Clinical trial NCT03653026
Conditions: Ulcerative Colitis (UC)
Keywords: Upadacitinib ABT-494 Ulcerative Colitis
Sponsor: AbbVie
Start date: 2018-12-06; Completion date: 2021-01-14
Enrollment: 522 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the efficacy and safety of upadacitinib compared to placebo in inducing clinical remission (per Adapted Mayo score) in participants with moderately to severely active ulcerative colitis (UC).

Detailed description:
Study M14-675 consists of 2 parts, Part 1 and Part 2. Part 1 is a randomized, double-blind, placebo-controlled 8-week induction period. Part 2 is an open-label, 8-week extended treatment period for participants who did not achieve clinical response at Week 8 in Part 1.

Eligible participants are randomized in a 2:1 ratio to one of the two treatment groups (upadacitinib 45 mg or matching placebo) for 8 weeks. The randomization is stratified by biologic inadequate responder (bio-IR) status (bio-IR vs non-bio-IR), corticosteroid use (yes or no), and Adapted Mayo score (≤ 7 or \> 7) at Baseline. Within bio-IR, the randomization is further stratified by number of prior biologic treatments (≤ 1 or \> 1). Within non-bio-IR, the randomization is further stratified by previous biologic use (yes or no).

Participants who achieve clinical response defined by Adapted Mayo Score at Week 8 or Week 16 and do not meet any study discontinuation criteria are eligible to enroll into Study M14-234 Substudy 3 (NCT02819635; 52-week maintenance study) or Study M14-533 Cohort 1 (NCT03006068; long-term follow-up study).

Arms: arm 1: Participants received 45 mg upadacitinib once daily (QD) for 8 weeks. Participants who did not achieve clinical response per Adapted Mayo score at Week 8 received upadacitinib 45 mg once daily for 8 additional weeks in the open-label extension period. arm 2: Participants received placebo matching to upadacitinib once daily for 8 weeks. Participants who did not achieve clinical response per Adapted Mayo score at Week 8 received upadacitinib 45 mg once daily for 8 weeks in the open-label extension period.
Interventions: intervention 1: Placebo intervention 2: Upadacitinib
Intervention descriptions: intervention 1: Tablet for oral administration intervention 2: Tablet for oral administration

Protocol documents:
Prot_000.pdf: 
Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
1
1.0
Title Page
Clinical Study Protocol M14-675
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Induction Study to Evaluate the 
Efficacy and Safety of Upadacitinib (ABT-494) in 
Subjects with Moderately to Severely Active 
Ulcerative Colitis 
Incorporating Administrative Change 1 (Canada 
Only) and Amendments 1, 1.01 (Ireland Only), 2, 
2.01 (France Only), 3, and 4
AbbVie Investigational
  Product:
Upadacitinib (ABT-494)
Date:
31 July 2020
Development Phase:
3
Study Design:
Phase 3, multicenter, randomized, double-blind, placebo-
controlled efficacy and safety study
EudraCT Number:
2016-000642-62
Investigators:
Multicenter.  Investigator information is on file at AbbVie
Sponsor:
For EU Member States:*
AbbVie Deutschland
GmbH & Co. KG
Knollstrasse 50
67061 Ludwigshafen
Germany *
For non-EU Member States:
AbbVie Inc.
1 North Waukegan Road, AP-31-2
North Chicago, IL 60064, United 
States
For Japan:
AbbVie GK
3-1-21 Shibaura, Minato-ku, 
Tokyo 108-0023, Japan
NCT03653026


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
2
Sponsor/Emergency 
  Contact:
1 North Waukegen Rd
North Chicago, IL 60064
United States
Phone:
Cell:
Fax:
Email:  
Emergency 24 hour Number:  
+1 973-784-6402
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
29 June 2018
Amendment 1
12 September 2018
Amendment 1.01 (Ireland Only)
09 November 2018
Amendment 2
24 April 2019
Admin Change 1 (Canada Only)
22 August 2019
Amendment 2.01 (France Only)
25 September 2019
Amendment 3
29 April 2020
The purpose of this amendment is to:
●
Apply administrative changes throughout the protocol.
Rationale:  Revised text to improve consistency and readability, provide 
clarity.
●
Synopsis
Rationale:  Revised to be consistent with Amendment 4 revisions.
●
Update Section 3.2 Benefits and Risks
o
Updated wording for Benefits and Risks
Rationale: Updated information on the re-evaluation of the benefit and 
risk to subjects participating in the study.
●
Update Section 5.1 Overall Study Design and Plan: Description
o
Included wording with relation to COVID-19.
Rationale:  to allow for changes in visits and procedures impacted by the 
COVID-19 pandemic and changes in global/local regulations due to the 
pandemic.
●
Update Section 5.1 Overall Study Design and Plan: Description
o
Updated wording on status of screening.
Rationale:  To acknowledge that screening is closed for the study.


Upadacitinib
M14-675 Protocol Amendment 4
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●
Update Section 5.3.1.1 Study Procedures
o
Updated Informed consent wording with relation to COVID-19
Rationale:  noted that AbbVie will modify the study protocol as necessary 
due to the pandemic and verbal consent may be obtained additionally to 
study informed consent.
o
Updated height and weight wording with relation to COVID-19
Rationale: noted that AbbVie will modify the study protocol as necessary 
due to the pandemic and vital signs may be taken by the subject or 
caregiver as needed.
o
Updated vital signs wording with relation to COVID-19
Rationale:  noted that AbbVie will modify the study protocol as necessary 
due to the pandemic and vital signs may be taken by the subject or 
caregiver as needed.
o
Updated CXR wording with relation to COVID-19
Rationale:  clarified when completion of CXR is not possible at study site 
or a different facility, it may be delayed (in the absence of symptoms or 
positive medical history) until the site re-opens.
o
Updated ECG wording with relation to COVID-19
Rationale:  clarified when completion of ECG is not possible at study site 
or a different facility it may be delayed until the site re-opens.
o
Updated TB Testing wording with relation to COVID-19
Rationale:  clarified TB Testing may be performed by a local lab.
o
Updated pregnancy testing wording with relation to COVID-19
Rationale:  clarified urine pregnancy tests may be performed by a local 
lab or at home and confirmed by site staff.
o
Updated HBV testing wording with relation to COVID-19
Rationale:  clarified HBV DNA testing may be performed by a local lab.
o
Updated Clinical Laboratory tests wording with relation to COVID-19
Rationale: if protocol required central clinical laboratory tests cannot be 
collected, identify the minimum tests to be collected at local labs and 
reviewed by the investigators for subject safety.


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
5
o
Updated Fecal Calprotectin and hs-CRP wording with relation to 
COVID-19
Rationale:  clarified Fecal Calprotectin and hs-CRP test may not be 
performed by a local lab.
o
Updated Outcomes and Questionnaires wording with relation to 
COVID-19.
Rationale:  noted guidance for how to carry the Patient Reported Outcome 
questionnaires and the minimum requirement when affected by COVID-19 
pandemic.
o
Updated Study Drug dispensation and administration wording with relation 
to COVID-19.
Rationale:  to allow flexibility during the COVID-19 pandemic if the 
subject cannot pick up study drug onsite, as needed and permitted by local 
regulations, and provide safety guidance for investigator consideration 
prior to DTP dispensation.
o
Updated endoscopy wording with relation to COVID-19.
Rationale:  noted guidance for how to manage patient subsequent 
treatment when scheduled endoscopies are affected by COVID-19 
pandemic.
o
Updated biopsy wording with relation to COVID-19.
Rationale:  noted guidance for how to manage biopsy collection for visits 
affected by COVID-19 pandemic.
o
Added Home Healthcare service with relation to COVID-19.
Rationale:  to allow for flexibility of visits to be carried out at an 
alternative location from the study site when visits are impacted by the 
COVID-19 pandemic.
o
Included wording with relation to COVID-19.
Rationale:  to provide guidance on how procedures can be performed for 
visits impacted by the COVID-19 pandemic and changes in global/local 
regulations due to the pandemic.
●
Update Section 5.3.1.2 Collection and Handling of Optional Samples for 
Exploratory Research and Validation studies


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
6
o
Updated wording for collection of optional samples for exploratory 
research and validation studies with relation to COVID-19.
Rationale:  noted guidance for how to manage collection of optional 
samples for visits affected by COVID-19 pandemic.
●
Update Section 5.3.2.1 Collection of Samples for Analysis
o
Updated wording for collection of PK samples with relation to COVID-19.
Rationale:  noted guidance for how to manage collection of PK samples 
for visits affected by COVID-19 pandemic.
●
Update Section 5.4.1 Discontinuation of Individual Subjects
o
Updated language for the event of a temporary study (Drug) 
interruption/halt
Rationale: added instructions to refer to study procedures for necessary 
changes to activities or procedures in the event of temporary study drug
interruption.
●
Update Section 5.5.1 Treatments Administered
o
Included instructions for Direct-to-Patient drug shipments
Rationale: to allow flexibility during the COVID-19 Pandemic if the 
subject cannot pick up study drug onsite, as needed and permitted by local 
regulations.
●
Update Section 5.5.7 Drug Accountability
o
Included instructions for remote Drug Accountability
Rationale: to allow flexibility during the COVID-19 Pandemic if the 
subject cannot return their used drug kits for site accountability due to not 
being able to attend an onsite visit.
●
Update Section 6.1.5 Adverse Event Reporting
o
Updated language for supplemental study case report forms.
Rationale: To capture COVID-19 related missed/virtual visits, study drug 
interruptions or discontinuations, or adverse events.
●
Update Section 7.0 Protocol Deviations
o
Updated Protocol deviation wording.


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
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Rationale:  clarified that protocol deviations may include modifications 
due to COVID-19.
●
Update Section 9.2 Ethical Conduction of the Study
o
Updated wording with relation to COVID-19
Rationale:  noted that AbbVie will modify the study protocol as necessary 
due to the pandemic.  Investigators must also notify AbbVie if any urgent 
safety measures are taken.
●
Update Section 9.3 Subject Information and Consent
o
Updated wording with relation to COVID-19
Rationale:  noted that AbbVie will modify the study protocol as necessary 
due to the pandemic and verbal consent may be obtained additionally to 
study informed consent.
●
Update Section 10.1 Source Documents
o
Updated wording with relation to remote monitoring of data
Rationale:  to allow for remote monitoring to be employed as needed, 
depending on local regulations.
●
Update Section 10.3 Electronic Patient Reported Outcomes
o
Updated wording with relation to COVID-19.
Rationale:  noted guidance for how to carry out the Patient Reported 
Outcome questionnaires and the minimum requirement when affected by 
COVID-19 pandemic.
●
Update Appendix C Schedule of Activities 
○
Addition of footnotes for procedures that could be affected by COVID-19 
pandemic.
Rationale:  to include details on how to perform specific 
activities/procedures that may be impacted by changes in global/local 
regulations due to the pandemic.
○
Addition of visit window extensions allowed for visits affected by 
COVID-19 pandemic.
Rationale:  to allow for flexibility on completion of visits that may be 
impacted the COVID-19 pandemic.


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
8
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix I.


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
9
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-675
Name of Study Drug:  Upadacitinib (ABT-494)
Phase of Development:  3
Name of Active Ingredient:  Upadacitinib 
(ABT-494)
Date of Protocol Synopsis:  31 July 2020
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study to 
Evaluate the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects with Moderately to Severely 
Active Ulcerative Colitis.
Objective:  The primary objective of Study M14-675 (Phase 3 induction) is to evaluate the efficacy and 
safety of upadacitinib 45 mg once daily (QD) compared to placebo in inducing clinical remission (per 
Adapted Mayo score) in subjects with moderately to severely active ulcerative colitis (UC).
At the time of this amendment, the study has closed screening.
Investigators:  Multicenter
Study Sites:  Approximately 400 sites worldwide.
Study Population:  Males and females between 18 and 75 years of age with a diagnosis of moderately 
to severely active UC. Adolescent males and females 16 and 17 years of age with body weight ≥ 40 kg 
and meet the definition of Tanner Stage 5 will be enrolled if approved by the country or 
regulatory/health authority. If these approvals have not been granted, only subjects ≥ 18 years old will 
be enrolled. The study will consist of a mixed population:  biologic-inadequate responders (bio-IR) and 
non-biologic-inadequate responders (non-bio-IR).   
Number of Subjects to be Enrolled:  A total of approximately 462 subjects will be enrolled worldwide.  
The number of non-bio-IR subjects enrolled will be at least 25% and not exceed 50% of the total number 
of subjects enrolled.
Methodology:
Study M14-675 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study designed 
to evaluate the efficacy and safety of oral administration of upadacitinib 45 mg QD compared to placebo 
as induction therapy for up to 16 weeks in subjects with moderately to severely active UC.
At the end of either Week 8 (Part 1) or Week 16 (Part 2), if subjects are eligible, they will be offered an 
opportunity to participate in Study M14-234 Substudy 3 which is a Phase 3 study designed to evaluate 
the efficacy and safety of oral administration of upadacitinib 15 mg or 30 mg compared to placebo as 
maintenance therapy in subjects with moderately to severely active UC who achieved clinical response 
following induction with upadacitinib in Study M14-675.  Please consult the Study M14-234 protocol 
for further details.
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes such as phone 
or virtual visits, visits at alternative locations, or changes in the visit frequency and timing of study 
procedures, among others.  Additional details are provided in the subsequent section.  Every effort 
should be made to ensure the safety of subjects and site staff, while maintaining the integrity of the 
study.  If visits cannot be conducted onsite due to travel restrictions or other pandemic-related reasons, 
follow the updates below on how to proceed.  These measures will only be implemented under the 
protocol in countries that are affected by the COVID-19 pandemic.


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
10
Methodology (Continued):
Subjects who consent and meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into Study M14-675, which consists of two parts:  (Part 1) a randomized, double-blind, placebo-
controlled 8-week induction study; and (Part 2) an 8-week Extended Treatment Period for clinical non-
responders from Part 1.
Part 1
In Part 1, approximately 462 subjects will be randomized in a 2:1 ratio to double-blind upadacitinib 
45 mg QD or matching placebo for 8 weeks.  The randomization will be stratified by bio-IR status (bio-
IR vs non-bio-IR), corticosteroid use (yes or no) and Adapted Mayo score (≤ 7 or > 7) at Baseline.  
Within bio-IR, the randomization will be further stratified by number of prior biologic treatments (≤ 1 or 
> 1).  Within non-bio-IR, the randomization will be further stratified by previous biologic use (yes or 
no).
Treatment groups for Part 1 include:
!
Group 1:  Upadacitinib 45 mg QD (blinded, n = 308)
!
Group 2:  Placebo QD (blinded, n = 154)
At Week 8, subjects achieving clinical response, defined as a decrease from Baseline in the Adapted 
Mayo score ≥ 2 points and ≥ 30% from Baseline, PLUS a decrease in rectal bleeding subscore (RBS) ≥ 1 
or an absolute RBS ≤ 1 may be eligible to enter the 52-week, double-blind, maintenance portion of 
Study M14-234 (Substudy 3). 
All subjects who do not achieve clinical response at Week 8 will be eligible to participate in Part 2 
(Extended Treatment Period) to receive open-label upadacitinib 45 mg QD for an additional 8 weeks.
Part 2
Part 2 is an open-label, 8-week Extended Treatment Period for subjects who do not achieve clinical 
response at Week 8 in Part 1.  The objectives of Part 2 are to offer upadacitinib induction treatment to 
placebo clinical non-responders from Part 1 and to evaluate delayed clinical response of upadacitinib in 
subjects who do not initially respond during Part 1.  The blind from Part 1 will not be broken for the 
duration of the study as subjects will be assessed as clinical non-responders at the 8 Week Visit of Part 1 
and will be moved to Part 2 for further treatment in the study without identifying their initial treatment 
assignment.  All eligible subjects entering Part 2 will receive open-label treatment with upadacitinib 
45 mg QD for 8 additional weeks (until Week 16).  At Week 16, an endoscopy will be performed to 
evaluate the treatment effect.  A flexible rectosigmoidoscopy is recommended.  However, the use of 
flexible sigmoidoscopy or colonoscopy is at the investigators' discretion based on local practice. 
During Part 2, subject with persistent symptoms or worsening UC may be discontinued at any time.  At 
Week 16, subjects who achieve clinical response may be eligible to enter Study M14-234 (Substudy 3) 
for further blinded treatment.  Subjects who do not achieve clinical response at Week 16 will be 
discontinued from the study and will not be eligible to enroll in Study M14-533 (long term extension).


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
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Methodology (Continued):
Part 2 (Continued)
All subjects will be provided with a Subject Diary (eDiary) at Screening in Study M14-675 where they 
will record UC-related symptoms, use of anti-diarrheals, and use of medications for endoscopy 
preparation.  For the assessment of the clinical endpoints, the stool frequency and the rectal bleeding 
subscore will be calculated as an average of the entries recorded into the subject's diary from the most 
recent consecutive 3-day period prior to each study visit.  If diary entries from the 3 consecutive days 
prior to the visit are not available, the 3 most recent consecutive days in the last 10 days will be utilized.  
If data is not available for 3 consecutive days, the average of the entries from the most recent 3 non-
consecutive days in the last 10 days will be utilized.  Clinical endpoints of abdominal pain and bowel 
urgency from subject diaries will be measured at the same time period as the stool frequency and rectal 
bleeding subscores.  Proportion of subjects who report no abdominal pain and proportion of subjects 
who report no bowel urgency in the 3 days will be estimated.  
At each study visit, a routine physical examination including evaluation of vital signs, evaluation of 
extra-intestinal manifestations (EIMs), diary review, monitoring for adverse events (AEs), review of 
concomitant medications, and completion of laboratory assessments will be performed.  A full physical 
examination will be performed at Screening, Baseline, Week 8 and Week 16/Premature Discontinuation 
(PD) (for subjects who enter the Extended Treatment Period) and must include an evaluation of extra-
intestinal manifestations.  Symptom based physical examinations will be performed at all other visits at a 
minimum, but evaluation of EIMs will still be completed at every study visit.
Subjects will undergo a full colonoscopy with biopsy for histologic assessment during Screening with 
local investigator assessment for Mayo endoscopic subscore for initial eligibility assessment, confirmed 
by a central reader prior to randomization.  At end of treatment (Week 8 in Part 1) a full colonoscopy or 
flexible sigmoidoscopy, depending on the extent of disease at Screening, will be performed.  
For subjects in Part 2, an endoscopy will be performed at Week 16/PD.  A flexible rectosigmoidoscopy 
is recommended at Week 16/PD, however, the use of flexible rectosigmoidoscopy or colonoscopy will 
be based on the investigator's discretion per local practice. 
The endoscopic subscore result from the central reader during the screening period will be used to 
evaluate the eligibility of a subject to enroll in the study and for all efficacy assessments at Week 8 of 
Part 1.  However, for re randomization into Substudy 3, the endoscopic subscore at Week 8 
(Study M14-675 Part 1) or Week 16 (Study M14-675 Part 2) based on the local reader's assessment will 
be used to determine clinical response status compared to the Baseline assessment of the central reader 
for enrollment into Study M14-234 Substudy 3.
In addition to the Mayo endoscopic subscore, the central reader will assess the endoscopy findings using 
the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scoring system for additional exploratory 
analyses.  Blood samples will be collected for high sensitivity C-reactive protein (hs-CRP), upadacitinib 
plasma concentrations and other biomarker analyses.  In addition, stool samples for fecal calprotectin 
will be collected.  The stool samples should be taken before starting bowel preparations for scheduled 
endoscopies.
Subjects will be asked to fill out the Inflammatory Bowel Disease Questionnaire (IBDQ), Work 
Productivity and Activity Impairment (WPAI), European Quality of Life 5 Dimensions 5 Levels 
(EQ-5D-5L), Short Form 36 Item (SF-36), and Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-F), Ulcerative Colitis Symptoms Questionnaire (UC-SQ), and Patient Global 
Impression of Severity (PGIS; only in select sites) during the study at Baseline, Week 2, and Week 8/PD 
for Part 1.  These same questionnaires will be completed at Week 16/PD for Part 2.  


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
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Methodology (Continued):
Subjects will be asked to fill out the Patient Global Impression of Change (PGIC) during the study at 
Week 2, and Week 8/PD for Part 1.  This same questionnaire will be completed at Week 16/PD for 
Part 2.  During each study visit subjects will also be asked to report UC-related hospitalizations and 
surgeries which will be captured as a part of the supplemental Health Care Resource Utilization (HCRU) 
form of Adverse Event collection in electronic data capture. 
Subjects will be discontinued from the study if they withdraw consent or if they are deemed unsuitable 
to continue for any reason by the investigator.
Washout Period:
Subjects, who have been taking exclusionary medications prior to screening must complete medication 
washout.  The duration is based on the excluded medication as described in the protocol.  However, for 
subjects who have discontinued infliximab, certolizumab, adalimumab, golimumab, vedolizumab, 
natalizumab, ustekinumab, if there is proper documentation of an undetectable drug level measured by a 
commercially available assay for any of the approved biologics above, there is no minimum washout 
prior to Baseline.  Protocol-related adverse events should be reviewed and subjects must complete the 
washout prior to the Baseline Visit. 
Concomitant UC-Related Medications (Oral Corticosteroids, Antibiotics, Aminosalicylates, and/or 
Methotrexate):
Parts 1 and 2
All UC-related concomitant medications should be kept on stable doses in Parts 1 and 2. All subjects 
receiving stable dose of UC-related antibiotics (those subjects who did not discontinue), 
aminosalicylates, or MTX at Week 0 will maintain their concomitant treatments and respective doses 
through the end of the study.  Dose may be decreased or terminated in the event of moderate to severe 
treatment related toxicity (e.g., leukopenia or elevated liver enzymes) in the opinion of the investigator.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
1.
Male or female between 16 and 75 years of age at Baseline.
!
Adolescent subjects 16 and 17 years old will only be enrolled if approved by the country or 
regulatory/health authority and must weigh ≥ 40 kg and meet the definition of Tanner Stage 5 
(refer to Appendix H) at the screening visit.  If these approvals have not been granted, only 
subjects ≥ 18 years old will be enrolled.  
2.
Diagnosis of UC for 90 days or greater prior to Baseline, confirmed by colonoscopy during the 
Screening Period, with exclusion of current infection, colonic dysplasia and/or malignancy. 
Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment 
of the Investigator, must be available. 
3.
Active UC with an Adapted Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3 
(confirmed by central reader).


Upadacitinib
M14-675 Protocol Amendment 4
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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion (Continued):
4.
Demonstrated an inadequate response, loss of response, or intolerance to at least one of the following 
treatments including, oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic 
therapies, in the opinion of the investigator, as defined below: 
Note:  An inadequate response, loss of response, or intolerance to Oral Aminosalicylates will NOT count 
towards eligibility for the following countries:  Austria, Czechia, Finland, France, Ireland, Italy, Latvia, 
Lithuania, Norway, Poland, Portugal, Spain, Sweden and United Kingdom.
!
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide)  
o
Signs and symptoms of persistently active disease, in the opinion of the investigator, during 
a current or prior course of at least 4 weeks of treatment with 2.4 g/day mesalamine, 
4 g/day sulfasalazine, 1 g/day olsalazine, or 6.75 g/day balsalazide.
!
Corticosteroids
o
Signs and symptoms of persistently active disease despite a history of at least one induction 
regimen that included a dose equivalent to prednisone ≥ 40 mg/day orally for at least 
3 weeks or intravenously for 1 week, OR
o
Unable to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally 
without recurrent active disease, OR
o
Signs and symptoms of persistently active disease during or after a course of at least 
4 weeks of treatment with 9 mg/day budesonide or 5 mg/day beclomethasone, OR
o
Unable to taper oral budesonide to at or below 6 mg/day without recurrent active disease, 
OR
o
History of intolerance to corticosteroids (including, but not limited to Cushing's syndrome, 
osteopenia/osteoporosis, hyperglycemia, insomnia, infection).
!
Immunosuppressants
o
Signs and symptoms of persistently active disease despite a history of at least one 90 day 
regimen of oral azathioprine (≥ 1.5 mg/kg/day; for subjects in Japan, China, and Taiwan 
only:  ≥ 1.0 mg/kg/day), 6-mercaptopurine (6-MP) (≥ 1 mg/kg/day; [for subjects in Japan, 
China, and Taiwan only:  ≥0.6 mg/kg/day, rounded to the nearest available tablet of half 
tablet formulation] or a documented 6-thioguanine nucleotide (6-TGN) level of 230 –
450 pmol/8 × 108 RBC or higher on the current dosing regimen), injectable methotrexate 
(MTX) (≥ 15 mg/week subcutaneous [SC] or intramuscular), or tacrolimus (for subjects in 
Japan and Taiwan only:  documented trough level of 5 – 10 ng/mL), OR
o
History of intolerance to at least one immunosuppressant (including, but not limited to 
nausea/vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia, 
infection)
Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not 
sufficient for inclusion into the study unless these subjects were previously treated with 
aminosalicylates, corticosteroids or immunosuppressants (azathioprine or 6-MP) and have inadequate 
response to, loss of response to or intolerance to the therapy as defined above.


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
14
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
!
Biologic Agents for UC
o
Signs and symptoms of persistently active disease despite a history of any of the following:
!
at least one 6-week induction regimen of infliximab (≥ 5 mg/kg IV at 0, 2, and 
6 weeks),
!
at least one 4-week induction regimen of adalimumab (one 160 mg SC dose followed 
by one 80 mg SC dose [or one 80 mg SC dose in countries where this dosing regimen 
is allowed] followed by one 40 mg SC dose at least 2 weeks apart),
!
at least one 2-week induction regimen of golimumab (one 200 mg SC dose followed 
by one 100 mg SC dose at least 2 weeks apart), 
!
at least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2, and 
6 weeks),
!
at least one induction regimen of ustekinumab, a single IV dose using weight-based 
dosing (260 mg for subjects with body ≤55 kg; 390 mg for subjects with body weight 
> 55 kg to ≤85 kg; 520 mg for subjects with body weight > 85 kg OR
o
Recurrence of symptoms during scheduled maintenance dosing following prior clinical 
benefit (discontinuation despite clinical benefit does not qualify), OR
o
History of intolerance to at least one biologic agent (including, but not limited to infusion-
related reaction, demyelination, congestive heart failure, infection)
Note:  Non-bio-IR subjects who have received a prior biologic for up to 1 year may be enrolled, 
however, subjects must have discontinued the biologic for reasons other than inadequate response or 
intolerance (e.g., change of insurance, well controlled disease), and must meet the criteria for inadequate 
response, loss of response or intolerance to aminosalicylates, corticorsteroids and/or 
immunosuppressants as defined above.
5.
Female subjects of childbearing potential (refer to Section 5.2.4) must have a negative serum 
pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit prior 
to study drug dosing.
6.
If female, subject must meet the criteria as stated in Section 5.2.4 of this protocol:  Contraception 
Recommendations.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:
1.
Subject with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC).
2.
Current diagnosis of fulminant colitis and/or toxic megacolon.
3.
Subject with disease limited to the rectum (ulcerative proctitis) during the Screening endoscopy.
4.
Received cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 30 days prior to 
Baseline. 
5.
Subject who received azathioprine or 6-MP within 10 days of Baseline.
6.
Received intravenous corticosteroids within 14 days prior to Screening or during the Screening 
Period. 
7.
Subject with previous exposure to JAK inhibitor (e.g., tofacitinib, baricitinib, filgotinib, 
upadacitinib).
8.
Screening laboratory and other analyses show any of the following abnormal results:
!
Serum Aspartate Transaminase (AST) or Alanine Transaminase (ALT) > 2.0 × upper limit of 
the reference range (ULN);
!
Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in 
Renal Disease (MDRD) formula < 30 mL/min/1.73 m2;
!
Total White Blood Cell (WBC) count < 2500/μL;
!
Absolute neutrophil count (ANC) < 1,200/μL;
!
Platelet count < 100,000/μL;
!
Absolute lymphocytes count < 750/μL;
!
Hemoglobin < 9g/dL.
Investigational Product:
Upadacitinib (ABT-494)
Doses:
Part 1:  Upadacitinib 45 mg QD (blinded)
Part 2:  Upadacitinib 45 mg QD (open-label)
Mode of Administration:
Oral
Reference Therapy:
Part 1:  Matching Placebo
Dose:
N/A
Mode of Administration:
Oral
Duration of Treatment:  8 weeks for subjects achieving clinical response at Week 8; or 16 weeks for 
subjects who do not achieve clinical response at Week 8.


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Criteria for Evaluation:
Efficacy:
Primary Endpoint:  
The primary endpoint for Study M14-675 is the proportion of subjects who achieve clinical remission 
per Adapted Mayo score (defined as stool frequency subscore [SFS] ≤ 1 and not greater than baseline, 
RBS of 0, and endoscopic subscore ≤ 1) at Week 8.  Note:  evidence of friability during endoscopy in 
subjects with otherwise "mild" endoscopy activity will confer an endoscopic subscore of 2.
Ranked Secondary Endpoints: 
1.
Proportion of subjects with endoscopic improvement at Week 8
2.
Proportion of subjects with endoscopic remission at Week 8
3.
Proportion of subjects achieving clinical response per Adapted Mayo Score at Week 8
4.
Proportion of subjects achieving clinical response per Partial Adapted Mayo score (defined as 
decrease from Baseline ≥ 1 points and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or an 
absolute RBS ≤ 1) at Week 2
5.
Proportion of subjects achieving histologic-endoscopic mucosal improvement at Week 8
6.
Proportion of subjects who reported no bowel urgency at Week 8
7.
Proportion of subjects who reported no abdominal pain at Week 8
8.
Proportion of subjects who achieved histologic improvement at Week 8 
9.
Change from Baseline in IBDQ total score at Week 8
10. Proportion of subjects with mucosal healing at Week 8
11. Change from Baseline in FACIT-F score at Week 8.
Pharmacokinetic:  Blood samples will be collected for measurement of upadacitinib plasma 
concentration at Week 2, Week 6, and Week 8/PD in Part 1.
Safety:  Safety analyses will be performed on all subjects who receive at least one dose of study drug.  
Incidence of AEs, changes in vital signs, electrocardiogram, physical examination results, and clinical 
laboratory data will be assessed.
Exploratory Research Variables and Validation Studies (Optional):
Prognostic, predictive and pharmacodynamics biomarkers signatures may be investigated.  Samples for 
different applications, including pharmacogenetic, epigenetic, transcriptomic, proteomic and targeted 
investigations will be collected at various time points.  Assessments will include but may not be limited 
to nucleic acids, proteins, metabolites or lipids.


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Statistical Methods:
Efficacy:
For Study M14-675, the efficacy analysis will be based on intent-to-treat (ITT) analysis set.  The ITT 
analysis set includes all randomized subjects who received at least one dose of study drug from 
Study M14-675.  The ITT analysis set that includes all subjects in Part 1 who received blinded 
upadacitinib 45 mg QD or matching placebo is denoted as ITT1 population.  The ITT analysis set that 
includes all subjects in Part 2 who received open label upadacitinib 45 mg QD dose is denoted as ITT2 
population.  ITT1 is the primary analysis set of Study M14-675.  The comparisons between upadacitinib 
and placebo treatment groups in the ITT1 population for the primary efficacy and key ranked secondary 
endpoints will be performed using the Cochran-Mantel-Haenszel (CMH) test and will be stratified by 
bio-IR status (bio-IR vs non-bio-IR), corticosteroid use (yes or no), and Adapted Mayo score (≤ 7 or > 7) 
at Baseline.  Non-responder imputation (NRI) method, where subjects with missing data at scheduled 
assessment visits will be considered as "not achieved" for the clinical remission, will be used for primary 
analysis.  Primary and key secondary efficacy endpoints will be summarized descriptively for ITT2 
population.
Pharmacokinetic:
Individual plasma concentrations of upadacitinib will be tabulated and summarized.  A non-linear 
mixed-effects modeling approach will be used to estimate the population central values and the empirical 
Bayesian estimates of the individual values for upadacitinib oral clearance (CL/F) and volume of 
distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of the data.
Safety:
The safety analysis set consists of all subjects who received at least one dose of study medication.  For 
the safety analysis, subjects are assigned to a treatment group based on the treatment actually received, 
regardless the treatment randomized.  Incidence of AEs, changes in vital signs, physical examination 
results, electrocardiograms (ECGs), and clinical laboratory values will be analyzed.  Treatment-emergent 
adverse events will be tabulated by system organ class and by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term for each treatment group for each Substudy and over the entire 
study.  Mean change from Baseline for laboratory and vital signs data will be summarized.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
6-MP
6-Mercaptopurine
6-TGN
6-Thioguanine Nucleotide
AD
Atopic Dermatitis
AE
Adverse Event
ALC
Absolute Lymphocyte Count
ALT
Alanine Transaminase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AST
Aspartate Transaminase
ANC
Absolute Neutrophil Count
AUC
Area under the plasma concentration-time curve
AZA
Azathioprine
ATEMS
AbbVie Temperature Excursion Management System
BCG
Bacille Calmette-Guérin
BID
Twice daily
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CAC
Cardiovascular Adjudication Committee
CD
Crohn's Disease
CDC
Centers for Disease Control and Prevention
CD4, CD8
Cluster of Differentiation
CFR
Code of Federal Regulations
CGC
Common Gamma-Chain
CI
Confidence Interval
CL/F
Oral Clearance
Cmax
Maximum Observed Plasma Concentration
CMH 
Cochran-Mantel-Haenszel
CNS
Central Nervous System
COVID-19
Coronavirus Disease - 2019
CPK
Creatine Phosphokinase


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CR
Clinical Remission
CRA
Clinical Research Associate
CRF
Case Report Form
CRP
C-Reactive Protein
Cmin
Minimum Plasma Concentration During a Dosing Interval
CT
Computed Tomoraphy
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest X-Ray
CYP3A
Cytochrome P450 3A
DMARD
Disease-Modifying Anti-Rheumatic Drug
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DTP
Direct-to-patient
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC 
Electronic Data Capture
EIM
Extra-Intestinal Manifestations
EMA
European Medicines Agency
EMEA
European Agency for the Evaluation of Medicinal Products
ePRO
Electronic Patient Reported Outcomes
EQ-5D-5L
European Quality of Life-5 Dimensions 5 Levels
ER
Extended Release
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FDA
US Food and Drug Administration
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
gp130
Glycoprotein 130
GPRD
Global Pharmaceutical Research and Development
HBc Ab 
Hepatitis B Core Antibody
HBs Ab
Hepatitis B Surface Antibody
HBs Ag
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCRU
Health Care Resource Utilization


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HCV
Hepatitis C Virus
HCV Ab
Hepatitis C Virus Antibody
HDL-C
High Density Lipoprotein - Cholesterol
HIV
Human Immunodeficiency Virus
HIV Ab
Anti-HIV antibody
HCRU
Health Care Resource Utilization
hs-CRP
High-Sensitivity C-Reactive Protein
IBD
Inflammatory Bowel Disease
IBDQ
Inflammatory Bowel Disease Questionnaire
IC
Indeterminate Colitis
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IGRA
Interferon-Gamma Release Assay
IL
Interleukin
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IR
Immediate Release
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IV
Intravenously
JAK
Janus Activated Kinase
LDL-C
Low Density Lipoprotein – Cholesterol
LOCF
Last Observation Carried Forward
MACE
Major Adverse Cardiovascular Event
MCP-Mod
Multiple Comparison Procedure – Modeling
MCS
Mental Component Summary
MDRD
Modification of Diet in Renal Disease
MED
Minimum Effective Dose
MedDRA
Medical Dictionary for Regulatory Activities


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MMRM
Mixed Effect Repeated Measure 
MTX
Methotrexate
NCI
National Cancer Institute
NK
Natural Killer Cells
NKT
Natural Killer T Cells
NOAEL
No Observable Adverse Effect Level
NMSC
Nonmelanoma Skin Cancer
NRI
Non-Responder Imputation
NSAID
Non-Steroidal Anti-Inflammatory Drug
OC
Observed Cases
PCS
Physical Component Summary
PCR
Polymerase Chain Reaction
PD
Premature Discontinuation
PGA
Physician's Global Assessment
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
Pharmacokinetic
PPD
Purified Protein Derivative
PRO
Patient Reported Outcomes
PsA
Psoriatic arthritis
QTcF
QT Interval Corrected for Heart Rate by Fridericia's Correction Formula
RA
Rheumatoid Arthritis
RAVE®
EDC System from Medidata
RBC
Red Blood Cell Count
RNA
Ribonucleic Acid
RBS
Rectal Bleeding Subscore
RSI
Reference Safety Information
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SF-36
Short Form 36 
SFS
Stool Frequency Subscore
SOC
System Organ Class
STAT
Signal Transduction Activators of Transcription


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SUSAR
Suspected Unexpected Adverse Reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
TEAE
Treatment-Emergent Adverse Event
TNF
Tumor Necrosis Factor
TPN
Total Parenteral Nutrition
UC
Ulcerative Colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity
UC-SQ
Ulcerative Colitis Symptoms Questionnaire
ULN
Upper Limit of Normal
US
United States
V/F
Volume of Distribution
VAS
Visual Analogue Scale
WBC
White Blood Cell Count
WHO
World Health Organization
WPAI
Work Productivity and Impairment Questionnaire
Definition of Terms
Bio-IR
Biologic inadequate responders:  inadequate response, loss of response, 
or intolerance to biologic therapy  
Non-bio-IR
Non-biologic-inadequate responders:  inadequate response, loss of 
response, or intolerance to conventional therapy but have not failed 
biologic therapy. 


