Conditions: Rheumatoid Arthritis
Keywords: Musculoskeletal Disease Arthritis Joint Diseases Anti-inflammatory Agents Antirheumatic agents
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 493
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib in adults with rheumatoid arthritis (RA) who have completed a preceding randomized controlled trial with upadacitinib.

Detailed description:
This is an open-label extension study to assess the long-term safety, tolerability, and efficacy of upadacitinib in adults with RA who have completed Study M13-550 (NCT01960855) or Study M13-537 (NCT02066389) Phase 2 randomized controlled trial (RCT) with upadacitinib.

All participants received treatment with 6 mg upadacitinib twice a day at the start of the study. Participants may have been up-titrated to 12 mg BID based on protocol-specified criteria. In Protocol Amendment 2 (January 2016) the study treatment was changed to a once daily (QD) formulation. Participants receiving 6 mg BID were transitioned to 15 mg QD and participants receiving 12 mg BID were transitioned to 30 mg QD dosing.

An optional 12-week vaccine sub-study was added in Protocol Amendment 3 (November 2017) to assess the impact of upadacitinib treatment (15 mg QD and 30 mg QD) with background methotrexate on immunological responses to pneumococcal 13-valent conjugate vaccine (PCV-13; Prevnar 13®) in RA patients. The vaccine substudy included 111 participants who were enrolled in the main study, the first participant was enrolled on 13 February 2018 and the the last participant completed the sub-study on 9 April 2020.

In Protocol Amendment 5 (December 2019), the protocol was revised to allow a decrease in upadacitinib dosing from 30 mg QD to 15 mg QD, as appropriate, based on investigator's medical decision or for safety/tolerability concerns.

Arms:
arm 1: Participants received treatment with upadacitinib for up to 312 weeks. The starting dose was 6 mg twice a day (BID). Participants who did not achieve a 20% improvement from RCT Baseline in both Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 6 or Week 12 were up-titrated to 12 mg BID. From January 2017 participants were transitioned to a once-daily (QD) regimen of upadacitinib, either 15 mg QD (participants who were taking 6 mg BID) or 30 mg QD (participants taking 12 mg BID). Starting with Protocol Amendment 5 participants receiving 30 mg QD upadacitinib had the option to decrease the dose to 15 mg QD at the investigator's discretion.

A subset of participants who opted-in to the vaccine substudy received a single-dose of 0.5 mL intramuscular injection of pneumococcal 13-valent conjugate vaccine (PCV-13).

Interventions: intervention 1: Upadacitinib intervention 2: Pneumococcal 13-valent conjugate vaccine (PCV-13)
Intervention descriptions: intervention 1: Tablet taken orally intervention 2: Administered by intramuscular injection

Protocol document:
Prot_000.pdf: 
Upadacitinib
M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
1
1.0
Title Page
Clinical Study Protocol M13-538
Phase 2 Study, Multicenter, Open-Label Extension 
(OLE) Study in Rheumatoid Arthritis Subjects Who 
Have Completed a Preceding Phase 2 Randomized 
Controlled Trial (RCT) with Upadacitinib (ABT-494)
Incorporating Administrative Changes 1 and 2 and 
Amendments 0.01, 0.02, 0.03, 1, 2, 3, 4, 5 and 6
AbbVie 
Investigational
  Product:
Upadacitinib
Date:
01 December 2020
Development Phase:
2
Study Design:
This is a multicenter open-label study.
EudraCT Number:
2013-003530-33
Investigators:
Multicenter Trial (Investigator information is on file at AbbVie)
Sponsor:
AbbVie Inc.*
1 North Waukegan Road 
North Chicago, IL  60064
Sponsor/Emergency 
Medical Contact:
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Mobile:
Email:
EMERGENCY 24 hour Number:
                          +1 973-784-6402
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
*
The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country 
are provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
application with the Competent Authority.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
 
NCT02049138


Upadacitinib
M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
30 September 2013
Administrative Change 1
28 March 2014
Amendment 0.01 (UK Only)
23 July 2014
Administrative Change 0.01 (Romania Only)
19 August 2014
Amendment 1
19 November 2014
Amendment 0.02 (UK Only)
18 December 2014
Amendment 2
12 January 2016
Amendment 0.03 (UK Only)
25 February 2016
Administrative Change 2
10 March 2017
Amendment 3
10 November 2017
Amendment 4
13 February 2019
Amendment 5
09 November 2019
The purpose of this amendment is to incorporate changes summarized below:
●
Apply administrative changes throughout protocol
Rationale:  Revised text to improve consistency and readability and/or provide 
clarification.
●
Update Section 1.0, Title Page
Rationale: Revised to update the sponsor Emergency/Medical Contact for the 
study.
●
Update Section 1.2, Synopsis
Rationale:  Revised to be consistent with current Amendment revisions. 
●
Update Section 1.3, List of Abbreviations and Definition of Terms
Rationale:  Updated to include new terms, Coronavirus Disease – 2019 
(COVID-19) and Direct-to-Patient (DTP)
●
Update Section 3.2, Benefits and Risks
 


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M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
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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.
Updated to allow the 30-day follow up visit to be a phone call or site visit.
●
Update Section 5.2.3.1, 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.
Added the footnote "q" to the Table 2 "Study Activities" to clarify that the 30-
day follow up visit can be a phone call or site visit.
●
Update Section 5.3.1.1, Study Procedures
○
Patient's Global Assessment of Disease Activity Visual Analog Scale 
(VAS), Patient's Assessment of Pain Visual Analog Scale (VAS), Health 
Outcomes Questionnaires.
Specified that these questionnaires are 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 
patient at the next earliest feasible subject's visit
○
Physical Examination
Added provision allowing the complete physical examination to be 
performed at the next earliest feasible visit.
 


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M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
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○
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.
○
TB (tuberculosis) Testing/Chest X-ray (CXR)
Specified that chest X-rays can be performed at the next earliest feasible 
visit unless the Investigator has determined that a CXR is required to 
ensure that it is safe to continue study drug administration (e.g., subjects 
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.
○
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 
 


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M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
5
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 and Section 6.10
Toxicity Management
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 6.10 "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 TAMD should be contacted before discontinuing a subject to ensure all 
acceptable mitigation steps have been explored.
●
Update Section 5.5.1, Treatments Administered
Rationale:  Added specifications in order to provide the study drug through 
DTP shipment in the event pandemic situation like COVID-19 or state of 
emergency prevent the study drug dispensation to the subject onsite, if 
permitted by local regulations.  
●
Update Section 6.4, Adverse Events of Special Interest
 


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M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
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Rationale:  Clarified and updated the list of the adverse events of special 
interest according to the revised sponsor guidelines.
●
Update Section 6.7, Adverse Event Collection Period
Rationale: Added supplemental COVID-19 case report forms (CRFs) for 
missed or virtual visits, study drug interruptions or discontinuations, or 
adverse events and instructions to collect safety information related to 
COVID-19.
Clarified that supplemental CRFs should be completed for renal and herpes 
zoster infection adverse events and for CPK increase considered by the 
Investigator to be an adverse event.
●
Update Section 6.8, Serious Adverse Event Reporting
Rationale: Updated telephone number to contact the Immunology Safety Team 
for safety concerns and Therapeutic Area Medical Director contact 
information.
●
Update Section 6.9, Pregnancy
Rationale: Updated text to define Pregnancy reporting timeline as 24 hours 
from site staff awareness according to the sponsor requirements.
●
Update Section 6.10, Toxicity Management
Rationale: Added guidance for investigators on the management of subjects
with suspected or confirmed COVID-19 infection during the study.
●
Update Table 5, Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values
Rationale: Clarified that Investigator should contact the AbbVie TA MD for 
confirmed ALT or AST > 8 x ULN in addition to the immediate study drug 
interruption.
●
Added Section 6.12 Product Complaint 
Rationale: Updated text to included product complaint definition and 
reporting expectations 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 
 


Upadacitinib
M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
7
emergency situations in order to guide investigators to notify IRB/EC when 
deviations occur. Updated contact information for current study team.
●
Update Section 9.2, Ethical Conduct of the Study
Rationale: Inclusion of information regarding COVID-19 or any 
pandemic/state of emergency-related acceptable protocol modifications.
●
Update Section 9.3, Subject Information and Consent
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 15.0 Reference List
Rationale: Included the most recent Upadacitinib Investigator Brochure
●
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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M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M13-538
Name of Study Drug:  Upadacitinib
Phase of Development:  2
Name of Active Ingredient:  Upadacitinib
Date of Protocol Synopsis:  01 December 2020
Protocol Title:  Phase 2 Study, Multicenter, Open-Label Extension (OLE) Study in Rheumatoid 
Arthritis Subjects who have Completed a Preceding Phase 2 Randomized Controlled Trial (RCT) with 
Upadacitinib (ABT-494)
Objective:
Main Study
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib RA subjects who have 
completed Study M13-550 or Study M13-537 Phase 2 RCT with upadacitinib.
Optional Vaccine Sub-study:  To assess the impact of upadacitinib treatment (15 mg QD or 30 mg QD) 
with a stable background of MTX on immunological responses following administration of Prevnar 13®
pneumococcal vaccine in RA patients (Appendix O).
Investigators:  Multicenter
Study Sites:  118 sites
Study Population:  Adult female and male RA subjects who have completed the Last Visit (Week 12) 
of Study M13-550 or Study M13-537 Phase 2 RCT with upadacitinib, and who have met all of the 
specified inclusion and exclusion criteria.
Number of Subjects to be Enrolled:  494 subjects have been enrolled in this OLE study.
Methodology:
This is an extension study to assess the long-term safety, tolerability, and efficacy of upadacitinib in RA 
subjects who have completed Study M13-550 or Study M13-537 RCT with upadacitinib.  Only those 
subjects who have met all of the specified inclusion and exclusion criteria will have an option to enter 
into the OLE study to receive upadacitinib, as long as the subject is willing and the Investigator believes 
that continuing the therapy with upadacitinib is appropriate.
All eligible subjects will be assigned to upadacitinib 6 mg BID immediately after or up to 30 days 
following the Last Visit (Week 12) of Study M13-550 or Study M13-537.  Subjects who are unable to 
tolerate 6 mg BID will be discontinued from the study.  At Week 6, if a subject fails to achieve at least 
20% improvement from RCT Baseline in both Tender Joint Count (TJC) and Swollen Joint Count 
(SJC), upadacitinib dose should be increased to 12 mg BID as long as the Investigator has no safety 
concerns.  After 6 weeks of treatment with upadacitinib 12 mg BID, the improvement in TJC and SJC 
will be re-assessed at next scheduled visit (Week 12).  If the subject on 12 mg BID fails to achieve at 
least 20% improvement in both TJC and SJC from RCT Baseline the subject will be discontinued.  At 
Week 12, the same process will be followed.  If a subject still on 6 mg BID fails to achieve at least 20% 
improvement from RCT Baseline in both TJC and SJC, upadacitinib dose should be increased to 12 mg 
BID.  The improvement in TJC and SJC will be re-assessed after 6 weeks of treatment with 12 mg BID 
at Week 18 (an optional study visit).  Subjects who fail to achieve at least 20% improvement from RCT 
Baseline in both TJC and SJC with 12 mg BID at Week 18 will be discontinued.
 


Upadacitinib
M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
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Methodology (Continued):
After Week 12, if a subject fails to show at least 20% improvement from RCT Baseline in TJC and SJC 
at 2 consecutive scheduled study visits then the subject will be discontinued.
Starting at Week 6 and during any scheduled or unscheduled visits thereafter, upadacitinib dose may be 
increased from 6 mg BID to 12 mg BID (or 30 mg QD from January 2017, see below for more details) if 
a subject fails to achieve Low Disease Activity (LDA) status (CDAI > 10) and has no safety concerns 
per Investigator's judgment.
At any visit, upadacitinib dose may be decreased back to 6 mg BID (or 15 mg QD from January 2017) 
per Investigator's judgment if there are safety and/or tolerability concerns due to an adverse event or 
reaching one of the protocol specific toxicity management thresholds.  Dose increase back to 12 mg BID 
(or 30 mg QD from January 2017) is not allowed.
From January 2017, all subjects who are at Week 72 or beyond will receive a once-daily tablet 
formulation.  Subjects who are on 6 mg BID capsule dosing will be transitioned to 15 mg QD tablet 
dosing.  Subjects who are on 12 mg BID capsule dosing will be transitioned to 30 mg QD tablet dosing.  
The capsule formulation will not be available to subjects once the transition to tablet formulation has 
occurred.  Please see additional details in Section 5.1.  Starting with Amendment 5, subjects who are 
receiving 30 mg QD open-label upadacitinib will have the option to decrease the dose to 15 mg QD 
based on investigator's discretion.
Prohibited Concomitant Medication
The following medications are prohibited throughout the study:

All biologic therapies

High potency opiates 

Live vaccines

Anti-retroviral therapy

Use of known strong CYP3A inhibitors (e.g., clarithromycin, conivaptan, itraconazole, 
ketoconazole, posaconazole, telithromycin, voriconazole, grapefruit (fruit or juice) or strong 
CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort)

Oral DMARDs (except MTX) are prohibited up to Week 24 but are allowed thereafter per 
Investigator's clinical judgment

JAK inhibitors other than upadacitinib (including but not limited to tofacitinib [Xeljanz®], 
baricitinib and filgotinib)
Concomitant Therapy

Subjects should continue with a stable prescription of methotrexate (MTX) treatment (7.5 to 
25 mg/week) along with a stable dose of folic acid (or equivalent).  If a subject experiences 
MTX-induced toxicity, MTX dose can be reduced or discontinued as per Investigator's medical 
judgment

Stable doses of NSAIDs, acetaminophen

PRN use of NSAIDs and acetaminophen is allowed, but should not be dosed during the 
24 hours prior to a study visit

Oral corticosteroids (equivalent to prednisone ≤ 10 mg but can be increased after Week 24)

Intra-articular, intra-muscular, intra-bursa and intra-tendon sheath injections of corticosteroids
 


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M13-538 Protocol Amendment 6
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Methodology (Continued):
Study Drug Interruption
Subjects who, in the opinion of the investigator, develop adverse events that require study drug 
interruption and/or reach protocol specified toxicity management thresholds, can have the study drug 
interrupted for up to 30 days while recovering from the adverse event.
Pharmacokinetic Sample Collection
A single pharmacokinetic sample will be collected at study visits BL, Weeks 6, 12, 24, 36, 48, 72 and 96 
without regard to the time of dosing.  Blood samples for PK will be collected at any time during the visit, 
and preferably within 1 to 8 hours after the last dose.  The exact date, time and number of capsules of the 
last 2 doses of study drug taken prior to the pharmacokinetic sample collection will be recorded to the 
nearest minute starting with the dose prior to PK collection.
Scheduled Study Visits
Study visits will occur at BL, Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96 and every 12 weeks thereafter until 
the end of the study, including a 30-day follow up (phone call or site) visit.
Optional Study Visit
At Week 18.
Duration
Approximately 312 weeks.
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.
Subjects who have completed Study M13-550 or Study M13-537 with upadacitinib and has not 
developed any discontinuation criteria, defined in Section 5.4.1 of that study.
2.
Subjects with new evidence of latent TB should initiate prophylactic treatment immediately per 
local guidelines while continuing study drug treatment.  Prophylactic treatment must be completed.
3.
If female, subject must be postmenopausal, OR permanently surgically sterile, OR for women of 
childbearing potential, practicing at least one protocol-specified method of birth control (refer to 
Section 5.2.4), that is effective from Study Day 1 through at least 30 days after the last dose of 
study drug.
4.
If male, and subject is sexually active with female partner(s) of childbearing potential, he must 
agree, from Study Day 1 through 30 days after the last dose of study drug, to practice the protocol-
specified contraception (refer to Section 5.2.4).
5.
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.
6.
Subject is judged to be in good health as determined by the Investigator based on the results of 
medical history, physical examination and laboratory profile performed.
 


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued)
Main Exclusion:
1.
Pregnant or breastfeeding female.
2.
Ongoing infections at Week 0 that have NOT been successfully treated.  Subjects with ongoing 
infections undergoing treatment may be enrolled BUT NOT dosed until the infection has been 
successfully treated.
3.
Anticipated requirement or receipt of any live vaccine during study participation including up to 
30 days after the last dose of study drug.
4.
Laboratory values from the visit immediately prior to Baseline Visit* meeting the following 
criteria:

Serum aspartate transaminase (AST) or alanine transaminase (ALT) > 3.0 × ULN

Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal 
Disease (MDRD) formula < 40 mL/min/1.73m2

Total white blood cell count (WBC) < 2,000/µL

Absolute neutrophil count (ANC) < 1,000/µL

Platelet count < 50,000/µL

Absolute lymphocytes count < 500/µL

Hemoglobin < 8 gm/dL
*Local requirements may apply.  Refer to Appendix N for local requirements (United Kingdom).
5.
Enrollment in another interventional clinical study while participating in this study.
6.
Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to 
receive study drug.
Investigational Product:
Upadacitinib 3 mg capsules, 12 mg capsules, 15 mg tablets, 30 mg 
tablets
Doses:
6 mg BID (initial dose assignment for all subjects).  Upadacitinib doses 
of 6 mg BID, 12 mg BID, 15 mg QD and 30 mg QD are allowed during 
the OLE treatment period.
Mode of Administration:
Oral
Reference Therapy:
None (Open-Label Extension)
Duration of Treatment:  Approximately 312 weeks
Criteria for Evaluation:
Efficacy:
ACR20/50/70 response rates at Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96 and every 24 weeks thereafter 
until the end of the study will be evaluated based on 20/50/70% improvement in TJC, SJC, and ≥ 3 of 
the 5 measures of Patient's Assessment of Pain (VAS), Patient's Global Assessment of Disease Activity, 
Physician's Global Assessment of Disease Activity, Health Assessment Questionnaire Disability Index 
(HAQ-DI), and hsCRP.
 


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M13-538 Protocol Amendment 6
EudraCT 2013-003530-33
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Criteria for Evaluation (Continued):
Efficacy (Continued):
Change from Baseline in individual ACR components at Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96 and 
every 24 weeks thereafter until the end of the study will also be evaluated: TJC, SJC, Patient's 
Assessment of Pain (VAS), Patient's Global Assessment of Disease Activity, Physician's Global 
Assessment of Disease Activity, Health Assessment Questionnaire Disability Index (HAQ-DI), and 
hsCRP.  For analyses purposes, the baseline data for each subject will be the data collected immediately 
prior to starting double-blind-treatment.
The proportion of subjects achieving Low Disease Activity (LDA) or Clinical Remission (CR), and the 
proportion of subjects achieving CR will be evaluated at Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96 and 
every 24 weeks thereafter until the end of the study.  The criteria will be based on DAS28 [CRP] or 
CDAI as follows:
DAS28 [CRP]
CDAI
LDA
2.6 ≤ to < 3.2
2.8 < to ≤ 10
CR
< 2.6
≤ 2.8
Change from Baseline in DAS28 [CRP] disease activity score, CDAI and Patient Reported Outcomes 
including FACIT-Fatigue Scale, RA-WIS, and EQ-5D will be analyzed at Weeks 6, 12, 24, 36, 48, 72, 
96 and every 24 weeks thereafter until the end of the study.
Pharmacokinetic:
Individual plasma concentrations of upadacitinib will be tabulated and summarized.
Pharmacodynamic/Efficacy:
Changes from Baseline in in-vivo pharmacodynamic biomarkers and RA disease response biomarkers 
will be analyzed at Weeks 6, 12, 24 and 48.
Safety:
Safety evaluations will include adverse event monitoring, physical examinations, vital sign 
measurements, and clinical laboratory testing (hematology, chemistry, and urinalysis).  Toxicity 
management guidelines are included in the protocol.
Statistical Methods:
Efficacy:
Baseline data for each subject will be the data collected at the visit immediately prior to starting 
double-blind treatment.
The response rates of ACR20/50/70 will be summarized with 95% confidence intervals by visit.
Change from Baseline will be summarized with descriptive statistics for TJC, SJC, Patient's Assessment 
of Pain, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease 
Activity, HAQ-DI, hsCRP, DAS28[CRP], CDAI, and Patient Reported Outcomes, including FACIT 
Fatigue Scale, RA-WIS and EQ-5D by visit.
 


Upadacitinib
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Statistical Methods (Continued):
Efficacy (Continued):
The proportion of subjects achieving LDA (2.6 ≤ DAS28 [CRP] < 3.2 or 2.8 < CDAI ≤ 10) or CR 
(DAS28 [CRP] < 2.6 or CDAI ≤ 2.8), and the proportion of subjects achieving CR (DAS28 [CRP] < 2.6 
or CDAI ≤ 2.8) will be summarized with 95% confidence intervals by visit.
In an alternate assessment for summarizing the response rates, baseline data will be assumed to be the 
data collected at the visit immediately prior to starting treatment with active upadacitinib.
Pharmacokinetic:
Individual plasma concentrations of upadacitinib will be tabulated and summarized.  A mixed-effect 
modeling approach may be used to estimate the population central value and the empirical Bayesian 
estimates of the individual values for upadacitinib oral clearance (CL/F) and volume of distribution 
(Vss/F).  Additional parameters may be estimated if useful in the interpretation of the data.
Pharmacodynamic:
Changes from Baseline in in-vivo pharmacodynamic biomarkers and RA disease response biomarkers 
will be summarized with descriptive statistics by visit.
Safety:
All subjects who receive at least one dose of upadacitinib during the OLE period will be included in the 
safety analysis.  Incidence of adverse events, serious adverse events, premature discontinuation, and 
changes from Baseline in vital signs, physical examination results and clinical laboratory values will be 
analyzed by visit.  Treatment-emergent adverse events will be tabulated by system organ class and by 
MedDRA preferred term.  Mean change from Baseline for laboratory and vital signs data will be 
summarized by visit.  For analyses purposes, baseline for vital signs, physical examination results, and 
clinical laboratory results for subjects will be the data collected at the visit immediately prior to starting 
double-blind treatment.
In an alternate assessment for summarizing the safety and laboratory data, baseline data will be assumed 
to be the data collected at the visit immediately prior to starting treatment with active upadacitinib.
 


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
α-CCP Ab
Anti-Cyclic Citrullinated Antibody
ACR
American College of Rheumatology
AE
Adverse Event
ALT
Alanine Transaminase
AST
Aspartate Transaminase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AUC
Area under the plasma concentration-time curve
BID
Twice daily
BP
Blood pressure
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CDAI
Clinical Disease Activity Index
CD4, CD8
Cluster Of Differentiation
CGC
Common Gamma-Chain
CHF
Congestive Heart Failure
CI
Confidence Interval
Cmax
Maximum Observed Plasma Concentration
COVID-19
Coronavirus Disease - 2019
CPK
Creatine Phosphokinase
CR
Clinical Remission
CRF
Case Report Form
CRP
C-Reactive Protein
CXR
Chest X-Ray
DAS
Disease Activity Score
DM
Diabetes Mellitus
DMARD
Disease-Modifying Anti-Rheumatic Drug
DNA
Deoxyribonucleic Acid
DTP
Direct-to-Patient
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
 


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EDC 
Electronic Data Capture
EQ-5D
EuroQoL-5D
EULAR
European League against Rheumatism
eGFR
Estimated glomerular filtration rate
ET
Early termination
FACIT
Functional Assessment of Chronic Illness Therapy – Fatigue
FDA
US Food and Drug Administration
FPG
Fasting plasma glucose
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GMCSF
Granulocyte macrophage colony-stimulating factor 
gp130
Glycoprotein 130
HAQ-DI
Health Assessment Questionnaire – Disability Index
HDL
High Density Lipoprotein
hsCRP
High-Sensitivity C-Reactive Protein
HV
Healthy Volunteer
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IL
Interleukin
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
JAK
Janus Activated Kinase
LDA
Low Disease Activity
LDL
Low Density Lipoprotein
MAD
Multiple Ascending Dose
MedDRA
Medical Dictionary for Regulatory Activities
MTX
Methotrexate
NK
Natural Killer Cells
NKT
Natural Killer T Cells 
 


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NCS
Non-Clinically Significant
NOAEL
No Observable Adverse Effect Level
NRI
Non Responder Imputation
NSAID
Non-Steroidal Anti-Inflammatory Drug
NYHA
New York Heart Association
OC
Observed Cases
OLE
Open-Label Extension
PE
Physical Examination
PG
Pharmacogenetic
PhGA
Physician's Global Assessment of Disease Activity on VAS
PK
Pharmacokinetic
PPD
Purified Protein Derivative
PtGA
Patient's Global Assessment of Disease Activity on VAS
QD
Once Daily
RA
Rheumatoid Arthritis
RAVE®
EDC System from Medidata
RBC
Red Blood Cell Count
RCT
Randomized Control Trial
RF
Rheumatoid Factor
RR
Respiratory Rate
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SGOT/AST
Serum Glutamic-Oxaloacetic Transaminase/Aspartate Transaminase
SGPT/ALT
Serum Glutamic-Pyruvic Transaminase/Alanine Transaminase
SJC
Swollen Joint Count
SOC
System Organ Class
STAT
Signal Transduction Activators of Transcription
TB
Tuberculosis
TEAE
Treatment Emergent Adverse Event
TJC
Tender Joint Count
Tmax
Time to Maximum Observed Plasma Concentration
Tyk2
Tyrosine Kinase 2
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
 


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VTE
Venous Thromboembolic Events
WBC
White Blood cell Count
RA-WIS
Work Instability Scale – Rheumatoid Arthritis
 


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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........................................14
2.0
Table of Contents...................................................................18
3.0
Introduction ...........................................................................23
3.1
Differences Statement..............................................................................26
3.2
Benefits and Risks....................................................................................26
4.0
Study Objective......................................................................27
5.0
Investigational Plan...............................................................28
5.1
Overall Study Design and Plan:  Description ..........................................28
5.2
Selection of Study Population..................................................................33
5.2.1
Inclusion Criteria .....................................................................................33
5.2.2
Exclusion Criteria ....................................................................................34
5.2.3
Prior and Concomitant Therapy...............................................................35
5.2.3.1
Prohibited Therapy...................................................................................36
5.2.4
Contraception Recommendations ............................................................37
5.3
Efficacy and Safety Assessments/Variables ............................................39
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................39
5.3.1.1
Study Procedures .....................................................................................48
5.3.1.2
Collection and Handling of Pharmacodynamic Variables.......................63
5.3.1.3
Disease Response Biomarkers .................................................................63
5.3.2
Drug Concentration Measurements .........................................................64
5.3.2.1
Collection of Samples for Analysis .........................................................64
5.3.2.2
Measurement Methods.............................................................................64
5.3.3
Efficacy Variables....................................................................................64
5.3.4
Safety Variables.......................................................................................65
5.3.5
Pharmacokinetic Variables ......................................................................65
5.3.6
RA Disease Response Biomarkers Variables ..........................................65
5.3.7
Pharmacodynamic Variables....................................................................66
5.4
Removal of Subjects from Therapy or Assessment.................................66
 


