Laboratory Variables (Continued)
Laboratory Variables
Urinalysis (continued)
Nitrites
Other 
hs-CRP
QuantiFERON-TB Gold
IgG and IgM
ESR
10.3.2
Analysis of Laboratory Data Prior to Protocol-Defined 
Treatment Switching at Week 26
10.3.2.1
Assessment of Mean 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. 
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.
Plot for each treatment group over time will be provided for key lab parameters.
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 


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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.
No statistical tests will be performed for this analysis.
10.3.2.3
Assessment of Potentially Clinical 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 and 
overall.  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 


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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
●
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 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" exposure sequences as described in Section 10.1.2. 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.


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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.
Plot for each exposure sequence over time will be provided for key lab parameters up to 
Week 48.
Starting with Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects 
receiving upadacitinib 30 mg QD will be switched to upadacitinib 15 mg QD.  Mean 
change from baseline in laboratory values for subjects who switched from upadacitinib 
30 mg QD to 15 mg QD will be censored at the time of dose switch, and mean change 
from baseline for values post switch will be summarized separately, as described in 
Section 10.1.2.
10.3.3.2
Assessment of Potentially Clinical Significant Laboratory 
Values 
Long-term laboratory data will be summarized based on the number and percentage of 
subjects meeting the criteria for potentially clinical significant laboratory values and by 
the actual treatment received at the time of the event occurrence.  Starting with
Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects receiving 
upadacitinib 30 mg QD will be switched to upadacitinib 15 mg QD. The treatment 
exposure groups for summarizing potentially clinical significant laboratory values are the 
same as the ones for long-term AE analysis as described in Section 8.1 and 
Section 10.1.2.
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 study drug in the corresponding treatment group (which may be different 
than the first dose of study drug received in the study).  For example, for a subject who 
started on MTX and switched to Upadacitinib 15 mg QD + MTX combo therapy, 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 


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first dose of Upadacitinib 15 mg QD. For subjects who switched from upadacitinib 30 mg 
QD to upadacitinib 15 mg QD, lab values under upadacitinib 15 mg QD exposure would 
still be evaluated against the baseline defined based on the first dose of Upadacitinib 30 
mg QD.
A listing of all subjects with any laboratory determination meeting OMERACT criteria of 
Grade 3 or 4 will be provided by Grade.  For creatinine phosphokinase and creatinine, 
NCI CTC criteria will be used.  Only subjects with worsening in grade compared to 
baseline grade will be captured.  For each 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 criteria of potential clinical interest (as described in Section 10.3.2.4) 
will be summarized by the actual treatment received at the time of the event occurrence. 
Starting with Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects 
receiving upadacitinib 30 mg QD will be switched to upadacitinib 15 mg QD. The 
treatment exposure groups for summarizing liver elevations are the same as the ones for 
long-term AE analysis as described in Section 8.1 and Section 10.1.2.
A subject can be counted under different exposure groups if he/she switched study drug 
and experienced potentially clinical significant laboratory values under different exposure 
groups.
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.


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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 14.
Table 14.
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
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
10.4.2
Analysis of Vital Sign Prior to Protocol-Defined Treatment 
Switching at Week 26
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.  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 and 
overall. 
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" exposure 


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sequences as described in Section 10.1.2.  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.
Long Term Vital Sign will also be summarized based on the number and percentage of 
subjects meeting the criteria for potentially clinical significant vital sign values and by the 
actual treatment received at the time of the event occurrence.  The treatment exposure 
groups are the same as the ones for long-term AE analysis as described in Section 8.1. 
In the evaluation of potentially clinically significant vital sign values, the baseline value 
will be determined by the last non-missing measurement recorded on or before the date of 
the first dose of study drug in the corresponding treatment group, similarly as described in 
Section 10.3.3.2.
Starting with Amendment 5.01.01 (for Japan) and Amendment 6 (for global), subjects 
receiving upadacitinib 30 mg QD will be switched to upadacitinib 15 mg QD. Mean 
change from baseline in vital signs for subjects who switched from upadacitinib 30 mg 
QD to 15 mg QD will be censored at the time of dose switch, and mean change from 
baseline for values post switch will be summarized separately, as described in Section 
10.1.2.  The treatment exposure groups for summarizing potentially clinical significant 
vital sign values are the same as the ones for long-term AE analysis as described in 
Section 10.2.2 and Section 10.1.2.  For the purpose of evaluating potentially clinical 
significant vital sign values, for subjects who switched from upadacitinib 30 mg QD to 
upadacitinib 15 mg QD, baseline is defined based on the first dose of Upadacitinib 30 mg 
QD, similarly as described in Section 10.3.3.2.
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.