Upadacitinib
M14-675 Protocol Amendment 4
EudraCT 2016-000642-62
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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................9
1.3
List of Abbreviations and Definition of Terms........................................18
2.0
Table of Contents...................................................................23
3.0
Introduction ...........................................................................28
3.1
Differences Statement..............................................................................32
3.2
Benefits and Risks....................................................................................32
3.3
Safety Evaluations ...................................................................................34
4.0
Study Objective......................................................................34
5.0
Investigational Plan...............................................................35
5.1
Overall Study Design and Plan:  Description ..........................................35
5.2
Selection of Study Population..................................................................42
5.2.1
Inclusion Criteria .....................................................................................42
5.2.2
Exclusion Criteria ....................................................................................46
5.2.3
Prior and Concomitant Therapy...............................................................52
5.2.3.1
Prior Therapy ...........................................................................................52
5.2.3.2
Concomitant Therapy...............................................................................52
5.2.3.3
Prohibited Therapy...................................................................................53
5.2.4
Contraception Recommendations ............................................................57
5.3
Efficacy and Safety Assessments/Variables ............................................59
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................60
5.3.1.1
Study Procedures .....................................................................................60
5.3.1.2
Collection and Handling of Optional Samples for Exploratory 
Research and Validation Studies .............................................................89
5.3.2
Drug Concentration Measurements .........................................................91
5.3.2.1
Collection of Samples for Analysis .........................................................91
5.3.2.2
Handling/Processing of Samples .............................................................91
5.3.2.3
Disposition of Samples ............................................................................92
5.3.2.4
Measurement Methods.............................................................................92
5.3.3
Efficacy Variables....................................................................................92


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5.3.3.1
Primary Variable......................................................................................93
5.3.3.2
Secondary Variables ................................................................................93
5.3.3.3
Additional Variables ................................................................................94
5.3.4
Safety Variables.......................................................................................96
5.3.5
Pharmacokinetic Variables ......................................................................96
5.3.6
Exploratory Research Variables and Validation Studies.........................96
5.4
Removal of Subjects from Therapy or Assessment.................................97
5.4.1
Discontinuation of Individual Subjects....................................................97
5.4.2
Discontinuation of Entire Study.............................................................100
5.5
Treatments..............................................................................................100
5.5.1
Treatments Administered.......................................................................101
5.5.2
Identity of Investigational Product.........................................................102
5.5.2.1
Packaging and Labeling.........................................................................102
5.5.2.2
Storage and Disposition of Study Drug .................................................102
5.5.3
Method of Assigning Subjects to Treatment Groups.............................103
5.5.4
Selection and Timing of Dose for Each Subject....................................103
5.5.5
Blinding..................................................................................................104
5.5.5.1
Blinding of Investigational Product.......................................................105
5.5.5.2
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ..................................................................................................105
5.5.6
Treatment Compliance...........................................................................106
5.5.7
Drug Accountability...............................................................................106
5.6
Discussion and Justification of Study Design........................................107
5.6.1
Discussion of Study Design and Choice of Control Groups..................107
5.6.2
Appropriateness of Measurements.........................................................108
5.6.3
Suitability of Subject Population ...........................................................108
5.6.4
Selection of Doses in the Study .............................................................109
6.0
Complaints ...........................................................................110
6.1
Medical Complaints...............................................................................110
6.1.1
Definitions..............................................................................................111
6.1.1.1
Adverse Event........................................................................................111
6.1.1.2
Serious Adverse Events .........................................................................112
6.1.1.3
Adverse Events of Special Interest ........................................................113


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6.1.2
Adverse Event Severity..........................................................................114
6.1.3
Relationship to Study Drug....................................................................114
6.1.4
Adverse Event Collection Period...........................................................115
6.1.5
Adverse Event Reporting.......................................................................116
6.1.6
Pregnancy...............................................................................................119
6.1.7
Toxicity Management ............................................................................119
6.1.8
Cardiovascular Adjudication Committee (CAC)...................................124
6.1.9
Data Monitoring Committee (DMC) .....................................................124
6.2
Product Complaint .................................................................................125
6.2.1
Definition ...............................................................................................125
6.2.2
Reporting................................................................................................126
7.0
Protocol Deviations..............................................................126
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................127
8.1
Statistical and Analytical Plans..............................................................127
8.1.1
Datasets for Analysis .............................................................................128
8.1.1.1
Intent-to-Treat Analysis Sets .................................................................128
8.1.1.2
Safety Analysis Set ................................................................................128
8.1.2
Subject Accountability...........................................................................128
8.1.3
Definition of Missing Data Imputation..................................................128
8.1.4
Demographics and Baseline Characteristics..........................................129
8.1.4.1
Baseline Characteristics.........................................................................130
8.1.4.2
Medical Histories...................................................................................130
8.1.4.3
Prior Therapy and Medications..............................................................130
8.1.4.4
Concomitant Medications ......................................................................130
8.1.5
Subject Disposition and Study Drug Exposure......................................131
8.1.5.1
Subject Disposition ................................................................................131
8.1.5.2
Study Drug Exposure.............................................................................131
8.1.6
Efficacy Analysis ...................................................................................131
8.1.6.1
Primary Efficacy Variables....................................................................132
8.1.6.1.1
Analysis of Primary Endpoint................................................................132
8.1.6.2
Secondary Efficacy Variables................................................................132
8.1.7
Other Statistical Analyses of Efficacy ...................................................133


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8.1.8
Safety Analysis ......................................................................................134
8.1.8.1
General Considerations..........................................................................134
8.1.8.2
Analysis of Adverse Events...................................................................134
8.1.8.2.1
Treatment-Emergent Adverse Events ....................................................134
8.1.8.2.2
Serious Adverse Events and Death ........................................................136
8.1.8.3
Analysis of Laboratory and Vital Sign Data..........................................136
8.1.9
Pharmacokinetic and Exposure-Response Analyses .............................136
8.2
Determination of Sample Size ...............................................................138
9.0
Ethics.....................................................................................139
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................139
9.2
Ethical Conduct of the Study .................................................................139
9.3
Subject Information and Consent...........................................................140
9.3.1
Informed Consent Form and Explanatory Material ...............................142
9.3.2
Revision of the Consent Form and Explanatory Material .....................142
10.0
Source Documents and Case Report Form 
Completion ...........................................................................143
10.1
Source Documents .................................................................................143
10.2
Case Report Forms.................................................................................143
10.3
Electronic Patient Reported Outcomes (ePRO).....................................144
11.0
Data Quality Assurance ......................................................146
12.0
Use of Information...............................................................146
13.0
Completion of the Study .....................................................147
14.0
Investigator's Agreement....................................................149
15.0
Reference List ......................................................................150
List of Tables
Table 1.
Clinical Laboratory Tests.........................................................................76
Table 2.
Treatments Administered.......................................................................101
Table 3.
Identity of Investigational Product.........................................................102
Table 4.
Toxicity Management Guidelines for Abnormal Lab Values................122


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List of Figures
Figure 1.
Study M14-675 Study Design..................................................................38
Figure 2.
Interpretation and Management of HBV Serologic Test Results ............73
Figure 3.
Adverse Event Collection ......................................................................116
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................154
Appendix B.
List of Protocol Signatories....................................................................156
Appendix C.
Study Activities (Part 1; 8 Week Double-Blind Induction and 
Part 2; Extended Treatment Period).......................................................157
Appendix D.
Study Activities – Optional Samples for Exploratory Research 
and Validation Studies ...........................................................................165
Appendix E.
Patient Reported Outcomes Descriptions in Upadacitinib 
(ABT-494) UC Programs.......................................................................167
Appendix F.
Mayo Scoring System for Assessment of Ulcerative Colitis 
Activity ..................................................................................................170
Appendix G.
Latent TB Risk Assessment Form Example ..........................................171
Appendix H.
Tanner Staging Example........................................................................172
Appendix I.
Protocol Amendment:  List of Changes.................................................174


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3.0
Introduction
Ulcerative colitis (UC) is one of the two primary forms of idiopathic inflammatory bowel 
disease (IBD).  It is postulated that UC is caused by unregulated and exaggerated local 
immune response to environmental triggers in genetically susceptible individuals.1  UC is 
a chronic, relapsing inflammatory disease of the large intestine characterized by 
inflammation and ulceration of mainly the mucosal and occasionally submucosal 
intestinal layers.  The highest annual incidence of UC was 24.3 per 100,000 person-years 
in Europe, 6.3 per 100,000 person-years in Asia and the Middle East, and 19.2 per 
100,000 person-years in North America, with a prevalence of 505 cases per 
100,000 persons in Europe and 249 cases per 100,000 persons in North America.2  The 
burden of UC on the healthcare system is profound, accounting for nearly 
500,000 physician visits and more than 46,000 hospitalizations per year in the United 
States (US) alone.3
The hallmark clinical symptoms include bloody diarrhea associated with rectal urgency 
and tenesmus.  The clinical course is marked by exacerbation and remission.  The 
diagnosis of UC is suspected on clinical grounds and supported by diagnostic testing, and 
elimination of infectious causes.4
The most severe intestinal manifestations of UC are toxic megacolon and perforation.  
Extraintestinal complications include arthritis (peripheral or axial involvement), 
dermatological conditions (erythema nodosum, aphthous stomatitis, and pyoderma 
gangrenosum), inflammation of the eye (uveitis), and liver dysfunction (primary 
sclerosing cholangitis).  Patients with UC are at an increased risk for colon cancer, and the 
risk increases with the duration of disease as well as extent of colon affected by the 
disease.5
The aim of medical treatment in UC is to control inflammation and reduce symptoms.  
Available pharmaceutical therapies are limited, do not always completely abate the 
inflammatory process, and may have significant adverse effects.  Therapies for mild to 
moderate active UC include 5-aminosalicylic acid derivatives and immunosuppressants.  


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Corticosteroids are used in patients with more severe symptoms but are not useful for 
longer term therapy.6  The frequency and severity of corticosteroid toxicities are 
significant, including infections, emotional and psychiatric disturbances, skin injury, and 
metabolic bone disease.  Corticosteroids are not effective for the maintenance of 
remission and the UC practice guidelines from the American College of Gastroenterology 
recommend against chronic steroid treatment.7  Patients with moderate to severe 
symptoms may derive some benefits from immunomodulatory agents (azathioprine 
[AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]); however, the use of these 
agents is limited as induction treatment due to a slow onset of action (3 to 6 months) and 
as maintenance therapy due to adverse events (AEs), including bone marrow suppression, 
infections, hepatotoxicity, pancreatitis, and malignancies.7,8  Despite these therapies, 
approximately 15% of UC patients experience a severe clinical course, and 30% of these 
patients require removal of the colon/rectum, to eliminate the source of the inflammatory 
process, although accompanied by significant morbidity.9,10
Biological agents targeting specific immunological pathways have been evaluated for 
their therapeutic effect in treating patients with UC.  Anti-tumor necrosis factor (TNF) 
agents were the first biologics to be used for IBD.  Infliximab, adalimumab, and 
golimumab are successfully being used for the treatment of UC.  Vedolizumab, an anti-
adhesion therapy, has been approved for the treatment of IBD. 
Anti-TNF therapies are an effective treatment for patients who are steroid refractory or 
steroid dependent, who had inadequate response to a thiopurine, or who are intolerant to 
these medications.  Potential risks with anti-TNF therapies include infusion or injection 
site reactions, serious infections, lymphoma, heart failure, lupus-like syndromes, and 
demyelinating conditions.11  Despite the beneficial results achieved with the available 
biologic agents, only 17% to 45% of patients who receive them are able to achieve 
clinical remission.12-15  Thus, there remains a clear medical need for additional therapeutic 
options in UC for patients with inadequate response to or intolerance to conventional 
therapies and biologic therapies.


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Rationale for Development of a JAK Inhibitor in UC
The Janus kinases or JAKs are a family of intracellular tyrosine kinases that function as 
dimers in the signaling process of many cytokine receptors.  The JAKs play a critical role 
in both innate and adaptive immunity, making them attractive targets for the treatment of 
inflammatory diseases.  Targeting the Janus activated kinase (JAK) signaling pathway for 
autoimmune diseases, is supported by the involvement of various pro-inflammatory 
cytokines that signal via JAK pathways in the pathogenesis of these immune-related 
disorders.  The activation of JAK signaling initiates expression of survival factors, 
cytokines, chemokines, and other molecules that facilitate leukocyte cellular trafficking 
and cell proliferation, which contribute to inflammatory and autoimmune disorders.16
Tofacitinib is an oral JAK inhibitor that inhibits JAK1, JAK2 and JAK3 with high in vitro 
functional specificity for kinases 1 and 3.  In completed Phase 3 studies in patients with 
moderately to severely active UC, tofacitinib was more effective than placebo as 
induction and maintenance therapy.17
JAK inhibitors have been associated with infections, including herpes zoster reactivation, 
malignancies, and asymptomatic, mild and reversible changes in levels of hemoglobin, 
lymphocyte counts, white blood cell counts, serum creatinine, total cholesterol, high 
density liporprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) 
and liver transaminases (alanine transaminase [ALT], aspartate transaminase [AST]) and 
creatine phosphokinase (CPK).18,19
Upadacitinib is a novel selective Janus kinase (JAK) 1 inhibitor.  JAK1 inhibition blocks 
the signaling of many important pro-inflammatory cytokines, including interleukin (IL)-2, 
IL-6, IL-7, and IL-15, which are known contributors to inflammatory disorders.  Through 
modulation of these proinflammatory cytokine pathways, upadacitinib offers the potential 
for effective treatment of inflammatory or autoimmune disorders such as rheumatoid 
arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), giant cell arteritis 
(GCA), Takayasu arteritis, polyarticular course juvenile idiopathic arthritis (pcJIA), 
Crohn's disease (CD), UC and atopic dermatitis (AD).  The clinical hypothesis is that, 


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based on the differentiated selectivity profile for JAK inhibition, upadacitinib could 
demonstrate an improved benefit/risk profile compared to other less selective JAK 
inhibitors or other therapeutic strategies for patients with inflammatory diseases. 
To date, upadacitinib has been investigated in 22 Phase 1 studies with healthy volunteers 
(one of which also employed a substudy in subjects with mild to moderate RA), and 
multiple Phase 2 or Phase 3 studies for indications of RA, CD, AD, PsA and UC.  
Upadacitinib has been shown to be effective in the treatment of the indicated medical 
conditions based on the data available from the various studies.  Safety results across the 
studies showed that upadacitinib was well tolerated and the types and frequencies of AEs 
were consistent with subjects with the medical conditions receiving immunomodulatory 
therapy.  Many of the safety findings are expected for the class products with JAK 
inhibition, such as infections, increase in LDL-C and HDL-C, and asymptomatic and 
transient CPK elevation.   
Upadacitinib has been evaluated in Phase 2b dose ranging placebo-controlled study in 
subjects with moderately to severely active UC with a history of inadequate response to or 
intolerant to immunosuppressants, corticosteroids or biologic therapies (Study M14-234 
Substudy 1).  At the time of this protocol development, Phase 2b interim results from 
Study M14-234 Substudy 1 Part 1 became available.  The primary objective of 
demonstrating statistically significant dose-response relationship of upadacitinib 
compared to placebo for the primary endpoint and all ranked secondary endpoints was 
met, with the highest rates observed in 45 mg once daily (QD) treatment group for both 
clinical and endoscopic endpoints.  Upadacitinib was generally safe and well tolerated.  
No new safety concerns were identified compared to what has been observed in studies of 
upadacitinib in other disease indications.
A detailed discussion of the preclinical toxicology, metabolism, pharmacology and safety 
experience with upadacitinib can be found in the current Investigator's Brochure.20


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3.1
Differences Statement
This Phase 3 study differs from other upadacitinib studies as it is one of the two large-
scale studies to evaluate the efficacy, safety and pharmacokinetics of upadacitinib in 
subjects with moderately to severely active UC.
3.2
Benefits and Risks
Despite the availability of various UC therapies, including biologic therapies such as anti-
TNFs, many patients still do not respond adequately to these treatments, or gradually lose 
response over time.  Thus, there remains a clear medical need for additional therapeutic 
options in UC for patients with inadequate response to, loss of response to, or intolerance 
to conventional therapies but have not failed biologic therapy.
Clinical efficacy of JAK inhibition has been demonstrated in the treatment of UC.  
Tofacitinib is recently approved for the treatment of UC.21  However, the non-selectivity 
of tofacitinib targeting JAK1, JAK2 and JAK3 has been associated with a number of 
safety issues.17-19,22,23
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 inhibition which are thought to be mediated by inhibition of JAK2 and 
JAK3 signaling pathways.  
The available long-term safety data from the Phase 3 rheumatoid arthritis (RA) studies 
with upadacitinib did not show any new significant safety concerns compared to the 
marketed JAK inhibitors. The findings of an increased risk of infections, herpes zoster, 
and abnormal laboratory changes have been observed (e.g., elevations of serum 
transaminases, lipids, creatine phosphokinase, and reductions in hemoglobin and white 
blood cells) with upadacitinib. The incidence rates of other clinically important adverse 
events such as cardiovascular events, malignancies and mortality reported during the RA 
studies were within the expected range for the general population or for a population of 
patients with moderately to severely active RA. Events of deep vein thrombosis (DVT) 


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and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors 
including upadacitinib.
The results of genetic toxicology testing indicate that upadacitinib is not genotoxic; 
however, upadacitinib is teratogenic based on animal studies, which necessitates 
avoidance of pregnancy in females of childbearing potential. Based on the calculated 
safety margins for human fetal exposure with seminal fluid transfer, there is judged to be 
no risk to the pregnancy of female partners of male subjects who are treated with 
upadacitinib. Male trial participants are therefore not required to use contraception when 
participating in upadacitinib clinical trials.
We propose to initiate a Phase 3 study in UC subjects based on the following supportive 
findings:  1) demonstrated improved potency of upadacitinib versus tofacitinib in 
preclinical models of inflammation; 2) confirmed JAK1 selectivity of upadacitinib in both 
preclinical and clinical settings; 3) acceptable preclinical toxicological findings in chronic 
toxicity studies in two species; 4) acceptable safety and tolerability profile of upadacitinib 
in single ascending dose and multiple ascending dose studies in healthy volunteers; 
5) evidence that JAK inhibition in inflammatory bowel disease results in clinical and 
endoscopic improvement; and 6) evidence of efficacy and safety in a different 
inflammatory disease (rheumatoid arthritis).  The current Phase 3 Study M14-675 will 
assess the benefit to risk profile of upadacitinib in subjects with moderately to severely 
active UC who have had an inadequate response or intolerance to oral aminosalicylates, 
immunosuppressants, corticosteroids, and/or biologic therapies.
As presented above, the completed Phase 2 dose ranging Study M14-234 Substudy 1 has 
demonstrated superior efficacy of upadacitinib with an acceptable safety profile compared 
to placebo in subjects with moderately to severely active UC.  The benefit-risk profile of 
upadacitinib in this Phase 2 study supports further evaluation of upadacitinib in subjects 
with UC.24


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In view of the coronavirus (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.
3.3
Safety Evaluations
Safety will be assessed by AE monitoring, physical examination, vital signs, ECG, 
imaging and clinical laboratory testing during the study.  Laboratory assessments will 
include hematologic parameters, chemistry, liver function tests, and lipid parameters.
4.0
Study Objective
The primary objective of Study M14-675 (Phase 3 induction) is to evaluate the efficacy 
and safety of upadacitinib 45 mg once daily (QD) compared to placebo in inducing 
clinical remission (per Adapted Mayo score) in subjects with moderately to severely 
active UC who have demonstrated inadequate response, loss of response, or intolerance to 
oral aminosalicylates, immunosuppressants, corticosteroids, and/or biologic therapies.
The secondary objectives of the study are to evaluate the efficacy of upadacitinib 45 mg 
QD comparing with placebo in ranked secondary endpoints of achieving endoscopic 
improvement, endoscopic remission, clinical response per Adapted Mayo Score, clinical 
response per Partial Adapted Mayo score, histologic-endoscopic mucosal improvement, 
no bowel urgency, no abdominal pain, histologic improvement, mucosal healing, and 
change in IBDQ total score and FACIT-F score.
The study will allow enrollment of up to 30% of enrolled bio-IR subjects who have failed 
3 or more biologics.  Among non-bio-IR subjects, subjects who have used a biologic up to 
1 year and have discontinued for reasons other than inadequate response, loss of response, 
or intolerance (e.g., change of insurance/reimbursement, well-controlled disease, etc.) 
may be enrolled but must meet other criteria for inadequate response, loss of response, or 
intolerance to aminosalicylates, corticosteroids, or immunosuppressants as defined in the 
protocol.  The study will allow for enrollment of up to 20% enrolled non-bio-IR subjects 
who could also have previous use of a biologic therapy but discontinued based on reasons 


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35
other than inadequate response, loss of response, or intolerance.  The study will also 
evaluate the efficacy of an additional 8-week upadacitinib 45 mg QD treatment in subjects 
who did not achieve clinical response in the initial 8-week induction phase.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
At the time of this amendment, screening for the study has closed.
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy, safety, and pharmacokinetics of upadacitinib as 
induction therapy in subjects with moderately to severely active UC who have been 
inadequate responders or intolerant to oral aminosalicylates, immunosuppressants, 
corticosteroids, and/or biologic therapies.  The number of enrolled non-biologic-
inadequate responders (non-bio-IR) subjects will be at least 25% and not exceed 50%. 
Study M14-675 will allow enrollment of up to 30% of enrolled bio-IR subjects who have 
failed 3 or more biologics.  Among non-bio-IR subjects, subjects who have used a 
biologic up to 1 year and have discontinued for reasons other than inadequate response, 
loss of response, or intolerance (e.g., change of insurance/reimbursement, well-controlled 
disease, etc.) may be enrolled but must meet other criteria for inadequate response, loss of 
response, or intolerance to aminosalicylates, corticosteroids, or immunosuppressants as 
defined in the protocol.  The study will allow for enrollment of up to 20% enrolled non-
bio-IR subjects who could also have previous use of biologic therapy but discontinued 
based on reasons other than inadequate response, loss of response, or intolerance.  
The study is designed to enroll approximately 462 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.


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The study duration could be up to 25 weeks (excluding a possible washout period), 
including a Screening Period of up to 5 weeks, an 8-week double-blind Induction Period, 
an 8-week Open Label Extended Treatment Period (for eligible subjects), and a 30-day 
Follow-Up Period, if the subject does not meet eligibility to proceed to Study M14-234 
Substudy 3.
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided 
in the subsequent section.  Every effort should be made to ensure the safety of subjects 
and site staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, follow the updates 
below on how to proceed.  These measures will only be implemented under the protocol 
in countries that are affected by the COVID-19 pandemic.
Subjects (n = 462) who consent and meet all of the inclusion and none of the exclusion 
criteria as defined in Section 5.2.1 and Section 5.2.2 will be enrolled into Study M14-675, 
which consists of two parts:  (Part 1) a randomized, double-blind, placebo-controlled 
8-week induction study; (Part 2) an 8-week open-label Extended Treatment Period for 
clinical non-responders from Part 1.  The number of non-bio-IR subjects will be at least 
25% and not exceeding 50%.
In Part 1, approximately 462 subjects will be enrolled.  Eligible subjects will be 
randomized in a 2:1 ratio to one of the two treatment groups (double-blind upadacitinib 
45 mg QD or matching placebo) for 8 weeks.  
The following are the treatment groups for Part 1 of Study M14-675:
●
Group 1:  Upadacitinib 45 mg QD (blinded, n = 308)
●
Group 2:  Placebo QD (blinded, n = 154)


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Part 2 is an open-label, 8-week Extended Treatment Period for subjects who did not 
achieve clinical response at Week 8 in Part 1.  The objectives of Part 2 are to offer 
upadacitinib induction treatment to placebo clinical non-responders (defined by Adapted 
Mayo Score) from Part 1, and to evaluate delayed clinical response to upadacitinib in 
subjects who do not initially respond to upadacitinib during Part 1.
During COVID-19 pandemic, investigators should make the best effort to perform the 
endoscopies required per protocol. For subjects with missing endoscopy at Week 8/16
when endoscopies cannot be performed due to the COVID-19 pandemic, the site should 
assess the status of clinical response defined by the Partial Adapted Mayo Score. If the 
subject is a clinical responder at Week 8/16, the subject may enter Study M14-533
Cohort 1.  If the subject is a clinical non-responder at Week 8, the subject may enter 
Part 2.  If the subject is a clinical non-responder at Week 16 the subject will discontinue 
from the study.  A notification should be sent to the TAMD as to the responder status and 
which part of the program the subject will be going to prior to the transfer taking place.
The blind from Part 1 will be maintained as these subjects will be assessed simply as non-
responders and moved to Part 2 for further treatment in the study.  All eligible subjects 
entering Part 2 will receive open-label treatment with upadacitinib 45 mg QD for 
8 additional weeks (until Week 16). 
Subjects who achieve clinical response defined by Adapted Mayo Score at Week 8 or 
Week 16 and do not meet any study discontinuation criteria will be eligible to enroll into 
Study M14-234 Substudy 3 following written informed consent. They do not need to 
meet the listed inclusion and exclusion criteria in the Study M14-234 protocol prior to this 
transfer to Substudy 3.  Subjects with missing Week 8 or/and Week 16 endoscopy during 
the period of COVID-19 pandemic will not be eligible to enter Study M14-234 
Substudy 3. Subjects who do not achieve clinical response at Week 16 will be 
discontinued from the study and will not be eligible to enroll in Study M14-234.  Subjects 
who are discontinued will complete the 30-Day Follow-up Visit as noted in Appendix D.


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The data collected from subjects in Part 2 will not be part of the primary efficacy analysis 
for the induction study; descriptive statistics will be used, and the results will be reported 
separately in the clinical study report.
Subjects are not eligible to enter into Part 2 until the Week 8 endoscopy has been 
completed, except for subjects missing endoscopy due to COVID-19 pandemic.  The 
central reader will also review the endoscopy video, but movement of the subject to Part 2 
will be based on the local reader scoring.  Visits will occur at Week 10, 12, 14, and 16, 
and an endoscopy will be performed at Week 16. A flexible sigmoidoscopy is 
recommended, however the use of colonoscopy or flexible sigmoidoscopy is at the 
investigator's discretion based on local practice.
Figure 1 shows the schematic for Study M14-675.
Figure 1.
Study M14-675 Study Design


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Screening
Subjects should receive a full explanation of the study design and study procedures and 
provide a written informed consent prior to performing any screening procedure.  Once 
written informed consent is obtained, subjects will undergo screening procedures as 
outlined in Appendix C with a maximum of 35 days allowed for the screening period.  
The Baseline Visit can be scheduled and a subject randomized at any point during this 
35-day period once all eligibility criteria have been met.
An electronic diary (e-diary) will be dispensed and training will be provided to the subject 
at the Screening Visit in Study M14-675 (see Section 10.3 details).
With the exception of the QuantiFERON TB-Gold Plus and PPD tests (requirements 
outlined in Section 5.3.1 [Clinical Laboratory Tests]), exclusionary laboratory values can 
be re-tested once during the Screening Period. If the re-tested lab value(s) remain(s) 
exclusionary, the subject will be considered a screen failure. Redrawing samples if 
previous samples were unable to be analyzed would not count as a retest since previous 
result was never obtained.
Subjects who have been taking exclusionary medications prior to screening or Baseline 
must complete medication washout.  The duration is based on the excluded medication as 
described in the protocol.  During Screening, biologic drug levels may be optionally 
assessed at the investigator's discretion as an alternative to completing the required 
washout period: (1) infliximab and natalizumab:  may be tested approximately 4 weeks or 
later from the last dose; (2) adalimumab, certolizumab, golimumab, or vedolizumab: may 
be tested approximately 6 weeks or later from the last dose; (3) ustekinumab:  may be 
tested approximately 8 weeks or later from the last dose.  If the biologic drug is not 
detected, the subject will be considered as eligible and the washout period is not required.
Protocol-related adverse events should be reviewed and subjects must complete the 
washout prior to the Baseline Visit. 


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If some subjects screen and are unable to enter Study M14-675 due to enrollment limits, 
these subjects may be moved to Study M14-234, Substudy 2 for induction treatment if 
enrollment limits on that study have not been fulfilled.
8-Week Induction Period – Part 1
This period will begin at the Baseline Visit (Week 0) and will end at the Week 8 Visit.  At 
the Baseline Visit, subjects who meet all the inclusion criteria and none of the exclusion 
criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the study and 
randomized to the double-blind induction period.  During this period of the study, subjects 
will visit the study site at Weeks 2, 4, 6, and 8.  A ± 3-day window is permitted around 
scheduled study visits.  The last dose of study drug during this period is recommended to 
be taken the day prior to the Week 8 Visit when possible.
NOTE: All Baseline Visit procedures must be performed onsite.
8-Week Extended Treatment Period - Part 2
The period will begin after the Week 8 endoscopy in Part 1 and will end at the Week 16 
Visit. 
At Week 8, subjects in Part 1 who did not achieve clinical response (defined by Adapted 
Mayo Score) will be enrolled into Part 2 and receive open label upadacitinib 45 mg QD 
for an additional 8 weeks.  Clinical response is defined as decrease from baseline in the 
Adapted Mayo score ≥ 2 points and ≥30% from baseline, PLUS a decrease in rectal 
bleeding score (RBS) ≥ 1 or an absolute RBS ≤ 1.
During COVID-19 pandemic, investigators should make the best effort to perform the 
endoscopies required per protocol.  For subjects with missing endoscopy at Week 8/16
when endoscopies cannot be performed due to the COVID-19 pandemic, the site should 
assess the status of clinical response defined by the Partial Adapted Mayo Score.  If the 
subject is a clinical responder at Week 8/16, the subject may enter Study M14-533
Cohort 1.  If the subject is a clinical non-responder at Week 8, the subject may enter 


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Part 2.  If the subject is a clinical non-responder at Week 16 the subject will discontinue 
from the study.  A notification should be sent to the TAMD as to the responder status and 
which part of the program the subject will be going to prior to the transfer taking place.
During this period of the study, subjects will visit the study site at Weeks 10, 12, 14, and 
16.  A ± 3-day window is permitted around scheduled study visits.  The last dose of study 
drug during this period is recommended to be taken the day prior to the Week 16 Visit 
when possible.
Re-Screen
Subjects that initially screen fail for the study will be permitted to re-screen following re-
consent.  For any subjects who screened and who were unable to enter the program during 
Study M14-234 Substudy 1 due to enrollment limits, these subjects may also be 
rescreened into Study M14-234 Substudy 2 or Study M14-675.
The subject must meet all the inclusion and none of the exclusion criteria at the time of re-
screening in order to qualify for the study.  There is no minimum period of time a subject 
must wait to re-screen for the study and there is no maximum number of re-screens 
allowed for a given subject.  If the subject had a complete initial screening evaluation 
including the assessment of a purified protein derivative (PPD) test (or equivalent), or 
Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold Plus test or T-SPOT 
TB test), chest x-ray, hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, Beta-D-
glucan (Japan only) and electrocardiogram (ECG), these tests will not be required to be 
repeated for re-screening provided the conditions noted in Section 5.3.1.1 are met and no 
more than 90 calendar days have passed since the date of testing.
If a subject is being rescreened within 14 days (from the date of the previous screening 
testing), it is not required to repeat Screening testing for chemistry/hematology, urinalysis, 
serum pregnancy, and Clostridium difficile (C. difficile). 


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An endoscopy with biopsy will not be required to be repeated for re-screening provided 
the conditions noted in Section 5.3.1.1 are met and re-consent is no more than 30 calendar 
days after the initial screening endoscopy.
All other screening procedures will be repeated.  As appropriate, sites are encouraged to 
contact the AbbVie TA MD to confirm if subjects should or should not be re-screened.
Re-screened subjects will retain the same subject number assigned at the initial screening.
5.2
Selection of Study Population
It is anticipated that approximately 462 subjects with moderately to severely active UC 
who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized at approximately 400 study centers worldwide.  Approximately 210 subjects 
from Study M14-675 who achieve clinical response per Adapted Mayo score following 
induction with upadacitinib will be re-randomized into Study M14-234 Substudy 3 
(52-Week maintenance).
A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria specified in Section 5.2.1 and none of the exclusion criteria specified in 
Section 5.2.2 of this protocol.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Male or female ≥ 16 and ≤ 75 years of age at Baseline.
●
Adolescent subjects at the age of 16 and 17 years old will be enrolled if 
approved by the country or regulatory/health authority.  If these approvals 
have not been granted, only subjects ≥ 18 years old will be enrolled
●
Adolescent subjects at the age of 16 and 17 years old must weigh ≥ 40 kg and 
meet the definition of Tanner Stage 5 (refer to Appendix H) at the screening 
Visit


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2.
Diagnosis of UC for 90 days or greater prior to Baseline, confirmed by 
colonoscopy during the Screening Period, with exclusion of current infection, 
colonic dysplasia and/or malignancy.  Appropriate documentation of biopsy results 
consistent with the diagnosis of UC, in the assessment of the investigator, must be 
available.  
3.
Active UC with an Adapted Mayo Score of 5 to 9 points and endoscopy subscore 
of 2 to 3 (confirmed by central reader). 
4.
Demonstrated an inadequate response to, loss of response to, or intolerance to at 
least one of the following treatments including, oral aminosalicylates, 
corticosteroids, immunosuppressants, and/or biologic therapies, in the opinion of 
the investigator, as defined below: 
Note: An inadequate response, loss of response, or intolerance to Oral 
Aminosalicylates will NOT count towards eligibility for the following countries: 
Austria, Czechia, Finland, France, Ireland, Italy, Latvia, Lithuania, Norway, 
Poland, Portugal, Spain, Sweden and United Kingdom.
●
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide)
○
Signs and symptoms of persistently active disease, in the opinion of the 
investigator, during a current or prior course of at least 4 weeks of 
treatment with 2.4 g/day mesalamine, 4 g/day sulfasalazine, 1 g/day 
olsalazine, or 6.75 g/day balsalazide.
●
Corticosteroids 
○
Signs and symptoms of persistently active disease despite a history of at 
least one induction regimen that included a dose equivalent to prednisone 
≥40 mg/day orally for at least 3 weeks or intravenously for 1 week, OR
○
Unable to taper corticosteroids to below a dose equivalent to prednisone 
10 mg daily orally without recurrent active disease, OR
○
Signs and symptoms of persistently active disease during or after a course 
of at least 4 weeks of treatment with 9 mg/day budesonide or 5 mg/day 
beclomethasone, OR


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○
Unable to taper oral budesonide to at or below 6 mg/day without recurrent 
active disease, OR
○
History of intolerance to corticosteroids (including, but not limited to 
Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, 
infection).
●
Immunosuppressants
○
Signs and symptoms of persistently active disease despite a history of at 
least one 90-day regimen of oral azathioprine (≥ 1.5 mg/kg/day; for 
subjects in Japan, China, and Taiwan only:  ≥1.0 mg/kg/day), 
6-mercaptopurine (≥1 mg/kg/day [for subjects in Japan, China, and 
Taiwan only:  ≥ 0.6 mg/kg/day, rounded to the nearest available tablet or 
half tablet formulation] or a documented 6-thioguanine nucleotide 
[6-TGN] level of 230 – 450 pmol/8 × 108 red blood cell [RBC] count or 
higher on the current dosing regimen), injectable methotrexate (MTX 
≥15 mg/week subcutaneous [SC] or intramuscular), or tacrolimus (for 
subjects in Japan and Taiwan only:  documented trough level of 5 –
10 ng/mL, OR
○
History of intolerance to at least one immunosuppressant (including, but 
not limited to nausea/vomiting, abdominal pain, pancreatitis, liver enzyme 
abnormalities, lymphopenia, infection)
Note:  Oral MTX use is allowed during the study, however prior or current 
use of oral MTX is not sufficient for inclusion into the study unless these 
subjects were previously treated with aminosalicylates, corticosteroids or 
immunosuppressants (azathioprine or 6-MP) and have inadequate response 
to, loss of response to or intolerance to the therapy as defined above.
●
Biologic Agents for UC
Signs and symptoms of persistently active disease despite a history of any of 
the following:
○
at least one 6-week induction regimen of infliximab (≥ 5 mg/kg 
intravenously [IV] at 0, 2, and 6 weeks),
○
at least one 4-week induction regimen of adalimumab (one 160 mg 
subcutaenous [SC] dose followed by one 80 mg SC dose [or one 80 mg SC 


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dose in countries where this dosing regimen is allowed] followed by 
one 40 mg SC dose at least 2 weeks apart),
○
at least one 2-week induction regimen of golimumab (one 200 mg SC dose 
followed by one 100 mg SC dose at least 2 weeks apart), 
○
at least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2, 
and 6 weeks), 
○
at least one induction regimen of ustekinumab, a single IV using weight-
based dosing (260 mg for subjects with body ≤ 55 kg; 390 mg for subjects 
with body weight > 55 kg and ≤ 85 kg; 520 mg for subjects with body 
weight > 85 kg OR
●
Recurrence of symptoms during scheduled maintenance dosing following prior 
clinical benefit (discontinuation despite clinical benefit does not qualify), OR
●
History of intolerance to at least one biologic agent (including, but not limited 
to infusion-related reaction, demyelination, congestive heart failure, infection)
Note:  Non-bio-IR subjects who have received a prior biologic for up to 1 year may 
be enrolled, however, subjects must have discontinued the biologic for reasons 
other than inadequate response or intolerance (e.g., change of insurance, well 
controlled disease), and must meet the criteria for inadequate response, loss of 
response or intolerance to aminosalicylates, corticorsteroids and/or 
immunosuppressants as defined above.
5.
Female subjects of childbearing potential must have a negative serum pregnancy 
test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit 
prior to study drug dosing
Note:  subjects with borderline serum pregnancy test at Screening must have 
absence of clinical suspicion of pregnancy or other pathological cause of borderline 
result and a serum pregnancy test ≥ 3 days later to document continued lack of 
positive result.  For subjects in Ireland and Argentina, a repeat serum pregnancy 
test ≥ 3 days later that is still borderline will result in screen failure.
6.
If female, subject must meet the criteria as stated in Section 5.2.4 Contraception 
Recommendations.