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5.4.1
Discontinuation of Individual Subjects....................................................66
5.4.2
Discontinuation of Entire Study...............................................................68
5.5
Treatments................................................................................................69
5.5.1
Treatments Administered.........................................................................69
5.5.1.1
Packaging and Labeling...........................................................................70
5.5.1.2
Storage and Disposition of Study Drugs..................................................70
5.5.2
Method of Assigning Subjects to Treatment Groups...............................70
5.5.3
Selection and Timing of Dose for Each Subject......................................71
5.5.4
Blinding....................................................................................................72
5.5.5
Treatment Compliance.............................................................................72
5.5.6
Drug Accountability.................................................................................73
5.6
Discussion and Justification of Study Design..........................................73
5.6.1
Appropriateness of Measurements...........................................................75
5.6.2
Suitability of Subject Population .............................................................75
5.6.3
Selection of Doses in the Study ...............................................................75
6.0
Adverse Events.......................................................................76
6.1
Complaints ...............................................................................................76
6.2
Medical Complaints.................................................................................76
6.3
Definitions................................................................................................77
6.3.1
Adverse Event..........................................................................................77
6.3.2
Serious Adverse Events ...........................................................................78
6.4
Adverse Events of Special Interest ..........................................................79
6.5
Adverse Event Severity............................................................................80
6.6
Relationship to Study Drug......................................................................80
6.7
Adverse Event Collection Period.............................................................80
6.8
Serious Adverse Event Reporting............................................................82
6.9
Pregnancy.................................................................................................84
6.10
Toxicity Management ..............................................................................84
6.11
Cardiovascular Adjudication Committee.................................................89
6.12
Product Complaint ...................................................................................89
6.12.1
Definition .................................................................................................89
6.12.2
Reporting..................................................................................................90
7.0
Protocol Deviations................................................................90
 


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8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................92
8.1
Statistical and Analytical Plans................................................................92
8.1.1
Dataset for Analysis.................................................................................92
8.1.2
Subject Accountability.............................................................................92
8.1.3
Baseline Characteristics...........................................................................92
8.1.4
Subject Disposition and Study Drug Exposure........................................93
8.1.4.1
Subject Disposition ..................................................................................93
8.1.4.2
Study Drug Exposure...............................................................................93
8.1.5
Efficacy Analysis .....................................................................................93
8.1.5.1
Efficacy Variables....................................................................................93
8.1.5.2
Efficacy Analysis .....................................................................................96
8.1.5.3
Multiple Comparisons..............................................................................96
8.1.6
Safety Analysis ........................................................................................97
8.1.6.1
General Considerations............................................................................97
8.1.6.2
Analysis of Adverse Events.....................................................................97
8.1.6.2.1
Treatment-Emergent Adverse Events ......................................................97
8.1.6.2.2
Serious Adverse Events and Death ..........................................................99
8.1.6.3
Analysis of Laboratory and Vital Sign Data............................................99
8.1.7
Pharmacokinetic and Exposure-Response Analyses .............................100
8.1.8
Statistical Analysis of Biomarker Data..................................................100
8.1.9
Interim Analysis.....................................................................................101
8.2
Determination of Sample Size ...............................................................101
9.0
Ethics.....................................................................................101
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................101
9.2
Ethical Conduct of the Study.................................................................102
9.3
Subject Information and Consent...........................................................102
10.0
Source Documents and Case Report Form 
Completion ...........................................................................103
10.1
Source Documents .................................................................................103
10.2
Case Report Forms.................................................................................104
10.3
Data Collection Process .........................................................................106
 


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11.0
Data Quality Assurance ......................................................106
12.0
Use of Information...............................................................107
13.0
Completion of the Study .....................................................107
14.0
Investigator's Agreement....................................................109
15.0
Reference List ......................................................................110
16.0
Objective...............................................................................145
16.1
Overall Sub-Study Design and Plan:  Description.................................145
16.2
Selection of Vaccine Sub-Study Population..........................................146
16.2.1
Inclusion Criteria ...................................................................................146
16.2.2
Exclusion Criteria ..................................................................................147
16.2.3
Prohibited Therapy.................................................................................148
16.2.4
Efficacy and Safety Assessments/Variables ..........................................148
16.2.5
Statistical Analysis of Efficacy..............................................................150
16.2.6
Statistical Methods and Determination of Sample Size.........................150
List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers....................................................................................................37
Table 2.
Study Activities........................................................................................42
Table 3.
Clinical Laboratory Tests.........................................................................60
Table 4.
Identity of Investigational Products.........................................................70
Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values....................................................................................87
Table 6.
Sub-Study Activities ..............................................................................149
List of Figures
Figure 1.
Study Design Schematic ..........................................................................31
Figure 2.
Adverse Event Collection ........................................................................81
 


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List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................112
Appendix B.
List of Protocol Signatories....................................................................114
Appendix C.
Joint Evaluation Worksheet Example....................................................115
Appendix D.
Physician's Global Assessment of Disease Activity Example...............117
Appendix E.
Patient's Global Assessment of Disease Activity Example ...................118
Appendix F.
Patient's Assessment of Pain Example...................................................119
Appendix G.
Health Assessment Questionnaire (HAQ-DI) Example.........................120
Appendix H.
FACIT – Fatigue Scale Example...........................................................123
Appendix I.
Work Instability Scale for Rheumatoid Arthritis (RA-WIS) 
Example .................................................................................................124
Appendix J.
EuroQoL-5D Example...........................................................................125
Appendix K.
Dosing Diary Example...........................................................................127
Appendix L.
Latent TB Risk Factor Questionnaire Example.....................................129
Appendix M.
Rheumatology Common Toxicity Criteria v.2.0 Example ....................130
Appendix N.
Local Requirements ...............................................................................142
Appendix O.
Prevnar 13® Vaccine Sub-Study............................................................145
 


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3.0
Introduction
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown 
etiology.  The hallmark feature of patients affected by RA is an inflammatory process 
manifested by persistent symmetric polyarthritis of synovial joints, and oftentimes 
includes systemic inflammatory manifestations in extra-articular organ systems.  Early 
therapy with disease-modifying antirheumatic drugs (DMARDs) is the standard of care, 
although a significant proportion of patients either do not achieve disease remission or 
become refractory to available therapies as the disease progresses.  Novel therapies are 
therefore required to complement the available interventions to address the unmet need in 
the treatment of patients with RA.  Evidence suggests that inhibition of the Janus 
activated kinase (JAK)-mediated pathways is a promising approach for the treatment of 
patients with this chronic disorder.1
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 (CGC) receptors and the glycoprotein 
130 (gp130) transmembrane proteins.2  Almost 40 cytokine receptors signal through 
combinations of these four JAKs and their seven downstream substrates of the Signal 
Transduction Activators of Transcription (STAT) family.3  Activation of these 
JAK-related 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.
JAK3 and JAK1 are components of the CGC cytokine receptor complexes and blockade 
of either inhibits signaling by the inflammatory cytokines interleukin (IL)-2, 4, 7, 9, 15 
and 21.3  Furthermore, other pathologically relevant cytokines such as IL-6 are known to 
recruit JAK1, JAK2 and Tyk2 upon binding to its receptor, with IL-6 appearing to signal 
predominantly via JAK1.4,5  Hence, the JAK family has evoked considerable interest in 
the area of inflammatory diseases leading for the development of various JAK inhibitors 
with different selectivity profiles against JAK1, JAK2, JAK3 and Tyk2.  Tofacitinib 
(Xeljanz®; Pfizer®) is a non-selective JAK inhibitor that targets all 4 members of the JAK 
 


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family; the rank order of cellular potency is JAK3, JAK1, JAK2 and Tyk2.1  Tofacitinib is 
approved in the United States and is indicated for treatment of adult patients with 
moderately to severely active RA who have had an inadequate response or intolerance to 
MTX.9  The approved dose is 5 mg BID and it can be used as monotherapy or in 
combination with MTX or other non-biologic disease-modifying antirheumatic drugs 
(DMARDs).  Recently tofacitinib was approved in Japan, Russia, and Switzerland.
Upadacitinib is a novel JAK1 inhibitor being developed for the treatment of adult patients 
with moderately to severely active RA, either alone or in combination with methotrexate 
(MTX) or other non-biologic DMARDs.  Based on in vitro selectivity assays and in-vivo
animal models, upadacitinib has demonstrated that inhibiting JAK1 with minimal impact 
on JAK2 is feasible at efficacious drug exposure levels.  Thus, the enhanced selectivity of 
upadacitinib has the potential for an improved benefit/risk profile in treating patients with 
RA by mitigating JAK2 inhibitory effects on erythropoiesis and myelopoiesis.  Also, the 
minimum of activity of upadacitinib against JAK3, which is involved in IL-15 signal 
transduction cascade, could potentially minimize a decrease in NK cell counts observed 
with tofacitinib clinical development program that may have contributed to increased 
incidences of viral infection, re-activation of herpes zoster, and malignancies.
The toxicology profile of upadacitinib has been evaluated in multiple chronic studies in 
rats and dogs.  Briefly, nonadverse findings in rats included mild decreases in red blood 
cell counts, hemoglobin and dose-dependent decreases in circulating lymphocytes.  At 
very high doses of upadacitinib (50 to 100 mg/kg/day) the adverse findings included 
mortality as well as tubular degeneration/regeneration in the kidney and liver necrosis.  In 
dog studies there were dose-related decreases in hemoglobin and red cell mass (red blood 
cell counts, hemoglobin concentration, hematocrit) and microscopic findings in popliteal 
lymph nodes (mixed cell inflammation in inter-digital skin of paws and draining lymph 
nodes) considered secondary to potential upadacitinib-related immunomodulation.  A 
detailed summary of the pre-clinical toxicology results can be found in the current 
Investigator's Brochure.6
 


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There have been two clinical studies of upadacitinib.  The clinical conduct of 
Study M13-401, a single-dose ascending dose study of upadacitinib at 1 mg up to 48 mg, 
has been completed.  This study also included an assessment of the effect of food on the 
pharmacokinetics of upadacitinib.  Preliminary results indicated that food had no effect on 
the exposure (AUC) of upadacitinib.  Therefore, upadacitinib can be administered with or 
without food in the present study.
Preliminary results after multiple ascending doses of upadacitinib in healthy volunteers 
are available from Study M13-845.  The randomized, double-blind, placebo controlled 
study was designed to evaluate the safety, tolerability and PK of upadacitinib at four dose 
levels of 3 mg, 6 mg, 12 mg and 24 mg BID.  In each dose group, 8 subjects were 
randomly assigned to receive upadacitinib and 3 subjects received placebo administered 
twice daily (BID) for 14 consecutive days.  No serious or fatal adverse events or AEs 
leading to discontinuation were reported during the study.  Treatment-emergent adverse 
events (TEAE) were reported in 7 (58.3%) subjects receiving placebo and in 
11 (34.3%) subjects receiving ABT-494 with the overall incidence of TEAEs at 
2 (25.0%), 2 (25.0%), 3 (37.5%) and 4 (50%) of subjects experienced TEAEs in the 3 mg, 
6 mg, 12 mg and 24 mg dose groups, respectively.  All TEAEs were considered mild 
(Grade 1) in severity and reported to have a reasonable possibility of being related to 
study drug except 2 events in one subject in the placebo group were considered as having 
no reasonable possibility of being related.  The most common TEAEs in the upadacitinib 
treatment groups (n = 32) were headache (15.6%), abdominal pain (6.3%), diarrhea 
(6.3%), and nasopharyngitis (6.3%).  No clinically meaningful changes in laboratory 
values, vital signs or ECG findings were observed during the study.
Preliminary results indicated that at steady state, upadacitinib had minimal to no 
accumulation with a median Tmax of approximately 2 hours and an effective half-life of 
approximately 3 hours.  Upadacitinib exposure was approximately dose-proportional 
across the dose range studied.  Approximately 19% to 21% of upadacitinib was excreted 
as unchanged parent in the urine during a dose interval in the steady state.
 


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A detailed discussion of the pre-clinical toxicology, metabolism, pharmacology and safety 
experience with upadacitinib can be found in the current Investigator's Brochure.6
3.1
Differences Statement
This OLE study is designed to collect long-term safety, tolerability, and efficacy data.  
Collecting long-term safety data is important to assess the risk to benefit profile of 
upadacitinib.  All subjects who have completed the Last Visit (Week 12) of 
Study M13-550 or Study M13-537 upadacitinib Phase 2 RCT (12 – 24 weeks) will have 
an opportunity to enroll into this OLE study.  This is the first study with upadacitinib of 
treatment durations longer than 24 weeks.
3.2
Benefits and Risks
Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease characterized by
inflammation of the articular synovial membrane.  If left untreated, RA causes damage to 
cartilage, bone, and adjoining tissues which ultimately leads to severe disability, impaired 
function, and marked reduction in the quality of life of subjects.  The prevalence of RA in 
the general population is approximately 1%, and increases with age in both genders, with 
women being more prone for developing RA than men.
The etiology of RA has not been fully elucidated, but based on the pathologic mechanisms 
of RA, several pro-inflammatory pathways and cytokines such as TNF, interferon gamma, 
IL-1 and other interleukins have been identified in promoting synovial inflammation and 
bone and cartilage destruction.  Clinical efficacy in targeting these proinflammatory 
cytokines and downstream signaling pathways has been well validated in RA.  Several 
inhibitors of Janus activated kinases (JAKs), a family of intracellular tyrosine kinases that 
transduces cytokine-mediated signals, demonstrated proof of concept first with currently 
marketed tofacitinib and with other emerging second generation JAK inhibitors that are in 
the clinic for reducing the signs and symptoms in RA subjects.11,12
The JAK family of tyrosine kinases comprises 4 members, JAK1, JAK2, JAK3 and 
TYK2.  The second generation of JAK inhibitors currently in development for RA 
 


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displays a varying potency and selectivity directed at members of the JAK family.1  
Tofacitinib is a non-selective JAK inhibitor targeting JAK1, JAK2 and JAK3, but most 
potently inhibits JAK3.1  Although tofacitinib improves the clinical signs and symptoms 
of RA, questions remain surrounding the safety profile regarding the incidences of serious 
infection, malignancies, herpes zoster, and hematologic adverse events.
Data from clinical studies in RA subjects with tofacitinib showed reduced levels of 
hemoglobin, absolute lymphocytes counts, and total white blood cell counts in some 
subjects and also increased serum creatinine; total cholesterol, LDL cholesterol (LDL-C), 
and HDL cholesterol (HDL-C); and liver transaminases (ALT and AST).7,8  The increases 
in serum creatinine, lipids, and liver transaminase values typically have been 
asymptomatic, reversible, and were not associated with any overt declines in renal or 
hepatic function.
Upadacitinib is a novel JAK1 selective inhibitor with minimal inhibitory effects on JAK2 
and JAK3, which could potentially minimize some of the reported safety concerns with 
non-selective JAK inhibitors which are thought to be mediated by inhibition of JAK2 and 
JAK3 signaling pathways.  Initiation of Phase 2 studies with upadacitinib was feasible 
based on acceptable safety and tolerability profile of upadacitinib in single ascending dose 
and multiple ascending dose studies in healthy volunteers.  The current OLE study will 
allow the collection of long-term safety data to better assess the risk to benefit profile of 
upadacitinib.
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 Objective
The primary objective is to evaluate the long-term safety, tolerability, and efficacy of 
upadacitinib in RA subjects who have completed Study M13-550 or Study M13-537 
Phase 2 RCT with upadacitinib.
 


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5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2, multicenter, OLE study to assess the long-term safety, tolerability, and 
efficacy of upadacitinib in RA subjects who have completed Study M13-550 or 
Study M13-537 Phase 2 RCT with upadacitinib.  This study is designed to enroll up to 
500 subjects.  Subjects will be treated for approximately 312 weeks.
Only those subjects who have met all of the specified inclusion criteria and none of the 
exclusion criteria will have an option to enter into the OLE study to receive upadacitinib, 
as long as the subject is willing and the Investigator believes that continuing therapy with 
upadacitinib is appropriate.
All eligible subjects will be assigned to upadacitinib 6 mg BID immediately after or up to 
30 days following the Last Visit (Week 12) of Study M13-550 or Study M13-537 Phase 2 
RCT.
Subjects who are unable to tolerate 6 mg BID will be discontinued from the study.
At Week 6, if a subject fails to achieve at least 20% improvement from RCT Baseline in 
both Tender Joint Count (TJC) and Swollen Joint Count (SJC), upadacitinib dose should 
be increased to 12 mg BID as long as the Investigator has no safety concerns.  After 
6 weeks of treatment with upadacitinib 12 mg BID, the improvement in TJC and SJC will 
be re-assessed at next scheduled visit (Week 12).
If the subject on 12 mg BID fails to achieve at least 20% improvement in both TJC and 
SJC from RCT Baseline the subject will be discontinued. 
At Week 12, the same process will be followed.  If a subject still on 6 mg BID fails to 
achieve at least 20% improvement from RCT Baseline in both TJC and SJC, upadacitinib 
dose should be increased to 12 mg BID.  The improvement in both TJC and SJC will be 
re-assessed after 6 weeks of treatment with 12 mg BID at Week 18 (an optional study 
visit).
 


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Subjects who fail to achieve at least 20% improvement from RCT Baseline in both TJC 
and SJC with 12 mg BID at Week 18 will be discontinued. 
After Week 12, if a subject fails to show at least 20% improvement from RCT Baseline in 
both TJC and SJC at 2 consecutive scheduled study visits, the subject will be 
discontinued.
Starting at Week 6 and during any scheduled or unscheduled visits thereafter, upadacitinib 
dose may be increased from 6 mg BID to 12 mg BID (or 30 mg QD from January 2017, 
see below) if a subject fails to achieve Low Disease Activity (LDA) status (defined by 
CDAI > 10) and has no safety concerns per Investigator's judgment.
At any visit, upadacitinib dose may be decreased back to 6 mg BID (or 15 mg QD from 
January 2017) per Investigator's judgment if there are safety and/or tolerability concerns, 
due to an adverse event or reaching one of the protocol specific toxicity management 
thresholds.  Dose increase back to 12 mg BID (or 30 mg QD from January 2017) is not 
allowed.
From January 2017, all subjects who are at Week 72 or beyond will receive a once-daily 
tablet formulation.  Subjects who are on 6 mg BID capsule dosing will be transitioned to 
15 mg QD tablet dosing.  Subjects who are on 12 mg BID capsule dosing will be 
transitioned to 30 mg QD tablet dosing.  The capsule formulation will not be available to 
subjects once the transition to tablet formulation has occurred.
Starting with Amendment 5, subjects who are receiving 30 mg QD open-label 
upadacitinib will have the option to decrease the dose to 15 mg QD based on 
investigator's discretion.
The change to once daily tablet formulation in this study is based on extrapolation of 
pre-clinical efficacy models and analyses of PK, pharmacodynamic, safety, and efficacy 
data from the Phase 1 studies in healthy volunteers (single and multiple ascending dose 
Studies M13-401 and M13-845, respectively) and completed Phase 2b randomized, 
controlled studies (RCTs) in RA subjects (Studies M13-537 and M13-550).  The doses 
 


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selected, 15 mg QD and 30 mg QD, are expected to approximate the exposures achieved 
with the 6 mg BID and 12 BID immediate release formulations, respectively, which 
should be efficacious with an acceptable safety profile.  Preliminary results from an 
ongoing relative bioavailability study demonstrated that single 15 mg and 30 mg doses of 
the once-daily formulation provide comparable AUC and significantly lower Cmax than 
single doses of 12 mg immediate release (IR) formulation (AUC equivalent to 6 mg BID 
dose tested in Phase 2) and 24 mg IR formulation (AUC equivalent to 12 mg BID dose 
tested in Phase 2), respectively, under fasting conditions.  At steady-state, the once-daily 
dose of 15 mg QD is predicted to achieve comparable daily AUC and Cmax, and 
non-inferior Ctrough to 6 mg BID IR formulation.  In the Phase 2 RCTs, the 6 mg BID dose 
was shown to achieve the near maximum efficacy.  The once-daily dose of 30 mg QD is 
predicted to achieve comparable daily AUC and Cmax, and non-inferior Ctrough to 12 mg 
BID IR formulation.  In the Phase 2 RCTs, the 12 mg BID dose was clearly shown to 
achieve the plateau of efficacy.
A schematic of the overall study design is shown in Figure 1.
 


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Figure 1.
Study Design Schematic
Prevnar 13® Sub-study
This optional sub-study of Study M13-538 will assess the impact of upadacitinib 
treatment (15 mg QD or 30 mg QD) with a stable background of MTX on immunological 
responses following administration of Prevnar 13® pneumococcal vaccine in RA patients.  
Methods, procedures and statistical analyses pertaining to this sub-study are provided in 
Appendix O.
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment Period
The treatment period for OLE can begin immediately after or up to 30 days following the 
Last Visit (Week 12) of Study M13-550 or Study M13-537 RCT and will continue for 
approximately 312 weeks in OLE.  At Last Visit (Week 12) or up to 30 days following the 
Last Visit (Week 12) of Study M13-550 or Study M13-537, 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.  Subjects will visit the study site at Weeks 6, 
12, 18 (Optional), 24, 36, 48, 60, 72, 84, 96 and every 12 weeks thereafter until the end of 
the study or if they terminate early from the study.  A ± 7-day window is permitted around 
scheduled study visits.  The last dose of study drug is taken the evening prior to the final 
visit.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have a Premature Discontinuation Visit 
and complete the procedures outlined for Premature Discontinuation Visit in Table 2 as 
soon as possible, preferably within 2 weeks of study drug discontinuation and preferably 
prior to initiation of another therapy.
Starting with Amendment 5, subjects who are receiving 30 mg QD open-label 
upadacitinib will have the option to decrease to the 15 mg QD dose based on 
investigator's discretion.
Follow-Up Period
All subjects will have a follow-up visit approximately 30 days after the last administration 
of study drug to obtain information on any new or ongoing adverse events (AEs), and to 
collect vital signs and clinical laboratory tests. 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.
 


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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 up to 500 subjects, who have completed Study M13-550 or 
Study M13-537 RCT with upadacitinib, will enroll in this OLE study. 
Only those subjects who have met all of the specified inclusion and none of the exclusion 
criteria in Section 5.2.1 and Section 5.2.2 will have an option to enter into the OLE study 
to receive upadacitinib, as long as the subject is willing and the Investigator believes that 
continuing the therapy with upadacitinib is appropriate.
5.2.1
Inclusion Criteria
1.
Subjects who have completed preceding RCT study with upadacitinib and have not 
developed any discontinuation criteria, defined in Section 5.4.1 of that study.
2.
Subject with new evidence of latent TB should initiate prophylactic treatment 
immediately per local guidelines while continuing study drug treatment.  
Prophylactic treatment must be completed.
3.
If female, subject must be postmenopausal, OR permanently surgically sterile, OR 
for women of childbearing potential practicing at least one protocol-specified 
method of birth control (refer to Section 5.2.4), that is effective from Study Day 1 
through at least 30 days after the last dose of study drug.
 


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4.
If male, and subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 30 days after the last dose of 
study drug, to practice the protocol-specified contraception (refer to Section 5.2.4).
5.
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.
6.
Subject is judged to be in good health as determined by the Investigator based on 
the results of medical history, physical examination and laboratory profile 
performed.
Criteria
Rationale
1 – 2
To select the appropriate subject population.
3 – 4
The effect of upadacitinib on pregnancy and reproduction is unknown.
5 – 6 
In accordance with harmonized Good Clinical Practice (GCP).
5.2.2
Exclusion Criteria
1.
Pregnant or breastfeeding female.
2.
Ongoing infections at Week 0 that have NOT been successfully treated.  Subjects 
with ongoing infections undergoing treatment may be enrolled BUT NOT dosed 
until the infection has been successfully treated.
3.
Anticipated requirement or receipt of any live vaccine during study participation 
including up to 30 days after the last dose of study drug.
4.
Laboratory values from the visit immediately prior to Baseline Visit* meeting the 
following criteria:
●
Serum aspartate transaminase (AST) or alanine transaminase (ALT) > 3.0 × 
ULN
●
Estimated glomerular filtration rate by simplified 4-variable Modification of 
Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73m2
 


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●
Total white blood cell count (WBC) < 2,000/µL
●
Absolute neutrophil count (ANC) < 1,000/µL
●
Platelet count < 50,000/µL
●
Absolute lymphocytes count < 500/µL
●
Hemoglobin < 8 gm/dL
*Local requirements may apply.  Refer to Appendix N for local requirements
  (United Kingdom).
5.
Enrollment in another interventional clinical study while participating in this study.
6.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive study drug.
Criteria
Rationale
1 
The impact of upadacitinib on pregnancy and nursing is unknown
2 – 6 
To ensure safety of the subjects throughout the study
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements including folic acid) that the subject is receiving at the 
time of enrollment, 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 eCRF.
Subjects should remain on a stable dose of MTX throughout the first 24 weeks of 
Study M13-538.  However, if a subject experiences MTX-induced toxicity, MTX dose 
can be reduced or discontinued as per Investigator's medical judgment. 
After 24 weeks of treatment with open-label upadacitinib, initiation of or change in a 
subject's concomitant medications for RA, including MTX and other csDMARDs or 
corticosteroids (oral or parenteral) is allowed.
 


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Stable doses of non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or oral 
corticosteroids (equivalent to prednisone ≤ 10 mg) are allowed throughout the study.  
PRN use of NSAIDs, acetaminophen, tramadol, codeine, propoxyphene and hydrocodone 
is allowed except 24 hours prior to any study visit.
Intra-articular, intra-muscular, intra-bursa and intra-tendon sheath injections of 
corticosteroids, dosage and frequency per standard of care, are allowed during the study.  
Details of each injection, along with the name of the joint injected, must be captured on 
appropriate eCRF as mentioned above.  Subjects should have their joint(s) scored prior to 
receiving the injection.  Any injected joints will be scored as "NA = no assessment" for 
90 days from the time of injection.
The AbbVie Therapeutic Area Medical Director identified in Section 6.8 (Adverse Event 
Reporting) should be contacted if there are any questions regarding concomitant or prior 
therapy(ies).
5.2.3.1
Prohibited Therapy
The following medications are prohibited throughout the study:
●
All biologic therapies
●
JAK inhibitors other than upadacitinib (including but not limited to tofacitinib, 
baricitinib and filgotinib)
●
High potency opiates 
●
Live vaccines
○
If the subject and investigator choose to administer live vaccines, these 
vaccinations must be completed (per local label) 4 weeks before first dose 
of study drug with appropriate precautions or administered at least 30 days 
after last dose of study drug.
●
Anti-retroviral therapy
●
Use of known strong CYP3A inhibitors or strong CYP3A inducers.  The most 
common strong CYP3A inhibitors and inducers are listed in Table 1.
 


