Conditions: Rheumatoid Arthritis
Keywords: Musculoskeletal Disease Arthritis Joint Disease Anti-inflammatory agents Antirheumatic agents ABT-494 upadacitinib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 499
Healthy volunteers: no

Brief summary:
The study objective of Period 1 (Day 1 to Week 24) is to compare the safety and efficacy of upadacitinib 30 mg once daily (QD) and 15 mg QD versus placebo for the treatment of signs and symptoms of participants with moderately to severely active rheumatoid arthritis (RA) who are on a stable dose of csDMARDs and had an inadequate response to or intolerance to at least 1 bDMARD.

The study objective of Period 2 (Week 24 to Week 260) is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 15 mg QD and 30 mg QD in participants with RA who completed Period 1.

Detailed description:
This study includes a 35-day screening period; a 24-week randomized, double-blind, parallel-group, placebo controlled treatment period (Period 1); a 236-week blinded long-term extension period (Period 2); and a 30-day follow-up period (call or visit).

Period 1 consists of a 12-week double-blind, placebo-controlled treatment phase plus a 12-week double-blind phase where all participants were to receive upadacitinib; at Week 12 participants assigned to placebo will be switched to upadacitinib according to their randomization assignment.

Participants who meet eligibility criteria will be randomized in a 2:2:1:1 ratio to one of four treatment groups:

* Group 1: Upadacitinib 30 mg QD (Day 1 to Week 12) → upadacitinib 30 mg QD (Week 12 and thereafter)
* Group 2: Upadacitinib 15 mg QD (Day 1 to Week 12) → upadacitinib 15 mg QD (Week 12 and thereafter)
* Group 3: Placebo (Day 1 to Week 12) → upadacitinib 30 mg QD (Week 12 and thereafter)
* Group 4: Placebo (Day 1 to Week 12) → upadacitinib 15 mg QD (Week 12 and thereafter)

Participants will continue stable dose of csDMARD therapy for the first 24 weeks of the study.

Participants who complete the Week 24 visit (end of Period 1) will enter the blinded long-term extension portion of the study, Period 2 and continue to receive the same dose of upadacitinib per original randomization assignment in a blinded manner. Starting at Week 24, at least 20% improvement in both swollen joint count (SJC) and tender joint count (TJC) compared to Baseline is required to remain on study drug. Starting at Week 24, initiation of or change in corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or adding or increasing doses in up to 2 csDMARDs (concomitant use of up to 2 csDMARDs except the combination of methotrexate and leflunomide) is allowed as per local label.

With the implementation of Protocol Amendment 4, all participants in the extension period will receive open-label upadacitinib 15 mg QD, including those currently on upadacitinib 30 mg QD.

Arms:
arm 1: Period 1: Participants receive upadacitinib 15 mg once daily for 24 weeks.

Period 2: Participants will continue on upadacitinib 15 mg once daily from Week 24 to Week 260. arm 2: Period 1: Participants receive upadacitinib 30 mg once daily for 24 weeks.

Period 2: Participants continue on upadacitinib 30 mg once daily until implementation of Protocol Amendment 4, then participants begin to receive upadacitinib 15 mg once daily up to Week 260. arm 3: Period 1: Participants receive placebo once daily for 12 weeks followed by upadacitinib 15 mg once daily for 12 weeks.

Period 2: Participants will continue on upadacitinib 15 mg once daily from Week 24 to Week 260. arm 4: Period 1: Participants receive placebo once daily for 12 weeks followed by upadacitinib 30 mg once daily for 12 weeks.

Period 2: Participants continue on upadacitinib 30 mg once daily until implementation of Protocol Amendment 4, then participants begin to receive upadacitinib 15 mg once daily up to Week 260.

Interventions: intervention 1: Placebo intervention 2: Upadacitinib
Intervention descriptions: intervention 1: Tablet; Oral intervention 2: Tablet; Oral

Protocol document:
Prot_002.pdf: 


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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
21 January 2016
Amendment 1
29 February 2016
Amendment 1.01 (Sweden Only)
06 May 2016
Amendment 1.02 (France Only)
09 May 2016
Amendment 1.03 (Denmark Only)
16 June 2016
Amendment 2
10 October 2016
Amendment 2.01 (Sweden Only)
26 October 2016
Amendment 2.02 (France Only)
26 October 2016
Amendment 2.03 (Denmark Only)
26 October 2016
Amendment 2.02.01 (France Only)
09 December 2016
Amendment 2.02.02 (France Only)
17 April 2017
Amendment 2.02.03 (France Only)
21 June 2017
Amendment 3
26 October 2017
Amendment 3.01 (Sweden Only)
20 November 2017
Amendment 3.02 (France Only)
13 November 2017
Amendment 3.03 (Germany Only)
10 January 2018
Amendment 3.02.01 (France Only)
21 September 2018
Amendment 4
13 December 2019
Administrative Change 1
03 January 2020
Administrative Change 2
31 January 2020
Amendment 5 
30 June 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 1.0, Title Page
Rationale: Update the sponsor/emergency contact.
 


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●
Update Section 1.2, Synopsis
Rationale: Revised to be consistent with Amendment 6 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)
 


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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 
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.
○
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.  Removed 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 
 


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emergency prevent the study drug dispensation to the subject onsite, if 
permitted by local regulations.
●
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 x 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.
 


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●
Update Section 9.3, Subject Information and Consent
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
Protocol Number:  M13-542
Name of Study Drug:  Upadacitinib
Phase of Development:  3
Name of Active Ingredient:  Upadacitinib
Date of Protocol Synopsis:  08 December 2020
Protocol Title:  A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to 
Placebo on Stable Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) in 
Subjects with Moderately to Severely Active Rheumatoid Arthritis with Inadequate Response or 
Intolerance to Biologic DMARDs (bDMARDs)
Objectives:
Period 1
To compare the safety and efficacy of upadacitinib 30 mg once daily (QD) and 15 mg QD versus 
placebo on a background of csDMARD(s) for the treatment of signs and symptoms of rheumatoid 
arthritis (RA) in bDMARD-inadequate response (bDMARD-IR) or bDMARD-intolerant subjects with 
moderately to severely active RA.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib 30 mg QD and 15 mg QD in 
subjects with RA who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 300
Study Population:  
Adult female and male subjects who are at least 18 years of age with a diagnosis of RA for ≥ 3 months 
who also fulfill the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria 
for RA.  Subjects who have been treated ≥ 3 months prior to the first dose of study drug with 
≥1 bDMARD therapy for RA in the past and failed at least 1 bDMARD therapy may be enrolled.  
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) ≥ 3 mg/L (central lab) at Screening.  Subjects must have been on a stable dose of csDMARD 
therapy (restricted to methotrexate [MTX], chloroquine, hydroxychloroquine, sulfasalazine, or 
leflunomide) for ≥ 4 weeks prior to the first dose of study drug.
Number of Subjects to be Enrolled:  Approximately 450
 


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Methodology:  
This is a Phase 3, multicenter study that includes two periods.  Period 1 is the 24-week randomized, 
double-blind, parallel-group, placebo-controlled treatment period designed to compare the safety and 
efficacy of upadacitinib 30 mg QD and 15 mg QD versus placebo for the treatment of signs and 
symptoms of subjects with moderately to severely active RA who have an inadequate response to or 
intolerance to bDMARD therapy and are currently on a stable dose of csDMARDs.  Period 2 is a blinded 
long-term extension to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 30 mg QD 
and 15 mg QD in subjects with RA who have completed Period 1.  Starting with Amendment 4, all 
subjects will  receive open-label upadacitinib 15 mg QD, including those currently on upadacitinib 30 
mg QD.
The study duration will include a 35-day maximum screening period; a 24-week randomized, 
double-blind, parallel-group, placebo controlled treatment period (Period 1); a blinded extension period 
(236 weeks) (Period 2); and a 30-day follow-up period.
Subjects who meet eligibility criteria will be randomized in a 2:2:1:1 ratio to one of four treatment 
groups:  

Group 1:  upadacitinib 30 mg QD, N = 150 (Day 1 to Week 12) → upadacitinib 30 mg QD 
(Week 12 and thereafter)

Group 2:  upadacitinib 15 mg QD, N = 150 (Day 1 to Week 12) → upadacitinib 15 mg QD 
(Week 12 and thereafter)

Group 3:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib 30 mg QD (Week 12 and 
thereafter)

Group 4:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib 15 mg QD (Week 12 and 
thereafter)
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the first dose of study 
drug and must remain on a stable dose until Week 24; the csDMARD dose may be decreased only for 
safety reasons.  Subjects who do not achieve CDAI ≤ 10 at Week 24 should have background 
medication(s) adjusted or initiated after assessments for Week 24 have been completed.  Starting at 
Week 24 (after Week 24 assessments have been performed), initiation of or change in corticosteroids, 
non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or adding or increasing doses for up to 
2 csDMARDs (concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide) is allowed as per local label.
Subjects who complete the Week 24 visit (end of Period 1) will enter the blinded long term extension 
portion of the study, Period 2 (236 weeks).  Subjects who are assigned to upadacitinib treatment groups 
in Period 1 will continue to receive upadacitinib 15 mg QD or 30 mg QD per original randomization 
assignment in a blinded manner.  Subjects who are assigned to placebo for the first 12 weeks of Period 1 
and subsequently switched to receive upadacitinib 15 mg QD or 30 mg QD per their pre-specified 
randomization assignments at Week 12, will continue to receive the same dose of upadacitinib per 
original randomization assignment in a blinded manner.  Starting with Amendment 4, all subjects will 
receive open-label upadacitinib 15 mg QD, including those currently on upadacitinib 30 mg QD.  
An unblinded analysis will be conducted after all subjects have completed Period 1 (Week 24) for the 
purpose of regulatory submission.  Study sites and subjects will remain blinded for the duration of the 
study (Periods 1 and 2).
 


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Methodology (Continued):
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.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who also fulfill the 2010 ACR/EULAR classification criteria for 
RA.
3.
Subjects have been treated with bDMARD therapy for RA in the past and failed at least 1 bDMARD 
therapy prior to first dose of study drug as defined by at least one of the following criteria:

did not show an adequate response to at least 1 bDMARD after a treatment of ≥ 3 months

had to discontinue at least 1 bDMARD due to intolerability or toxicity, irrespective of treatment 
duration
Subjects who are discontinued from prior bDMARD therapy only due to other reasons (good 
response or non-medical reasons including insurance/financial issues, clinical trial completed, etc) 
are not eligible for the study.
4.
Subjects have been receiving csDMARD therapy ≥ 3 months and on a stable dose for ≥ 4 weeks 
prior to the first dose of study drug:

The following csDMARDs are allowed (stable dose for ≥ 4 weeks prior to the first dose of 
study drug):  oral or parenteral MTX (7.5 to 25 mg/week), sulfasalazine (≤ 3000 mg/day), 
hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and leflunomide 
(≤20 mg/day).

A combination of up to two background csDMARDs is allowed EXCEPT the combination of 
MTX and leflunomide.
5.
Subject meets both of the following minimum 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 ≥ 3 mg/L (central lab) at Screening Visit.
 


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:  
1.
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint 
disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic 
arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms]).  Current diagnosis of secondary 
Sjogren's Syndrome is permitted.
3.
Laboratory values meeting the following criteria within the Screening period prior to the first dose 
of study drug:  serum aspartate transaminase > 2 × upper limit of normal (ULN); serum alanine 
transaminase > 2 × ULN; estimated glomerular filtration rate by simplified 4-variable Modification 
of Diet in Renal Disease formula < 40 mL/min/1.73 m2; total white blood cell count < 2,500/µL; 
absolute neutrophil count < 1,500/µL; platelet count < 100,000/µL; absolute lymphocyte count 
< 800/µL; and hemoglobin < 10 g/dL.
Investigational Product:
Upadacitinib
Doses:
15 mg QD
30 mg QD
Mode of Administration:
Oral
Reference Therapy:
Only for Period 1 first 12 Weeks:  Matching placebo for upadacitinib 
QD
Dose:
N/A
Mode of Administration:
Oral
Duration of Treatment:  260 weeks (Period 1:  24 weeks; Period 2:  236 weeks)
 


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Criteria for Evaluation:
Efficacy:
Period 1
The primary endpoint is the proportion of subjects achieving ACR20 response (US/FDA regulatory 
purposes) or the proportion of subjects achieving low disease activity (LDA) (EU/EMA regulatory 
purposes) at Week 12.
ACR20 response rate will be determined based on 20% or greater improvement in Tender Joint Count 
(TJC) and Swollen Joint Count (SJC) and ≥ 3 of the 5 measures of Patient's Assessment of Pain (Visual 
Analog Scale [VAS]), Patient's Global Assessment of Disease Activity (VAS), Physician's Global 
Assessment of Disease Activity (VAS), Health Assessment Questionnaire Disability Index (HAQ-DI), 
or hsCRP.
LDA is defined as Disease Activity Score (DAS)28 (C-reactive protein [CRP]) ≤ 3.2.
Ranked key secondary endpoints (at Week 12) for US/FDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
LDA based on DAS28 (CRP);
4.
Change from baseline in Short Form-36 (SF-36) Physical Component Score (PCS);
Ranked key secondary endpoints (at Week 12) for EU/EMA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
ACR20 response rate;
3.
Change from baseline in HAQ-DI;
4.
Change from baseline in SF-36 PCS;
Other key secondary endpoints (at Week 12, if not specified) for both US/FDA and EU/EMA regulatory 
purposes are:
1.
ACR50 response rate;
2.
ACR70 response rate;
3.
ACR20 response rate at Week 1.
 


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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 1 (Continued)
Additional endpoints at all visits are:

Change from baseline in individual components of ACR response;

ACR20/50/70 response rates;

Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation rate [ESR]);

Change from baseline in CDAI and SDAI;

Change from baseline in morning stiffness;

Proportion of subjects achieving change from baseline in HAQ-DI ≤ –0.3;

Proportion of subjects achieving LDA and proportion of subjects achieving CR based on 
DAS28 (CRP), DAS28 (ESR), Simplified Disease Activity Index (SDAI), and Clinical Disease 
Activity Index (CDAI) criteria (see below);

ACR/EULAR Boolean remission;
DAS28 (CRP) and 
DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
  
Additional endpoints (at Weeks 4, 12, and 24) are:

Change from baseline in EQ-5D-5L;

Change from baseline in ISI (sleep);

Change from baseline in SF-36.
Period 2
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 36, 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 morning stiffness;

Proportion of subjects achieving change from baseline in HAQ-DI ≤ –0.3;

Proportion of subjects achieving LDA and proportion of subjects achieving CR based on 
DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined for Period 1);

Concomitant corticosteroid use.
 


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Criteria for Evaluation (Continued):
Efficacy (Continued):
Period 2 (Continued)
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Week 48 only:

Change from baseline in EQ-5D-5L;

Change from baseline in ISI;

Change from baseline in SF-36.
Pharmacokinetic (Period 1 Only):
Blood samples for assay of upadacitinib and possibly other concomitant medications in plasma will be 
collected at Weeks 1, 2, 4, 8, 12, 16, 20, and 24/Premature Discontinuation.
In Vivo Pharmacodynamic Biomarkers (Periods 1 and 2):
Period 1
Change from Baseline in lymphocyte subsets (including but not limited to natural killer cells, natural 
killer T cells, B cells, and T cells) will be evaluated at Weeks 8, 12, 16 and 24/Premature 
Discontinuation. 
Period 2
Change from baseline in lymphocyte subsets (including but not limited to natural killer cells, natural 
killer T cells, B cells, and T cells) will be evaluated at Weeks 36, 48, and every 24 weeks thereafter.
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.
 


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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:
Comparisons of the primary and key secondary efficacy endpoints will be made between each 
upadacitinib group and the combined placebo groups.  The overall type I error rate of the primary and 
key secondary endpoints for the two doses will be strongly controlled.
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons between each upadacitinib group and the combined placebo groups 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 
combined placebo groups will be carried out using the analysis of covariance model with treatment 
group as the fixed factor, and the corresponding baseline value and the main stratification factors as the 
covariates.
Non-responder imputation approach will serve as the primary analysis approach for binary endpoints and 
multiple imputations will serve as the primary analysis approach for continuous endpoints.  Sensitivity 
analyses based on observed cases approach and 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.
 


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ACR
American College of Rheumatology
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine transaminase
ANC
absolute neutrophil count
anti-CCP
anti-cyclic citrullinated peptide
AST
aspartate transaminase
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
COVID-19
Coronavirus Disease - 2019
CPK
creatine phosphokinase
CR
clinical remission
CRF
case report form
CRP
C-reactive protein
csDMARD
conventional synthetic disease-modifying anti-rheumatic drug
CSR
clinical study report
CXR
chest x-ray
CYP
Cytochrome
DAS
disease activity score
DMARD
disease-modifying anti-rheumatic drug
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DTP
Direct-to-Patient
ECG
Electrocardiogram
eCRF
electronic case report form
 


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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
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
ICH
International Conference On Harmonization
IEC
independent ethics committee
IGRA
interferon-gamma release assay
IMP
investigational medicinal product
INR
international normalized ratio
IR
inadequate response
IRB
institutional review board
IRT
interactive response technology
ISI
insomnia severity index
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JAK
Janus kinase
LDA
low disease activity
 


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


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SAP
statistical analysis plan
SDAI
simplified 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
Tyk2
Tyrosine kinase 2
ULN
upper limit of normal
V/F
apparent volume of distribution
VAS
visual analog scale
VTE
venous thromboembolic events
WBC
white blood cell
 


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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........................................16
2.0
Table of Contents...................................................................20
3.0
Introduction ...........................................................................26
3.1
Differences Statement..............................................................................29
3.2
Benefits and Risks....................................................................................30
4.0
Study Objectives....................................................................30
5.0
Investigational Plan...............................................................31
5.1
Overall Study Design and Plan:  Description ..........................................31
5.2
Selection of Study Population..................................................................38
5.2.1
Inclusion Criteria .....................................................................................38
5.2.2
Exclusion Criteria ....................................................................................41
5.2.3
Prior, Concomitant, and Prohibited Therapy ...........................................44
5.2.3.1
Permitted Background RA Therapy.........................................................45
5.2.3.2
Prohibited Therapy...................................................................................46
5.2.4
Contraception Recommendations ............................................................51
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Exploratory 
Research and Validation Studies, and Safety 
Assessments/Variables.............................................................................53
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................53
5.3.1.1
Study Procedures .....................................................................................55
5.3.1.2
Collection and Handling of In Vivo Pharmacodynamic Biomarker 
and Optional Samples for Exploratory Research and Validation 
Studies......................................................................................................77
5.3.1.2.1
In Vivo Pharmacodynamic Biomarker Samples......................................77
5.3.1.2.2
Optional Samples for Exploratory Research and Validation 
Studies......................................................................................................77
5.3.2
Drug Concentration Measurements .........................................................79
5.3.2.1
Collection of Samples for Analysis .........................................................79
5.3.2.2
Measurement Methods.............................................................................80
 


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5.3.3
Efficacy Variables....................................................................................80
5.3.3.1
Period 1 Variables....................................................................................80
5.3.3.1.1
Primary Variable......................................................................................80
5.3.3.1.2
Key Secondary Variables.........................................................................81
5.3.3.1.3
Additional Variables ................................................................................82
5.3.3.2
Period 2 Variables....................................................................................83
5.3.4
Safety Variables.......................................................................................83
5.3.5
Pharmacokinetic Variables ......................................................................84
5.3.6
In Vivo Pharmacodynamic Biomarker Samples and Exploratory 
Research Variables and Validation Studies .............................................84
5.3.6.1
In Vivo Pharmacodynamic Biomarker Samples......................................84
5.3.6.2
Exploratory Research Variables and Validation Studies.........................84
5.4
Removal of Subjects from Therapy or Assessment.................................85
5.4.1
Discontinuation of Individual Subjects....................................................85
5.4.2
Discontinuation of Entire Study...............................................................87
5.5
Treatments................................................................................................88
5.5.1
Treatments Administered.........................................................................88
5.5.2
Identity of Investigational Product...........................................................88
5.5.2.1
Packaging and Labeling...........................................................................88
5.5.2.2
Storage and Disposition of Study Drugs..................................................89
5.5.3
Method of Assigning Subjects to Treatment Groups...............................89
5.5.4
Selection and Timing of Dose for Each Subject......................................90
5.5.5
Blinding....................................................................................................91
5.5.5.1
Blinding of Investigational Product.........................................................91
5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)......................92
5.5.6
Treatment Compliance.............................................................................92
5.5.7
Drug Accountability.................................................................................93
5.6
Discussion and Justification of Study Design..........................................94
5.6.1
Discussion of Study Design and Choice of Control Groups....................94
5.6.2
Appropriateness of Measurements...........................................................94
5.6.3
Suitability of Subject Population .............................................................95
5.6.4
Selection of Doses in the Study ...............................................................95
6.0
Complaints .............................................................................96
 