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7.
Subject is judged to be in otherwise good health as determined by the Investigator 
based upon the results of medical history, laboratory profile, physical examination 
and a 12-lead electrocardiogram (ECG) performed during Screening.
8.
Subject must be able and willing to give written informed consent and to comply 
with the requirements of this study protocol.  In Japan, if the subject is < 20 years 
old, a subject's parent or legal guardian must be willing to give written informed 
consent.
Rationale for the Inclusion Criteria
Criteria
Rationale
1 – 4, 7
In order to select the appropriate subject population with a disease status 
representative of the target population for evaluation
5 – 6 
The effect of upadacitinib on pregnancy and reproduction is unknown
8
In accordance with good clinical practice (GCP) and in order to select 
subjects who will comply with study procedures for adequate evaluation
5.2.2
Exclusion Criteria
1.
Subject with current diagnosis of Crohn's disease (CD) or diagnosis of 
indeterminate colitis (IC).
2.
Current diagnosis of fulminant colitis and/or toxic megacolon.
3.
Subject with disease limited to the rectum (ulcerative proctitis) during the 
screening endoscopy.
4.
History of colectomy (total or subtotal), ileoanal pouch, Kock pouch, or ileostomy 
or is planning bowel surgery.
5.
Received treatment with rectal aminosalicylates or corticosteroids, other 
enemas/suppositories (other than required for endoscopy), within 14 days prior to 
the Screening endoscopy and during the remainder of the Screening Period. 


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6.
Received cyclosporine, tacrolimus, mycophenolate mofetil, or thalidomide within 
30 days prior to Baseline. 
7.
Subjects who received azathioprine or 6-mercaptopurine within 10 days of 
Baseline.
8.
Received intravenous corticosteroids within 14 days prior to Screening or during 
the Screening Period.
9.
Subject on MTX or oral aminosalicylates who:
●
Has not been on the current course of MTX for at least 42 days prior to 
Baseline, and has not been on stable doses for at least 28 days prior to 
Baseline; 
●
has not been on stable doses of oral aminosalicylates for at least 14 days prior 
to Baseline; 
●
has discontinued use of aminosalicylates within 14 days of Baseline.
10.
Subject on treatment with corticosteroids who meet the following:
●
Oral corticosteroid dose > 30 mg/day (prednisone or equivalent) or has not 
been on the current course for at least 14 days prior to baseline and on a stable 
dose for at least 7 days prior to Baseline;
●
Oral budesonide dose > 9 mg/day or has not been on the current course for at 
least 14 days prior to Baseline and on a stable dose for at least 7 days prior to 
Baseline
●
Oral beclomethasone dose > 5 mg/day; or has not been on the current course 
for at least 14 days prior to baseline and on a stable dose for at least 7 days 
prior to Baseline
●
Subject has been taking both oral budesonide (or oral beclomethasone) and 
oral prednisone (or equivalent) simultaneously, with the exception of topical or 
inhalers within 14 days prior to Screening or during the Screening Period.
11.
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB.


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12.
Subject who received fecal microbial transplantation within 30 days prior to 
Baseline.
13.
Subject on UC-related antibiotics who has not been on stable doses for at least 
14 days prior to Baseline or has discontinued these medications within 14 days of 
Baseline.
14.
Subjects who received any of the following biologic therapy:
!
Infliximab, certolizumab, adalimumab, golimumab, vedolizumab and 
natalizumab within 8 weeks prior to Baseline.  OR
!
Ustekinumab within 12 weeks prior to Baseline.
Note:  If there is proper documentation of undetectable drug level measured by a 
commercially available assay for any of the approved biologics above, there is no 
minimum washout prior to Baseline.
15.
Subject with previous exposure to JAK inhibitor (e.g., tofacitinib, baricitinib, 
filgotinib, upadacitinib).
16.
Subject who received non-steroidal anti-inflammatory drugs (NSAIDs) (except 
topical NSAIDs and the use of low dose aspirin for cardiovascular [CV] protection) 
within 7 days prior to Baseline.
17.
Subject received traditional Chinese medicine within 30 days prior to baseline. 
18.
Subject received live vaccine(s) within 30 days (8 weeks for Japan) prior to 
Baseline, or who is expected to need live vaccination during study participation 
including at least 30 days (or longer if required locally) (8 weeks for Japan) after 
the last dose of study drug.
19.
Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong 
CYP3A inducers during the Screening Period and through the end of the study, as 
specified in Section 5.2.3.3
20.
Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN 
at any time during study treatment.


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21.
Subject who received any investigational agent or procedure within 30 days or 
5 half-lives prior to Baseline, whichever is longer or is currently enrolled in an 
interventional study.
22.
Subject with positive Clostridium difficile (C. difficile) toxin stool assay during 
Screening.
23.
Infection(s) requiring treatment with intravenous anti-infectives within 30 days 
prior to the Baseline Visit or oral/intramuscular anti-infectives within 14 days prior 
to the Baseline Visit.
24.
Chronic recurring infection and/or active viral infection that, based on the 
investigator's clinical assessment, makes the subject an unsuitable candidate for the 
study.
25.
Subject has current or past history of recurrent or disseminated (even a single 
episode) herpes zoster.
26.
Subject has current or past history of disseminated (even a single episode) herpes 
simplex
27.
Subject has HBV, HCV, or human immunodeficiency virus (HIV) infection 
defined as:
●
HBV:  hepatitis B surface antigen, (HBs Ag) positive (+) or detected 
sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain 
reaction (PCR) qualitative test for subject who are hepatitis B core antibody; 
(HBc Ab) positive (+) (and for Hepatitis B surface antibody positive (+) 
subjects where mandated by local requirements); 
●
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV 
antibody (HCV Ab);
●
HIV:  confirmed positive anti-HIV antibody (HIV Ab).
28.
Prior or current gastrointestinal dysplasia, other than completely removed low-
grade dysplastic lesion in any biopsy performed during or before the Screening 
endoscopy.


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29.
History of any malignancy except for successfully treated nonmelanoma skin 
cancer (NMSC) or localized carcinoma in situ of the cervix. 
30.
History of spontaneous gastrointestinal (GI) perforation (other than appendicitis or 
mechanical injury), diverticulitis or significantly increased risk of GI perforation 
per investigator's judgment. 
31.
Screening laboratory and other analyses show any of the following abnormal 
results:
●
Serum Aspartate Transaminase (AST) or Alanine Transaminase (ALT) 
> 2 × upper limit of the reference range (ULN);
●
Estimated glomerular filtration rate (eGFR) by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula 
< 30 mL/min/1.73 m2;
●
Total White Blood Cell (WBC) count < 2,500/μL;
●
Absolute neutrophil count (ANC) < 1,200/μL;
●
Platelet count < 100,000/μL;
●
Absolute lymphocytes count < 750/μL;
●
Hemoglobin < 9 g/dL.
32.
Female subject who is pregnant, breastfeeding or considering becoming pregnant 
during the study and within 30 days after the last dose of study drug, or has positive 
pregnancy test at Screening (serum) or Baseline (urine).  
33.
History of an allergic reaction or significant sensitivity to constituents of the study 
drug (and its excipients) and/or other products in the same. 
34.
History of clinically significant (per investigator's judgment) drug or alcohol abuse 
in the last 6 months.
35.
Subject who previously received stem cell transplantation.
36.
Subject has been a previous recipient of an organ transplant which requires 
continued immunosuppression.


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37.
For Japan subjects only:  positive result of beta-D-glucan or two consecutive 
indeterminate results of beta-D-glucan (screening for pneumocystis jiroveci 
infection);
38.
Received cytapheresis treatment (GCAP, LCAP etc.) within 60 days prior to 
Screening.
39.
For Japan subjects only:  received ATM treatment (antibiotic combination therapy 
with amoxicillin, tetracycline and metronidazole) during the Screening Period.
40.
Any of the following cardiovascular or thrombotic conditions:
●
Recent (within past 6 months) cerebrovascular accident, myocardial infarction 
or coronary stenting
●
Recent (within past 6 months) moderate to severe congestive heart failure 
(New York Heart Association class III or IV)
●
Prior history of thrombotic events, including deep vein thrombosis and 
pulmonary embolism
●
Known inherited conditions that predispose to hypercoagulability. 
41.
Conditions that could interfere with drug absorption including but not limited to 
short bowel syndrome or gastric bypass surgery; subjects with a history of gastric 
banding/segmentation are not excluded.
42.
History of clinically significant medical condition or any other reason which, in the 
opinion of the investigator, would interfere with the subject's participation in this 
study, would make the subject an unsuitable candidate to receive study drug, or 
would put the subject at risk by participating in the protocol.
Rationale for the Exclusion Criteria
Criteria
Rationale
1 – 19
To select the appropriate subject population
20 – 31, 33 – 42
To ensure safety of the subjects throughout the study
32
The impact of upadacitinib on pregnancies is unknown


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5.2.3
Prior and Concomitant Therapy
5.2.3.1
Prior Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject has received within 30 days prior to 
Baseline, 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 in source documents 
and the electronic case report forms (eCRFs).  
If subjects have/had ever been treated with, including, but not limited to UC-related 
antibiotics, corticosteroid, immunosuppressant, aminosalicylates or biologic agents, the 
duration of therapy, maximum dose, reason for use and reason(s) for termination of 
treatment will be recorded in appropriated eCRF.  The details of dates of administration 
and dosages will be also recorded within the past 90 days.
The history of previous use (including the duration of therapy, the highest known dose 
taken, reason for use and reason[s] for termination of treatment) of UC related 
corticosteroids, immunosuppressant, aminosalicylates, UC-related antibiotics or biologic 
agents will be recorded in the appropriate eCRF.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapy.
5.2.3.2
Concomitant Therapy
Concomitant UC-Related Medications (Oral Corticosteroids, Antibiotics, 
Aminosalicylates, and/or Methotrexate):
All UC-Related Concomitant Medications should be kept on the stable dose in 
Study M14-675.  Dose may be decreased or terminated in the event of moderate-to-severe 
treatment related toxicity (e.g., leukopenia or elevated liver enzymes) in the opinion of the 
investigator. 


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Changes in all concomitant medications will be assessed at each study visit from Baseline 
(Week 0) through Week 8/Premature Discontinuation (PD) Visits in Part 1 and through 
Week 16/PD Visits in the extended treatment period, as applicable.  Any changes will be 
documented in the source documents and captured on the appropriate eCRF page.
Vaccines
Vaccines recommended by local guidelines should be considered.  If the investigator 
chooses to administer a vaccine, this should be completed before first dose of study drug 
with appropriate precautions and time interval.  It is recommended that subjects be up to 
date for recommended inactivated, toxoid or biosynthetic vaccines, such as injectable flu 
vaccine, pneumococcal, and pertussis (Tdap). 
If the subject and investigator choose to receive/administer live vaccines, these 
vaccinations must be completed (per local label) at least 30 days (8 weeks for subjects in 
Japan) before first dose of study drug.  Live vaccinations are prohibited during study 
participation including at least 30 days (or longer if required locally) after the last dose of 
study drug. 
If the live herpes zoster vaccine is to be administered and there is no known history of 
primary varicella (chicken pox), preexisting immunity to varicella should be confirmed 
with antibody testing at or prior to Screening and prior to administration of the herpes 
zoster vaccine.  If screening varicella antibody testing is negative, the live herpes zoster 
vaccine should not be administered. 
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding concomitant or prior therapies.
5.2.3.3
Prohibited Therapy
The following are prohibited medications during the study:


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Biologic Therapies
Subjects must have discontinued any biologic therapy prior to the first dose of study drug 
as specified in the washout procedures (Exclusion Criterion 14, Section 5.2.2).  For all 
other biologic therapies the required washout period is at least five times the mean 
terminal elimination half-life of the medication prior to the first dose of study drug.  No 
minimum washout prior to Baseline is required for a biologic therapy if an undetectable 
drug level measured by a commercially available assay is documented.
●
All biologic therapy including but not limited to the following:
○
Etanercept;
○
Abatacept;
○
Anakinra;
○
Rituximab;
○
Natalizumab;
○
Tocilizumab;
○
Efalizumab;
○
Ustekinumab;
○
Belimumab;
○
Golimumab;
○
Vedolizumab;
○
Infliximab;
○
Adalimumab;
○
Certolizumab pegol
○
Secukinumab
●
Other JAK inhibitors (e.g., tofacitinib [Xeljanz®], ruxolitinib [Jakafi®], 
baricitinib [Olumiant®], peficitinib, [Smyraf®], abrocitinib [PF-04965842], and 
filgotinib)


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Vaccines
If the subject and investigator choose to receive/administer live vaccines, these 
vaccinations must be completed (per local label) at least 30 days (8 weeks for subjects in 
Japan) before first dose of study drug (see Section 5.2.3 Prior and Concomitant Therapy).  
Live vaccinations are prohibited during study participation including at least 30 days (or 
longer if required locally) after the last dose of study drug.
Examples of live vaccines include, but are not limited to, the following: 
●
Monovalent live influenza A (H1N1) (intranasal) 
●
Seasonal trivalent live influenza (intranasal) 
●
Zostavax (herpes zoster, live attenuated)
●
Rotavirus; 
●
Varicella (chicken pox) 
●
Measles-mumps-rubella or measles-mumps-rubella-varicella 
●
Oral polio vaccine 
●
Smallpox 
●
Yellow fever 
●
Bacille Calmette-Guérin (BCG) 
●
Typhoid (oral)
Administration of inactivated (non-live) vaccines is permitted prior to or during the study 
according to local practice guidelines.  Examples of common vaccines that are 
inactivated, toxoid or biosynthetic include, but are not limited to, injectable influenza 
vaccine, pneumococcal, Shingrix (zoster vaccine, recombinant, adjuvanted) and pertussis 
(Tdap) vaccines. 
Other Medications
●
Intravenous corticosteroid use is prohibited within 14 days prior to Screening 
or during the Screening Period and during the study.  (Initiating rectal or 
systemic corticosteroids use is prohibited during the induction treatment 


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period.  Patients who initiate rectal or systemic corticosteroid for any reason 
during the study must be discussed with the TA MD.)
●
Rectal aminosalicylates or corticosteroid enemas/suppositories are prohibited 
within 14 days prior to Screening endoscopy, during the remainder of the 
Screening Period, and during the study.
●
Cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide use is 
prohibited within 30 days prior to Baseline and during the study.
●
Azathioprine or 6-mercaptopurine (6-MP) use is prohibited within 10 days 
prior to Baseline and during the study.
●
NSAID (except topical NSAIDs and the use of low dose aspirin for 
cardiovascular protection) within 7 days prior to Baseline and during the study.
●
Total parenteral nutrition is prohibited during the study.
●
Cytapheresis treatment is prohibited within 60 days prior to Screening and 
during the study.
●
Concomitant cannabis use, either recreational or for medical reasons, is 
prohibited at least 14 days prior to Baseline and during the study.
●
Traditional Chinese medicines are prohibited within 30 days prior to Baseline 
and during the study.
Investigational Drugs
Investigational drugs of a chemical or biologic nature are prohibited within 30 days, or 
5 half-lives (whichever is longer) of the drug prior to the Baseline and during the study.
Strong CYP3A Inhibitors or Inducers
Systemic use of strong CYP3A inhibitors or strong CYP3A inducers is prohibited from 
the Screening Visit through the end of the study.  Examples of the most common strong 
CYP3A inhibitors and inducers are shown below:


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Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (juice or fruit)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Avasimibe
Carbamazepine
Phenytoin
Rifampin (Rifampicin)
St. John's Wort
In Japan, the following therapies are also prohibited:  
●
ATM treatment (antibiotic combination therapy with amoxicillin, tetracycline 
and metronidazole) during the Screening Period and during the study.
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding prohibited therapy.
5.2.4
Contraception Recommendations
Contraception Recommendation for Females
Subjects must follow the following contraceptive guidelines as specified.
Females of Non-childbearing Potential:
Females do not need to use birth control during or following study drug treatment if 
considered of non-childbearing potential due to meeting any of the following criteria:


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●
Postmenopausal, age > 55 years with no menses for 12 or more months 
without an alternative medical cause.
●
Postmenopausal, age ≤ 55 years with no menses for 12 or more months 
without an alternative medical cause AND a follicle-stimulating hormone 
(FSH) level > 40 IU/L.
●
Permanently surgically sterile (bilateral oophorectomy, bilateral 
salpingectomy, or hysterectomy)
Females of Childbearing Potential:
Females of childbearing potential must avoid pregnancy while taking study drug(s) and 
for at least 30 days after the last dose of study drug.  Females must commit to one of the 
following methods of highly effective birth control:
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal, injectable) associated with the inhibition of 
ovulation, initiated at least 30 days prior to Study Baseline.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Baseline.
●
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure) (For Japan: only 
bilateral tubal ligation).
●
Vasectomized partner(s) provided the vasectomized partner has received 
medical confirmation of the surgical success and is the sole sexual partner of 
the trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence (if acceptable per local requirements): defined as refraining 
from heterosexual intercourse when this is in line with the preferred and usual 
lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable).


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o
In the US, true abstinence applies only to women of childbearing potential 
who do not have male partners and are not engaging in heterosexual 
intercourse as their preferred and usual lifestyle (periodic abstinence [e.g., 
calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
For subjects in the US, Colombia, and where appropriate per local requirements, females 
of child bearing potential must commit to using two methods of contraception (either 
two highly effective methods or one highly effective method combined with one effective 
method).  Effective methods of birth control are the following:
●
Progestogen-only oral hormonal contraception, where inhibition of ovulation 
is not the primary mode of action, initiated at least 30 days prior to study 
Baseline.
●
Male or female condom with or without spermicide.
●
Cap, diaphragm, or sponge with spermicide.
●
A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier method).
Contraception recommendations related to use of concomitant therapies prescribed per 
standard of care should be based on the local label.
Refer to Section 5.3.1.1 for information on Pregnancy Testing.
5.3
Efficacy and Safety Assessments/Variables
Study procedures will be performed as summarized in Section 5.3.1.1.  All subjects must 
meet the study selection criteria outlined in Section 5.2.1 and Section 5.2.2 in order to be 
randomized in to the study.


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5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
The study procedures outlined in the Study Activities in Appendix C and Appendix D are 
discussed in detail in this section, with the exception of exploratory research and 
validation studies (discussed in Section 5.3.1.2), drug concentration measurements 
(discussed in Section 5.3.2), the collection of prior and concomitant medication 
information (discussed in Section 5.2.3), and the collection of AE information (discussed 
in Section 6.1.1.1).  All study data will be recorded in source documents and on the 
appropriate eCRFs.
Informed Consent
At the Screening Visit, the subject will sign and date a study specific, Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) approved, Informed Consent Form 
(ICF) before any study procedures are performed or any medications are withheld from 
the subject in order to participate in this study.  A separate informed consent will be 
required for each subject in order to participate in the optional exploratory research and 
validation studies.  Clinical responders at either Week 8 or Week 16 will provide consent 
for participation in Substudy 3 of Study M14-234; a separate informed consent will be 
required for each subject in order to participate in the Study M14-234 Substudy 3 optional 
exploratory research and validation studies.  Details regarding how informed consent will 
be obtained and documented are provided in Section 9.3. 
Subjects, who have been taking exclusionary medications prior to screening must 
complete medication washout.  The duration is based on the excluded medication as 
described in the protocol.  Protocol-related adverse events should be reviewed and 
subjects must complete the washout prior to the Baseline Visit.


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, 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.
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at both Screening and Baseline Visits.
Medical and Surgical History
A complete medical and surgical history, including UC-onset date, history of UC 
medication use, and history of alcohol and tobacco use will be obtained from each subject 
at the Screening Visit.  History of herpes zoster, herpes zoster vaccination, and hepatitis B 
vaccination status will be recorded as part of the medical history.  An updated medical 
history will be obtained prior to study drug administration at Baseline, to ensure the 
subject is still eligible for enrollment, and updated as necessary.
Prior corticosteroid, aminosalicylate, azathioprine, 6-MP and MTX use will be asked.  In 
addition, for subjects in Japan and Taiwan, prior tacrolimus use will be asked.  If subjects 
have/had ever been treated with these medications, the duration of therapy, maximum 
dose, reason for use and reason(s) for termination of treatment will be recorded in 
subjects' source document and in the appropriate eCRF.  The details of dates of 
administration and dosages within the past 90 days will also be recorded.
A detailed biologic therapy history (e.g., anti-TNF, anti-adhesion therapies) will be 
recorded, this includes names of biologic therapy used, duration of therapy, doses,
reason(s) for use and reason(s) for termination of treatment with these products must be 
documented in the subjects' source documents and in the appropriate eCRF.


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A detailed medical history with respect to inadequate response, loss of response and/or 
intolerance to aminosalicylates, immuno-modulators, corticosteroids and/or therapies 
must be documented in the subjects' source documents.  A detailed medical history with 
respect to TB exposure will be documented.  This information will include Bacille 
Calmette-Guérin (BCG) vaccination, cohabitation with individuals who have had TB, and 
residence or work in TB endemic locations.
Physical Examination
A full physical examination will be required to be performed at Screening, Baseline and 
Week 8 and Premature Discontinuation Visit (Part 1) Week 16 and Premature 
Discontinuation Visit (Part 2) and must include an assessment of extra-intestinal 
manifestations (EIMs).  
For subjects aged 16 or 17 a Tanner Stage assessment will be completed at the screening 
visit to confirm eligibility.  This may be completed by the investigator or by self-
assessment (completed by the subject/legally authorized representative) per local 
requirements. If completed by self-assessment, study site is responsible for training the 
subject/legally authorized representative appropriately.
The physical examination at the Baseline Visit will serve as the Baseline physical 
examination for the entire study.  Abnormalities noted after the Baseline Visit and 
first dose of study drug will be evaluated and documented by the investigator as to 
whether or not these are adverse events.  All findings whether related to an adverse event 
or part of each subject's medical history will be captured on the appropriate eCRF page.
A symptom-directed physical examination will be performed at all other visits when 
necessary.  If a subject reports any symptoms that requires additional physical 
examination besides the extra-intestinal manifestation (EIM), a symptom-based physical 
examination will be performed.  The assessment of EIMs must be completed at all study 
visits.  Please refer to Appendix C.


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Height and Weight
For Subjects ≥18 years of age, height (with shoes off) will be measured at the Screening 
Visit.  For subjects 16 or 17 years of age, height (with shoes off) will be measured at the 
Screening Visit, Week 8 and Week 16.  Body weight will be measured at all scheduled 
visits.  All measurements will be recorded in metric units where applicable.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference. In these situations, height and weight measurements may be performed by 
the subject or caregiver as needed.
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 each visit.  Blood pressure 
(BP), pulse rate and respiratory rate should be performed before blood draws are 
performed.  
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, vital signs may be obtained by the subject or caregiver as 
needed.
Chest X-Ray (CXR)
A CXR (posterior-anterior and lateral views) is required for all subjects at Screening to 
rule out the presence of TB or other clinically relevant findings (In Japan, a computed 
tomagraphy (CT) scan of the chest may be performed in lieu of a CXR, at investigator's 
discretion).
The CXR will not be required if the subject had a previous normal CXR (posterior-
anterior and lateral views) (or normal CT Scan of the chest for subjects in Japan) within 


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90 days of Screening, provided all source documentation is available at the site, as 
outlined below and provided nothing has changed in the subject's medical history to 
warrant a repeat test.  The investigator may obtain a Baseline CXR if clinically indicated 
for a specific subject.
Subjects can have a repeat CXR anytime during the study as warranted based on the 
opinion of the investigator.
A radiologist (or pulmonologist) must perform an assessment of the CXR (or CT Scan of 
the chest for subjects in Japan).  The Principal Investigator or designee will indicate the 
clinical significance of any findings and will sign and date the report.  In the assessment 
of the CXR (or CT Scan of the chest for subjects in Japan) for the presence of TB, the 
radiologist (or pulmonologist for subjects in Japan) and/or Principal Investigator (or 
designee) must indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.  In case of any abnormality indicative of 
active TB, the subject should not be enrolled into the study.  If the chest x-ray 
demonstrates changes suggestive or previous TB (e.g., calcified nodule, fibrotic scar, 
apical or basilar pleural thickening) or other findings that are clinically significant, the 
principal investigator should contact the AbbVie TA MD before enrolling the subject. 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the absence of symptoms or positive medical history, if CXR cannot be done due to 
COVID-19 restrictions, the subject may continue in the study after discussion with TA 
MD.  CXR should be performed as soon as restrictions allow at study site or local 
hospital/facility.
12-Lead Electrocardiogram (ECG)
For all subjects, a resting 12-lead ECG will be performed at Screening and 
Week 8/Premature Discontinuation Visit and Week 16 of the extended treatment period, 
as applicable.  The ECG at Week 8 or ECG at Week 16 of the extended treatment phase of 
Study M14-675 will serve as the baseline ECG for Substudy 3 of Study M14-234.  A 


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qualified physician will interpret the clinical significance of any abnormal finding, sign, 
and date each ECG.  If there are any findings that are clinically significant, the Principal 
Investigator must contact the TA MD before enrolling the subject.  In addition, any 
clinically significant findings will be documented in the source documents and later 
transcribed on to the appropriate eCRF.  Each signed original ECG will be kept with 
subject's source documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided all protocol required documentation is available 
and provided nothing has changed in the subject's medical history to warrant a repeat test.
ECG should always be performed prior to obtaining blood samples. Subjects can have a 
repeat ECG at any time during the study as warranted based on the opinion of the 
investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event this may not be performed due to study modifications related to the 
COVID-19 pandemic, perform the 12-lead ECG at the next earliest feasible visit or 
arrange to have an alternative acceptable local facility perform the ECG for the subject.
TB Testing/TB Prophylaxis
Screening
All subjects must be evaluated for TB at screening and annually, unless the subject is 
considered to be TB test positive prior to screening. The TB screening tests are diagnostic 
test results to be interpreted in the context of the subject's epidemiology, history, exam 
findings, etc. and it is the responsibility of the investigator to determine if a subject has 
active or latent tuberculosis.  Expert consultation for the evaluation and/or management of 
TB may be considered per Investigator discretion.
For all subjects, evidence of increased risk for TB will be assessed by a questionnaire 
(Appendix G) and tested for TB infection by QuantiFERON-TB Gold Plus test.  The site 


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staff will complete the TB risk assessment form in its entirety (Part 1 and Part 2) and enter 
the data into the appropriate eCRF.  The TB risk assessment form will be completed 
annually (Part 1 only) for all subjects, regardless of TB test results.  One or more "yes" 
response on the TB risk assessment form indicates increased risk of TB.
If a subject has a QuantiFERON-TB Gold Plus test within 90 days prior to Screening and 
source documentation is available, TB testing does not need to be performed by the 
central laboratory at Screening provided nothing has changed in the subject's medical 
history to warrant a repeat test. If a subject only had a negative PPD test within 90 days 
prior to Screening, a QuantiFERON-TB Gold Plus test is required at Screening. If the 
QuantiFERON-TB Gold Plus test cannot be performed by the central laboratory at 
Screening and source documentation is available the PPD Skin Test (also known as a TB 
Skin Test or Mantoux Test) does not need to be repeated, provided nothing has changed in 
the subject's medical history to warrant a repeat test.  These cases may be discussed with 
the AbbVie TA MD.  The results of the TB test(s) will be retained at the site as the 
original source documentation.
Subjects with a negative TB test and chest x-ray (CXR) not suggestive of active TB may 
be enrolled. Subjects with history of active TB may be enrolled if it has been adequately 
treated with no evidence of current active TB; subjects with inadequate documentation of 
treatment should be cleared by a TB specialist prior to enrollment.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent 
TB, including signs and symptoms and CXR.  Subjects with no signs or symptoms and a 
CXR not suggestive of active TB may be enrolled after initiation of TB prophylaxis (see 
below).  Subjects with evidence of active TB must not be enrolled.
For subjects with a negative TB test result at Screening or the most recent evaluation, an 
annual TB follow-up test will be performed. 
If an annual TB test is newly positive (seroconversion), a chest x-ray (CXR) needs to be 
performed as soon as possible to aid in distinguishing active versus latent TB, and 


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subsequent annual TB follow-up tests are not required.  Any positive TB test after the 
patient has started the study should be reported as an AE of latent TB or active TB (as 
applicable).
If the subject is experiencing signs or symptoms suspicious for TB or something has 
changed in the subject's medical history to warrant investigation and a repeat test before 
the next scheduled annual TB retest, the case (including the TB test results) should be 
discussed with the AbbVie TA MD.
TB Testing
The QuantiFERON-TB Gold Plus test (or equivalent) should be performed at Screening 
on all subjects.  The PPD skin test should be utilized when the QuantiFERON-TB Gold 
Plus test (or equivalent) is not possible or if both tests are required per local guidelines:
●
Subjects with documentation of prior positive result of QuantiFERON-TB 
Gold Plus Test and/or PPD Skin Test and/or history of latent or active TB.  It 
is not required to repeat either test at Screening or during the study and should 
be considered positive.
●
For regions that require both PPD and QuantiFERON-TB Gold Plus testing, 
both will be performed.  If either PPD or QuantiFERON-TB Gold Plus is 
positive, the TB test is considered positive.  
●
If TB testing is done at Screening for subjects with a prior positive TB test and 
a positive result is reported, the subject is considered TB test positive.
If TB testing is done for subjects with a prior positive TB test at the annual 
evaluation, repeated TB prophylaxis in not required for a positive result unless 
indicated by the subject's medical history.  The PPD Skin Test should be 
utilized only when a QuantiFERON-TB Gold Plus Test is not possible for any 
reason (unless both tests are required per local guidelines).
●
If only a PPD is placed at screening, then the TB test to be used for the 
remainder of the study for that subject is the PPD.  Similarly, if a subject 
enters the study with a QuantiFERON-TB Gold Plus test alone, then the 


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subject should have their annual TB test performed with a QuantiFERON-TB 
Gold Plus test.
●
If the QuantiFERON-TB Gold Plus Test is NOT possible (or if both the 
QuantiFERON-TB Gold Plus Test and the PPD are required per local 
guidelines) the PPD will be performed.  The PPD should be read by a licensed 
healthcare professional between 48 and 72 hours after administration.  A 
subject who does not return within 72 hours will need to be rescheduled for 
another skin test.  The reaction will be measured in millimeters (mm) of 
induration and induration ≥ 5 mm is considered a positive reaction.  The 
absence of induration will be recorded as "0 mm" not "negative."  
●
Subjects who have an ulcerating reaction to PPD in the past should not be re-
exposed and the PPD should be considered positive. 
●
If the QuantiFERON-TB Gold Plus test is indeterminate, then the investigator 
should perform a local QuantiFERON-TB Gold Plus test (or through the 
central laboratory if not locally available) to rule out a positive test result.  If 
testing remains indeterminate or is positive, then the subject is considered to 
be positive for the purpose of this study.  If the testing result is negative, then 
the patient is considered to be negative. 
●
Interpretation of a positive 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 (i.e., no risk factors 
identified using the T Part I and Part II questions of the TB risk assessment 
questionnaire at Screening or Part I questionnaire annually) 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 alternative Interferon Gamma Release Assay (IGRA) (such as T-SPOT TB 
test) may be substituted for the QuantiFERON-TB Gold Plus.


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the absence of symptoms or positive medical history, if QuantiFERON TB test or PPD
cannot be done due to COVID-19 restrictions, the subject may continue in the study. 
QuantiFERON TB test or PPD should be performed as soon as restrictions allow at study 
site or local hospital/facility.
TB prophylaxis
At screening, if the subject has evidence of latent TB infection (no symptoms, positive TB 
test and the subject has a chest x-ray not suggestive of active TB), prophylactic treatment 
must be initiated at least 2 weeks prior to administration of the study drug (or per local 
guidelines, whichever is longer).  At least 6 months of prophylaxis need to be completed; 
however, the full course of prophylaxis does not need to be completed prior to the 
first dose of study drug.  If the investigator deems that it is necessary, consultation with a 
TB expert can be considered.  
In Ireland, the full course of prophylaxis treatment must be completed prior to the first 
dose of the study drug.
Note:  Rifampicin or rifapentine are not allowed for TB prophylaxis.
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy will be allowed to enter the study provided nothing has changed
in the subject's medical history warrant repeat treatment. 
For subjects with completion of a full course of anti-TB therapy but insufficient 
documentation the investigator should consult with the AbbVie TA MD prior to enrolling 
the subject.
Newly initiated prophylactic treatment should be captured in the eCRF and in the source 
documents.  Prior therapy should be captured in the eCRF.


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During the study, subjects with new evidence of latent TB should initiate prophylactic 
treatment immediately per local guidelines and complete at least 6 months of prophylaxis.  
Study drug (s) should not be withheld.  Two to four weeks later, the subject should be re-
evaluated (unscheduled visit) for signs and symptoms as well as laboratory assessment of 
toxicity to TB prophylaxis.
If the subject is experiencing signs of symptoms suspicious of active TB or something has 
changed in the subject's medical history to warrant a repeat test, the case (including the 
TB test results) must be discussed with the AbbVie TA MD prior to enrolling the subject.
Pregnancy Tests
A serum pregnancy test will be performed by the central lab at the Screening Visit on all 
female subjects of childbearing potential.  If the serum pregnancy test is positive the 
subject is considered a screen failure.  If the serum pregnancy test is borderline, it should 
be repeated ≥ 3 days later to determine eligibility.  If the repeat serum pregnancy test is:
●
Positive, the subject is considered a screen failure;
●
Negative, the subject can be enrolled into the trial;
●
Still borderline ≥ 3 days later, this will be considered documentation of 
continued lack of a positive result and the subject can be enrolled into the 
study in the absence of clinical suspicion of pregnancy and other pathological 
causes of borderline results.  Where mandated by local requirements a negative 
serum pregnancy test will be required for subject enrolment.
●
For subjects in Ireland and Argentina, a repeat serum pregnancy test ≥ 3 days 
later that is still borderline will result in screen failure.  (A borderline serum 
pregnancy test may be repeated more than once during the screening period.)
Women of childbearing potential includes all women who are not surgically sterile (both 
ovaries and or both fallopian tubes removed or uterus removed) or post-menopausal 
(defined as at least 55 years of age with no menses for at least one year, without an 
alternate medical reason for amenorrhea, or less than 55 years of age with no menses for 


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at least one year, without an alternate medical reason for amenorrhea and a FSH level 
> 40 IU/L).
Women of childbearing potential will have a urine pregnancy test performed locally by 
designated study personnel at Baseline and all subsequent visits.
Women of childbearing potential will also have a urine pregnancy test performed at home 
30 days after the last visit.  The results of follow up pregnancy test should be 
communicated during the telephone follow up call. 
If any urine pregnancy test is positive, a serum pregnancy test will be performed by the 
central laboratory.  If the serum pregnancy test is positive, dosing must be stopped and the 
subject must be discontinued from the study or, if pregnancy identified at end of study 
visit, pregnancy must be reported to AbbVie as outlined in Section 6.1.6.
A lactating or pregnant female will not be eligible for participation or continuation in this 
study.
If during the course of the study a woman becomes surgically sterile or postmenopausal 
and complete documentation as described in Section 5.2.4 is available, pregnancy testing 
is no longer required.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Monthly urine pregnancy testing must be performed for women of child-bearing potential 
and results confirmed prior to administration of study drug to the subject.  Urine 
pregnancy tests may be performed at the local lab or at home and confirmed by site staff 
via phone, telemedicine or video call.  Pregnancy test results must be available before 
drug dispensation.
Hepatitis Screen
All subjects will be tested for the presence of HBV and HCV at Screening.


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Hepatitis B
Subjects will be tested for the presence of HBV at screening using the following tests:
●
HBs Ag (Hepatitis B surface antigen)
●
HBc Ab/anti-HBc (Hepatitis B core antibody)
●
HBs Ab/anti-HBs (Hepatitis B surface antibody)
HBV serologic test results will be interpreted and managed as shown in Figure 2.
●
A positive result for HBs Ag will be exclusionary.
●
A negative result for HBs Ag will trigger automatic reflex testing for core 
antibodies (HBc Ab) and surface antibodies (HBs Ab).
●
For a subject who has had an HBV vaccination (should document in the 
medical history), a positive test result for HBs Ab is expected, the HBV DNA 
PCR qualitative testing is not required and the subject may be enrolled 
(Scenario B). 
●
A negative test result for HBc Ab does not require HBV DNA PCR qualitative 
testing and the subject may be enrolled (Scenarios A and B).  
●
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic 
reflex testing) (Scenarios C and D).
●
A positive result for HBV DNA or a result that exceeds detection sensitivity 
will be exclusionary.
●
A subject with a negative result for HBV DNA may be enrolled.