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Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Avasimibe
Carbamazepine
Phenytoin
Rifampin
Rifapentine
St. John's Wort
●
Oral DMARDs (except MTX) are prohibited up to Week 24 but are allowed 
thereafter per Investigator's clinical judgment.  The following csDMARDs are 
allowed:  MTX, sulfasalazine, hydroxychloroquine, chloroquine, and 
leflunomide.  A combination of up to two background csDMARDs is allowed 
except the combination of MTX and leflunomide
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:
 


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●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 mIU/mL.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following highly effective methods of birth control that is effective from Study Day 1 (or 
earlier) through at least 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).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the highly 
effective birth control methods listed above (excluding true abstinence).
 


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If, during the course of the study, a woman becomes surgically sterile or post-menopausal 
and complete documentation is available, contraception measures as defined above are no 
longer required.
Contraception Recommendation for Males
There are no contraception requirements for male subjects or their female partner(s).  
It is important to note that subjects taking concomitant csDMARDs (i.e., methotrexate, 
sulfasalazine, hydroxychloroquine, chloroquine and leflunomide) the duration of 
contraception and requirement not to donate sperm after discontinuation of these 
prescribed csDMARDs should be based on the local label.
5.3
Efficacy and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures will be performed as summarized in Table 2.  All subjects must meet 
the study selection criteria outlined in Section 5.2.1 and Section 5.2.2 in order to be 
eligible for the study.
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. 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 
 


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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 including Patient's Global Assessment of Disease 
Activity and Patient's Assessment of Pain
○
Vital Signs and Body Weight
○
Physical Examination
○
Physician's Global Disease Activity VAS (PhGA)
○
Tender Joint Count (TJC) 68/Swollen Joint Count (SJC)66
●
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 
 


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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)
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.
 


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Table 2.
Study Activities
Activity
BL/Wk 0a
Wk 6
Wk 12
Wk 18 
(Optional)b
Wk 24
Wk 36
Unscheduled 
Visitc
Premature 
Discontinuation
30-Day 
Follow-Up 
Visitq
Informed Consentd
X
Patient's Global Assessment of Disease 
Activity (PtGA)e
X
X
X
X
X
X
Patient's Assessment of Pain (VAS)e
X
X
X
X
X
X
HAQ-DIe
X
X
X
X
X
X
Work Instability Scale for RA 
(RA-WIS)e
X
X
X
X
X
X
FACITe
X
X
X
X
X
X
EuroQol-5D (EQ-5D)e
X
X
X
X
X
X
Medical/Surgical Historyf
X
Vital Signsg
X
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
Physical Examinationh
X
Physician's Global Disease Activity VAS 
(PhGA)
X
X
X
X
X
X
Tender Joint Count (TJC)68
X
X
X
X
X
X
X
X
X
Swollen Joint Count (SJC)66
X
X
X
X
X
X
X
X
X
Concomitant Therapyi
X
X
X
X
X
X
X
X
X
Adverse Event Assessmentj
X
X
X
X
X
X
X
X
X
Pregnancy Testk
X
X
X
X
X
X
X
X
 


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Table 2.
Study Activities (Continued)
Activity
BL/Wk 0a
Wk 6
Wk 12
Wk 18 
(Optional)b
Wk 24
Wk 36
Unscheduled 
Visitc
Premature 
Discontinuation
30-Day 
Follow-Up 
Visitq
Blood Chemistryl
X
X
X
X
X
X
X
X
Hematology (CBC)l
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
hsCRPl
X
X
X
X
X
X
X
Disease Response Biomarker
X
X
X
X
In-vivo Pharmacodynamic Biomarker 
Sample
X
X
X
X
Blood Sample for upadacitinib PK 
Assaym
X
X
X
X
X
X
Latent TB Risk Factor Questionnairen
X
PPD Skin Test or Quanti-FERON-TB 
Gold Testn
X
Chest X-Rayn
X
X
12-Lead ECGo
X
Enrollment
X
Dispense Study Drug
X
X
X
X
X
X
X
Dispense Dosing Diary
X
X
X
X
X
X
Review and Copy Subject Dosing Diary 
and Returned Used/Unused Study Drug
X
X
X
X
X
X
X
X
 


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Table 2.
Study Activities (Continued)
Activity
Wk 
48
Wk 
60
Wk 
72
Wk 
84
Wk 
96
Every 
12 Weeks 
Until Study 
Completion
Every 48 Weeks 
Until Study 
Completion 
(Wk 132, Wk 180 
Wk 228 and 
Wk 276)
Final 
Visit
Unscheduled 
Visitc
Premature 
Discontinuation
30-Day 
Follow-Up 
Visitq
Patient's Global Assessment of Disease 
Activity (PtGA)e
X
X
X
X
X
X
X
X
Patient's Assessment of Pain (VAS)e
X
X
X
X
X
X
X
X
HAQ-DIe
X
X
X
X
X
X
X
X
Work Instability Scale for RA (RA-
WIS)e
X
X
X
X
X
X
FACIT e
X
X
X
X
X
X
EuroQol-5D (EQ-5D)e
X
X
X
X
X
X
Vital Signsg
X
X
X
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
X
X
Physical Examinationh
X
X
X
X
Physician's Global Disease Activity 
VAS (PhGA)
X
X
X
X
X
X
X
X
Tender Joint Count (TJC)68
X
X
X
X
X
X
X
X
X
X
Swollen Joint Count (SJC)66
X
X
X
X
X
X
X
X
X
X
Concomitant Therapyi
X
X
X
X
X
X
X
X
X
X
Adverse Event Assessmentj
X
X
X
X
X
X
X
X
X
X
Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
Blood Chemistryl
X
X
X
X
X
X
X
X
X
X
 


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Table 2.
Study Activities (Continued)
Activity
Wk 
48
Wk 
60
Wk 
72
Wk 
84
Wk 
96
Every 
12 Weeks 
Until Study 
Completion
Every 48 Weeks 
Until Study 
Completion 
(Wk 132, Wk 180 
Wk 228 and 
Wk 276)
Final 
Visit
Unscheduled 
Visitc
Premature 
Discontinuation
30-Day 
Follow-Up 
Visitq
Hematology (CBC)l
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
hsCRPl
X
X
X
X
X
X
X
X
X
Disease Response Biomarker
X
In-vivo Pharmacodynamic Biomarker 
Sample
X
Blood Sample for upadacitinib PK 
Assaym
X
X
X
X
Latent TB Risk Factor Questionnairen
X
X
PPD Skin Test or Quanti-FERON-TB 
Gold Testn
X
X
Chest X-Rayn
X
X
X
12-Lead ECGo
X
X
X
X
Dispense Study Drugp
X
X
X
X
X
X
X
Dispense Dosing Diary
X
X
X
X
X
X
Review and Copy Subject Dosing Diary 
and Returned Used/Unused Study Drug
X
X
X
X
X
X
X
X
X
BL = Baseline; Wk = Week
 


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Table 2.
Study Activities (Continued)
a.
These procedures are completed at the Last Visit (Week 12) of preceding RCTs and results will serve as Baseline/Week 0 (Day 1) Visit results for Study M13-538.  This 
applies to patients who enroll into OLE within 14 days following the last visit in RCTs.  For subjects who enroll after 14 days following Week 12 of preceding RCTs, all 
procedures for Baseline (Week 0) visit will need to be repeated.
b.
Subjects who do not achieve 20% improvement from Baseline (RCT period) in TJC and SJC, and their study drug dose is increased to 12 mg BID at Week 12, will have to 
return to clinic at Week 18 in order to accommodate TJC and SJC assessment after 6 weeks of treatment with 12 mg BID.  Subjects who fail to achieve at least 20% 
improvement from Baseline (RCT period) in TJC and SJC with 12 mg BID at Week 18 in OLE will be discontinued.
c.
Unscheduled Visit study activities should only be done as clinically indicated per Investigator's judgment.
d.
Obtain prior to performing/collecting any study related procedures.
e.
Prior to any procedures performed at all clinic visits.
f.
Update Medical/Surgical History.
g.
Blood pressure, pulse rate, temperature and respiratory rate should be obtained before blood draws are performed.
h.
A complete physical examination will be done at Weeks 0, 48, 96 and every 48 weeks until end of the study and at the Final Visit.  A symptom-directed physical exam will be 
performed when necessary, as per Investigator's judgment.
i.
Concomitant Medication ending prior to first dose in Study M13-538 will be recorded in preceding RCT trials.  Ongoing medications from preceding RCT trials after 
first dose in Study M13-538 will be recorded in Study M13-538.
j.
Adverse Events ending prior to first dose in Study M13-538 will be recorded in preceding RCT trials.  Ongoing Adverse Events from preceding RCT trials after first dose in 
Study M13-538 will be recorded in Study M13-538.
k.
For women of childbearing potential, urine pregnancy test will be performed monthly at home between scheduled study visits.  The results of these tests will be verbally 
communicated (via telephone) to the site.  If a urine pregnancy test is positive, the subject must stop dosing, come in to clinic and have blood drawn for a serum pregnancy 
test that will be analyzed at the central laboratory.  A urine pregnancy test will be performed at all scheduled study visits as specified in Table 2, on all female subjects of 
childbearing potential.  If urine pregnancy test (which is performed at the site) is negative, begin or continue dosing.  If urine pregnancy test is positive at any visit, withhold 
dosing and perform a serum pregnancy test for confirmation.  The serum pregnancy test will be sent to and performed by the central laboratory.  Pregnant subjects must be 
discontinued from the study.  In the event a pregnancy test comes back borderline or indeterminate, a repeat test is required.
l.
Fasting status for each subject should be documented in the source documents.  Fasting is NOT required for this study.
m.
Blood samples for PK will be collected at any time during the visit, and preferably within 1 to 8 hours after the last dose.  The exact date, time and number of capsules of the 
last 2 doses of study drug taken prior to the pharmacokinetic sample collection will be recorded to the nearest minute starting with the dose prior to PK collection.
 


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Table 2.
Study Activities (Continued)
n.
TB testing should be performed every 48 weeks after Week 84 in subjects with previous negative QuantiFERON-TB Gold and/or PPD tests.  Subjects with documentation of 
a prior positive result of QuantiFERON-TB Gold and/or PPD tests are not required to repeat either test during the study and should be considered positive.  Subjects with new 
evidence of latent TB should initiate prophylactic treatment immediately per local guidelines.  Refer to Section 5.3.1.1 TB Testing/TB Prophylaxis for additional details.  
Study drug(s) should not be withheld at the time of the first positive TB test.  Obtain chest x-ray for subjects with new TB risk factors as identified by the TB risk factor 
questionnaire or for subjects living in areas endemic for TB or for subjects with newly positive PPD or QuantiFERON-TB Gold at Week 36, Week 84, and every 48 weeks 
(Wk 132, Wk 180, Wk 228 and Wk 276) until the end of the study or as clinically indicated during the study.
o.
12-Lead ECG will only be done for those subjects who did not have ECG done at their Last Visit (Week 12) in Study M13-550 or Study M13-537 or if it is required in the 
opinion of the Investigator.  ECG should be done for all subjects at Weeks 0, 48, 96 and every 48 weeks after Wk 84 (Wk 132, Wk 180, Wk 228 and Wk 276) until the end of 
the study or as clinically indicated during the study.
p.
From January 2017, all subjects who are at Week 72 or beyond will receive once-daily tablet formulation.  Subjects who are on 6 mg BID dosing will be transitioned to 15 mg 
QD dosing.  Subjects who are on 12 mg BID dosing will be transitioned to 30 mg QD dosing.  The capsule formulation will not be available to subjects once the transition to 
tablet formulation has occurred.
q.
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.
 


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5.3.1.1
Study Procedures
Study procedures will be performed during study visits as specified in Table 2.  The study 
procedures outlined in Table 2 are discussed in detail in this section, with the exception of 
drug concentration measurements (discussed in Section 5.3.2), disease response 
biomarkers (Section 5.3.1.3), and the collection of Concomitant Medication (discussed in 
Section 5.2.3) and adverse event (AE) information (discussed in Section 6.0).  All study 
data will be recorded in source documents and on the appropriate eCRFs.
Informed Consent
Subjects will sign and date a study specific, Independent Ethics Committee 
(IEC)/Independent Review Board (IRB) approved, informed consent form before any 
study procedures are performed on the subject in order to participate in this study.  Details 
regarding how informed consent will be obtained and documented are provided in 
Section 9.3.  Written consent will be required for a subject in order to participate in the 
optional vaccine sub-study (Appendix O).  
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at the Baseline/Week 0 visit.
Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS)
At visits specified in Table 2, the subject will rate the severity of the RA symptoms within 
the last 24 hours and how he/she is doing from 0 to 100 using the Visual Analog Scale, 
which consists of a horizontal 100 mm line anchored at either end by opposite adjectives 
reflecting the spectrum/severity of the parameters assessed.  This assessment will be used 
for the DAS28 [CRP] calculation in this study (Appendix E).
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 Patient's Global 
 


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Assessment of Disease Activity will be completed by the physician at the next feasible 
visit.
Patient's Assessment of Pain Visual Analog Scale (VAS)
At visits specified in Table 2, the subject will rate the severity of pain due to rheumatoid 
arthritis in the past week from 0 to 100 (Appendix F) using the Visual Analog Scale, 
which consists of a horizontal 100 mm line anchored at either end by opposite adjectives 
reflecting the spectrum/severity of the parameters assessed.
The subject should complete the VAS 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, the Patient's Assessment of 
Pain will be completed by the physician at the next feasible visit.
Health Outcomes Questionnaires
Subjects will complete the following questionnaires as specified in Table 2:
●
Health Assessment Questionnaire – Disability Index (HAQ-DI) to assess the 
physical function and health-related quality of life of each subject 
(Appendix G)
●
FACIT – Fatigue Scale (Appendix H)
●
Work Instability Score for Rheumatoid Arthritis (RA-WIS) (Appendix I) is 
only required for those subjects who are currently working at the time that the 
questionnaire is administered
●
EuroQoL-5D (EQ-5D) (Appendix J)
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 
 


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the subject's response.  The patient reported outcome questionnaires will only be 
administered to patients and analyzed where a validated translation is available in their 
local language.
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.
Medical and Surgical History
Any updates to the Medical and Surgical History will be obtained at the Baseline/Week 0 
or at any visit during the study.
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 scheduled study visits as 
specified in Table 2 prior to blood draws.
Body Weight
Body weight will be measured at all scheduled visits as specified in Table 2.
Physical Examination
A complete physical examination will be performed at the designated study visits as 
specified in Table 2.  Any physical examination abnormalities assessed by the investigator 
at Week 0 (Day 1) after first dose of study medication in Study M13-538 should be 
recorded as adverse events and captured on the appropriate eCRF in Study M13-538.  All 
findings whether related to an adverse event or part of each subject's medical history will 
be captured on the appropriate eCRF page.  Any physical examination abnormalities 
assessed by the investigator prior to the first dose of study medication should be recorded 
in Study M13-550 or Study M13-537 RCT as appropriate, as adverse events and captured 
on the appropriate eCRF.
 


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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.  A symptom-directed physical examination may be performed at any visits when 
necessary.
Physician Global Assessment of Disease Activity Visual Analog Scale (VAS)
At visits specified in Table 2, the Physician will rate global assessment of subject's current 
disease activity ranging from 0 to 100 independent of the subject's self-assessment 
(Appendix D) using the Visual Analog Scale, which consists of a horizontal 100 mm line 
anchored at either end by opposite adjectives reflecting the spectrum/severity of the 
parameters assessed.
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.
Tender Joint Count (TJC) and Swollen Joint Count (SJC) Assessment
Tender Joint Count (TJC)
An assessment of 68 joints (Appendix C) will be done for tenderness by pressure 
manipulation on physical examination at visits specified in Table 2.  Joint pain/tenderness 
will be classified as:  present ("1"), absent ("0"), replaced ("9") or no assessment ("NA").
Swollen Joint Count (SJC)
An assessment of 66 joints (Appendix C) will be done by directed physical examination at 
visits specified in Table 2.  The joints to be examined for swelling are the same as those 
 


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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").
If a patient receives an intra-articular injection during the study, the injected joint(s) 
should be scored as "NA = no assessment" for 90 days following injection.
If possible, the TJC and SJC should be performed by an independent joint assessor who 
should not perform any other study related procedures, as much as possible.  In order to 
minimize variability, the same independent joint assessor should evaluate the subject at 
each visit for the duration of the trial.  A back-up independent assessor, who is trained and 
competent in performing such assessments, should be identified.  It is the responsibility of 
the Principal Investigator to ensure all assessors are qualified to perform joint assessments 
and that all training is documented.  If the independent assessor is not available, the 
pre-identified back-up assessor will 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.
Pregnancy Test
●
For women of childbearing potential, urine pregnancy test will be performed 
monthly at home between scheduled study visits.  The results of these tests will 
be verbally communicated (via telephone) to the site.  If a urine pregnancy test 
is positive, the subject must stop dosing, come in to clinic and have blood 
drawn for a serum pregnancy test that will be analyzed at the central laboratory.  
A urine pregnancy test will be performed at all scheduled study visits as 
specified in Table 2, on all female subjects of childbearing potential.  If urine 
pregnancy test (which is performed at the site) is negative, begin or continue 
dosing.  If urine pregnancy test is positive at any visit, withhold dosing and 
perform a serum pregnancy test for confirmation.  The serum pregnancy test 
will be sent to and performed by the central laboratory.  Pregnant subjects must 
be discontinued from the study.  In the event a pregnancy test comes back 
borderline, a repeat test is required.
 


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At each visit, the study staff should review the pregnancy avoidance recommendations 
with each subject of childbearing potential and male subjects with a partner of 
childbearing potential, and document this discussion in the subject's source records.
Female subjects who are either postmenopausal, 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 IU/L.
and/or surgically sterile (bilateral oophorectomy or hysterectomy) are exempt from 
pregnancy testing.
In the event a urine pregnancy test may not be performed at the protocol specified visits
due to study modifications related a state of emergency or pandemic situation like 
COVID-19, it can be performed by subjects at a local laboratory or it is possible for the 
Investigator to arrange a shipment from the study site directly to the subject's home of 
urine pregnancy test kits to have the urine pregnancy test done at home (see 
Section 5.3.1.1 - Sub-Section "Study Drug Dispensing, Dosing, and Compliance" for 
details). Home urine pregnancy test should be performed monthly, regardless of ability to 
obtain other laboratory samples.
If, during the course of the study, a woman becomes surgically sterile or post-menopausal 
and complete documentation as described as above is available, pregnancy testing will no 
longer be required.
A breastfeeding or pregnant female will not be eligible for participation or continuation in 
this study.
 


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TB Testing
For subjects with a negative QuantiFERON-TB Gold (or PPD) test at screening of the 
preceding RCT, an annual QuantiFERON-TB Gold (or protein purified derivative [PPD]) 
re-test will be required at visits indicated in Table 2.  All subjects will be assessed for 
evidence of increased risk for TB by a questionnaire (Appendix L).
Subjects with a negative QuantiFERON®-TB Gold test OR negative PPD TB skin test 
AND no new evidence of increased TB risk based on the questionnaire may continue in 
the study.
Subjects with documentation of prior positive result of QuantiFERON-TB Gold Test (or 
equivalent) and/or PPD are not required to repeat either test during the study and should 
be considered positive.
If the QuantiFERON-TB Gold test is indeterminate, the QuantiFERON-TB Gold test 
should be performed locally (or through the central laboratory if not locally available) to 
rule out a positive test result.  If testing remains indeterminate or is positive, then the 
subject is considered to be positive for the purpose of this study.  If the local testing result 
is negative, then the patient is considered to be negative.
●
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.
 


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If one of the annual tests has a positive test result (seroconversion), a chest x-ray (CXR) 
needs to be performed as soon as possible to aid in distinguishing active versus latent TB.  
Expert consultation can be considered per Investigator's discretion.  Any positive TB 
screen after the patient has started the study should be reported as an adverse event (AE).
Subjects with evidence of active TB infection will be discontinued from the trial.
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.   
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 must be discussed with the AbbVie Therapeutic Area Medical 
Director.
Obtain a CXR for subjects with newly identified positive PPD or QuantiFERON-TB Gold 
test and every 48 weeks for subjects with TB risk factors as determined by the TB risk 
assessment form (Appendix H) or for subjects living in areas endemic for TB.  Any 
positive TB test result after the subject has started study drug should be reported as an 
adverse event (AE).
The results of the TB test(s) will be retained at the site as the original source 
documentation.
TB Prophylaxis
If the subject has evidence of latent TB infection (newly positive TB test and the subject 
has a CXR not suggestive of active TB), prophylactic treatment must be initiated (per 
local guidelines).  The prophylaxis needs to be completed.
Of note:  Rifampicin or rifapentine is not allowed for TB prophylaxis
 


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QuantiFERON-TB Gold Test
QuantiFERON-TB Gold test will be performed at visits specified in Table 2.  The 
analyses will be performed by a certified laboratory.
OR
TB Skin Test
A PPD skin test (alternatively, also known as a TB Skin Test) will be performed as 
specified in Table 2 according to standard clinical practice.  The TB Skin Test should be 
read by a licensed healthcare professional between 48 and 72 hours after administration.  
A subject who does not return within 72 hours will need to be rescheduled for another 
skin test.  The reaction will be measured in millimeters (mm) of induration and induration 
equal to or greater than 5 mm for RA subjects is considered a positive reaction.  The 
absence of induration will be recorded as "0 mm" not "negative."
Chest X-Ray (CXR)
A CXR (posterior-anterior and lateral views) is required at the visits indicated in Table 2
for those subjects with new TB risk factors per the latent TB risk factor questionnaire 
(Appendix L), or for those subjects living in areas endemic for TB or for those subjects 
with a newly positive PPD or QuantiFERON-TB Gold.  Subjects can have a CXR any 
time during the study as warranted based on the opinion of the Investigator.
A radiologist 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.
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 
 


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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.   
12-Lead Electrocardiogram (ECG)
An ECG will be performed for all subjects at Weeks 0, 48, 96 and every 48 weeks 
afterwards (Wk 132, Wk 180, Wk 228 and Wk 276), until the end of the study or as 
clinically indicated during the study.  An ECG may be administered at any time during the 
study 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.   
hsCRP
Blood samples for high-sensitivity C-reactive protein (hsCRP) will be obtained at the time 
points specified in Table 2.
Pharmacokinetic (PK)
Blood collection will be performed at the scheduled study visits as specified in Table 2.
Clinical Laboratory Tests
Samples will be obtained at minimum for the clinical laboratory tests outlined in Table 3.  
A certified central laboratory will be utilized to process and provide results for the clinical 
 


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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.
The fasting status will be recorded in the study source documentation.
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/two consecutive 12-week 
intervals, study drug dispensation is not allowed until the required laboratory tests are 
completed to ensure the safety assessments are conducted per protocol. 
Blood and samples will be obtained for the laboratory tests as specified in Table 2.  Blood 
draws should be performed after all clinical assessments and questionnaires (HAQ-DI, 
Patient's Assessment of Pain, FACIT, etc.), and vital sign determinations are obtained and 
before study drug administration during a visit.
 


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Urine samples will be obtained for urinalysis testing as specified in Table 3.  The central 
laboratory will be responsible for performing a macroscopic urinalysis (urine dipstick) on 
the collected urine specimens.  Specified abnormal macroscopic urinalyses defined as 
protein, ketones or blood greater than negative, or glucose greater than normal will be 
followed up with a microscopic analysis at the central laboratory.
 


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Table 3.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysisa
Other Laboratory Tests
Hematocrit
Hemoglobin
Red Blood Cell
(RBC) count
White Blood Cell 
(WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Reticulocytes
Platelet count 
(estimate not 
acceptable)
Blood Urea Nitrogen 
(BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase 
(SGPT/ALT)
Serum glutamic-
oxaloacetic 
transaminase 
(SGOT/AST)
Alkaline phosphatase
Creatinine Phospho-
Kinase (CPK)
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
LDL cholesterol
HDL cholesterol
Total protein
Glucose
Triglycerides
Albumin
INR (reflex only)d
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Microscopic 
examination, if 
needed
Serum pregnancy Test 
(Human Chorionic 
Gonadotropin 
[HCG])b
High sensitivity C-reactive 
protein (hs-CRP)
FSHc
a.
A dipstick 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 protein, ketones or blood greater than negative.
b.
Urine pregnancy test will be done at all scheduled clinic visits and at home between visits.  Serum pregnancy test 
will be done if urine test is positive.  Note that pregnancy tests are being performed only for women of childbearing 
potential.
c.
FSH will be done to confirm post-menopausal status if age of the female is less than 55 years with no menses for 
12 or more months without an alternative medical cause AND an FSH level > 40 IU/L.
d.
INR will only be measured with a separate blood sample at repeat testing if ALT and/or AST > 3 × ULN.
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
 


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●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range (Clinically Significant) value(s) to 
a satisfactory clinical resolution.
A laboratory test value(s) that requires a subject to be discontinued from the study or 
requires a subject to receive treatment will be recorded as an adverse event.
Concomitant Medication
All concomitant medications and treatments are to be recorded in the appropriate eCRF as 
outlined in Section 5.2.3.
Enrollment and Assignment of Subject Numbers
Subjects who meet the inclusion criteria and do not meet any of the exclusion criteria will 
keep the same subject number that they were assigned in Study M13-550 or 
Study M13-537.
Study Medication Dispensing, Dosing and Compliance
Study drug and Dosing Diary (Appendix K) will be dispensed to subjects beginning at the 
Baseline (Week 0) in this OLE study and at all scheduled and unscheduled study visits as 
specified in Table 2.  No study medication will be dispensed at Final Visit.  First dose of 
study medication will occur after all other Baseline (Week 0) procedures are completed.  
At each visit, the site personnel will review and copy the Dosing Diary and review the 
drug bottles to verify compliance.  The dosing records, returned unused bottles and empty 
used bottles will be reviewed and verified for compliance at each visit by the research 
personnel at the study center.  All relevant dosing information will be entered into the 
eCRF at each visit, as applicable.
(Refer to Section 5.5 for additional information).
 