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11.0
Summary of Changes
11.1
Summary of Changes between the Previous Version and the 
Current Version 
The primary efficacy analysis and Period 1 reporting have been completed under the SAP 
version 2.0. The current SAP update applies only to future reporting of long term 
analysis.
1.
Updated throughout the SAP to align with Protocol Amendment 6, including 
handling of dose switch from upadacitinib 30 mg QD to 15 mg QD (hereafter 
referred to as "dose switch").
2.
Updated Section 7.0 to clarify analysis details and incorporate additional summary 
of dose switch.
3.
Updated Section 8.0 study drug exposure groups to accommodate dose switch. 
4.
Updated Section 9.1 to clarify the definition of treatment group sequences.
5.
Updated Sections 9.1 and Section 9.4 to incorporate handling of dose switch for 
long-term efficacy analysis.
6.
Updated Section 9.1.1 to describe the missing data handling approach for the 
additional sensitivity analysis using longitudinal models for long-term efficacy.
7.
Updated Section 9.4 to incorporate the additional sensitivity analysis for long-term 
efficacy. 
8.
Added language to clarify analysis details in Sections 10.2.1.1, Section 10.2.2.1, 
Section 10.2.2.3.
9.
Updated Sections 10.2.1.6 and Section 10.4.1 to align with the latest upadacitinib 
AESI definitions in PSSAP V4.0.
10.
Updated Section 10.1.2, Section 10.2.2, Section 10.2.2.1, Section 10.3.3.1, Section 
10.3.3.2, Section 10.3.3.3 and Section 10.4.3 to incorporate handling of dose 
switch for long-term safety analysis.


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11.
Updated Section 10.1.2, Section 10.3.3.1 and Section 10.4.3 to clarify the use of 
exposure sequences.
12.
Added Appendix B to describe analysis accounting for impact of COVID-19 
pandemic.
12.0
Version History
Table 15.
SAP Version History Summary
Version
Date
Summary
1.0
28 Mar 2017
SAP for Data Monitoring Committee
2.0
16 Apr 2018
Original version of study SAP. Version 2.0 was used for the 
primary analysis.
3.0
11 Sep 2020
Updated to align with Protocol Amendment 6, including 
handling of dose switch from upadacitinib 30 mg QD to 15 mg 
QD. Included additional sensitivity analysis for long-term 
efficacy, and analyses due to COVID-19 impact. 
13.0
Appendices
Appendix A
OMERACT Criteria
Appendix B
Statistical Analysis to Account for Impact of COVID-19 Pandemic


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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
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
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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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
B7.  Pericarditis/ 
pericardial effusion
Rub heard, asymptomatic
Detectable effusion by 
echocardiogram, symptomatic 
NSAID required
Detectable on chest x-ray, 
dyspnoea; or pericardiocentesis; 
requires corticosteroids
Pulsus alternates with low cardiac 
output; requires surgery


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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
D2.  Bullous eruption
Localised, asymptomatic
Localised, symptomatic, requiring 
treatment
Generalised, responsive to 
treatment; reversible
Prolonged, generalised, or 
requiring hospitalisation for 
treatment


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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
E4.  Taste 
disturbance 
(dysgeusia)
Transiently altered; metallic
Persistently altered; limited effect 
on eating
Disabling, effect on nutrition
NA