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Figure 2.
Interpretation and Management of HBV Serologic Test Results
*
A positive test result for HBs Ab is expected for subjects who have had a HBV vaccination.  For subjects without a 
history of HBV vaccination (and for subjects in Japan) a positive result for HBs Ab/anti-HBs requires HBV DNA 
PCR testing.
**
Where mandated by local requirements; subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at 
Screening should have HBV DNA PCR testing performed approximately every 12 weeks. HBV DNA PCR testing 
every 12 weeks is not necessary when the subject has a history of HBV vaccine and HBs Ab+ and HBc Ab–. If 
necessary, HBV DNA PCR may be tested at unscheduled visits.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event that the HBV DNA PCR cannot be performed for subjects who require the 
test due to study modifications related to the COVID-19 pandemic, perform the HBV 
DNA PCR at the next earliest feasible visit or arrange to have it completed by a local 
laboratory.
Hepatitis C
Blood samples for Hepatitis C serology will be obtained at the Screening Visit.  A 
positive HCV Ab will trigger an HCV RNA test.  A subject will not be eligible for study 
participation if test results indicate active Hepatitis C (HCV RNA detectable in any 
subject with anti HCV Ab).


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HIV
Subjects with HIV infection (positive HIV test) are excluded from study participation.  An 
anti-HIV antibody (Ab) test will be performed at Screening, unless prohibited by local 
regulations.  The investigator must discuss any local reporting requirements to local health 
agencies with the subject.  The site will report confirmed positive results to their health 
agency per local regulations, if necessary.  If a subject has a confirmed positive result, the 
investigator must discuss with the subject the potential implications to the subject's health 
and subject should receive or be referred for clinical care promptly.  AbbVie will not 
receive results from the testing and will not be made aware of any positive result.
Clinical Laboratory Tests
Blood samples will be obtained for the laboratory tests listed in Table 1.  Tests should 
always be performed only after all clinical assessments, questionnaires (Inflammatory 
Bowel Disease Questionnaire [IBDQ], etc.) and vital sign determinations are obtained 
during a visit.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  All abnormal laboratory tests that are considered clinically significant by 
the investigator will be followed to a satisfactory resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing and shipping of these samples.
The blood samples for serum chemistry tests should be collected following a minimum 
8-hour fast, when possible.  If a subject is not able to fast when necessary, due to 
unforeseen circumstances, the non-fasting status will be recorded in study source 
documentation.  The fasting status will be recorded in the laboratory request, source 
document and eCRF.


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Urinalysis
Urine samples will be obtained and sent to the central laboratory for the tests listed in 
Table 1.  Microscopic urinalysis will only be performed by the central laboratory if the 
dipstick UA results are abnormal, where abnormal is defined as leukocytes, nitrite, 
ketone, protein, blood or glucose value of greater than a trace.  Sites will not be provided 
with urinalysis dipsticks.
Other Laboratory Assessments
High Sensitivity C-Reactive Protein
Blood samples for high-sensitivity C-reactive protein (hs-CRP) will be obtained.  Blood 
draws should be performed after all clinical assessments, questionnaires (IBDQ, etc.), and 
vital sign determinations are obtained.  The hs-CRP test will be performed by the Central 
Lab for all subjects as indicated in Appendix C and Appendix D.  The results will be 
blinded to the sponsor, investigator, study site personnel, and the subject.  Local 
laboratory or site testing for CRP is not allowed after Baseline with the exception when 
the subject has a medical condition in which CRP level is deemed to be necessary for the 
diagnosis and treatment in Investigator's discretion and after consulting with the AbbVie 
TA MD.  For future data assessments, it may be required to unblind the CRP data in an 
interim interval.
Lymphocyte Subsets (TBNK)
Blood samples will be collected at Baseline, Week 8 and Premature Discontinuation in 
Part 1 or at Week 16/Premature Discontinuation, as applicable, of the Extended Treatment 
Period of Part 2 to assess the effects of upadacitinib inhibition on lymphocyte subsets:  T 
(CD4+ and CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and natural killer T 
(NKT) cells.  These tests will be performed by the Central Lab.


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Table 1.
Clinical Laboratory Tests
Hematology
Clinical Chemistrya
Urinalysisb
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
Reticulocyte count
White Blood Cell (WBC) 
count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count 
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Aspartate aminotransferase 
(AST)
Alanine aminotransferase 
(ALT)
Alkaline phosphatase
Creatine phosphokinase (CPK) 
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Inorganic phosphorus
Uric acid
Total protein
Albumin
Glucose
Gamma glutamyl transferase 
(GGT)
Lipid Test:
Cholesterol
LDL-C
HDL-C
Triglycerides
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Nitrite
Bilirubin
Urobilinogen
Leukocytes
Microscopic Examination
Other Laboratory Tests
Serum pregnancy test
Urine pregnancy test
High sensitivity C-reactive protein 
(hs-CRP)
Hepatitis B Surface Antigen
Hepatitis B Surface Ab
Hepatitis B Core Ab
Hepatitis B Core Ab IgM
Hepatitis C Ab Screen
HBV DNA PCR reflex only
HCV RNA reflex only
QuantiFERON-TB Gold Plus
Pharmacokinetic
eGFR
Lymphocyte Subsets (TBNK Panel)c
HIV Ab
Beta-D-Glucan (Japan Only)
Stool Samples Collected
C. difficile toxin
Fecal calprotectin
Additional Samples Collected (Optional)
Blood, serum, plasma, stool and intestinal tissue samples for exploratory research, validation studiesd
and biologic drug level.e
a.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-
fasting status will be recorded in study source documentation.
b.
The Central Laboratory will perform the urinalysis.  A microscopic analysis will be performed by the central 
laboratory, in the event the dipstick results show leukocytes, nitrite, ketone, protein, blood or glucose value of 
greater than a trace.  Sites will not be provided with urinalysis dipsticks.
c.
Lymphocyte subsets include T (CD4+ and CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and natural 
killer-T (NKT) cells.
d.
Preferably collected while subjects are in a fasting condition.


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Table 1.
Clinical Laboratory Tests (Continued)
e.
During Screening, biologic drug levels may be optionally assessed at the investigator's discretion as an alternative 
to completing the required washout period: (1) infliximab and natalizumab: may be tested approximately 4 weeks
or later from the last dose; (2) adalimumab, certolizumab, golimumab, or vedolizumab: may be tested 
approximately 6 weeks or later from the last dose; (3) ustekinumab: may be tested approximately 8 weeks or later
from the last dose.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  It is recommended to perform all scheduled tests in the protocol, except 
for hs-CRP, fecal calprotectin, PK and optional samples for exploratory research which 
should not be collected.  For hs-CRP local testing can only be performed if deemed to be 
necessary by PI after discussion with TA MD.
Local lab results should be obtained along with reference ranges and kept within the 
subjects' source documentation.  The results should be reviewed by the investigator and 
documented in EDC as an unscheduled lab as soon as possible.
If it is not possible to perform all the tests, the tests in the below table should be 
performed at minimum for safety evaluation.
Hematology 
Clinical Chemistry 
Urine 
Tuberculosis tests* 
Hematocrit
Hemoglobin
RBC count
WBC count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count 
BUN
Creatinine
Total bilirubin
ALT
AST
Alkaline phosphatase
CPK 
Pregnancy test 
QuantiFERON TB test 
or PPD 
(Study M14-234 
SS3 and 
Study M14-533)
Chest X-Ray 
(Study M14-234 
SS3 and 
Study M14-533) 
*
TB Test and Chest X-Rays to be completed only at the required visits per protocol.


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If laboratory samples cannot be obtained, study drug administration may be continued 
provided that the following criteria are met:
The study drug may be dispensed if:
1.
There is at least 1 post-Baseline lab assessment (either Week 2 or Week 4 visit)
AND 
2.
The investigator has reviewed all prior laboratory results and confirms and 
discusses with the subject via a phone/video call that there is no safety concern for 
the subject to continue use of the study drug in the absence of current labs
AND
3.
No longer than 4 weeks have passed from the last safety lab tests.
Stool Samples Collected
Fecal Calprotectin
Fecal calprotectin will be performed for all subjects as indicated in Appendix C and 
Appendix D.  Subjects will be asked to provide a stool sample, subjects will be sent home 
with instructions and stool sample supplies (supplies will be provided).
The fecal calprotectin results will remain blinded to the sponsor, investigator, study site 
personnel and the subject throughout the study.  Local laboratory or site testing for fecal 
calprotectin is not allowed after Baseline. 
All stool samples should be collected before any bowel preparation for endoscopy is 
started.  The central laboratory will be utilized to process and provide results for these 
laboratory tests.  For future data assessments, it may be required to unblind the CRP data 
in an interim interval.


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
If subject is unable to attend visit where fecal calprotectin stool samples are collected, 
these should not be collected at a local lab.
C. Difficile
During the Screening Period a stool sample will be collected and sent to the central 
laboratory for testing.  The sample will be assessed for the presence of C. difficile toxin.
The sample must be shipped to the central laboratory using dry ice.  Additional 
information is available in the Investigator Manual provided by the central laboratory.
Subjects who are positive for C. difficile toxin should be screen-failed; these subjects may 
be re-screened after completing the appropriate treatment.  For subjects who are 
borderline for C. difficile toxin, the investigator may send another sample for a test. If the 
result is negative, the investigator may consider the test to be negative based on his/her 
judgment. If the result is positive or borderline, the test is considered positive and subject 
should be screen failed. For those subjects with two borderline results, the PI can decide 
if C. difficile treatment is needed based on his/her clinical judgment; these subjects may 
be re-screened with or without C. difficile treatment.
Outcomes and Questionnaires
The following outcomes and questionnaires will be completed at the time points indicated 
in Appendix C and Appendix D.  However, please ensure questionnaires are always 
completed prior to obtaining blood samples.  Refer to Appendix E for descriptions of 
Patient Reported Outcomes.
●
IBDQ – Inflammatory Bowel Disease Questionnaire 
●
SF-36 – Short Form 36
●
EQ-5D-5L – European Quality of Life 5 Dimensions 5 Levels
●
FACIT-F – Functional Assessment of Chronic Illness Therapy-Fatigue


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●
WPAI – Work Productivity and Activity Impairment Questionnaire Ulcerative 
Colitis
●
PGIC – Patient Global Impression of Change
●
PGIS – Patient Global Impression of Severity (only in select sites)
●
UC-SQ – Ulcerative Colitis Symptoms Questionnaire
●
HCRU – Supplemental Hospitalization and Surgery forms 
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference, except baseline. All PROs, except EQ-5D-5L scale, are eligible for 
completion by interview.  If there are time constraints to the phone visit, at a minimum, 
the following PROs must be completed:
●
Inflammatory Bowel Disease Questionnaire (IBDQ) 
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
●
Patient Global Impression of Change (PGIC) 
●
Patient Global Impression of Severity (PGIS) 
Prior to conducting any phone visits to obtain PRO data the site staff person should be 
delegated this task on the Delegation of Authority log. Sites will read the PRO questions 
and response options to the subject and record the subject's responses.  The subject's 
ability to view the PRO to understand the questions and response options should be 
preserved.  Sites must share a local language version of the questionnaire by 
videoconference or send the questionnaires (email or hard copy) to the subjects to allow 
them to read/understand the questions and responses when the subject is providing 
responses over the phone.  The date and start and stop time of PRO data collection should 
be recorded along with who collected the information, their role and which questionnaires 
were completed.


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Subject Diary
Subjects will be dispensed an electronic diary (eDiary) at Screening and the site staff will 
enter the NORMAL baseline number of stools in a 24-hour period when the subject's UC 
is not active to allow for scores to be calculated.
Subjects will be trained on how to complete the diary by site staff during the Screening 
Visit.  All subjects should complete their subject diary on a daily basis throughout the 
entire study.  The diary will be reviewed by site personnel with the subject at each visit 
and collected at the Final/PD Visit.  If subjects require re-training during the study, the 
site staff will accommodate this requirement.
In case of missing diary information, or when discrepancies are discovered, site personnel 
should discuss with the subject and document changes in site records, if applicable.  
Completion will be reinforced during study visits as necessary as the diary data required 
to be entered by the subject(s) cannot be changed or altered in any way.
Study Drug Dispensing/Administration
Study drug will be dispensed to subjects at the time points indicated in Appendix C and 
Appendix D. 
Study drug will be taken orally once daily beginning at the Baseline Visit and should be 
taken at approximately the same time each day.  At scheduled visits, study drug should be 
administered after all assessments and examinations scheduled for that day have been 
completed if the visit occurs at the time the subject is taking study drug each day.  If study 
drug is being taken earlier then when the visit is set to occur, the time of the last two doses 
will be documented in the eCRF and pharmacokinetic (PK) samples drawn at the visit.
Refer to Section 5.5 for additional information.


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
Drug may be only dispensed to subjects if specific Laboratory result criteria are met;
please see these outlined below and refer to the Clinical Laboratory Tests section above 
for more information.
If laboratory samples cannot be obtained, study drug administration may be continued 
provided that the following criteria are met:
The study drug may be dispensed if:
1.
There is at least 1 post-Baseline lab assessment (either Week 2 or Week 4 visit)
AND
2.
The investigator has reviewed all prior laboratory results and confirms and 
discusses with the subject via a phone/video call that there is no safety concern for 
the subject to continue use of the study drug in the absence of current labs
AND
3.
No longer than 4 weeks have passed from the last safety lab tests.
Study drug may be shipped from the study site directly to the study subject's home 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, 
paper copies of PROs).  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; 


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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.
DTP study drug shipment will be allowed on the study for the duration of the COVID-19 
pandemic and will be removed once the pandemic is considered to be resolved.
Mayo Score/Partial Mayo Score
Data from the subject diaries will be collected in order to calculate Mayo Score/Partial 
Mayo Score at the time points indicated in Appendix C and Appendix D.
Whenever possible, the same physician (investigator or sub-investigator) should 
determine the Physician's Global Assessment (PGA) subscore for an individual subject 
through the duration for the study.  The directions for capturing the stool frequency 
subscore (SFS), rectal bleeding subscore (RBS), and PGA subscores of the Mayo score 
are described in Appendix F. 
Diary entries from the most recent 3 consecutive days prior to the visit should be utilized 
for calculation purposes.  If diary entries from the 3 most recent consecutive days prior to 
the visit are not available, the 3 most recent consecutive days in the last 10 days will be 
utilized.  If data are not available for 3 consecutive days, the average of the entries from 
the most recent 3 non-consecutive days in the last 10 days will be utilized.
Endoscopy
All endoscopies should be recorded in a color video format at the time points noted in 
Appendix C and Appendix D.  There will be a window of 7 days prior to the scheduled 


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visit to conduct the endoscopy.  For the screening endoscopy, this procedure may be 
completed at any time during the Screening Period but not on the date the subject is 
randomized as the central reader review of the endoscopy video is required for study entry 
(central reading can take up to 3 business days).  For other scheduled visits, the endoscopy 
may not occur after the visit, only on the day of or in advance of the scheduled visit.  This 
window may be extended as necessary after consultation with the AbbVie TA MD in case 
of external, not subject-related circumstances (e.g., scheduling conflict).
Endoscopies will be reviewed by a primary central reader who is blinded to the subject's 
clinical data, the site's endoscopy assessment and the subject's therapy.  If, in the 
assessment of the endoscopist at the site, the Screening endoscopy shows a normal 
colonic mucosa, the subject should be screen-failed and the video should not be sent for 
central reading.  The endoscopy will be used for calculation of the endoscopy subscore of 
the Mayo Score.  The endoscopy subscore will be documented by the endoscopist at the 
site and maintained in the subject's source documents.  In addition to endoscopic 
evaluation using Mayo endoscopic sub-score, the endoscopy findings using the Ulcerative 
Colitis Endoscopic Index of Severity (UCEIS) scoring system will be used for additional 
exploratory analyses.  During all endoscopy procedures, the endoscopist at the site should 
determine the segment where there is a clear demarcation between normal and inflamed 
mucosa and document the distance from the anal verge (in centimeters) in the eCRF.
Screening Endoscopy:  A full colonoscopy will be performed at Screening.  The 
endoscopy subscore result from the central reader will be entered into the eCRF by the 
site and used to evaluate the eligibility of a subject at Baseline for the study.  The central 
reader's assessment will be used in the Mayo score calculations for all efficacy endpoint 
assessments.
Week 8 (Part 1), Week 16 (Part 2 – Extended Treatment Period) Endoscopy:  The 
Week 8 endoscopy may be either a full colonoscopy or a flexible sigmoidoscopy 
depending on the extent of the disease at Screening.  The endoscopy should be performed 
up to the segment where a clear demarcation of inflammation is observed.  For subjects 
that entered Part 2 (Extended Treatment Period), an endoscopy will be performed at 


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Week 16.  A flexible sigmoidoscopy is recommended at Week 16; however, the use of a 
flexible sigmoidoscopy or colonoscopy will be based on the investigator's discretion per 
local practice.  The site's endoscopist scoring will be entered into the eCRF by the site and 
used for the Mayo score calculation for the purposes of re-randomization into Substudy 3.  
For the Week 8 or Week 16 re-randomization, the local reading will be compared with the 
baseline central reading in order to determine clinical response status.  The central reader's 
assessment will be used for the Mayo scores used in all efficacy endpoint assessments.  
The same endoscopist should, where possible, perform all endoscopies for an individual 
subject throughout the study.  In addition, where possible, the investigator or 
subinvestigator should be the endoscopist for the study.  The endoscopy subscores by 
segment will be noted in the subject's source documents and in the database but the 
central reader's endoscopy subscore will be used for the efficacy analyses.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If an Endoscopy required at Week 8 and Week 16 is not able to be scheduled at the study 
site in the required protocol window due to COVID-19, then this may be performed 
± 7 days from the planned visit and can be completed at a different Hospital/facility.
If the endoscopy cannot be performed during this extended window at the site or another 
location, please refer to the guidance for subjects outlined in Section 5.1.
Biopsy During Endoscopy
Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the 
assessment of the investigator, must be available in order to confirm the subject's 
eligibility for the study.  If this documentation is not available a diagnostic biopsy from 
the most affected observed area of the colon must be performed during the Screening 
endoscopy and read by a qualified local pathologist and the results reviewed by the 
investigator, the central laboratory will not provide a pathology report during the 
screening endoscopy to document UC diagnosis.  Biopsies to rule out dysplasia and colon 


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cancer may be taken per the investigator's discretion during any endoscopy performed
during this study and evaluated by the local pathologist.
Biopsies sent to the central laboratory will not be returned to sites and will be retained for 
study use only.
Obtainment of biopsy samples should also be recorded on the video.
The signed pathology report will be monitored by the responsible clinical research 
associate and kept with the subject's source documents onsite.  Subjects should not be 
enrolled if high grade colonic dysplasia or colon cancer is discovered at the Screening 
endoscopy.  Subjects may be enrolled if low grade colonic dysplasia is discovered during 
endoscopy and is completely removed.  If a diagnosis of high grade colonic dysplasia or 
colon cancer is discovered during any subsequent endoscopic evaluation during the course 
of the study, the findings should be recorded as an AE and the subject should be 
discontinued from the study.  If low grade colonic dysplasia is discovered during any 
subsequent endoscopic evaluation during the course of the study, the findings should be 
entered as an AE and the subject can continue in the study if the lesion has been 
completely removed.
During all endoscopies up to 3 sets of biopsies are to be collected; one mandatory set of 
biopsies and, if consented for, two optional sets of biopsies. Each set of biopsies should 
consist of 2 samples each obtained from the rectosigmoid colon (approximately 15 –
30 cm from the anal verge) for histologic assessment. For each set of 2 samples, 
one should be taken from the area of most inflammation (if the area is ulcerated, the 
sample should be obtained from the edge of the ulcer), and one from an area that is 
representative of the general degree of mucosal inflammation present in that segment.  For 
all histology biopsies, the location of the biopsy specimen (distance from the anal margin) 
should be recorded.
For China only:  only a single biopsy at each endoscopy from the most inflamed area 
(HistoMOST) will be required per local requirements.  The single, required biopsy will be 


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taken from the area of most inflammation (if the area is ulcerated, the sample should be 
obtained from the edge of the ulcer) for histologic assessment at each required timepoint 
as per Appendix C.
For follow-up endoscopies, in the absence of any visible lesions or areas of general 
inflammation characteristic of UC, up to 3 sets of biopsies should be collected from 
normal mucosa in the same segments as noted above.
Biopsy Sample Collection, Storage and Shipping:
Biopsies performed to confirm the diagnosis of UC or to rule out current 
dysplasia/malignancy should be processed and read locally per site standards.
Biopsy specimens per subject should be obtained by endoscopy for histologic assessment 
at the time points indicated in Appendix C and Appendix D.  Using routine forceps for 
tissue collection, obtain the required number of biopsy specimens and process the 
specimens following the instructions in the study-specific laboratory manual.
Intestinal Tissue Analysis
The following analyses will be sent to the central laboratory and performed on tissue 
samples: 
●
Qualitative UC histological assessment using Geboes histologic activity 
score,25 and other histologic scoring systems.  These samples may not be read 
in real time, however if unexpected findings, such as dysplasia, are noted on 
the histology biopsies, the central laboratory will contact the investigator to 
inform him/her about the unexpected finding.  Subjects who are found to have 
high grade colonic dysplasia on the submitted biopsy will be terminated from 
the trial at the time the dysplasia is discovered.  Unexpected findings should be 
recorded as an adverse event.  
●
Subjects will have the option to provide tissue biopsies (per local 
requirements) for future exploratory research and/or validation studies.  For 
more information, please refer to Section 5.3.1.2.


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
Biopsy completion should follow the endoscopy guidance if the visit is affected by 
COVID-19.  If an endoscopy is completed at an alternative location from the study site 
the study required biopsy is not required.  Biopsy can be completed per endoscopist's 
discretion for local evaluation.
Follow-Up Period
Subjects will be contacted approximately 30 days after the last administration of study 
drug to obtain information on any new or ongoing adverse events (AEs).  If subject is 
enrolled into Substudy 3 of Study M14-234 they would not be required to complete the 
follow-up period in Study M14-675 and would be completed under that protocol, as 
applicable. 
During this follow-up call the results of the follow-up at home pregnancy test should be 
communicated to the site and follow reporting found in Section 6.1.6.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have a Premature Discontinuation (PD) 
Visit and complete the procedures outlined for the PD Visit in Appendix C and 
Appendix D as soon as possible after the last dose of study drug and preferably prior to 
the administration of any new therapies.
Unscheduled Visits
An Unscheduled Visit should be performed when the subject comes in for a medical visit 
for evaluation and assessment.  During Unscheduled Visits, blood and urine samples will 
be obtained for the laboratory tests listed in Table 1, or for other tests at the investigator's 
discretion.
Visits for dispensing new study drug in case of temperature excursion, loss or damage are 
not considered an Unscheduled Visit.  In addition, visits to only retest a lab will not be 
considered an Unscheduled Visit.


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Home Healthcare Service Due to COVID-19 Pandemic
Subjects may be offered the option of home healthcare visits provided by a licensed health 
care provider, such as a study nurse or third-party vendor.  Study procedures conducted in 
the home setting may include physical examination, vital signs, laboratory tests and 
Patient Reported Outcomes.  This option can only be offered in countries and sites that 
comply with local regulatory and IRB/IEC requirements for homecare.
Finally, 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.
Protocol deviations must be recorded per AbbVie's standard process.
If the home visits will not be performed by site personnel, the site may be responsible for 
selecting a vendor, contracting with a vendor, and for ensuring continued compliance with 
the terms of the Clinical Study Agreement.
Individuals performing home visits need to be added to the delegation log.
5.3.1.2
Collection and Handling of Optional Samples for 
Exploratory Research and Validation Studies 
Subjects will have the option to provide samples for exploratory research and validation 
studies.  Subjects may still participate in the main study even if they decide not to 
participate in this optional exploratory research/validation study.  The procedures for 
obtaining and documenting informed consent are discussed in Section 9.3.
Exploratory research can help to improve our understanding of how individuals respond 
to drugs and our ability to predict which subjects would benefit from receiving specific 
therapies. In addition, exploratory research may help to improve our understanding of 
how to diagnose and assess/monitor UC by assessing associations between disease 
characteristics, outcomes data, and biomarkers of interest. 


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Validation studies, including those related to the development of potential in vitro 
diagnostic tests, may be carried out retrospectively in order to assess associations between 
events of interest (i.e., efficacy and/or safety events) and candidate biomarkers.
AbbVie (or people or companies working with AbbVie) will store the biomarker 
exploratory research/validation studies samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
upadacitinib (or drugs of this class) or UC and related conditions continues, but for no 
longer than 20 years after study completion.
The following samples will be collected according to Appendix D and Appendix F from 
each subject who consents to provide samples for exploratory research/validation studies:
●
Blood samples for pharmacogenetic and epigenetic analyses (DNA)
●
Blood samples for transcriptomic and/or epigenetic analyses (RNA) [if 
possible, subjects should be fasted for approximately 8 hours prior to 
collection]
●
Serum and plasma samples for systemic analyses including, but not limited to, 
proteomics and metabolomics (if possible, subjects should be fasted for 
approximately 8 hours prior to collection)
●
Stool for biomarker analysis
●
Rectosigmoid biopsy for exploratory research (frozen) and transcriptomic 
and/or epigenetic analysis (RNAlater).
Samples will be shipped to AbbVie or a designated laboratory for DNA/RNA extraction, 
if applicable, and/or analyses or long-term storage.  Instructions for the preparation and 
shipment of the samples will be provided in the laboratory manual.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If subject is unable to attend visit where optional exploratory samples are collected, these 
should not be collected at a local lab.


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for assay of upadacitinib and possibly other concomitant medications will 
be collected at the following times:
●
Part 1:  Week 2, Week 6 and Week 8/PD 
On visits where the blood samples for assay of upadacitinib are being collected as noted, 
samples should be collected prior to dosing and the subjects should take the study drug 
dose at the clinic after collecting the PK blood sample, when possible.  However, if the 
subject normally takes the study drug dose at a time that is much earlier or after the time 
of the scheduled study visit, the subject should follow the regular dosing schedule and the 
PK sample will be collected at any time during the visit.
The date and accurate time of the PK sample collection and the last two study drug doses 
will be recorded on the applicable requisition forms and in the eCRF to the nearest 
minute.
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If subject is unable to attend visit where pharmacokinetic samples are collected, these 
should not be collected at a local lab.
5.3.2.2
Handling/Processing of Samples
The blood samples for upadacitinib assays will be labeled with the type of sample, the 
protocol number, the subject number, and the visit week.  Additional detailed instructions 
for the handling and processing of samples will be provided from the Central Lab.


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5.3.2.3
Disposition of Samples
Frozen samples will be packed in dry ice (pellet form) sufficient to last 3 days during 
transport.  Samples will be shipped pursuant to the central laboratory manual instructions.  
An inventory of the samples will be included in the package for shipment.  Arrangements 
will be made with the central lab for the transfer of samples.
5.3.2.4
Measurement Methods
Plasma concentrations of upadacitinib will be determined under the supervision of the 
Drug Analysis Department at AbbVie using validated liquid chromatography/mass 
spectrometry methods.  Any additional metabolite(s) may be analyzed using non-validated 
methods.
5.3.3
Efficacy Variables
The following endpoint definitions apply to the efficacy variables described below:
Clinical Remission:  
●
Per Adapted Mayo:  SFS ≤ 1 and not greater than baseline, RBS of 0, and 
endoscopic subscore ≤ 1 (note:  evidence of friability during endoscopy in 
subjects with otherwise "mild" endoscopic activity will confer an endoscopic 
subscore of 2).   
●
Per Full Mayo:  Full Mayo score of ≤ 2 with no subscore > 1
Clinical Response:  
●
Per Adapted Mayo:  decrease from baseline in Adapted Mayo score ≥ 2 points 
and ≥ 30%, accompanied by a decrease in RBS of ≥ 1 or an absolute RBS of 0 
or 1
●
Per Full Mayo:  decrease from baseline in Full Mayo score ≥ 3 points and 
≥30%, accompanied by a decrease in RBS of ≥ 1 or an absolute RBS of 0 or 1
●
Per Partial Adapted Mayo:  decrease from Baseline ≥ 1 points and ≥ 30% from 
Baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1


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Endoscopic remission:  Endoscopic subscore of 0
Endoscopic improvement:  Endoscopic subscore ≤ 1
Histologic improvement:  Decrease from Baseline in Geboes score
Histologic-endoscopic mucosal improvement:  Endoscopic subscore ≤ 1 and Geboes 
score ≤ 3.1
Mucosal healing:  Endoscopic subscore = 0 and Geboes score < 2
5.3.3.1
Primary Variable
The primary endpoint is the proportion of subjects who achieve clinical remission per 
Adapted Mayo score (defined as SFS ≤ 1 and not greater than baseline, RBS of 0, and 
endoscopic subscore ≤ 1) at Week 8.  Note:  Evidence of friability during endoscopy in
subjects with otherwise "mild" endoscopic activity will confer an endoscopic subscore of 
2.
5.3.3.2
Secondary Variables
Ranked secondary efficacy variables are as follows: 
1.
Proportion of subjects with endoscopic improvement at Week 8
2.
Proportion of subjects with endoscopic remission at Week 8
3.
Proportion of subjects achieving clinical response per Adapted Mayo Score at 
Week 8
4.
Proportion of subjects achieving clinical response per Partial Adapted Mayo score
(defined as decrease from Baseline ≥ 1 points and ≥ 30% from Baseline, PLUS a 
decrease in RBS ≥ 1 or an absolute RBS ≤ 1) at Week 2
5.
Proportion of subjects achieving histologic-endoscopic mucosal improvement at 
Week 8


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6.
Proportion of subjects who reported no bowel urgency at Week 8
7.
Proportion of subjects who reported no abdominal pain at Week 8
8.
Proportion of subjects who achieved histologic improvement at Week 8
9.
Change from Baseline in IBDQ total score at Week 8
10.
Proportion of subjects with mucosal healing at Week 8
11.
Change from Baseline in FACIT-F score at Week 8
5.3.3.3
Additional Variables
Additional efficacy variables are as follows and will be evaluated.
●
Proportion of subjects achieving response in IBDQ Bowel Symptom domain 
(increase of IBDQ bowel symptom domain score ≥ 6) at Week 8
●
Proportion of subjects with UC-related hospitalizations through Week 8
●
Proportion of subjects with UC-related surgeries through Week 8
●
Proportion of subjects achieving response in IBDQ fatigue item (increase of 
IBDQ fatigue item score ≥ 1) at Week 8
●
Proportion of subjects with SFS of 0, RBS of 0 and endoscopic subscore of 0 
at Week 8
●
Proportion of subjects with SFS of 0, RBS of 0 and endoscopic subscore of ≤1
at Week 8
●
Proportion of subjects achieving clinical remission per Full Mayo Score 
(defined as a full Mayo score ≤ 2 with no sub-score > 1) at Week 8
●
Change in Full Mayo Score from Baseline to Week 8
●
Proportion of subjects achieving clinical remission per Partial Mayo score over 
time.
●
Proportion of subject achieving clinical response per Partial Adapted Mayo 
score over time
●
Proportion of subjects achieving clinical response per Partial Mayo score over 
time.


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●
Proportion of subjects with SFS ≤ 1 over time. 
●
Proportion of subjects with RBS = 0 over time.
●
Proportion of subjects with SFS ≤ 1 at Week 2.
●
Proportion of subjects with RBS of 0 at Week 2.
●
Proportion of subjects with fecal calprotectin below 150 mg/kg over time.
●
Change from Baseline in fecal calprotectin over time
●
Change from Baseline in hs-CRP over time.
●
Change from Baseline in Partial Adapted Mayo score, Partial Mayo score and 
SFS, RBS over time.
●
Change from Baseline in UCEIS score over time.
●
Change from Baseline in laboratory and nutritional parameters 
(e.g., hemoglobin, hematocrit, albumin, total protein concentration, and 
weight).
●
Change from Baseline in subject-reported stool frequency (absolute values).
●
Change from Baseline in IBDQ total and domain score over time.
●
Change from Baseline in individual IBDQ item under Bowel Symptom 
domain (for Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, and Q29) over time.
●
Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from 
Baseline) over time.
●
Proportion of subjects with IBDQ remission (IBDQ total score ≥ 170) over 
time.
●
Change from Baseline in EQ-5D-5L European Quality of Life – 5 Dimensions 
5 Levels (EQ-5D-5L) score over time.
●
Change from Baseline in WPAI scores over time.
●
Change from Baseline in SF-36 Physical Component Summary (PCS) and 
Mental Component Summary (MCS) components and domain scores over 
time.
●
Proportion of subjects by Patient Global Impression of Change (PGIC) 
category over time. 
●
Proportion of subjects by Patient Global Impression of Severity (PGIS) 
category over time.


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●
Change from Baseline in Functional Assessment of Chronic Illness Therapy –
Fatigue (FACIT-F) score over time.  
●
Change from Baseline in Ulcerative Colitis Symptoms Questionnaire (UC-SQ)
score over time
●
Proportion of subjects with all cause hospitalization through Week 8
●
Proportion of subjects with all cause surgery through Week 8
5.3.4
Safety Variables
Safety analyses will be performed on all subjects who receive at least one dose of study 
drug.  Incidence of adverse events, changes in vital signs, physical examination results, 
and clinical laboratory data will be assessed.
5.3.5
Pharmacokinetic Variables
Plasma upadacitinib concentrations will be obtained at the times indicated in Appendix C.  
A non-linear mixed-effect modeling approach will be used to estimate the population 
central value and the empirical Bayesian estimates of the individual values of upadacitinib 
oral clearance (CL/F) and volume of distribution (V/F).  Additional parameters may be 
estimated if useful in the interpretation of the data.
5.3.6
Exploratory Research Variables and Validation Studies
Optional samples may be collected to conduct exploratory investigations into known and 
novel biomarkers.  The types of biomarkers to be analyzed may include, but are not 
limited to nucleic acids, proteins, lipids, or metabolites. 
Biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  These assessments may be 
explored in the context of UC or related conditions and/or upadacitinib or drugs of similar 
classes.  The results from these analyses are exploratory in nature and may not be 
included with the clinical study report (CSR).


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The samples may also be used to develop new therapies, research methods or 
technologies.  In addition, samples from this study may be stored for future use.  Samples 
may then be used to validate putative biomarker signatures obtained from a prospective 
study, leading to the development of diagnostic tests.
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.  See Section 6.1.7 (Toxicity Management) for toxicity 
management criteria for events of serious infections, malignancy, cardiovascular events, 
gastrointestinal perforation, ECG abnormality, and select laboratory abnormalities. 
Subjects must have study drug discontinued 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 TA MD.
●
The investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from study drug or the study.
●
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 TA MD.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie TA 
MD.
●
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.


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●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial as determined by 
investigator or the AbbVie TA MD.
●
Serious infections (e.g., sepsis) which cannot be adequately controlled by anti-
infective treatment or would put the subject at risk for continuation of the 
study drug.
●
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix
●
Subject develops a gastrointestinal perforation (other than appendicitis or 
mechanical injury)
●
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus or non-
cardiac, non-neurologic arterial thrombosis
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment should continue to be followed for all 
regularly scheduled visits, as outline in the Activity Schedule, unless they have decided to 
discontinue the study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they 
discontinue treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed 
consent), the procedures outlined for the Premature Discontinuation Visit must be 
completed as soon as possible, preferably within 2 weeks.
A final telephone visit will occur for all subjects, approximately 30 days after the last dose 
of study medication to determine the status of any ongoing AEs/serious AEs (SAEs) or 
the occurrence of any new AEs/SAEs.
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for premature discontinuation or study participation.  The information will 
be recorded on the appropriate eCRF page.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
investigator feels are necessary to treat the subject's condition.  Following discontinuation 


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of the study drug, the subject will be treated in accordance with the investigator's best 
clinical judgment, irrespective of whether the subject decides to continue participation in 
the study.
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 attempted 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.
COVID-19 Pandemic-Related Acceptable Protocol Modification
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.  Acceptable 
mitigation strategies are identified and included in Section 5.3.1.1 and Appendix C.
The investigator should contact the sponsor medical contact before discontinuing a subject 
from the study for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored.
Refer to the Section 5.3.1.1 and Appendix C for details on how to handle study 
activities/procedures.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
For subjects with signs and/or symptoms and suspicion of COVID-19 or if a diagnosis has 
been confirmed, study drug should not be administered until the infection has resolved or 
coronavirus infection has been ruled out. There are no time limits for study drug 
interruption as long as no permanent study discontinuation criteria have been met. The PI 
should contact the TA MD before reintroducing study drug in subjects who were infected 
with COVID-19. The study drug interruption should be captured on related CRFs with 
reasons due to COVID-19.


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For subjects who are asymptomatic and had primary exposure to COVID-19 (e.g., family 
member tests positive) or have concerns about taking upadacitinib with ongoing 
COVID-19 transmission.  The investigator can decide to continue or interrupt study drug 
on a case-by-case basis taking into account the risk:benefit of continuing study drug. The 
investigator can temporarily interrupt study drug at any time for a safety issue, or for any 
reason if they feel that the risk outweighs the benefit of study treatment.
5.4.2
Discontinuation of Entire Study
The study will be discontinued or terminated in case of an unacceptable risk, any relevant 
toxicity, or a negative change in the risk/benefit assessment.  This might include the 
occurrence of AEs with a character, severity or frequency that is new in comparison to the 
existing risk profile.  In addition, any data deriving from other clinical trials or 
toxicological studies which negatively influence the risk/benefit assessment might cause 
discontinuation or termination of the study.
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
Study drug will be taken orally once daily beginning at the Baseline Visit and should be 
taken at approximately the same time each day.  The study drug can be taken with or 
without food.