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6.1
Medical Complaints.................................................................................96
6.1.1
Definitions................................................................................................96
6.1.1.1
Adverse Event..........................................................................................96
6.1.1.2
Serious Adverse Events ...........................................................................97
6.1.1.3
Adverse Events of Special Interest ..........................................................98
6.1.2
Adverse Event Severity............................................................................99
6.1.3
Relationship to Study Drug......................................................................99
6.1.4
Adverse Event Collection Period...........................................................100
6.1.5
Serious Adverse Event Reporting..........................................................102
6.1.6
Pregnancy...............................................................................................103
6.1.7
Toxicity Management ............................................................................104
6.1.8
Data Monitoring Committee..................................................................109
6.1.9
Cardiovascular Adjudication Committee...............................................109
6.2
Product Complaint .................................................................................109
6.2.1
Definition ...............................................................................................109
6.2.2
Reporting................................................................................................110
7.0
Protocol Deviations..............................................................110
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................111
8.1
Statistical and Analytical Plans..............................................................111
8.1.1
Analysis Populations..............................................................................112
8.1.1.1
Full Analysis Set....................................................................................112
8.1.1.2
Per Protocol Analysis Set.......................................................................112
8.1.1.3
Safety Analysis Set ................................................................................112
8.1.2
Subject Accountability, Disposition and Study Drug Exposure............112
8.1.2.1
Subject Accountability...........................................................................112
8.1.2.2
Subject Disposition ................................................................................113
8.1.2.3
Study Drug Exposure.............................................................................113
8.1.3
Analysis of Demographic and Baseline Characteristics ........................113
8.1.4
Efficacy Analyses ..................................................................................114
8.1.4.1
Efficacy Analysis for Period 1...............................................................114
8.1.4.1.1
Primary Efficacy Variable .....................................................................114
8.1.4.1.2
Key Secondary Efficacy Variables ........................................................115
 


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8.1.4.1.3
Other Efficacy Variables........................................................................115
8.1.4.1.4
Multiplicity Control for Primary and Ranked Secondary 
Endpoints ...............................................................................................116
8.1.4.1.5
Imputation Methods...............................................................................116
8.1.4.2
Long-Term Efficacy Analysis for Period 1 and Period 2 
Combined...............................................................................................117
8.1.5
Safety Analyses......................................................................................117
8.1.5.1
General Considerations..........................................................................117
8.1.5.2
Analysis of Adverse Events...................................................................117
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE) ......................................118
8.1.5.2.2
Serious Adverse Events and Death ........................................................119
8.1.5.3
Analysis of Laboratory, Vital Sign, and ECG Data...............................119
8.1.6
Pharmacokinetic and Exposure-Response Analyses .............................119
8.1.7
Statistical Analysis of Biomarker Data..................................................121
8.2
Determination of Sample Size ...............................................................122
8.3
Randomization Methods ........................................................................123
9.0
Ethics.....................................................................................123
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................123
9.2
Ethical Conduct of the Study.................................................................124
9.3
Subject Information and Consent...........................................................125
10.0
Source Documents and Case Report Form 
Completion ...........................................................................126
10.1
Source Documents .................................................................................126
10.2
Case Report Forms.................................................................................126
11.0
Data Quality Assurance ......................................................129
12.0
Use of Information...............................................................130
13.0
Completion of the Study .....................................................130
14.0
Investigator's Agreement....................................................132
15.0
Reference List ......................................................................133
 


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List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers....................................................................................................48
Table 2.
Clinical Laboratory Tests.........................................................................71
Table 3.
Identity of Investigational Product...........................................................88
Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values..................................................................................106
Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (For France).............................................................146
List of Figures
Figure 1.
Period 1 Study Design .............................................................................33
Figure 2.
Period 2 Study Design .............................................................................34
Figure 3.
Criteria for HBV DNA PCR Qualitative Testing ....................................73
Figure 4.
Adverse Event Collection ......................................................................100
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................136
Appendix B.
List of Protocol Signatories....................................................................138
Appendix C.
Local Requirements ...............................................................................139
Appendix D.
Study Activities (Period 1).....................................................................156
Appendix E.
Study Activities – Optional Samples for Exploratory Research 
and Validation Studies (Period 1 Only).................................................161
Appendix F.
Study Activities (Period 2).....................................................................162
Appendix G.
Physician's Global Assessment of Disease Activity Example...............165
Appendix H.
Joint Evaluation Worksheet Example....................................................166
Appendix I.
Latent TB Risk Assessment Form Example ..........................................168
Appendix J.
Patient's Global Assessment of Disease Activity Example ...................169
Appendix K.
Patient's Assessment of Pain Example...................................................170
Appendix L.
Health Assessment Questionnaire (HAQ-DI) Example.........................171
 


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Appendix M.
Patient's Assessment of Severity and Duration of Morning 
Stiffness Example ..................................................................................174
Appendix N.
EuroQoL-5D-5L Example .....................................................................175
Appendix O.
Short Form-36 (SF-36™) Health Status Survey Questionnaire 
Example .................................................................................................178
Appendix P.
Insomnia Severity Index Example.........................................................184
Appendix Q.
Rheumatology Common Toxicity Criteria v.2.0 Example ....................186
 


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


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


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


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of upadacitinib compared with placebo (50%).  At all doses of upadacitinib compared to 
placebo, significantly higher proportions of subjects achieved LDA and CR at Week 12.
Safety data 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 M13-542 differs from other upadacitinib studies as it is the first study to evaluate 
the safety and efficacy of upadacitinib in subjects with inadequate response to or 
intolerance to any bDMARDs.
 


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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.  For a 
detailed summary of upadacitinib benefit and safety, see the Investigator's Brochure.
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
To compare the safety and efficacy of upadacitinib 30 mg QD and 15 mg QD versus 
placebo on a background of csDMARD(s) for the treatment of signs and symptoms of RA 
in bDMARD-inadequate response (bDMARD-IR) or bDMARD-intolerant subjects with 
moderately to severely active RA.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib 30 mg QD and 
15 mg QD in subjects with RA who have completed Period 1.
 


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5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, multicenter study that includes two periods.  Period 1 is the 24-week 
randomized, double-blind, parallel-group, placebo-controlled period designed to compare 
the safety and efficacy of upadacitinib 30 mg QD and 15 mg QD versus placebo for the 
treatment of signs and symptoms of subjects with moderately to severely active RA who 
have an inadequate response to or intolerance to bDMARD therapy and are currently on a 
stable dose of csDMARDs.  Period 2 is a blinded long-term extension to evaluate the 
long-term safety, tolerability, and efficacy of upadacitinib 30 mg QD and 15 mg QD in 
subjects with RA who have completed Period 1.  Starting with Amendment 4, all subjects 
will  receive open-label upadacitinib 15 mg QD, including those currently on upadacitinib 
30 mg QD.
The study is designed to enroll approximately 450 subjects at approximately 300 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 24-week randomized, 
double-blind, parallel-group, placebo controlled treatment period (Period 1); a 236-week 
blinded extension period (Period 2); and a 30-day follow-up (call or site visit).
Subjects who meet eligibility criteria will be randomized in a 2:2:1:1 ratio to one of 
four treatment groups:
●
Group 1:  upadacitinib 30 mg QD, N = 150 (Day 1 to Week 12) → 
upadacitinib 30 mg QD (Week 12 and thereafter)
●
Group 2:  upadacitinib 15 mg QD, N = 150 (Day 1 to Week 12) → 
upadacitinib 15 mg QD (Week 12 and thereafter)
 


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●
Group 3:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib 30 mg QD 
(Week 12 and thereafter)
●
Group 4:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib 15 mg QD 
(Week 12 and thereafter)
Subjects must have been on a stable dose of csDMARD(s) for ≥ 4 weeks prior to the 
first dose of study drug and must remain on a stable dose until Week 24; the csDMARD 
dose may be decreased only for safety reasons.  Subjects who do not achieve CDAI ≤ 10 
at Week 24 should have background medication(s) adjusted or initiated after assessments 
for Week 24 have been completed.  Starting at Week 24 (after Week 24 assessments have 
been performed), initiation of or change in corticosteroids, non-steroidal 
anti-inflammatory drugs (NSAIDs), acetaminophen, or adding or increasing doses in up to 
2 csDMARDs (concomitant use of up to 2 csDMARDs except the combination of MTX 
and leflunomide) is allowed as per local label.  Subjects on a combination of MTX and 
leflunomide therapy should discontinue either MTX or leflunomide (see washout periods 
defined in Section 5.2.3) prior to first dose of study drug administration.
Starting at Week 24, at least 20% improvement in BOTH SJC AND TJC compared to 
baseline is required to remain on study drug.  Anyone who does not fulfill this criterion at 
2 consecutive visits (starting at Week 24) must be discontinued from study drug.
Subjects who complete the Week 24 visit (end of Period 1) will enter the blinded 
long-term extension portion of the study, Period 2 (236 weeks).  Subjects who are 
assigned to upadacitinib treatment groups in Period 1 will continue to receive upadacitinib 
15 mg QD or 30 mg QD per original randomization assignment in a blinded manner.  
Subjects who are assigned to placebo for the first 12 weeks of Period 1 and subsequently 
switched to receive upadacitinib 15 mg QD or 30 mg QD per their pre-specified 
randomization assignments at Week 12, will continue to receive the same dose of 
upadacitinib per original randomization assignment in a blinded manner.
 


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An unblinded analysis will be conducted after all subjects have completed Period 1 
(Week 24) for the purpose of regulatory submission.  Study sites and subjects will remain 
blinded for the duration of the study (Periods 1 and 2).
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.
Study design schematics of Period 1 and Period 2 are shown in Figure 1 and Figure 2, 
respectively.
Figure 1.
Period 1 Study Design
csDMARD = conventional synthetic disease modifying anti-rheumatic drug; DMARD = disease modifying 
anti-rheumatic drug; n = number; QD = once daily; RA = rheumatoid arthritis; W = week
*
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; QD = once daily; W = week
Note:
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, including those 
currently on upadacitinib 30 mg QD.
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 
the screening period.  If the re-tested lab value(s) remain(s) exclusionary, the subject will 
be considered a screen failure with no additional re-screening possible.  Redrawing 
samples if previous samples were unable to be analyzed would not count as a retest since 
previous result was never obtained.
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 Section 5.2 are met, there are no changes in 
the subject's medical history that would warrant re-testing, and no more than 90 days have 
passed.
Period 1 (24-Week Randomized, Double-Blind Treatment Period)
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 24 Visit.  At the 
Baseline Visit, subjects who meet all the inclusion criteria and none of the exclusion 
criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the study and 
randomized to double-blind treatment.  During this period of the study, subjects will visit 
the study site at Weeks 1, 2, 4, 8, 12, 16, 20, and 24.  A ± 3 day window is permitted 
around scheduled study visits.  The last dose of study drug in Period 1 is taken the day 
prior to the Week 24 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.
Period 2 (Long-Term Extension Period [236 Weeks])
Period 2 will begin at the Week 24 Visit after all assessments have been completed.  
During Period 2, subjects will have a study visit at Weeks 36, 48, every 12 weeks through 
Week 240, and Week 260/PD.  A ± 7 day window is permitted around scheduled study 
visits.  
 


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Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC is required to 
remain on study drug.  Anyone who does not fulfill this criterion at 2 consecutive visits 
(starting at Week 24) despite optimization of background RA therapies (see 
Section 5.2.3.1) must be discontinued from study drug.
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.
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.  As the subject has discontinued study drug, all rescue 
and efficacy driven discontinuation criteria no longer apply (e.g., CDAI calculation at 
Week 24, 20% TJC/SJC calculation for PD).  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 (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 24), but decided not to participate 
in the extension Period 2; OR
●
Completed the last visit of Period 2; OR
●
Prematurely discontinued study drug and/or study participation and have 
completed a PD visit.  In this case the 30 day Follow-Up 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 30 days after last dose of study drug.
 


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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 450 subjects with moderately to severely active RA 
will be randomized at approximately 300 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.
Diagnosis of RA for ≥ 3 months who also fulfill the 2010 ACR/EULAR 
classification criteria for RA.
3.
Subjects have been treated with bDMARD therapy for RA in the past and failed at 
least 1 bDMARD therapy prior to first dose of study drug as defined by at least 
one of the following criteria:
●
did not show an adequate response to at least 1 bDMARD after a treatment of 
≥ 3 months
●
had to discontinue at least 1 bDMARD due to intolerability or toxicity, 
irrespective of treatment duration
 


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Subjects who are discontinued from prior bDMARD therapy only due to other 
reasons (good response or non-medical reasons including insurance/financial 
issues, clinical trial ended, etc.) are not eligible for the study.
4.
Subjects have been receiving csDMARD therapy ≥ 3 months and on a stable dose 
for ≥ 4 weeks prior to the first dose of study drug.
●
The following csDMARDs are allowed (stable dose for ≥ 4 weeks prior to the 
first dose of study drug):  oral or parenteral MTX (7.5 to 25 mg/week), 
sulfasalazine (≤ 3000 mg/day), hydroxychloroquine (≤ 400 mg/day), 
chloroquine (≤ 250 mg/day), and leflunomide (≤ 20 mg/day).
●
A combination of up to two background csDMARDs is allowed EXCEPT the 
combination of MTX and leflunomide.
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 ≥ 3 mg/L (central lab) at Screening Visit.
6.
Stable doses of 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.
7.
Subjects must have discontinued all bDMARDs prior to the first dose of study 
drug.  The washout period for bDMARDs prior to the first dose of study drug is 
specified below or should be at least five times the mean terminal elimination 
half-life of a drug:
●
≥ 4 weeks for etanercept;
●
≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, 
and tocilizumab;
●
≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pretreatment 
level or normal reference range (central lab) if pretreatment levels are not 
available.
 


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8.
Subjects must have discontinued all high-potency opiates at least 1 week and oral 
traditional Chinese medicine for at least 4 weeks prior to the first dose of study 
drug (refer to Section 5.2.3.2 for prohibited medications).
9.
Women of childbearing potential (refer to Section 5.2.4), must not have a positive 
pregnancy test at the Screening or Baseline Visits.  Note:  subjects with borderline 
pregnancy test 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 either postmenopausal, OR permanently surgically 
sterile OR for women of childbearing potential practicing at least 
one protocol-specified method of birth control (refer to Section 5.2.4), that is 
effective from Study Day 1 through at least 30 days after the last dose of study 
drug.
●
Additional local requirements may apply.  Refer to Appendix C for local 
requirements.
11.
If the male subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 90 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)
 


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5.2.2
Exclusion Criteria
1.
Prior exposure to any JAK inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
History of any arthritis with onset prior to age 17 years or current diagnosis of 
inflammatory joint disease other than RA (including but not limited to gout, 
systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis including 
ankylosing spondylitis and non-radiographic axial spondyloarthritis, reactive 
arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms]).  Current 
diagnosis of secondary Sjogren's Syndrome is permitted.
3.
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.
4.
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.
5.
Female who is pregnant, breastfeeding, or is considering becoming pregnant during 
the study or for approximately 30 days after the last dose of study drug.
6.
Male who is considering fathering a child or donating sperm during the study or for 
approximately 90 days after the last dose of study drug.
7.
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: 
 


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●
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;
●
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV 
antibody (HCV Ab).
8.
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB testing).
9.
Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong 
CYP3A inducers from Screening through the end of the study (refer to Table 1 for 
examples of commonly used strong CYP3A inhibitors and inducers).
10.
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.
11.
History of any malignancy except for successfully treated NMSC or localized 
carcinoma in situ of the cervix.
12.
History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months.
13.
History of gastrointestinal perforation (other than appendicitis or penetrating 
injury), diverticulitis or significantly increased risk for GI perforation per 
investigator judgment.
14.
Conditions that could interfere with drug absorption including but not limited to 
short bowel syndrome.
15.
Subject has been a previous recipient of an organ transplant.
16.
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.
17.
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.
 


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18.
History of an allergic reaction or significant sensitivity to constituents of the study 
drug (and its excipients) and/or other products in the same class.
19.
Laboratory values meeting the following criteria within the Screening period prior 
to the first dose of study drug:
●
Serum aspartate transaminase (AST) > 2 × ULN;
●
Serum alanine transaminase (ALT) > 2 × ULN;
●
Estimated glomerular filtration rate (GFR) by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula 
< 40 mL/min/1.73 m2;
●
Total white blood cell (WBC) count < 2,500/µL;
●
Absolute neutrophil count (ANC) < 1,500/µL;
●
Platelet count < 100,000/µL;
●
Absolute lymphocyte count < 800/µL;
●
Hemoglobin < 10 g/dL.
20.
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 confirmed systolic blood pressure 
> 160 mmHg or diastolic blood pressure > 100 mmHg;
●
Any other condition which, in the opinion of the Investigator, would put the 
subject at risk by participating in the protocol.
21.
Clinically relevant or significant ECG abnormalities, including ECG with QT 
interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) 
> 500 msec.
 


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Rationale for Exclusion Criteria
1 – 2
To select the appropriate subject population
5 – 6 
Upadacitinib is teratogenic in both rats and rabbits.  
The impact of upadacitinib on human pregnancies is 
unknown
3, 4, 7 – 21
To ensure safety of the subjects throughout the study
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 
since date of RA diagnosis (based on subject recollection and available medical records) 
should be entered into the appropriate eCRF.
csDMARD Washout
The following washout periods should be met for subjects who are being treated with 
multiple csDMARDs if washout of 1 or more csDMARDs is required:
●
≥ 4 weeks prior to the first dose of study drug for MTX, minocycline, 
penicillamine, sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, 
gold formulations, cyclophosphamide, tacrolimus, cyclosporine, 
mycophenolate, mizolibine
●
≥ 8 weeks prior to the first dose of study drug for leflunomide if no elimination 
procedure was followed, or adhere to a washout procedure (i.e., 11 days with 
colestyramine, or 30 days washout with activated charcoal as per local label)
●
≥ five times the mean terminal elimination half-life for any other csDMARDs 
not listed above.
 


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The AbbVie Therapeutic Area Medical Director should be contacted if there are any 
questions regarding concomitant or prior therapies.
5.2.3.1
Permitted Background RA Therapy
Subjects should continue on their stable (≥ 4 weeks prior to the first dose of study drug) 
background csDMARD therapy (restricted to oral or parenteral MTX, [7.5 to 
25 mg/week], sulfasalazine [≤ 3000 mg/day], hydroxychloroquine, [≤ 400 mg/day], 
chloroquine [≤ 250 mg/day], and leflunomide [≤ 20 mg/day]) up to Week 24.  At any 
time, the csDMARD dose may be decreased only for safety reasons.  Subjects taking 
MTX should take a dietary supplement of oral folic acid (or equivalent, such as folinic 
acid) throughout study participation.  Folic acid dosing and timing of regimen should be 
followed according to Investigator's instructions.  AbbVie will not provide the 
csDMARDs (or folic acid, if taking MTX).  
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 at baseline, 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 (After Week 24 assessments have been 
performed);
●
If taking any of the above including low potency analgesics, i.e., tramadol, 
codeine, hydrocodone, or propoxyphene at baseline on an as-needed basis 
(PRN), they should continue to use them for the same reason and same dose 
each time but they should not be taken within 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 
 


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class (see Section 5.2.3.2 for prohibited therapies).  PRN use of inhaled corticosteroids is 
permitted at any time.
Subjects who do not achieve CDAI ≤ 10 at Week 24 should have background 
medication(s) adjusted or initiated (see below) after assessments for Week 24 have been 
completed.
Starting at Week 24 (after Week 24 assessments have been performed) and thereafter, 
intra-articular, intramuscular, intravenous, trigger point or tender point, intra-bursa, and 
intra-tendon sheath injections of corticosteroids, dosage and frequency per standard of 
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.  
In addition, in Period 2, starting at Week 24 (after Week 24 assessments have been 
performed) and thereafter, initiation of or change in corticosteroids, NSAIDs, 
acetaminophen/paracetamol or csDMARDs (restricted to oral or parenteral MTX, 
sulfasalazine, hydroxychloroquine, chloroquine, and leflunomide, and restricted to 
concomitant use of up to 2 csDMARDs except the combination of MTX and leflunomide) 
is allowed as per local label.  For RA flare treatment, no more than 3 consecutive days of 
systemic corticosteroids (maximum dose of 0.5 mg/kg/day of prednisone or its equivalent) 
is allowed, after which subject should resume their usual daily oral corticosteroid dose.
5.2.3.2
Prohibited Therapy
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.
 


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Corticosteroids
Oral corticosteroids > 10 mg prednisone/day or equivalent and intra-articular, 
intramuscular, intravenous, trigger point or tender point, intra-bursa, and intra-tendon 
sheath corticosteroids are NOT allowed in Period 1.
Biologic Therapies
All biologic therapies related to RA treatment are prohibited during the study 
(i.e., Periods 1 and 2).
Subjects must have discontinued the bDMARD prior to the first dose of study drug as 
specified in the washout procedures (Inclusion Criterion 7, Section 5.2.1).  For all other 
bDMARDs, contact the Therapeutic Area Medical Director for the washout period 
required prior to the first dose of study drug.
Examples of biologic therapies include but are not limited to the following:
●
Humira® (adalimumab)
●
Enbrel® (etanercept)
●
Remicade® (infliximab)
●
Orencia® (abatacept)
●
Kineret® (anakinra)
●
Rituxan® (rituximab)
●
Cimzia® (certolizumab pegol)
●
Simponi® (golimumab)
●
Actemra® (tocilizumab)
●
Raptiva® (efalizumab)
●
Tysabri® (natalizumab)
●
Stelara® (ustekinumab)
●
Benlysta® (belimumab)
●
Dupixent® (dupilumab)
 


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●
Taltz® (ixekizumab)
●
Cosentyx® (secukinumab)
●
Entyvio® (vedolizumab)
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors or strong CYP3A inducers is excluded 
from the Screening Visit through the end of the study (i.e., end of Period 2).  The most 
common strong CYP3A inhibitors and inducers are listed in Table 1.
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
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 
 


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high potency opiates at least 1 week prior to the first dose of study drug, including (but 
not limited to):
●
oxycodone
●
oxymorphone
●
fentanyl
●
levorphanol
●
buprenorphine
●
methadone
●
hydromorphone
●
morphine
●
meperidine
Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 
five half-lives of the drug (whichever is longer) prior to the first dose of study drug are 
excluded from participation in this study.  Investigational drugs are also prohibited during 
the study.
Vaccines
Although not mandated by the protocol, vaccines recommended by local guidelines 
should be considered.  If the subject and investigator choose to administer live vaccines, 
these vaccinations must be completed (per local label) at least 4 weeks before first dose of 
study drug with appropriate precautions.  Live vaccinations are prohibited during 
Period 1, including at least 30 days (or longer if required locally) after the last dose of 
study drug.  
Examples of live vaccines include, but are not limited to, the following:
●
Monovalent live influenza A (H1N1) (intranasal);
●
Seasonal trivalent live influenza (intranasal);
 


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●
Zostavax (herpes zoster, live attenuated);
●
Rotavirus;
●
Varicella (chicken pox);
●
Measles-mumps-rubella or measles mumps rubella varicella;
●
Oral polio vaccine;
●
Smallpox;
●
Yellow fever;
●
Bacille Calmette-Guérin (BCG);
●
Typhoid.
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.
Traditional Chinese Medicine
Oral traditional Chinese medicine is not permitted during the study, and subjects must 
have discontinued traditional Chinese medicine at least 4 weeks prior to the first dose of 
study drug.
 