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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
F6.  Xerophtalmia 
(dry eyes)
Mild scratchiness
Symptomatic without interfering 
with function, requires artificial 
tears
Interferes with vision/function, 
corneal ulceration
Loss of sight


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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
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)


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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
I4.  Depressed 
consciousness 
(somnolence)
Observed, transient, intermittent, 
not interfering with function
Somnolence or sedation, 
interfering with function
Persistent, progressive, obundation, 
stupor
Coma


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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
1.2 – 1.9 × ULN
2.0 – 4.0 × ULN
4.0 × ULN with weakness but 
without life-threatening signs or 
symptoms
> 4.0 × ULN with signs or 
symptoms of rhabdomyolysis or 
life-threatening
L10.  Serum uric acid
1.2 – 1.6 × ULN
1.7 – 2.9 × ULN
3.0 – 5.0 × ULN or gout
NA
L11.  Creatinine 
(mg/dl)
1.1 – 1.3 × ULN
1.4* – 1.8 × ULN
1.9 – 3.0 × ULN
> 3.0 × ULN
L12.  SGOT (AST)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.1 – 8.0 × ULN
> 8.0 × ULN
L13.  SGPT (ALT)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.0 – 8.0 × ULN
> 8.0 × ULN
L14.  Alkaline 
phosphatase
1.1 – 1.5** × ULN
1.6 – 3.0 × ULN
3.0 – 5.0 × ULN
> 5.0 × ULN
L15.  T. bilirubin
1.1 – 1.4 × ULN
1.5 – 1.9 × ULN
2.0 – 3.0 × ULN
> 3.0 × ULN
L16.  LDH
1.3 – 2.4 × ULN
2.5 – 5.0 × ULN
5.1 – 10 × ULN
> 10 × ULN


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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.


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Appendix B.
Statistical Analysis to Account for Impact of COVID-19 Pandemic
1.0
Overview
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and collection, analysis and the interpretation of 
clinical trial data. Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic. For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic. Impacted visits due to COVID-19 will be 
recorded in the database. 
This appendix describes the additional analyses and updates to existing analyses due to 
COVID-19 impact. At the time of COVID-19 pandemic, all study subjects are in Period 2 
of the study. The primary efficacy analysis and Period 1 reporting have been completed 
in 2018 and are not affected by the COVID-19 pandemic. The analyses described in this 
appendix are only applicable to Period 2 and future reporting of the long term analyses. 
2.0
Patient Disposition
Period 2 patient disposition and reason for discontinuation will be summarized as 
described in Section 7.0. For subjects who prematurely discontinued study drug or study 
participation, the reasons for discontinuation will be summarized with two additional 
categories capturing discontinuation due to COVID-19 infection or logistical restrictions 
related to the COVID-19 pandemic (as collected in CRF):
●
Adverse event (AE)
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy
●
COVID-19 infection
●
COVID-19 logistical restrictions


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●
Other
In addition, the number and percentage of subjects with scheduled study visits affected by 
COVID-19 pandemic will be summarized by treatment group sequences. The impact on 
study visits will be summarized by the following categories (as collected in CRF) by visit: 
●
Missed visit
●
Virtual visit
●
In person, partial assessments done
3.0
Long Term Efficacy Analysis
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the study, or missing due to COVID-19 infection or logistic 
restriction. The probability of having missed visits and missing data due to COVID-19 
infection or logistical restrictions related to the COVID-19 pandemic can be reasonably 
assumed to be unrelated to the unobserved values. Therefore, for the purpose of statistical 
analysis, it is reasonable to assume that these missing data are missing at random (MAR) 
and the statistical models that require MAR assumption are appropriate. 
As described in Section 9.4, longitudinal analysis models MMRM and GLMM will be 
used for long term efficacy analysis for the "non-switcher" treatment sequences, and will 
be maintained for long term efficacy analysis in the presence of missing data due to 
COVID-19.
4.0
Safety Analysis
In listings of adverse events and deaths, a flag indicating whether the event or death was 
related to COVID-19 infection will be presented. A listing of COVID-19 related adverse 
events may be provided.


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14.0
Reference
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.