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


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This option can only be offered in countries and sites that comply with local regulatory 
and IRB/IEC requirements for homecare.  Any pre-requisite submissions or notifications 
to the site IRB/IEC and local competent health authority should be made, and approvals 
must be obtained prior to implementation.
The investigator should be available via phone call if a consultation is necessary.
It is recommended that medical personnel entering a subject's home adhere to local health 
regulations during the COVID-19 pandemic, such as the use of Personal Protective 
Equipment (PPE), as required.
If the home visits will not be performed by site personnel, the site may be responsible for 
selecting a vendor, contracting with a vendor, and for ensuring continued compliance with 
the terms of the Clinical Study Agreement.
Individuals performing home visits need to be added to the delegation log.
5.3.1.2
Collection and Handling of Pharmacodynamic Variables
Instructions on preparation and shipment of pharmacodynamic samples will be provided 
by a certified laboratory or the sponsor outside this protocol.
5.3.1.3
Disease Response Biomarkers
Blood samples will be collected at time points specified in Table 2.  The panel may 
include but is not limited to:  IL-6, IL-1, TNFα, CXCL13, CXCL10, CRPM, C3M, C1M, 
MMP-3 and CTX-I.  The fasting status will be recorded in the study source 
documentation.  Separate instructions for the collection, handling and shipping of disease 
response biomarkers will be provided outside of the study protocol.  
 


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
A single pharmacokinetic sample will be collected at study visits BL, Weeks 6, 12, 24, 36, 
48, 72, and 96 without regard to the time of dosing.  Blood samples for PK will be 
collected at any time during the visit, and preferably within 1 to 8 hours after the last dose.  
The exact date, time and number of capsules of the last 2 doses of study drug taken prior 
to the pharmacokinetic sample collection will be recorded to the nearest minute starting 
with the dose prior to PK collection.
Blood samples for assay of upadacitinib will be collected in 3 mL K2EDTA containing 
tubes by venipuncture.  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
ACR20/50/70 response rates at Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96 and every 
24 weeks thereafter until the end of the study will be evaluated based on 20/50/70% 
improvement in TJC, SJC, and ≥ 3 of the 5 measures of Patient's Assessment of Pain 
(VAS), Patient's Global Assessment of Disease Activity, Physician's Global Assessment 
of Disease Activity, Health Assessment Questionnaire Disability Index (HAQ-DI), and 
hsCRP.  Change from Baseline in individual ACR components at Weeks 6, 12, 24, 36, 48, 
60, 72, 84, 96 and every 24 weeks thereafter until the end of the study will also be 
evaluated:  TJC, SJC, Patient's Assessment of Pain (VAS), Patient's Global Assessment of 
Disease Activity, Physician's Global Assessment of Disease Activity, hsCRP, and Health 
Assessment Questionnaire Disability Index (HAQ-DI).  Baseline data for each subject 
 


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will be the data collected at the visit immediately prior to starting treatment with active 
upadacitinib (this visit could be in RCT or OLE).
The proportion of subjects achieving Low Disease Activity (LDA) or Clinical Remission 
(CR), and the proportion of subjects achieving CR will be evaluated at Weeks 6, 12, 24, 
36, 48, 60, 72, 84, 96 and every 24 weeks thereafter until the end of the study.  The 
criteria will be based on DAS28 [CRP] or CDAI as follows:
DAS28 [CRP]
CDAI
LDA
2.6 ≤ to < 3.2
2.8 < to ≤ 10
CR
< 2.6
≤ 2.8
Change from Baseline in DAS28 [CRP] disease activity score, CDAI and Patient 
Reported Outcomes including FACIT-Fatigue Scale, RA-WIS, and EQ-5D will be 
analyzed at Weeks 6, 12, 24, 36, 48, 72, 96 and every 24 weeks thereafter until the end of 
the study.
5.3.4
Safety Variables
Incidence of adverse events, changes in vital signs, physical examination results and 
clinical laboratory data will be assessed throughout the study.
5.3.5
Pharmacokinetic Variables
Plasma upadacitinib concentrations will be determined at the times indicated in Table 2.  
A mixed-effects modeling approach may be used to estimate the population central value 
and the empirical Bayesian estimates of the individual values for upadacitinib oral 
clearance (CL/F) and volume of distribution (Vss/F).  Additional parameters may be 
estimated if useful in the interpretation of the data.
5.3.6
RA Disease Response Biomarkers Variables
Subjects will have additional blood samples collected to assess disease response.  Samples 
will be analyzed for measurement of non-genetic markers related to disease 
 


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activity/prognosis of RA, autoimmunity/inflammation, and/or response to upadacitinib.  
The panel may include but is not limited to:  IL-6, IL-1, TNFα, CXCL13, CXCL10, 
CRPM, C3M, C1M, MMP-3 and CTX-I.
Change from Baseline in RA disease response biomarkers at Weeks 6, 12, 24 and 48 will 
be evaluated.
5.3.7
Pharmacodynamic Variables
In-Vivo Biomarkers
Blood samples will be collected to assess JAK activity effects on certain lymphocyte 
subsets including T (CD4+ and CD8+), B, NK, NKT, reticulocyte and other cell types.
Change from Baseline in in-vivo pharmacodynamic biomarkers at Weeks 6, 12, 24 and 48
will be evaluated.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
A subject may withdraw from the study at any time.  The Investigator may discontinue 
any subject's participation for any reason, including an adverse event, safety concerns or 
failure to comply with the protocol.
Subjects will be withdrawn from the study immediately if any of the following occur:
●
Clinically significant abnormal laboratory results or adverse events, which rule 
out continuation of the study medication, as determined by the Investigator and 
the AbbVie Therapeutic Area Medical Director.
●
Serious infections (e.g., sepsis) which would put the subject at risk for 
continued participation in the trial as determined by the Investigator in 
consultation with the AbbVie Therapeutic Area Medical Director.
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from study drug or the study.
 


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●
Inclusion and 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 SDP.
●
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 medication.
●
Subject has known malignancy, except for localized non-melanoma skin 
cancer.  Discontinuation for carcinoma in-situ of the cervix is at the discretion 
of the Investigator.
●
Subject is diagnosed with lupus-like syndrome, multiple sclerosis or 
demyelinating disease (including myelitis).
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation as determined by the Investigator.
●
Subject has failed to achieve at least 20% improvement from Baseline (RCT 
period) in TJC and SJC with upadacitinib as described in Section 5.1.
●
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus or 
non-cardiac, non-neurologic arterial thrombosis.
●
Subject develops a gastrointestinal perforation (other than due to appendicitis 
or mechanical injury).
If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the premature discontinuation visit should be 
completed as soon as possible, preferably within 2 weeks of study drug discontinuation 
and preferably prior to the initiation of another therapy.  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 the study drug, the subject will be treated in accordance with the 
Investigator's best clinical judgment.
 


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A final visit (a telephone call is sufficient if a site visit is not possible) will occur for all 
subjects participating in the OLE study, approximately 30 days after the last dose of study 
medication to determine the status of any ongoing AEs/SAEs or the occurrence of any 
new AEs/SAEs.
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 TAMD 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.
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for premature discontinuation.  The information will be recorded on the 
appropriate eCRF page.
For subjects that are 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.
Subjects who discontinue the study prematurely will not be replaced.
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 
 


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notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Treatments administered during this OLE include upadacitinib 6 mg BID, 12 mg BID, 
(15 mg QD or 30 mg QD from January 2017).  All subjects start treatment with 6 mg 
BID.  Dose adjustments are allowed as described in Section 5.1.
Subject receiving 6 mg BID will dose with two 3 mg capsules twice a day.
Subjects receiving 12 mg BID will dose with one 12 mg capsule twice a day.
Subject receiving 15 mg QD will dose with one 15 mg tablet once a day.
Subject receiving 30 mg QD will dose with one 30 mg tablet once a day.
Study drug will be taken orally beginning at Baseline/Week 0 in OLE.  Subjects will be 
instructed to take study drug at approximately the same times each day.  The study drug 
can be taken with or without food.  Subjects will continue their weekly stable dose of 
MTX and folic acid.  AbbVie will not supply MTX or folic acid.
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.
Information about the Investigational Product is presented in Table 4.
 


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Table 4.
Identity of Investigational Products
Investigational Product
Upadacitinib
Mode of Administration
Oral
Oral
Dosage Form
Capsule
Capsule
Strength (mg)
3
12
Mode of Administration
Oral
Oral
Dosage Form
Film coated Tablet
Film coated Tablet
Strength (mg)
15
30
5.5.1.1
Packaging and Labeling
Upadacitinib will be packaged in bottles containing 100 capsules or 100 tablets per bottle.  
Each bottle (kit) label will contain a unique kit number.  This kit number is assigned to a 
subject via IRT and encodes the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  Each kit will be labeled as required per country requirements.
Labels must remain affixed to the bottles (kits) and must not be concealed by any 
over-labeling.  All blank spaces on the label will be completed by site staff prior to 
dispensing to the subjects.
5.5.1.2
Storage and Disposition of Study Drugs
The study drug 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 returned to AbbVie.
5.5.2
Method of Assigning Subjects to Treatment Groups
This is an open-label study.  The upadacitinib treatment is the same for all subjects so that 
there is no assignment of subjects to treatment groups.  As a subject is confirmed for 
Baseline (Week 0) in OLE to be appropriate for participation in the study, the site will 
 


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enter the subject's number from Study M13-550 or Study M13-537, based on which study 
the subject was enrolled in, into IVRS (Interactive Voice Response System)/IWRS 
(Interactive Web based Response System) to obtain study drug.  All eligible subjects will 
be assigned to upadacitinib 6 mg BID immediately after or up to 30 days following the 
Last Visit (Week 12) of Study M13-550 or Study M13-537 using an Interactive Voice 
Response System/Interactive Web Response System (IVRS/IWRS).  Before the study is 
initiated, the telephone number and call-in directions for the IVRS/IWRS will be provided 
to each site.  From Week 6 in OLE, subjects will receive subsequent treatment as 
described in Section 5.5.1.
5.5.3
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.5.1.
On scheduled study visit days, subject should follow their regular routine for study drug 
administration.
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 (Appendix K).
Capsule Formulation:
If a subject should forget to take his/her study drug dose at his/her regularly scheduled 
dosing time, he/she should take the forgotten dose as soon as he/she remembers the dose 
was missed as long as it is at least 6 hours before his/her next scheduled dose.  If a subject 
only remembers the missed dose within 6 hours before next scheduled dose, the subject 
should skip the missed dose and take the next dose at the scheduled time.  
Tablet Formulation:
If a subject should forget to take his/her study drug dose at his/her regularly scheduled 
dosing time, he/she should take the forgotten dose as soon as he/she remembers the dose 
was missed as long as it is at least 10 hours before their next scheduled dose.  If a subject 
 


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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 > 30 days, they should notify their 
investigator, and the investigator will determine if study drug should be restarted or if the 
subject should be discontinued from the study.
Subjects who, in the opinion of the Investigator, develop adverse events that require study 
drug interruption and/or reach protocol specified toxicity management thresholds can 
have the study drug interrupted for up to 30 days while recovering from the adverse event.
5.5.4
Blinding
This is an open-label study.
5.5.5
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subject dosing will be recorded on a subject dosing diary (Appendix K).  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.  Subjects will be counseled on missed doses of medication.  If the subject 
does not return the dosing diary, used and unused study drug bottles the site should 
question the subject and obtain as much information as possible as to the dosing of the 
study drug.
The information should be documented on the source documents as per "best recollection" 
and when possible, re-verified when the dosing diary is returned before completing on the 
applicable eCRF page.
 


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5.5.6
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 medication through 
the IRT.  The original Proof of Receipt Note and the faxed 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 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 
preapproved 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.
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
Subjects who have completed Study M13-550 or Study M13-537 RCT with upadacitinib 
will be allowed to enroll in the OLE study to continue to receive upadacitinib for up to 
approximately 312 weeks.  The primary objective of OLE study is to collect long-term 
 


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safety and tolerability data for upadacitinib.  All subjects who roll over into the OLE will 
be assigned to upadacitinib 6 mg BID initially, regardless of treatment assignment during 
RCT period, and the basis of this design is to preserve the blinding of treatment 
assignment in the RCT period.  All subjects assigned to 6 mg BID initially will have an 
option to increase the dose to 12 mg BID (or 30 mg QD from January 2017) throughout 
the treatment period if a subject is unable to achieve low disease activity with upadacitinib 
6 mg BID.  At any time during the treatment period, the upadacitinib dose can be 
decreased back to 6 mg BID (or 15 mg QD from January 2017) per Investigator's 
judgment if there are safety and tolerability concerns.  Those subjects who are unable to 
achieve at least 20% improvement in both SJC and TJC (minimum clinical efficacy) at 
defined time-points will be permanently discontinued.  This design allows for collection 
of long-term safety data and avoids continued treatment of those subjects who do not 
respond to study medication.
From January 2017, all subjects who are at Week 72 or beyond will receive once-daily 
tablet formulation (15 mg QD or 30 mg QD).  Preliminary results of a bioequivalent study 
demonstrated that single 15 mg and 30 mg doses of the once-daily formulation provide 
comparable AUC, but significantly lower Cmax than single doses of 12 mg immediate 
release (IR) formulation (equivalent to 6 mg BID dose) and 24 mg IR formulation 
(equivalent to 12 mg BID dose), respectively.  At steady-state, the once-daily dose of 
15 mg QD is predicted to achieve comparable daily AUC, lower or comparable Cmax, and 
comparable Ctrough to 6 mg BID IR formulation, and the once-daily dose of 30 mg QD is 
predicted to be equivalent to 12 mg BID IR.
Subjects who are on 6 mg BID (IR) capsule dosing will be transitioned to 15 mg QD 
tablet dosing.  Subjects who are on 12 mg BID dosing will be transitioned to 30 mg QD 
dosing.  Capsule formulation will not be available to the subjects after transition to tablet 
formulation.
Starting with Amendment 5, subjects who are receiving 30 mg QD open-label 
upadacitinib will have the option to decrease to the 15 mg QD dose based on 
investigator's discretion.
 


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5.6.1
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All 
efficacy measurements in this study are standard for assessing disease activity in subjects 
with RA.  All clinical and laboratory procedures in this study are standard and generally 
accepted.
5.6.2
Suitability of Subject Population
This OLE study will enroll subjects who have completed Study M13-550 or 
Study M13-537 RCT with upadacitinib.  Only those subjects who have met all of the 
specified inclusion and none of the exclusion criteria will have an option to enter into the 
OLE study to receive upadacitinib, as long as the subject is willing and the Investigator 
believes that continuing the therapy with upadacitinib is appropriate.
5.6.3
Selection of Doses in the Study
All subjects will be assigned to upadacitinib 6 mg BID at the beginning of OLE study.  
During the course of OLE treatment period the upadacitinib dose can be increased to 
12 mg BID based on clinical efficacy assessment and as long as the Investigator has no 
safety concerns.  From January 2017, all subjects who are at Week 72 or beyond will 
receive once-daily tablet formulation.  Subjects who are on 6 mg BID dosing will be 
transitioned to 15 mg QD dosing.  Subjects who are on 12 mg BID dosing will be 
transitioned to 30 mg QD dosing.  The capsule formulation will not be available to 
subjects once the transition to tablet formulation has occurred.
The change in dose selection in this study is based on extrapolation of pre-clinical 
efficacy models and analyses of PK, pharmacodynamic, safety, and efficacy data from the 
Phase 1 studies in healthy volunteers (single and multiple ascending dose 
Studies M13-401 and M13-845, respectively) and completed Phase 2b randomized, 
controlled studies (RCTs) in RA subjects (Studies M13-537 and M13-550).  The doses 
selected, 15 mg QD and 30 mg QD, are expected to approximate the exposures achieved 
with the 6 mg BID and 12 BID immediate release formulations, respectively, which 
 


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should be efficacious with an acceptable safety profile.  Preliminary results from an 
ongoing relative bioavailability study demonstrated that single 15 mg and 30 mg doses of 
the once-daily formulation provide comparable AUC and significantly lower Cmax than 
single doses of 12 mg immediate release (IR) formulation (AUC equivalent to 6 mg BID 
dose tested in Phase 2) and 24 mg IR formulation (AUC equivalent to 12 mg BID dose 
tested in Phase 2), respectively, under fasting conditions.  At steady-state, the once-daily 
dose of 15 mg QD is predicted to achieve comparable daily AUC and Cmax, and 
non-inferior Ctrough to 6 mg BID IR formulation.  In the Phase 2 RCTs, the 6 mg BID dose 
was shown to achieve the near maximum efficacy.  The once-daily dose of 30 mg QD is 
predicted to achieve comparable daily AUC and Cmax, and non-inferior Ctrough to 12 mg 
BID IR formulation.  In the Phase 2 RCTs, the 12 mg BID dose was clearly shown to 
achieve the plateau of efficacy.
Study drug will be given for approximately 312 weeks and will not exceed a dose of 
30 mg daily.
6.0
Adverse Events
6.1
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).  For adverse events, please refer to Section 6.1
through Section 6.9.
6.2
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
 


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any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.3
Definitions
6.3.1
Adverse Event
An adverse event (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 adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (meets protocol specific criteria [see Section 6.10 regarding toxicity 
management]) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
 


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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 adverse event.
6.3.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
 


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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 serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.4
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study (see detailed 
toxicity management in Section 6.10):
●
Serious infections, opportunistic infections, herpes zoster, and active TB;
●
Malignancy (all types);
●
Adjudicated Gastrointestinal perforations;
●
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;
●
Increased creatine phosphokinase (CPK);
 


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●
Adjudicated cardiac, embolic and thrombotic events (non-cardiac, non-CNS).
6.5
Adverse Event Severity
The Investigator will classify adverse events according to the Rheumatology Common 
Toxicity Criteria v.2.0 (Appendix M).10
6.6
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship. 
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a 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.
6.7
Adverse Event Collection Period
All adverse events reported from the time of study drug administration (Day 1) until 
30 days following discontinuation of study drug administration will be collected, whether 
 


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solicited or spontaneously reported by the subject.  In addition, serious adverse events will 
be collected from the time the subject signed the study-specific informed consent.
Adverse event information will be collected as shown in Figure 2, and recorded on the 
appropriate eCRFs.
Figure 2.
Adverse Event Collection
SAEs
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported




Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
30 Days
After Study 
Drug Stopped
Additionally, in order to assist the adjudication process, additional information on any 
potential cardiovascular events including thromboembolic events will be collected, if 
applicable.
In the 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);
●
Hepatic;
●
Renal;
●
Herpes Zoster Infection;
●
CPK increases considered by the investigator to be an AE;
●
Embolic and thrombotic events (non-cardiac, non-CNS);
●
COVID-19
 


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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
●
COVID-19 Status Form
6.8
Serious Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events 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 being made aware of the serious adverse event.
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847)-938-0660
 




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6.9
Pregnancy
Pregnancy in a study subject or the partner of an enrolled subject must be reported to 
AbbVie within 24 hours after the site becomes aware of the pregnancy.  Subjects who 
become pregnant during the study must be discontinued (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected after obtaining proper consent.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
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.
6.10
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.
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection or a serious opportunistic infection.  
A subject who develops a new infection during treatment with study drug should undergo 
prompt diagnostic testing appropriate for an immunocompromised subject.  As 
 


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appropriate, antimicrobial therapy should be initiated, and the subject should be closely 
monitored.  Study drug may be restarted once the infection has been successfully treated.  
If study drug administration is interrupted for more than 30 days, the subject should be 
discontinued from the study.  Subjects who develop active tuberculosis must be 
permanently 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 the diagnosis of gastrointestinal perforation is 
confirmed, (other than appendicitis or mechanical injury) the subject must be discontinued 
from study drug.
Cardiovascular Events:  Subjects presenting with potential cardiovascular events should 
be appropriately assessed and 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.  
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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Muscle-related symptoms:  If a subject experiences symptoms suggestive of myositis or 
rhabdomyolysis consider checking CPK and aldolase, with clinical management and/or 
study drug interruption as deemed appropriate by the treating physician.
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 5
(confirmation by repeat testing is required) 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
Laboratory Parameter
Toxicity Management Guideline
Hemoglobin 

If hemoglobin < 8 g/dL, interrupt study drug dosing and confirm by repeat testing 
with new sample.

If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample. 

If 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 < 1,000/µL, interrupt study drug dosing until ANC value returns to 
normal reference range or its Baseline value.

Discontinue study drug if confirmed < 500/µL by repeat testing with new sample.
Absolute lymphocytes 
counts (ALC)

If confirmed < 500/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 < 2,000/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/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 (Continued)
Laboratory Parameter
Toxicity Management Guideline
AST or ALT

Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat 
testing with new sample and either a total bilirubin > 2 × ULN or an international 
normalized ratio > 1.5. 
o
A separate blood sample for INR testing will be needed to measure INR at the 
time of repeat testing for ALT or AST.  A repeat test of INR is not needed for 
determination if above toxicity management criteria are met. 

Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat 
testing with new sample along with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).  

Interrupt study drug immediately if confirmed ALT or AST > 5 × ULN by repeat 
testing with new sample for more than 2 weeks. 

If ALT or AST > 8 × ULN, interrupt study drug immediately, confirm by repeat 
testing with a new sample and contact the TAMD. 
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 one 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 (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 contact AbbVie Therapeutic Area 
Medical Director.

For the above CPK elevation scenarios, complete supplemental CPK eCRF.
*
Local requirements may apply.  Refer to Appendix N for local requirements (United Kingdom).
If the subject must undergo elective surgery, the study drug should be interrupted at least 
1 week prior to the surgery.  If the subject must undergo emergency surgery, the study 
drug should be interrupted at the time of the surgery.  The study drug can recommence 
once the physician has examined the surgical site and determined that it has healed and 
there is no sign of infection.
6.11
Cardiovascular Adjudication Committee
An independent committee of physician experts in cardiovascular adjudication will be 
utilized to assess cardiovascular and embolic and thrombotic (non-cardiac, non-CNS)
adverse events as defined by the Cardiac Adjudication Committee charter.
6.12
Product Complaint
6.12.1
Definition
A Product Complaint is any Complaint (see Section 6.1 for the definition) related to the 
biologic or drug component of the product.
 


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For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.12.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with 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.  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 
 




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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
8.1.1
Dataset for Analysis
The analysis set consists of all subjects who enrolled into this OLE study and received at 
least one dose of open-label study medication upadacitinib.  This analysis set will be the 
primary analysis population for both efficacy and safety evaluation. 
8.1.2
Subject Accountability
The number of subjects who received at least one dose of study drug, the number of 
subjects who completed the study, and the number of subjects who prematurely 
discontinued will be calculated overall and for each investigational site.
8.1.3
Baseline Characteristics
For analyses purposes, baseline data for each subject will be the data collected at the visit 
immediately prior to starting double-blind treatment.  In an alternate assessment for 
summarizing the safety and laboratory data, baseline data will be assumed to be the data 
collected at the visit immediately prior to starting treatment with active upadacitinib.
Demographic variables such as age, gender, race, height, weight, BMI, race, ethnicity, 
duration of disease, vital signs (blood pressure, heart rate, and temperature), and planned 
efficacy assessments such as the counts for both SJC and TJC, Patient's Assessment of 
Pain (VAS), Patient's Global Assessment of Disease Activity, Physician's Global 
Assessment of Disease Activity, Patient's Assessment of Physical Function by Heath 
Assessment Questionnaire – Disability Index (HAQ-DI), and hsCRP will be summarized 
at Baseline.
Summary statistics for continuous variables will include the number of observations, 
mean, standard deviation, median, and range.  For other discrete variables, frequencies 
and percentages will be computed in each category.
 


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8.1.4
Subject Disposition and Study Drug Exposure
8.1.4.1
Subject Disposition
The number and percentage of subjects who are enrolled and received at least one dose of 
study drug, and the number of subjects who prematurely discontinued and the reason for 
premature discontinuation will be summarized.  Premature discontinuation of study drug 
will be summarized, with frequencies and percentages overall and by reason for 
discontinuation for all subjects who received at least one dose of study drug.  Subjects 
may have multiple reasons for prematurely discontinuing study drug, but will be counted 
no more than once for the total ("Any Reason").
8.1.4.2
Study Drug Exposure
Extent of exposure to study drug will be summarized for all subjects who received at least 
one dose of open-label study drug in Study M13-538.  The duration (days) of study drug 
treatment in both open-label treatment period and combined RCT (Study M13-550 or 
Study M13-537) plus open-label treatment period will be summarized with the mean, 
standard deviation, median and range.  
8.1.5
Efficacy Analysis
8.1.5.1
Efficacy Variables
The efficacy endpoints of this study include the ACR20/50/70 response rates at Weeks 6, 
12, 24, 36, 48, 60, 72, 84, 96 and every 24 weeks thereafter until the end of the study.
A subject will be considered an ACR20/50/70 responder if: 
1.
The counts for both SJC and TJC have reduced from Baseline by 20/50/70% or 
more; and 
2.
At least three of the five remaining ACR core set measures show reduction of 
20/50/70% or more in baseline assessment:
●
Patient's Assessment of Pain (VAS), 
 


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●
Patient's Global Assessment of Disease Activity, 
●
Physician's Global Assessment of Disease Activity, 
●
Patient's Assessment of Physical Function by Heath Assessment Questionnaire 
– Disability Index (HAQ-DI), 
●
hsCRP.
Other efficacy endpoints of this study are:
●
Individual components of ACR at every scheduled study visit (Weeks 6, 12, 24, 
36, 48, 60, 72, 84, 96 and every 24 weeks thereafter until end of the study):
○
TJC
○
SJC
○
Patient's Global Assessment of Disease Activity
○
Physician's Global Assessment of Disease Activity
○
Patient's Assessment of Pain
○
hsCRP
○
Health Assessment Questionnaire Disability Index (HAQ-DI)
●
Proportion of subjects achieving low disease activity (LDA) or clinical 
remission (CR) based on DAS28 [CRP] or CDAI criteria respectively at Weeks 
6, 12, 24, 36, 48, 60, 72, 84, 96 and every 24 weeks thereafter until the end of 
the study.
●
Proportion of subjects achieving CR at Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96 
and every 24 weeks thereafter until the end of the study.
●
Change from Baseline in DAS28 [CRP] at Weeks 6, 12, 24, 36, 48, 72, 96 and 
every 24 weeks thereafter until the end of the study.
●
Change from Baseline in CDAI at Weeks 6, 12, 24, 36, 48, 72, 96 and every 24 
weeks thereafter until the end of the study.
●
Change from Baseline in Patient Reported Outcomes at Weeks 6, 12, 24, 36, 
48, 72, 96 and every 24 weeks thereafter until the end of the study:
○
FACIT – Fatigue Scale,
 


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○
Work Instability Scale for RA (RA-WIS), 
○
EuroQoL-5D (EQ-5D).
The proportion of subjects achieving Low Disease Activity (LDA) or Clinical Remission 
(CR), and the proportion of subjects achieving CR will be evaluated at Weeks 6, 12, 24, 
36, 48, 60, 72, 84, 96 and every 24 weeks thereafter until the end of the study.  The 
criteria will be based on DAS28 [CRP] or CDAI as follows:
DAS28 [CRP]
CDAI
LDA
2.6 ≤ to < 3.2
2.8 < to ≤ 10
CR
< 2.6
≤ 2.8
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).
DAS28 [CRP] = 0.56 √("TJC28" )+ 0.28 √("SJC28" )+ 0.36 ln (CRP + 1) +
0.014 PtGA + 0.96,
where √ is square root and ln is natural log.  A score > 5.1 generally means high disease 
activity; 2.6 ≤ DAS28 [CRP] < 3.2 generally means low disease activity (LDA); DAS28 
[CRP] < 2.6 is generally considered clinical remission (CR).
Clinical Disease Activity Index (CDAI) is a composite index (without CRP) for assessing 
disease activity.  CDAI is based on the simple summation of the counts of SJC28 and 
TJC28 along with Patient's Global Assessment (VAS [0 – 10 cm]) (PtGA) and Physician's 
Global Assessment (VAS [0 – 10 cm]) (PhGA) for estimating disease activity.
CDAI = TJC28 + SJC28 + PtGA + PhGA.
% Improvement in Joint Count from Baseline in RCT = [(Number of Swollen/Tender 
Joints at Day 1 of RCT – Number of Swollen/Tender Joints at Current Visit)/Number of 
Swollen/Tender Joints at Day 1 of RCT]*100
 


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In this study, the level of disease activity is interpreted as remission (CDAI ≤ 2.8), low 
(2.8 < CDAI ≤ 10), moderate (10 < CDAI ≤ 22), or high (CDAI > 22).
8.1.5.2
Efficacy Analysis 
The efficacy analyses will be conducted with the analysis set described in Section 8.1.1
and the 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. 
Frequencies and relative frequencies (percentages) of ACR20/50/70 will be summarized 
with 95% confidence intervals at each post-baseline time point.  
The proportion of subjects achieving Low Disease Activity (LDA) or Clinical Remission 
(CR), and the proportion of subjects achieving CR will be evaluated at Weeks 6, 12, 24, 
36, 48, 60, 72, 84, 96 and every 24 weeks thereafter until the end of the study.  
Frequencies and relative frequencies will be reported with 95% confidence intervals by 
visit, and will be summarized based on DAS28 [CRP] and CDAI criteria respectively.
For each of the change from baseline measurement, namely, TJC, SJC, Patient's Global 
Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, 
Patient's Assessment of Pain (VAS), HAQ-DI, hsCRP, DAS28 [CRP] disease activity 
score, and CDAI, the mean, standard deviation, median, and range will be reported at each 
post-baseline time point.  For Patient Reported Outcomes variables including change from 
baseline analyses of FACIT, RA-WIS, and EQ-5D, the mean, standard deviation, median 
and range will be summarized by visit.  Confidence intervals at an overall level of 95% 
will be provided.
The impact of time between completion of RCT and roll-over to OLE will be explored.
8.1.5.3
Multiple Comparisons
Not applicable.
 