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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 a follicle stimulating hormone (FSH) level > 40 mIU/mL.
If the female subject is < 55 years of age:
AND has had no menses for ≥ 12 months AND has no history of permanent surgical 
sterilization (defined above), FSH should be tested at Screening.
●
If FSH is not tested, it is assumed that the subject is of childbearing potential 
and protocol-specified contraception is required.
●
If the FSH is tested and the result is consistent with post-menopausal status, 
contraception is not required.
●
If the FSH is tested and the result is consistent with pre-menopausal status, 
contraception is required, and a serum pregnancy test must be performed (see 
Section 5.3.1.1 pregnancy test).
For a female subject at any age:
●
Female subjects with menses within the past 12 months are of childbearing 
potential and FSH is therefore not required but contraception is required.
●
Female subjects who are surgically sterile (defined above) are not of 
childbearing potential and therefore no FSH testing or contraception is 
required.
 


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A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following highly effective methods of birth control that is effective from Study Day 1 (or 
earlier) through at least 30 days after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal, injectable) associated with the inhibition of 
ovulation, initiated at least 30 days prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.
●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of the medical assessment of the surgical success and is the only sexual 
partner.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  (if acceptable per local requirements):  Applies to women of 
childbearing potential who do not have male partners and are not engaging in 
heterosexual intercourse as their preferred and usual lifestyle (periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
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).
If during the course of the study a woman becomes surgically sterile or post-menopausal 
(defined above) and complete documentation is available, contraceptive measures as 
defined above are no longer required.  
 


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It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy upadacitinib.  
The concomitant csDMARDs (i.e., methotrexate, sulfasalazine, etc.) have been prescribed 
per standard of care prior to study entry and are allowed to be continued during the study.  
Contraception should continue while the subject is on the concomitant csDMARD(s) and 
that duration of contraception after discontinuation of the csDMARD(s) should be based 
on the local label.
Additional local requirements may apply.  Refer to Appendix C for local requirements for 
Canada, Germany, and Korea.
Contraception Recommendation for Males
There are no contraception requirements for upadacitinib for male subjects or their female 
partner(s).
Contraception requirements related to the use of background csDMARDS including 
MTX, as well as concomitant therapies prescribed per standard of care, should be based 
on the local label.
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Exploratory 
Research and Validation Studies, and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are
summarized in tabular format in Appendix D, Appendix E, and Appendix F.
Study visits may be impacted by 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.
 


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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
○
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
○
Vital signs and body weight
○
Physical exam
○
Physician Global Assessment (PhGA)
○
TJC68/SJC66
 


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●
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
●
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 in vivo pharmacodynamic biomarkers (discussed in 
Section 5.3.1.2.1), exploratory research and validation studies (discussed in 
Section 5.3.1.2.2), drug concentration measurements (discussed in Section 5.3.2), the 
collection of prior and concomitant medication information (discussed in Section 5.2.3), 
 


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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.
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 
 


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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)
●
Short Form-36 (SF-36) (Appendix O)
●
Insomnia Severity Index (ISI) (Appendix P)*
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)*
●
EQ-5D-5L (Appendix N) (Week 48 only)
●
SF-36 (Appendix O) (Week 48 only)
●
ISI (Appendix P)*(Week 48 only)
 


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*
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.  Expert 
consultation for the evaluation and/or management of TB may be considered per 
Investigator discretion.
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. 
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 (TA MD).  The results of 
the TB test(s) will be retained at the site as the original source documentation.
 


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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.  Any positive TB screen after the patient has started the study, should be 
reported as an adverse event (AE) of latent or active TB (as applicable).
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 
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.
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-TB Gold 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 the QuantiFERON-TB Gold Test is NOT possible (or if both the 
QuantiFERON-TB Gold Test and the PPD Skin Test are required per local 
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 
 


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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 Quanti-FERON-TB Gold Plus.
●
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 Plus 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 
Plus 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 Plus.
Subjects with a negative TB test and chest x-ray (CXR) not suggestive of active TB or 
prior TB exposure may be enrolled.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent 
TB, including signs and symptoms and CXR.  Subjects with no signs or symptoms and a 
 


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CXR not suggestive of active TB may be enrolled after initiation of TB prophylaxis (see 
below).  Subjects with evidence of active TB must not be enrolled.
TB prophylaxis:
At screening, if the subject has evidence of 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. 
Of note:  Rifampicin or Rifapentine are not allowed for TB prophylaxis.
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy 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 every 48 weeks 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.
Subjects with documented completion of a full course of anti-TB therapy greater than 
1 year prior to first study drug administration may be allowed to enter the study only after 
consultation with the AbbVie Therapeutic Area Medical Director.
Newly initiated prophylactic treatment should be captured in the eCRF and in the source 
documents.  Prior therapy should be captured in the eCRF.
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 should be initiated and 2 to 4 weeks later (per local guidelines), subject should 
 


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be re-evaluated (unscheduled visit) for signs and symptoms as well as laboratory 
assessment of toxicity to TB prophylaxis.
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.
●
Every 48 weeks 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.
 


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A radiologist or pulmonologist must perform an assessment of the CXR.  The Principal 
Investigator will indicate the clinical significance of any findings and will sign and date 
the report.  In the assessment of the CXR, the Principal Investigator or their delegate must 
indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.  If the CXR demonstrates changes 
suggestive of previous TB (e.g., calcified nodule, fibrotic scar, apical or basilar pleural 
thickening) or other findings that are clinically significant, the Principal Investigator 
should contact the AbbVie Medical Monitor before enrolling the subject.
12-Lead ECG
For all subjects, a resting 12-lead ECG will be performed at screening, Week 48 and every 
48 weeks thereafter, as specified in Appendix D and Appendix F.  For subjects who do 
not enter Period 2 or prematurely discontinue from study, an ECG will be performed at 
their final visit as indicated 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 ventricular 
conduction abnormalities.  In these cases, the baseline QTcF will need to be entered into 
the appropriate eCRF for comparison as well.  In addition, any clinically significant 
findings will be documented in the source documents and later transcribed on to the 
appropriate eCRF.  Each signed original ECG will be monitored by the responsible site 
monitor and kept with subject's source documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided source documentation is available and provided 
nothing has changed in the subject's medical history to warrant a repeat test.  If there are 
other findings that are clinically significant, the Investigator must contact the AbbVie 
Therapeutic Area Medical Director before enrolling the subject.
 


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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.
Height and Weight
Height will be measured at the Screening Visit only (with shoes off).  Body weight will be 
measured at all scheduled visits except Week 1, as specified in Appendix D and 
Appendix F.  All measurements will be recorded in metric units where applicable.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate, respiratory rate, and body temperature will be obtained at visits specified in 
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 
 


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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 
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").
 


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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 
independent joint assessor should be identified.  The independent joint assessors should 
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 low disease 
activity and will be performed at the Week 24 visit.  An Interactive Response Technology 
(IRT) will calculate CDAI with input from site personnel on joint counts and the subject's 
and physician's Global Assessment of RA Disease Activity score.
 


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The calculation used to determine CDAI score at Week 24 is as follows:
CDAI = TJC28 + SJC28 + PtGA (cm) + PhGA (cm)
NOTE:  Investigator should optimize background RA therapies in subjects who failed to 
achieve a CDAI ≤ 10.
Pregnancy Test
A serum pregnancy test will be performed for all female subjects of childbearing potential 
at the Screening Visit.  The serum pregnancy test will be sent to and performed by the 
central laboratory.  If the serum pregnancy test is positive the subject is considered a 
screen failure.  If the serum pregnancy test is borderline, it should be repeated ≥ 3 days 
later to determine eligibility.  If the repeat serum pregnancy test is:
●
Positive, the subject is considered a screen failure;
●
Negative, the subject can be enrolled into the trial;
●
Still borderline ≥ 3 days later, this will be considered documentation of 
continued lack of a positive result and the subject can be enrolled into the 
study.
In Period 1, a urine pregnancy test will be performed for all female subjects of 
childbearing potential at the Baseline Visit prior to the first dose of study drug and at all 
subsequent visits except Week 1.  More frequent pregnancy tests will be performed 
throughout the study if required per local/country requirements.
●
If the baseline urine pregnancy test performed at the site is negative, then 
dosing with study drug may begin.  
●
If the baseline or post-baseline urine pregnancy test performed at the site is 
positive, dosing with study drug must be withheld and a serum pregnancy test 
is required.  The serum pregnancy test will be sent to and performed by the 
central laboratory.  If the serum pregnancy test is negative, study drug may be 
started or resumed.  If the serum pregnancy test is positive, study drug must be 
permanently discontinued.  In the event a serum pregnancy test comes back 
 


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borderline, a repeat test is required (≥ 3 days later) to document continued lack
of a positive result.
In Period 2, for women of childbearing potential, a urine pregnancy test will be performed 
at all visits 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 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 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 the study or 
continuation on 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 
 


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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 
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, 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.
 


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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.
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.
 


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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 only)e
QuantiFERON-TB Goldf
Rheumatoid Factore
Anti-CCP autoantibodiese
hs-CRPg
IgG and IgM
FSHh
MRB Paneli
Local Lab Tests:
Urine pregnancy testj
ESR
HIV (if required)k
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; 
MRB = Minimal Residual B-cells; PCR = polymerase chain reaction; RBC = red blood cell; RNA = ribonucleic acid; 
TB = tuberculosis; WBC = white blood cell
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.
 


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Table 2.
Clinical Laboratory Tests (Continued)
c.
INR will only be measured with a separate blood sample at repeat testing if ALT and/or AST > 3 × ULN.
d.
A serum pregnancy test will be performed for all women of childbearing potential at the Screening Visit and if 
postbaseline urine pregnancy test turns positive.
e.
At Screening only.
f.
If PPD not performed.
g.
In Period 1, the central lab hsCRP results starting from Baseline (Day 1) will not be reported to the Sponsor, 
Investigator, study site personnel, and the subject.  Results of hsCRP may be blunted in subjects taking a JAK 
inhibitor, thereby limiting its clinical utility in the setting of a possible safety assessment or adverse event 
management.  Any local hsCRP or CRP tests should not be reported to the investigator until treatment allocation is 
unblinded or subject is known to be receiving upadacitinib.  In Period 2, the central lab hsCRP results will remain 
blinded to Investigator, study site personnel, and the subject.  Starting with Amendment 4, at a timepoint specified 
by the Sponsor in Period 2, central laboratory hsCRP results will be reported to the Investigator/study site 
personnel. After treatment assignment is unblinded, local hsCRP or CRP tests are allowed.
h.
At screening for female subjects < 55 years old AND has had no menses for ≥ 12 months AND has no history of 
permanent surgical sterilization (defined in Section 5.2.4) an FSH should be tested.
i.
If needed to assess B cell counts in subjects who have discontinued rituximab, see Inclusion Criterion 7.
j.
A urine pregnancy test will be performed for all female subjects of childbearing potential at the Baseline Visit prior 
to the first dose of study drug and all subsequent visits except Week 1.  If the baseline urine pregnancy test 
performed at the site is negative, then dosing with study drug may begin.  If the baseline urine pregnancy test 
performed at the site is positive, dosing with study drug must be withheld and a serum pregnancy test is required.  
The serum pregnancy test will be sent to and performed by the central laboratory.  If the serum pregnancy test is 
negative, study drug dosing may be started.  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 postbaseline is positive, study drug needs to be temporarily discontinued and a serum pregnancy test 
is required.  The serum pregnancy test will be sent to and performed by the central laboratory.  If the serum 
pregnancy test is negative, study drug may be restarted.  If the serum pregnancy test is positive, study drug must be 
permanently discontinued.
k.
If 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.
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
 


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●
HBc Ab/anti-HBc
●
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 3, 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 3, Scenario B).*
●
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic 
reflex testing) (Figure 3, 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.
Figure 3.
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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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Hepatitis C:
Blood samples for Hepatitis C serology will be obtained at the Screening Visit.  A subject 
will not be eligible for study participation if test results indicate active Hepatitis C (HCV 
RNA detectable in any subject with anti HCV Ab).
HIV
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.
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 2:2:1:1 ratio using interactive response technology (IRT) 
to receive double-blind study drug in one of the following treatment groups:
●
Group 1:  upadacitinib 30 mg QD, N = 150 (Day 1 to Week 12) → 
upadacitinib 30 mg QD (Week 12 and thereafter)
●
Group 2:  upadacitinib 15 mg QD, N = 150 (Day 1 to Week 12) → 
upadacitinib 15 mg QD (Week 12 and thereafter)
●
Group 3:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib 30 mg QD 
(Week 12 and thereafter)
 


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●
Group 4:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib 15 mg QD 
(Week 12 and thereafter)
Randomization will be stratified by number of prior bDMARD use (stratum 1:  failed 1 or 
2 biologics with the same mechanism of action; stratum 2:  failed ≥ 3 biologics with the 
same mechanism of action and/or multiple mechanisms of action) and geographic region.  
Once approximately 35% of the total subjects have been randomized in stratum 2, further 
screening of subjects who meet stratum 2 criteria may be suspended.
See Section 5.5.3 for details.
Study Drug Dispensing, Dosing, and Compliance
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in 
Appendix D and Appendix F.  The first dose of study drug will be administered after all 
other Baseline (Day 1) procedures are completed.  Subjects will maintain a dosing diary 
for all study drug administered outside of the study visit (i.e., at home) to capture dosing 
dates and times.  At visits specified in 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.
All relevant dosing information will be entered into the eCRF at each visit.
Refer to Section 5.5 for additional information.
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
●
Study drug can be administered by the subject (or subject's caregiver) at home
●
Subject agrees to have the study drug shipped directly to their home
 


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●
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.
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.
 


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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 In Vivo Pharmacodynamic 
Biomarker and Optional Samples for Exploratory Research 
and Validation Studies
5.3.1.2.1
In Vivo Pharmacodynamic Biomarker Samples
Blood samples will be collected at the visits indicated in Appendix D and Appendix F and 
will be utilized to assess effects of upadacitinib inhibition on certain lymphocyte subsets, 
including but not limited to T (CD4+ and CD8+) cells, B (CD19+) cells, natural killer 
(NK) cells, and natural killer-T (NKT) cells.
The samples should be labeled and shipped as outlined in the study-specific laboratory 
manual.
5.3.1.2.2
Optional Samples for Exploratory Research and Validation 
Studies
In Period 1, subjects will have the option to provide samples for exploratory research and 
validation studies.  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 
 


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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.
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.
 


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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.  The 
procedure for obtaining and documenting informed consent is discussed in Section 9.3.
Samples will be shipped to AbbVie or a designated laboratory for long-term storage 
and/or analyses.  Instructions for the preparation and shipment of the samples will be 
provided in a laboratory manual.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for assay of upadacitinib and possibly other concomitant medications will 
be collected as follows:
●
Weeks 1 and 2 prior to dosing;
●
Weeks 4, 8, 12, 16, 20, and 24/PD at any time during the visit.
On Week 1 and Week 2 visit days, if possible, subjects should take the study drug dose at 
the clinic after collecting the PK blood sample, except if the subjects regularly take the 
study drug dose at night.  Those subjects who regularly take the study drug dose at night 
should continue to take study drug according to their normal schedule.  For all other 
visits, subjects can take the study drug dose on visit days at their regular schedule and not 
necessarily at the clinic.
 


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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.
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 Variable
The primary endpoint is the proportion of subjects achieving ACR20 response (US/FDA 
regulatory purposes) or the proportion of subjects achieving LDA (EU/EMA regulatory 
purposes) at Week 12.  Analyses will be conducted separately for US/FDA regulatory 
purposes and EU/EMA regulatory purposes; for each set of analysis, only one primary 
endpoint is specified.
ACR20 response rate will be determined based on 20% or greater improvement in TJC 
and SJC and ≥ 3 of the 5 measures of Patient's Assessment of Pain (VAS), Patient's 
Global Assessment of Disease Activity (VAS), Physician's Global Assessment of Disease 
Activity (VAS), HAQ-DI, or hsCRP.
LDA is defined as DAS28 (CRP) ≤ 3.2.  DAS28 (CRP) score will be determined based on 
a continuous scale of combined measures of TJC, SJC, Patient's Global Assessment of 
Disease Activity (PtGA) (in mm), and hsCRP (in mg/L) at Week 12.
 


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DAS28 (CRP) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(hsCRP&
+ 1) + 0.014 × PtGA» + 0.96
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
&
hsCRP refers to the high-sensitivity c-reactive protein lab value.  hsCRP unit in the DAS28 (CRP) 
equation is expressed as mg/L.
»
PtGA refers to the Patient's Global Assessment of Disease Activity.
where √is square root and ln is natural log.
5.3.3.1.2
Key Secondary Variables 
Ranked key secondary endpoints (at Week 12) for US/FDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
LDA as measured by DAS28 (CRP);
4.
Change from baseline in SF-36 Physical Component Score (PCS);
Ranked key secondary endpoints in Period 1 (at Week 12) for EU/EMA regulatory 
purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
ACR20 response rate;
3.
Change from baseline in HAQ-DI;
4.
Change from baseline in SF-36 Physical Component Score (PCS);
Other key secondary endpoints (at Week 12) for both US/FDA and EU/EMA regulatory 
purposes are:
1.
ACR50 response rate;
2.
ACR70 response rate;
 


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3.
ACR20 response rate at Week 1.
ACR20/50/70 response rates will be determined based on 20%/50%/70% or greater 
improvement in TJC and SJC and ≥ 3 of the 5 measures of Patient's Assessment of Pain 
(VAS), Patient's Global Assessment of Disease Activity (VAS), Physician's Global 
Assessment of Disease Activity (VAS), HAQ-DI, or hsCRP.
5.3.3.1.3
Additional Variables
Additional endpoints at all visits are:
●
Change from baseline in individual components of ACR response;
●
ACR20/50/70 response rates;
●
Change from baseline in DAS28 (CRP) and DAS28 (erythrocyte 
sedimentation rate [ESR]);
●
Change from baseline in CDAI and SDAI;
●
Change from baseline in morning stiffness;
●
Proportion of subjects achieving change from baseline in HAQ-DI ≤ –0.3;
●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), DAS28 (ESR), Simplified Disease Activity Index 
(SDAI), and CDAI criteria (see below);
●
ACR/EULAR Boolean remission;
DAS28 (CRP) and 
DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
Additional endpoints (at Weeks 4, 12, and 24) are:
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in ISI (sleep);
●
Change from baseline in SF-36.
 


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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 36, 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 morning stiffness;
●
Proportion of subjects achieving change from baseline in HAQ-DI ≤ –0.3;
●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined 
for Period 1);
●
Concomitant corticosteroid use.
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the 
following measures at Week 48 only:
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in ISI (sleep);
●
Change from baseline in SF-36.
5.3.4
Safety Variables
Safety evaluations include adverse event 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.
 


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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
In Vivo Pharmacodynamic Biomarker Samples and 
Exploratory Research Variables and Validation Studies
5.3.6.1
In Vivo Pharmacodynamic Biomarker Samples
Blood samples will be collected to assess the effects of upadacitinib inhibition on 
lymphocyte subsets including but not limited to:  T (CD4+ and CD8+) cells, B (CD19+) 
cells, NK cells, and NKT cells.
5.3.6.2
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.  Theses assessments may be 
explored in the context of RA or related conditions and/or upadacitinib or drugs of similar 
classes.  The results from these analyses are exploratory in nature and may not be 
included with the clinical study report (CSR).
The samples may also be used to develop new therapies, research methods or 
technologies.  In addition, samples from this study may be stored for future use.  Samples 
may then be used to validate putative biomarker signatures obtained from a prospective 
study, leading to the development of diagnostic tests.
 


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects can request to be discontinued from 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 safe 
continuation of the study drug, as determined by the Investigator or the 
AbbVie Therapeutic Area Medical Director.
●
Serious infections (e.g., sepsis) which cannot be adequately controlled within 
2 weeks by anti-infective treatment or would put the subject at risk for 
continued participation in the trial as determined by the Investigator.
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion or exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie Therapeutic Area Medical Director.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk, as determined by the AbbVie 
Therapeutic Area Medical Director.
●
Subject is non-compliant with TB prophylaxis (if applicable) or develops 
active TB at any time during the study.
●
The subject becomes pregnant while on study drug.
●
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial as determined by the 
Investigator or the AbbVie Therapeutic Area Medical Director.
 


