A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis
Phase: PHASE2
Conditions: Ulcerative Colitis (UC)
Sponsor: AbbVie

Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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1.0
Title Page
Clinical Study Protocol M14-234
A Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study to Evaluate the Safety and 
Efficacy of Upadacitinib (ABT-494) for Induction and 
Maintenance Therapy in Subjects with Moderately to 
Severely Active Ulcerative Colitis
Incorporating Administrative Changes 1, 2, and 3 
(Canada Only), and Amendments 0.01, 0.02, 1, 2, 3, 
3.01, 4, 5, 6, and 7
AbbVie Investigational
  Product:
Upadacitinib (ABT-494)
Date:
10 May 2021
Development Phase:
2b/3
Study Design:
Phase 2b/3, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Efficacy and Safety Study
EudraCT Number:
2016-000641-31
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
NCT02819635

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Sponsor/Emergency 
  Contact:
200 Sydney Street
Cambridge, MA 02139
United States
Phone:
Cell:
Fax:
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.

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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date 
Original
03 June 2016
Amendment 0.01 (US and Japan Only)
25 July 2016
Administrative Change 1 (US/Puerto Rico, Japan, and Canada)
01 August 2016
Amendment 0.02 (United Kingdom, Ireland, Austria, Belgium, Finland, 
Germany, Greece, Italy, Hungary, Norway, Portugal, Spain, Sweden, 
Czech Republic, Estonia, Latvia, Lithuania, Poland, and Romania Only)
16 September 2016
Amendment 1
29 September 2016
Administrative Change 2
21 February 2017
Amendment 2
10 October 2017
Amendment 3
03 July 2018
Amendment 3.01 (Austria, Czechia, Finland, Ireland, Italy, Latvia, 
Lithuania, Norway, Poland, Portugal, Spain, Sweden, and United 
Kingdom Only)
01 November 2018
Amendment 4
24 April 2019
Administrative Change 3 (Canada Only)
22 August 2019
Amendment 5
29 April 2020
Amendment 6
31 July 2020
The purpose of this amendment is to:
●
Apply administrative changes throughout the protocol.
Rationale: Revised text to improve consistency and readability, provide 
clarity.
●
Update Section 1.2 Synopsis
○
Updated wording on the status of enrollment.
Rationale:  Revised to be consistent with Amendment 7 revisions.
○
Updated the Substudy 3 ranked secondary endpoints.
Rationale:  Updated to reflect revised secondary variables. 
○
Included use of NRI-C method primary analysis.

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Rationale:  clarified NRI-C approach is used for Substudy 2 and 
Substudy 3 primary analysis of the primary endpoint.
○
Clarified the primary ITT and Substudy 3 ITT populations.
Rationale:  Re-grouped the Substudy 3 non-primary ITT populations in 
order to increase the number of subjects in each non-primary population.  
Renamed the Substudy 3 primary ITT population. 
●
Update Section 1.3 List of Abbreviations and Definition of Terms
○
Added NRI-C to this section.
Rationale:  Updated to define NRI-C
●
Update Section 4.0 Study Objective
○
Removed UC-related hospitalizations and UC-related surgeries in the 
ranked secondary endpoints.  Also updated wording on the status of 
enrollment.
Rationale:  Updated to reflect secondary variables updated in 
Section 5.3.3.2.
●
Update Section 5.3.3.2 Secondary Variables 
○
Updated the Substudy 3 ranked secondary endpoints.
Rationale: To ensure the most clinically relevant endpoints are included 
in the type-I error-controlled endpoint testing procedure.
●
Update Section 5.3.3.3 Additional Variables  
○
Updated the Substudy 3 additional efficacy variables Substudy 3.
Rationale: To update time points to be consistent with study scheduled 
visits; to ensure clarity of the endpoints removal of duplicate endpoint.
●
Update Section 7.0 Protocol Deviations
○
Updated alternate contact information.
Rationale:  Updated to reflect study team changes. 
●
Update Section 8.1.1.1 Intent-to-Treat Analysis Sets
○
Clarified the primary ITT and Substudy 3 ITT populations.
Rationale: Re-grouped the Substudy 3 non-primary ITT populations in order to 
increase the number of subjects in each non-primary population. Renamed the 
Substudy 3 primary ITT population. 