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8.1.6
Safety Analysis
8.1.6.1
General Considerations
All subjects who receive at least one dose of upadacitinib in this OLE study will be 
included in the safety analysis.  Incidence of adverse events, serious adverse events, 
premature discontinuation, and changes from Baseline in vital signs, physical examination 
results, and clinical laboratory values will be analyzed by visit.  Treatment-emergent 
adverse events will be tabulated by system organ class and by MedDRA preferred term.  
Mean change from Baseline for laboratory and vital signs data will be summarized by 
visit.  For analyses purposes, baseline for vital signs, physical examination results, and 
clinical laboratory results for subjects will be the data collected at the visit immediately 
prior to starting double-blind treatment.  In an alternate assessment for summarizing the 
safety and laboratory data, baseline data will be assumed to be the data collected at the 
visit immediately prior to starting treatment with active upadacitinib.
Incidence of adverse events, changes in vital signs, physical examination results, and 
clinical laboratory values will be analyzed.
Treatment emergent adverse events will be tabulated by system organ class (SOC) and by 
the Medical Dictionary for Regulatory Activities (MedDRA) preferred term.  Mean 
change from baseline for laboratory and vital signs data will be summarized by visit.
Missing safety data will not be imputed.
The impact of time between completion of RCT and roll-over to OLE will be explored.
8.1.6.2
Analysis of Adverse Events
8.1.6.2.1
Treatment-Emergent Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary.  Treatment-emergent adverse events, defined as AEs 
that began or worsened in severity after initiation of open-label study drug upadacitinib in 
 


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this OLE study, will be tabulated by system organ class (SOC) and MedDRA preferred 
term.
Adverse events starting more than 30 days following discontinuation of study drug will 
not be included in summaries of treatment-emergent AEs.  Adverse events starting more 
than 30 days following discontinuation of study drug will be summarized separately as 
post-treatment AEs.
When summarizing adverse events by relationship or severity, if a subject has an event 
with unknown severity or relationship then the subject will be counted in the 
severity/relationship categories of "unknown" even if the subject has a second occurrence 
of the same event with a severity/relationship present.  The only exception is if the subject 
has a second occurrence of the same event with the most extreme severity (i.e., "severe") 
or a relationship category of "reasonable possibility."  In this case, the subject will be 
counted under these most extreme severity/relationship categories.
The AEs of special interest (including but not limited to serious infection, opportunistic 
infection, herpes zoster, TB, gastrointestinal perforations, malignancies, MACE, renal 
dysfunction, anemia, increased CPK, drug-related hepatic disorders and thrombotic and 
embolic events) will be summarized.
Subjects reporting more than 1 AE for a given MedDRA preferred term will be counted 
only once for that term using the most severe incident in each study period.  Subjects 
reporting more than 1 type of event within an SOC will be counted only once for that 
SOC.
Frequencies and percentages of subjects with treatment-emergent AEs will be 
summarized as follows:
●
Any event
●
By system organ class, and preferred term
●
By system organ class, preferred term and maximum relationship
 


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●
By system organ class, preferred term and maximum severity
●
Any event and by system organ class and preferred term for events resulting in 
death
●
Any event and by system organ class and preferred term for events resulting in 
study drug discontinuation
●
Any event and by system organ class and preferred term for serious events
●
Any event and by system organ class and preferred term for adverse events 
with a relationship of "reasonable possibility"
●
Any event and by system organ class and preferred term for adverse events of 
special interest
All AEs leading to premature discontinuation of study drug will be presented in listing 
format.
A listing of treatment-emergent AEs grouped by SOC and MedDRA preferred term with 
subject ID numbers will be generated.
The post-treatment AEs will be summarized in the same way as the treatment-emergent 
AEs described above.
8.1.6.2.2
Serious Adverse Events and Death
All treatment-emergent serious adverse events, adverse events leading to death, and 
adverse events leading to discontinuation will also be presented in listing format.  In 
addition, SAEs will be summarized by SOC and MedDRA preferred term.
8.1.6.3
Analysis of Laboratory and Vital Sign Data
Changes from baseline to minimum value, maximum value and final values in continuous 
laboratory and vital sign parameters will be summarized.  
Vital signs and laboratory data will be described by statistical characteristics and 
frequency of abnormal values.  Frequencies and percentages of subjects with laboratory 
shifts from baseline to the final values using normal ranges to define categories (low, 
 


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normal, high, and missing) will be summarized by the respective categories.  Values 
beyond the normal values will be listed.  Low or high laboratory values will also be 
flagged in the data listings.
8.1.7
Pharmacokinetic and Exposure-Response Analyses
Individual upadacitinib plasma concentrations at each study visit will be tabulated and 
summarized with appropriate statistical methods.  Upadacitinib pharmacokinetics may be 
evaluated using population PK modeling approach.  The relationship between 
upadacitinib exposure and clinical efficacy or safety response(s) may be explored.  The 
data from this study may be combined with the data from other studies of upadacitinib for 
the exposure-response analysis.  Data from this study may not be analyzed separately.  
Results of the population PK and exposure-response analyses may be presented in a 
separate report prior to regulatory filing of upadacitinib for treatment of RA.
Additional analyses will be performed if useful and appropriate.
8.1.8
Statistical Analysis of Biomarker Data
Summary statistics for the pharmacodynamic biomarkers and disease response biomarkers 
at baseline and post-treatment time points, 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.  Appropriate graphical visualizations such as association of each 
biomarker to the relevant efficacy endpoints, pairwise correlations between biomarkers, 
trellis/3D plots that condition on baseline factors, etc., will be provided.  The association 
of biomarkers to the efficacy and safety endpoints will be explored for each biomarker 
one at a time, and also for combinations of biomarkers via some multivariate predictive 
modeling algorithms.  Pairwise correlations and graphical summaries will be provided.  
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 will 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 
 


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will be explored.  The significance of these multivariate combinations of biomarkers will 
be assessed via at least 20 iterations of 5-fold cross-validation.
8.1.9
Interim Analysis
Interim analyses may be performed, as appropriate, to help plan future studies.
8.2
Determination of Sample Size
It is anticipated that up to 500 subjects will be enrolled in this OLE study.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events 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 
 


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affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
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.
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 form 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.
 


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Procedures for the Prevnar 13® pneumococcal vaccine sub-study will only be performed if 
the subject has voluntarily provided written informed consent for this sub-study, approved 
by an IRB/IEC, and after the nature of these activities has been explained and the subject 
has had an opportunity to ask questions.  This written consent must be signed before the 
sub-study activities are performed.  If the subject does not consent to the sub-study, it will 
not impact the subject's participation in the main study.
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 
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.
 


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


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investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
The adverse events electronic data capture eCRF data segments of:  alternative etiology, 
severity, frequency and relationship to study drug, may also be used as source and will 
require Investigator approval on the eCRF.
Electronic Patient Reported Outcomes (ePRO)
Patient reported data must be completed for each subject enrolled in this study.  Some of 
these data are being collected with an Electronic Patient Reported Outcome (ePRO) tool 
called Trialmax, provided by the technology vendor CRF Health of Lansdale, PA, USA.  
The ePRO system is in compliance with Title 21 CFR Part 11.  The documentation related 
to the system validation of the ePRO tool is available through the vendor, CRF Health, 
while the user acceptance testing of the study-specific ePRO design will be conducted and 
maintained at AbbVie.
The subject and physician will enter the data on an electronic device; these data will be 
uploaded to a server.  The data on the server will be considered source, maintained and
managed by CRF Health.
Internet access to ePRO data will be provided by CRF Health for the duration of the trial.  
This access will be available to the investigator and delegated personnel.  Such access will 
be removed at the end of the site's participation in the study.  Data from the ePRO tool 
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 printouts from that media.
The ePRO data will be collected electronically via a tablet device into which the subject 
and physician will record required information.  The electronic device will be 
programmed to allow data entry for only the visits specified in the protocol and will not 
allow for patients or physician to complete more than one of the same assessments at any 
one visit.  Data entered on the device will be immediately stored to the device itself and 
 


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automatically uploaded to a central server maintained and managed by CRF Health.  The 
investigator and delegated staff will be able to access all uploaded subject data via a 
password-protected website up until the generation, receipt and confirmation of the study 
archive.
The following assessments will be completed by the subject or physician in Electronic 
Patient-Reported Outcome (ePRO) device:
●
Physician's Global Assessment of Disease Activity VAS
●
Joint Evaluation Worksheet (Tender Joint Count and Swollen Joint Count)
●
Patient's Global Assessment of Disease Activity VAS
●
Patient's Assessment of Disease Pain VAS
●
HAQ-DI Questionnaire
●
Work Instability Scale for RA (RA-WIS)
●
FACIT – Fatigue Scale
●
EuroQol-5D (EQ-5D)
10.3
Data Collection Process
AbbVie is using an ePRO tool to capture portions of the clinical data defined in this 
protocol.  The use of ePRO requires certain process changes compared to the use of 
traditional paper patient reported outcomes.  Trial-Specific Guidelines have been 
developed to document changes from the traditional paper patient reported outcomes 
process.  These Trial-Specific Guidelines govern the ePRO processes in this trial.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
 


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12.0
Use of Information
All information concerning upadacitinib and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
upadacitinib.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
13.0
Completion of the Study
The end-of-study is defined as the date of the last subject's last visit or the actual date of 
follow-up contact, whichever is later.
 


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


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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: 
Phase 2 Study, Multicenter, Open-Label Extension (OLE) Study in 
Rheumatoid Arthritis Subjects who have Completed a Preceding 
Phase 2 Randomized Controlled Trial (RCT) with Upadacitinib 
(ABT-494)
Protocol Date:
01 December 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
1.
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.
2.
Murray PJ.  The Jak-STAT signaling pathway:  input and output integration.  
J Immunol.  2007;178(5):2623-9.
3.
Ghoreschi K, Laurence A, O'Shea JJ.  Janus kinases in immune cell signaling.  
Immunol Rev.  2009;228(1):273-87.
4.
Kontzias A, Kotlyar A, Laurance A, et al.  Jaknibs:  a new class of kinase inhibitors 
in cancer and autoimmune disease.  Curr Opin Pharmacol.  2012;12(4):464-70.
5.
Gushin D, Rogers N, Briscoe J, et al.  A major role for the protein tyrosine kinase 
JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.  
EMBO J.  1995;14(7):1421-9.
6.
AbbVie. ABT-494 (Upadacitinib) Investigator's Brochure Edition 11 dated 18 
August 2020.
7.
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.
8.
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.
9.
Prescribing information for Xeljanz®.  New York, NY; Pfizer, Inc., 
November 2012.
10.
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.
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.
 


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12.
Greenwald MW, 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.  Arthritis Rheum.  
2010;2(Suppl 10):2172.
 


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practices (GCP) and local regulations and guidelines governing the study at 
the site location.  In signing the Investigator Agreement in Section 14.0 of this protocol, 
the investigator is agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
 


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8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate 
individuals (e.g., coordinating investigator, institution director) and/or directly to 
the ethics committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
 


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


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Appendix C.
Joint Evaluation Worksheet Example
JOINT EVALUATION
JOINT
(Tick Correct Answer)
Subject Right
Subject Left
1 = Present
0 = Absent
9 = 
Replaced 
NA = No 
Assessment
0 = Absent
1 = Present
9 = 
Replaced 
NA = No 
Assessment
Pain/ 
Tenderness
Swelling
Joint
Pain/ 
Tenderness
Swelling
Joint
1.  Temporomandibular
0
1
0
1
9
NA
0
1
0
1
9
NA
2.  Sternoclavicular
0
1
0
1
9
NA
0
1
0
1
9
NA
3.  Acromio-clavicular
0
1
0
1
9
NA
0
1
0
1
9
NA
4.  Shoulder
0
1
0
1
9
NA
0
1
0
1
9
NA
5.  Elbow
0
1
0
1
9
NA
0
1
0
1
9
NA
6.  Wrist
0
1
0
1
9
NA
0
1
0
1
9
NA
7.  Metacarpophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
8.  Metacarpophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
9.  Metacarpophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
10.  Metacarpophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
11.  Metacarpophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
12.  Thumb Interphalangeal
0
1
0
1
9
NA
0
1
0
1
9
NA
13.  Prox. Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
14.  Prox. Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
15.  Prox. Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
16.  Prox. Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
17.  Distal Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
18.  Distal Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
19.  Distal Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
20.  Distal Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
21.  Hip
0
1
--
--
9
NA
0
1
--
--
9
NA
22.  Knee
0
1
0
1
9
NA
0
1
0
1
9
NA
23.  Ankle
0
1
0
1
9
NA
0
1
0
1
9
NA
24.  Tarsus
0
1
0
1
9
NA
0
1
0
1
9
NA
25.  Metatarsophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
26.  Metatarsophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
 


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JOINT EVALUATION
JOINT
(Tick Correct Answer)
Subject Right
Subject Left
1 = Present
0 = Absent
9 = 
Replaced 
NA = No 
Assessment
0 = Absent
1 = Present
9 = 
Replaced 
NA = No 
Assessment
Pain/ 
Tenderness
Swelling
Joint
Pain/ 
Tenderness
Swelling
Joint
27.  Metatarsophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
28.  Metatarsophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
29.  Metatarsophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
30.  Great Toe/Hallux
0
1
0
1
9
NA
0
1
0
1
9
NA
31.  Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
32.  Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
33.  Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
34.  Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
 


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


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Appendix E.
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:
●
Patient'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 F.
Patient's Assessment of Pain Example
Visual Analog Scale (VAS)
VAS will be used to the patient'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 G.
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:  __________________)
Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
  Dressing and Grooming
  Eating
  Arising
  Walking
 


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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 
yardwork?
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 H.
FACIT – Fatigue Scale Example
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
   
  
  
 
 
 
 
   
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
    
   
  
  
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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Appendix I.
Work Instability Scale for Rheumatoid Arthritis (RA-WIS) 
Example
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 


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Appendix J.
EuroQoL-5D Example
Under each heading, please check the ONE box that best describes your health TODAY:
Mobility
I have no problems walking
I have slight problems walking
I have moderate problems walking
I have severe problems walking
I am unable to walk 
Self-Care
I have no problems washing or dressing myself
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself
I have severe problems washing or dressing myself
I am unable to wash or dress myself 
Usual Activities (e.g., work, study, housework, family or leisure activities)
I have no problems with doing my usual activities 
I have slight problems with doing my usual activities 
I have moderate problems with doing my usual activities
I have severe problems with doing my usual activities
I am unable to do my usual activities 
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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Appendix K.
Dosing Diary Example 
Subject Number:  _______________________
Investigator, Dr:  _______________________________
Phone Number:  ________________________________
While dosing outside of the investigator's clinic, you are expected to maintain the 
established study drug dosing schedule, while continuing to take your methotrexate 
(MTX) weekly (in the morning or the evening).  Study drug can be taken with or without 
food.
You are being asked to keep a record of every study drug, MTX and folic acid (or 
equivalent) dose taken for the duration of this study.  In addition, record the dose of MTX 
taken.  
Please record the time to the nearest minute.  If for any reason a full dose was not taken, 
please enter in the comments field the details why a full dose was not taken.  Please 
record any missed doses.
Please return your dosing diary with used and unused containers at each clinic visit.
If you have any questions or concerns at any time, please contact your study doctor.
 


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Study Day
Date
Study Drug
MTX
Folic Acid
Comments
AM Dose
PM Dose
Dose 
Once 
Weekly
Time 
Taken
Daily 
Dose
Time 
Taken
Time of 
Dose
Time of 
Dose
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
24
 


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Appendix L.
Latent TB Risk Factor Questionnaire 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 M.
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 Antirheumatic Therapies
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
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 vocalize for extended
E7.  Xerostomia (dry 
mouth)
Transient dryness
Relief with meds
Interferes with nutrition, slowly 
reversible
Extended duration interference 
with nutrition, requires parenteral 
nutrition
F.  Eye/Ophthalmologic
F1.  Cataract
Asymptomatic, no change in 
vision, non-progressive
Symptomatic, partial visual loss, 
progressive
Symptoms impairing function, 
vision loss requiring treatment, 
including surgery
NA
F2. Conjunctivitis
Asymptomatic, transient, rapid 
response to treatment
Symptomatic, responds to 
treatment, changes not interfering 
with function
Symptoms prolonged, partial 
response to treatment, interferes 
with function
NA
F3.  Lacrimation 
increased (tearing, 
watery eyes)
Symptoms not requiring 
treatment, transient
Symptomatic, treatment required, 
reversible
Unresponsive to treatment with 
major effect on function
NA
F4.  Retinopathy
Asymptomatic, non-progressive, 
no treatment
Reversible change in vision; 
readily responsive to treatment
Disabling change in vision 
ophthalmological findings 
reversible, sight improves over time
Loss of sight
 


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


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


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Appendix N.
Local Requirements
United Kingdom
Section 1.2 Synopsis and Section 5.2.2 Exclusion Criteria
4.
Laboratory values from the visit immediately prior to Baseline Visit meeting the 
toxicity management criteria (Section 6.10) for abnormal laboratory values 
requiring study drug interruption/discontinuation.
Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values 
Laboratory Parameter
Toxicity Management Guideline
Hemoglobin 

If hemoglobin < 8 g/dL, interrupt study drug dosing and confirm by repeat testing 
with new sample.

If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample. 

If 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 < 1,000/µL, interrupt study drug dosing until ANC value returns to 
normal reference range or its Baseline value.

Discontinue study drug if confirmed < 500/µL by repeat testing with new sample.
Absolute lymphocytes 
counts

If confirmed < 500/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 < 2,500/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/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 (Continued)
Laboratory Parameter
Toxicity Management Guideline
AST or ALT

Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat 
testing with new sample and either a total bilirubin > 2 × ULN or an international 
normalized ratio > 1.5. 
o
A separate blood sample for INR testing will be needed to measure INR at the 
time of repeat testing for ALT or AST.  A repeat test of INR is not needed for 
determination if above toxicity management criteria are met. 

Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat 
testing with new sample along with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).  

Interrupt study drug immediately if confirmed ALT or AST > 5 × ULN by repeat 
testing with new sample for more than 2 weeks. 

Interrupt study drug immediately if confirmed ALT or AST > 8 × ULN by repeat 
testing with new sample. 
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 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.

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.  
o
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 one 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 (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 contact AbbVie Therapeutic Area 
Medical Director.
For the above CPK elevation scenarios, complete supplemental CPK eCRF.
 


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Appendix O.
Prevnar 13® Vaccine Sub-Study
This section describes the requirements, procedures and statistical analyses specific to this 
sub-study.
16.0
Objective
The objective of this sub-study is to assess the impact of upadacitinib treatment (15 mg 
QD and 30 mg QD) with background MTX on immunological responses to Prevnar 13®
in RA patients.
16.1
Overall Sub-Study Design and Plan:  Description
This sub-study will evaluate humoral immune response following Prevnar 13®
administration in RA subjects enrolled in the main Study M13-538 treated with either 
upadacitinib 15 mg QD or 30 mg QD on a stable dose of background MTX.  Immune 
response will be measured at three timepoints (pre-vaccination, 4 weeks post-vaccination, 
and 12 weeks post-vaccination).  Enrollment will continue until approximately 
150 subjects have been recruited to participate.
Subjects must be on a stable dose of:
●
upadacitinib (15 mg QD or 30 mg QD as assigned in the main study) for a 
minimum of 4 weeks prior to the Vaccination visit and for at least 4 weeks 
afterwards.
●
background methotrexate for a minimum of 4 weeks prior to the Vaccination 
visit and for at least 4 weeks afterwards.
The subject's background anti-rheumatic medications (oral or parenteral corticosteroids, if 
applicable) should also remain stable for a minimum of 4 weeks after the Vaccination 
visit.
At the Vaccination visit, subjects who have provided a written informed consent for the 
sub-study will be assessed for eligibility.  If eligible, blood samples for the measurement 
 


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of pre-vaccination antibody titers will be collected, followed by administration of 
Prevnar 13® as per the local label prescribing requirements.  The criteria and procedures 
of the main study must still be adhered to in addition to those for the sub-study.
Design Schematic
16.2
Selection of Vaccine Sub-Study Population
A subject may be enrolled in this sub-study provided that he/she has met all of the 
inclusion criteria specified in Section 16.2.1 and none of the exclusion criteria specified in 
Section 16.2.2.
16.2.1
Inclusion Criteria
1.
Must currently be enrolled in the main study.
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
  


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2.
Must have been receiving a stable dose of upadacitinib (either 15 mg QD or 30 mg 
QD) for a minimum of 4 weeks prior to the Vaccination visit.
3.
Must have been on a stable dose of background methotrexate (no change in dose or 
frequency) for a minimum of 4 weeks prior to the Vaccination visit.
4.
If subject is on corticosteroids, must remain on a stable dose of ≤ 10 mg/day of 
prednisone or equivalent corticosteroid therapy for at least 4 weeks after the 
Vaccination visit.
5.
Must meet the prescribing specifications as per local label requirements to receive 
Prevnar 13® vaccine.
6.
Willing to receive Prevnar 13® vaccine.
16.2.2
Exclusion Criteria
1.
Receiving any csDMARDs other than MTX.
2.
Receiving > 10 mg/day of prednisone or equivalent corticosteroid therapy.
3.
Receipt of any steroid injection within 4 weeks prior to Vaccination visit.
4.
History of severe allergic reaction (e.g., anaphylaxis) to any component of 
Prevnar 13®. 
5.
History of any documented pneumococcal infection within the last 6 months prior 
to the Vaccination visit.
6.
Receipt of any vaccine 4 weeks prior to the Vaccination visit and/or anticipation of 
any vaccination for 4 weeks after the Vaccination visit.
7.
Receipt of any pneumococcal vaccine.
8.
Subject is not suitable for the sub-study as per the Investigator's judgment.
 


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16.2.3
Prohibited Therapy
Subjects enrolled into this sub-study will continue on their assigned doses of upadacitinib 
for at least 4 weeks after the Vaccination visit.  Upadacitinib dose may be decreased per 
Investigator's judgment if there are safety and/or tolerability concerns due to an adverse 
event or reaching one of the protocol-specific toxicity management thresholds.  Subjects 
will be required to continue on stable doses of background MTX until after the Sub-Study 
Week 4 visit (4 weeks post-vaccination).  Any dosage adjustment and/or initiation of oral 
or parenteral corticosteroids, or csDMARDs is prohibited until after the Sub-Study Week 
4 visit.  Adjustment and/or initiation of background anti-rheumatic medications will be 
allowed at any time after the collection of the Sub-Study Week 4 post-vaccination titer 
sample.
16.2.4
Efficacy and Safety Assessments/Variables
The study will include a Vaccination visit, followed by a visit 4 weeks post-vaccination 
for the short-term assessment of immunological responses to Prevnar-13®, and a 
visit 12 weeks post-vaccination visit for the long-term assessment of immunological 
responses to Prevnar-13®.
Vaccination Visit
The Vaccination visit (Sub-study Week 0) should occur during any scheduled main study 
visit.  At this visit, subjects will be reviewed against the sub-study inclusion and exclusion 
criteria (Refer to Section 16.2.1 and Section 16.2.2).  Activities for the sub-study should 
occur only after all procedures for the main study visit have been completed, with the 
vaccination occurring at the very end of sub-study visit.  Subjects enrolled into this sub-
study will have a blood draw for the assessment of pre-vaccination antibodies levels 
specific to Prevnar-13®.  Afterwards, subjects will be administered Prevnar-13® as per the 
local label requirements.  The vaccination should occur at the end of the Vaccination visit 
after all other procedures, including procedures from main study visit, are completed.
 