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●
Subject develops a gastrointestinal perforation (other than due to appendicitis 
or mechanical injury).
●
Starting at Week 24 and thereafter, subject fails to show at least 20% 
improvement in both TJC and SJC compared to baseline at 2 consecutive 
visits, despite optimization of background RA therapies.
●
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus or non-
cardiac, non-neurologic arterial thrombosis.
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment should complete a Premature 
Discontinuation visit (PD visit) as soon as possible, preferably within 2 weeks.  
Afterwards, subjects should continue to be followed for all regularly scheduled visits, 
unless they have decided to discontinue the study participation entirely (withdrawal 
informed consent).  Subjects should be advised on the continued scientific importance of 
their data even if they discontinue treatment with study drug early.
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 subject is willing, a 30-day 
follow-up phone call (or visit) after the last dose of study drug may be completed to 
ensure all treatment emergent AEs/SAEs have been resolved or the occurrence of any new 
AEs/SAEs.  Subjects who discontinue the study prematurely after randomization will not 
be replaced.  
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study 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.
 


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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
or study drug for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored.
Additional local requirements may apply.  Refer to Appendix C for local requirements for 
France.
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.
 


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5.5
Treatments
5.5.1
Treatments Administered
Study drug will be taken orally once daily, beginning on Day 1 (Baseline), and should be 
taken at approximately the same time each day.  The study drug can be taken with or 
without food.  Subjects will continue their weekly stable background therapy of 
csDMARD(s).  AbbVie will not supply csDMARD(s) (nor folic acid or equivalent, such 
as folinic acid, for subjects who are on MTX).
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.
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 
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
30 mg 
15 mg
AbbVie
upadacitinib (ABT-494) 
matching placebo
oral
tablet
NA
AbbVie
5.5.2.1
Packaging and Labeling
Upadacitinib (ABT-494) and matching placebo will be packaged in bottles with quantities 
sufficient to accommodate study design.  Each kit label will contain a unique kit number.  
This kit number is assigned to a subject via IRT and encodes the appropriate study drug to 
 


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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 2:2:1:1 ratio using interactive response technology (IRT) 
to receive double-blind study drug in one of the following treatment groups:
●
Group 1:  upadacitinib (ABT-494) 30 mg QD, N = 150 (Day 1 to Week 12) → 
upadacitinib (ABT-494) 30 mg QD (Week 12 and thereafter)
●
Group 2:  upadacitinib (ABT-494) 15 mg QD, N = 150 (Day 1 to Week 12) → 
upadacitinib (ABT-494) 15 mg QD (Week 12 and thereafter)
●
Group 3:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib (ABT-494) 
30 mg QD (Week 12 and thereafter)
 


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●
Group 4:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib (ABT-494) 
15 mg QD (Week 12 and thereafter)
Randomization will be stratified by number of prior bDMARD use (stratum 1:  failed 1 or 
2 biologics with the same mechanism of action; stratum 2:  failed ≥ 3 biologics with the 
same mechanism of action and/or multiple mechanisms of action) and geographic region.  
Once approximately 35% of the total subjects have been randomized in stratum 2, further 
screening of subjects who meet stratum 2 criteria may be suspended.
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 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.5.1.
On dosing days that occur on study visit days, subjects should follow the regular dosing 
schedule (refer to Section 5.3.2.1 regarding Week 1 and Week 2 visits).
Each subject's dosing schedule should be closely monitored by the site at each study visit 
by careful review of the subject's dosing diary.  This will ensure that all subjects enrolled 
into the study maintain their original dosing schedule beginning with the first dose of 
study drug (Baseline/Day 1).
If a subject should forget to take their upadacitinib (ABT-494) (or matching placebo) dose 
at their regularly scheduled dosing time, they should take the forgotten dose as soon as 
 


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they remember the dose was missed as long as it is at least 10 hours before their next 
scheduled dose.  If a subject only remembers the missed dose within 10 hours before next 
scheduled dose, the subject should skip the missed dose and take the next dose at the 
scheduled time.  If the subject experiences a study drug interruption > 7 consecutive days 
during Weeks 1 through 24 (Period 1) or > 30 consecutive days after Week 24 (Period 2), 
they should notify the Investigator, and the Investigator will determine if study drug 
should be restarted.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
All AbbVie personnel with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie Drug Supply Management Team), the Investigator, study 
site personnel, and the subject will remain blinded to each subject's treatment throughout 
the study.  Starting with Amendment 4, all subjects will receive open-label upadacitinib 
15 mg QD, including those currently on upadacitinib 30 mg QD.  
In order to maintain the blind, the upadacitinib (ABT-494) tablets and placebo tablets 
provided for the study will be identical in appearance.  The IRT will provide access to 
unblinded subject treatment information in the case of medical emergency.
In the event of a medical emergency 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 
 


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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.
An unblinded analysis will be conducted after all subjects have completed Period 1 
(Week 24) for the purpose of regulatory submission.  Study sites and subjects will remain 
blinded for the duration of the study.
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.  Study sites and subjects will no 
longer be blinded after this point.
5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)
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 
 


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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 
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.
 


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Monitors will reconcile the site's processes, source documents, subject's dosing diaries, 
IRT or site accountability records, and destruction records to assure site compliance.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This study includes two periods:
Period 1 is a 24-week, randomized, double-blind, placebo-controlled period to compare 
safety and efficacy of upadacitinib versus placebo in subjects with moderately to severely 
active RA who have an inadequate response to or intolerance to bDMARD therapy and 
who are on a stable dose of csDMARDs.  Period 1 is designed to test superiority of 
upadacitinib versus placebo for achieving the primary endpoint (ACR20 for US/FDA 
regulatory purposes or LDA for EU/EMA regulatory purposes) at Week 12, and other 
secondary efficacy parameters, all on a stable background csDMARD therapy.
The purpose of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of 
upadacitinib 30 mg QD and 15 mg QD in a blinded fashion in subjects with RA who have 
completed Period 1.  Subjects will continue to receive upadacitinib 15 mg QD or 30 mg 
QD per original randomization assignment in a blinded manner.  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.
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All 
efficacy measurements in this study are standard for assessing disease activity in subjects 
with RA.  All clinical and laboratory procedures in this study are standard and generally 
accepted.
 


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5.6.3
Suitability of Subject Population
The intended study population is moderately to severely active RA patients who have had 
an inadequate response to or intolerance to prior bDMARD treatment.  Key entry criteria 
are to enroll adult female and male subjects who are at least 18 years of age with a 
diagnosis of RA for ≥ 3 months who also fulfill the 2010 ACR/EULAR classification 
criteria for RA.  Eligible study subjects must have ≥ 6 swollen joints (based on 66 joint 
counts) and ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits, 
and hsCRP level ≥3 mg/L (central lab) at Screening.  Subjects who have been treated 
≥3 months prior to the screening visit with ≥ 1 bDMARD therapy for RA in the past and 
failed at least 1 bDMARD therapy may be enrolled.  Subjects must have been on a stable 
background of csDMARD therapy (restricted to MTX, chloroquine, hydroxychloroquine, 
sulfasalazine, or leflunomide) for ≥4 weeks prior to the first dose of study drug.  
5.6.4
Selection of Doses in the Study
Two doses of the once-daily formulation of upadacitinib will be evaluated:  upadacitinib 
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, 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 M13-542, upadacitinib 
15 mg QD and 30 mg QD, dosed for up to 260 weeks, are expected to be efficacious with 
an acceptable safety profile.
Doses of 15 mg QD and 30 mg QD using the once-daily formulation provide equivalent 
daily AUC and comparable Cmax and Cmin to 6 mg BID and 12 mg BID, respectively, of 
the immediate-release formulation tested in Phase 2 studies in subjects with RA.  In 
Phase 2 studies, the 6 mg BID dose was shown to achieve the near maximum efficacy and 
the 12 mg BID dose was clearly shown to achieve the plateau of efficacy.
 


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6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For AEs, please refer to Section 6.1.  For product 
complaints, please refer to Section 6.2.
6.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of AEs on 
a routine basis throughout the study.  The Investigator will assess and record any AE in 
detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drug, and 
any action(s) taken.  For SAEs considered as having "no reasonable possibility" of being 
associated with study drug, the Investigator will provide other cause(s) of the event.  For 
AEs to be considered intermittent, the events must be of similar nature and severity.  AEs, 
whether in response to a query, observed by site personnel, or reported spontaneously by 
the subject will be recorded.
All AEs will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
 


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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 AE meets any of the following criteria, it is to be reported to AbbVie as an SAE 
within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
 


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Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  
Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in
inpatient hospitalization, or the development of drug 
dependency or drug abuse.
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
6.1.1.3
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study (see detailed 
toxicity management in Section 6.1.7):
●
Serious infections
●
Opportunistic infections
●
Herpes zoster
●
Active tuberculosis
●
Malignancy (all types)
●
Adjudicated gastrointestinal perforations
 


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●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE])
●
Anemia 
●
Neutropenia
●
Lymphopenia
●
Increased serum creatinine and renal dysfunction
●
Hepatic events and increased hepatic transaminases
●
Elevated 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 Q).22
6.1.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship
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."  
 


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In addition, when the investigator has not reported a relationship or deemed it not 
assessable, AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All AEs reported from the time of study drug administration until 30 days following 
discontinuation of study drug administration have elapsed will be collected, whether 
solicited or spontaneously reported by the subject.  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 4.
Figure 4.
Adverse Event Collection
*
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.
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 increases 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 
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
 


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●
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:
Immunology Safety Team
1 North Waukegan Road
North Chicago, IL  60064
Toll Free +1 833-942-2226
Email:
GPRD_SafetyManagement_Immunology@abbvie.com
 




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Information regarding a pregnancy occurrence in a study subject or the partner of an 
enrolled subject and the outcome of the pregnancy will be collected.  Pregnancies in study 
subjects and their partners will be identified from the date of the first dose through 
30 days following the last dose of study drug and the pregnancy will be followed to 
outcome.
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 should avoid pregnancy throughout the course of the study, starting with the 
Screening Visit through 30 days after the last study drug administration.  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 
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 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 
 


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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.
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.
 


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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.
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 a new sample

If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample.

If 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.
 


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory Parameter
Toxicity Management Guideline
Platelet count 

If confirmed < 50,000 cells/µL by repeat testing with new sample, interrupt study 
drug dosing until platelet count returns to normal reference range or its baseline 
value.
AST or ALT

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 a 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.
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.
 


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory Parameter
Toxicity Management Guideline
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.
Creatine Phosphokinase

If confirmed CPK ≥ 4 × ULN, and there are no symptoms suggestive of myositis 
or rhabdomyolysis subjects may continue study drug at the investigator's 
discretion.

If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and inform AbbVie Therapeutic Area 
Medical Director.
For the above CPK elevation scenarios, complete supplemental CPK eCRF.
For allowed study drug interruption, the following rules apply:
Period 1
●
Allow study drug interruption up to 7 consecutive days for AEs and 
emergency surgery.  Elective surgery will not be allowed during this 24-week 
period.
●
If the subject must undergo emergency surgery, the study drug should be 
interrupted at the time of the surgery.  After emergency surgery, allow 
reintroduction of study drug once the physician has examined the surgical site 
and determined that it has healed and there is no sign of infection.
Period 2
●
Allow study drug interruption up to 30 consecutive days.  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 
 


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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.
Additional local requirements may apply.  Refer to Appendix C for local requirements for 
France.
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.
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.
 


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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.  Product Complaints occurring during the study will be followed-
up to a satisfactory conclusion.  All follow-up information is to be reported to the Sponsor 
(or an authorized representative) and documented in source as required by the Sponsor.  
Product Complaints associated with adverse events will be reported in the study summary.  
All other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
Investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
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 
emergency situation) after a subject has been enrolled, the Principal Investigator is 
responsible for notifying IEC/IRB regulatory authorities (as applicable), and the following 
AbbVie Clinical Contacts:
 




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Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.  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.
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.
 


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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.
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 taken (i.e., the difference between the 
number of tablets dispensed and the number of tablets returned) during the subject's 
participation in Period 1 divided by the number of tablets a subject is supposed to take 
each day 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.
 


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Medical history will be presented by counts and percentages of subjects, broken down by 
Body System and Diagnosis. 
Prior therapy and medication will be summarized by treatment group.  Prior therapy and 
medication will include all therapies and medications with a start date prior to the date of 
first dose of study drug.
Concomitant medications will also be summarized with frequencies and percentages for 
each treatment group.  All medications administered during study drug exposure will be 
included.
8.1.4
Efficacy Analyses
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
For all efficacy analysis in Period 1, the two placebo groups (Groups 3 and 4) will be 
combined and treated as one placebo group for analysis purposes.  Each upadacitinib dose 
will be compared with the combined placebo group.
8.1.4.1.1
Primary Efficacy Variable
The primary endpoint (at Week 12) for US/FDA regulatory purposes is listed in 
Section 5.3.3.1.1.  The primary endpoint (at Week 12) for EU/EMA regulatory purposes 
is also listed in Section 5.3.3.1.1.  Analyses will be conducted separately for US/FDA 
regulatory purposes and EU/EMA regulatory purposes; for each set of analysis, only 
one primary endpoint is specified.
Analysis of the primary endpoint will be conducted on the FAS based on treatment as 
randomized.  Comparisons of the primary endpoint will be made between each
upadacitinib dose and the combined placebo group using the Cochran-Mantel-Haenszel 
test adjusting for main stratification factors.  For the primary analysis, non-responder 
 


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imputation (NRI) will be used.  The analysis will be repeated using Observed Cases (OC).  
Supportive analysis will also be conducted on the Per Protocol Analysis Set.
The primary efficacy analyses will 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 (at Week 12):  Key secondary endpoints (at Week 12) for 
US/FDA regulatory purposes are listed in Section 5.3.3.1.2.  Key secondary endpoints (at 
Week 12) for EU/EMA regulatory purposes are also listed in Section 5.3.3.1.2.
For binary endpoints, frequencies and percentages will be reported for each treatment 
group.  Similar analyses as for the primary endpoint will be conducted.
For continuous endpoints, the mean, standard deviation, median, and range will be 
reported for each treatment group.  Between-group comparisons for each upadacitinib 
treatment group and the combined placebo groups will be performed using the analysis of 
covariance model with treatment 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 12.  For binary endpoints, frequencies and 
percentages will be reported for each treatment group.  For continuous endpoints, the 
change from baseline mean, standard deviation, median, and range will be reported for 
each treatment group.
 


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8.1.4.1.4
Multiplicity Control for Primary and Ranked Secondary 
Endpoints
The overall type I error rate of the primary and 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 followed by key 
secondary endpoints, 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.  
8.1.4.1.5
Imputation Methods
The following methods will be used for missing data imputation:
Observed Cases (OC):  The OC analysis will not impute values for missing evaluations, 
and thus a subject who does not have an evaluation on a scheduled visit will be excluded 
from the OC analysis for that visit. 
Multiple Imputation (MI):  The MI analysis imputes missing data multiple times under 
appropriate random variation and thus generates multiple imputed "pseudo-complete" 
datasets.  Results will be aggregated across the multiple imputed datasets, overcoming 
drawbacks of the single imputation methods.
Non-Responder Imputation (NRI):  NRI applies to binary endpoints only.  In NRI 
analysis, subjects who prematurely discontinue study drug will be considered 
non-responders on or after discontinuation date.
The NRI approach will serve as the primary analysis approach for key binary endpoints.  
The MI approach will serve as the primary analysis approach for key continuous 
endpoints.  Sensitivity analyses based on OC will also be conducted for key endpoints.
 


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8.1.4.2
Long-Term Efficacy Analysis for Period 1 and Period 2 
Combined
The efficacy endpoints of long-term efficacy analysis are listed in Section 5.3.3.2 and will 
be summarized for all visits.
Long-term efficacy by time point will be summarized using descriptive statistics.  For 
binary endpoints, frequencies and percentages will be summarized.  For continuous 
endpoints, the mean and standard deviation will be reported.
8.1.5
Safety Analyses
8.1.5.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set.  Analyses will be 
conducted for Period 1 alone, as well as for Period 1 and Period 2 combined.
Safety analyses are based on treatments actually received.  Safety will be assessed by 
AEs, physical examination, laboratory assessments, ECG, and vital signs.  Frequency 
tables and lists of subjects with treatment-emergent AEs by preferred term as in the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary, by system organ 
class, by severity, and by relationship to the study drug as assessed by the Investigator 
will be provided.  The changes from baseline in vital signs, physical examination results, 
and clinical laboratory values will be analyzed 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.
 


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8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE)
AEs will be coded using MedDRA.  A TEAE is defined as AE that began or worsened in 
severity after initiation of study drug.
AEs starting more than 30 days following the last dose of study drug will not be included 
in summaries of TEAEs.  For subjects who continued into Period 2, AEs that are reported 
in Period 2 will be captured in the combined safety analysis of Period 1 and Period 2.
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 
 


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dysfunction, anemia, increased CPK, and drug-related hepatic disorders) 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.
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.
 


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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 
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 
 


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


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Treatment × Time interaction as fixed-effects, the corresponding baseline biomarker score 
as a covariate, and "subjects nested within the treatment group" as a random-effect.  Other 
baseline variables such as age, weight, etc., may be considered as appropriate.  For 
biomarkers identified to have significant overall treatment effect via the non-linear 
mixed-effects modeling analysis, dose-response models with the biomarker as a 
continuous response will be explored.  In addition to the above analyses of biomarkers 
individually, the effect of certain combination of biomarkers on the treatment groups may 
be explored.
If the optional exploratory research variables including an additional panel of prognostic, 
predictive, and pharmacodynamic biomarkers are evaluated, then those data may be 
analyzed as follows.  The association of biomarkers to the efficacy and safety endpoints 
may be explored for each biomarker one at a time, and also for combinations of 
biomarkers via some multivariate predictive modeling algorithms.  Optimal multivariate 
combinations of biomarkers that associate with efficacy endpoints, subject 
response/non-response (with respect to appropriate clinical endpoints), and also with 
safety endpoints may be explored via a variety of statistical predictive modeling 
algorithms.  Also cut-points for individual biomarkers and optimal combinations of 
biomarkers that differentiate the subject response with respect to efficacy/safety endpoints 
may be explored.  The significance of these multivariate combinations of biomarkers may 
be assessed via at least 20 iterations of 5-fold cross-validation.
8.2
Determination of Sample Size
The planned total sample size of 450 can provide approximately 90% power to detect a 
20% difference in ACR20 rates (assuming a placebo ACR20 response rate of 27%), at 
two-sided α = 0.025 and accounting for 10% dropout rate.  This sample size also provides 
approximately 90% power for a 17% difference in DAS28 LDA response rate (assuming a 
placebo DAS28 LDA response rate of 12%), at two-sided α = 0.025 and accounting for 
10% dropout rate.  It can also provide at least 90% power for most key secondary 
endpoints, at two-sided significance level of 0.025 and accounting for a 10% dropout rate.
 


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8.3
Randomization Methods
Subjects will be randomly assigned in a 2:2:1:1 ratio to one of the four treatment groups:  
●
Group 1:  upadacitinib 30 mg QD, N = 150 (Day 1 to Week 12) → 
upadacitinib 30 mg QD (Week 12 and thereafter)
●
Group 2:  upadacitinib 15 mg QD, N = 150 (Day 1 to Week 12) → 
upadacitinib 15 mg QD (Week 12 and thereafter)
●
Group 3:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib 30 mg QD 
(Week 12 and thereafter)
●
Group 4:  Placebo, N = 75 (Day 1 to Week 12) → upadacitinib 15 mg QD 
(Week 12 and thereafter)
Randomization will be stratified by number of prior bDMARD use (stratum 1:  failed 1 or 
2 biologics with the same mechanism of action; stratum 2:  failed ≥ 3 biologics with the 
same mechanism of action and/or multiple mechanisms of action) and geographic region.  
Once approximately 35% of the total subjects have been randomized in stratum 2, further 
screening of subjects who meet stratum 2 criteria may be suspended.
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.
 


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Any amendments to the protocol will require IEC/IRB approval and approval by 
Regulatory Authority(ies), if required by local law regulations, prior to implementation of 
any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
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/validation 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 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.
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, 
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 
 


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study-specific eCRFs will be conducted by AbbVie and will be maintained in the Trial 
Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The Investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the 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:
 


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●
Patient Global Assessment of Disease Activity VAS
●
Patient's Assessment of Pain VAS
●
HAQ-DI
●
SF-36
●
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
○
ISI
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
 


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●
The instrument/scale will be collected electronically via a tablet device into 
which the subject will directly enter the required pieces of information.  The 
electronic device will be programmed to allow data entry for only the visits 
specified in the protocol and will not allow for subjects to complete more than 
one of the same assessment at any one visit.  All data entered on the device 
will be immediately stored to the device itself and automatically uploaded to a 
central server administrated by CRF Health.  The Investigator and delegated 
staff will be able to access all uploaded subject entered data via a password 
protected website, up until the generation, receipt and confirmation of the 
study archive.
11.0
Data Quality Assurance
Prior to the initiation of the study, a meeting will be held with AbbVie personnel, the 
investigators and appropriate site personnel.  This meeting will include a detailed 
discussion of the protocol, performance of study procedures, CRF, subject dosing diary, 
and specimen collection methods.  Another alternative of site training may include 
module training via a study portal.
To ensure data integrity and subject safety, a study monitor will continuously and 
throughout the study, verify that all subjects sign the informed consent prior to any study 
specific procedures being conducted, that the protocol procedures are being followed 
appropriately, and that the information provided in the eCRF is complete, accurate, and 
supported by information in the source documents.
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.
 