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●
Update Section 8.1.3 Definition of Missing Data Imputation
○
Added NRI-C and MMRM methods for better clarification.
Rationale:  added NRI-C and MMRM methods to ensure clarity of 
statistical analysis; clarified rescue handling approaches used for 
Substudy 1, Substudy 2, and Substudy 3.
●
Update Section 8.1.6.1 Primary Efficacy Variables
○
Clarified Substudy 3 subjects included in primary efficacy.
Rationale: updated language for clarity.
●
Updated Section 8.1.6.1.1 and Section 8.1.6.2 Analysis of Primary 
Endpoint; Secondary Efficacy Variables
○
Clarified approach for primary analysis.
Rationale:  clarified NRI-C approach is used for Substudy 2 and 
Substudy 3 primary analysis of categorical endpoints.
●
Updated Section 8.1.7 Other Statistical Analyses of Efficacy
○
Added Substudy 3 subgroup to analysis.
Rationale:  added a subgroup for Substudy 3 subgroup analysis.
●
Updated Section 8.1.8.3 Analysis of Laboratory and Vital Sign Data
○
Clarified the analysis for continuous lab and vital sign parameters.
Rationale:  updated language for clarity.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix K.

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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-234
Name of Study Drug:  Upadacitinib (ABT-494)
Phase of Development:  2b/3
Name of Active Ingredient:  Upadacitinib 
(ABT-494)
Date of Protocol Synopsis: 10 May 2021
Protocol Title:
A multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of 
upadacitinib (ABT-494) for induction and maintenance therapy in subjects with moderately to severely 
active ulcerative colitis.
Objective(s):
Study M14-234 comprises 3 substudies.
The primary objective of Substudy 1 (Phase 2b induction) is to characterize the dose-response, efficacy, 
and safety of upadacitinib compared to placebo in inducing clinical remission defined by Adapted Mayo 
score (using the Mayo Scoring System for Assessment of Ulcerative Colitis Activity, excluding 
Physician's Global Assessment) in subjects with moderately to severely active ulcerative colitis (UC) in 
order to identify the induction dose of upadacitinib for further evaluation in Phase 3 studies, including 
Substudy 2.
At the time of this amendment, Substudy 1 has closed enrollment and all subjects have completed the 
induction phase.
The primary objective of Substudy 2 (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.
At the time of this amendment, Substudy 2 has closed enrollment and all subjects have completed the 
induction phase.
The primary objective of Substudy 3 (Phase 3 maintenance) is to evaluate the efficacy and safety of 
upadacitinib compared to placebo in achieving clinical remission (per Adapted Mayo score) in subjects 
with moderately to severely active UC who achieved clinical response (per Adapted Mayo score) 
following induction with upadacitinib in Study M14-234 Substudy 1 or 2 or in Study M14-675.  At the 
time of this amendment, Substudy 3 has closed enrollment. 
Investigator(s):
Multicenter.
Study Site(s):
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 in Sub-
Study 2 in addition to the adult subjects.  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).