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5.5.1
Treatments Administered
Subjects will be randomized into a 2:1 ratio to double-blind upadacitnib 45 mg QD or 
matching placebo for 8 weeks.  The randomization will be stratified by bio-IR status (bio-
IR vs non-bio-IR), corticosteroid use (yes or no) and Adapted Mayo score (≤ 7 or > 7) at 
Baseline.  Within bio-IR, the randomization will be further stratified by number of prior 
biologic treatments (≤ 1 or > 1).  Within non-bio-IR, the randomization will be further 
stratified by previous biologic use (yes or no). 
Subjects that do not achieve clinical response after induction will be offered open-label 
upadacitinib 45 mg QD for an additional 8 weeks (until Week 16 in the Extended 
Treatment Period). 
If a subject is unable to come to the study site to pick up their study drug due to 
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 see Section 5.3.1.1 for 
details on DTP shipment of study drug.
DTP study drug shipment will be allowed for the duration of the COVID-19 pandemic 
and will be removed once the pandemic is considered to be resolved.
Table 2.
Treatments Administered
Substudies
Treatment Group
Treatment Administered
Double-Blind Induction 
Doses – Phase 3 (Part 1):
Upadacitinib 45 mg 
or Placebo
Upadacitinib 45 mg QD
Matching Placebo QD
Open-Label Induction Doses 
– Phase 3 (Part 2):
Upadacitinib 45 mg  
Upadacitinib 45 mg QD


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5.5.2
Identity of Investigational Product
Table 3.
Identity of Investigational Product
Investigational Product
Upadacitinib
Mode of Administration
Oral
Oral
Dosage Form
Film-coated tablet
Film-coated tablet
Strength (mg)
45
Matching placebo
Manufacturer
AbbVie
AbbVie
5.5.2.1
Packaging and Labeling
Upadacitinib and matching placebo will be packaged in bottles with quantities sufficient 
to accommodate study design.  Each kit label will contain a unique kit number.  This kit 
number is assigned to a subject via Interactive Response Technology (IRT) and encodes 
the appropriate study drug to be dispensed at the subject's corresponding study visit.  Each 
kit will be labeled as required per country requirements.  Labels must remain affixed to 
the kits.  All blank spaces, if applicable, on the label will be completed by the site staff 
prior to dispensing to the subjects.
5.5.2.2
Storage and Disposition of Study Drug
The study drug must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  
The controlled storage area should have a temperature recording device.  A storage 
temperature log is to be maintained to document proper storage conditions.  Malfunctions 
or temperature excursions must be reported to the sponsor immediately.  In case of a 
temperature excursion, study medication should be quarantined and not dispensed until 
AbbVie Clinical Drug Supply Management (CDSM) or AbbVie Temperature Excursion 
Management System (ATEMS) deems the medication as acceptable.  The investigational 
products are for investigational use only and are to be used only within the context of this 
study.  The study drug supplied for this study must be maintained under adequate security 
and stored under the conditions specified on the label until dispensed for subject use or 
destroyed on site according to local procedures or regulations or returned to the 


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destruction depot.  Upon receipt of study drugs the site will acknowledge receipt within 
the interactive response technology (IRT) system.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be centrally randomized using a web based Interactive Response 
Technology (IRT).
All subjects will be assigned a unique identification number by the IRT at the Screening 
Visit.  In Part 1, 462 subjects who meet all the inclusion and none of the exclusion criteria 
defined in Section 5.2.1 and Section 5.2.2 will be centrally randomized in a 2:1 ratio to 
receive one of two treatment groups at Baseline (Week 0) in a double-blind manner 
(upadacitinib 45 mg QD, or placebo QD).  The randomization will be stratified by bio-IR 
status (bio-IR vs non-bio-IR), corticosteroid use (yes or no) and Adapted Mayo score 
(≤7 or > 7) at Baseline.  Within bio-IR, the randomization will be further stratified by 
number of prior biologic treatments (≤ 1 or > 1).  Within non-bio-IR, the randomization 
will be further stratified by previous biologic use (yes or no).
The IRT will assign a randomization number that will encode the subject's treatment 
group assignment according to the randomization schedule generated by the Statistics 
Department at AbbVie and as per Section 5.1 definitions.
IRT will provide the appropriate medication kit number(s) to dispense to each subject as 
per Section 5.1.  Study drug will be administered at the study visits as summarized in 
Section 5.1.  Returned study medication should not be re-dispensed to any subject.
All subjects will keep the same unique subject identification number throughout the study 
and program.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects will be randomly assigned to receive one of the treatment groups at Baseline by 
the IRT system as described in Section 5.5.3. 


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Part 1
●
Upadacitinib 45 mg QD
●
Placebo QD
Part 2 – Extended Treatment Period
●
Upadacitinib 45 mg QD
Subjects should take study medication as outlined in Section 5.5.
On dosing days that occur on study visit days, subjects should follow the regular dosing 
schedule (refer to Section 5.3.2.1 regarding Week 2 and Week 4 Visits).
Each subject's dosing schedule should be reviewed by the site at each study visit and 
accountability performed to ensure compliance.
If a subject should forget to take their upadacitinib (or matching placebo) dose at their 
regularly scheduled dosing time, they should take the forgotten dose as soon as they 
remember the dose was missed as long as it is at least 10 hours before their next scheduled 
dose.  If a subject only remembers the missed dose within 10 hours before next scheduled 
dose, the subject should skip the missed dose and take the next dose at the scheduled time.  
5.5.5
Blinding
The investigator, study site personnel, the subject and all AbbVie personnel with direct 
oversight of the conduct and management of the trial (with the exception of AbbVie Drug 
Supply Management Team) will remain blinded to each subject's treatment throughout the 
course of the study with the exception of subjects enrolled in the open-label extended 
treatment period (Part 2).  The IRT will provide access to blinded subject treatment 
information in the case of a medical emergency.  In the event of medical situation that 
requires unblinding of the study drug assignment the investigator is requested to contact 
the AbbVie TA MD prior to breaking the blind, as long as this communication does not 
compromise subject safety.  However, if an urgent therapeutic intervention is necessary 


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which warrants breaking the blind prior to contacting AbbVie TA MD, the investigator 
can directly access the IRT system to break the blind without AbbVie agreement.  In the 
event that the blind is broken before notification to AbbVie TA MD, it is requested that 
the AbbVie TA MD be notified within 24 hours of the blind being broken.  Also, the date 
and reason that the blind was broken must be recorded in the source documentation and
eCRF, as applicable.  Throughout the duration of the double-blind periods of the study, 
the investigator, site personnel, and subjects will remain blinded to the subject's treatment 
group.  AbbVie will remain blinded to the induction period data until that data is locked 
and analyzed as part of the planned analysis.
5.5.5.1
Blinding of Investigational Product
In order to maintain the blind, the upadacitinib tablets and Placebo tablets provided for the 
study will be identical in appearance.
5.5.5.2
Blinding of Data for Independent Data Monitoring 
Committee (IDMC)
Data will be unblinded for review by the independent safety Data Monitoring Committee 
(DMC) by an unblinded statistician not involved in the planning, execution or analysis of 
the study.  The process for unblinding study data and ensuring its confidentiality will be 
described in the Data Monitoring Committee Charter for this study.  The DMC will advise 
the sponsor as to either i) study continuation without modification, ii) study continuation 
with modification, iii) temporary suspension of study enrollment and/or treatment, or 
iv) the study should be stopped.
The external DMC composed of persons independent of AbbVie and with relevant 
expertise in their field will review unblinded safety and if necessary, efficacy data from 
the ongoing study.  The DMC members consist of two clinicians and one biostatistician, 
with one clinician being an expert in the management of subjects with UC.  The primary 
responsibility of the DMC will be to protect the safety of the subjects participating in this 
study.


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5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subjects will be instructed to return all drug containers (even if empty) to the study site 
personnel at each site visit.  The study site personnel will document compliance in the 
study source documents.
Subjects will be counseled on missed doses of study drug.  If the subject does not return 
the bottles (when applicable), 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" before completing on the 
applicable eCRF page.
5.5.7
Drug Accountability
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 returned study drug bottles will be inventoried by the site.  Study drug bottles should 
be returned by the subject at each visit for accountability and compliance purposes and 
new containers issued as necessary.  Site staff will complete study medication 
accountability via IRT, by using source documents and by visually inspecting the study 
drug bottles whenever possible.  During the COVID-19 pandemic if a visit is completed 
virtually study drug accountability can be conducted remotely with the subject.  Any kits 
who are accounted for remotely should be retained by the subject and when the subject is 
then able to complete an onsite visit, they should return all kits for verification of the drug 
accountability by the site staff. After drug accountability has been completed, unused 
medication will be destroyed on site according to local procedures or regulations or 


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returned to the destruction depot.  A copy of the destruction methodology should be 
maintained at the site's facility.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Upadacitinib is a potent JAK1 selective inhibitor that may provide an improved clinical 
benefit to risk profile in UC patients.  The proposed study is a Phase 3, randomized, 
double-blind, placebo-controlled study to evaluate the safety and efficacy of upadacitinib 
compared to placebo in subjects with moderately to severely active UC who have had 
inadequate response to, loss of response to, or intolerance to aminosalicylates, 
corticosteroids, immunosuppressants or biologic therapies. 
The study consists of two parts, in Part 1, upadacitinib 45 mg QD is compared with 
placebo as induction therapy for 8 weeks.  Part 2 consists of open-label upadacitinib 
45 mg QD in an Extended Treatment Period for an additional 8 weeks to provide 
treatment for those who were treated with placebo or who did not respond to the initial 
8-week upadacitinib treatment.
A comparative study utilizing a placebo control design provides an unbiased assessment 
of the efficacy and safety profile of upadacitinib.  In order to provide a potentially 
efficacious regimen to all participating subjects, subjects in Study M14-675 who do not 
achieve clinical response after completion of the 8-week induction treatment will be 
received oral upadacitinib therapy for an additional 8 weeks. 
Rationale of placebo use in this study
A placebo controlled study is necessary for new medication registrational purposes.  
Based on the guidance provided in the International Conference on Harmonization (ICH) 
Tripartite Guideline, Topic E10 "Choice of Control Group in Clinical Trials,"34 a placebo-
controlled trial design, using randomization and blinding has been implemented in the 
study in order to minimize subject and investigator bias, and support an objective 
assessment of all study endpoints.  Current EMA guidelines on the development of new 


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medicinal products for the treatment of Ulcerative Colitis (UC)35 state that "unless the 
study is aiming at demonstrating superiority against an existing treatment, it is critical that 
assay sensitivity can be demonstrated, ideally by adding a placebo arm."  A placebo 
control is the most objective comparator and a prerequisite for confirmation of clinical 
benefit in a Phase 3 trial.
In order to minimize the exposure to placebo during the studies, in the induction phase,
subjects will be randomized in a 2:1 ratio to receive upadacitinib or placebo for 8 weeks. 
If subjects do not respond at Week 8, an open label treatment of upadacitnib 45 mg QD 
will be provided for an additional 8 weeks.
It should also be noted that in this program, if the subjects are at stable and permitted dose
of aminosalicylates, corticosteroids and/or methotrexate at Baseline, the treatment can be 
continued in the study.  Also, at any time of the study, subjects may discontinue from the 
study for any reason, including lack of response.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All 
efficacy measurements in this study are standard for assessing disease activity in subjects 
with UC.  All clinical and laboratory procedures in this study are standard and generally 
accepted.  Central reading of endoscopy will increase study rigor and ensure enrollment of 
patients with moderately to severely active UC.
5.6.3
Suitability of Subject Population
Male and female subjects, including adults and adolescents (16 or 17 years old) when 
locally permissible, with moderately to severely active UC who meet all of the inclusion 
criteria and none of the exclusion criteria are eligible for enrollment in this study.  The 
specific population chosen was based on the unmet medical need of those subjects with a 
history of inadequate response, loss of response, or intolerance to oral aminosalicylates, 
immunosuppressants, corticosteroids, and/or biologic therapies.


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5.6.4
Selection of Doses in the Study
The results from the Substudy 1 of Study M14-234 in subjects with UC show that all 
evaluated doses using the extended release (ER) tablet formulation (7.5 mg QD to 45 mg 
QD) were generally well tolerated and without unexpected safety concerns consistent with 
the observations in Phase 2b studies in CD (Study M13-740; up to 24 mg twice daily 
using the immediate-release [IR] capsule formulation [exposures equivalent to 60 mg ER 
QD]), AD (Study M14-680; up to 30 mg ER QD), two Phase 2 studies in RA 
(Studies M13-537 and M13-550; up to 18 mg IR twice daily [BID] [exposures equivalent 
to 45 mg ER QD]) and three Phase 3 studies in RA (Studies M13-549, M13-542 and 
M15-555; 15 and 30 mg ER QD).
Results from the Phase 2b Induction Study M14-234 (Substudy 1) showed that 
upadacitinib plasma exposures associated with the 45 mg QD regimen maximize the 
therapeutic benefit across endpoints and across bio-IR and non-bio-IR subpopulations, at 
Week 8 with effect on laboratory parameters consistent with previous indications.
Preliminary exposure-response analyses for the Phase 2b Study M14-234 (Substudy 1) 
show that at Week 8, the percentage of subjects achieving clinical remission based on the 
Adapted Mayo Score (primary endpoint for Phase 3), clinical response, and the 
endoscopic endpoints (improvement and remission) increased with increasing 
upadacitinib plasma exposures.  With the exception of endoscopic remission, the plateau 
of key efficacy endpoints (clinical remission, clinical response, and endoscopic 
improvement) was established at Week 8 within the range of exposures evaluated in this 
study.  Simulations using exposure-response models indicate that the upadacitinib 45 mg 
QD regimen is predicted to maximize efficacy across efficacy endpoints and across bio-IR 
and non-bio-IR sub-populations after 8 weeks of induction treatment in subjects with UC. 
The selection of the induction dose in subjects with UC is also supported by the efficacy 
and safety results observed in the Phase 2 study in subjects with CD (Study M13-740), 
wherein the two highest upadacitinib doses evaluated were 12 mg IR BID and 24 mg IR 
BID (equivalent of 30 mg ER QD and 60 mg ER QD).  Simulations using the exposure 


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response models indicated that a dose higher than 45 mg ER QD (60 mg ER QD) would 
result in only a 1% to 2% incremental efficacy in terms of clinical response and remission 
endpoints, and 3% to 4% higher proportions for endoscopic response and remission, while 
simultaneously resulting in greater decreases in NK cells and increases in CPK.  Thus, the 
45 mg QD dose offers the optimal benefit-risk profile and was selected as the induction 
dose for Phase 3 in CD.
In summary, exposures associated with upadacitinib 45 mg QD regimen are predicted to 
maximize efficacy across efficacy endpoints and across bio-IR and non-bio-IR sub-
populations in subjects with UC while resulting in acceptable impact on laboratory 
parameters.  Given the plateau has been established in the evaluated dose and exposure 
range of the Phase 2b study, a dose higher than 45 mg QD is projected to have no 
additional benefit for Adapted Mayo based clinical remission (primary endpoint) but can 
have incremental negative impact on laboratory parameters (e.g., NK cells).  A dose lower 
than 45 mg QD is predicted to provide lower efficacy across endpoints (~2% to 10% 
relative to 45 mg QD).
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Section 6.1
through Section 6.1.8.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 


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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 another 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.
6.1.1
Definitions
6.1.1.1
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 including UC 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 6.1.7 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 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 


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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.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
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.
6.1.1.3
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study (see detailed 
toxicity management in Section 6.1.7):
●
Serious infections,
●
Opportunistic infections;
●
Herpes zoster;
●
Active TB;
●
Malignancy (all types);
●
Adjudicated gastrointestinal perforations;
●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE]);
●
Anemia;
●
Neutropenia;
●
Lymphopenia;


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●
Renal dysfunction;
●
Hepatic disorders;
●
Elevated creatine phosphokinase (CPK);
●
Adjudicated embolic and thrombotic events (non-cardiac, non-central nervous 
system [CNS]).
6.1.2
Adverse Event Severity
When criteria are available, events should be graded as described in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03,26 which can be accessed at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
If no grading criteria are provided for the reported event, then the event should be graded 
as mild, moderate, or severe per the investigator's judgment. 
Mild (Grade 1)
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Moderate (Grade 2)
Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL) (instrumental ADL refers to 
preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.).
Severe (Grade 3 - 5)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (self-care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden).
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:


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Reasonable Possibility
An adverse event where there is evidence to suggest a 
causal relationship between the study drug and the 
adverse event.
No Reasonable Possibility
An adverse event where there is no evidence to suggest a 
causal relationship between the study drug and the 
adverse event.
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 causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, another cause of event must be provided by the investigator for the serious adverse 
event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 30 days 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, serious adverse 
events and protocol-related nonserious 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 3.




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Clinical Pharmacovigilance within 24 hours of the site being made aware of the serious 
adverse event.
Email:  PPDINDPharmacovigilance@AbbVie.com
FAX to:  +1 (847) 938-0660
For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
Dept. R48S
1 North Waukegan Road
North Chicago, IL 60064
Office:
(847) 938-8737
Email:
GPRD_SafetyManagement_Immunology@abbvie.com
For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director (TA MD):
1 North Waukegen Rd
North Chicago, IL 60064
Telephone Contact Information:
Phone:
Cell:
Fax:
Email:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:


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Phone:  +1 (973) 784-6402
AbbVie will be responsible for Suspected Unexpected Adverse Reactions (SUSAR) 
reporting for the Investigational Medicinal Product (IMP) in accordance with global and 
local guidelines and Appendix A of the Investigator Brochure will serve as the Reference 
Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting period
serves as the RSI during the reporting period. For follow-up reports, the RSI in place at 
the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to assess 
expectedness. 
In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
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 capture 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:
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form
If a subject has a confirmed or suspected COVID-19 infection and study drug was 
interrupted, the investigator should contact the sponsor emergency medical contact listed 
above before reintroducing study drug.


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6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
6.1.7
Toxicity Management
The toxicity management of the AEs including AEs of special interest consists of safety 
monitoring (review of AEs on an ongoing basis, and periodic/ad hoc review of safety 
issues by an independent Data Monitoring Committee), and if applicable interruption of 
study drug dosing with appropriate clinical management and/or discontinuation of the 
subjects from study drug.  The management of specific AEs and laboratory parameters is 
described below.
For subjects who discontinue study drug but continue study participation and are on 
standard of care therapies, these toxicity management requirements do not apply 
(including alerts from the central laboratory) and any intolerability to standard of care 
therapies should be managed by the prescribing physician.
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection.  A subject who develops a new 
infection during treatment with study drug should undergo prompt diagnostic testing 
appropriate for an immunocompromised subject.  As appropriate, antimicrobial therapy 


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should be initiated, and the subject should be closely monitored.  Study drug may be 
restarted once the infection has been successfully treated.  These subjects will continue to 
be clinically monitored and will be evaluated in the safety analyses.
Subjects who develop active tuberculosis must be permanently discontinued from study 
drug (refer to "TB Testing/TB Prophylaxis" under Section 5.3.1.1).
Herpes zoster: If a subject develops herpes zoster, consider temporarily interrupting 
study drug until the episode resolves.
Gastrointestinal Perforation:  Subjects presenting with the onset of signs or symptoms 
of a gastrointestinal perforation should be evaluated promptly for early diagnosis and 
treatment.  If the diagnosis of spontaneous gastrointestinal perforation is confirmed (other 
than appendicitis or mechanical injury), the subject must be permanently discontinued 
from study drug.
Cardiovascular Events:  Subjects presenting with potential cardiovascular events 
including non-cardiac, non-CNS thrombotic and embolic events should be carefully 
monitored.  These events will be reviewed and adjudicated by an independent 
Cardiovascular Adjudication Committee in a blinded manner.
Malignancy and Gastrointestinal (GI) Dysplasia:  Subjects who develop malignancy 
other than nonmelanoma skin cancer (NMSC) or carcinoma in situ of the cervix should be 
discontinued.  Subjects who develop high grade colonic dysplasia, should be 
discontinued.  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. 
Thrombosis Events:  Subjects who develop symptoms of thrombosis should be promptly 
evaluated and treated appropriately.  If the diagnosis of deep vein thrombosis, pulmonary 
embolus or non-cardiac, non-neurologic arterial thrombosis is confirmed, the subject must 
be discontinued from study drug.


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ECG Abnormality:  Subjects must be permanently discontinued from study drug for an 
ECG change considered clinically significant and with reasonable possibility of 
relationship to study drug.
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 and follow any local guidelines.  Specific toxicity 
management guidelines for abnormal laboratory values are described in Table 4, and may 
require a supplemental eCRF to be completed.  All abnormal laboratory tests that are 
considered clinically significant by the investigator will be followed to a satisfactory 
resolution.  If a repeat test is required per Table 4, the repeat testing must occur as soon as 
possible. 


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Table 4.
Toxicity Management Guidelines for Abnormal Lab Values
Hemoglobin
!
If hemoglobin < 8.0 g/dL interrupt study drug dosing and confirm by 
repeat testing with new sample.
!
If hemoglobin decreases from Baseline ≥ 3.0 g/dL without an 
alternative etiology, interrupt study drug dosing and confirm by repeat 
testing with new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from Baseline and an alternative 
etiology is known or the hemoglobin value remains in the normal 
reference range, the subject may remain on study drug at the 
investigator's discretion.
!
If confirmed, continue to withhold study drug until hemoglobin value 
returns to normal reference range or its Baseline value.
Absolute neutrophil count 
(ANC)
!
If confirmed < 1000 cells/μL by repeat testing with new sample, 
interrupt study drug dosing until ANC value returns to normal 
reference range or its Baseline value. 
!
Interrupt study drug if confirmed < 500/μL by repeat testing with new
sample. If value returns to normal reference range or its Baseline 
value, restarting study drug is allowed if there is an alternative 
etiology identified; documentation should include reason that 
rechallenge is expected to be safe for the subject. Study drug should 
be discontinued if no alternative etiology can be found.
Absolute lymphocyte 
count (ALC)
!
If confirmed < 500 cells/μL by repeat testing with new sample, 
interrupt study drug dosing until ALC returns to normal reference 
range or its Baseline value.
Total white blood cell 
count
!
If confirmed < 2000 cells/μL by repeat testing with new sample, 
interrupt study drug dosing until white blood cell count returns to 
normal reference range or its Baseline value.
Platelet count
!
If confirmed < 50,000 cells/μL by repeat testing with new sample, 
interrupt study drug dosing until platelet count returns to normal 
reference range or its Baseline value.


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Table 4.
Toxicity Management Guidelines for Abnormal Lab Values 
(Continued)
AST or ALT
!
Interrupt study drug immediately if confirmed ALT or AST 
> 3 × ULN by repeat testing with new sample and either a total 
bilirubin > 2 × ULN or an international normalized ratio (INR) > 1.5. 
o
A separate blood sample for INR testing will be needed to 
measure INR at the time of repeat testing for ALT or AST.  A 
repeat test of INR is not needed for determination if above 
toxicity management 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 with HBc Ab+ (irrespective of HBs Ab status) and negative 
HBV DNA PCR testing at screening who develop the following 
should have HBV DNA by PCR testing performed within 1 week 
(based on initial elevated value):
o
ALT > 5 × ULN OR
o
ALT or AST > 3 × ULN if an alternative cause is not readily 
identified.
!
A separate blood sample for HBV DNA PCR testing will be 
needed at the time of repeat testing for ALT or AST
!
A positive result for HBV DNA PCR testing in these subjects will 
require immediate interruption of study drug (unless not acceptable by 
local practices) and a hepatologist consultation should occur within 
one week for recommendation regarding subsequent treatment.
Subjects who meet any of the above criteria should be evaluated for an 
alternative etiology of the ALT or AST elevation and managed as 
medically appropriate.  If applicable, the alternative etiology should be 
documented in the eCRF.  If ALT or AST values return to the normal 
reference range or its Baseline value, study drug may be restarted.  If 
restarting study drug, documentation should include reason that 
rechallenge is expected to be safe.  If after clinically appropriate 
evaluation, no alternative etiology for ALT or AST elevation is found or 
the ALT or AST elevation has not resolved or is not trending down toward 
normal, the subject should be discontinued from study drug 
For any confirmed ALT or AST elevations > 3 ULN, complete 
supplemental hepatic eCRF


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Table 4.
Toxicity Management Guidelines for Abnormal Lab Values 
(Continued)
Serum Creatinine (sCr)
!
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 restart study drug once serum 
creatinine returns to ≤ 1.5 × Baseline value and ≤ULN.
For the above serum creatinine elevation scenario, complete supplemental 
renal eCRF(s).
Creatine Phosphokinase
!
If confirmed CPK value > 4 × ULN and there are no symptoms 
suggestive of myositis or rhabdomyolysis, the subject may continue 
study drug at the investigator's discretion.
!
If CPK > 4 × ULN accompanied by symptoms suggestive of myositis 
or rhabdomyolysis, interrupt study drug and contact AbbVie TA MD.
For above CPK elevation scenarios, complete supplemental CPK eCRF.
If the subject must undergo elective surgery, the study drug should be interrupted 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.
Repeat testing must be performed by central laboratory.
6.1.8
Cardiovascular Adjudication Committee (CAC)
An independent, external committee of physician experts in cardiac adjudication will be 
utilized to assess cardiovascular, embolic and thrombotic adverse events in a blinded 
manner as defined by the Cardiovascular Adjudication Committee charter.
6.1.9
Data Monitoring Committee (DMC)
An external independent safety Data Monitoring Committee (DMC) comprised of persons 
independent of AbbVie and with relevant expertise in their field will review unblinded 
safety and if necessary, efficacy data from the ongoing studies.  The DMC members 
consist of two clinicians and one biostatistician, with one clinician being an expert in the 


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management of subjects with UC.  The primary responsibility of the DMC will be to 
protect the safety of the subjects participating in this study.
A separate DMC charter will be prepared outside of the protocol and approved by AbbVie 
and the DMC members before a subject is initiated into the study.  The DMC charter 
describes the composition of the DMC, the roles and responsibilities of the DMC 
members, frequency of data reviews and relevant safety data to be assessed, meeting 
occasions, and communication with AbbVie as well as relevant competent authorities.  
The DMC is responsible for monitoring safety data and alerting AbbVie to possible safety 
concerns related to the conduct of the study.  
Data for DMC review will be prepared by AbbVie (for blinded data) and an independent 
CRO (Axio Research for unblinded data to DMC).  The DMC will review safety data at a 
minimum of 6-month intervals throughout the course of the study.  The DMC will 
determine if more frequent DMC meetings are required based on review of the 
accumulating safety data.  In addition, ad-hoc DMC meetings will be scheduled in the 
event of any significant safety concerns.  Based on these reviews, the DMC will make 
recommendations, as appropriate, regarding the conduct and management of the study.  
DMC recommendations will be triaged by the AbbVie Contact to the appropriate parties 
(AbbVie Study Management Team or Internal Review Committee).
Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 


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discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified, 
including those that may be due to the COVID-19 pandemic) after a subject has been 
enrolled, the principal investigator is responsible for notifying Independent Ethics 


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Committee (IEC)/Independent Review Board (IRB) regulatory authorities (as applicable), 
and the following AbbVie Clinical Monitors:
Primary Contact:
1 North Waukegan Road
North Chicago, IL  60064
Office:
Email:
Alternate Contact:
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
In Japan, the Investigator will record all protocol deviations in the appropriate medical 
records at site.
For the purposes of this protocol, reportable deviations are defined as:
●
Subject entered into the study even though she/he did not satisfy entry criteria.
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject who received wrong treatment or incorrect dose.
●
Subject who received excluded or prohibited concomitant treatment.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objective of the statistical analyses is to evaluate the efficacy and safety of the 
selected induction dose of upadacitinib 45 mg QD compared to placebo in subjects with 
moderately to severely active UC.


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Complete, specific details of the statistical analyses will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 
database lock.
8.1.1
Datasets for Analysis 
8.1.1.1
Intent-to-Treat Analysis Sets
The intent-to-treat (ITT) analysis set includes all randomized subjects who received at 
least one dose of double-blinded study drug from Part 1 (denoted as ITT1). The ITT 
analysis set that includes all subjects who received the open label upadacitinib induction 
of 45 mg QD in the Extended Treatment Period is denoted as ITT2.
For the ITT analysis sets, subjects are assigned to a treatment group based on the 
randomization schedule, regardless of the treatment actually received.  The efficacy 
analysis will be based on the corresponding ITT analysis set.
8.1.1.2
Safety Analysis Set
The safety analysis set consists of all subjects who received at least one dose of study 
medication in each part of the study, respectively.  For the safety analysis sets, subjects 
are assigned to a treatment group based on the treatment actually received, regardless the 
treatment randomized.  Safety analyses of the entire study will be carried out using the 
union of all safety analysis sets for all treated subjects.
8.1.2
Subject Accountability
The number of subjects randomized, 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 by treatment group.
8.1.3
Definition of Missing Data Imputation
Missing data will be imputed using one or more of the following methods:


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Non-Responder Imputation (NRI):  In NRI analyses, subjects who prematurely 
discontinue the study prior to efficacy assessment at Week 8/Week 16 will be considered 
non-responders with respect to the efficacy endpoint.
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.
Depending on the magnitude of missing data due to COVID-19, additional appropriate 
analysis of missing data may be performed with details included in the SAP.
The SFS and RBS at an assessment visit will be calculated as an average of the entries 
recorded into the subject's diary from the most recent consecutive 3-day period prior to 
each study visit.  If diary entries from the 3 consecutive days prior to the visit are not 
available, the 3 most recent consecutive days in the last 10 days will be utilized.  If data 
are not available for 3 consecutive days, the average of the entries from the most recent 
3 non-consecutive days in the last 10 days will be utilized.  If less than 3 days of diary 
data are available, SFS and RBS will be considered missing.  Clinical endpoints of 
abdominal pain and bowel urgency from subject diaries will be measured at the same time 
period as the SFS and RBS.
Subjects in whom UC-related corticosteroids are initiated during treatment (not taken at 
Baseline) or who have dosages of these medications increased to greater than the dose 
taken at Baseline will be considered a failure for categorical efficacy endpoints and will 
have the last values carried forward for non-categorical assessments from that time point 
through the end of the study.
8.1.4
Demographics and Baseline Characteristics
Baseline demographics and characteristics will be summarized for ITT analysis sets.


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8.1.4.1
Baseline Characteristics
Summary statistics for continuous variables will include the number of observations, 
mean, standard deviation, median, and range for each treatment group.  For other 
categorical or discrete variables, frequencies and percentages will be computed in each 
category for each treatment group, as well as for all subjects combined.
8.1.4.2
Medical Histories
Frequencies and relative frequencies (percentages) will also be computed for each 
treatment group for general medical history items.
8.1.4.3
Prior Therapy and Medications
Prior therapy and medications will include all therapies and medications administered 
prior to the date of the first dose of study drug.  Prior therapy and medication will be 
summarized for the ITT analysis set.  No statistical test will be performed.
8.1.4.4
Concomitant Medications
Concomitant drugs will be summarized for the ITT analysis set.  Concomitant drugs will 
be summarized using the World Health Organization (WHO) Drug Dictionary with 
frequencies and percentages for each treatment group.  All medications administered 
between the date of the first dose of study drug and the date of the last dose of study drug, 
inclusive, (i.e., all medications starting or ongoing during the time interval) will be 
included.  Thus, all medications with an end date prior to the first study drug dose will be 
excluded from the summary table.  No statistical test will be performed.
A subject who reports two or more uses of the same concomitant medication will be 
counted only once within each generic name.  A subject with concomitant medications 
with more than one generic name will be counted only once in the overall total.


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8.1.5
Subject Disposition and Study Drug Exposure
8.1.5.1
Subject Disposition
The number and percentage of subjects who are enrolled, randomized and received at 
least one dose of study drug, and the number of subjects who prematurely discontinued 
and the reason for early termination will be summarized by treatment group in each part.  
Premature discontinuation of study drug will be summarized for each treatment group, as 
well as for all subjects combined, with frequencies and percentages overall and by reason 
for discontinuation for all randomized 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").
8.1.5.2
Study Drug Exposure
Exposure to study drug will be summarized for all subjects who have received at least 
one dose of study drug for each part and over the entire study.  The duration (days) of 
study drug treatment will be summarized with the mean, standard deviation, median and 
range for each treatment group.  The duration of treatment is defined as the difference 
between the dates of the first and last doses of the treatment plus 1 day.  Study drug 
compliance will be summarized for each treatment group.  Compliance is defined as the 
number of tablets taken (i.e., the difference between the number of tablets dispensed and 
the number of tablets returned) divided by the number of tablets a subject is supposed to 
take each day times the length of time that the subject was in the Treatment Phase of the 
study (i.e., Final/Discontinuation Visit date during Treatment Phase – Day 1 [Baseline] 
Visit date + 1).  Subjects with missing data for the number of tablets returned will be 
excluded from the summary.
8.1.6
Efficacy Analysis
The primary and ranked secondary efficacy endpoints as specified in Section 5.3.3 will be 
tested with multiplicity adjustment to ensure a strong control of family-wise type I error 


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rate at significance level alpha = 0.05 (2-sided).  The details of the testing procedure will 
be specified and documented in the SAP.
8.1.6.1
Primary Efficacy Variables
The primary endpoint is the proportion of subjects who achieve clinical remission per 
Adapted Mayo score (defined as SFS ≤ 1 and not greater than baseline, RBS of 0, and 
endoscopic subscore ≤ 1.  Note:  evidence of friability during endoscopy in subjects with 
otherwise "mild" endoscopic activity will confer an endoscopic subscore of 2) at Week 8.
8.1.6.1.1
Analysis of Primary Endpoint
The primary analysis will compare the subjects in upadacitinib treatment group and 
placebo group in the ITT1 analysis set.  The difference between the treatment groups in 
the primary efficacy endpoint will be assessed using the Cochran-Mantel-Haenszel 
(CMH) test and will be stratified by baseline corticosteroid use, baseline Adapted Mayo 
score (≤ 7 or > 7), and bio-IR status (yes or no).  The NRI method, where subjects with 
missing data at scheduled assessment visits will be considered as "not achieved" for the 
clinical remission, will be used for primary analysis.
Primary efficacy endpoint will be summarized descriptively for the ITT2 population. 
Subgroup (characterized by the varying inclusion and exclusion criteria) analysis for the 
primary endpoint, clinical remission per Adapted Mayo Score, will be conducted.
8.1.6.2
Secondary Efficacy Variables
All secondary efficacy variables are listed in Section 5.3.3.2.  
In general, continuous secondary efficacy variables with repeated measurements will be 
analyzed using a Mixed Effect Repeated Measure (MMRM) model.  Continuous 
secondary efficacy variables which are collected at only one post-baseline visit (such as 
Mayo score) will be analyzed using an Analysis of Covariance (ANCOVA) model.  
Categorical secondary efficacy variables will be analyzed using the CMH test controlling 


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for stratification variables.  NRI for missing data will be used for categorical secondary 
endpoints.  The ranked secondary analysis will be repeated in the ITT2 population.
8.1.7
Other Statistical Analyses of Efficacy
The subgroups listed below will be used in subgroup analyses of the primary endpoint.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Bio-IR (yes, no)
●
Baseline corticosteroid use (yes, no)
●
Baseline Adapted Mayo Score (≤ 7, > 7)
●
Baseline Full Mayo Score (≤ 9, > 9)
●
Prior exposure to anti-TNF (yes, no)
●
Prior exposure to biologic therapy (yes, no)
●
Baseline weight (≤ median, > median)
●
Presence of pancolitis at Baseline (yes, no)
●
Disease duration at Baseline (≤ median, > median)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Region (US versus non-US)
In addition, the following key secondary endpoints will be analyzed in bio-IR and non-
bio-IR subgroup.
●
Endoscopic remission at Week 8
●
Endoscopic improvement at Week 8
●
Clinical response per adapted Mayo score at Week 8


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8.1.8
Safety Analysis
8.1.8.1
General Considerations
Safety analyses will be carried out using the safety analysis sets, which includes all 
subjects who receive at least one dose of study medication in each part of the study.  
Incidence of adverse events, including those related to study drug, changes in vital signs, 
physical examination results, ECGs, 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 for each 
treatment group.  Mean change from Baseline for laboratory and vital signs data will be 
summarized.
Missing safety data will not be imputed.
8.1.8.2
Analysis of Adverse Events
8.1.8.2.1
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 study drug in each period of the 
study, will be tabulated by system organ class (SOC) and MedDRA preferred term for 
each treatment group.
Adverse events starting more than 30 days following discontinuation of study drug will 
not be included in summaries of treatment-emergent 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 category 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 


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categories of "reasonable possibility."  In this case, the subject will be counted under these 
most extreme severity/relationship categories.
Subjects reporting more than one 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 one 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 for each treatment group as follows:
●
Any event
●
By system organ class, and preferred term
●
By system organ class, preferred term and maximum relationship
●
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 (serious infection, opportunistic infection, gastrointestinal 
perforations, malignancies, cardiovascular events [adjudicated events], drug-
related hepatic disorders, increased serum creatinine and renal dysfunction, 
and increased CPK)
All AEs leading to early termination of study drug will be presented in listing format.