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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 optional exploratory research/validation samples 
from this study will be experimental in nature and the results will not be suitable for 
clinical decision making or patient management.  Hence, the subject will not be informed 
of individual results, should analyses be performed, nor will anyone not directly involved 
in this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory 
research/validation studies may be provided to investigators and used in scientific 
publications or presented at medical conventions.  Exploratory research/validation 
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 and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the Investigator and AbbVie.  The Investigator will provide a final report to the 
 


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


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for upadacitinib.
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) to Placebo on Stable Conventional 
Synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) 
in Subjects with Moderately to Severely Active Rheumatoid 
Arthritis with Inadequate Response or Intolerance to Biologic 
DMARDs (bDMARDs)
Protocol Date:
08 December 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
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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 
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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.
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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.
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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.
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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.
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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.
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van Vollenhoven RF, Fleischmann R, Cohen S, et al.  Tofacitinib or adalimumab 
versus placebo in rheumatoid arthritis.  N Engl J Med.  2012;367(6):508-19.
17.
Burmester GR, Blanco R, Charles-Schoeman C, et al.  Tofacitinib (CP-690,550) in 
combination with methotrexate in patients with active rheumatoid arthritis with an 
inadequate response to tumour necrosis factor inhibitors:  a randomized phase 3 
trial.  Lancet.  2013;381(9865):451-60.
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Kremer J, Li Z-G, Hall S, et al.  Tofacitinib in combination with nonbiologic 
disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis.  
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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.
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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.
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Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
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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 Pharmceuticals 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
Senior Medical Director
Therapeutic Area
Senior Medical Director
Pharmacovigilance and Patient Safety
Director
Statistics
Senior Director, Statistics TA Head
Statistics
 
Assistant Director 
Clinical Pharmacology and 
Pharmacometrics
Study Project Manager II
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 150 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 30 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 subject 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 
150 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.
It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy upadacitinib.  
The concomitant csDMARDs (i.e., methotrexate, sulfasalazine, etc.) have been prescribed 
per standard of care prior to study entry and are allowed to be continued during the study.  
Contraception should continue while the subject is on the concomitant csDMARD(s) and 
that duration of contraception after discontinuation of the csDMARD(s) should be based 
on the local label.
Contraception Recommendation for Males
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of study drug to practice 
contraception with:
●
Condom use and female partner(s) using at least one of the highly effective 
contraceptive methods as defined in the protocol for female study subjects of 
childbearing potential.
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of study drug. 
 


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Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.
It is important to note that contraception and sperm donation recommendations described 
above are specifically intended to prevent pregnancy during and after exposure to the 
investigational therapy upadacitinib.  The concomitant csDMARDs (i.e., methotrexate, 
sulfasalazine, etc.) have been prescribed per standard of care prior to study entry and are 
allowed to be continued during the study.  Contraception should continue while the 
subject is on the concomitant csDMARD(s) and that duration of contraception and the 
requirement not to donate sperm after discontinuation of the csDMARD(s) should be 
based on the local label.
France
Section 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.
 


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●
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.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial as determined by the 
Investigator or the AbbVie Therapeutic Area Medical Director.
●
Subject develops a gastrointestinal perforation.
●
Starting at Week 24 and thereafter, subject fails to show at least 20% 
improvement in both TJC and SJC compared to baseline at 
2 consecutive visits, despite optimization of background RA therapies.
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment should complete a Premature 
Discontinuation visit (PD visit) as soon as possible, preferably within 2 weeks.  
Afterwards, subjects should continue to be followed for all regularly scheduled visits, 
unless they have decided to discontinue the study participation entirely (withdrawal 
informed consent).  Subjects should be advised on the continued scientific importance of 
their data even if they discontinue treatment with study drug early.
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 subject is willing, a 30-day 
follow-up phone call (or visit) after the last dose of study drug may be completed to 
 


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ensure all treatment emergent AEs/SAEs have been resolved or the occurrence of any new 
AEs/SAEs.  Subjects who discontinue the study prematurely after randomization will not 
be replaced.  
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study 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.
Section 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
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 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 
 


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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.
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.
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 
should be discontinued from study drug.  
Malignancy:  Subjects who develop malignancy 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.
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 5 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 5, the repeat testing must 
occur as soon as possible.
 


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Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (For France)
Laboratory Parameter
Toxicity Management Guideline
Hemoglobin

If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by 
repeat testing with a new sample.

If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative 
etiology, interrupt study drug dosing and confirm by repeat testing with 
new sample. 

If 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 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (For France) (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 (INR) > 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 
critieria 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 > 8 × ULN 
by repeat testing with new sample.

Interrupt study drug immediately if confirmed ALT or AST > 5 × ULN 
by repeat testing with new sample for more than 2 weeks.
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 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 one week: 
o
ALT > 5 × ULN OR
o
ALT or AST > 3 × ULN if an alternative cause is not readily 
identified.

A positive result for HBV DNA PCR testing in these subjects will 
require immediate interruption of study drug and a hepatologist 
consultation should occur within 1 week for recommendation regarding 
subsequent treatment
For any confirmed ALT or AST elevations > 3 ULN, complete supplemental 
hepatic eCRF.
 


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Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (For France) (Continued)
Laboratory Parameter
Toxicity Management Guideline
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.
Creatine Phosphokinase

If confirmed CPK value ≥ 4 × ULN and there are no symptoms 
suggestive of myositis or rhabdomyolysis, the subjects may continue 
study drug at the investigator's discretion.

If CPK ≥4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and inform AbbVie Therapeutic 
Area Medical Director.
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 up to 7 consecutive days for AEs and 
emergency surgery.
●
MTX/Placebo capsules (weekly dosing):
○
Allow study drug interruption up to 2 consecutive missed doses for AEs 
and emergency surgery.
●
If the subject must undergo emergency surgery, the study drug should be 
interrupted at the time of the surgery.  After emergency surgery, allow 
reintroduction of study drug once the physician has examined the surgical site 
and determined that it has healed and there is no sign of infection.
●
Elective surgery will not be allowed during this 14-week-period.
 


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Period 2
●
Upadacitinib tablet (daily dosing):  
○
Up to 30 consecutive days of study drug interruption is allowed. 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 the surgery.  After emergency surgery, allow 
reintroduction of study drug once the physician has examined the surgical site 
and determined that it has healed and there is no sign of infection.
Germany
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 a follicle stimulating hormone (FSH) level > 40 mIU/mL.
If the female subject is < 55 years of age:
 


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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 30 days after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal, injectable) associated with the inhibition of 
ovulation, initiated at least 30 days prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.
 


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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): Applies to women of 
childbearing potential who do not have male partners and are not engaging in 
heterosexual intercourse as their preferred and usual lifestyle (periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
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).
If during the course of the study a woman becomes surgically sterile or post-menopausal 
(defined above) and complete documentation is available, contraceptive measures as 
defined above are no longer required.  
It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy upadacitinib.  
The concomitant csDMARDs (i.e., methotrexate, sulfasalazine, etc.) have been prescribed 
per standard of care prior to study entry and are allowed to be continued during the study.  
Contraception should continue while the subject is on the concomitant csDMARD(s) and 
that duration of contraception after discontinuation of the csDMARD(s) should be based 
on the local label.
Korea
Section 5.2.1 Inclusion Criteria
10.
If female, subject must be either postmenopausal, OR permanently surgically 
sterile OR for women of childbearing potential practicing at least 
 


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one protocol-specified method of birth control (refer to Contraception 
Recommendations for Females, below), that is effective from Study Day 1 
through at least 30 days after the last dose of study drug.
11.
If the male subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 90 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.
●
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.
 


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●
If the FSH is tested and the result is consistent with pre-menopausal status, 
contraception is required and a serum pregnancy test must be performed (see 
Section 5.3.1.1 pregnancy test).
For a female subject at any age:
●
Female subjects with menses within the past 12 months are of childbearing 
potential and FSH is therefore not required but contraception is required.
●
Female subjects who are 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 30 days after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical confirmation of the surgical success and is the sole sexual partner of 
the women of childbearing potential trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the highly 
effective birth control methods listed above.
 


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It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy upadacitinib. 
The concomitant csDMARDs (i.e., methotrexate, sulfasalazine, etc.) have been prescribed 
per standard of care prior to study entry and are allowed to be continued during the study.  
Contraception should continue while the subject is on the concomitant csDMARD(s) and 
that duration of contraception after discontinuation of the csDMARD(s) should be based 
on the local label.
Contraception Recommendation for Males
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of study drug to practice 
contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures as defined in the protocol for female study subjects of childbearing 
potential.
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of study drug. 
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.
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 upadacitinib.  The concomitant csDMARDs (i.e., methotrexate, 
sulfasalazine, etc.) have been prescribed per standard of care prior to study entry and are 
 


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allowed to be continued during the study.  Contraception should continue while the 
subject is on the concomitant csDMARD(s) and that duration of contraception and the 
requirement not to donate sperm after discontinuation of the csDMARD(s) should be 
based on the local label.
 


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Appendix D.
Study Activities (Period 1)
Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24/
PDa
30-Day 
F/U Visitc
D –35 to D –1
D1b
D8
D15
D29
D57
D85
D113
D141
D169
Informed consentd
Xd
Inclusion/exclusion criteria
X
X
Medical/surgical historye
X
X
Alcohol and nicotine use
X
Adverse event assessmentf
Only SAEs and 
protocol-related 
nonserious AEs
X
X
X
X
X
X
X
X
X
X
Prior/concomitant therapy
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
Patient questionnairesh
EQ-5D-5L 
SF-36 
ISI
X
X
X
X
Latent TB risk assessment formi
X
Central lab QuantiFERON-TB Gold testi
(and/or local PPD skin test)
X
Chest x-rayj
X
 


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Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24/
PDa
30-Day 
F/U Visitc
D –35 to D –1
D1b
D8
D15
D29
D57
D85
D113
D141
D169
12-lead ECG
Xk
Xl
Height (screening only) and weight
X
X
X
X
X
X
X
X
X
X
Vital signsm
X
X
X
X
X
X
X
X
X
X
Physical examn
X
X
X
Physician Global Assessment (PhGA)
X
X
X
X
X
X
X
X
X
TJC68/SJC66
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test at central labo
X
Local urine pregnancy testp
X
X
X
X
X
X
X
X
X
Central Lab Tests
hsCRPq
Blood chemistryr
Hematology (CBC)
Urinalysiss
X
X
X 
(hsCRP 
only)
X
X
X
X
X
X
X
X
ESR (local lab)
X
X
X
X
X
X
X
X
X
X
Other Central Lab Tests
Rheumatoid factor
Anti-CCP autoantibodies
HBV/HCV screening
FSH (as applicable)t
X
HIV local lab (if required)u
Xu
IgG and IgM (central lab)
X
X
X
Blood samples for upadacitinib PK assay
Xv
Xv
Xw
Xw
Xw
Xw
Xw
Xw
In vivo pharmacodynamic biomarkers
X
X
X
X
X
X
 


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Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24/
PDa
30-Day 
F/U Visitc
D –35 to D –1
D1b
D8
D15
D29
D57
D85
D113
D141
D169
Blood samples for exploratory research and 
validation studies (optional – see 
Appendix Ex)
X
X
X
X
X
Randomization/Drug assignment
X
CDAI IRT Calculation
Xy,z
20% joint assessment (TJC and SJC)
Xaa
Dispense study drug and subject dosing 
diary
X
X
X
X
X
X
Xbb
Review and copy subject dosing diary and 
perform drug reconciliation
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; 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; ISI = Insomnia Severity Index; NRS = numerical rating scale; PD = Premature Discontinuation (completely 
from study [withdrawal of consent]); PhGA = Physician's Global Assessment of Disease Activity; PK = pharmacokinetics; PPD = purified protein derivative; PtGA = Patient's 
Global Assessment of Disease Activity; SAE = serious adverse event; SJC = Swollen Joint Count; SF-36 = 36-Item Short Form Health Survey; TB = tuberculosis; TJC = Tender 
Joint Count; VAS = visual analog scale; Wk = Week
a.
If a subject prematurely discontinues study drug or prematurely discontinues study drug 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.
b.
The Baseline visit procedures will serve as the reference for all subsequent visits with the exception of the ECG, which will be obtained at Screening only and used as the 
baseline reference.
c.
This visit is 30 days after last dose of study drug for those subjects who complete Period 1 and do NOT enter Period 2.  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.
d.
Informed consent should be obtained at Screening prior to performing any study related procedures.
e.
Document 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.
 


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g.
At Week 24 (after Week 24 assessments have been performed), per Investigator judgment, may add concomitant use of up to 2 csDMARDs, except the combination of MTX 
and leflunomide, or may increase csDMARD dose(s).  Subjects who do not achieve CDAI ≤ 10 at Week 24 should have background medication(s) adjusted or initiated after 
assessments for Week 24 have been completed.
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.
j.
The chest x-ray will not be required if a subject had a previous normal chest-x-ray within 90 days of Screening, provided that all source documentation is available at the site 
(refer to Section 5.3.1.1 Chest X-Ray for specific requirements).
k.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required, provided all source documentation is available.  Refer to 
Section 5.3.1.1 12-Lead ECG for additional details.
l.
For subjects who do not enter Period 2 or prematurely discontinue from the study, an ECG will be performed.
m.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.
n.
A full physical exam is required at the visits indicated.  A symptom-directed physical exam may be performed when necessary.
o.
For all women of childbearing potential, collect serum for pregnancy test only at Screening.  If serum pregnancy test comes back borderline, a repeat test is necessary 
(pregnancy is an exclusion criterion).  If still borderline ≥ 3 days later, this will be considered documentation of continued lack of a positive result and the subject can be 
enrolled into the study.  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
p.
For all women of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits except Week 1.  If urine pregnancy test (which is performed at 
the site) is negative, begin or continue dosing.  If urine pregnancy test is positive, withhold dosing and perform a serum pregnancy test.  Pregnant subjects must permanently 
discontinue study drug.  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
q.
In Period 1, the central lab hsCRP results starting from Baseline (Day 1) will not be reported to the Sponsor, Investigator, study site personnel, and the subject.  Results of 
hsCRP may unblind the treatment assignment, and the results may be blunted in subjects taking a JAK inhibitor, thereby limiting its clinical utility in the setting of a possible 
safety assessment or adverse event management.  Therefore, any local testing of hsCRP or CRP is strongly discouraged.  In Period 2, the central lab hsCRP results will remain 
blinded to Investigator, study site personnel, and the subject.
r.
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.
s.
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.
t.
FSH should be tested at Screening if the female subject is < 55 years of age AND has had no menses ≥ 12 months AND has no history of permanent surgical sterilization 
(defined in Section 5.2.4).
 


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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.
At Week 1 and Week 2 visits, PK samples should be collected prior to dosing and the subjects should take the study drug dose at the clinic after collecting the PK blood 
sample.  However, if the subject normally takes the study drug dose at a time that is after the time of the scheduled study visit, the subject should follow the regular dosing 
schedule and the PK sample should be collected at any time during the visit.
w.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.
x.
Samples only collected if subject provides written consent.
y.
Refer to Section 5.2.3.1.
z.
CDAI calculation requires input of SJC + TJC (based on a 28 joint count) + PtGA + PhGA into IRT system.  At Week 24, investigator should optimize background RA 
therapies in subjects who failed to achieve CDAI ≤ 10.
aa.
Starting at Week 24 and thereafter, study drug should be discontinued for 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.  
bb. For subjects entering Period 2.
Note:
Visit window is ± 3 days for Period 1.  Any of the procedures may be performed at an unscheduled visit at the discretion of the Investigator.  Subjects who 
choose to discontinue study drug treatment, but continue to participate in the study complete a PD visit as soon as possible, preferably within 2 weeks.  
Afterwards, subjects should follow the regular visit schedule and adhere to all study procedures except for dispensing study drug, PK sample collection, and 
blood sample collection for optional exploratory research and validation studies.  As the subject has discontinued study drug, all rescue and efficacy driven 
discontinuation criteria no longer apply (e.g., CDAI calculation at Week 24, 20% TJC/SJC calculation for PD).
 


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Appendix E.
Study Activities – Optional Samples for Exploratory Research and Validation Studies (Period 1 Only)
Activity
Screening
BL
Wk 1
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24/
PD
30-Day 
F/U Visit
D –35 to D –1
D1
D8
D15
D29
D57
D85
D113
D141
D169
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; F/U = Follow-up; PD = Premature Discontinuation; Wk = Week
a.
The sample is preferred to be collected at BL, but can be drawn at any time during the subject's participation.
b.
Based on the value of the different technologies, samples may also be used to assess other biomarker signatures, including but not limited to metabolomics, lipidomics, and 
other approaches.
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 36
Wk 48
Monthly
Every 12 
Weeksa
Every 24 
Weeksa
Every 48 
Weeksa
Final
(Week 
260)/
PD Visit
30-Day 
F/U Visitb
Adverse event assessment
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
Patient questionnairesc
PtGA
Pain (VAS)
HAQ-DI
Morning Stiffness (severity and duration)
X
X
X
X
Patient questionnairesc
EQ-5D-5L
SF-36
ISI
X
Latent TB risk assessment form
X
X
Central lab QuantiFERON-TB Gold testd (and/or 
local PPD skin test)
Xd
Xd
Chest x-raye
Xe
Xe
12-lead ECGf
X
X
X
Vital signs and body weightg
X
X
X
X
X
Physical examh
X
X
X
Physician Global Assessment (PhGA)
X
X
X
X
TJC68/SJC66
X
X
X
X
20% joint assessment (TJC and SJC)i
X
X
X
 


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Activity
Wk 36
Wk 48
Monthly
Every 12 
Weeksa
Every 24 
Weeksa
Every 48 
Weeksa
Final
(Week 
260)/
PD Visit
30-Day 
F/U Visitb
Local urine pregnancy testj
X
X
X
X
X
At home urine pregnancy testj
Xj
Central lab tests
hsCRPk
Blood chemistryl
Hematology (CBC)
Urinalysism
X
X
X
X
X
ESR (local lab)
X
X
X
X
In vivo pharmacodynamic biomarkers
X
X
X
Dispense study drug and subject dosing diary
X
X
X
Review and copy subject dosing diary and perform 
drug reconciliation
X
X
X
X
BL = Baseline Visit; CBC = complete blood count; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ECG = electrocardiogram; F/U = Follow-up; 
HAQ-DI = Health Assessment Questionnaire - Disability Index; hsCRP = high-sensitivity C-reactive protein; NRS = numerical rating scale; PD = Premature Discontinuation; 
PhGA = Physician's Global Assessment of Disease Activity; PPD = purified protein derivative; PtGA = Patient's Global Assessment of Disease Activity; SAE = serious adverse 
event; 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 48 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 be allowed after 30 days from last dose of 
study drug for subjects who have completed PD visit 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 48 in subjects with previous negative TB test.  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.
e.
Obtain chest x-ray every 48 weeks after Week 48 for subjects with newly identified TB risk factors as determined by the TB risk assessment form, or for subjects living in 
areas endemic for TB, or for subjects with a newly positive TB test after baseline.
 


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f.
In addition to ECG assessments as indicated above, an ECG may be performed at any visit if deemed necessary by the Investigator.
g.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.
h.
A full physical exam is required every 24 weeks after Week 48.  A symptom-directed physical exam may be performed when necessary.
i.
Starting at Week 24 and thereafter, study drug will be discontinued for subjects who fail to show at least 20% improvement in TJC and SJC compared to baseline at 
2 consecutive visits, despite optimization of background RA therapies.
j.
For all 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 permanently discontinue study drug. Refer to Section 5.3.1.1 Study Procedures 
Pregnancy Test for additional details.
k.
In Period 1, the central lab hsCRP results starting from Baseline (Day 1) will not be reported to the Sponsor, Investigator, study site personnel, and the subject.  Results of 
hsCRP may unblind the treatment assignment, and the results may be blunted in subjects taking a JAK inhibitor, thereby limiting its clinical utility in the setting of a possible 
safety assessment or adverse event management.  Therefore, any local testing of hsCRP or CRP is strongly discouraged.  In Period 2, the central lab hsCRP results will remain 
blinded to Investigator, study site personnel, and the subject.  Starting with Amendment 4, at a timepoint specified by the Sponsor in Period 2, central laboratory hsCRP 
results will be reported to the Investigator/study site personnel. After treatment assignment is unblinded, local hsCRP or CRP tests are allowed.
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.
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-5L Example
Under each heading, please check the ONE box that best describes your health TODAY:
Mobility
I have no problems walking
☐
I have slight problems walking
☐
I have moderate problems walking
☐
I have severe problems walking
☐
I am unable to walk 
☐
Self-Care
I have no problems washing or dressing myself
☐
I have slight problems washing or dressing myself 
☐
I have moderate problems washing or dressing myself
☐
I have severe problems washing or dressing myself
☐
I am unable to wash or dress myself 
☐
Usual Activities (e.g., work, study, housework, family or leisure activities)
I have no problems with doing my usual activities 
☐
I have slight problems with doing my usual activities 
☐
I have moderate problems with doing my usual activities
☐
I have severe problems with doing my usual activities
☐
I am unable to do my usual activities 
☐
 


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


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


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Appendix O.
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 P.
Insomnia Severity Index Example
For each question, please CIRCLE the number that best describes your answer.
Please rate the CURRENT (i.e., LAST 2 WEEKS) SEVERITY of your insomnia 
problem(s).
Insomnia Problem
None
Mild
Moderate
Severe
Very Severe
1.  Difficulty falling asleep
0
1
2
3
4
2.  Difficulty staying asleep
0
1
2
3
4
3.  Problem waking up too early
0
1
2
3
4
4. How SATISFIED/DISSATISFIED are you with your CURRENT sleep pattern?
Very Satisfied
Satisfied
Moderately 
Satisfied
Dissatisfied
Very Dissatisfied
0
1
2
3
4
5. How NOTICEABLE to others do you think your sleep problem is in terms of 
impairing the quality of your life?
Not at All
Noticeable
A Little
Somewhat
Much
Very Much 
Noticeable
0
1
2
3
4
6. How WORRIED/DISTRESSED are you about your current sleep problem?
Not at All
Worried
A Little
Somewhat
Much
Very Much 
Worried
0
1
2
3
4
 
 
 
 
 
 
 
 
 
 


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7. To what extent do you consider your sleep problem to INTERFERE with your 
daily functioning (e.g., daytime fatigue, mood, ability to function at work/daily 
chores, concentration, memory, mood, etc.)?
Not at All
Interfering
A Little
Somewhat
Much
Very Much 
Interfering
0
1
2
3
4
Guidelines for Scoring/Interpretation:
Add the scores for all seven items (questions 1 + 2 + 3 + 4 + 5 +6 + 7) = _____ your total 
score
Total score categories:
0 – 7 = No clinically significant insomnia
8 – 14 = Subthreshold insomnia
15 – 21 = Clinical insomnia (moderate severity)
22 – 28 = Clinical insomnia (severe)
1.
Morin CM.  Insomnia: psychological assessment and management.  New York:  Guilford Press; 1993.
2.
Bastien CH, Vallie'res A, Morin CM.  Validation of the Insomnia Severity Index as an outcome measure for 
insomnia research.  Sleep Med.  2000;2:297-307.
 