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The central laboratory chosen for this study will provide instructions regarding the 
collection, processing and shipping of these samples.
Post-Vaccination Visits
Subjects should return to the site for 4 week and 12 week post-vaccination visits (Sub-
study Week 4 and Sub-Study Week 12) to complete the sub-study procedures identified in 
Table 6.  The 12 week post-vaccination visit should coincide with the subject's regularly 
scheduled main study visit.  At the 4-week post-vaccination visit, blood will be drawn for 
the assessment of humoral immune responses to Prevnar-13® and assessment of adverse 
events will be performed.  At the 12-week post-vaccination visit, in addition to the main 
study procedures, collection of blood samples to measure immune response to Prevnar-
13® will occur. 
Table 6.
Sub-Study Activities
Activity
Vaccination Visita
(Sub-Study Week 0)
4-Week Post 
Vaccination Visit 
(Sub-Study Week 4)
12-Week Post 
Vaccination Visit 
(Sub-Study Week 12)
Informed Consentb
X
Inclusion/Exclusion 
review
X
Pre-vaccination blood 
sample collection
X
Prevnar-13® vaccination
X
Post-vaccination blood 
sample collection
X
X
Adverse event assessmentc
X
a.
The Vaccination and 12 week post-vaccination visits should coincide with the regularly scheduled visits of the 
main study.
b.
The subject must provide consent specific to the sub-study before any related procedures are performed.  If the 
subject does not consent to participate in the sub-study, it will not impact the subject's participation in the main 
study.
c.
Collection and assessment of AEs will be completed as outlined in the main study.
 


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16.2.5
Statistical Analysis of Efficacy
Primary Variables
1.
Proportion of subjects with satisfactory humoral response to Prevnar 13® at the 
Week 4 visit of the sub-study (4 weeks post-vaccination).
Satisfactory humoral response to Prevnar 13® is defined as greater than or equal to 
(≥) 2-fold increase in antibody concentration from the vaccination baseline in at least 6 
out of the 12 pneumococcal antigens (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F).
Secondary Variables
1.
Proportion of subjects with satisfactory humoral response to Prevnar 13® at the 
Week 12 visit of the sub-study (12 weeks post-vaccination).
2.
Geometric Mean Fold Rise (GMFR) of anti-pneumococcal antibody levels to each 
of the 12 pneumococcal antigens above vaccination baseline values at Week 4 and 
Week 12 of the sub-study
16.2.6
Statistical Methods and Determination of Sample Size
Statistical and Analytical Plans
All efficacy analyses will be carried out using the Full Analysis Set population of the 
Vaccine Sub-study, which includes all enrolled subjects who were vaccinated and 
received at least one dose of study drug after vaccination during the sub-study.  Subjects 
will be classified into upadacitinib 15 mg QD dose group or upadacitinib 30 mg QD dose 
group based on their upadacitinib dose at the vaccination visit.
The proportion of subjects achieving Satisfactory Humoral Response will be summarized 
by count and percentages for each upadacitinib dose group at 4 weeks post-vaccination 
 


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and 12 weeks post-vaccination.  95% confidence intervals for each upadacitinib dose 
group will be provided.
At 4 weeks post-vaccination and 12 weeks post-vaccination, the geometric mean fold rise 
(GMFR) and corresponding 95% confidence intervals of anti-pneumococcal antibodies as 
compared with pre-vaccination will be summarized for each upadacitinib dose group.  
Calculations will be done using logarithmically transformed assay results, and then back-
transformed to the original scale. 
All efficacy analyses will be based on observed cases.  No multiplicity adjustment is 
planned for any analysis in this vaccine sub-study.
Determination of Sample Size
A total sample size of approximately 150 subjects is planned for the sub-study, where 
approximately 100 subjects are expected to be on upadacitinib 15 mg QD dose.  
Assuming a satisfactory humoral response rate of 60%, the planned sample size of 
approximately 100 subjects for upadacitinib 15 mg QD group will provide a margin of 
error of approximately 10% for this dose group when using a 95% confidence interval.
 

SAP_001.pdf: 
ABT-494
M13-538 – Statistical Analysis Plan
Version 3.0 – 03 May 2021
1
1.0
Title Page
Statistical Analysis Plan
Study M13-538
Phase 2 Study, Multicenter, Open-Label Extension 
(OLE) Study in Rheumatoid Arthritis Subjects Who 
Have Completed a Preceding Phase 2 Randomized 
Controlled Trial (RCT) with ABT-494
Date:  03 May 2021
Version 3.0
 
NCT02049138


ABT-494
M13-538 – Statistical Analysis Plan
Version 3.0 – 03 May 2021
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................5
4.0
Study Objectives, Design and Procedures.............................5
4.1
Study Objectives ........................................................................................5
4.2
Overall Study Design and Plan..................................................................5
4.3
Interim Analysis and Data Base Lock......................................................10
4.4
Data Monitoring Committee (DMC) Activities.......................................10
5.0
Analysis Populations and Analysis Windows .....................10
5.1
Analysis Populations................................................................................10
5.2
Definition of Baseline..............................................................................10
5.3
Analysis Windows ...................................................................................11
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............13
6.1
Demographic and Baseline Characteristics .............................................13
6.2
Medical History .......................................................................................15
6.3
Previous Treatment and Concomitant Medications.................................15
6.4
Protocol Deviations..................................................................................16
7.0
Patient Disposition.................................................................16
8.0
Study Drug Exposure and Compliance...............................17
8.1
Study Drug Exposure...............................................................................17
8.2
Compliance ..............................................................................................18
9.0
Efficacy Analysis....................................................................19
9.1
General Considerations............................................................................19
9.1.1
Definition of Missing Data Imputation....................................................19
9.2
Long-Term Efficacy Analysis..................................................................20
9.3
Handling of Multiplicity ..........................................................................21
9.4
Efficacy Variables Definitions and Conventions.....................................22
9.4.1
ACR Criteria ............................................................................................22
9.4.2
Joint Evaluation .......................................................................................23
 


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9.4.3
Patient's Global Assessment of Disease Activity Visual Analog 
Scale (VAS) .............................................................................................24
9.4.4
Physician's Global Assessment of Disease Activity Visual Analog 
Scale (VAS) .............................................................................................25
9.4.5
Patient's Global Assessment of Pain........................................................25
9.4.6
Disease Activity Score Based on CRP (DAS28 [CRP])..........................25
9.4.7
Clinical Disease Activity Index (CDAI)..................................................26
9.4.8
Simplified Disease Activity Index (SDAI) ..............................................26
9.4.9
Clinical Remission (CR) and Low Disease Activity (LDA)....................27
9.4.10
Disability Index of Health Assessment Questionnaire (HAQ-DI)...........27
9.4.11
Functional Assessment of Chronic Illness Therapy (FACIT) –
Fatigue Scale............................................................................................28
9.4.12
Work Instability Scale for RA (RA-WIS)................................................28
9.4.13
EuroQoL-5D (EQ-5D).............................................................................29
10.0
Safety Analysis.......................................................................29
10.1
General Considerations............................................................................29
10.2
Analysis of Adverse Events.....................................................................30
10.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................31
10.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by System Organ Class and Preferred Term............................32
10.2.3
Serious Adverse Events (Including Deaths) and Adverse Events 
Leading to Study Drug Discontinuation Rates per 100 Patient-
Years of Study Drug Exposure ................................................................33
10.2.4
Frequent Adverse Events by System Organ Class and Preferred
Term.........................................................................................................33
10.2.5
Adverse Events of Special Interests Rates per 100 Patient-Years 
of Study Drug Exposure...........................................................................33
10.2.6
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation ........................35
10.3
Analysis of Laboratory Data....................................................................36
10.3.1
Variables and Units..................................................................................36
10.3.2
Assessment of Mean Change from Baseline in Clinical 
Laboratory Values....................................................................................38
 


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10.3.3
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................38
10.3.4
Potentially Clinically Significant Laboratory Values ..............................39
10.3.5
Analyses for Liver Elevations..................................................................39
10.4
Analysis of Vital Signs and Weight.........................................................40
10.4.1
Variables and Criteria Defining Abnormality..........................................40
10.4.2
Analysis of Long-Term Vital Signs.........................................................41
11.0
Summary of Changes ............................................................42
12.0
Appendix.................................................................................48
List of Tables
Table 1.
Analysis Windows for Efficacy, Laboratory Assessments and 
Vital Signs................................................................................................12
Table 2.
Summary of Long-Term Efficacy Analysis.............................................21
Table 3.
Anatomical Joints Assessed for Calculation of Tender and 
Swollen Joint Counts (TJC68 and SJC66)...............................................24
Table 4.
Anatomical Joints for DAS28 (CRP) Calculation ...................................26
Table 5.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................34
Table 6.
List of Laboratory Variables....................................................................36
Table 7.
Criteria for Potentially Clinically Significant Vital Sign Findings..........40
List of Figures
Figure 1.
Study Design Schematic ............................................................................8
List of Appendices
Appendix A.
FACIT-Fatigue Scale Calculation............................................................49
Appendix B.
EQ5D-5L Manual ....................................................................................51
Appendix C.
OMERACT Criteria.................................................................................52
Appendix D.
Statistical Analysis to Account for Impact of COVID-19 
Pandemic..................................................................................................65
 


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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 M13-538.  It provides 
details to further elaborate statistical methods as outlined in the protocol and describes
analysis conventions to guide the statistical programming work.
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
The primary objective is to evaluate the long-term safety, tolerability, and efficacy of 
upadacitinib in RA subjects who have completed Study M13-550 or Study M13-537 
Phase 2 RCT with upadacitinib.
4.2
Overall Study Design and Plan
This is a Phase 2, multicenter, open-label extension (OLE) study to assess the long-term 
safety, tolerability, and efficacy of upadacitinib in RA subjects who have completed 
Study M13-550 or Study M13-537 Phase 2 RCT with upadacitinib.  This study has 
enrolled 494 subjects.  Subjects will be treated for approximately 312 weeks.
Only those subjects who have met all of the specified inclusion criteria and none of the 
exclusion criteria will have an option to enter into the OLE study to receive upadacitinib, 
as long as the subject is willing and the Investigator believes that continuing therapy with 
upadacitinib is appropriate.
All eligible subjects will be assigned to upadacitinib 6 mg BID immediately after or up to 
30 days following the Last Visit of Study M13-550 or Study M13-537 Phase 2 RCT.  
Subjects who are unable to tolerate 6 mg BID will be discontinued from the study.  At 
Week 6, if a subject fails to achieve at least 20% improvement from RCT Baseline in 
 


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Tender Joint Count (TJC) and Swollen Joint Count (SJC), upadacitinib dose should be 
increased to 12 mg BID as long as the Investigator has no safety concerns.  After 6 weeks 
of treatment with upadacitinib 12 mg BID, the improvement in TJC and SJC will be 
re-assessed at next scheduled visit (Week 12).  If the subject on 12 mg BID fails to 
achieve at least 20% improvement in TJC and SJC from RCT Baseline the subject will be 
discontinued.
At Week 12, the same process will be followed.  If a subject still on 6 mg BID fails to 
achieve at least 20% improvement from RCT Baseline in TJC and SJC ABT-494 dose 
should be increased to 12 mg BID.  The improvement in TJC and SJC will be re-assessed 
after 6 weeks of treatment with 12 mg BID at Week 18 (an optional study visit).  Subjects 
who fail to achieve at least 20% improvement from RCT Baseline in TJC and SJC with 
12 mg BID at Week 18 will be discontinued.
After Week 12, if a subject fails to show at least 20% improvement from RCT Baseline in 
TJC and SJC at 2 consecutive scheduled study visits then the subject will be discontinued.
Starting at Week 6 and during any scheduled visits thereafter, upadacitinib dose may be 
increased from 6 mg BID to 12 mg BID (or 30 mg QD from January 2017) if a subject 
fails to achieve the Low Disease Activity (LDA) status (CDAI > 10) and has no safety 
concerns per Investigator's judgment.
At any visit, upadacitinib dose may be decreased back to 6 mg BID per Investigator's 
judgment due to either an adverse event or reaching one of the protocol specific toxicity 
management thresholds. Dose increase back to 12 mg BID (or 30 mg QD from 
January 2017) is not allowed.
From January 2017, all subjects who are at Week 72 or beyond will receive a once–daily 
tablet formulation.  Subjects who are on 6 mg BID capsule dosing will be transitioned to 
15 mg QD tablet dosing.  Subjects who are on 12 mg BID capsule dosing will be 
transitioned to 30 mg QD tablet dosing.  The capsule formulation will not be available to 
subjects once the transition to tablet formulation has occurred.  The change to once daily 
 


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tablet formulation in this study is based on extrapolation of pre-clinical efficacy models 
and analyses of PK, pharmacodynamic, safety, and efficacy data from the Phase 1 studies 
in healthy volunteers (single and multiple ascending dose Studies M13-401 and M13-845, 
respectively) and completed Phase 2b randomized, controlled studies (RCTs) in RA 
subjects (Studies M13-537 and M13-550).  The doses selected, 15 mg QD and 30 mg QD, 
are expected to approximate the exposures achieved with the 6 mg BID and 12 BID 
immediate release formulations, respectively, which should be efficacious with an 
acceptable safety profile.  Preliminary results from an ongoing relative bioavailability 
study demonstrated that single 15 mg and 30 mg doses of the once-daily formulation 
provide comparable AUC and significantly lower Cmax than single doses of 12 mg 
immediate release (IR) formulation (AUC equivalent to 6 mg BID dose tested in Phase 2) 
and 24 mg IR formulation (AUC equivalent to 12 mg BID dose tested in Phase 2), 
respectively, under fasting conditions.  At steady-state, the once-daily dose of 15 mg QD 
is predicted to achieve comparable daily AUC and Cmax, and non-inferior Ctrough to 6 mg 
BID IR formulation.  In the Phase 2 RCTs, the 6 mg BID dose was shown to achieve the 
near maximum efficacy.  The once-daily dose of 30 mg QD is predicted to achieve 
comparable daily AUC and Cmax, and non-inferior Ctrough to 12 mg BID IR formulation.  
In the Phase 2 RCTs, the 12 mg BID dose was clearly shown to achieve the plateau of 
efficacy.
Starting with Amendment 5, subjects who are receiving 30 mg QD open-label 
upadacitinib will have the option to decrease the dose to 15 mg QD based on 
investigator's discretion.
A schematic of the overall study design is shown in Figure 1.
 


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Figure 1.
Study Design Schematic
Treatment Period
The treatment period for OLE can begin immediately after or up to 30 days following the 
Last Visit of Study M13-550 or Study M13-537 RCT and will continue for approximately
312 weeks in OLE.  At Last Visit (Week 12) or up to 30 days following the Last Visit 
(Week 12) of Study M13-550 or Study M13-537, subjects who meet all the inclusion 
criteria and none of the exclusion criteria described in protocol Section 5.2.1 and 
Section 5.2.2 will be enrolled into the study.  Subjects will visit the study site at Weeks 6, 
12, 18 (Optional), 24, 36, 48, 60, 72, 84, 96 and every 12 weeks thereafter until the end of 
the study or if they terminate early from the study.  A ± 7-day window is permitted around
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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scheduled study visits.  The last dose of study drug is taken the evening prior to the final
visit.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have a Premature Discontinuation Visit 
and complete the procedures outlined for Premature Discontinuation Visit as soon as 
possible after the last dose of study drug and preferably prior to the administration of any 
new therapies.
Starting with Amendment 5, subjects who are receiving 30 mg QD open-label 
upadacitinib will have the option to decrease to the 15 mg QD dose based on 
investigator's discretion.
Follow-Up Period
All subjects will have a follow-up visit approximately 30 days after the last administration 
of study drug to obtain information on any new or ongoing adverse events (AEs), and to 
collect vital signs and clinical laboratory tests. The 30 day follow up visit may be a 
telephone call if a site visit is not possible. Vital signs and laboratory tests may not be 
required.
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.
 


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4.3
Interim Analysis and Data Base Lock
Interim Analyses may be performed, as appropriate, to generate long term safety and 
efficacy data and to help plan future studies.
Prior to interim analyses, interim data cuts will be taken, where database versions will be 
preserved and discrepant data will be clarified.  The analyses will be conducted by the 
clinical statistics department at AbbVie.
4.4
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
Open-Label Treated Population
The open-label treated population consists of all subjects who have received at least 
one dose of open-label study medication.  It will be used for all long-term efficacy, safety, 
and baseline analysis.
5.2
Definition of Baseline
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 RCT. This applies to both efficacy and 
safety analysis.
 


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5.3
Analysis Windows
Definition of OL-Rx Days (Days Relative to the First Dose of Open-Label Study 
Drug)
For the purpose of defining analysis windows for the open-label study, OL-Rx Days are 
calculated for each time point relative to the first dose of open-label study drug.  They are 
defined as the number of days between the day of the first dose of open-label study drug 
and the specific time point.  OL-Rx days are negative values when the time point of 
interest is prior to the first dose day of the open-label study drug, while OL-Rx days are 
positive values when the time point of interest is on or after the first dose day of open-
label study drug.  The day of the first dose of open-label study drug is defined as OL-Rx 
Day 1, while the day immediately prior to the first dose day of open-label study drug is 
defined as OL-Rx Day –1 (there is no OL-Rx Day 0).  OL-Rx days are used to map actual 
study visits to the protocol specified study visits.
Definition of Analysis Windows
The following rules will be applied to assign actual subject visits to protocol-specified 
visits.  For each protocol-specified study visit, a target study day will be identified to 
represent the corresponding visit along with a window around the target day.  Windows 
will be selected in a non-overlapping fashion so that a collection date does not fall into 
multiple visit windows.  If a subject has two or more actual visits in one visit window, the 
visit closest to the target day will be used for analysis.  If two visits are equidistant from 
the target day, then the later visit will be used for analysis.
The visit window and the target OL-Rx day for each protocol-specified visit are displayed 
in Table 1.
 


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Table 1.
Analysis Windows for Efficacy, Laboratory Assessments and Vital 
Signs
Protocol Specified Visit Week
Lower Bound
Target Daya
Upper Bound
Baseline
Last non-missing measurement recorded on or before the date of the 
first dose of study drug in RCT
6
2
43
64
12
65
85
127
24
128
169
211
36
212
253
295
48
296
337
379
60
380
421
463
72
464
505
547
84
548
589
631
96
632
673
715
108
716
757
799
120
800
841
883
132
884
925
967
144
968
1009
1051
156
1052
1093
1135
168
1136
1177
1219
180
1220
1261
1303
192
1304
1345
1387
204
1388
1429
1471
216
1472
1513
1555
228
1556
1597
1639
240
1640
1681
1723
252
1724
1765
1807
264
1808
1849
  1891
276
1892
1933
1975
288
1976
2017
2059
300
2060
2101
2143
312
2144
2185
2227
a.
Relative to the day of first dose of open-label study drug.
 


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6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
6.1
Demographic and Baseline Characteristics
The demographic data and baseline characteristics will be reported for the Baseline visit 
of the preceding RCT Studies M13-537 and M13-550.  Demographic and baseline 
characteristics will be summarized for the Open-Label Treated Population.  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.  The summary statistics will be computed 
for each treatment group, and the combined upadacitinib group.
Main Demographic and Baseline Characteristics
●
Sex (male/female)
●
Age (years)
●
Age Categories (< 45, [45,65), ≥ 65 years)
●
Race (White, Black, American Indian/Alaska Native, Native Hawaiian or Other 
Pacific Islander, Asian, Other)
●
Geographic region (Western Europe, Eastern Europe, North America, 
South/Central America, 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) (< 18.5, [18.5,25), [25,30), ≥ 30)
RA Medical History and Characteristics 
●
Duration of RA in years
●
Number of prior DMARDs used (for Study M13-537 subjects)
 


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●
MTX as first prior DMARD (Yes/No) (for Study M13-537 subjects)
●
Number of prior biologic DMARD(s) used (for Study M13-550 subjects)
●
Oral steroid use at baseline (yes, no)
●
Oral steroid dose (prednisone equivalent) at baseline
Baseline RA Disease Characteristics 
●
Individual scores of each ACR component (e.g., hsCRP, SJC, TJC, etc.)
●
DAS28 (CRP)
●
DAS28 categories:
○
DAS28 > 5.1 (High Disease Activity)
○
DAS28 ≤5.1
●
Clinical Disease Activity Index (CDAI) and categories:
○
CDAI > 22 (High Disease Activity)
○
CDAI ≤ 22
●
Simplified Disease Activity Index (SDAI) and categories:
○
SDAI > 26 (High Disease Activity)
○
SDAI ≤ 26
●
Anti-cyclic citrullinated peptide (Anti-CCP) (units)
●
Anti-CCP status (Positive or Negative)
●
Rheumatoid Factor (RF) (KU/L)
●
RF status (Positive or Negative)
Patient Report Outcomes at Baseline
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
Work Instability Scale for Rheumatoid Arthritis (RA-WIS)
●
EQ-5D-5L
 


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Clinical Tests at Screening
●
Chest x-ray
●
ECG
●
Tuberculin PPD skin test, QuantiFERON TB Gold test
●
Serum pregnancy test
Immunization History
●
BCG immunization
●
Herpes Zoster immunization
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 (defined relative to the preceding RCT studies) will be summarized 
and presented for Open-Label Treated 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 by treatment group sequence (defined in 
Section 9.1) as well total as for Open-Label Treated Population.  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
Previous Treatment and Concomitant Medications
Prior and concomitant medications will be summarized by treatment group sequence 
(defined in Section 9.1) as well as total for Open-Label Treated Population.  A prior 
 


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medication is defined as any medication taken prior to the first dose of study drug in the 
preceding RCT study.  This includes medications with a start date before the first study 
drug administration date, regardless of the end date of these medications.  Medications 
taken on the day of the first dose of study drug are not counted as prior medications.  A 
concomitant medication is defined as any medication, other than study drug, that started 
prior to the first dose of open-label study drug and continued to be taken after the first 
dose of open-label study drug or any medication that started after the first dose of open-
label study drug and within 1 day of the last dose of study drug.
The number and percentage of subjects who received a prior or 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 criteria 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
sequence (defined in Section 9.1) as well as overall for the Open-Label Treated 
Population.
7.0
Patient Disposition
The number of subjects treated, completed or discontinued in the open-label treatment 
period will be summarized by treatment group sequence (defined in Section 9.1) as well 
as overall for the Open-Label Treated Population.  The number of subjects discontinuing 
 


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from the open-label treatment period will also be summarized with the reasons for 
discontinuation collected from CRF by the following categories:
●
Adverse event
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy
●
Subject non-compliance
●
Requires alternative (or prohibited) therapy
●
COVID-19 infection
●
COVID-19 logistical restrictions
●
Other
8.0
Study Drug Exposure and Compliance
8.1
Study Drug Exposure
The duration of exposure to study drug in M13-538 will be summarized for the Open-
Label Treated Population by the following groups:
1.
Upadacitinib 6 mg BID/15 mg QD
This includes upadacitinib 6 mg BID or 15 mg QD exposure from subjects who 
never titrated, as well as the upadacitinib 6 mg BID or 15 mg QD exposure prior 
to dose titration for subjects who titrated (censored at the time of up titration to 
12 mg BID/30 mg QD).
2.
Upadacitinib 12 mg BID/30 mg QD
This includes upadacitinib 12 mg BID or 30 mg QD exposure for subjects who 
titrated up (censored at the time of down titration to 6 mg BID/15 mg QD for 
subjects who titrated up and back down).
 


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3.
Upadacitinib 6 mg BID/15 mg QD post down titration
This includes upadacitinib 6 mg BID/15 mg QD exposure after down titration for 
subjects who titrated up and back down.
4.
Any upadacitinib 
This includes any upadacitinib exposure in Study M13-538.
The first three exposure groups are mutually exclusive in terms of exposure, and the three
groups combined is represented by the fourth group.
The duration of exposure to study drug will be summarized for each exposure 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.
Open-label exposure:
●
≥ 6 months
●
≥ 12 months
●
≥ 18 months
●
≥ 2 years
●
≥ 2.5 years
●
≥ 3 years
●
≥ 4 years
●
≥ 5 years
8.2
Compliance
Study drug compliance (TC) will summarized for the Open-Label Treated Population.  
The treatment compliance is defined as the number of capsules/tablets taken (i.e., the 
difference between the number of capsules/tablets dispensed and the number of 
 


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capsules/tablets returned) during the subject's participation in the open-label treatment 
period divided by the number of capsules/tablets planned to be taken by the subject during 
the open-label treatment period of the study.  In Study M13-538, subjects will switch from 
twice-daily formulation (capsules) to once-daily formulation (tablets).  The impact of 
missing a once-daily tablet should be weighted twice as much as that for a twice-daily 
capsule.  Specifically, TC will be calculated using the following formula:
%
100
2
)
drug
study 
label
open 
of
dose
last 
first to
from
days
of
(Number 
2
 taken
ets
daily tabl
once
of
number 
 taken 
capsules
daily 
 twice
of
number 





TC
9.0
Efficacy Analysis
9.1
General Considerations
Long-term efficacy analysis will be performed on the Open-Label Treated Population by 
the treatment group sequences as defined below:
1.
Upadacitinib never titrated (6 mg BID/15 mg QD),
2.
Upadacitinib titrated up and not down (6 mg BID/15 mg QD to 12 mg BID/30 mg 
QD), and
3.
Upadacitinib titrated up and down (6 mg BID/15 mg QD to 12 mg BID/30 QD and 
then back down to 6 mg BID/15 mg QD).
No statistical tests will be conducted; only descriptive statistics and confidence intervals 
will be provided. All data will be summarized based on As Observed data (defined in 
Section 9.1.1).
9.1.1
Definition of Missing Data Imputation
As Observed (AO)
The AO analysis will not impute values for missing evaluations.  All observed data will 
be used in the analysis.  The AO analysis will be applied to long-term efficacy analysis.
 