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The adverse events of special interest (infection, opportunistic infection, and 
gastrointestinal perforations, malignancies and drug related hepatic disorders) will be 
specified in the SAP.
A listing by treatment group 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.
8.1.8.2.2
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.
8.1.8.3
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 by treatment group.  Treatment 
group differences for mean changes from Baseline will be analyzed using ANOVA.
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, 
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.  Analysis details will be specified in the SAP.
8.1.9
Pharmacokinetic and Exposure-Response Analyses
Individual upadacitinib plasma concentrations at each study visit will be tabulated and 
summarized with appropriate statistical methods.


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


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identification of all relevant covariates, a stepwise backward elimination of covariates 
from the full model will be employed to evaluate the significance (at P < 0.005, 
corresponding to a decrease in objective function > 7.88 for one degree of freedom) of 
each covariate in the full model.
Linear or non-linear relationships of primary PK parameters with various covariates will 
be explored.
Relationships between upadacitinib exposure and clinical observations (primary efficacy 
variable) will be explored.  Exposure-response relationships for secondary efficacy 
variables and/or some safety measures of interest may also be explored.  The relationship 
between exposure (e.g., population PK model predicted average concentrations, area 
under the curve, trough concentrations, the individual model-predicted PK profiles, or 
some other appropriate measure of exposure) and drug effect will be explored.  Several 
classes of models (e.g., linear, log-linear, exponential, Emax, sigmoid Emax, etc.) will be 
evaluated to characterize the exposure-response relationship based on observed data.  
Results of the PK and exposure-response analyses may be summarized in a separate report 
prior to regulatory filing of upadacitinib for the treatment of UC, rather than in the CSR.
Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
For Study M14-675 (Part 1), a total of 462 subjects will be allocated to upadacitinib 
treatment group or placebo in a randomization ratio of 2:1.  The sample size for this study 
is based on the expected proportion of subjects who achieve clinical remission per 
Adapted Mayo score at Week 8.  Assuming clinical remission rate of 5% in the placebo 
arm and 18% of the upadacitinib QD treatment arms at Week 8, a sample size of 
154 subjects in placebo and 308 subjects in upadacitinib dose will have > 95% power to 
detect the 13% treatment difference in the primary endpoint between an upadacitinib 
45 mg QD and placebo using two-sided Fisher's exact test at a 0.05 significant level.


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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 and all other 
applicable regulatory requirements.
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 
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.


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In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will engage with study site 
personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., phone contacts or 
virtual site visits), alternative locations for data collection (e.g., use of a local lab instead 
of a central lab), and shipping investigational product and/or supplies direct to subjects to 
ensure continuity of treatment where allowed. Refer to Section 5.3.1.1 for additional 
details.  In all cases, these alternative measures must be allowed by local regulations and 
permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures 
are taken to protect the subjects against any immediate hazard.
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. 
For US subjects:  at Week 8 or Week 16 subjects who will continue into Study M14-234 
Substudy 3 will sign and date a study specific IEC/IRB approved Informed Consent Form 
before Substudy 3 procedures are performed.  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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Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
Samples for exploratory research/validation studies will only be collected if the subject 
has voluntarily signed and dated the consent for exploratory research/validation studies, 
approved by an IRB/IEC, after the nature of the testing has been explained and the subject 
has had an opportunity to ask questions.  The written consent must be signed before the 
exploratory research/validation studies samples are collected and testing is performed.  If 
the subject does not consent to the exploratory research/validation studies, it will not 
impact the subject's participation in the study.
For adolescent subjects, the investigator or his/her representative will explain the nature of 
the study and optional exploratory research samples to the subject and the subject's 
parent/legal guardian and answer all questions regarding this study. Adolescent subjects 
will be included in all discussions in order to obtain verbal or written assent. 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's parent/legal guardian, the 
person who administered the informed consent, and any other signatories according to 
local requirements. Additionally, in keeping with each institution's IRB/IEC 
requirements, an informed assent form may also be obtained by each subject prior to any 
study-related procedures being performed. If a subject becomes of legal age during the 
course of the study, that subject will need to be re-consented. A copy of the informed 
consent form and the assent form will be given to the subject and the subject's parent/legal 
guardian 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.
In the event a subject withdraws from the main study, optional exploratory 
research/validation studies samples will continue to be stored and analyzed unless the 
subject specifically withdraws consent for research involving these optional samples.  If 


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consent is withdrawn for the optional sampling, the subject must inform their investigator, 
and once AbbVie is informed, the optional samples will be destroyed.  However, if the 
subject withdraws his/her consent and the samples have already been tested, those results 
will still remain as part of the overall research data.
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional verbal consent may be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.


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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 to the appropriate 
source document.  The Investigator Awareness Date (SAE CRF) may serve as the source 
for this data point.  This adverse event data point required for eCRF completion can be 
entered directly in the eCRF.
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, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an 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 


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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 
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.
10.3
Electronic Patient Reported Outcomes (ePRO)
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) system called Trialmax, provided by the technology vendor CRF Health of 
Plymouth Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR 
Part 11.  The documentation related to the system validation of the ePRO system is 
available through the vendor, CRF Health, while the user acceptance testing of the study-
specific PRO design will be conducted and maintained at AbbVie.


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The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source and maintained and managed 
by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
trial.  This access will be available for the duration of the trial to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO system will be archived 
on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media. 
The ePRO data (IBDQ, Short Form 36 (SF-36), PGIC, PGIS, FACIT-F, WPAI, 
EQ-5D-5L, UC-SQ) will be collected electronically via an onsite device at visits specified 
in Appendix C and Appendix E.  Stool information, abdominal pain, bowel urgency, use 
of anti-diarrheals and endoscopy prep will be collected electronically via a handheld 
device provided to the subject.  The electronic device will be programmed to allow data 
entry once per day.  All data entered on the device will be immediately stored to the 
device itself and manually/automatically uploaded to a central server administrated by 
CRF Health.  The investigator and delegated staff, will be able to access all uploaded 
patient entered data via a password protected website, up until the generation, receipt and 
confirmation of the study archive.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference, except baseline.  All PROs, except EQ-5D-5L scale, are eligible for 
completion by interview.  If there are time constraints to the phone visit, at a minimum, 
the following PROs must be completed:
●
Inflammatory Bowel Disease Questionnaire (IBDQ)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)


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●
Patient Global Impression of Change (PGIC)
●
Patient Global Impression of Severity (PGIS)
Prior to conducting any phone visits to obtain PRO data the site staff person should be 
delegated this task on the Delegation of Authority log. Sites will read the PRO questions 
and response options to the subject and record the subject's responses.  The subject's 
ability to view the PRO to understand the questions and response options should be 
preserved.  Sites must share a local language version of the questionnaire by 
videoconference or send the questionnaires (email or hard copy) to the subjects to allow 
them to read/understand the questions and responses when the subject is providing 
responses over the phone.  The date and start and stop time of PRO data collection should 
be recorded along with who collected the information, their role and which questionnaires 
were completed.
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.
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 


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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.
Any exploratory research/validation studies that may be done using the samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management, hence, neither the investigator, the subject, nor 
the subject's physician (if different from the investigator) will be informed of individual 
subject results, should analyses be performed, nor will anyone not directly involved in this 
research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from exploratory research/validation 
studies from this study may be used in scientific publications or presented at medical 
conventions.  Exploratory research/validation data will be published or presented only in a 
way that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the investigator (Director of the Site in Japan) 
and AbbVie.  The investigator will provide a final report to the IEC/IRB following 


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conclusion of the study and will forward a copy of this report to AbbVie or their 
representative.
The investigator (Director of the Site in Japan) must submit, maintain, and archive any 
records related to the study according to ICH GCP and all other applicable regulatory 
requirements.  If the investigator (Director of the Site in Japan) is not able to retain the 
records, he/she must notify AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for upadacitinib.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Induction Study to Evaluate the Efficacy and Safety of Upadacitinib 
(ABT-494) in Subjects with Moderately to Severely Active 
Ulcerative Colitis
Protocol Date:
31 July 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
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3.
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4.
Dignass A, Eliakim R, Magro F, et al.  Second European evidence-based consensus 
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Sandborn WJ.  State-of-the-art:  immunosuppression and biologic therapy.  Dig 
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http://labeling.pfizer.com/Showlabeling.aspx?id=959.
22.
Sandborn W, Ghosh S, Panes J, et al.  Tofacitinib, an oral Janus kinase inhibitor, in 
active ulcerative colitis.  N Engl J Med.  2012;367(7):616-24.


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23.
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.
24.
Sandborn, WJ., et al. Presentation #OP195.  United European Gastroenterology 
(UEG) Week 2018.
25.
Geboes K, Riddell R, Ost A, et al.  A reproducible grading scale for histological 
assessment of inflammation in ulcerative colitis.  Gut.  2000;47(3):404-9.
26.
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE).  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_4
0.
27.
Irvine EJ, Feagan B, Rochon J, et al.  Quality of life:  a valid and reliable measure 
of therapeutic efficacy in the treatment of inflammatory bowel disease.  Canadian 
Crohn's Relapse Prevention Trial Study Group.  Gastroenterology.  
1994;106(2):287-96.
28.
Higgins PD, Schwartz M, Mapili J, et al.  Patient defined dichotomous end points 
for remission and clinical improvement in ulcerative colitis.  Gut.  
2005;54(6):782-8.
29.
Ware JE Jr, Sherbourne CD.  The MOS 36-item short-form health survey (SF-36).  
I.  Conceptual framework and item selection.  Med Care.  1992;30(6):473-83.
30.
Ware JE Jr.  SF-36 health survey update.  Spine (Phila Pa 1976).  
2000;25(24):3130-9.
31.
Janssen MF, Pickard AS, Golicki D, et al.  Measurement properties of the 
EQ-5D-5L compared to the EQ-5D-3L across eight patient groups:  a multi-country 
study.  Qual Life Res.  2013;22(7):1717-27.
32.
Chandran V, Bhella S, Schentag C, et al.  Functional assessment of chronic illness 
therapy-fatigue scale is valid in patients with psoriatic arthritis.  Ann Rheum Dis.  
2007; 66(7):936-9.
33.
Reilly M.  Work Productivity and Activity Impairment Questionnaire (WPAI).  
Reilly Associates.  2002.


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34.
Conference on Harmonization (ICH) Tripartite Guideline, Topic E10 "Choice of 
Control Group in Clinical Trials, available at:  
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficac
y/E10/Step4/E10_Guideline.pdf.
35.
EMA draft guidelines on the development of new medicinal products for the 
treatment of Ulcerative Colitis (28 June 2018 CHMP/EWP/18463/2006 Rev.1).


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Pharmacovigilance
Statistics
Statistics
Clinical Operations
Bioanalysis
Clinical Pharmacology and 
Pharmacometrics












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e.
Subjects will be contacted 30 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects who will continue on to 
Substudy 3 of Study M14-234, this will not be required until the subject completes the UC program.  The home pregnancy test results will be reported at this visit, as 
applicable, and if a pregnancy is identified, the pregnancy must be reported to AbbVie as outlined in Section 6.1.6.  The 30 day follow up visit should not take place sooner 
than 30 days after the last dose of study drug, the allowable visit window is dependent upon what phase of the study the subject was at when discontinuing study drug. During 
Part 1 and 2 of the induction period a + 3 day window (30 to 33 days after last study drug date) is allowed.
f.
Update inclusion/exclusion, medical/surgical history information, and prior and concomitant therapy to assure subject eligibility.
g.
In Part 1, Physical examinations performed at Screening, Baseline, Week 8/PD and Part 2 at Week 16/PD Visits are full physical examinations which must include an 
assessment of extra-intestinal manifestations (EIMs).  Physical exams at all other visits are symptom-based as necessary.  Assessment of EIMs are required at every visit.  For 
subjects 16 or 17 years of age a Tanner Stage check is to be completed during the physical examination at the screening visit, this may be completed by the investigator or by 
self-assessment (completed by the subject/legally authorized representative) per local requirements.
h.
Height (with shoes off) will be measured at Screening only for subjects ≥ 18 years of age.  For Subjects 16 or 17 years of age, where locally permitted, height (with shoes off) 
will be measured at screening, Week 8 and Week 16.
i.
Subjects will undergo a full colonoscopy with biopsy for histologic assessment during Screening, and a full colonoscopy or flexible sigmoidoscopy, depending on the extent 
of disease at Screening, at Week 8.  For subjects in Part 2 (Extended Treatment Period), an endoscopy will be performed at Week 16, for this a flexible sigmoidoscopy is 
recommended, however the use of flexible rectosigmoidoscopy or colonoscopy will be based on the investigator's discretion per local practice.  
j.
Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the investigator, must be available in order to confirm the subject's 
eligibility for the study.  If this documentation is not available a diagnostic biopsy from the most affected observed area of the colon must be performed during the Screening 
endoscopy and evaluated by a qualified local pathologist and the results reviewed by the investigator.  Biopsies to rule out current dysplasia and colon cancer may be taken 
during any study endoscopy per the investigator's discretion and evaluated by the local pathologist.  During all endoscopies, up to 3 sets of biopsies will be taken (see 
Section 5.3.1.1 for details about biopsy sampling).
k.
Subjects with normal ECG within 90 days of Screening will not require a repeat ECG, if documentation is available.  The Week 8 ECG will serve as the Baseline ECG for 
Part 2 (Extended Treatment Period), as applicable or for Baseline of Study M14-234 Substudy 3.  For subjects who enter Part 2 (Extended Treatment Period), Week 16 ECG 
will serve as the baseline ECG for Study M14-234 Substudy 3.
l.
Chest x-ray includes posterior-anterior [PA] and lateral views.  Subjects with normal chest x-ray within 3 months of Screening will not require a repeat chest x-ray, if 
documentation is available.  In Japan, a CT scan of the chest may be performed in lieu of a CXR, at investigator's discretion.
m.
If a subject had a negative QuantiFERON-TB Gold Plus test within 90 days of Screening and source documentation is available, the test does not need to be repeated, 
provided nothing has changed in the subject's medical history to warrant a repeat test.  PPD skin test is only to be used if the site is unable to perform the QuantiFERON-TB 
Gold Plus testing and is to be read 48 to 72 hours after placement.
n.
It is requested to have a minimum of 8 hours fasting before any chemistry and lipid.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-
fasting status will be recorded in study source documentation test.


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o.
During screening, biologic drug levels may be optionally assessed at the investigator's discretion as an alternative to completing the required washout period:  (1) infliximib 
and natalizumab:  may be tested approximately 4 weeks or later from the last dose; (2) adalimumab, certolizumab, golimumab, or vedolizumb:  may be tested approximately 
6 weeks or later from the last does; (3) ustekinumab:  may be tested approximately 8 weeks or later from the last dose.
p.
The Central Laboratory will perform the urinalysis macro and micro (if applicable).  A microscopic analysis will be performed by the central laboratory, in the event the 
dipstick results show leukocytes, nitrite, ketone, protein, blood, or glucose value of greater than a trace.  Sites will not be provided with urinalysis dipsticks.
q.
A serum pregnancy test will be performed on all women of childbearing potential at Screening.  In Part 1, a urine pregnancy test will be performed at the site at Baseline and 
at Weeks 2, 4, 6, 8 and PD Visits.  In Part 2 (Extended Treatment Period), a urine pregnancy test it will be done at Weeks 10, 12, 14 and 16, and a home pregnancy test will be 
performed at the 30-Day Follow-up Visit, if applicable, for all women of child bearing potential.  If any urine pregnancy test is positive, a serum pregnancy test will be 
performed by the central laboratory.  If a pregnancy is identified, the pregnancy must be reported to AbbVie as outlined in Section 6.1.6.
r.
Subjects will be tested for the presence of the hepatitis B and C virus (HBV and HCV) at Screening.  A positive result for the hepatitis B surface antigen (HBs Ag) or 
hepatitis C (HCV RNA detectable for any subject with positive anti-HCV AB) will be exclusionary.  For subjects who are negative for HBsAg but positive for core antibody 
(HBcAb), HBV DNA PCR will be performed and any result that meets or exceeds detection sensitivity will be exclusionary.  HBV testing is done every 12 weeks where 
required.
s.
For Japan subjects only:  Subjects with positive HBs Ab and/or positive HBc Ab results at Screening should have HBV-DNA PCR test performed at Week 8 in the induction 
period; in cases where recurrence of HBV-DNA is observed, the subject should be discontinued from the study.  This measure is not necessary in patients with history of 
HBV vaccination and positive HBs Ab result.
t.
Stool sample will be collected at each time point indicated.  For the visit that an endoscopy will be conducted, stool sample should be collected prior to the endoscopy.  If a 
sample cannot be obtained during the site visit, the site will give instructions and a stool sample supply kit (supplies will be provided at the time-points indicated).  All stool 
samples should be collected before any bowel preparation for endoscopy is started and should be returned to the site within 3 days of collection.  Stool sample supply kit to be 
provided at Week 8 visit for subjects entering into the extended treatment program.
u.
Reference Section 5.3.2.1 regarding PK sample collection.  The PK sample at Week 8 will be the baseline PK sample for Study M14-234 Substudy 3.  PK should only be 
collected at the Premature discontinuation visit if the subject discontinues before the Week 8 visit, it is not relevant for subjects discontinuing during Part 2.
v.
Blood samples will be collected at the visits indicated and will be utilized to assess effects of upadacitinib inhibition on certain lymphocyte subsets, including T (CD4+ and 
CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and natural killer-T (NKT) cells.
w.
IBDQ = Inflammatory Bowel Disease Questionnaire; SF-36 = Short-Form 36; EQ-5D-5L = European Quality of Life 5 Dimensions 5 Levels; WPAI = Work Productivity and 
Activity Impairment; FACIT F = Functional Assessment of Chronic Illness Therapy – Fatigue; PGIC = Patient Global Impression of Change; UC-SQ = UC Symptoms 
Questionnaire.  PGIS = Patient Global Impression of Severity (only at select sites).
x.
Collection of Serious Adverse Events (SAEs) begins the day the subject signs the informed consent.  During each study visit subjects will also be asked to report UC related 
Health Care Resource Utilization (Unscheduled Outpatient Visits, Emergency Room Visits and Hospitalizations and surgeries) and will be captured as a part of supplemental 
Health Care Resource Utilization (HCRU) form of AE collection in EDC.


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y.
Subjects will be dispensed the subject diary at Screening and will be trained on how to complete the diary by site staff during the Screening Visit. All subjects should 
complete their subject diary on a daily basis throughout the entire study, including during hospitalizations whenever possible.  The diary will be reviewed by site personnel 
with the subject at each visit and collected at the Final/PD Visit.
z.
Study drug will be dispensed for once daily oral intake and should be taken at the same time each day.
aa.
When central or local labs cannot be collected as scheduled in the protocol during the period of COVID-19 pandemic, drug may be dispensed if the following criteria are 
confirmed. (1) There is at least 1 post-Baseline lab assessment (either Week 2 or Week 4 visit) AND (2) The investigator feels it is safe to continue based on prior labs and a 
phone/video call AND (3) No longer than 4 weeks have passed from the last safety lab tests.
bb. If a subject is entering Part 2 (Extended Treatment Period), investigational product will be dispensed at this visit.  This is not applicable for subjects in Part 1 who are 
responders and move into Study M14-234 Substudy 3 at Week 8.






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Appendix E.
Patient Reported Outcomes Descriptions in Upadacitinib
(ABT-494) UC Programs 
IBDQ – Inflammatory Bowel Disease Questionnaire
The IBDQ is a disease-specific instrument composed of 32 Likert-scaled items.  The total 
score ranges from 32 to 224 using the 7-point response options, with higher scores 
indicating better health-related quality of life.  The IBDQ scale contains 4 component 
subscales:  bowel symptoms, systemic symptoms, emotional function, and social function.  
Each subscale can be computed with total scores ranging from 10 to 70, 5 to 35, 12 to 84, 
and 5 to 35, respectively.27,28
SF-36 – Short Form 36
The SF-36 questionnaire is a self-administered multi-domain scale with 36 items.  
Eight subscales cover a range of functioning:  physical functioning, role-physical, bodily 
pain, general health, vitality, social functioning, role-emotional, and mental health.  The 
scoring yields a physical component score, a mental component summary score, and 
subscale scores.  Higher scores represent better outcomes.  The concepts measured by the 
SF-36 are not specific to any age, disease, or treatment group, allowing comparison of 
relative burden of different diseases and the benefit of different treatments.29,30
EQ-5D-5L – European Quality of Life 5 Dimensions 5 Levels
The EQ-5D-5L is a standardized non-disease specific instrument for describing and 
valuing health-related quality of life.  The EQ-5D-5L consists of 5 dimensions:  mobility, 
self-care, usual activity, pain/discomfort, and anxiety/depression.  Each dimension has 
5 levels:  no problem, slight problem, moderate problem, severe problem or unable to do 
the activity.  It also contains a Visual Analogue Scale (VAS).  Subjects are asked to 
indicate the level that describes their current level of function or experience for each 
dimension.  As a measure of health status, it provides a descriptive profile and can be used 
to generate a single index value for health status, where full health is equal to 1 and death 
is equal to 0.  The VAS records the subject's assessment of his/her own health along a 
vertical 20 cm line, which has health state scores between 0 and 100.31


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PGIC – Patient Global Impression of Change
The PGIC is a self-administered instrument that assesses change in the overall symptoms 
due to ulcerative colitis.  The PGIC is one item in which subjects are asked to rate overall 
improvement since start of the treatment.  Subjects rate their change as "Very much 
improved," "Much improved," "Minimally improved," "No change," "Minimally worse," 
"Much worse" and "Very much worse."
PGIS - Patient Global Impression of Severity
The PGIS is a self-administered instrument that assesses the severity of the overall 
symptoms due to ulcerative colitis.  The PGIS is one item in which subjects are asked to 
rate overall severity of symptoms over the past week.  Subjects rate their change as 
"Absent," "Minimal," "Mild," "Moderate," "Moderately severe," "Severe" and "Very 
severe."
FACIT-F – Functional Assessment of Chronic Illness Therapy-Fatigue
The FACIT system is a collection of quality of life (QOL) questionnaires targeted to the 
management of cancer and other chronic illnesses.  The FACIT fatigue (FACIT-F) 
questionnaire was developed to assess fatigue associated with anemia.  It consists of 
13 fatigue-related questions. The responses to the 13 items on the FACIT fatigue 
questionnaire are each measured on a 4-point Likert scale. The responses to the answers 
are the following: (i) not at all: 0 points; (ii) a little bit: 1 point; (iii) somewhat:  
2 points; (iv) quite a bit:  3 points; (v) very much:  4 points.  Thus, the total score ranges 
from 0 to 52.  High scores represent less fatigue.32
WPAI – Work Productivity and Activity Impairment Questionnaire Ulcerative 
Colitis
The Work Productivity and Activity Index assesses the impact of the condition on work 
productivity losses and impairment in daily activity.  WPAI has six items covering 
four domains:  (1) Absenteeism (work time missed), measured as the number of hours 
missed from work in the past 7 days due to a condition related problems.  Scores are 


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expressed as impairment percentages, adjusting for hours actually worked according to 
the WPAI scoring algorithm; (2) Presenteeism (impairment at work/reduced on-the-job 
effectiveness), measured as the impact of the condition on productivity while at work 
(i.e., reduced amount or kind of work, or not as focused as usual).  Responses are recorded 
on a 0 – 10 Likert scale (where, 0 = no effect of UC on work and 10 = severe impact of 
UC while at work); (3) Productivity loss (overall work impairment), measured as the sum 
of hours missed due to condition i.e., absenteeism and number of hours worked with 
impairment i.e., product of number of hours worked and presenteeism; and (4) Activity 
impairment (i.e., activities other than paid work like work around house, cleaning, 
shopping, traveling, studying), recorded and scored in the same way as presenteeism.  
Higher numbers indicate greater impairment and less productivity.33
UC-SQ – Ulcerative Colitis Symptoms Questionnaire
The Ulcerative Colitis Symptoms Questionnaire (UC-SQ) is a UC-specific instrument 
composed of 17 items.  UC-SQ was developed to assess UC related gastrointestinal 
symptoms (e.g., frequent bowel movements, abdominal pain, cramping) and non-
gastrointestinal symptoms (e.g., joint pain and sleep difficulties).  Each symptom item 1 -
9 can be responded on Likert-type of options such as (i) Not at all:  0 points; (ii) A little 
bit:  1 point; (iii) Somewhat:  2 points; (iv) Quite a bit:  3 points; (v) Very much:  4 points.  
Each symptom item 10 - 17 can be responded on Likert-type of options such as (i) Never:  
0 points; (ii) Rarely:  1 point; (iii) Sometimes:  2 points; (iv) Often:  3 points; (v) Always:  
4 points.  Overall symptom scores are calculated by combining ratings of the individual 
items, with higher scores indicating greater severity.
HCRU – Health Care Resource Utilization
Health Care Resource Utilization data on number of all-cause and UC-related 
hospitalizations and surgeries will be collected through subject Administration module 
SAE supplemental Page.


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Appendix F.
Mayo Scoring System for Assessment of Ulcerative Colitis Activity
The Mayo Scores range from 0 to 12, with higher scores indicating more severe disease.  
It consists of 4 subscores.  Each sub-score ranges from 0 to 3.  The 4 components of the 
Mayo Score are:  
Stool Frequency: 
0 = Normal number of stools for this subject 
1 = 1 – 2 stools more than normal 
2 = 3 – 4 stools more than normal 
3 = 5 or more stools more than normal 
Rectal Bleeding:
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passed 
Findings on Endoscopy:
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration)
Physician's Global Assessment:
0 = Normal
1 = Mild disease
2 = Moderate disease 
3  = Severe disease
Note:
In Study M14-675, evidence of friability during endoscopy in subjects with otherwise "mild" endoscopic 
activity will confer an endoscopic subscore of 2.


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Appendix G.
Latent TB Risk Assessment Form Example
For Screening TB risk assessment, ask Part I and Part II questions. 
For Annual TB risk assessment, only ask the Part I questions.
Part 1 
1.
Has an immediate family member or other close contact been newly diagnosed 
with or treated for active or latent tuberculosis during the last 3 months? 
2.
Within the past year, have you, or an immediate family member, had any of the 
following problems lasting for 3 weeks or longer which remained unexplained: 
●
Chronic Cough 
●
Production of Sputum 
●
Blood-Streaked Sputum 
●
Weight Loss 
●
Fever 
●
Fatigue/Tiredness 
●
Night Sweats 
●
Shortness of Breath 
(Reference:  https://www.cdc.gov/tb/topic/testing/diagnosingltbi.htm)
Part II 
3.
Have you ever been diagnosed or treated for active or latent tuberculosis?
4.
Have you lived in or had prolonged travels to a TB endemic region?
(reference:  http://gamapserver.who.int/gho/interactive_charts/tb/cases/atlas.html)
5.
Have you lived or worked in a prison, refugee camp, homeless shelter, immigration 
center, or nursing home?


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Appendix H.
Tanner Staging Example
Boys


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Girls


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Appendix I.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.0  Title Page
"Sponsor:," "For non-EU Member States:" previously read:
For non-EU Member States:
AbbVie Inc.
1 North Waukegan Road, AP-31-2
North Chicago, IL 60064
Has been changed to read:
For non-EU Member States:
AbbVie Inc.
1 North Waukegan Road, AP-31-2
North Chicago, IL 60064, United States
Section 1.2  Synopsis
Subsection Objective:
Add:  new last paragraph
At the time of this amendment, the study has closed screening.
Section 1.2  Synopsis
Subsection Methodology:
Add:  new third paragraph
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided 
in the subsequent section.  Every effort should be made to ensure the safety of subjects 
and site staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, follow the updates 


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below on how to proceed.  These measures will only be implemented under the protocol 
in countries that are affected by the COVID-19 pandemic.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
COVID-19
Coronavirus Disease - 2019
DTP
Direct-to-patient
Section 3.2  Benefits and Risks
Add:  new last paragraph
In view of the coronavirus (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.
Section 5.1  Overall Study Design and Plan:  Description
Add:  new first paragraph
At the time of this amendment, screening for the study has closed.
Section 5.1  Overall Study Design and Plan:  Description
Add:  new fifth paragraph
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided 
in the subsequent section.  Every effort should be made to ensure the safety of subjects 
and site staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, follow the updates 
below on how to proceed.  These measures will only be implemented under the protocol 
in countries that are affected by the COVID-19 pandemic.


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Section 5.1  Overall Study Design and Plan:  Description
Subsection 8-Week Induction Period – Part 1
Add: new last paragraph
NOTE: All Baseline Visit procedures must be performed onsite.
Section 5.3.1.1  Study Procedures
Subsection Informed Consent
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, 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.
Section 5.3.1.1  Study Procedures
Subsection Height and Weight
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference. In these situations, height and weight measurements may be performed by 
the subject or caregiver as needed.


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Section 5.3.1.1  Study Procedures
Subsection Vital Signs
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, vital signs may be obtained by the subject or caregiver as 
needed.
Section 5.3.1.1  Study Procedures
Subsection Chest X-Ray (CXR)
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the absence of symptoms or positive medical history, if CXR cannot be done due to 
COVID-19 restrictions, the subject may continue in the study after discussion with TA 
MD.  CXR should be performed as soon as restrictions allow at study site or local 
hospital/facility.
Section 5.3.1.1  Study Procedures
Subsection 12-Lead Electrocardiogram (ECG)
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event this may not be performed due to study modifications related to the 
COVID-19 pandemic, perform the 12-lead ECG at the next earliest feasible visit or 
arrange to have an alternative acceptable local facility perform the ECG for the subject.


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Section 5.3.1.1  Study Procedures
Subsection TB Testing/TB Prophylaxis
Heading "TB Testing"
Subheading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new subheading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the absence of symptoms or positive medical history, if QuantiFERON TB test or PPD
cannot be done due to COVID-19 restrictions, the subject may continue in the study. 
QuantiFERON TB test or PPD should be performed as soon as restrictions allow at study 
site or local hospital/facility.
Section 5.3.1.1  Study Procedures
Subsection Pregnancy Tests
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Monthly urine pregnancy testing must be performed for women of child-bearing potential 
and results confirmed prior to administration of study drug to the subject.  Urine 
pregnancy tests may be performed at the local lab or at home and confirmed by site staff 
via phone, telemedicine or video call.  Pregnancy test results must be available before 
drug dispensation.
Section 5.3.1.1  Study Procedures
Subsection Hepatitis Screen
Heading "Hepatitis B"
Subheading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new subheading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event that the HBV DNA PCR cannot be performed for subjects who require the 
test due to study modifications related to the COVID-19 pandemic, perform the HBV 


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DNA PCR at the next earliest feasible visit or arrange to have it completed by a local 
laboratory.
Table 1.  Clinical Laboratory Tests
Table note "e." previously read:
During Screening, biologic drug levels may be optionally assessed at the investigator's 
discretion as an alternative to completing the required washout period: (1) infliximab and 
natalizumab: may be tested at least 4 weeks from the last dose; (2) adalimumab, 
certolizumab, golimumab, or vedolizumab: may be tested at least 6 weeks from the last 
dose; (3) ustekinumab: may be tested at least 8 weeks from the last dose.
Has been changed to read:
During Screening, biologic drug levels may be optionally assessed at the investigator's 
discretion as an alternative to completing the required washout period: (1) infliximab and 
natalizumab: may be tested approximately 4 weeks or later from the last dose; (2) 
adalimumab, certolizumab, golimumab, or vedolizumab: may be tested approximately
6 weeks or later from the last dose; (3) ustekinumab: may be tested approximately
8 weeks or later from the last dose.
Section 5.3.1.1  Study Procedures
Subsection Other Laboratory Assessments
Heading "Lymphocyte Subsets (TBNK)"
Subheading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new subheading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  It is recommended to perform all scheduled tests in the protocol, except 
for hs-CRP, fecal calprotectin, PK and optional samples for exploratory research which 


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should not be collected.  For hs-CRP local testing can only be performed if deemed to be 
necessary by PI after discussion with TA MD.
Local lab results should be obtained along with reference ranges and kept within the 
subjects' source documentation.  The results should be reviewed by the investigator and 
documented in EDC as an unscheduled lab as soon as possible.
If it is not possible to perform all the tests, the tests in the below table should be 
performed at minimum for safety evaluation.
Hematology 
Clinical Chemistry 
Urine 
Tuberculosis tests* 
Hematocrit
Hemoglobin
RBC count
WBC count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count 
BUN
Creatinine
Total bilirubin
ALT
AST
Alkaline phosphatase
CPK 
Pregnancy test 
QuantiFERON TB test 
or PPD 
(Study M14-234 
SS3 and 
Study M14-533)
Chest X-Ray 
(Study M14-234 
SS3 and 
Study M14-533) 
*
TB Test and Chest X-Rays to be completed only at the required visits per protocol.
If laboratory samples cannot be obtained, study drug administration may be continued 
provided that the following criteria are met:
The study drug may be dispensed if:
1.
There is at least 1 post-Baseline lab assessment (either Week 2 or Week 4 visit)
AND 
2.
The investigator has reviewed all prior laboratory results and confirms and 
discusses with the subject via a phone/video call that there is no safety concern for 
the subject to continue use of the study drug in the absence of current labs
AND


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3.
No longer than 4 weeks have passed from the last safety lab tests.
Section 5.3.1.1  Study Procedures
Subsection Stool Samples Collected
Heading "Fecal Calprotectin"
Subheading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new subheading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If subject is unable to attend visit where fecal calprotectin stool samples are collected, 
these should not be collected at a local lab.
Section 5.3.1.1  Study Procedures
Subsection Outcomes and Questionnaires
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference, except baseline. All PROs, except EQ-5D-5L scale, are eligible for 
completion by interview.  If there are time constraints to the phone visit, at a minimum, 
the following PROs must be completed:
●
Inflammatory Bowel Disease Questionnaire (IBDQ) 
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
●
Patient Global Impression of Change (PGIC) 
●
Patient Global Impression of Severity (PGIS) 
Prior to conducting any phone visits to obtain PRO data the site staff person should be 
delegated this task on the Delegation of Authority log. Sites will read the PRO questions 
and response options to the subject and record the subject's responses.  The subject's 
ability to view the PRO to understand the questions and response options should be 
preserved.  Sites must share a local language version of the questionnaire by 


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videoconference or send the questionnaires (email or hard copy) to the subjects to allow 
them to read/understand the questions and responses when the subject is providing 
responses over the phone.  The date and start and stop time of PRO data collection should 
be recorded along with who collected the information, their role and which questionnaires 
were completed.
Section 5.3.1.1  Study Procedures
Subsection Study Drug Dispensing/Administration
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Drug may be only dispensed to subjects if specific Laboratory result criteria are met;
please see these outlined below and refer to the Clinical Laboratory Tests section above 
for more information.
If laboratory samples cannot be obtained, study drug administration may be continued 
provided that the following criteria are met:
The study drug may be dispensed if:
1.
There is at least 1 post-Baseline lab assessment (either Week 2 or Week 4 visit)
AND
2.
The investigator has reviewed all prior laboratory results and confirms and 
discusses with the subject via a phone/video call that there is no safety concern for 
the subject to continue use of the study drug in the absence of current labs
AND
3.
No longer than 4 weeks have passed from the last safety lab tests.
Study drug may be shipped from the study site directly to the study subject's home if all 
the following criteria are met:


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●
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, 
paper copies of PROs).  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.
DTP study drug shipment will be allowed on the study for the duration of the COVID-19 
pandemic and will be removed once the pandemic is considered to be resolved.
Section 5.3.1.1  Study Procedures
Subsection Endoscopy
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If an Endoscopy required at Week 8 and Week 16 is not able to be scheduled at the study 
site in the required protocol window due to COVID-19, then this may be performed 
± 7 days from the planned visit and can be completed at a different Hospital/facility.


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If the endoscopy cannot be performed during this extended window at the site or another 
location, please refer to the guidance for subjects outlined in Section 5.1.
Section 5.3.1.1  Study Procedures
Subsection Biopsy During Endoscopy
Heading "Intestinal Tissue Analysis"
Subheading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new subheading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Biopsy completion should follow the endoscopy guidance if the visit is affected by 
COVID-19.  If an endoscopy is completed at an alternative location from the study site 
the study required biopsy is not required.  Biopsy can be completed per endoscopist's 
discretion for local evaluation.
Section 5.3.1.1  Study Procedures
Subsection Home Healthcare Service Due to COVID-19 Pandemic
Add:  new subsection title and text
Home Healthcare Service Due to COVID-19 Pandemic
Subjects may be offered the option of home healthcare visits provided by a licensed health 
care provider, such as a study nurse or third-party vendor.  Study procedures conducted in 
the home setting may include physical examination, vital signs, laboratory tests and 
Patient Reported Outcomes.  This option can only be offered in countries and sites that 
comply with local regulatory and IRB/IEC requirements for homecare.
Finally, 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.
Protocol deviations must be recorded per AbbVie's standard process.


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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.
Section 5.3.1.2  Collection and Handling of Optional Samples for Exploratory 
Research and Validation Studies
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If subject is unable to attend visit where optional exploratory samples are collected, these 
should not be collected at a local lab.
Section 5.3.2.1  Collection of Samples for Analysis
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If subject is unable to attend visit where pharmacokinetic samples are collected, these 
should not be collected at a local lab.
Section 5.4.1  Discontinuation of Individual Subjects
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modification
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modification
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.  Acceptable 
mitigation strategies are identified and included in Section 5.3.1.1 and Appendix C.