 
 


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Appendix Q.
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, 
arrthymia or/and CHF
 


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


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


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E.  Ear/Nose/Throat (continued)
E3.  Stomatitis
Asymptomatic
Painful, multiple, can eat
Interferes with nutrition, slowly 
reversible
Requires enteral support; residual 
dysfunction
E4.  Taste 
disturbance 
(dysgeusia)
Transiently altered; metallic
Persistently altered; limited effect 
on eating
Disabling, effect on nutrition
NA
E5.  Tinnitus
Intermittent, transient, no 
interference with function
Requires treatment, reversible
Disabling, or associated with 
hearing loss
Irreversible deafness
E6.  Voice changes 
(includes hoarseness, 
loss of voice, 
laryngitis)
Intermittent hoarseness, able to 
vocalise
Persistent hoarseness, able to 
vocalise
Whispered speech, slow return of 
ability to vocalise
Unable to vocalise 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 therefore 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
M13-542 – Statistical Analysis Plan
Version 3.0 – 18 Dec 2020
1
1.0
Title Page
Statistical Analysis Plan
Study M13-542
A Phase 3, Randomized, Double-Blind Study 
Comparing Upadacitinib to Placebo on Stable 
Conventional Synthetic Disease-Modifying 
Anti-Rheumatic Drugs (csDMARDs) in Subjects with 
Moderately to Severely Active Rheumatoid Arthritis 
with Inadequate Response or Intolerance to Biologic 
DMARDs (bDMARDs)
Date:  18 Dec 2020
Version 3.0
 
NCT02706847


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M13-542 – Statistical Analysis Plan
Version 3.0 – 18 Dec 2020
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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................6
4.0
Study Objectives, Design and Procedures.............................6
4.1
Study Objectives ........................................................................................6
4.2
Overall Study Design and Plan..................................................................6
4.3
Sample Size..............................................................................................13
4.4
Interim Analysis and Date Base Lock......................................................14
4.5
Data Monitoring Committee (DMC) Activities.......................................14
5.0
Analysis Populations and Analysis Windows .....................14
5.1
Analysis Populations................................................................................14
5.2
Analysis Windows ...................................................................................15
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............17
6.1
Demographics and Baseline Characteristics............................................17
6.2
Medical History .......................................................................................20
6.3
Prior Treatment and Concomitant Medications.......................................20
6.4
Protocol Deviations..................................................................................21
7.0
Patient Disposition.................................................................21
8.0
Study Drug Exposure and Compliance...............................23
8.1
Study Drug Exposure...............................................................................23
8.2
Compliance ..............................................................................................25
9.0
Efficacy Analysis....................................................................25
9.1
General Considerations............................................................................25
9.1.1
Efficacy Analysis at Different Phases of the Study.................................25
9.1.2
Definition of Missing Data Imputation....................................................26
9.2
Efficacy Analysis by Week 12.................................................................28
9.2.1
Primary Efficacy Analysis .......................................................................28
9.2.2
Sensitivity Analysis of Primary Efficacy Variables ................................29
9.2.3
Key Secondary Efficacy Analyses...........................................................29
9.2.4
Exploratory Efficacy Analyses ................................................................30
 


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9.2.5
Handling of Multiplicity ..........................................................................32
9.2.6
Efficacy Subgroup Analysis ....................................................................34
9.2.7
Summary of Efficacy Analysis by Week 12............................................35
9.3
Long-Term Efficacy Analysis..................................................................38
9.4
Efficacy Variables Definitions and Conventions.....................................40
9.4.1
ACR Criteria ............................................................................................40
9.4.2
Joint Evaluation .......................................................................................43
9.4.3
Patient's Global Assessment of Disease Activity Visual Analog 
Scale (VAS) .............................................................................................44
9.4.4
Physician's Global Assessment of Disease Activity Visual Analog 
Scale (VAS) .............................................................................................45
9.4.5
Patient's Global Assessment of Pain........................................................45
9.4.6
Disease Activity Score (DAS28) .............................................................45
9.4.7
Simplified Disease Activity Index (SDAI) ..............................................46
9.4.8
Clinical Disease Activity Index (CDAI)..................................................46
9.4.9
Clinical Remission (CR) and Low Disease Activity (LDA)....................47
9.4.10
ACR/EULAR Boolean Remission...........................................................47
9.4.11
Disability Index of Health Assessment Questionnaire (HAQ-DI)...........47
9.4.12
EuroQoL-5D (EQ-5D-5L) .......................................................................48
9.4.13
Insomnia Severity Index (ISI)..................................................................48
9.4.14
Form SF-36v2 ..........................................................................................49
10.0
Safety Analysis.......................................................................49
10.1
General Considerations............................................................................49
10.2
Analysis of Adverse Events.....................................................................51
10.2.1
Analysis of Adverse Events Prior to Protocol-Defined Treatment 
Switching .................................................................................................52
10.2.1.1
Adverse Events Overview........................................................................52
10.2.1.2
Adverse Events by System Organ Class and Preferred Term..................53
10.2.1.3
TEAEs by Maximum Severity.................................................................53
10.2.1.4
TEAEs by Relationship............................................................................54
10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and Preferred 
Term.........................................................................................................54
 


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10.2.1.6
Adverse Events of Special Interest ..........................................................54
10.2.2
Analysis of Long-Term Adverse Event Rates .........................................56
10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................57
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT ........................................................................58
10.2.2.3
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................59
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation ........................59
10.3
Analysis of Laboratory Data....................................................................60
10.3.1
Variables and Units..................................................................................60
10.3.2
Analysis of Laboratory Data by Week 12................................................62
10.3.2.1
Assessment of Mean Change from Baseline and Percentage 
Change from Baseline in Clinical Laboratory Variables.........................62
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................62
10.3.2.3
Assessment of Potentially Clinical Significant Laboratory Values.........63
10.3.2.4
Assessment of Liver Elevations...............................................................63
10.3.3
Analysis of Long-Term Laboratory Data.................................................64
10.3.3.1
Assessment of Mean Change from Baseline and Percentage 
Change from Baseline in Clinical Laboratory Variables.........................64
10.3.3.2
Assessment of Potentially Clinical Significant Laboratory Values .........65
10.3.3.3
Assessment of Liver Elevations...............................................................66
10.4
Analysis of Vital Signs ............................................................................66
10.4.1
Variables and Criteria Defining Abnormality..........................................66
10.4.2
Analysis of Vital Sign by Week 12..........................................................67
10.4.3
Analysis of Long-Term Vital Sign...........................................................67
11.0
Summary of Changes ............................................................69
11.1
Summary of Changes between the Previous Version and the 
Current Version........................................................................................69
12.0
Version History......................................................................70
13.0
Appendix.................................................................................70
14.0
References...............................................................................86
 


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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) .........................................................16
Table 2.
Analysis Windows for Efficacy Analysis for Period 1 (for 
EQ-5D-5L, SF-36, and ISI)......................................................................16
Table 3.
Subgroups for Efficacy Analysis .............................................................35
Table 4.
Summary of Efficacy Variables and Corresponding Analyses for 
Efficacy Analysis by Week 12.................................................................36
Table 5.
Summary of Efficacy Variables and Corresponding Analyses for 
Long-Term Efficacy Analysis..................................................................40
Table 6.
Anatomical Joints Assessed for Calculation of Tender and 
Swollen Joint Counts (TJC68 and SJC66)...............................................44
Table 7.
Anatomical Joints for DAS28 (CRP) Calculation ...................................46
Table 8.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................55
Table 9.
List of Laboratory Variables....................................................................60
Table 10.
Criteria for Potentially Clinically Significant Vital Sign Findings..........67
Table 11.
SAP Version History Summary...............................................................70
List of Figures
Figure 1.
Period 1 Study Design ...............................................................................9
Figure 2.
Period 2 Study Design .............................................................................10
Figure 3.
Graphical Multiple Testing Procedure for US/FDA Regulatory 
Purposes ...................................................................................................33
Figure 4.
Graphical Multiple Testing Procedure for EU/EMA Regulatory 
Purposes ...................................................................................................34
List of Appendices
Appendix A.
OMERACT Criteria.................................................................................71
Appendix B.
Statistical Analysis to Account for Impact of COVID-19 
Pandemic..................................................................................................84
 


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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 M13-542.  It provides 
details to further elaborate statistical methods as outlined in the protocol.  
Pharmacokinetic and biomarker analyses will be performed separately and the 
corresponding analysis plan is documented separately.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC 27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Study Objectives
Period 1
To compare the safety and efficacy of Upadacitinib 30 mg QD and 15 mg QD versus 
placebo on a background of csDMARD(s) for the treatment of signs and symptoms of RA 
in bDMARD-inadequate response (bDMARD-IR) or bDMARD-intolerant subjects with 
moderately to severely active RA.
Period 2
To evaluate the long-term safety, tolerability, and efficacy of Upadacitinib 30 mg QD and 
15 mg QD in subjects with RA who have completed Period 1.
4.2
Overall Study Design and Plan
This is a Phase 3, multicenter study that includes two periods.  Period 1 is the 24-week 
randomized, double-blind, parallel-group, placebo-controlled period designed to compare 
the safety and efficacy of Upadacitinib 30 mg QD and 15 mg QD versus placebo for the 
treatment of signs and symptoms of subjects with moderately to severely active RA who 
have an inadequate response to or intolerance to bDMARD therapy and are currently on a 
stable dose of csDMARDs.  Period 2 is a blinded long-term extension to evaluate the 
 


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long-term safety, tolerability, and efficacy of Upadacitinib 30 mg QD and 15 mg QD in 
subjects with RA who have completed Period 1.  Starting with Amendment 4, all subjects 
will receive open-label upadacitinib 15 mg QD, including those currently on upadacitinib 
30 mg QD.
The study is designed to enroll approximately 450 subjects at approximately 350 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 24-week randomized, double-
blind, parallel-group, placebo controlled treatment period (Period 1); a 236-week blinded 
extension period (Period 2); and a 30-day follow-up (call or site visit).
Subjects who meet eligibility criteria will be randomized in a 2:2:1:1 ratio to one of 
four treatment groups:
●
Group 1:  Upadacitinib 30 mg QD, N = 150 (Day 1 to Week 12) → 
Upadacitinib 30 mg QD (Week 12 and thereafter)
●
Group 2:  Upadacitinib 15 mg QD, N = 150 (Day 1 to Week 12) → 
Upadacitinib 15 mg QD (Week 12 and thereafter)
●
Group 3:  Placebo, N = 75 (Day 1 to Week 12) → Upadacitinib 30 mg QD 
(Week 12 and thereafter)
●
Group 4:  Placebo, N = 75 (Day 1 to Week 12) → Upadacitinib 15 mg QD 
(Week 12 and thereafter)
Randomization is stratified by number of prior bDMARD (stratum 1:  failed 1 or 
2 biologics with the same mechanism of action; stratum 2:  failed ≥ 3 biologics with the 
same mechanism of action and/or multiple mechanisms of action) and geographic region.
Subjects must have been receiving csDMARD therapy ≥ 3 months and have been on a 
stable dose of csDMARD(s) for ≥4 weeks prior to the first dose of study drug and must 
 


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remain on a stable dose until Week 24; the csDMARD dose may be decreased only for 
safety reasons.  Subjects who do not achieve CDAI ≤ 10 at Week 24 should have 
background medication(s) adjusted or initiated after assessments for Week 24 have been 
completed.  Starting at Week 24 (after Week 24 assessments have been performed), 
initiation of or change in corticosteroids, non-steroidal anti-inflammatory drugs 
(NSAIDs), acetaminophen, or adding or increasing doses in up to 2 csDMARDs 
(concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide) is allowed as per local label.  Subjects on a combination of MTX and 
leflunomide therapy should discontinue either MTX or leflunomide prior to first dose of 
study drug administration per washout criteria defined in Section 5.2.3 of the protocol.  
Subjects who complete the Week 24 visit (end of Period 1) will enter the blinded long-
term extension portion of the study, Period 2 (236 weeks).  Subjects who are assigned to 
Upadacitinib treatment groups in Period 1 will continue to receive Upadacitinib 15 mg 
QD or 30 mg QD per original randomization assignment in a blinded manner.  Subjects 
who are assigned to placebo for the first 12 weeks of Period 1 and subsequently switched 
to receive Upadacitinib 15 mg QD or 30 mg QD per their pre-specified randomization 
assignments at Week 12, will continue to receive the same dose of Upadacitinib per 
original randomization assignment in a blinded manner.  Starting with Amendment 4, all 
subjects will receive open-label upadacitinib 15 mg QD, including those currently on 
upadacitinib 30 mg QD.
An unblinded analysis will be conducted after all subjects have completed Period 1 
(Week 24) for the purpose of regulatory submission.  Study sites and subjects will remain 
blinded for the duration of the study (Periods 1 and 2).
Study design schematics of Period 1 and Period 2 are shown in Figure 1 and Figure 2, 
respectively.
 


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Version 3.0 – 18 Dec 2020
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Figure 1.
Period 1 Study Design
csDMARD = conventional synthetic disease modifying anti-rheumatic drug; DMARD = disease modifying anti-
rheumatic drug; n = number; QD = once daily; RA = rheumatoid arthritis; W = week
*
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; QD = once daily; W = week
Note:
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, including those 
currently on upadacitinib 30 mg QD.
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 
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.
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 (24-Week Randomized, Double-Blind Treatment Period)
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 24 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 1, 2, 4, 8, 12, 16, 20, and 24.  A ± 3 day window is permitted around scheduled 
study visits.  The last dose of study drug in Period 1 is taken the day prior to the Week 24 
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.
Period 2 (Blinded Long-Term Extension Period [236 Weeks])
Period 2 will begin at the Week 24 Visit after all assessments have been completed.  
During Period 2, subjects will have a study visit at Weeks 36, 48, and every 12 weeks 
through Week 240, and Week 260/PD.  A ± 7 day window is permitted around scheduled 
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Starting at Week 24, at least 20% improvement in BOTH TJC AND SJC is required to 
remain on study drug.  Anyone who does not fulfill this criterion at 2 consecutive visits 
(starting at Week 24) despite optimization of background RA therapy must be 
discontinued from study drug.
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.
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.  As the subject has discontinued 
study drug, all rescue and efficacy driven discontinuation criteria no longer apply 
(e.g., CDAI calculation at Week 24, 20% TJC/SJC calculation for PD).  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.  If a subject prematurely discontinues study drug treatment and 
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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 phone call 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 24), but decided not to participate 
in the extension Period 2; OR
●
Completed the last visit of Period 2; OR
●
Prematurely discontinued study drug and/or study participation and have 
completed a PD visit.  In this case the 30 day Follow-Up 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 of study 
drug.
4.3
Sample Size
The planned total sample size of 450 can provide approximately 90% power to detect a 
20% difference in ACR20 rates at Week 12 (assuming a placebo ACR20 response rate of 
27%), at two-sided α = 0.025 and accounting for 10% dropout rate.  This sample size also 
provides approximately 90% power for a 17% difference in DAS28 (CRP) LDA response 
rate at Week 12 (assuming a placebo DAS28 LDA response rate of 12%), at two-sided 
α = 0.025 and accounting for 10% dropout rate.  It can also provide at least 90% power 
 


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for most key secondary endpoints, at two-sided significance level of 0.025 and accounting 
for a 10% dropout rate.
4.4
Interim Analysis and Date Base Lock
An unblinded analysis will be conducted after all subjects have completed Period 1 
(Week 24) for the purpose of regulatory submission.  Study sites and subjects will remain 
blinded for the duration of the study (Periods 1 and 2).
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.
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 up to Week 12 in Period 1 of the 
study.  Additional analysis of the primary efficacy endpoint will be conducted on the Per 
Protocol analysis set, in order to evaluate the impact of major protocol deviations.
 


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Major protocol deviations (ICH deviation and other clinically significant non-ICH 
deviation) 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.
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. 
 


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The visit window and the target study day for each protocol-specified visit in Period 1 are 
displayed in Table 1 and Table 2 (depending on the different visit schedules of different 
endpoints).  Visit windows for protocol-specified visits in Period 2 are defined similarly. 
Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ACR 
Components and Morning Stiffness) 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
1
2
8
11
2
12
15
22
4
23
29
43
8
44
57
71
12
72
85
first dose date from Week 
12 dispensed kit
16
first dose date from Week 12 
dispensed kit + 1
113
127
20
128
141
155
24
156
169
first dose date of Period 2
a.
Day of first dose of study drug.
Table 2.
Analysis Windows for Efficacy Analysis for Period 1 (for 
EQ-5D-5L, SF-36, and ISI)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
4
2
29
57
12
58
85
first dose date from 
Week 12 dispensed kit
24
first dose date from Week 
12 dispensed kit + 1
169
first dose date of Period 2
a.
Day of first dose of study drug.
 