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Mixed Model Repeated Measures (MMRM) and Generalized Linear Mixed Model 
(GLMM) 
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. Prior RCT study will 
also be included as a fixed factor in the model. 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 included in the model as appropriate.  Unstructured, Toeplitz, compound 
symmetry, or other covariance structures may be considered.
9.2
Long-Term Efficacy Analysis
Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96 and every 12 weeks until Week 312.
●
ACR20/50/70 response rates;
●
Change from baseline in individual ACR components;
●
Change from baseline in DAS28 (CRP);
●
Change from baseline in CDAI and SDAI;
●
Proportion of subjects achieving LDA and proportion of subjects achieving CR 
based on DAS28 (CRP), CDAI and SDAI criteria;
●
Change from baseline in Patient Reported Outcomes, including FACIT-Fatigue 
Scale, RA-WIS, and EQ-5D;
Analyses will be based on As Observed (AO) data.  Descriptive statistics will be provided 
for each treatment group sequence in the Open-Label Treated Population as defined in
Section 9.1.  These include the number of observations, mean, standard deviation, and 
95% CI for continuous endpoints; and frequencies and percentages with 95% CI using 
normal approximation for binary endpoints.  In addition, longitudinal analysis will be 
 


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performed using MMRM or GLMM as described in Section 9.1.1 for all endpoints for
treatment sequences 1 and 2.  Point estimates and 95% CI from the model will be 
provided.  Plots over time will be provided.
Table 1 below provides the overview of the long-term efficacy analysis to be performed 
on different endpoints.
Table 2.
Summary of Long-Term Efficacy Analysis
Measure of Interest
Analysis Method
Binary endpoints:

ACR20 at each visit

ACR50 at each visit

ACR70 at each visit

LDA based on DAS28 (CRP) at each visit

LDA based on CDAI and SDAI at each visit

CR based on DAS28 (CRP) at each visit

CR based on CDAI and SDAI at each visit

Point estimate and 95% CI of the 
response rate for each treatment 
sequence

Point estimate and 95% CI of the 
response rate using GLMM model for 
treatment sequences 1 and 2

Plots over time (for ACR responses 
and LDA/CR based on DAS28 and 
CDAI)

Imputation: AO

Population:  open-label treated 
population
Continuous endpoints:

Change from baseline for DAS28 (CRP) at each 
visit

Change from baseline for CDAI and SDAI at each 
visit

Change from baseline for each ACR individual 
component (i.e., TJC, SJC, Physician's Global 
Assessment of Disease Activity, Patient's Global 
Assessment of Disease Activity, Patient's 
Assessment of Pain, HAQ-DI, hsCRP) at each 
visit

Change from baseline for other PROs (FACIT, 
RA-WIS, EQ-5D) at each visit

Point estimate and 95% CI of mean 
change from baseline for each 
treatment sequence together with SD 

Point estimate and 95% CI of change 
from baseline using MMRM model 
for treatment sequences 1 and 2

Plots over time (for DAS28 (CRP), 
CDAI and SDAI)

Imputation: AO

Population:  open-label treated 
population
9.3
Handling of Multiplicity
There is no statistical testing, and therefore multiplicity adjustment is not applicable.
 


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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 and US FDA to evaluate the effectiveness of 
investigational drug in RA clinical trials.  It is a composite measurement calculated based 
on the improvement over a set of core measurements.
ACR20 is defined as at least 20% improvement (compared to baseline values) in tender 
and swollen joint counts and at least 20% improvement in 3 of the remaining 
5 core set measures (subject global assessment of pain, subject global assessment of 
disease activity, physician global assessment of disease activity, subject assessment of 
physical function and acute phase reactant hsCRP).
ACR50 and ACR70 are similarly defined with at least 50% and 70% improvement, 
respectively.
A subject will be classified as an ACR20 (ACR50, ACR70) responder, if the following 
conditions are met:
1.
≥20 % (50%, 70%) improvement from baseline in tender joint count (TJC68) and
2.
≥20 % (50%, 70%) improvement from baseline in swollen joint count (SJC66) and
3.
≥20% (50%, 70%) improvement from baseline in at least 3 of the following 5:
●
Patient's assessment of pain
●
Patient's global assessment of disease activity (PGA)
●
physician's global assessment of disease activity (PhGA)
●
patient's self-assessment of physical function (i.e., measured by Health 
Assessment Questionnaire (HAQ-DI score)
●
Acute-phase reactant value hsCRP/ESR
The following table illustrates examples for As Observed ACR calculations.
 


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Example
TJC 
68
SJC 
66
Component 
1
Component 
2
Component 
3
Component 
4
Component 
5
ACR20-
Response?
A
1
1
1
1
1
.
.
Yes
B
1
0
1
1
1
1
1
No
C
.
0
.
.
.
.
.
No
D
1
.
1
1
1
1
1
.
E
1
1
0
0
0
1
1
No
F
.
.
0
0
0
.
.
No
G
1
1
1
1
0
0
.
.
Legend:  1 = ≥ 20% improved compared to baseline; 0 = < 20% improved compared to baseline; "." Missing
Windowing Rule for ACR Response Calculation:
●
ACR component values will first be determined at each date within a visit 
window.
●
ACR component values at each date will be combined to determine the 
observed ACR composite score at each date in each window.
●
After this calculation, if multiple non-missing ACR composite scores are 
available within a given visit window, the non-missing ACR composite score 
closest to the target day will be used.  If two composite scores have the same 
distance from the target day, the later one will be used.  The corresponding date 
will be used as the observed ACR response date in the derived efficacy dataset.
●
If a non-missing ACR composite score is not available for any day within a 
given visit window, the windowed component values for that visit will be used 
to calculate the ACR composite score for that visit window (component value 
windowing follow the same rules as in steps described above).  The date of 
observed ACR composite score will be determined by the first available ACR 
component date, in the order of TJC, SJC, Pain, PGA, PhGA, HAQ-DI, 
CRP/ESR, in the derived efficacy dataset.
9.4.2
Joint Evaluation
Anatomical joints are evaluated for swelling and tenderness at every study visit.  The 
34 anatomical joints in Table 3 are assessed in this study for both the left and right side of 
the body.
 


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Table 3.
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" 
thus collected and no penalty will be considered for the joints not assessed or those which 
have been replaced.  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 Based on CRP (DAS28 [CRP])
DAS28 (CRP) is a composite index to assess disease activity in RA patients using hsCRP 
measurement.  The DAS provides a score between 0 and 10, indicating how active the 
rheumatoid arthritis is at the time of measurement.
It 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).
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.
#
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.
TJC28 and SJC28 represent total tender joint count and total swollen joint count, 
respectively, based on the 28 joints (including the left and right side of the body) listed in 
the table below.
 


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Table 4.
Anatomical Joints for DAS28 (CRP) Calculation
Shoulder
Elbow
Wrist
Thumb Interphalangeal
Metacarpophalangeal I
Metacarpophalangeal II
Metacarpophalangeal III
Metacarpophalangeal IV
Metacarpophalangeal V
Proximal Interphalangeal 
II hand
Proximal Interphalangeal 
III hand
Proximal Interphalangeal 
IV hand
Proximal Interphalangeal 
V hand
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 DAS28 formula.  If 
any observed component is missing in a window, then the observed DAS28 score will be 
missing.
9.4.7
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).
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.
9.4.8
Simplified Disease Activity Index (SDAI)
SDAI is a composite continuous index to assess disease activity based on TJC28, SJC28, 
Patient's Global Assessment of Disease Activity (PtGA) (in cm, 0 – 10), Physician's 
 


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Global Assessment of Disease Activity (PhGA) (in cm, 0 – 10) and hsCRP (mg/dL).  It 
can be derived as follows:
SDAI = TJC28 + SJC28 + PtGA (cm) + PhGA (cm) + hsCRP (mg/dL).
To calculate observed SDAI scores, the observed component value will be calculated first.  
Then the components will be included in the calculation per the SDAI formula selected.  
If any observed component is missing in a window, then the observed SDAI score will be 
missing.
9.4.9
Clinical Remission (CR) and Low Disease Activity (LDA)
Clinical remission (CR) and low disease activity (LDA) based on DAS28 (CRP) and 
CDAI are defined as follows:
Disease Status
DAS28 [CRP]
CDAI
LDA
≤ 3.2
≤ 10
CR
< 2.6
≤ 2.8
9.4.10
Disability Index of Health Assessment Questionnaire 
(HAQ-DI)
HAQ-DI is a self-reported patient outcome measurement.  It is calculated as the mean of 
the scores from 8 following categories with a range 0 – 3:  Dressing and Grooming, 
Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities.  The higher the score, the 
more likely to associate with morbidity and mortality for the RA patient.
The maximum score for all the questions in each category is considered as the score for 
the category.  The Standard disability index (HAQ DI) takes into account the subject's use 
of aids or devices or assistance in the scoring algorithm for a disability category.  For each 
of the eight disability categories these 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 
 


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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.
Minimum clinically important difference in HAQ-DI is defined as change from Baseline 
≤–0.22.
9.4.11
Functional Assessment of Chronic Illness Therapy
(FACIT) – Fatigue Scale
Fatigue is one of the most frequent complaints of individuals with RA and is strongly 
associated with loss of independence, decreased physical activity and functional decline.  
One validated tool to measure fatigue is the FACIT Fatigue scale v4.  The FACIT Fatigue 
Scale is a short, 13-item, easy to administer tool that measures an individual's level of 
fatigue during their usual daily activities over the past week.  The level of fatigue is 
measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued).  
The Fatigue scale is ranged from 0 to 52 and the higher the score, the better the quality of 
life.
Item score for each item is calculated by either subtracting from 4 or adding 0 depending 
on whether it is a reversal item or not.  FACIT Fatigue Scale is then calculated by adding 
up all item scores, multiplying by 13 and dividing by the number of items answered.  It is 
essentially a prorated subscale if there are missing values for some items.  If less than or
equal to 50% of the items are answered (e.g., 6 out of 13), the proration is not acceptable 
and the scale will not be computed.  Detailed calculation and missing value handling are 
documented in Appendix A.
9.4.12
Work Instability Scale for RA (RA-WIS)
The 23-item RA-WIS is a simple validated tool to evaluate Work Instability (the 
consequence of a mis-match between an individual's functional ability and their work 
tasks).  It can be self-administered by the patients.  To calculate the RA-WIS score, 
 


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one can simply add up the number of "true" responses.  The RA-WIS can be scored in 
three bands indicating low (< 10), medium (10 – 17), and high (> 17) risk of work 
disability.  The state of 'mismatch' between functional incapacity and work demands can 
threaten continuing employment if not resolved.
9.4.13
EuroQoL-5D (EQ-5D)
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.  The details of conversion and missing data handling can be found in EQ-5D 
manual (Appendix B).  UK scoring algorithm will be used.
10.0
Safety Analysis
10.1
General Considerations
Safety analyses will include reporting of adverse events, laboratory, and vital signs 
measurements in open-label treatment period only.  Safety analyses will be carried out 
using the Open-Label Treated Population, which includes all subjects who received at 
least one dose of open-label study medication.
Long-term safety analyses include reporting of AE rate adjusted by cumulative exposure, 
mean change from baseline in laboratory parameters and vital sign variables, and 
frequency of potentially clinically significant laboratory and vital signs values.
 


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The treatment-emergent adverse event (TEAE) rate per 100 patient-years of exposure will 
be presented by the exposure groups defined in Section 8.1, namely
1.
Upadacitinib 6 mg BID/15 mg QD
2.
Upadacitinib 12 mg BID/30 mg QD 
3.
Upadacitinib 6 mg BID/15 mg QD post down titration
4.
Any upadacitinib
Listing of subjects with TEAEs by SOC and PT will be provided.  Frequency tables and 
listings of subjects meeting criteria for potentially clinically significant vital sign values 
and for potentially clinically significant laboratory values will be provided by the 
exposure groups defined in Section 8.1.
Mean changes from baseline in all continuous laboratory parameters and vital signs 
variables at each visit will be summarized by the treatment group sequences defined in 
Section 9.1, namely
1.
Upadacitinib never titrated (6 mg BID/15 mg QD),
2.
Upadacitinib titrated up and not down (6 mg BID/15 mg QD to 12 mg BID/30 mg 
QD), and
3.
Upadacitinib titrated up and down (6 mg BID/15 mg QD to 12 mg BID/30 QD and 
then back down to 6 mg BID/15 mg QD).
10.2
Analysis of Adverse Events
A treatment-emergent Adverse Event (TEAE) is defined as an adverse event with an onset 
date that is on or after the first dose of open-label study drug, and no more than 30 days 
after the last dose of open-label study drug; or an adverse event with onset date before the 
first dose of open-label study drug, but increased in severity on or after the first dose of 
 


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open-label study drug, and no more than 30 days after the last dose of open-label study 
drug.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent.  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 open-label study drug start date).
Adverse event data will be presented by system organ classes (SOCs) and preferred terms 
(PTs) using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 
version 19.0 or most up to date version.  All adverse event tables will be sorted in 
alphabetical order by SOC and PT and descending percentages in the Any upadacitinib 
group.
10.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure
The number and percentage of subjects experiencing TEAEs will be summarized for each 
exposure group in the open-label treated population 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
●
All death
For this calculation, 1 year will be considered to be 365.25 days. For each exposure
group, the numerator of the overall rate will be the total number of TEAEs reported for 
 


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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 8.1 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 exposure group.
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.
10.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by System Organ Class and Preferred Term
the TEAE rate per 100 patient-years of exposure will be tabulated by SOC and MedDRA 
PT for each exposure group in the open-label treated population.  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
●
Frequent TEAEs (reported at ≥ 2 E/100PYin any exposure group)
●
TEAEs leading to discontinuation of study drug
●
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10.2.3
Serious Adverse Events (Including Deaths) and Adverse 
Events Leading to Study Drug Discontinuation Rates per 
100 Patient-Years of Study Drug Exposure
All serious adverse events (SAEs), deaths, and adverse events leading to discontinuation 
of study drug will be summarized by SOC and PT or each exposure group.
10.2.4
Frequent Adverse Events by System Organ Class and 
Preferred Term
TEAEs occurring at ≥ 2 E/100PY in any of the exposure groups will be summarized by 
MedDRA PT in decreasing rate.
10.2.5
Adverse Events of Special Interests Rates per 100 Patient-
Years of Study Drug Exposure
The Adverse Events of Special Interests (AESI) categories will be summarized and 
presented for each exposure group using SOC and MedDRA PT. The AESI categories 
will be identified per Standard MedDRA Queries (SMQs)/Company MedDRA Queries 
(CMQs) in Table 5 below. Adjudicated cardiovascular events will be summarized and 
presented by treatment groups using CAC adjudicated categories.
 


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Table 5.
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 5.
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.
10.2.6
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 6.
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  
Reticulocytes
Bands
Chemistry
Total Bilirubin
Alkaline Phosphatase (ALP)
Serum glutamic oxaloacetic transaminase (SGOT/AST)
Serum glutamic pyruvic transaminase (SGPT/ALT)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Uric acid
 


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Table 6.
List of Laboratory Variables (Continued)
Laboratory Variables
Chemistry (Continued)
Sodium
Potassium
Calcium
Inorganic Phosphorus
Creatine Phosphokinase (CPK)
Chloride
Bicarbonate
Cholesterol
LDL cholesterol
HDL cholesterol
Urinalysis
Specific Gravity
pH
Protein
Glucose  
Ketones
Blood
Microscopic Examination
Immunologic Laboratory Assessments
Rheumatoid Factor (RF)
Anti-CCP antibody
Advanced Lipid Panel
Apo A1
Apo B
Other 
hSCRP
HBs Ab
HBc Ab
Hbs Ag
 


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Table 6.
List of Laboratory Variables (Continued)
Laboratory Variables
Other (Continued)
HBV DNA PCR reflex only
HCV Ab
HCV RNA reflex only
QuantiFERON-TB Gold
10.3.2
Assessment of Mean Change from Baseline in Clinical 
Laboratory Values
Analyses of mean change from baseline in continuous hematology, chemistry, and 
urinalysis variables which are measured longitudinally will be performed by visits and by 
treatment group.  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.
10.3.3
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 treatment sequence:
●
Category of the baseline value versus category of the final value.
●
Category of the baseline value versus maximum 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.
10.3.4
Potentially Clinically 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, creatinine, and 
parameters that are not covered in the OMERACT criteria, NCI CTC criteria will instead 
be used.  For laboratory parameters where values available, a listing of all subjects with 
any laboratory determination during each period meeting OMERACT criteria of Grade 3 
or 4 will be provided by Grade.  For each of these subjects, the whole course of the 
respective parameter will be listed.
10.3.5
Analyses for 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 exposure group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
 


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40
●
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
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 and Weight
10.4.1
Variables and Criteria Defining Abnormality
Vital sign variables include sitting systolic blood pressure, sitting diastolic blood pressure, 
pulse, body temperature, and weight.  The criteria for potentially clinically significant 
vital sign findings are presented in Table 7.
Table 7.
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
 


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10.4.2
Analysis of Long-Term Vital Signs
Mean changes from Baseline to post-baseline visits will be summarized with the baseline 
mean, the visit mean, change from baseline mean, standard deviation, and median.  The 
number and percentage of subjects meeting the criteria for potentially clinically 
significant vital sign values will be summarized.
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
Version 
Number
Date
Description of Revision
1.0
15 July 2015
Original Version
2.0
25 October 2016
This version of SAP includes the changes summarized below:
Section 4.2 – Design Diagram

Update the length of study from 96 week to 264 week and the 
actual number of subjects participating in the study.

Update the information on switching to once-daily tablet 
formulation.
Section 4.3 (in version 1.0) – Sample Size

Delete the section because it does not provide useful 
information.
Section 4.3 – Interim Analysis

Remove the part of the description of efficacy/safety analysis 
that is no longer applicable to our updated analysis scheme.

Change the title to Interim Analysis because the section only 
contains information on interim analysis.
Section 5.1 – Open-Label Treated Population

Change the wording for three treatment groups in open-label 
treated population to make them it clear.

Include the information on the use of as randomized 
open-label treated population for supportive efficacy analysis 
up to Week 24.
Section 6.1 – Demographic and Baseline Characteristics

Include information to clarify that baseline is calculated at the 
baseline visit of the preceding RCT studies.

Include geographic region for demographic characteristics.

Include duration of prior DMARDs used (for Study M13-537 
subjects), number of mechanisms of action for prior biologic 
DMARD(s) used (for Study M13-550 subjects).
Section 6.3 – Previous Treatment and Concomitant Medications

Change the definition of prior medication to be any 
medication taken prior to the first dose of open-label study 
drug.
 


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Version 
Number
Date
Description of Revision
Section 8.1 – Study Drug exposure

Change the duration intervals from exclusive to cumulative.

Delete the part for the calculation of study drug exposure 
based on double-blind and open-label periods combined.
Section 8.2 – Compliance

Change the definition of treatment compliance to account for 
the fact of switching to once-daily formulation.
Section 9.1 – General Considerations

Update the analysis scheme to include a long term efficacy 
analysis as the main analysis, which is based on the open-
label treated population.

Update the analysis scheme to include a supportive efficacy 
analysis up to Week 24, which is based on the as randomized 
open-label treated population and a subset of most important 
endpoints.
Section 9.2 (in Version 1.0) – Exploratory Efficacy Variables

Delete the section because it is redundant.
Section 9.2 – Handling of Multiplicity

Add information to clarify why handling of multiplicity is not 
needed.
Section 9.4 – Efficacy Variables Definitions and Conventions

Include the suggestion of the use of the corresponding 
programming specification for details on the computation of 
composite endpoints.

Add a subsection for Joint Evaluation.

Add a subsection for Patient's Global Assessment of Disease 
Activity Visual Analog Scale (VAS).

Add a subsection for Physician's Global Assessment of 
Disease Activity Visual Analog Scale (VAS).

Add a subsection for Patient's Global Assessment of Pain.

Add a subsection for Simplified Disease Activity Index 
(SDAI).

Delete the subsection for SF-36.
Section 9.4.1 – ACR Criteria

Remove the detailed instructions for the computation of ACR 
and relocate them into the programming specification.
Section 9.4.9 – Low Disease Activity

Change the Criterion for LDA base on DAS28 (CRP) to be 
2.6 ≤DAS28 (CRP) ≤ 3.2.
 


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Version 
Number
Date
Description of Revision
Section 10 – Safety Analysis

Remove the language involving statistical testing 
(i.e., ANCOVA, Fisher's exact test) because it is not 
meaningful to compare treatment groups in open-label treated 
population.

Update MedDRA version to 19.0.

Add the phrase "in open-label treated population" in multiple 
places to clarify the population on which analysis will be 
performed.
Section 10.2 – Analysis of Adverse Events

Remove the part for summarizing SAEs collected between 
the signing of the informed consent and the first dose.
Section 10.2.1.1 – Adverse Event Overview

Delete the description regarding how to handle unknown 
severity.
Section 10.2.1.2 – Adverse Events by System Organ Class and 
Preferred Term

Update the language according to the current Immunology 
convention.
Section 10.2.1.3 – Adverse Events by Maximum Severity

Change "Select TEAEs" to "TEAEs."
Section 10.2.1.4 – Adverse Events by Maximum Relationship

Update the language regarding TEAE summarization to be 
"TEAEs will be summarized by maximum relationship to 
ABT-494 only."

Change "probably related or possibly related" to "Reasonable 
Possibility."
Section 10.2.1.5 (in version 1.0) – Adverse Events by "Reasonably 
Possibly Related" Relationship

Delete the section due to redundancy.
Section 10.2.1.7 – Adverse Events of Special Interests

Update the list for summarizing AESI.
Section 10.2.1.8 – Adverse Events by 100 Patient Years

Include information on summarizing AESI.
Section 10.3.2.4 – Potentially Clinically Significant Laboratory Values

Add NCI CTC criteria for parameters not covered in the 
OMERACT criteria.
 


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Version 
Number
Date
Description of Revision
Section 10.4.1 – Variables and Criteria Defining Abnormality

Update the table "Criteria for Potentially Clinically 
Significant Vital Sign Findings" according to the current 
Immunology convention.
3.0
03 May 2021
This version of SAP includes the changes summarized below:
Section 3.0 – Introduction

Remove disease background to align with phase 3 standards.
Section 4.2 – Overall Study Design and Plan

Update the length of study from 264 weeks to 312 weeks.

Include details of Amendment 5 providing the option to 
decrease dose to 15 mg QD.

Add clarification that follow-up visit is available after 
completion of OLE last visit or after PD visit.
Section 4.3 – Data Monitoring Committee (DMC) Activities

Include to align with phase 3 standards.
Section 5.1 – Analysis Populations

Remove treatment group sequences and relocate to efficacy 
analysis.

Remove As Randomized Open-Label Treated Population.
Section 5.2 – Definition of Baseline

Add clarification that RCT baseline will be used for both 
efficacy and safety analysis.
Section 5.3 – Analysis Windows

Include to align with phase 3 standards.
Section 5.3 (in Version 2.0) – Variables Used for Stratification of 
Randomization

Remove since it is not needed for this study.
Section 5.4 (in Version 2.0) – Subgroups Definition

Remove since it is not needed for this study.
Section 6.1 – Demographics and Baseline Characteristics

Update to align with phase 3 standards where applicable.
Section 6.3 – Prior medication

Update to define prior medication as any medication prior to 
the first dose of preceding RCT study.

Update language to align with phase 3 standards.
Section 6.4 – Protocol Deviations

Include to align with phase 3 standards.
Section 7.0 – Patient Disposition
 


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Version 
Number
Date
Description of Revision

Add Other category in reasons for discontinuation.
Section 8.1 – Study Drug Exposure

Add exposure groups for the Open-Label Treated Population.

Update duration of exposure to utilize exposure group rather 
than treatment sequence group.
Section 9.1 – Efficacy Analysis General Considerations

Remove Supportive Efficacy Analysis Up to Week 24.

Add treatment group sequences relocated from analysis 
population.
Section 9.1.1 – Definition of Missing Data Imputation

Add to describe imputation for MMRM and GLMM models.
Section 9.2 – Long-Term Efficacy Analysis

Add to elaborate on long-term efficacy analysis.

Update assessments after Week 96 to occur every 12 weeks 
to be consistent with data collection.

Add proportion of subjects achieving SDAI criteria as 
reported measurement.

Add long-term longitudinal analysis performed using 
MMRM or GLMM performed only for treatment sequences 1 
and 2.

Update Table 2 according to above changes.
Section 9.3 (in Version 2.0) – Efficacy Subgroup Analysis

Remove since it is not needed for this study.
Section 9.3.1 – ACR Criteria

Add definition of ACR20, ACR50, and ACR70 along with 
illustrated example

Add windowing rule for ACR response calculation.
Section 9.3.6 – Disease Activity Score Based on CRP (DAS28[CRP])

Update formula to provide descriptive footnotes.

Add description of Observed DAS28 score calculation.
Section 9.3.7 – Clinical Disease Activity Index (CDAI)

Add description of Observed CDAI score calculation.
Section 9.3.8 – Simplified Disease Activity Index (SDAI)

Add description of Observed SDAI score calculation.
Section 9.3.9 – Clinical Remission (CR) and Low Disease Activity 
(LDA)

Replace Section 9.4.9 (in Version 2.0) and Section 9.4.10 (in 
Version 2.0) with table of definitions.
Section 10.1 – Safety Analysis General Considerations
 


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Version 
Number
Date
Description of Revision

Change the AE summary to be presented by the added 
exposure groups.

Add clarification that the laboratory value analysis will be 
presented by treatment sequence groups.
Section 10.2.1 – Adverse Event Rates per 100 Patient-Years

Change the TEAE summary to be presented by the added 
exposure groups.

Remove Frequent TEAE categories.
Section 10.2.1 – Adverse Event Rates per 100 Patient-Years

Change the TEAE by SOC and MedDRA PT summary to be 
presented by the added exposure groups.

Redefine Frequent TEAE category to greater-than or equal-to 
2 events per 100 patient-years.

Remove Frequent TEAE reasonably possibly related to study 
drug category.
Section 10.2.3 (in Version 2.0) – TEAEs by Maximum Severity

Delete since this is not reported for long-term.
Section 10.2.4 (in Version 2.0) – TEAEs by Maximum Relationship

Delete since this is not reported for long-term.
Section 10.2.3 – Serious Adverse Events and Adverse Events Leading 
to Study Drug Discontinuation

Change the SAE, deaths, and adverse events leading to study 
drug discontinuation summary to be presented by the added 
exposure groups.
Section 10.2.4 – Frequent AE by SOC and MedDRA PT

Redefine Frequent TEAEs to greater-than or equal-to 2 
events per 100 patient-years.
Section 10.2.5 – Safety Analysis General Considerations

Change the AESI summary to be presented by exposure 
groups.
Section 10.3.3 – Assessment of Shift from Baseline in Clinical 
Laboratory Variables

Update shift from baseline analysis to align with phase 3 
standards where applicable.
Section 10.5 (in Version 2.0) – Analysis of ECG Parameters

Delete due to redundancy with baseline characteristics.
Appendix D – Statistical Analysis to Account for Impact of COVID-
19 Pandemic
 


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Version 
Number
Date
Description of Revision

Add detail of additional patient disposition summaries and 
long-term data handling required to account for impact of 
COVID-19
12.0
Appendix
Appendix A
FACIT-Fatigue Scale Calculation
Appendix B
EQ5D-5L Manual
Appendix C
OMERACT Criteria
Appendix D
Statistical Analysis to Account for Impact of COVID-19 Pandemic
 


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Appendix A.
FACIT-Fatigue Scale Calculation
FACIT-Fatigue Subscale Scoring Guidelines (Version 4)
Instructions:*
1.
Record answers in "item response" column.  If missing, mark with an X.
2.
Perform reversals as indicated, and sum individual items to obtain a score.
3.
Multiply the sum of the item scores by the number of items in the subscale, then 
divide by the number of items answered.  This produces the subscale score.
4.
The higher the score, the better the QOL.
Subscale
Item Code
Reverse Item?
Item Response
Item Score
FATIGUE
HI7
4
-
________
=
________
SUBSCALE
HI12
4
-
________
=
________
An1
4
-
________
=
________
An2
4
-
________
=
________
An3
4
-
________
=
________
An4
4
-
________
=
________
Score range:  0 – 52
An5
0
+
________
=
________
An7
0
+
________
=
________
An8
4
-
________
=
________
An12
4
-
________
=
________
An14
4
-
________
=
________
An15
4
-
________
=
________
An16
4
-
________
=
________
Sum individual item scores:  ________
Multiply by 13:  ________
Divide by number of items answered:  ________ = Fatigue
 


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Subscale Score
Handling missing items.  If there are missing items, subscale scores can be prorated.  This 
is done by multiplying the sum of the subscale by the number of items in the subscale, 
then dividing by the number of items actually answered.  This can be done on the scoring 
guide or by using the formula below:
Prorated subscale score = [Sum of item scores] × [N of items in subscale]÷ 
[N of items answered]
 


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Appendix B.
EQ5D-5L Manual
Please refer
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/
UserGuide_EQ-5D-5L_v2.0_October_2013.pdf.
 