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The investigator should contact the sponsor medical contact before discontinuing a subject 
from the study for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored.
Refer to the Section 5.3.1.1 and Appendix C for details on how to handle study 
activities/procedures.
Section 5.4.1  Discontinuation of Individual Subjects
Subsection Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
Add:  new subsection title and text
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
For subjects with signs and/or symptoms and suspicion of COVID-19 or if a diagnosis has 
been confirmed, study drug should not be administered until the infection has resolved or 
coronavirus infection has been ruled out. There are no time limits for study drug 
interruption as long as no permanent study discontinuation criteria have been met. The PI 
should contact the TA MD before reintroducing study drug in subjects who were infected 
with COVID-19. The study drug interruption should be captured on related CRFs with 
reasons due to COVID-19.
For subjects who are asymptomatic and had primary exposure to COVID-19 (e.g., family 
member tests positive) or have concerns about taking upadacitinib with ongoing 
COVID-19 transmission.  The investigator can decide to continue or interrupt study drug 
on a case-by-case basis taking into account the risk:benefit of continuing study drug. The 
investigator can temporarily interrupt study drug at any time for a safety issue, or for any 
reason if they feel that the risk outweighs the benefit of study treatment.
Section 5.5.1  Treatments Administered
Add:  new third and fourth paragraph
If a subject is unable to come to the study site to pick up their study drug due to 
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 


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notifications to the regulatory authority as applicable. Refer to see Section 5.3.1.1 for 
details on DTP shipment of study drug.
DTP study drug shipment will be allowed for the duration of the COVID-19 pandemic 
and will be removed once the pandemic is considered to be resolved.
Section 5.5.7  Drug Accountability
Last paragraph
Add:  new fourth and fifth sentence
During the COVID-19 pandemic if a visit is completed virtually study drug accountability 
can be conducted remotely with the subject.  Any kits who are accounted for remotely 
should be retained by the subject and when the subject is then able to complete an onsite 
visit, they should return all kits for verification of the drug accountability by the site staff.
Section 6.1.5  Adverse Event Reporting
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
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 capture 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:
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form


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If a subject has a confirmed or suspected COVID-19 infection and study drug was 
interrupted, the investigator should contact the sponsor emergency medical contact listed 
above before reintroducing study drug.
Section 7.0  Protocol Deviations
First paragraph, last sentence previously read:
If a protocol deviation occurs (or is identified) after a subject has been enrolled, the 
principal investigator is responsible for notifying Independent Ethics Committee 
(IEC)/Independent Review Board (IRB) regulatory authorities (as applicable), and the 
following AbbVie Clinical Monitors:
Has been changed to read:
If a protocol deviation occurs (or is identified, including those that may be due to the 
COVID-19 pandemic) after a subject has been enrolled, the principal investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) regulatory authorities (as applicable), and the following AbbVie Clinical 
Monitors:
Section 9.2  Ethical Conduct of the Study
Add:  new last paragraph
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will engage with study site 
personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., phone contacts or 
virtual site visits), alternative locations for data collection (e.g., use of a local lab instead 
of a central lab), and shipping investigational product and/or supplies direct to subjects to 
ensure continuity of treatment where allowed. Refer to Section 5.3.1.1 for additional 
details.  In all cases, these alternative measures must be allowed by local regulations and 
permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures 
are taken to protect the subjects against any immediate hazard.


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Section 9.3  Subject Information and Consent
Add:  new last paragraph
Due to the COVID-19 pandemic, 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.
Section 10.1  Source Documents
Add:  new last paragraph
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
Section 10.3  Electronic Patient Reported Outcomes (ePRO)
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference, except baseline.  All PROs, except EQ-5D-5L scale, are eligible for 
completion by interview.  If there are time constraints to the phone visit, at a minimum, 
the following PROs must be completed:
●
Inflammatory Bowel Disease Questionnaire (IBDQ)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
Patient Global Impression of Change (PGIC)
●
Patient Global Impression of Severity (PGIS)
Prior to conducting any phone visits to obtain PRO data the site staff person should be 
delegated this task on the Delegation of Authority log. Sites will read the PRO questions 
and response options to the subject and record the subject's responses.  The subject's 
ability to view the PRO to understand the questions and response options should be 
preserved.  Sites must share a local language version of the questionnaire by 


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videoconference or send the questionnaires (email or hard copy) to the subjects to allow 
them to read/understand the questions and responses when the subject is providing 
responses over the phone.  The date and start and stop time of PRO data collection should 
be recorded along with who collected the information, their role and which questionnaires 
were completed.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Pharmacovigilance
Statistics
Statistics
Clinical Operations
Bioanalysis
Clinical Pharmacology and 
Pharmacometrics
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Pharmacovigilance
Statistics
Statistics
Clinical Operations
Bioanalysis
Clinical Pharmacology and 
Pharmacometrics












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f.
Update inclusion/exclusion, medical/surgical history information, and prior and concomitant therapy to assure subject eligibility.
g.
In Part 1, Physical examinations performed at Screening, Baseline, Week 8/PD and Part 2 at Week 16/PD Visits are full physical examinations which must include an 
assessment of extra-intestinal manifestations (EIMs).  Physical exams at all other visits are symptom-based as necessary.  Assessment of EIMs are required at every visit.  For 
subjects 16 or 17 years of age a Tanner Stage check is to be completed during the physical examination at the screening visit, this may be completed by the investigator or by 
self-assessment (completed by the subject/legally authorized representative) per local requirements.
h.
Height (with shoes off) will be measured at Screening only for subjects ≥ 18 years of age.  For Subjects 16 or 17 years of age, where locally permitted, height (with shoes off) 
will be measured at screening, Week 8 and Week 16.
i.
Subjects will undergo a full colonoscopy with biopsy for histologic assessment during Screening, and a full colonoscopy or flexible sigmoidoscopy, depending on the extent 
of disease at Screening, at Week 8.  For subjects in Part 2 (Extended Treatment Period), an endoscopy will be performed at Week 16, for this a flexible sigmoidoscopy is 
recommended, however the use of flexible rectosigmoidoscopy or colonoscopy will be based on the investigator's discretion per local practice.  
j.
Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the investigator, must be available in order to confirm the subject's 
eligibility for the study.  If this documentation is not available a diagnostic biopsy from the most affected observed area of the colon must be performed during the Screening 
endoscopy and evaluated by a qualified local pathologist and the results reviewed by the investigator.  Biopsies to rule out current dysplasia and colon cancer may be taken 
during any study endoscopy per the investigator's discretion and evaluated by the local pathologist.  During all endoscopies, up to 3 sets of biopsies will be taken (see 
Section 5.3.1.1 for details about biopsy sampling).
k.
Subjects with normal ECG within 90 days of Screening will not require a repeat ECG, if documentation is available.  The Week 8 ECG will serve as the Baseline ECG for 
Part 2 (Extended Treatment Period), as applicable or for Baseline of Study M14-234 Substudy 3.  For subjects who enter Part 2 (Extended Treatment Period), Week 16 ECG 
will serve as the baseline ECG for Study M14-234 Substudy 3.
l.
Chest x-ray includes posterior-anterior [PA] and lateral views.  Subjects with normal chest x-ray within 3 months of Screening will not require a repeat chest x-ray, if 
documentation is available.  In Japan, a CT scan of the chest may be performed in lieu of a CXR, at investigator's discretion.
m.
If a subject had a negative QuantiFERON-TB Gold Plus test within 90 days of Screening and source documentation is available, the test does not need to be repeated, 
provided nothing has changed in the subject's medical history to warrant a repeat test.  PPD skin test is only to be used if the site is unable to perform the QuantiFERON-TB 
Gold Plus testing and is to be read 48 to 72 hours after placement.
n.
It is requested to have a minimum of 8 hours fasting before any chemistry and lipid.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-
fasting status will be recorded in study source documentation test.
o.
During screening, biologic drug levels may be optionally assessed at the investigator's discretion as an alternative to completing the required washout period: (1) infliximib 
and natalizumab: may be tested at least 4 weeks from the last dose; (2) adalimumab, certolizumab, golimumab, or vedolizumb: may be tested at least 6 weeks from the last 
does; (3) ustekinumab: may be tested at least 8 weeks from the last dose.


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p.
The Central Laboratory will perform the urinalysis macro and micro (if applicable).  A microscopic analysis will be performed by the central laboratory, in the event the 
dipstick results show leukocytes, nitrite, ketone, protein, blood, or glucose value of greater than a trace.  Sites will not be provided with urinalysis dipsticks.
q.
A serum pregnancy test will be performed on all women of childbearing potential at Screening.  In Part 1, a urine pregnancy test will be performed at the site at Baseline and 
at Weeks 2, 4, 6, 8 and PD Visits.  In Part 2 (Extended Treatment Period), a urine pregnancy test it will be done at Weeks 10, 12, 14 and 16, and a home pregnancy test will be 
performed at the 30-Day Follow-up Visit, if applicable, for all women of child bearing potential.  If any urine pregnancy test is positive, a serum pregnancy test will be 
performed by the central laboratory.  If a pregnancy is identified, the pregnancy must be reported to AbbVie as outlined in Section 6.1.6.
r.
Subjects will be tested for the presence of the hepatitis B and C virus (HBV and HCV) at Screening.  A positive result for the hepatitis B surface antigen (HBs Ag) or 
hepatitis C (HCV RNA detectable for any subject with positive anti-HCV AB) will be exclusionary.  For subjects who are negative for HBsAg but positive for core antibody 
(HBcAb), HBV DNA PCR will be performed and any result that meets or exceeds detection sensitivity will be exclusionary.  HBV testing is done every 12 weeks where 
required.
s.
For Japan subjects only:  Subjects with positive HBs Ab and/or positive HBc Ab results at Screening should have HBV-DNA PCR test performed at Week 8 in the induction 
period; in cases where recurrence of HBV-DNA is observed, the subject should be discontinued from the study.  This measure is not necessary in patients with history of 
HBV vaccination and positive HBs Ab result.
t.
Stool sample will be collected at each time point indicated.  For the visit that an endoscopy will be conducted, stool sample should be collected prior to the endoscopy.  If a 
sample cannot be obtained during the site visit, the site will give instructions and a stool sample supply kit (supplies will be provided at the time-points indicated).  All stool 
samples should be collected before any bowel preparation for endoscopy is started and should be returned to the site within 3 days of collection.  Stool sample supply kit to be 
provided at Week 8 visit for subjects entering into the extended treatment program.
u.
Reference Section 5.3.2.1 regarding PK sample collection.  The PK sample at Week 8 will be the baseline PK sample for Study M14-234 Substudy 3.  PK should only be 
collected at the Premature discontinuation visit if the subject discontinues before the Week 8 visit, it is not relevant for subjects discontinuing during Part 2.
v.
Blood samples will be collected at the visits indicated and will be utilized to assess effects of upadacitinib inhibition on certain lymphocyte subsets, including T (CD4+ and 
CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and natural killer-T (NKT) cells.
w.
IBDQ = Inflammatory Bowel Disease Questionnaire; SF-36 = Short-Form 36; EQ-5D-5L = European Quality of Life 5 Dimensions 5 Levels; WPAI = Work Productivity and 
Activity Impairment; FACIT F = Functional Assessment of Chronic Illness Therapy – Fatigue; PGIC = Patient Global Impression of Change; UC-SQ = UC Symptoms 
Questionnaire.  PGIS = Patient Global Impression of Severity (only at select sites).
x.
Collection of Serious Adverse Events (SAEs) begins the day the subject signs the informed consent.  During each study visit subjects will also be asked to report UC related 
Health Care Resource Utilization (Unscheduled Outpatient Visits, Emergency Room Visits and Hospitalizations and surgeries) and will be captured as a part of supplemental 
Health Care Resource Utilization (HCRU) form of AE collection in EDC.
y.
Subjects will be dispensed the subject diary at Screening and will be trained on how to complete the diary by site staff during the Screening Visit.  All subjects should 
complete their subject diary on a daily basis throughout the entire study, including during hospitalizations whenever possible.  The diary will be reviewed by site personnel 
with the subject at each visit and collected at the Final/PD Visit.


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z.
Study drug will be dispensed for once daily oral intake and should be taken at the same time each day.
aa.
When central or local labs cannot be collected as scheduled in the protocol during the period of COVID-19 pandemic, drug may be dispensed if the following criteria are 
confirmed. (1) There is at least 1 post-Baseline lab assessment (either Week 2 or Week 4 visit) AND (2) The investigator feels it is safe to continue based on prior labs and a 
phone/video call AND (3) No longer than 4 weeks have passed from the last safety lab tests.
bb. If a subject is entering Part 2 (Extended Treatment Period), investigational product will be dispensed at this visit.  This is not applicable for subjects in Part 1 who are 
responders and move into Study M14-234 Substudy 3 at Week 8.












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ee.
Subjects will be contacted 30 days following study drug discontinuation for an assessment of any new or ongoing AEs, except those subjects who will continue on to 
Substudy 3 of Study M14-234, this will not be required until the subject completes the UC program.  The home pregnancy test results will be reported at this visit, as 
applicable, and if a pregnancy is identified, the pregnancy must be reported to AbbVie as outlined in Section 6.1.6.  The 30 day follow up visit should not take place sooner 
than 30 days after the last dose of study drug, the allowable visit window is dependent upon what phase of the study the subject was at when discontinuing study drug. During 
Part 1 and 2 of the induction period a + 3 day window (30 to 33 days after last study drug date) is allowed.
ff.
Update inclusion/exclusion, medical/surgical history information, and prior and concomitant therapy to assure subject eligibility.
gg. In Part 1, Physical examinations performed at Screening, Baseline, Week 8/PD and Part 2 at Week 16/PD Visits are full physical examinations which must include an 
assessment of extra-intestinal manifestations (EIMs).  Physical exams at all other visits are symptom-based as necessary.  Assessment of EIMs are required at every visit.  For 
subjects 16 or 17 years of age a Tanner Stage check is to be completed during the physical examination at the screening visit, this may be completed by the investigator or by 
self-assessment (completed by the subject/legally authorized representative) per local requirements.
hh. Height (with shoes off) will be measured at Screening only for subjects ≥ 18 years of age.  For Subjects 16 or 17 years of age, where locally permitted, height (with shoes off) 
will be measured at screening, Week 8 and Week 16.
ii.
Subjects will undergo a full colonoscopy with biopsy for histologic assessment during Screening, and a full colonoscopy or flexible sigmoidoscopy, depending on the extent 
of disease at Screening, at Week 8.  For subjects in Part 2 (Extended Treatment Period), an endoscopy will be performed at Week 16, for this a flexible sigmoidoscopy is 
recommended, however the use of flexible rectosigmoidoscopy or colonoscopy will be based on the investigator's discretion per local practice.  
jj.
Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the investigator, must be available in order to confirm the subject's 
eligibility for the study.  If this documentation is not available a diagnostic biopsy from the most affected observed area of the colon must be performed during the Screening 
endoscopy and evaluated by a qualified local pathologist and the results reviewed by the investigator.  Biopsies to rule out current dysplasia and colon cancer may be taken 
during any study endoscopy per the investigator's discretion and evaluated by the local pathologist.  During all endoscopies, up to 3 sets of biopsies will be taken (see 
Section 5.3.1.1 for details about biopsy sampling).
kk. Subjects with normal ECG within 90 days of Screening will not require a repeat ECG, if documentation is available.  The Week 8 ECG will serve as the Baseline ECG for 
Part 2 (Extended Treatment Period), as applicable or for Baseline of Study M14-234 Substudy 3.  For subjects who enter Part 2 (Extended Treatment Period), Week 16 ECG 
will serve as the baseline ECG for Study M14-234 Substudy 3.
ll.
Chest x-ray includes posterior-anterior [PA] and lateral views.  Subjects with normal chest x-ray within 3 months of Screening will not require a repeat chest x-ray, if 
documentation is available.  In Japan, a CT scan of the chest may be performed in lieu of a CXR, at investigator's discretion.
mm. If a subject had a negative QuantiFERON-TB Gold Plus test within 90 days of Screening and source documentation is available, the test does not need to be repeated, 
provided nothing has changed in the subject's medical history to warrant a repeat test.  PPD skin test is only to be used if the site is unable to perform the QuantiFERON-TB 
Gold Plus testing and is to be read 48 to 72 hours after placement.
nn. It is requested to have a minimum of 8 hours fasting before any chemistry and lipid.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-
fasting status will be recorded in study source documentation test.


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oo. During screening, biologic drug levels may be optionally assessed at the investigator's discretion as an alternative to completing the required washout period:  (1) infliximib 
and natalizumab:  may be tested approximately 4 weeks or later from the last dose; (2) adalimumab, certolizumab, golimumab, or vedolizumb:  may be tested approximately 
6 weeks or later from the last does; (3) ustekinumab:  may be tested approximately 8 weeks or later from the last dose.
pp. The Central Laboratory will perform the urinalysis macro and micro (if applicable).  A microscopic analysis will be performed by the central laboratory, in the event the 
dipstick results show leukocytes, nitrite, ketone, protein, blood, or glucose value of greater than a trace.  Sites will not be provided with urinalysis dipsticks.
qq. A serum pregnancy test will be performed on all women of childbearing potential at Screening.  In Part 1, a urine pregnancy test will be performed at the site at Baseline and 
at Weeks 2, 4, 6, 8 and PD Visits.  In Part 2 (Extended Treatment Period), a urine pregnancy test it will be done at Weeks 10, 12, 14 and 16, and a home pregnancy test will be 
performed at the 30-Day Follow-up Visit, if applicable, for all women of child bearing potential.  If any urine pregnancy test is positive, a serum pregnancy test will be 
performed by the central laboratory.  If a pregnancy is identified, the pregnancy must be reported to AbbVie as outlined in Section 6.1.6.
rr.
Subjects will be tested for the presence of the hepatitis B and C virus (HBV and HCV) at Screening.  A positive result for the hepatitis B surface antigen (HBs Ag) or 
hepatitis C (HCV RNA detectable for any subject with positive anti-HCV AB) will be exclusionary.  For subjects who are negative for HBsAg but positive for core antibody 
(HBcAb), HBV DNA PCR will be performed and any result that meets or exceeds detection sensitivity will be exclusionary.  HBV testing is done every 12 weeks where 
required.
ss.
For Japan subjects only:  Subjects with positive HBs Ab and/or positive HBc Ab results at Screening should have HBV-DNA PCR test performed at Week 8 in the induction 
period; in cases where recurrence of HBV-DNA is observed, the subject should be discontinued from the study.  This measure is not necessary in patients with history of 
HBV vaccination and positive HBs Ab result.
tt.
Stool sample will be collected at each time point indicated.  For the visit that an endoscopy will be conducted, stool sample should be collected prior to the endoscopy.  If a 
sample cannot be obtained during the site visit, the site will give instructions and a stool sample supply kit (supplies will be provided at the time-points indicated).  All stool 
samples should be collected before any bowel preparation for endoscopy is started and should be returned to the site within 3 days of collection.  Stool sample supply kit to be 
provided at Week 8 visit for subjects entering into the extended treatment program.
uu. Reference Section 5.3.2.1 regarding PK sample collection.  The PK sample at Week 8 will be the baseline PK sample for Study M14-234 Substudy 3.  PK should only be 
collected at the Premature discontinuation visit if the subject discontinues before the Week 8 visit, it is not relevant for subjects discontinuing during Part 2.
vv. Blood samples will be collected at the visits indicated and will be utilized to assess effects of upadacitinib inhibition on certain lymphocyte subsets, including T (CD4+ and 
CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and natural killer-T (NKT) cells.
ww. IBDQ = Inflammatory Bowel Disease Questionnaire; SF-36 = Short-Form 36; EQ-5D-5L = European Quality of Life 5 Dimensions 5 Levels; WPAI = Work Productivity and 
Activity Impairment; FACIT F = Functional Assessment of Chronic Illness Therapy – Fatigue; PGIC = Patient Global Impression of Change; UC-SQ = UC Symptoms 
Questionnaire.  PGIS = Patient Global Impression of Severity (only at select sites).
xx. Collection of Serious Adverse Events (SAEs) begins the day the subject signs the informed consent.  During each study visit subjects will also be asked to report UC related 
Health Care Resource Utilization (Unscheduled Outpatient Visits, Emergency Room Visits and Hospitalizations and surgeries) and will be captured as a part of supplemental 
Health Care Resource Utilization (HCRU) form of AE collection in EDC.


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yy. Subjects will be dispensed the subject diary at Screening and will be trained on how to complete the diary by site staff during the Screening Visit.  All subjects should 
complete their subject diary on a daily basis throughout the entire study, including during hospitalizations whenever possible.  The diary will be reviewed by site personnel 
with the subject at each visit and collected at the Final/PD Visit.
zz.
Study drug will be dispensed for once daily oral intake and should be taken at the same time each day.
aa.
When central or local labs cannot be collected as scheduled in the protocol during the period of COVID-19 pandemic, drug may be dispensed if the following criteria are 
confirmed. (1) There is at least 1 post-Baseline lab assessment (either Week 2 or Week 4 visit) AND (2) The investigator feels it is safe to continue based on prior labs and a 
phone/video call AND (3) No longer than 4 weeks have passed from the last safety lab tests.
bb. If a subject is entering Part 2 (Extended Treatment Period), investigational product will be dispensed at this visit.  This is not applicable for subjects in Part 1 who are 
responders and move into Study M14-234 Substudy 3 at Week 8.


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Appendix D.  Study Activities – Optional Samples for Exploratory Research and 
Validation Studies
Add:  new table note "All optional samples for exploratory research and validation 
studies must be collected at the study site."
All optional samples for exploratory research and validation studies must be collected at 
the study site.

SAP_001.pdf: 
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M14-675 – Statistical Analysis Plan
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Statistical Analysis Plan for Study M14-675
A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Induction Study to Evaluate the Efficacy 
and Safety of Upadacitinib (ABT-494) in Subjects 
with Moderately to Severely Active Ulcerative 
Colitis
Date:  19 January 2021
Version 6.0
NCT03653026


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives, and Hypotheses and Estimands...............................................5
2.2
Study Design Overview .............................................................................7
2.3
Treatment Assignment and Blinding .........................................................9
2.4
Sample Size Determination......................................................................10
3.0
Endpoints................................................................................10
3.1
Primary Endpoint.....................................................................................12
3.2
Secondary Endpoints ...............................................................................12
3.3
Other Efficacy Endpoints.........................................................................12
3.4
Safety Endpoints ......................................................................................15
4.0
Analysis Populations .............................................................15
5.0
Subject Disposition................................................................16
6.0
Study Drug Duration and Compliance................................17
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................17
7.1
Demographics and Baseline Characteristics............................................17
7.2
Medical History .......................................................................................19
7.3
Prior and Concomitant Medications ........................................................19
8.0
Efficacy Analyses...................................................................20
8.1
General Considerations............................................................................20
8.2
Handling of Potential Intercurrent Events ...............................................20
8.2.1
Premature Discontinuation of Study Drug...............................................21
8.2.2
UC-Related Corticosteroids.....................................................................21
8.3
Handling of Missing Data........................................................................21
8.3.1
Categorical Endpoints..............................................................................22
8.3.2
Continuous Endpoints..............................................................................24
8.4
Primary Efficacy Endpoint and Analyses ................................................25
8.4.1
Primary Efficacy Endpoint ......................................................................25
8.4.2
Handling of Missing Data for the Primary Efficacy Endpoint ................25
8.4.3
Primary Efficacy Analysis .......................................................................25


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8.4.4
Additional Analyses of the Primary Efficacy Endpoint...........................25
8.5
Secondary Efficacy Analyses...................................................................26
8.5.1
Key Secondary Efficacy Analyses...........................................................26
8.5.2
Supportive Secondary Efficacy Analyses ................................................26
8.6
Additional Efficacy Analyses ..................................................................27
8.7
Efficacy Subgroup Analyses....................................................................27
9.0
Safety Analyses ......................................................................28
9.1
General Considerations............................................................................28
9.2
Adverse Events ........................................................................................29
9.2.1
Treatment-Emergent Adverse Events ......................................................29
9.2.2
Adverse Event Overview .........................................................................31
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................31
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................32
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................33
9.2.6
Adverse Events of Special Interest ..........................................................33
9.3
Analysis of Laboratory Data....................................................................33
9.4
Analysis of Vital Signs ............................................................................35
10.0
Other Analyses.......................................................................36
11.0
Interim Analyses....................................................................36
11.1
Data Monitoring Committee....................................................................36
12.0
Overall Type-I Error Control ..............................................37
13.0
Version History......................................................................38
14.0
References...............................................................................39
List of Tables
Table 1.
SAP Version History Summary...............................................................38
List of Figures
Figure 1.
Study Schematic.........................................................................................8


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List of Appendices
Appendix A.
Protocol Deviations..................................................................................40
Appendix B.
Definition of Adverse Events of Special Interest ....................................41
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints ...............43
Appendix D.
Random Seeds..........................................................................................44
Appendix E.
Attributes of the Estimand for Primary and Ranked Secondary 
Endpoints .................................................................................................45


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Study M14-675,
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study to 
Evaluate the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects with Moderately 
to Severely Active Ulcerative Colitis.
The analyses of pharmacokinetic endpoints, pharmacodynamic biomarker endpoints and 
exploratory research and validation endpoints will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives, and Hypotheses and Estimands
The objective of the Induction Study is to evaluate efficacy and safety of upadacitinib 
45 mg QD compared to placebo in inducing clinical remission (per Adapted Mayo scire) 
in subjects with moderately to severely active UC who demonstrated inadequate response 
to, loss of response to, or intolerance to either biologic therapy (Bio-IR) or to 
conventional therapy (aminosalicylates, corticosteroids or immunosuppressants) but had 
not failed biologic therapy (non-Bio-IR).
Primary Efficacy Objective
The primary efficacy objective of the Induction Study is to demonstrate efficacy based on 
a higher rate of clinical remission per Adapted Mayo score after 8 weeks of treatment with 


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upadacitinib 45 mg QD when compared to placebo in subjects with moderately to 
severely active UC who have demonstrated inadequate response, loss of response, or 
intolerance to oral aminosalicylates, immunosuppressants, corticosteroids, and/or biologic 
therapies.  The primary efficacy objective will be assessed based on Intent-to-Treat (ITT) 
population, which consists of all randomized subjects who have received at least one dose 
of double-blinded study drug.
Hypothesis corresponding to the primary efficacy objective and endpoint is:
●
The proportion of subjects achieving clinical remission per Adapted Mayo 
score treated with upadacitinib 45 mg QD is greater than those treated with 
placebo at Week 8.
The estimand corresponding to the primary efficacy objective is defined as follows:
●
Difference in the percentage of subjects achieving clinical remission per 
Adapted Mayo score at Week 8 regardless of premature discontinuation of 
study drug and without initiation or dose escalation of UC-related 
corticosteroids (See Section 8.2.2) in the upadacitinib 45 mg QD and placebo 
groups in the ITT population.
Secondary Efficacy Objectives
The secondary efficacy objectives of the Induction Study are to demonstrate higher 
efficacy of treatment with upadacitinib 45 mg QD when compared to placebo with respect 
to the ranked secondary endpoints specified in Section 3.2. The ranked secondary 
efficacy objectives will be assessed based on ITT population.
Hypotheses corresponding to the secondary efficacy objectives and endpoints are:
1.
For each of the ranked binary secondary endpoints (Section 3.2), greater proportion 
of subjects with improvement for the endpoint is achieved with upadacitinib 45 mg
QD when compared to placebo;


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2.
For each of the ranked continuous endpoints (Section 3.2), greater mean change 
from baseline for the endpoint is achieved with upadacitinib 45 mg QD when 
compared to placebo.
The estimands corresponding to the secondary efficacy objectives are defined for each of 
the binary ranked secondary endpoints as follows: Difference in the percentage of subjects 
achieving binary endpoints regardless of premature discontinuation of study drug and 
without initiation or dose escalation of UC-related corticosteroids (See Section 8.2.2) in 
the upadacitinib 45 mg QD and placebo groups in the ITT population.
The estimands corresponding to the secondary efficacy objectives are defined for each of 
the continuous ranked secondary endpoints as follows: difference in the mean change 
from baseline regardless of premature discontinuation of study drug and if subjects would 
not initiate or escalate dose of UC-related corticosteroids (See Section 8.2.2) in the 
upadacitinib 45 mg QD and placebo groups in the ITT population.
2.2
Study Design Overview
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy, safety, and pharmacokinetics of upadacitinib as 
induction therapy in adult subjects with moderately to severely active UC who have been 
inadequate responders or intolerant to oral aminosalicylates, immunosuppressants, 
corticosteroids, and/or biologic therapies.
The number of enrolled non-biologic-inadequate responders (non-bio-IR) subjects will be 
at least 25% and not exceed 50%.  Among bio-IR subjects, this study will allow 
enrollment of up to 30% of subjects who have failed 3 or more biologics. Among non-
bio-IR subjects, it will allow enrollment of up to 20% subjects who could also have 
previous use of biologic therapy but discontinued based on reasons other than inadequate 
response, loss of response, or intolerance.  Subjects who have used a biologic up to 1 year 
and have discontinued for reasons other than inadequate response, loss of response, or 
intolerance (e.g., change of insurance/reimbursement, well-controlled disease, etc.) may 


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be enrolled but must meet other criteria for inadequate response, loss of response, or 
intolerance to aminosalicylates, corticosteroids, or immunosuppressants as defined in the 
protocol.
The study consists of:
1.
Screening period of up to a maximum of 35 days;
2.
Part 1:  a randomized, placebo-controlled 8-week double-blind (DB) induction 
period;
3.
Part 2:  an 8-week open-label (OL) extended treatment period for subjects who do 
not achieve clinical response at Week 8 of Part 1;
4.
30-day follow-up period.
The schematics of the study design are shown in Figure 1.
Figure 1.
Study Schematic


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In Part 1, approximately 462 subjects will be enrolled.  Eligible subjects will be 
randomized in a 2:1 ratio to one of the two treatment groups (DB upadacitinib 45 mg QD 
or matching placebo) for 8 weeks.
●
Group 1:  Upadacitinib 45 mg QD (blinded, n = 308)
●
Group 2:  Placebo QD (blinded, n = 154)
Part 2 is an 8-week OL extended treatment period for subjects who did not achieve 
clinical response at Week 8 in Part 1.  The objectives of Part 2 are to offer upadacitinib 
induction treatment to placebo clinical non-responders from Part 1, and to evaluate 
delayed clinical response to upadacitinib in subjects who do not initially respond to 
upadacitinib during Part 1.
Subjects who achieve clinical response at Week 8 (Part 1) or Week 16 (Part 2) will be 
eligible to enroll into Study M14-234 Substudy 3 (denoted by Maintenance Study 
thereafter) following written informed consent.  Subjects who do not achieve clinical 
response at Week 16 will be discontinued from the study and will not be eligible to enroll 
into the Maintenance Study.  Subjects who discontinued will complete the 30-Day follow-
up visit.
The data collected from subjects in Part 2 will be exploratory in nature and will not be 
part of the primary efficacy analysis for the study; only descriptive statistics will be 
provided for Part 2.
2.3
Treatment Assignment and Blinding
In Part 1, approximately 462 subjects will be randomized in a 2:1 ratio to DB upadacitinib 
45 mg QD or matching placebo for 8 weeks.  The randomization will be stratified by bio-
IR status (bio-IR vs. non-bio-IR), corticosteroid use (yes vs. no) and Adapted Mayo score 
(≤ 7 vs. > 7) at Baseline.  Within bio-IR, the randomization will be further stratified by 
number of prior biologic treatments (≤ 1 vs. > 1).  Within non-bio-IR, the randomization 
will be further stratified by previous biologic use (yes vs. no).


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All eligible subjects entering Part 2 will receive OL upadacitinib 45 mg QD for an 
additional 8 weeks (until Week 16).
The primary analysis will be performed after all ongoing subjects have completed the
study activities and the database has been locked. Treatment assignments will be 
unblinded to AbbVie for statistical analyses.  The study sites and subjects will remain 
blinded to the DB induction treatment assignments until all subjects have completed the 
Maintenance Study.
2.4
Sample Size Determination
For Part 1, approximately 462 subjects are expected to be randomized to upadacitinib 
45 mg QD or placebo in a randomization ratio of 2:1. The sample size for this study is 
based on the expected proportion of subjects who achieve clinical remission per Adapted 
Mayo score at Week 8. Based on the results from Phase 2b upadacitinib Study M14-234 
(Substudy 1), the proportions of subjects achieving clinical remission per Adapted Mayo 
score in upadacitinib 45 mg QD group and placebo group are 19.6% and 0%, respectively.  
Considering the small sample size in Phase 2b study and more stringent definition of 
primary endpoint used for Phase 3 studies, clinical remission rate is assumed to be 5% in 
the placebo group and 18% in the upadacitinib 45 mg QD treatment group. Based on 
these assumptions, a sample size of 154 subjects in placebo and 308 subjects in 
upadacitinib dose will have > 95% power to detect the 13% treatment difference in the 
primary endpoint between upadacitinib 45 mg QD group and placebo group using 
two-sided Fisher's exact test at a 0.05 significant level.
3.0
Endpoints
The terminologies and efficacy variables are defined as below:
●
Mayo Score
○
Full Mayo Score: composite score of UC disease activity based on the 
stool frequency subscore [SFS] (0 – 3), rectal bleeding subscore [RBS] 
(0 – 3), physician's global assessment [PGA] subscore (0 – 3) and 


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endoscopic subscore (0 – 3).  This score ranges from 0 – 12 points with 
higher scores representing more severe disease.
○
Partial Mayo Score: Full Mayo score minus the endoscopic subscore.
○
Adapted Mayo Score: Full Mayo score minus the PGA subscore.
○
Partial Adapted Mayo Score: Adapted Mayo score minus the 
endoscopic subscore.
●
Clinical Remission 
○
per Full Mayo Score:  Full Mayo score ≤ 2 with no subscore > 1.
○
per Adapted Mayo Score:  Adapted Mayo score ≤ 2, with SFS ≤ 1 and 
not greater than baseline, RBS of 0, and endoscopic subscore ≤ 1.
○
per Partial Mayo Score:  Partial Mayo score ≤ 2, with no subscore > 1.
●
Clinical Response 
○
per Full Mayo Score:  decrease in Full Mayo score of ≥ 3 points and 
≥30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute 
RBS ≤1.
○
per Adapted Mayo Score:  decrease in Adapted Mayo score ≥2 points 
and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute 
RBS ≤ 1.
○
per Partial Mayo Score:  decrease in Partial Mayo score ≥ 2 points and 
≥30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute 
RBS ≤1.
○
per Partial Adapted Mayo Score:  decrease in Partial Adapted Mayo 
score ≥ 1 point and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or 
an absolute RBS ≤ 1.
●
Endoscopic Improvement: Endoscopic subscore of 0 or 1.
●
Endoscopic Remission: Endoscopic subscore of 0.
●
Histologic Improvement: decrease from Baseline in Geboes score.
●
Histologic Endoscopic Mucosal Improvement:  Endoscopic subscore of 0 or 
1 and Geboes score ≤ 3.1.
●
Mucosal Healing:  Endoscopic score of 0 and Geboes score < 2.0.