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6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
6.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics information will be collected at the Baseline 
visit of the study and will be summarized for the FAS.  The number of observations, 
mean, standard deviation, median, minimum and maximum will be summarized for 
continuous variables.  Categorical or discrete variables will be summarized via 
frequencies and percentages.  Summary statistics will be computed for each treatment 
group and overall.
Main Demographic and Baseline Characteristics
●
Sex (male, female)
●
Age (years)
●
Age Categories (< 40, [40, 65), ≥ 65 years)
●
Race (White, Black or African American, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Asian, Other)
●
Geographic Region (North America, South/Central America, Western Europe, 
Eastern Europe, Asia, 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, BMI ≥ 25)
RA Medical History and Characteristics
●
Duration of RA Symptoms in years 
●
Duration of RA Diagnosis in years 
●
Duration of RA Categories (< 10 year, ≥ 10 year)
 


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●
Number of prior bDMARD received (1, 2, ≥ 3)
●
Prior failed bDMARD (stratum 1:  failed 1 or 2 biologics with the same 
mechanism of action; stratum 2:  failed ≥ 3 biologics with the same mechanism 
of action and/or multiple mechanisms of action)
●
Failed at least one prior bDMARD due to lack of efficacy (yes, no)
●
Failed at least one anti-TNF (yes, no)
●
Corticosteroids use at baseline (yes, no)
●
Oral steroid dosing (prednisone equivalent) at baseline 
●
Concomitant csDMARD at baseline (MTX alone, MTX and other csDMARD, 
csDMARD other than MTX)
ACR and/or DAS Components at Baseline
●
Tender joint count (TJC68) defined as the number of tender joints out of 
68 assessed joints
●
Swollen joint count (SJC66) defined as the number of swollen joints out of 
66 assessed joints
●
Tender joint count (TJC28) defined as the number of tender joints out of 
28 assessed joints used for DAS28 calculation
●
Swollen joint count (SJC28) defined as the number of swollen joints out of 
28 assessed joints used for DAS28 calculation
●
Physician's global assessment of disease activity (mm on a 100-mm horizontal 
visual analogue scale [VAS])
●
Patient's assessment of pain within last week (mm on a 100-mm horizontal 
(VAS)
●
Patient's global assessment of disease activity within last 24 hours (mm on a 
100-mm horizontal VAS)
●
Health Assessment Questionnaire Disability Index of the (HAQ – DI) (range:  
0 to 3)
●
High sensitivity C-reactive protein (hsCRP) (mg/L) 
●
Erythrocyte sedimentation rate (ESR) (mm/hr)
 


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Other Baseline RA Disease Characteristics
●
Anti-cyclic citrulliated peptide (Anti-CCP) (units)
●
Anti-CCP status:  Positive or Negative
●
Rheumatoid Factor (RF) (units)
●
Rheumatoid Factor (RF) status:  Positive or Negative
●
DAS28 [hsCRP]
●
DAS28 [ESR]
●
DAS28 Categories:
○
DAS28 > 5.1 (High Disease Activity)
○
DAS28 ≤ 5.1
●
Clinical Disease Activity Index (CDAI)
●
CDAI categories:
○
CDAI > 22 (High Disease Activity)
○
CDAI ≤ 22 
●
Simplified Disease Activity Index (SDAI)
●
SDAI categories:
○
SDAI > 26 (High Disease Activity)
○
SDAI ≤ 26 
Patient Report Outcomes at Baseline
●
Morning stiffness (severity and duration)
●
EQ-5D-5L
●
ISI (sleep)
●
36-Item Short Form Health Survey (SF-36) Version 2:  physical component 
summary, mental component summary and the 8 sub-domain scores
Clinical Tests at Screening
●
Chest x-ray
●
ECG
 


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●
Tuberculin PPD skin test, QuantiFERON TB Gold test
●
Hepatitis Testing
●
Serum pregnancy test
Immunization History
●
BCG immunization
●
Herpes Zoster immunization
●
Hepatitis B immunization
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [user, ex-user, non-user, unknown]
●
Alcohol Use [drinker, ex-drinker, non-drinker, unknown]
6.2
Medical History
Medical history data will be summarized and presented for FAS population using body 
systems and conditions/diagnoses as captured on the CRF.  The body systems will be 
presented in alphabetical order and the conditions/diagnoses will be presented in 
alphabetical order within each body system.  The number and percentage of subjects with 
a particular condition/diagnosis will be summarized for each randomized treatment group 
as well as overall.  Subjects reporting more than one condition/diagnosis within a body 
system will be counted only once for that body system.  No statistical comparison will be 
performed for medical history reporting.
6.3
Prior Treatment and Concomitant Medications
Prior and concomitant medications will be summarized by each randomized treatment 
group as well as overall for FAS.  Prior medications are those medications taken prior to 
the first dose of study drug.  This includes medications with a start date before the 
first study drug administration date, regardless of the end date of these medications.  
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medications.  Concomitant medications are those medications, other than study drug, 
taken after the first dose of study drug and within 1 day of the last dose of study drug.  
This includes medications with a start date between first study drug administration and 
last study drug administration + 1 day, as well as, medications with a start date prior to 
first dose of study drug and which are ongoing after first dose of study drug.  Medications 
taken on the day of the first dose of study drug are counted as concomitant medications.
The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
6.4
Protocol Deviations
Protocol deviations based on ICH deviation critieria are categorized as follows:
1.
Those who entered the study even though they did not satisfy the entry criteria
2.
Those who developed withdrawal criteria during the study and were not withdrawn
3.
Those who received the wrong treatment or incorrect dose, and
4.
Those who received an excluded or prohibited concomitant medication.
The protocol deviations listed above will be summarized and listed by treatment group.
7.0
Patient Disposition
The following will be summarized by randomized treatment group as well as overall:
●
number of subjects randomized,
●
number of subjects included in key analysis populations (Full Analysis Set and 
Per Protocol Analysis Set for primary efficacy analysis, Safety Analysis Set 
for analysis prior to Week 12 treatment switching),
●
number of subjects who completed Period 1 study participation,
 


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●
number of subjects who entered Period 2,
●
number of subjects who completed overall study (Period 1 and Period 2) 
participation (not applicable for Period 1 reporting).
This summary will be repeated by site.
Premature discontinuation details will be further summarized separately for Period 1 and 
Period 2 as follows.
Period 1
The number and percentage of subjects completed Period 1 and prematurely discontinued 
in Period 1 will be summarized by randomized treatment group, separately by study drug 
and study participation completion/discontinuation, with the primary reason for 
discontinuation collected from CRF by the following categories:
●
Adverse event (AE)
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy
●
Other.
Subjects may have more than one reason for discontinuing, but only the primary reason 
will be summarized.
In addition, the number and percentage of subjects enrolled in Period 2 will also be 
summarized by randomized treatment group.
Period 2
Period 2 patient dispositions and reason for discontinuation will be summarized for 
overall and by treatment regimen when entering Period 2 defined as follows:
1.
Upadacitinib 15 mg QD
 


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2.
Upadacitinib 30 mg QD
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 
completed and 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 prematurely discontinued 
study drug in Period 2 will be summarized.
For subjects who prematurely discontinued study drug or study participation, the primary 
reason as well as all reasons for discontinuation will be summarized by the following 
categories (as collected in CRF):
●
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 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 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.
 


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1.
Placebo
2.
Upadacitinib 15 mg QD
This includes Upadacitinib 15 mg QD exposure from subjects starting on 
Upadacitinib 15 mg QD and subjects switching from placebo to Upadacitinib 
15 mg QD.
3.
Upadacitinib 30 mg QD
4.
This includes Upadacitinib 30 mg QD exposure from subjects starting on 
Upadacitinib 30 mg QD and subjects switching from placebo to Upadacitinib 
30 mg QD.  Exposure is censored at time of dose switch from Upadacitinib 30 mg 
QD to Upadacitinib 15 mg QD.  Upadacitinib 15 mg QD switched from 
Upadacitinib 30 mg QD
This includes Upadacitinib 15 mg QD exposure from subjects who switched dose 
from Upadacitinib 30 mg QD to Upadacitinib 15 mg QD.
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.  Exposure to upadacitinib 30 mg QD 
(Group 3) 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 
a separate group (Group 4).
The duration of exposure to study drug will be summarized for each group as specified 
above, with the number of subjects, mean, standard deviation, median, minimum and 
maximum values.  In addition, the number and percentage of subjects exposed to study 
drug will be summarized for the following cumulative duration intervals.
●
≥ 2 weeks
●
≥ 1 month
●
≥ 3 months
●
≥ 6 months
 


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●
≥ 9 months
●
≥ 12 months
●
≥ 18 months
●
≥ 2 years
●
≥ 2.5 years
●
≥ 3 years
●
≥ 4 years
8.2
Compliance
Study drug compliance will be summarized for each treatment group for Period 1.  The 
compliance is defined as the number of tablets taken (i.e., the difference between the 
number of tablets dispensed and the number of tablets returned) during the subject's 
participation in Period 1 divided by the number of days that the subject was in the 
Treatment Phase of Period 1.
9.0
Efficacy Analysis
9.1
General Considerations
There are two sets of planned efficacy analysis: efficacy analysis by Week 12 and long-
term efficacy analysis.  All efficacy analyses will be carried out using the FAS population.
9.1.1
Efficacy Analysis at Different Phases of the Study
Efficacy Analysis by Week 12
Standard efficacy analysis by randomized treatment groups (Upadacitinib 15 mg QD, 
Upadacitinib 30 mg QD and the combined placebo groups) will be performed on efficacy 
data up to Week 12.  No protocol-defined treatment switching will occur prior to the time 
point.  Formal statistical inference will be generated, and results from this set of analysis 
will be used as the key efficacy findings of this study.
 


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Long-Term Efficacy Analysis
Long-term efficacy analysis will be performed on As Observed data (defined in 
Section 9.1.2) by randomized treatment group sequence as described below:
1.
Placebo →Upadacitinib 15 mg QD
2.
Placebo →Upadacitinib 30 mg QD
3.
Upadacitinib 15 mg QD
4.
Upadacitinib 30 mg QD
There will be no statistical testing; only descriptive statistics and confidence intervals will 
be provided.
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 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 2 and 4, 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.
9.1.2
Definition of Missing Data Imputation
Non-Responder Imputation (NRI) Approach
The NRI approach will categorize any subject who has a missing value for categorical 
variables at a specific visit as non-responder for that visit.  In addition, subjects who 
prematurely discontinue from study drug will be considered as non-responders for all 
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Observed Cases (OC)
The OC analysis will not impute values for missing evaluations.  In addition, the OC will 
not use values after premature discontinuation of study drug.  This sensitivity analysis will
only be applied to the analysis prior to treatment switching.
As Observed (AO)
The AO analysis will not impute values for missing evaluations.  Regardless of treatment 
switching or premature discontinuation of study drug, all observed data will be used in the 
analysis.  The AO analysis will be applied to long-term efficacy analysis.
Mixed Effect Model Repeat Measurement (MMRM) for Short-Term Analysis
The repeated measure analysis will be conducted using mixed model including observed 
measurements at all visits.  The mixed model includes the categorical fixed effects of 
treatment, visit and treatment-by-visit interaction, main stratification factors at 
randomization and the continuous fixed covariates of baseline measurement.  An 
unstructured variance covariance matrix will be used.  The parameter estimations are 
based on the assumption of data being missing at random and using the method of 
restrictive maximum likelihood (REML).  The missing at random assumption is 
considered reasonable given the high placebo response rate typically seen in RA trials.  
Additionally in RA trials, the proportion of discontinuation is relatively small (10 – 15% 
only) and the rate of discontinuation due to lack of efficacy is generally low (< 5%).
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 main stratification 
factor prior bDMARD use. 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 may also be 
 


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included in the model as appropriate.  Unstructured, Toeplitz, compound symmetry, or 
other covariance structures may be considered.
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 and 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 the assumption of data being missing at random.  
The missing at random assumption is considered reasonable given the high placebo 
response rate typically seen in RA trials.  Additionally in RA trials, the proportion of 
discontinuation is relatively small (10 – 15% only) and the rate of discontinuation due to 
lack of efficacy is generally low (< 5%).
9.2
Efficacy Analysis by Week 12
9.2.1
Primary Efficacy Analysis
The primary endpoint for US/FDA regulatory purposes is ACR20 response at Week 12.  
The primary endpoint for EU/EMA regulatory purposes is LDA (based on DAS28 (CRP) 
≤ 3.2) at Week 12.  Analyses will be conducted separately for US/FDA regulatory 
purposes and EU/EMA regulatory purposes; for each set of analysis, only one primary 
endpoint is specified.
Analysis of the primary endpoint will be conducted on the FAS based on randomized 
treatment groups (Upadacitinib 15 mg QD, Upadacitinib 30 mg QD and the combined 
placebo groups).  Point estimate and 95% CI using normal approximation will be 
 


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provided for the response rate for each randomized treatment group.  Comparisons of the 
primary endpoint will be made between each Upadacitinib dose and the combined placebo 
group using the Cochran-Mantel-Haenszel test adjusting for stratification factor prior 
bMDARD use.  Point estimate, 95% CI using normal approximation and p-value for the 
treatment comparison will be presented.  Both the nominal p-value constructed using the 
Cochran-Mantel-Haenszel test and the 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.
9.2.2
Sensitivity Analysis of Primary Efficacy Variables
The primary analysis for point estimate and CI will be repeated using Observed Cases 
without any imputation as a sensitivity analysis.  This will be conducted on the FAS based 
on randomized treatment groups.
Supportive NRI analysis will also be conducted on the Per Protocol Analysis Set.
9.2.3
Key Secondary Efficacy Analyses
Ranked key secondary endpoints (at Week 12) for US/FDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
Change from baseline in HAQ-DI;
3.
LDA as measured by DAS28 (CRP);
4.
Change from baseline in SF-36 Physical Component Score (PCS).
Ranked key secondary endpoints (at Week 12) for EU/EMA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP);
2.
ACR20 response rate;
3.
Change from baseline in HAQ-DI;
 


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4.
Change from baseline in SF-36 Physical Component Score (PCS).
Other key secondary endpoints (at Week 12) for both US/FDA and EU/EMA regulatory 
purposes are:
1.
ACR50 response rate;
2.
ACR70 response rate;
3.
ACR20 response rate at Week 1.
For binary endpoints, frequencies and percentages will be reported for each randomized 
treatment group.  Similar analyses as for the primary endpoint will be conducted.
For the major RA continuous endpoints DAS28 and HAQ-DI change from baseline, 
statistical inference will be conducted using analysis of covariance (ANCOVA) coupled 
with MI for missing data handling.  Specifically, the ANCOVA model will include 
treatment as the fixed factor, and the corresponding baseline value and the stratification 
factor prior bDMARD use (Yes/No) as the covariates.  For other continuous endpoints, 
statistical inference will be conducted using the MMRM model as described in 
Section 9.1.2, with the main stratification factor being prior bDMARD use (Yes/No).  
From both the MI and MMRM analyses, the LS mean and 95% CI will be reported for 
each randomized treatment group; the LS mean treatment difference and associated 95% 
CI and p-value will be reported comparing each Upadacitinib dose group with the 
combined placebo group.  Both nominal p-value and adjusted p-value through the 
graphical multiplicity procedure described in Section 9.2.5 will be provided.
9.2.4
Exploratory Efficacy Analyses
Additional efficacy analysis includes the following endpoints at Week 1, 2, 4, 8 and 12:
●
Change from baseline in individual components of ACR response;
●
ACR20/50/70 response rates;
 


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●
Change from baseline in DAS28 (CRP) and DAS28 (erythrocyte 
sedimentation rate [ESR]);
●
Change from baseline in CDAI and SDAI;
●
Change from baseline in morning stiffness (severity and duration);
●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), DAS28 (ESR), Simplified Disease Activity Index 
(SDAI), and CDAI criteria;
●
Proportion of subjects achieving MCID in change from baseline in HAQ-DI 
(defined as change from baseline in HAQ-DI ≤ –0.3) among those with 
baseline HAQ-DI ≥ 0.3;
●
ACR/EULAR Boolean remission.
Additional endpoints (at Weeks 4 and 12) are:
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in ISI (sleep);
●
Change from baseline in SF-36.
For binary endpoints, point estimate and 95% CI using normal approximation will be 
provided for the response rate for each randomized treatment group.  Point estimate, 95% 
CI and p-value will be provided for the treatment comparison between each Upadacitinib   
dose group and the combined placebo group using the Cochran-Mantel-Haenszel test 
adjusting for stratification factor prior bDMARD use.  Only the nominal p-value will be 
provided, and the 95% CI will be based on normal approximation.  NRI will be used as 
primary analysis and OC will be used as sensitivity analysis.
For continuous endpoints, the LS mean and 95% CI will be reported for each randomized 
treatment group.  The LS mean treatment difference and associated 95% CI and p-values 
between each Upadacitinib dose group and the combined placebo group will be provided 
using MMRM model with fixed effects of treatment, visit and treatment-by-visit 
interaction, prior bDMARD use and baseline value as covariate.  Only the nominal 
p-value will be provided.
 


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9.2.5
Handling of Multiplicity
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.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 and Figure 4, for US/FDA 
and EU/EMA regulatory purposes respectively.  In the graph, 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 
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
9.2.6
Efficacy Subgroup Analysis
The primary efficacy endpoint will be examined in the subgroups listed in Table 3 below.  
Treatment difference between each Upadacitinib dose and the combined placebo group 
will be presented with point estimate and 95% confidence interval using normal 
approximation.  No p-value will be provided for subgroup analysis.  If any of the resulting 
subgroups has fewer than 10% of the planned study size (i.e., < 45 subjects), the subgroup 
analyses for that variable will not be presented.
 
 
 
 


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Table 3.
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
Duration of RA diagnosis
< 10 year or ≥ 10 year
Baseline Rheumatoid Factor Status
Positive or Negative
Baseline Anti-CCP Antibody Status
Positive or Negative
Baseline both RF positive and Anti-CCP positive
Yes or No
Baseline DAS28[hsCRP)
≤ 5.1 or > 5.1
Prior failed bDMARD 
stratum 1:  failed 1 or 2 biologics with the same 
mechanism of action; stratum 2:  failed
≥ 3 biologics with the same mechanism of action 
and/or multiple mechanisms of action
Failed at least one Prior bDMARD due to lack of 
efficacy
Yes or No
Failed anti-IL6 due to lack of efficacy
Yes or No
9.2.7
Summary of Efficacy Analysis by Week 12
Table 4 below provides the overview of the efficacy analyses by Week 12 to be performed 
on different endpoints.
 


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Table 4.
Summary of Efficacy Variables and Corresponding Analyses for 
Efficacy Analysis by Week 12
Efficacy Variables
Analysis Method
Primary Variables

ACR20 response at Week 12a

LDA as measured by DAS28(CRP) at 
Week 12b

Point estimate and 95% CI of the response 
rate for each Upadacitinib dose group and the 
combined placebo 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 combined 
placebo group, where the p-value is 
constructed using the Cochran-Mantel-
Haenszel test adjusting for stratification factor 
prior bDMARD use.  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:

ACR50/70 response at Week 12

ACR20 response at Week 12b

LDA as measured by DAS28(CRP) at 
Week 12a

ACR20 response at Week 1

Point estimate and 95% CI of the response 
rate for each treatment group.  The 95% CI 
will be based on normal approximation.

Point estimate, 95% CI and p-value for the 
treatment comparison between each 
Upadacitinib dose group and the combined 
placebo group using the Cochran-Mantel-
Haenszel test adjusting for stratification factor 
prior bDMARD use.  For ranked key 
secondary endpoints, 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.

Imputation:  NRI for primary analysis and OC 
for sensitivity analysis

Analysis Set:  FAS
 


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Table 4.
Summary of Efficacy Variables and Corresponding Analyses for 
Efficacy Analysis by Week 12 (Continued)
Efficacy Variables
Analysis Method
Key Secondary Variables (Continued)
Continuous Endpoints:

Change from baseline in DAS28(CRP) at 
Week 12

Change from baseline in HAQ-DI at Week 12

LS mean, and 95% CI within each treatment 
group and LS mean, 95% CI and p-values 
between each Upadacitinib dose group and the 
combined placebo group using ANCOVA 
model with treatment, prior bDMARD use 
and baseline value as covariates.  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
Change from baseline in SF-36 Physical 
Component Score (PCS) at Week 12

LS mean and 95% CI within each treatment 
group and LS mean, 95% CI and p-values 
between each Upadacitinib dose group and the 
combined placebo group using MMRM model 
with fixed effects of treatment, visit and 
treatment-by-visit interaction, prior bDMARD 
use 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.

Analysis Set:  FAS
Additional Variables (summarized at all visits up to Week 12)
Binary Endpoints:

ACR20/50/70

LDA and CR based on DAS28(CRP), DAS28 
(ESR), SDAI, and CDAI criteria

Proportion of subjects achieving MCID in 
change from baseline in HAQ-DI among those 
with baseline HAQ-DI ≥ 0.3;

ACR/EULAR Boolean remission;

Point estimate and 95% CI of the response 
rate for each treatment group.  The 95% CI 
will be based on normal approximation.

Point estimate, 95% CI and p-value for the 
treatment comparison between each 
Upadacitinib dose group and the combined 
placebo group using the Cochran-Mantel-
Haenszel test adjusting for stratification factor 
prior bDMARD use.  Only nominal p-value 
will be provided, and the 95% CI will be 
based on normal approximation.

Imputation:  NRI for primary analysis and OC 
for sensitivity analysis

Analysis Set:  FAS
 


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Table 4.
Summary of Efficacy Variables and Corresponding Analyses for 
Efficacy Analysis by Week 12 (Continued)
Efficacy Variables
Analysis Method
Additional Variables (summarized at all visits up to Week 12) (Continued)
Continuous Endpoints:

Change from baseline in individual ACR 
components

Change from baseline in DAS28 (CRP) and 
DAS28 (ESR)

Change from baseline in CDAI and SDAI

Change from baseline in morning stiffness 
(severity and duration)

Change from baseline in EQ-5D-5L

Change from baseline in ISI (sleep)

Change from baseline in SF-36

LS mean and 95% CI within each treatment 
group and LS mean, 95% CI and p-values 
between each Upadacitinib dose group and the 
combined placebo group using MMRM model 
with fixed effects of treatment, visit and 
treatment-by-visit interaction, prior bDMARD 
use and baseline value as covariate.  Only 
nominal p-value will be provided.

Analysis Set:  FAS
a.
US/FDA regulatory purposes.
b.
EU/EMA regulatory purposes.
9.3
Long-Term Efficacy Analysis
Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Week 1, 2, 4, 8, 12, 24, 36, 48, every 12 weeks through Week 240, and at Week 260.
●
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;
●
Change from baseline in SDAI;
●
Change from baseline in morning stiffness (severity and duration);
●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria;
●
Proportion of subjects achieving MCID in change from baseline in HAQ-DI 
(defined as change from baseline in HAQ-DI ≤ –0.3);
 


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●
ACR/EULAR Boolean remission;
●
Proportion of subjects with no concomitant corticosteroid use (among subjects 
with corticosteroid use at baseline).
Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Week 4, 12, 24, 48:
●
Change from baseline in EQ-5D-5L;
●
Change from baseline in ISI (sleep);
●
Change from baseline in SF-36.
Analyses will be based on As Observed (AO) data.  Descriptive statistics will be provided 
for each randomized treatment group sequence as defined in Section 9.1.1.  These include 
the number of observations, mean, standard deviation, 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 9.1.2 for all endpoints except 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 randomized treatment group 
sequence over time will be provided.  
For the purpose of Period 1 CSR, response rate and 95% CI using NRI for binary 
endpoints will be provided for each randomized treatment group sequence by visits up to 
Week 24.  For continuous endpoints, the LS mean and 95% CI based on MMRM will be 
reported for each randomized treatment group sequence by visits up to Week 24. 
Table 5 below provides the overview of the long-term efficacy analyses to be performed 
on different endpoints.
 