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


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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 Antirheumatic Therapies
A.  Allergic/Immunologic (Continued)
A4.  Serum sickness
Transient, non-prescription meds 
relieve
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Prolonged; symptoms only partially 
relieved by meds; parenteral 
corticosteroids required
Major organ dysfunction, requires 
long-term high-dose 
immunosuppressive therapy
A5.  Vasculitis
Localised, not requiring 
treatment; or rapid response to 
meds; cutaneous
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Generalised, parenteral 
corticosteroids required or/and short 
duration hospitalisation
Prolonged, hospitalisation, 
ischemic changes, amputation
B.  Cardiac
B1.  Arrhythmia
Transient, asymptomatic
Transient, but symptomatic or 
recurrent, responds to meds
Recurrent/persistent; maintenance 
prescription
Unstable, hospitalisation required, 
parenteral meds
B2.  Cardiac function 
decreased
Asymptomatic decline in resting 
ejection fraction by > 10%, but 
< 20% of baseline value
Asymptomatic decline of resting 
ejection fraction ≥ 20% of 
baseline value
CHF responsive to treatment
Severe or refractory CHF
B3.  Edema
Asymptomatic
(e.g., 1 + feet/calves), 
self-limited, no therapy required
Symptomatic
(e.g., 2 + feet/calves), requires 
therapy
Symptoms limiting function 
(e.g., 3 + feet/calves, 2 + thighs), 
partial relief with treatment 
prolonged
Anasarca; no response to 
treatment
B4.  Hypertension (new 
onset or worsening)
Asymptomatic, transient increase 
by > 20 mmHg (diastolic) or to 
> 150/100 if previously normal, 
no therapy required
Recurrent or persistent increase 
> 150/100 or by > 10 mmHg 
(diastolic), requiring and 
responding readily to treatment
Symptomatic increase > 150/100, 
> 20 mmHg, persistent, requiring 
multi agency therapy, difficult to 
control
Hypertensive crisis
B5.  Hypotension 
(without underlying 
diagnosis)
Transient, interOpen-label 
treatedent, 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
 


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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 Antirheumatic Therapies
B.  Cardiac (Continued)
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 
interOpen-label treatedently 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 interOpen-label 
treatedent, 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
 


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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 Antirheumatic Therapies
C.  General (Constitutional) (Continued)
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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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
D.  Dermatologic (Continued)
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, interOpen-label 
treatedent, 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
InterOpen-label treatedent, 
transient, no interference with 
function
Requires treatment, reversible
Disabling, or associated with 
hearing loss
Irreversible deafness
 


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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 Antirheumatic Therapies
E.  Ear/Nose/Throat (Continued)
E6.  Voice changes 
(includes hoarseness, 
loss of voice, laryngitis)
InterOpen-label treatedent 
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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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
F.  Eye/Ophthalmologic (Continued)
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, interOpen-label 
treatedent, 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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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
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, interOpen-label 
treatedent, 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, 
interOpen-label treatedent
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 
interOpen-label treatedent, 
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
InterOpen-label treatedent 
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, interOpen-label 
treatedent, 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
 


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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 Antirheumatic Therapies
H.  Musculoskeletal (Continued)
H4.  Myalgia
Occasional; does not interfere 
with function
Frequent, requires meds 
(non-narcotic); minor effects on 
function
Major change in function/lifestyle, 
narcotic pain meds
Debilitating, profound weakness, 
requires wheelchair, unresponsive 
to meds
I.  Neuropsychiatric
I1.  Anxiety or 
Depression (mood 
alteration)
Symptomatic, does not interfere 
with function; no meds
Frequent symptoms, responds to 
meds; interferes with ADL at 
times
Persistent, prolonged symptoms, 
partial or no response to meds, 
limits daily function
Suicidal ideation or danger to self
I2.  Cerebrovascular 
ischaemia
NA
Single transient ischaemic event, 
responsive to treatment
Recurrent transient ischaemic 
events
Cerebrovascular vascular accident 
with permanent disability
I3.  Cognitive 
disturbance
Subjective symptoms, transient, 
interOpen-label treatedent, 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, 
interOpen-label treatedent, 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 interOpen-label 
treatedent, 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
 


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Version 3.0 – 03 May 2021
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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 Antirheumatic Therapies
I.  Neuropsychiatric (Continued)
I8.  Peripheral motor 
neuropathy
Subjective or transient loss of 
deep tendon reflexes; function 
maintained
Objective weakness, persistent, no 
significant impairment of daily 
function
Objective weakness with substantial 
impairment of function
Paralysis
I9.  Peripheral sensory 
neuropathy (sensory 
disturbance)
Subjective symptoms without 
objective findings, transient, not 
interfering with function
Objective sensory loss, persistent, 
not interfering with function
Prolonged sensory loss or 
paraethesias interfering with 
function
NA
I10.  Seizure
NA
Recurrence of old seizures, 
controlled with adjustment of 
medication
Recurrence/exacerbation with 
partial response to medication
Recurrence not controlled, 
requiring hospitalization; new 
seizures
I11.  Vertigo (dizziness)
Subjective symptoms, transient, 
interOpen-label treatedent, 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, interOpen-label 
treatedent, 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, interOpen-label 
treatedent or recurring, interferes 
with exertional activities
Symptomatic during daily routine 
activities, interferes with function, 
treatment with interOpen-label 
treatedent nasal O2 relieves
Symptomatic at rest, debilitating, 
requires constant nasal O2
 


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


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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
L.  Chemistry
L1.  Hypercalcaemia 
(mg/dl)
1.1 × ULN – 11.5
11.6 – 12.5
12.6 – 13.5; or symptoms present
> 13.5; or associated coma
L2.  Hyperglycemia 
(mg/dl) Fasting
140 – 160
161 – 250
251 – 500
> 500, or associated with 
ketoacidosis
L3.  Hyperkalaemia 
(mmol/l)***
5.5 – 5.9
6.0 – 6.4
6.5 – 7.0 or any ECG change
> 7.0 or any arrhythmia
L5.  Hypocalcaemia 
(mg/dl)
0.9 × LLN – 7.8
7.7 – 7.0
6.9 – 6.5; or associated with 
symptoms
< 6.5 or occurrence of tetany
L6.  Hypoglycemia 
(mg/dl)
55 – 64 (no symptoms)
40 – 54 (or symptoms present)
30 – 39 (symptoms impair function)
< 30 or coma
L7.  Hyponatraemia 
(mmol/l)***
-
125 – 129
120 – 124
< 120
L8.  Hypokalaemia 
(mg/dl)
-
3.0 – 3.4
2.5 – 2.9
< 2.5
L9.  CPK (also if 
polymyositis-disease
1.2 – 1.9 × ULN
2.0 – 4.0 × ULN
4.0 × ULN with weakness but 
without life-threatening signs or 
symptoms
> 4.0 × ULN with signs or 
symptoms of rhabdomyolysis or 
life-threatening
L10.  Serum uric acid
1.2 – 1.6 × ULN
1.7 – 2.9 × ULN
3.0 – 5.0 × ULN or gout
NA
L11.  Creatinine (mg/dl)
1.1 – 1.3 × ULN
1.4* – 1.8 × ULN
1.9 – 3.0 × ULN
> 3.0 × ULN
L12.  SGOT (AST)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.1 – 8.0 × ULN
> 8.0 × ULN
L13.  SGPT (ALT)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.0 – 8.0 × ULN
> 8.0 × ULN
L14.  Alkaline 
phosphatase
1.1 – 1.5** × ULN
1.6 – 3.0 × ULN
3.0 – 5.0 × ULN
> 5.0 × ULN
 


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Version 3.0 – 03 May 2021
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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 Antirheumatic Therapies
Laboratory Data (Continued)
L.  Chemistry (Continued)
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
*
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 D.
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.
2.0
Patient Disposition
Patient disposition and reason for discontinuation will be summarized as described in 
Section 7.0.  For subjects who prematurely discontinued study drug, 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 described in Section 7.0.
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
 


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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 9.2, 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.
 


Upadacitinib
M13-538 – Statistical Analysis Plan; Prevnar 13® Vaccine Sub-Study
Version 2.0 – 06 March 2020
1
Statistical Analysis Plan for Study M13-538
Phase 2 Study, Multicenter, Open-Label Extension 
(OLE) Study in Rheumatoid Arthritis Subjects Who 
Have Completed a Preceding Phase 2 Randomized 
Controlled Trial (RCT) with Upadacitinib (ABT-494)
Prevnar 13® Vaccine Sub-Study
Date:  06 March 2020
Version 2.0
 


Upadacitinib
M13-538 – Statistical Analysis Plan; Prevnar 13® Vaccine Sub-Study
Version 2.0 – 06 March 2020
2
Table of Contents
1.0
Introduction .............................................................................4
2.0
Study Design and Objectives..................................................4
2.1
Objectives and Hypotheses ........................................................................4
2.2
Study Design Overview .............................................................................4
2.3
Treatment Assignment and Blinding .........................................................6
2.4
Sample Size Determination........................................................................6
3.0
Endpoints..................................................................................7
3.1
Primary Endpoint(s)...................................................................................7
3.2
Secondary Endpoint(s)...............................................................................7
3.3
Other Efficacy Endpoint(s)........................................................................7
3.4
Safety Endpoint(s) .....................................................................................7
4.0
Analysis Populations ...............................................................8
5.0
Subject Disposition..................................................................8
6.0
Study Drug Duration...............................................................8
7.0
Analysis Conventions ..............................................................8
8.0
Demographics, Baseline Characteristics, Medical 
History, and Concomitant Medications ................................9
8.1
Demographics and Baseline Characteristics............................................10
8.2
Medical History .......................................................................................10
8.3
Concomitant Medications ........................................................................10
9.0
Efficacy Analyses...................................................................11
9.1
General Considerations............................................................................11
9.2
Handling of Missing Data........................................................................11
9.3
Primary Efficacy Endpoint(s) and Analyses............................................11
9.3.1
Primary Efficacy Endpoint(s) ..................................................................11
9.3.2
Handling of Missing Data for the Primary Efficacy Endpoint(s)............11
9.3.3
Primary Efficacy Analysis .......................................................................11
9.3.4
Additional Analyses of the Primary Efficacy Endpoint(s) ......................12
9.4
Secondary Efficacy Analyses...................................................................12
9.4.1
Key Secondary Efficacy Analyses...........................................................12
9.4.2
Supportive Secondary Efficacy Analyses ................................................12
 


Upadacitinib
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Version 2.0 – 06 March 2020
3
9.5
Additional Efficacy Analyses ..................................................................12
9.6
Efficacy Subgroup Analyses....................................................................12
10.0
Safety Analyses ......................................................................13
10.1
General Considerations............................................................................13
10.2
Adverse Events ........................................................................................13
10.2.1
Treatment-Emergent Adverse Events ......................................................13
10.2.2
Adverse Event Overview .........................................................................13
10.2.3
Adverse Events by SOC and/or PT..........................................................14
10.2.4
Adverse Events per 100 Patient-Years of Exposure................................15
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................15
10.3
Analysis of Laboratory Data....................................................................15
10.4
Analysis of Vital Signs ............................................................................15
10.5
Safety Subgroup Analyses .......................................................................15
10.6
Other Safety Analyses..............................................................................16
11.0
Other Analyses.......................................................................16
12.0
Interim Analyses....................................................................16
12.1
Data Monitoring Committee....................................................................16
13.0
Overall Type-I Error Control ..............................................16
14.0
Summary of Changes ............................................................16
14.1
Summary of Changes between the Previous Version and the 
Current Version........................................................................................16
15.0
Version History......................................................................17
List of Tables
Table 1.
Visit Windows for Satisfactory Humoral Response, and anti-
pneumococcal antibody levels ...................................................................9
Table 2.
SAP Version History Summary...............................................................17
List of Figures
Figure 1.
Study Schematic.........................................................................................6
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for the Prevnar 13®
vaccine sub-study of upadacitinib Study M13-538 titled "Phase 2 Study, Multicenter, 
Open-Label Extension (OLE) Study in Rheumatoid Arthritis Subjects who have 
Completed a Preceding Phase 2 Randomized Controlled Trial (RCT) with Upadacitinib 
(ABT-494)."
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
The objective of this sub-study is to assess the impact of upadacitinib treatment (15 mg 
QD and 30 mg QD) with background MTX on immunological responses to Prevnar 13®
in RA patients. 
2.2
Study Design Overview
This sub-study will evaluate humoral immune response following Prevnar 13®
administration in RA subjects enrolled in the main Study M13-538 treated with either 
upadacitinib 15 mg QD or 30 mg QD on a stable dose of background MTX.  Immune 
response will be measured at three timepoints (pre-vaccination, 4 weeks post-vaccination, 
and 12 weeks post-vaccination).  Enrollment will continue until approximately 
150 subjects have been recruited to participate.
Subjects must be on a stable dose of:
 


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●
upadacitinib (15 mg QD or 30 mg QD as assigned in the main study) for a 
minimum of 4 weeks prior to the Vaccination visit and for at least 4 weeks 
afterwards.
●
background methotrexate for a minimum of 4 weeks prior to the Vaccination 
visit and for at least 4 weeks afterwards.
If subject is on corticosteroids, they must remain on a stable dose of ≤10 mg/day of 
prednisone or equivalent corticosteroid therapy for at least 4 weeks after the Vaccination 
visit.
At the Vaccination visit, subjects who have provided a written informed consent for the 
sub-study will be assessed for eligibility.  If eligible, blood samples for the measurement 
of pre-vaccination antibody titers will be collected, followed by administration of 
Prevnar 13® as per the local label prescribing requirements.  The criteria and procedures 
of the main study must still be adhered to in addition to those for the sub-study.
The schematic of the sub-study is shown in Figure 1.
 


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Figure 1.
Study Schematic
2.3
Treatment Assignment and Blinding
This is a sub-study of the open-label extension Study M13-538.  All eligible subjects will 
receive Prevnar 13®.
2.4
Sample Size Determination
A total sample size of approximately 150 subjects is planned for the sub-study, where 
approximately 100 subjects are expected to be on the upadacitinib 15 mg QD dose.  
Assuming a satisfactory humoral response rate of 60%, the planned sample size of 
approximately 100 subjects for upadacitinib 15 mg QD group will provide a margin of 
error of approximately 10% for this dose group when using a 95% confidence interval.
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  


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3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint is:
●
Proportion of subjects with satisfactory humoral response to Prevnar 13® at the
Week 4 visit of the sub-study (4 weeks post-vaccination).
Satisfactory humoral response to Prevnar 13® is defined as greater than or equal to 
(≥) 2 fold increase in antibody concentration from the vaccination baseline in at least 6 out 
of the 12 pneumococcal antigens (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F).
3.2
Secondary Endpoint(s)
The secondary endpoints are:
●
Proportion of subjects with satisfactory humoral response to Prevnar 13® at the 
Week 12 visit of the sub-study (12 weeks post-vaccination).
●
Geometric Mean Fold Rise (GMFR) of anti-pneumococcal antibody levels to 
each of the 12 pneumococcal antigens above vaccination baseline values at 
Week 4 and Week 12 of the sub-study.
3.3
Other Efficacy Endpoint(s)
Other endpoints:
●
Proportion of subjects with at least 2-fold increase in antibody concentration 
from the vaccination baseline in each of the 12 pneumococcal antigens at the 
Week 4 and Week 12 visit of the sub-study.
3.4
Safety Endpoint(s)
The safety endpoints will include Adverse events (AEs). 
 


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4.0
Analysis Populations
The Full Analysis Set (FAS) includes all subjects enrolled in the sub-study who received 
Prevnar 13® and received at least one dose of study drug (upadacitinib) after vaccination 
during the sub-study.  The FAS will be used for all baseline analyses and analyses of 
humoral response.
The Safety Analysis Set includes all subjects who received Prevnar 13® in the sub-study. 
5.0
Subject Disposition
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized (by upadacitinib treatment and 
overall):
●
Subjects who received Prevnar 13® vaccination (i.e., Safety Analysis Set)
●
Subjects in the FAS 
●
Subjects who completed the vaccine sub-study (defined as subjects who 
completed Week 12 visit of the sub-study)
For subjects who discontinued upadacitinib during the first 4 weeks of the vaccine sub-
study, the reasons for discontinuation will be summarized. 
6.0
Study Drug Duration
Not applicable.
7.0
Analysis Conventions
Definition of Baseline
In this sub-study, a subject's baseline is defined as the last non-missing observation on or 
before the date of receiving Prevnar 13® vaccination. 
 


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Definition of Rx Days (Days Relative to the Date of Vaccination)
Rx Days are defined as the number of days between the day of vaccination and the 
specific time point.  Rx days are negative values when the time point of interest is prior to 
the vaccination.  Rx days are positive values when the time point of interest is on or after 
the date of vaccination.  The day of vaccination is defined as Rx Day 1, while the day 
prior to vaccination is defined as Rx Day –1 (there is no Rx Day 0).  Rx days are used to 
map actual study visits to the protocol-specified study visits.
Definition of Analysis Windows
Table 1 displays the visit window and the target/nominal day for each study visit.
Table 1.
Visit Windows for Satisfactory Humoral Response, and anti-
pneumococcal antibody levels
Window Label
Nominal Day
Interval
Baseline
1
≤ 1
Week 4
29
[15, 57]
Week 12
85
[58, 112]
8.0
Demographics, Baseline Characteristics, Medical 
History, and Concomitant Medications
Demographics and baseline disease characteristics will be summarized for FAS of the 
sub-study overall and by upadacitinib dose groups.  Demographics and baseline disease 
characteristics will be defined relative to the baseline of the vaccine sub-study.
Categorical variables will be summarized with the number and percentage of subjects; 
percentages will be calculated based on the number of non-missing observations.  
Continuous variables will be summarized with descriptive statistics (number of 
non-missing observations, mean and standard deviation, median, minimum and 
maximum).
 


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8.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight and body mass index (BMI).  
Categorical demographic variables include sex, race, ethnicity, age (< 40, ≥ 40 –
< 65 years, ≥ 65), BMI (< 18.5, ≥18.5 - < 25, ≥25 - < 30, ≥30).
Disease characteristics include the following:
●
Duration of any upadacitinib treatment up to the sub-study baseline
●
Duration of RA in years
●
Concomitant csDMARD at baseline (MTX alone, MTX and other csDMARD, 
csDMARD other than MTX, none) 
●
MTX dose at baseline
●
Oral steroid use at baseline
●
Oral steroid dose at baseline
●
CDAI
●
CDAI (≤ 2.8, > 2.8 – ≤ 10, > 10)
●
DAS28 (CRP)
8.2
Medical History
Not Applicable.  This is a short-term sub-study, and any medical history will be 
summarized for the main study.
8.3
Concomitant Medications
Not Applicable.  This is a short-term sub-study, and any concomitant medications will be 
summarized for the main study. 
 


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9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted in the FAS Population.  Subjects will be classified 
into upadacitinib 15 mg QD dose group or upadacitinib 30 mg QD dose group based on 
their upadacitinib dose at the vaccination visit.
9.2
Handling of Missing Data
All efficacy analyses will be based on observed cases, which 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 analysis for that visit.  
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint(s)
The primary endpoint is:
●
Proportion of subjects with satisfactory humoral response to Prevnar 13® at the 
Week 4 visit of the sub-study (4 weeks post-vaccination).
Satisfactory humoral response to Prevnar 13® is defined as greater than or equal to 
(≥) 2-fold increase in antibody concentration from the vaccination baseline in at least 
6 out of the 12 pneumococcal antigens (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 
23F).
9.3.2
Handling of Missing Data for the Primary Efficacy 
Endpoint(s)
All efficacy analyses will be based on observed cases.
9.3.3
Primary Efficacy Analysis
The proportion of subjects achieving Satisfactory Humoral Response, defined as greater 
than or equal to (≥) 2-fold increase in antibody concentration from the vaccination 
 


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baseline in at least 6 out of the 12 pneumococcal antigens (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 
19A, 19F and 23F), will be summarized by count and percentages for each upadacitinib 
dose group at 4 weeks post-vaccination and 12 weeks post-vaccination.  95% confidence 
intervals for each upadacitinib dose group will be provided.
9.3.4
Additional Analyses of the Primary Efficacy Endpoint(s)
None.
9.4
Secondary Efficacy Analyses
9.4.1
Key Secondary Efficacy Analyses
At 4 weeks post-vaccination and 12 weeks post-vaccination, the geometric mean fold rise 
(GMFR) and corresponding 95% confidence intervals of anti-pneumococcal antibodies as 
compared with pre-vaccination will be summarized for each upadacitinib dose group. 
Calculations will be done using logarithmically transformed assay results, and then back-
transformed to the original scale.  Lower limit of quantification of 0.005 will be assigned 
to the zero concentration values.
9.4.2
Supportive Secondary Efficacy Analyses
None.
9.5
Additional Efficacy Analyses
The proportion of subjects achieving at least 2-fold increase in antibody concentration 
from the vaccination baseline in each of the 12 pneumococcal antigens will be 
summarized by count and percentages for each upadacitinib dose group at 4 weeks post-
vaccination and 12 weeks post-vaccination.  95% confidence intervals for each 
upadacitinib dose group will be provided.
9.6
Efficacy Subgroup Analyses
To evaluate the consistency of the efficacy over different groups, the primary efficacy 
endpoint will be analyzed in the following subgroups:
 


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●
Age group (< 40, ≥40 – < 65 years, ≥65)
●
Oral steroid use at baseline (Yes/No)
●
Concomitant csDMARD at baseline (MTX alone, MTX and other csDMARD, 
csDMARD other than MTX, none)
●
CDAI (≤ 2.8, > 2.8 – ≤ 10, > 10)
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Analysis Set.  Safety summaries will be 
presented by treatment group, in which treatment group is based on subjects' upadacitinib 
dose at the vaccination visit, including a total group for all subjects.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Any AEs with onset after the vaccination and no more than 30 days post-
vaccination will be summarized, overall and by upadacitinib dose groups.  The SOCs will 
be presented in alphabetical order, and the PTs will be presented in alphabetical order 
within each SOC.  Specific adverse events will be counted once for each subject for 
calculating percentages, unless stated otherwise.
10.2.1
Treatment-Emergent Adverse Events
No treatment-emergent AEs are defined in this sub-study.  All AEs will be summarized.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
 


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●
Any AE
●
Any serious AE
●
Any AE leading to discontinuation of upadacitinib
●
Any severe AE
●
Any AE with reasonable possibility of being related to upadacitinib
●
Any AE leading to death
●
All deaths
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 upadacitinib.
10.2.3
Adverse Events by SOC and/or PT
Adverse events will be summarized by SOC and PT; by maximum relationship to 
upadacitinib as assessed by the investigator (e.g., reasonable possibility or no reasonable 
possibility) and SOC and PT; by maximum severity and SOC and PT; and by subject 
number and SOC and PT.  Severe AEs will be summarized by SOC and PT.  Specific 
adverse events will be counted once for each subject for calculating percentages, unless 
stated otherwise.  
In the summary of AEs by maximum severity and by maximum relationship, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to upadacitinib will be reported.  If a subject has an AE with an unknown 
severity, then the subject will be counted in the severity category of unknown, even if the 
subject has another occurrence of the same event with a severity present. The only 
exception is 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. If a 
subject has an AE 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 
 


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occurrence of the same AE with a relationship assessment of "reasonable possibility." In 
this case, the subject will be counted under the "reasonable possibility" category.
Adverse events will also be summarized by PT and sorted by decreasing frequency for the 
total group.
In addition, to assess potentially vaccine-related adverse events, events with onset within 
7 days post-vaccination will be summarized by SOC and PT and by maximum severity 
and SOC and PT.
10.2.4
Adverse Events per 100 Patient-Years of Exposure
Not applicable.  This is a short-term study with 12-week duration. No adverse events per 
100 Patient-Years of exposure will be summarized.
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths), AEs leading to study drug discontinuation and AEs leading to 
death will be summarized by SOC and PT and in listing format. 
10.3
Analysis of Laboratory Data
Not applicable.  The clinical laboratory tests defined in the protocol (e.g., hematology and 
clinical chemistry) will be summarized for the main study.
10.4
Analysis of Vital Signs
Not applicable, vital sign measurements of systolic and diastolic blood pressure, pulse 
rate, respiratory rate, body temperature and weight will be summarized for the main study.
10.5
Safety Subgroup Analyses
None.
 


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10.6
Other Safety Analyses
Not applicable.
11.0
Other Analyses
Not applicable.
12.0
Interim Analyses
Not applicable.
12.1
Data Monitoring Committee
Not applicable.
13.0
Overall Type-I Error Control
No multiplicity adjustment is planned for any analysis in this vaccine sub-study.
14.0
Summary of Changes
14.1
Summary of Changes between the Previous Version and the 
Current Version 
1.
Addition of other efficacy endpoint and the analysis method for this endpoint in 
Section 3.3 and Section 9.5, respectively. 
2.
Defined the Safety Analysis Set in Section 4.0. 
3.
Summary of concomitant medication in Section 8.3 has been removed from 
analysis.  
4.
The period for AE summaries has been updated to up to 30 days post-vaccination 
in Section 10.0.
5.
Clarified the summary of AEs including potentially vaccine-related adverse events 
in Section 10.2.3.
 


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6.
Laboratory tests in Section 10.3 and Vital signs in Section 10.4 have been removed 
from the safety analyses.  
15.0
Version History
Table 2.
SAP Version History Summary
Version
Date
Summary
1.0
05 Aug 2019
Original version
2.0
06 March 2020
Amendment 1