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Note:  Evidence of friability during endoscopy in subjects with otherwise "mild" 
endoscopic activity will confer an endoscopic subscore of 2.
3.1
Primary Endpoint
The primary efficacy endpoint is the achievement of clinical remission per Adapted Mayo 
score at Week 8 in Part 1.
3.2
Secondary Endpoints
The ranked secondary efficacy endpoints for Part 1 under overall type I error control are 
as follows:
1.
The achievement of endoscopic improvement at Week 8;
2.
The achievement of endoscopic remission at Week 8;
3.
The achievement of clinical response per Adapted Mayo score at Week 8;
4.
The achievement of clinical response per Partial Adapted Mayo score at Week 2;
5.
The achievement of histologic-endoscopic mucosal improvement at Week 8;
6.
The achievement of no bowel urgency at Week 8;
7.
The achievement of no abdominal pain at Week 8;
8.
The achievement of histologic improvement at Week 8;
9.
Change from Baseline in IBDQ total score at Week 8;
10.
The achievement of mucosal healing at Week 8;
11.
Change from Baseline in FACIT-F score at Week 8.
3.3
Other Efficacy Endpoints
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●
The achievement of response in IBDQ Bowel Symptom domain (defined as 
increase of IBDQ bowel symptom domain score ≥ 6 from Baseline) at Week 8;
●
The achievement of response in IBDQ fatigue item (defined as increase of 
IBDQ fatigue item score ≥ 1 from Baseline) at Week 8;
●
The achievement of SFS of 0, RBS of 0 and endoscopic subscore of 0 at 
Week 8;
●
The achievement of SFS of 0, RBS of 0 and endoscopic subscore of ≤1 at 
Week 8;
●
The achievement of clinical remission per Full Mayo score at Week 8;
●
Change in Full Mayo score from Baseline at Week 8;
●
The achievement of clinical remission per Partial Mayo score over time;
●
The achievement of clinical response per Partial Adapted Mayo score over 
time;
●
The achievement of clinical response per Partial Mayo score over time;
●
The achievement of SFS ≤ 1 over time;
●
The achievement of RBS of 0 over time;
●
The achievement of Fecal calprotectin below 150 mg/kg over time;
●
Change from Baseline in fecal calprotectin over time;
●
Change from Baseline in hs-CRP over time;
●
Change from Baseline in Partial Adapted Mayo score, Partial Mayo score and 
SFS, RBS over time;
●
Change from Baseline in UCEIS score over time;
●
Change from Baseline in laboratory and nutritional parameters 
(e.g., hemoglobin, hematocrit, albumin, total protein concentration, and 
weight);
●
Change from Baseline in subject-reported stool frequency (absolute values)
over time;
●
Change from Baseline in IBDQ total and domain score over time;
●
Change from Baseline in individual IBDQ item under Bowel Symptom 
domain (for Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, and Q29) over time;


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●
The achievement of IBDQ response (defined as increase of IBDQ total score 
≥16 from Baseline) over time;
●
The achievement of IBDQ remission (defined as IBDQ total score ≥ 170) over 
time;
●
Change from Baseline in EQ-5D-5L score over time;
●
Change from Baseline in WPAI scores over time;
●
Change from Baseline in SF-36 Physical Component Summary (PCS) and 
Mental Component Summary (MCS) components and domain scores over 
time;
●
Summary of PGIC improvement category over time;
●
Summary of PGIS severity category over time;
●
Change from Baseline in FACIT-F score over time;
●
Change from Baseline in UC-SQ score over time;
●
UC-related hospitalizations through Week 8;
●
UC-related surgeries through Week 8;
●
All-cause hospitalizations through Week 8;
●
All-cause surgeries through Week 8.
The following additional efficacy endpoints will be evaluated for Part 2:
●
The achievement of clinical remission per Adapted Mayo score at Week 16;
●
The achievement of endoscopic improvement at Week 16;
●
The achievement of endoscopic remission at Week 16;
●
The achievement of clinical response per Adapted Mayo score at Week 16;
●
The achievement of clinical response per Partial Adapted Mayo score at 
Week 10;
●
The achievement of histologic-endoscopic mucosal improvement at Week 16;
●
The achievement of no bowel urgency at Week 16;
●
The achievement of no abdominal pain at Week 16;
●
The achievement of histologic improvement at Week 16;
●
Change from Baseline in IBDQ total score at Week 16;


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The achievement of mucosal healing at Week 16;
●
Change from Baseline in FACIT-F score at Week 16.
3.4
Safety Endpoints
The following endpoints will be included in the safety analyses:
●
Treatment emergent adverse events (TEAEs);
●
Serious adverse events (SAEs);
●
Adverse events of special interest (AESIs);
●
Adverse events (AEs) leading to discontinuation of study drug;
●
Vital signs and laboratory tests.
4.0
Analysis Populations
Significant non-compliance was identified at a site (Investigator ID 527969).  As a result 
of this finding, efficacy data for the subjects enrolled at this investigational site will be 
excluded from the statistical analyses. Safety data for those subjects will be included in 
the statistical analyses.  There were 6 subjects enrolled at this site in this study.
Intent-to-Treat (ITT) Populations
The ITT population for the 8-week DB induction period (Part 1) (denoted by ITT1) 
includes all randomized subjects who received at least one dose of double-blinded study 
drug in Part 1.  The ITT1 population will be used for all efficacy and baseline analyses for 
Part 1.
The ITT population for the 8-week OL extended treatment period (Part 2) (denoted by 
ITT2) includes all subjects who received at least one dose of upadacitinib 45 mg QD in 
Part 2.
For ITT1 population, subjects will be included in the analysis according to the treatment 
groups that they are randomized to.


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Safety Populations
The safety population for Part 1 (denoted by SA1) includes all randomized subjects who 
received at least one dose of study drug in Part 1.
The safety population for Part 2 (denoted by SA2) includes all subjects who received at 
least one dose of the upadacitinib 45 mg QD in Part 2.
The all upadacitinib treated safety population (denoted by SA-UPA) includes all subjects 
who received at least one dose of upadacitinib in Part 1 or Part 2.
For the safety populations, subjects are assigned to a treatment group based on the "as 
treated" treatment group, regardless of the treatment randomized.  The "as treated" will be 
determined by the most frequent dose regimen received in the analysis period.
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 for each treatment group:
●
Subjects randomized in Part 1;
●
Subjects who took at least one dose of study drug (Part 1 and Part 2);
●
Subjects who completed protocol-specified treatment (Part 1 and Part 2);
●
Subjects who prematurely discontinued study drug (Part 1 and Part 2);
●
Subjects who prematurely discontinued from study. 
Number and percentage of subjects who discontinued study drug and who withdrew from 
the study will be summarized by reason (primary reason and all reasons) for each 
treatment group within Part 1 and Part 2.  Subjects with multiple reasons for premature
discontinuation will be counted once in the calculation of the number and percentage of 
total discontinuations.


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6.0
Study Drug Duration and Compliance
For the safety populations (SA1 and SA2), duration of treatment will be summarized for 
each treatment group.  Duration of treatment is defined for each subject as last dose date 
minus first dose date + 1.  Duration of treatment will be summarized using the number of 
subjects treated, mean, standard deviation, median, minimum and maximum.  In addition, 
the number and percentage of subjects in each treatment duration interval (≥ 2 weeks, 
≥4 weeks, ≥ 6 weeks, ≥ 8 weeks) will be summarized.
Treatment compliance will be summarized for each treatment period by treatment group.  
Treatment compliance is defined as the number of tablets actually taken divided by the 
number of tablets that should have been taken.  Percent compliance will be summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, Baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the ITT1 population overall and by 
treatment group.  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).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include:
●
Sex (Male, Female)
●
Age Group 1 (< 18 year, ≥ 18 years – < 40 years, ≥ 40 years – < 65 years, 
≥65 years)
●
Age Group 2 (≤ median, > median)


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Weight Group (≤ median, > median)
●
BMI Group (normal:  < 25 kg/m2, overweight:  ≥ 25 – 30 kg/m2, obese:  
≥30 kg/m2)
●
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
●
Race (White, Black/African American, American Indian/Alaska Native, 
Native Hawaiian or Other Pacific Islander, Asian, Other)
●
Region (US, ex-US)
●
Tobacco user (current, former, never, unknown)
●
Alcohol user (current, former, never, unknown)
Continuous baseline or disease characteristics variables include:
●
Weight (kg)
●
Height (cm)
●
BMI (kg/m2)
●
Disease duration (years)
●
Full Mayo score and its components (stool frequency, rectal bleeding, 
Physician Global Assessment, and endoscopy subscores)
●
Partial Mayo score
●
Adapted Mayo score
●
hs-CRP (mg/L)
●
Fecal Calprotectin (μg/g)
●
IBDQ total and domain score
●
Short Form 36 Health Survey (SF-36) and its components
●
European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
WPAI and its components
●
Ulcerative Colitis Symptoms Questionnaire (UC-SQ)


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Categorical baseline or disease characteristics variables include:
●
Bio-IR status (Bio-IR, non-Bio-IR),
●
Prior exposure to biologic therapy (yes, no) for non-Bio-IR 
●
Number of prior biologic treatments (≤ 1 or > 1) for Bio-IR
●
Prior exposure to anti-TNF (yes, no)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Baseline aminosalicylates use (yes, no)
●
Baseline Adapted Mayo score (≤ 7, > 7)
●
Baseline Full Mayo score (≤ 9, > 9)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Disease duration Group 1 (≤ 3 years, > 3 years)
●
Disease duration Group 2 (≤ median, > median)
●
Disease extent (rectosigmoid, left-sided, extensive/pancolitis)
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group.  The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC.  Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name (ITT1 population 
for prior medication; ITT1 and ITT2 populations for concomitant medications).  A prior 
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drug in Part 1.  A concomitant medication is defined as any medication that started prior 
to the date of the first dose of study drug and continued to be taken after the first dose of 
study drug or any medication that started on or after the date of the first dose of study 
drug, but not after the date of the last dose of study drug + 1 day.  The number and 
percentage of subjects taking medications will be summarized by generic drug name 
based on the World Health Organization (WHO) Drug Dictionary for both prior and 
concomitant medications.
8.0
Efficacy Analyses
8.1
General Considerations
The efficacy analyses for the 8-week DB induction period (Part 1) will be conducted in 
the ITT1 population.  The efficacy analyses for the 8-week OL extended treatment period 
(Part 2) will be conducted in the ITT2 population.  All tests will be at the α level of 0.05 
(2-sided).  "Baseline" refers to the last non-missing observation prior to the first 
administration of the study drug or prior to the randomization if no study drug is given.
Unless otherwise specified, categorical variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) test, stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline 
corticosteroid use (yes vs. no) and Baseline Adapted Mayo score (≤7 vs. > 7).  Any 
subject who was randomized under the wrong stratum will be analyzed according to the 
actual stratum the subject belongs to.  Continuous variables collected longitudinally will 
be analyzed using Mixed-Effect Model Repeat Measurement (MMRM) method.  
Continuous variables collected at only one post-baseline visit (such as Mayo score) will 
be analyzed using an Analysis of Covariance (ANCOVA) model.
8.2
Handling of Potential Intercurrent Events
Potential intercurrent events considered in the Induction Study include 1) premature 
discontinuation of study drug and 2) initiation or dose escalation of UC-related 
corticosteroids defined in Section 8.2.2.  Intercurrent events will be handled using the 
following methods for the efficacy analysis:


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8.2.1
Premature Discontinuation of Study Drug
Data collected will be used regardless of premature discontinuation of study drug.
8.2.2
UC-Related Corticosteroids
The UC-related corticosteroids intercurrent event is defined as follows.
●
subjects not on UC-related corticosteroids (systemic or locally acting 
corticosteroids for UC) at Baseline who initiated UC-related corticosteroids 
during the Induction Study;
●
subjects on UC-related systemic corticosteroids at Baseline who have dosages 
increased to greater than the prednisone equivalent dose of corticosteroid taken 
at Baseline, or initiation of any rectal corticosteroids during the Induction 
Study regardless of rectal corticosteroid dose;
●
subjects on UC-related rectal corticosteroids at Baseline who have dosages 
increased to greater than the dose taken at Baseline, or initiation of any new 
type of rectal or any systemic corticosteroids during the Induction Study.
The time point of the UC-related corticosteroids intercurrent event is defined as the date 
when one of the scenarios above occurs for a subject.  As such, subjects will be 
considered as "non-responder" for binary endpoints at or after the occurrence of the UC-
related corticosteroids intercurrent event through the end of the Induction Study.  For 
continuous endpoints, all measurements at or after the occurrence of the UC-related 
corticosteroids intercurrent event through the end of the Induction Study will not be used 
in the analysis.
8.3
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the Induction Study, or missing due to COVID-19 infection or 
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The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the 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.  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.  
The intent is to provide reliable estimates of the treatment effects under the scenario 
without the impact of COVID-19 pandemic.
Handling of missing data for the efficacy analyses is described below.
8.3.1
Categorical Endpoints
For binary efficacy endpoints, missing data will be handled using the following 
approaches:
●
The primary approach for handling missing data in the analysis of binary
endpoints will use Non-Responder Imputation while incorporating Multiple 
Imputation (MI) to handle missing data due to COVID-19 (NRI-C).
The NRI-C will categorize any subject who does not have an evaluation during 
a pre-specified visit window (either due to missing assessment or due to early 
withdrawal from the study) as a non-responder for the visit. The only 
exception is that missing data due to COVID-19 infection or logistical 
restrictions related to the COVID-19 pandemic will be handled by Multiple 
Imputation (MI). At each visit, subjects will be characterized as responders or 
non-responders based on MI imputed values if missing due to COVID-19; 
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other reasons in the NRI-C approach. In addition, at or after the occurrence of 
the UC-related corticosteroids intercurrent event (see Section 8.2.2), subjects 
will be counted as non-responders.
●
A sensitivity analysis for categorical endpoints will use NRI with No special 
data handling for missing due to COVID-19 (NRI-NC).
NRI-NC will be performed in the same way as NRI-C without the exception
above. Missing due to COVID-19 infection or logistical restrictions will also 
be counted as non-responders.  Subjects at or after the occurrence of the UC-
related corticosteroids intercurrent event will still be counted as non-
responders.  This is the same method as the "NRI" defined in the protocol.
●
Hybrid Multiple Imputation Method (HMI):  Sensitivity analysis will be 
performed using hybrid multiple imputation method for the primary endpoint.  
Subjects who discontinue study drug prior to Week 8 due to lack of efficacy or 
AEs and have no available measurements will be considered as "non-
responder" for clinical remission.  Subjects who discontinue for other reasons 
and have no available measurements will be categorized according to the data 
from multiple imputations.
●
Multiple Imputation (MI) for NRI-C and HMI:  Markov Chain Monte Carlo
(MCMC) will be first applied to augment data into monotonic missing pattern, 
where applicable, and PROC MI will be used to generate 30 datasets using the 
regression method.  The variables to be included in the imputation model are:  
treatment group, stratification factors (bio-IR status (bio-IR vs. non-bio-IR), 
Baseline corticosteroid use (yes vs. no) and Baseline Adapted Mayo score (≤7 
vs. > 7)), Baseline measurement, and if applicable, post-baseline 
measurements at each visit up to the end of the analysis period.  The random 
seed for MCMC and the random seed for PROC MI are specified in 
Appendix D. The imputed post-baseline measurements will be rounded to the 
same precision as the observed data before the determination of responder 
status.  Subjects will be characterized as responders or non-responders based 
on MI imputed datasets.  Using the CMH model adjusted by stratification 
factors (bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes 
vs. no) and Baseline Adapted Mayo score (≤7 vs. > 7)), the imputed endpoints 
will be analyzed using each of the 30 datasets.  SAS PROC MIANALYZE will 
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treatment group and placebo group and statistical inferences of the risk 
difference, including hypothesis testing, and 95% CI using Rubin's rule and 
T-distribution1.  Note that measurements will be set as missing at or after the 
occurrence of the UC-related corticosteroids intercurrent event before applying 
MI.  After the MI imputation, an NRI override will be implemented for 
missing values 1) due to reasons other than COVID-19 infection or logistic 
reasons, or 2) at or after the occurrence of the UC-related corticosteroids 
intercurrent event, that is, regardless of MI imputed values, subjects satisfying 
1) or 2) will be considered as "non-responder" for binary efficacy.
●
As Observed (AO):  The AO analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the AO analysis for that visit.  AO will include all 
values collected in the study.
8.3.2
Continuous Endpoints
For continuous endpoints, missing data will be handled using Mixed-Effect Model Repeat 
Measurement (MMRM).
The MMRM will be conducted using mixed model including observed measurements at 
all visits, except that measurements at or after the occurrence of UC-related 
corticosteroids intercurrent event will be excluded (see Section 8.2.2).  The mixed model 
includes the categorical fixed effects of treatment, visit and treatment-by-visit interaction, 
randomization stratification factors (bio-IR status [bio-IR vs. non-bio-IR], Baseline 
corticosteroid use [yes vs. no] and Baseline Adapted Mayo score [≤7 vs. > 7]), and the 
continuous fixed covariates of Baseline measurements.  An unstructured variance 
covariance matrix (UN) will be used.  If the model cannot converge, an autoregressive (1) 
or compound symmetric (CS) covariance structure matrix will be used.  The parameter 
estimations are based on the method of restrictive maximum likelihood (REML).  The 
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8.4
Primary Efficacy Endpoint and Analyses
8.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the achievement of clinical remission per Adapted Mayo 
score at Week 8. The primary estimand is the difference in the percentage of subjects 
achieving clinical remission per Adapted Mayo score at Week 8 regardless of premature 
discontinuation of study drug and without initiation or dose escalation of UC-related 
corticosteroids (See Section 8.2.2) in the upadacitinib 45 mg QD and placebo groups in 
the ITT population.  Details of the estimands definition are outlined in Appendix E.
8.4.2
Handling of Missing Data for the Primary Efficacy Endpoint
The NRI-C will be the primary approach for missing data handling in the analyses of the 
primary efficacy endpoint.
The NRI-NC and HMI approaches will be used as sensitivity analyses.
8.4.3
Primary Efficacy Analysis
The primary analysis will compare the proportion of subjects achieving clinical remission 
in upadacitinib treatment group and placebo group in the ITT1 population.  The difference 
between the treatment groups in the primary efficacy endpoint will be assessed using the 
CMH test and will be stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline 
corticosteroid use (yes vs. no) and Baseline Adapted Mayo score (≤7 vs. > 7).  A CMH 
based two-sided 95% confidence interval for the difference between treatment groups will 
be calculated.
8.4.4
Additional Analyses of the Primary Efficacy Endpoint
For the primary efficacy endpoint, the same CMH analysis as detailed in Section 8.1 will 
be performed using As Observed (AO) data handling without any imputation as an 
additional analysis. The analysis will be conducted on the ITT1 population who have the 
efficacy measurement at Week 8 visit.


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For the primary efficacy endpoint, a supplementary analysis will be conducted to evaluate 
the potential impact of deviations. In this analysis, subjects with deviations that could 
potentially impact the analysis of primary endpoint will be excluded.  The criteria will be 
fully defined in the classification plan. Exclusion of subjects will be adjudicated by the 
therapeutic area medical director (TAMD) and reasons for the subjects to be excluded will 
be documented and finalized before the Induction Study database lock for the primary 
analysis.  Treatment difference between upadacitinib 45 mg QD and placebo with point 
estimate and 95% CI will be presented using NRI-C approach with the CMH method as 
detailed in Section 8.1.
8.5
Secondary Efficacy Analyses
8.5.1
Key Secondary Efficacy Analyses
The key secondary endpoints are defined in Section 3.2. The estimands corresponding to 
the secondary efficacy endpoints are defined in Section 2.1.  Details of the estimand 
definitions are outlined in Appendix E.  For ITT1 Population, secondary efficacy 
endpoints in Part 1 will be analyzed by comparing upadacitinib treatment group and 
placebo group.  The binary secondary endpoints will be analyzed by CMH and the 
corresponding analyses are specified in Section 8.3.1.  The NRI-C will be the primary 
approach for missing data handling in the analyses of binary secondary efficacy 
endpoints.  The NRI-NC approach will be used as sensitivity analyses.
The continuous secondary endpoints will be analyzed by MMRM and the corresponding 
analyses are specified in Section 8.3.2.
8.5.2
Supportive Secondary Efficacy Analyses
The secondary efficacy endpoints will also be analyzed for ITT1 population using As 
Observed (AO) data handling without any imputation.  The categorical endpoints and 
continuous endpoints will be analyzed by CMH and MMRM, respectively, and the 
corresponding analyses are specified in Section 8.1.


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8.6
Additional Efficacy Analyses
Additional efficacy endpoints are defined in Section 3.3. The estimands corresponding to 
the additional efficacy endpoints are defined for each of the binary additional endpoints as 
follows: difference in the percentage of subjects achieving binary endpoints; regardless of 
premature discontinuation of study drug and without initiation or dose escalation of UC-
related corticosteroids (See Section 8.2.2) in the upadacitinib 45 mg QD and placebo 
groups in the ITT population.  The estimands corresponding to the additional efficacy 
endpoints are defined for each of the continuous additional endpoints as follows: 
difference in the mean change from baseline regardless of premature discontinuation of 
study drug and if subjects would not initiate or escalate dose of UC-related corticosteroids
(See Section 8.2.2) in the upadacitinib 45 mg QD and placebo groups in the ITT 
population.  For ITT1 Population, additional efficacy endpoints in Part 1 will be analyzed 
by comparing upadacitinib treatment group and placebo group.  The categorical endpoints 
and continuous endpoints will be analyzed by CMH and MMRM (or ANCOVA), 
respectively, and the corresponding analyses are specified in Section 8.3.  The NRI-C 
approach will be used for missing data handling in the analyses of categorical efficacy 
endpoints.
For ITT2 population, descriptive statistics will be provided for additional efficacy 
endpoints in Part 2.  The NRI-C approach will be used for missing data handling in the 
analyses of categorical efficacy endpoints.
8.7
Efficacy Subgroup Analyses
The following subgroup analyses will be conducted for the primary efficacy endpoint in 
the ITT1 population.  Treatment difference between upadacitinib treatment group and 
placebo group with point estimate and 95% confidence interval using normal 
approximation will be presented.  The NRI-C approach will be used for missing data 
handling.  No p-value will be provided for subgroup analysis.
●
Sex (male, female)
●
Age (≤ median, > median)


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●
Race (white, non-white)
●
Bio-IR status (Bio-IR, non-Bio-IR)
●
Baseline corticosteroid use (yes, no)
●
Baseline Adapted Mayo score (≤ 7, > 7)
●
Baseline Full Mayo score (≤ 9, > 9)
●
Prior exposure to anti-TNF (yes, no) for non-Bio-IR
●
Prior exposure to biologic therapy (yes, no) for non-Bio-IR
●
Baseline weight (≤ median, > median)
●
Presence of pancolitis at Baseline (yes, no)
●
Disease duration at Baseline (≤ median, > median)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Region (US versus non-US)
In addition, the following key secondary efficacy endpoints will be analyzed in the Bio-IR 
and non-Bio-IR subgroups in the ITT1 population.
●
Endoscopic remission at Week 8
●
Endoscopic improvement at Week 8
●
Clinical response per adapted Mayo score at Week 8
9.0
Safety Analyses
9.1
General Considerations
Safety analyses will be performed on the safety populations in the 8-week DB induction 
period (Part 1, SA1 population) and the 8-week OL extended treatment period (Part 2, 
SA2 population).  In addition, safety summaries will be provided on the all upadacitinib 
treated safety population (SA-UPA).
The standard safety analyses will include reporting of adverse events (AEs), adverse 
events of special interest (AESIs), laboratory, and vital signs measurements.  Frequency 
tables and exposure adjusted event rate per 100 patient-years tables of subjects with 


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treatment-emergent adverse events (TEAEs) by system organ class (SOC) and by 
preferred term (PT) as in the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary will be provided by treatment group.  All continuous laboratory parameters and 
vital signs variables at each visit will also be summarized by treatment group.  Frequency 
tables of subjects meeting criteria for potentially clinically important vital sign values and 
for potentially clinically important laboratory values will be provided by treatment group.
The Baseline for safety analysis will be treatment dependent.  For SA1 population, 
laboratory and vital signs measurements, the Baseline value is defined as the last available 
measurement before study drug administration for each subject.  For SA2 and SA-UPA 
populations, the Baseline value is defined as the last available measurement before 
first dose of upadacitinib.
Missing safety data will not be imputed.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
The Treatment-Emergent Adverse Events (TEAEs) for SA1, SA2 and the SA-UPA 
populations are defined as follows.
Part 1 (SA1 population):  TEAEs for Part 1 are defined as events that begin either on or 
after the first dose of the study drug in Part 1 and


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●
until first dose of study drug in Part 2 if the subject is enrolled into Part 2 or
●
until first dose of study drug in the Maintenance Study if the subject is enrolled 
into the Maintenance Study or 
●
within 30 days after the last dose administration of the study drug for subjects 
who are not enrolled in Part 2 and do not participate in the Maintenance Study.
Part 2 (SA2 population):  TEAEs for Part 2 are defined as events that begin either on or 
after the first dose of OL upadacitinib study drug in Part 2 and
●
until first dose of study drug in the Maintenance Study if the subject is enrolled 
into the Maintenance Study or
●
within 30 days after the last dose administration of the study drug for subjects 
who do not participate in the Maintenance Study. 
SA–UPA population:  TEAEs are defined as events that begin either on or after the 
first dose of upadacitinib study drug in either Part 1 or Part 2 and
●
until first dose of study drug in the Maintenance Study if the subject is enrolled 
into the Maintenance Study or
●
within 30 days after the last dose administration of the study drug in Part 1 for 
subjects who are not enrolled in Part 2 and do not participate in the 
Maintenance Study or
●
within 30 days after the last dose of the study drug in Part 2 for subjects who 
are enrolled in Part 2 and do not participate in the Maintenance Study.
If an incomplete onset date was collected for an adverse event, the event will be assumed 
to be treatment-emergent unless there is other evidence that confirms that the event was 
not treatment-emergent (e.g., the event end date was prior to the study drug start date).  
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.


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9.2.2
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:
●
Any TEAE
●
Any TEAE related to study drug according to the investigator
●
Any severe TEAE
●
Any serious TEAE
●
Any TEAE leading to discontinuation of study drug
●
Any TEAE leading to death
●
TEAEs of Special Interest (as defined in Appendix B)
●
All deaths
○
Deaths occurring ≤ 30 days after last dose of study drug
○
Deaths occurring > 30 days after last dose of study drug
In addition, an overview of AEs per 100 patient-years of study exposure will be presented 
for the AE categories defined above. The number of TEAEs reported, the total number of 
years of study drug exposure, and the TEAE rate per 100 patient-years will be presented.  
For the SA1 population, 95% CI will be provided for the treatment differences between 
upadacitinib 45 mg QD and placebo.
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug 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.  Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to investigational product will be reported.  The SOCs will be presented in 
alphabetical order, and the PTs will be presented in alphabetical order within each SOC.


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For summary by maximum severity, 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.
For summary by maximum relationship to study drug, 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 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.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the upadacitinib 45 mg QD treatment group.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
exposure in 100 patient-years, i.e.,
100 * (Number of TEAEs) / (Total Patient Years)
where total patient years is defined as the sum of the study drug exposure of all subjects, 
normalized by 365.25, and rounded to 1 decimal place.  Note that one event per preferred 
term per day per subject will be counted in the calculation of the number of AEs (i.e., a 
preferred term will not be counted twice on the same day for the same subject).
The TEAE rates per 100 patient-years of exposure will be provided for each AE category 
in the AE overview summary (defined in Section 9.2.2) and for TEAE summary by SOC 
and PT. 


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9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
9.2.6
Adverse Events of Special Interest
The AESI categories will be identified by the search criteria per Standard MedDRA 
Queries (SMQs)/Company MedDRA Queries (CMQs) specified in Appendix B.
Treatment-emergent Adverse events of special interest will be summarized by SOC and 
PT and listing format. Additionally, AESI rates per 100 patient years of exposure will be 
provided for each AESI category (Appendix B) in the AE overview summary.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol (e.g., hematology and clinical chemistry) 
will be summarized.
Analysis of Quantitative Laboratory Parameters
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from Baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from Baseline 
within each treatment group.


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For SA1 population, treatment group differences between upadacitinib treatment group 
and placebo group for changes from Baseline will be analyzed using a one-way Analysis 
of Variance (ANOVA) model with treatment as a fixed factor and 95% CI for treatment 
difference will be presented for selected laboratory parameters.
Shift Table Analyses
Changes in laboratory parameters will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample.  A 
shift table from Baseline to minimum and maximum value (based on normal range) will 
be created.  A similar shift table will be provided to summarize shifts from Baseline to the 
final post-baseline value.
Potentially Clinically Significant Laboratory Values
The criteria for potentially clinically significant laboratory values will be determined by 
CTCAE criteria of Grade 3, Grade 4 and ≥Grade 3, with a grade worsening compared to 
baseline.  Toxicity grading scale is based on National Cancer Institute Common Toxicity 
Criteria (NCI CTC) AE version 4.03.  The number and percentage of subjects meeting the 
criteria for potentially clinically significant laboratory values will be summarized by 
treatment group.  Listings will be provided to summarize subject-level laboratory data for 
subjects meeting the criteria.
Assessment of Liver Elevations
The liver-specific laboratory tests include the serum glutamic pyruvic transaminase 
(SGPT/ALT), serum glutamic-oxaloacetic transaminase (SGOT/AST), alkaline 
phosphatase (ALP), and total bilirubin (TBL).  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 treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN


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●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
ALP ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and TBL ≥ 2 × ULN,
where ULN is the upper normal limit.  The maximum ratio relative to the ULN will be 
used to determine if subjects meet any of the criteria listed above.
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
●
ALT ≥ 2.5 × ULN, or
●
AST ≥ 2.5 × ULN, or
●
ALP ≥ 1.5 × ULN, or
●
TBL ≥ 1.5 × ULN.
In addition, eDISH plots will be created displaying post-baseline total bilirubin versus 
post-baseline ALT, in terms of the maximum ratio relative to the ULN (not necessarily 
concurrent).
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, body weight, 
respiratory rate and body temperature will be summarized.


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Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from Baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
Baseline mean, and visit mean.  The change from Baseline mean, standard error, and 
95% confidence interval will be presented for the mean change from Baseline within each 
treatment group.
For SAh1 population, treatment group differences between upadacitinib treatment group 
and placebo group for changes from Baseline will be analyzed using a one-way Analysis 
of Variance (ANOVA) with treatment as a fixed factor and 95% CI for treatment 
difference will be presented for each vital sign variable.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C).  For each vital sign PCI criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized.  Listings 
will be provided to summarize subject-level vital sign data for subjects meeting PCI 
criteria.
10.0
Other Analyses
No other analyses are planned.
11.0
Interim Analyses
There will be no efficacy interim analyses planned for the study.
11.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study.  The primary responsibility of the DMC will be to protect the safety of 
the subjects participating in this study.


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A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no multiplicity adjustment is 
needed.
12.0
Overall Type-I Error Control
The overall type I error rate of the primary and the ranked secondary endpoints will be 
strongly controlled using the fixed-sequence multiple testing procedure.2  Specifically, the 
testing will utilize the endpoint sequence of the primary and ranked secondary endpoints 
in the order as specified in Section 3.1 and Section 3.2 at the α level of 0.05 (two-sided).
No multiplicity adjustment will be applied to the additional efficacy endpoints listed in 
Section 3.3.  The analysis for additional efficacy endpoints will be performed at the 
nominal α level of 0.05 (two-sided).
Since there are no efficacy analyses for early stopping planned for the DMC review, no α
spending is needed due to the DMC review.


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13.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
17 July 2018
Original version
2.0
13 July 2020
!
Revised the SAP per the latest SAP template.
!
The following changes have occurred in order to reflect changes in 
the protocol amendment and regulatory guideline.
o
Updated secondary endpoints:  added histologic-endoscopic 
mucosal improvement, change from baseline in IBDQ total 
score and change from baseline in FACIT-F score; moved 
response in IBDQ Bowel Symptom domain, UC-related 
hospitalizations and surgeries and response in IBDQ fatigue 
item to other efficacy endpoints.
o
Non-ranked secondary endpoints are now listed under Other 
Efficacy Endpoints.
o
Added NRI-C method for handling missing data due to 
COVID-19.  NRI-C will be used for the primary efficacy 
analysis and NRI-NC will be considered as sensitivity 
analysis.
o
Removed the Last Observation Carried Forward (LOCF) 
approach from the missing data imputation as LOCF 
potentially can result in a biased estimation of treatment effect 
and underestimate the variability.
o
Removed Holm procedure from the multiplicity control 
method as the number of ranked secondary endpoints was 
reduced.
o
Added the bio-IR and non-bio-IR subgroup analysis for the 
secondary endpoints: endoscopic remission, endoscopic 
improvement and clinical response per adapted Mayo score.
o
Remove subgroup analyses including Baseline 
immunosuppressant use (yes, no), Baseline Adapted Mayo 
Score (≤ median, > median), Baseline Full Mayo Score 
(≤median, > median), Baseline hs-CRP (≤ median, 
> median), Baseline fecal calprotectin (≤ 150 mg/kg, 
> 150 mg/kg), Baseline fecal calprotectin (≤ median, 
> median), and Baseline albumin (≤median, > median).
3.0
15 September 2020
!
Added definitions of estimand for primary and key secondary 
endpoints.
!
Clarified the MI method to handle missing data due to COVID-19 
and other reasons.


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Table 1.
SAP Version History Summary (Continued)
Version
Date
Summary
4.0
05 November 2020
!
Added supplementary analysis for the primary endpoint to exclude 
subjects with deviations that could potentially impact the primary 
analysis.
5.0
13 November 2020
!
Added exclusion of subjects from efficacy analysis due to site 
non-compliance. 
6.0
19 January 2021
!
Clarified how CIs are derived for the difference in proportions 
between treatment groups based on the NRI-C approach. 
!
Added comparative safety analyses (risk difference and 95% CI) 
for TEAE overview analysis of SA1 population.
14.0
References
1.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data:  a case 
study using agriculture industry codes.  Journal of the American Statistical 
Association.  1987;81:366-74.
2.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.


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Appendix B.
Definition of Adverse Events of Special Interest
AEs of Special Interest (AESI) will be identified by the following CMQ, SMQ, and other 
search criteria:
Table B-1.
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"
Active Tuberculosis
CMQ
"Active Tuberculosis"
Herpes Zoster
CMQ
"Herpes Zoster"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Creatine Phosphokinase (CPK) 
Elevation
PT
PT of "Blood creatine phosphokinase 
increased"
Possible Malignancies
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
Narrow
"Malignant Tumours"
Malignancies excluding NMSC
SMQ
Narrow
"Malignant Tumours" removing 
NMSC output
Non-Melanoma Skin Cancer (NMSC)
SMQ
Narrow
"Skin Malignant Tumours" removing 
Melanoma CMQ
Lymphoma
SMQ
Broad
"Malignant Lymphomas"
Renal Dysfunction
SMQ
Narrow
"Acute Renal Failure"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders –
Comprehensive Search"
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
Anemias"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia"
Adjudicated Gastrointestinal 
Perforation
Based on adjudicated results (the 
identification of events to be 
adjudicated are described in the GI 
Perforation charter)


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Table B-1.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches 
(Continued)
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Adjudicated Cardiovascular Events:
MACE*
Cardiovascular Death
Non-fatal Myocardial Infarction
Non-fatal Stroke
Undetermined/Unknown Cause of 
Deaths
Other Cardiovascular events
Output from 
CAC
Adjudicated Thrombotic Events:
VTE**
Deep Vein Thrombosis
Pulmonary Embolism
Other Venous Thrombosis
Output from 
CAC
Adjudicated Arterial 
Thromboembolic Events
Output from 
CAC
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.
**
VTE:  Venous thromboembolic events, defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) 
(fatal and non-fatal).
a.
Reviewed and adjudicated by an independent Cardiovascular Adjudication Committee in a blinded manner.


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCI) criteria for vital sign findings are 
described in Table C-1.
Table C-1.
Criteria for Potentially Clinically Important Vital Sign Values
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 ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight (Adults)
High
> 7% increase from baseline
Low
> 7% decrease from baseline
Weight (Adolescents)
Low
> 7% decrease from baseline


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Appendix D.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 100000 at each 
attempt until convergence of model happens.
The missing Mayo subscores are imputed to calculate the Adapted Mayo score, Partial 
Mayo score, Partial Adapted Mayo score, and Full Mayo score.
Table D-1.
Random Seeds for NRI-C
Endpoints
Random Seed
MCMC Procedure
PROC MI
Rectal bleeding subscore (0, 1, 2, 3)
21481*
22061#
Stool frequency subscore (0, 1, 2, 3)
21482
22062
Endoscopic subscore (0, 1, 2, 3)
21483
22063
Physician's global assessment (0, 1, 2, 3)
21484
22064
Geboes grade score (0, 1, 2, 3, 4, 5)
21485
22065
Geboes Grade 3 subscore (3.1, 3.2, 3.3)
21486
22066
No bowel urgency (0, 1)
21487
22067
No abdominal pain (0, 1, 2, 3)
21488
22068
Fecal Calprotectin (< 150 mg/kg)
21489
22069
IBDQ response and remission in domain and total 
score
21490
22070
PGIC (0, 1, 2, 3, 4, 5, 6)
21491
22071
PGIS (0, 1, 2, 3, 4, 5, 6)
21492
22072
*
This is SAS numerical form of Oct 24, 2018, which is the first subject randomized in this study.
#
This is SAS numerical form of May 26, 2020, which is the last subject randomized in this study.
Table D-2.
Random Seeds for HMI
Endpoints
Random Seed
MCMC Procedure
PROC MI
Rectal bleeding subscore (0, 1, 2, 3)
21501
22501
Stool frequency subscore (0, 1, 2, 3)
21502
22502
Endoscopic subscore (0, 1, 2, 3)
21503
22503


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Appendix E.
Attributes of the Estimand for Primary and Ranked Secondary 
Endpoints
Estimand
Attributes of the Estimand
Population
Endpoint
Treatment
Intercurrent Events
Statistical 
Summary
Primary
ITT1 
population 
(Subjects 
who were 
randomized 
and 
received at 
least one 
dose of 
study drug 
in Part1) 
Achievement of clinical 
remission per Adapted 
Mayo score at Week 8
Upadacitinib 
45 mg QD 
vs. placebo
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of UC-
related corticosteroids
All data after IE1 will 
be used
All subjects will be 
considered as non-
responders at or after 
IE2
Difference 
in the 
percentage 
of subjects 
achieving 
clinical 
remission 
per Adapted 
Mayo score
Categorical 
Key 
Secondary
ITT1 
population
Achievement of 
Endoscopic 
improvement/Endoscopic 
remission/Adapted Mayo 
Score response/HEMI/no 
bowel urgency/no 
abdominal pain/histologic 
improvement/mucosal 
healing at Week 8
Partial Adapted Mayo 
Score response at Week 2
Upadacitinib 
45 mg QD 
vs. placebo
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of UC-
related corticosteroids
All data after IE1 will 
be used
All subjects will be 
considered as non-
responders at or after 
IE2
Difference 
in the 
percentage 
of subjects 
achieving 
each binary 
secondary 
endpoint
Continuous 
Key 
Secondary
ITT1 
population 
Change from Baseline in 
IBDQ total score/FACIT-
F score at Week 8
Upadacitinib 
45 mg QD 
vs. placebo
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of UC-
related corticosteroids
All data after IE1 will 
be used
All Data after IE2 will 
not be used for 
continuous endpoints
Difference 
in mean 
change from 
Baseline in 
IBDQ total 
score and 
FACIT-F 
score


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In addition, a supplementary analysis will be conducted in which all data after IE1 and 
IE2 will be used for the primary and key binary secondary endpoints.  This supplementary 
analysis corresponded to the AO analysis specified in Section 8.3.1 will provide 
additional insights into the understanding of the treatment effect.