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Table 5.
Summary of Efficacy Variables and Corresponding Analyses for 
Long-Term Efficacy Analysis
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

Proportion of subjects with change from 
baseline in HAQ-DI ≤ –0.3 and ≤ –0.22, 
respectively

Boolean remission

Proportion of subjects with no concomitant 
corticosteroid use (among subjects with 
corticosteroid use at baseline)*

Point estimate and 95% CI of the response 
rate for each randomized treatment group 
sequence

Point estimate and 95% CI of the response 
rate using GLMM model for each randomized 
treatment group sequence (*endpoint 
excluded from this analysis)

Plot for each randomized 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 by 
visit

Change from baseline in morning stiffness 
(severity and duration) by visit

Change from baseline in EQ-5D-5L by visit

Change from baseline in ISI (sleep) by visit

Change from baseline in SF-36 by visit

Point estimate, and 95% CI of mean change 
from baseline together with SD for each 
randomized treatment group sequence

Point estimate and 95% CI of change from 
baseline using MMRM model for each 
randomized treatment group sequence 

Plot for each randomized treatment group 
sequence over time for key endpoints#

Imputation:  AOAnalysis 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.
Note:
NRI for binary endpoints and MMRM for continuous endpoints were used for analysis up to Week 24, as 
described in this section.  The analyses had been completed prior to SAP Version 3.0 and is no longer 
mentioned in Table 5 for streamlined summary of future long-term efficacy analysis.
9.4
Efficacy Variables Definitions and Conventions
9.4.1
ACR Criteria
ACR criteria are a commonly used standard criteria set mentioned in the guidance of 
American College of Rheumatology to evaluate the effectiveness of investigation drug in 
 


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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
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.
 


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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.
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. 
 


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●
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.
●
Non-Responder Imputation (NRI) for ACR response:
○
Step 1:  all missing components will be imputed using LOCF, and then the 
ACR composite score can be calculated.
○
Step 2:  if the ACR composite score cannot be determined by step 1, the 
ACR composite score will be imputed as 0.  In addition, subjects who 
prematurely discontinue from the study drug will be considered as non-
responders (ACR = 0) for all subsequent visits after the discontinuation 
date.
9.4.2
Joint Evaluation
Anatomical joints are evaluated for swelling and tenderness at every study visit.  The 
34 anatomical joints in Table 6 are assessed in this study for both the left and right side of 
the body.
 


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Table 6.
Anatomical Joints Assessed for Calculation of Tender and Swollen 
Joint Counts (TJC68 and SJC66)
Temporomandibular
Sternoclavicular
Acromio-clavicular
Shoulder
Elbow
Wrist
Metacarpophalangeal I
Metacarpophalangeal II 
Metacarpophalangeal 
III
Metacarpophalangeal 
IV
Metacarpophalangeal V
Thumb Interphalangeal
Proximal 
Interphalangeal II
Proximal 
Interphalangeal III
Proximal 
Interphalangeal IV
Proximal 
Interphalangeal V
Distal
Interphalangeal II
Distal
Interphalangeal III
Distal
Interphalangeal IV
Distal
Interphalangeal V
Hipa
Knee
Ankle
Tarsus
Metatarsophalangeal I
Metatarsophalangeal II 
Metatarsophalangeal III
Metatarsophalangeal IV
Metatarsophalangeal V
Great Toe/Hallux
Interphalangeal II
Interphalangeal III
Interphalangeal IV
Interphalangeal V
a.
Hip joints are not assessed for swelling.
At each study visit, a joint evaluator assessed whether a particular joint was "tender or 
painful" where presence of tenderness was scored as "1" and the absence of tenderness 
was scored as "0," provided the joint was not replaced ("9") or could not be assessed 
("NA") due to other reasons (e.g., post-corticosteroid joint injection).  The total tender 
joint count (TJC68), which is based on 68 joints, will be derived as the sum of all "1s" and 
proportional extrapolation will be used to impute joint counts for the joints that are 
replaced or not assessed.  A similar method will be followed for the derivation of total 
swollen joint count (SJC66), which is based on 66 joints as the hip joints are excluded.  
Thus, the range for TJC68 will be 0 to 68 and 0 to 66 for SJC66.
9.4.3
Patient's Global Assessment of Disease Activity Visual 
Analog Scale (VAS)
The subject will assess his/her disease activity for the past 24 hours using a Patient's 
Global Assessment of Disease VAS.  The range is 0 to 100 mm with no activity being 
indicated by 0 and severe activity by 100.
 


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


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Table 7.
Anatomical Joints for DAS28 (CRP) Calculation
Shoulder
Elbow
Wrist
Thumb Interphalangeal
Metacarpophalangeal I
Metacarpophalangeal II
Metacarpophalangeal 
III
Metacarpophalangeal IV
Metacarpophalangeal V
Proximal 
Interphalangeal II
Proximal 
Interphalangeal III
Proximal Interphalangeal 
IV
Proximal 
Interphalangeal V
Knee
To calculate observed DAS28 scores, the observed component value will be calculated 
first.  Then the components will be included in the calculation per the DAS formula 
selected.  If any observed component is missing in a window, then the observed DAS28 
score will be missing.
9.4.7
Simplified Disease Activity Index (SDAI)
SDAI is a composite continuous index to assess disease activity based on TJC28, SJC28, 
Patient's Global Assessment of Disease Activity (PtGA) (in cm, 0 – 10), Physician's 
Global Assessment of Disease Activity (PhGA) (in cm, 0 – 10) and hsCRP (mg/dL).  It 
can be derived as follows:
SDAI = TJC28 + SJC28 + PtGA (cm) + PhGA (cm) + hsCRP (mg/dL).
To calculate observed SDAI scores, the observed component value will be calculated first.  
Then the components will be included in the calculation per the SDAI formula selected.  
If any observed component is missing in a window, then the observed SDAI score will be 
missing.
9.4.8
Clinical Disease Activity Index (CDAI)
CDAI is a composite continuous index to assess disease activity without using hsCRP 
measurement.  It can be calculated based on TJC28, SJC28, Patient's Global Assessment 
of Disease Activity (PtGA) (in cm, 0 – 10) and Physician's Global Assessment of Disease 
Activity (PhGA) (in cm, 0 – 10).  It can be derived as follows:
 


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


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Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities.  The higher the score, the 
more likely to associate with morbidity and mortality for the RA patient.
The maximum score for all the questions in each category is considered as the score for 
the category.  The Standard disability index (HAQ-DI) takes into account the subject's use 
of aids or devices or assistance in the scoring algorithm for a disability category.  For each 
of the eight disability categories there is an AIDS OR DEVICES companion variable(s) 
that is used to record the type of assistance, if any, a subject uses for his/her usual 
activities.  If aids or devices and/or assistance from another person are checked for a 
disability category, the score for this category is set to 2 (much difficulty), if the original 
score is 0 (no difficulty) or 1 (some difficulty).  The HAQ-DI is then calculated by 
summing the adjusted categories scores and dividing by the number of categories 
answered.  The HAQ-DI cannot be calculated if the patient does not have scores for at 
least 6 categories.
9.4.12
EuroQoL-5D (EQ-5D-5L)
EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal.  
The EQ-5D consists of 2 pages.  The first page measures 5 dimensions of the health status 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with 
5 levels per dimension (no problems, slight problems, moderate problems, severe 
problems, and extreme problems corresponding to Level 1 to Level 5 respectively).  The 
second page is an EQ Visual Analogue Scale (EQ VAS).  EQ-5D health states, defined by 
the EQ-5D-5L descriptive system on the first page, may be converted into a single index 
value.  The change from baseline of the index value and EQ VAS will be analyzed and 
reported.  UK scoring algorithm will be used.
9.4.13
Insomnia Severity Index (ISI)
ISI is a 7 item questionnaire that assess, (1) difficulty with sleep onset, (2) difficulty with 
sleep maintenance (3) problem with early awakening, (4) satisfaction with sleep pattern, 
(5) interference with daily functioning as a result of sleep problems, (6) noticeability of 
 


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sleep problem to others, and (7) degree of distress caused by sleep problem.  The severity 
of insomnia items are rated on a likert type of scale, (0) "None," 1- "Mild," 2- "Moderate," 
3- "Severe" and 4- "Very Severe."  Other items on satisfaction, noticeability on 
impairment, worry/distress about sleep and interference are similarly rated on 5-point 
likert type scale form.  The scoring algorithm is in the protocol.
9.4.14
Form SF-36v2
The 36-Item Short Form, Version 2 (SF-36v2) Questionnaire with 4 week recall will be 
completed by the subject at Baseline, Weeks 4, 8 and at study completion (Week 12 or at 
PD).  The SF-36v2 health survey 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.
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 by Week 12, and long-term safety analysis.
Safety Analysis by Week 12
Standard safety analysis by the "as treated" treatment groups of Upadacitinib 15 mg QD, 
Upadacitinib 30 mg QD, and combined placebo groups will be performed on safety data 
up to Week 12.  No protocol-defined treatment switching will occur prior to these time 
points.
The standard safety analyses will include reporting of adverse events (AEs), laboratory, 
and vital signs measurements.  Frequency tables of subjects with treatment-emergent 
 


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adverse events (TEAEs) by system organ class (SOC) and by preferred term (PT) as in the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be provided by 
treatment group.  Mean changes from baseline in all continuous laboratory parameters and 
vital signs variables at each visit will be summarized by "as treated" treatment group.  
Frequency tables of subjects meeting criteria for potentially clinically significant vital sign 
values and for potentially clinically significant laboratory values will be provided by 
treatment group.  Missing safety data will not be imputed.
Long-Term Safety Analysis
Long-term safety analyses that account for protocol-defined treatment switching include 
reporting of AE rate adjusted by cumulative exposure, mean change from baseline in 
laboratory parameters and vital sign variables, and rate of potentially clinically significant 
laboratory and vital signs values.  The treatment-emergent adverse event (TEAE) rate per 
100 patient-years of exposure will be presented by actual treatment received at the time of 
AE (as described in Section 10.2.2).  Listing of subjects with TEAEs by SOC and PT will 
be provided.  Mean changes from baseline in all continuous laboratory parameters and 
vital signs variables at each visit will be summarized by "as treated" treatment group 
sequences defined as follows (as described in Section 10.3.3 and Section 10.4.3).  
Frequency tables and listings of subjects meeting criteria for potentially clinically 
significant vital sign values and for potentially clinically significant laboratory values will 
be provided by actual treatment received at the time of event.  Missing safety data will not 
be imputed.
"As treated" treatment group sequences:
1.
Placebo →Upadacitinib 15 mg QD
2.
Placebo →Upadacitinib 30 mg QD
3.
Upadacitinib 15 mg QD
4.
Upadacitinib 30 mg QD.
 


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Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.  For subjects who previously 
received upadacitinib 30 mg QD, 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 of upadacitinib 15 mg QD will be summarized under a 
separate group, as defined in Section 9.1.  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 2 and 4 (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 19.1 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.
 


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10.2.1
Analysis of Adverse Events Prior to Protocol-Defined 
Treatment Switching
10.2.1.1
Adverse Events Overview
The number and percentage of subjects experiencing TEAEs will be summarized by "as 
treated" 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
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 combined placebo group.
As a sensitivity analysis, the AE overview summary will be repeated by randomized 
treatment groups (Upadacitinib 15 mg QD, Upadacitinib 30 mg QD and the combined 
placebo 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 
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10.2.1.2
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing adverse events a will be tabulated by 
SOC and MedDRA PT by "as treated" treatment group and overall.  The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC.
The following summaries of adverse events will be generated:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
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 (Upadacitinib 15 mg QD, Upadacitinib 30 mg QD and the 
combined placebo 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 
 


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counted in the severity category of unknown, even if the subject has another occurrence of 
the same event with a severity present.  The only exception is that if the subject has 
another occurrence of the same AE with the most extreme severity – severe.  In this case, 
the subject will be counted under the severe category.
10.2.1.4
TEAEs by Relationship
TEAEs will also be summarized by relationship to 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 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 by the following search criteria per Standard MedDRA 
Queries (SMQs)/Company MedDRA Queries(CMQs) in Table 8 below.  Adjudicated 
cardiovascular events will be summarized and presented by treatment group using the 
CAC adjudicated categories.
 


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Table 8.
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 8.
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 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 mg QD.  For subjects who previously 
received upadacitinib 30 mg QD, adverse events and exposure to upadacitinib 30 mg QD 
will be censored at the time of dose switch; subsequent adverse events and exposure 
 


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starting the day of first dose of upadacitinib 15 mg QD will be summarized under a 
separate group.  The detailed treatment 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, 1 year will be considered to be 365.25 days.  For each treatment 
group, the numerator of the overall rate will be the total number of TEAEs reported for 
the event; that is, a subject can contribute more than one event to the numerator.  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 6.0 for the calculation of study drug exposure.  The AE rate per 100 patient-years 
of exposure will be calculated as ([numerator/denominator])*100.  The number of AEs 
reported (numerator), the total number of years of study drug exposure (denominator), and 
the AE 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.
 


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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 rate per 100 patient-
years between each Upadacitinib dose group and the combined placebo group.
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT
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, 1 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 6.0 for the calculation of study drug exposure.  The AE rate per 100 patient-years 
of exposure will be calculated as [(numerator/denominator)]*100.  The number of AEs 
reported (numerator), the total number of years of study drug exposure (denominator), and 
the AE rate per 100 patient-years will be presented overall, for each SOC, and for each PT 
for each treatment group.  
 


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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.  The AESI 
categories will be identified as defined in Table 8.  Adjudicated cardiovascular events will 
be summarized and presented by treatment group using the CAC adjudicated categories.
For each treatment group, the 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, 1 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 6.0 for the calculation of study drug exposure.  The AE rate per 
100 patient-years of exposure will be calculated as [(numerator/denominator)]*100.  The 
number of AEs reported (numerator), the total number of years of study drug exposure 
(denominator), and the AE 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.
 


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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 9.
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)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Uric acid
Sodium
 


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Table 9.
List of Laboratory Variables
Laboratory Variables
Chemistry (Continued)
Potassium
Calcium
Inorganic Phosphorus
Creatine Phosphokinase (CPK)
Chloride
Bicarbonate
Cholesterol
LDL cholesterol
HDL cholesterol
LDL/HDL ratio
Cholesterol/HDL ratio
Urinalysis
Specific Gravity
pH
Protein
Glucose
Ketones
Blood
Microscopic Examination (if needed)
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Other
hs-CRP
QuantiFERON-TB Golda
IgG and IgM
ESR
TBNK
Additional TBNK
a.
For annual follow-up QFT is captured only for those with negative QFT at Screening.
 


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10.3.2
Analysis of Laboratory Data by Week 12
The laboratory data will be summarized by the "as treated" treatment groups 
(Upadacitinib 15 mg QD, Upadacitinib 30 mg QD, and combined placebo groups) and 
overall.
10.3.2.1
Assessment of Mean Change from Baseline and Percentage 
Change from Baseline in Clinical Laboratory Variables
Analyses of mean change from baseline in continuous hematology, chemistry, and 
urinalysis variables which are measured longitudinally will be performed by visits and by 
"as treated" treatment group.  For each change from baseline analysis, the following 
summary statistics will be presented for each treatment group:  sample size, baseline 
mean, visit mean, and the mean, standard deviation, and median of the changes from 
baseline.  An ANOVA model with treatment as a factor will be used to test statistical 
significance for the change from baseline mean among different treatment groups.
In addition, similar analyses will be conducted for percentage change from baseline in 
LDL, HDL and cholesterol.
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables
The baseline and post-baseline laboratory observations will be categorized as Grade 1, 
Grade 2, Grade 3, and Grade 4 according to OMERACT criteria (Rheumatology Common 
Toxicity Criteria v.2.0).  For creatine phosphokinase and creatinine, NCI CTC criteria will 
be used.
For each laboratory variable, shift tables will be generated that cross tabulate the subjects 
as deemed appropriate by "as treated" treatment group:
●
Category of the baseline value versus category of the final value.
●
Category of the baseline value versus maximum category.
●
Category of the baseline value versus minimum category.
 


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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 
Values
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.  Comparisons of the percentage of subjects experiencing a value meeting the 
criteria between treatment groups will be performed using Fisher's exact tests.  Only 
p-values ≤ 0.100 when rounded to three digits will be presented.
10.3.2.4
Assessment of Liver Elevations
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation" (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by "as treated" treatment group:
●
ALT ≥ 3 × ULN
 


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●
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 and Percentage 
Change from Baseline in Clinical Laboratory Variables
Analyses of mean change from baseline in continuous hematology, chemistry, and 
urinalysis variables which are measured longitudinally will be performed by visits and by 
"as treated" treatment group sequences as described in Section 10.1.  For each change 
from baseline analysis, the following summary statistics will be presented for each 
treatment group sequence:  sample size, baseline mean, visit mean, and the mean, standard 
deviation, and median of the changes from baseline.
In addition, similar analyses will be performed for percentage change from baseline in 
LDL-C, HDL-C and total cholesterol.
Starting with Amendment 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 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 
 


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post switch will be summarized separately, as described in Section 10.1.  The original 
study baseline will used for calculating change from baseline.
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 4, all subjects will receive open-label upadacitinib 15 mg QD, including 
those currently on upadacitinib 30 QD.  The treatment 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 10.2.2.  A subject can be counted under different 
treatment groups if he/she switched treatment and experienced potentially clinical 
significant laboratory values under different treatment groups.
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 Placebo and switched to Upadacitinib 15 mg QD, lab values under Upadacitinib 
15 mg QD exposure would be evaluated against the baseline value defined as the last non-
missing measurement recorded on or before the date of the first dose of Upadacitinib 15 
mg QD.  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 creatine phosphokinase and creatinine, NCI 
CTC criteria will be used.  For each of these subjects, the whole course of the respective 
parameter will be listed.
 


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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 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 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 10.2.2.
A subject can be counted under different treatment groups if he/she switched treatment 
and experienced potentially clinical significant laboratory values under different treatment 
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.
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 10.
 


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Table 10.
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 by Week 12
Analyses of mean change from baseline in continuous vital sign variables which are 
measured longitudinally will be performed by visits and by the "as treated" treatment 
groups of Upadacitinib 15 mg QD, Upadacitinib 30 mg QD, and combined placebo 
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.  An ANOVA model 
with treatment as factor, will be used to test statistical significance for the change from 
baseline mean among different treatment groups.
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" treatment group 
sequences as described in Section 10.1.  For each change from baseline analysis, the 
following summary statistics will be presented for each treatment group: sample size, 
baseline mean, visit mean, and the mean, standard deviation, and median of the changes 
from baseline.
 


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Long-Term Vital Sign will also be summarized based on the number and percentage of 
subjects meeting the criteria for potentially clinical significant vital sign values and by the 
actual treatment received at the time of the event occurrence.  The treatment groups are 
the same as the ones for long-term AE analysis as described in Section 8.1 and 
Section 10.2.2.  A subject can be counted under different treatment groups if he/she 
switched treatment and experienced potentially clinical significant laboratory values under 
different treatment groups.
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 4, all subjects will receive open-label upadacitinib 15 mg QD, 
including those currently on upadacitinib 30 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, similarly as described in Section 10.3.3.1.  The treatment 
groups for summarizing potentially clinical significant vital sign values are the same as 
the ones for long-term AE analysis as described in Section 8.1 and Section 10.2.2.  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 4, 5, and 6, 
including handling of dose switch from upadacitinib 30 mg QD to 15 mg QD 
(hereafter referred to as "dose switch") and change of study length from 240 to 260 
weeks.
2.
Updated Section 7.0 to clarify analysis details and incorporate additional summary 
of dose switch.
3.
Updated Section 8.1 study drug exposure groups to accommodate dose switch.
4.
Updated Section 9.1.1 and Section 9.3 to incorporate handling of dose switch for 
long-term efficacy analysis.
5.
Updated Section 9.1.2 to describe the missing data handling approach for the 
additional sensitivity analysis using longitudinal models for long-term efficacy.
6.
Updated Section 9.3 to incorporate the additional sensitivity analysis for long-term 
efficacy.
7.
Added language to clarify analysis details in Section 10.2.1.1, Section 10.2.1.6, 
Section 10.2.2.1, Section 10.2.2.3, Section 10.3.3.2, and Section 10.4.3.
8.
Updated Section 10.2.1.6 and Section 10.4.1 to align with the latest upadacitinib 
AESI definitions in PSSAP V4.0.
9.
Updated Section 10.1, Section 10.2.2, 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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10.
Added Appendix B to describe analysis accounting for impact of COVID-19 
pandemic.
11.
Added Section 11.0 for summary of changes and Section 12.0 for SAP version 
history summary.
12.0
Version History
Table 11.
SAP Version History Summary
Version
Date
Summary
1.0
27 Dec 2016
Original version (submitted to FDA to gain feedback).
2.0
29 Jun 2017
Updated to incorporate FDA feedback. Version 2.0 was used 
for the primary analysis.
3.0
18 Dec 2020
Updated to align with Protocol Amendment 4, and 5 and 6, 
including handling of dose switch from upadacitinib 30 mg QD 
to 15 mg QD and change of study length from 240 to 260 
weeks. Included additional sensitivity analysis for long-term 
efficacy, and analyses due to COVID-19 impact. 
13.0
Appendix
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
 


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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
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
 


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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
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
 


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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
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
 


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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
E5.  Tinnitus
Intermittent, transient, no 
interference with function
Requires treatment, reversible
Disabling, or associated with 
hearing loss
Irreversible deafness
 


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


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


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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
 


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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
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
 


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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
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
 


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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
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
 


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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.
****For CPK and Creatinine NCI CTC grading will be used.  For CPK therefore 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.
 
 
 


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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 2017 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 9.1.2, longitudinal analysis models MMRM and GLMM will be 
used for long term efficacy analysis 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
References
1.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  28(4)2009;586-604.