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Number of Subjects to be Enrolled:
A total of approximately 844 subjects will be enrolled worldwide:  382 subjects in Substudy 1 (Phase 2b 
induction) and approximately 462 subjects in Substudy 2 (Phase 3 induction).  For Substudy 2 the 
number of non-bio-IR subjects enrolled will be at least 25% and not exceed 50% of the total number of 
subjects enrolled.  A total of approximately 750 subjects from Substudy 1, Substudy 2, and 
Study M14-675 who achieved response following induction will be eligible to enroll in Substudy 3 
(Phase 3 maintenance).
Methodology:
This is a Phase 2b/3, multicenter, randomized, double-blind, placebo-controlled study consisting of the 
following substudies:
Substudy 1 is a Phase 2b dose-ranging study designed to evaluate the efficacy and safety of different oral 
doses of upadacitinib compared to placebo as induction therapy for 8 weeks in subjects with moderately 
to severely active UC.
Substudy 2 is a two-part Phase 3 dose-confirming 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.
All subjects diagnosed with moderately to severely active UC defined as an Adapted Mayo score of 5 to 
9 (consisting of stool frequency subscore [SFS], rectal bleeding subscore [RBS] and endoscopy 
subscore) with endoscopy subscore of 2 or 3 (confirmed by a central reader) and meet other eligibility 
criteria will be eligible to participate in Substudies 1 and 2.  The population includes subjects who have 
demonstrated inadequate response to, loss of response to, or intolerance to biologic therapy (biologic 
inadequate responders [bio-IR]) and subjects who have demonstrated inadequate response to, loss of 
response to, or intolerance to aminosalicylates, immunosuppressants, or corticosteroids but have not 
failed biologic therapy (non-bio-IR).  Approximately 75% of subjects enrolled in Substudy 1 were bio-
IR.  The number of non-bio-IR subjects will be at least 25% enrolled and not exceed 50% enrolled in 
Substudy 2.
Substudy 3 is a Phase 3 study designed to evaluate the efficacy and safety of oral administration of 
15 mg QD and 30 mg QD of upadacitinib compared to placebo as maintenance therapy in subjects with 
moderately to severely active UC who achieved clinical response following induction with upadacitinib 
in Study M14-234 Substudy 1 or 2, or Study M14-675.
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.
Substudy 1:
Subjects who consent and meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into Substudy 1 (Phase 2b 8-week induction study) and randomized in a 1:1:1:1:1 ratio to one of 
the five treatment groups (double-blind upadacitinib induction doses or matching placebo; 50 subjects 
per treatment group).  The randomization will be stratified by previous biologic use, baseline 
corticosteroid use and baseline Adapted Mayo score (≤ 7 or > 7).

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Methodology (Continued):
The following are the treatment groups for Substudy 1:
!
Group 1:  upadacitinib 7.5 mg QD (n = 50)
!
Group 2:  upadacitinib 15 mg QD (n = 50)
!
Group 3:  upadacitinib 30 mg QD (n = 50)
!
Group 4:  upadacitinib 45 mg QD (n = 50)
!
Group 5:  Placebo QD (n = 50)
After the 250 randomized subjects completed the 8-week induction, an analysis of efficacy and safety 
(selected laboratory parameters) of upadacitinib versus placebo was performed.  This analysis is referred 
to as dose-selection analysis thereafter.  Based on this analysis, one induction dose (upadacitinib 45 mg 
QD was identified for further evaluation in Substudy 2 and Study M14-675.  The results of this analysis 
were reviewed and discussed with regulatory authorities, as applicable, prior to initiation of enrollment 
of subjects in Substudy 2 and/or Study M14-675.
During the analysis period, additional subjects (132 total) continued to be enrolled into Groups 3 and 4 
of Substudy 1 (upadacitinib 30 mg QD and 45 mg QD dose groups; approximately 66 subjects per dose 
group).  The objectives of enrolling these additional subjects are to avoid interrupting the study activities 
during the analysis period and to support a sufficient number of subjects with clinical response to be re-
randomized into the maintenance portion in Substudy 3.
Substudy 2:
Subjects who consent and meet all of the inclusion and none of the exclusion criteria will be enrolled 
into Substudy 2, which consists of 2 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 of Substudy 2.
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 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 following are the treatment groups for Part 1 of Substudy 2:
!
Group 1:  Upadacitinib 45 mg QD (blinded, n = 308)
!
Group 2:  Placebo QD (blinded, n = 154)
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 of Substudy 2.  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 in 
subjects who do not initially respond to upadacitinib during Part 1.  The blind from Substudy 2 Part 1 
will be maintained for the duration of Study M14-234.
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 at Week 8 or Week 16 will 
be eligible to enroll into Substudy 3.  Subjects who do not achieve clinical response at Week 16 will be 
discontinued from the study.

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Methodology (Continued):  
Substudy 3:
Subjects in Substudies 1, 2, or Study M14-675 who achieved clinical response after completion of the 
8-week induction treatment or subjects who achieved clinical response after completion of the Extended 
Treatment Period in Substudy 2 or Study M14-675 will be enrolled into Substudy 3 and treated with a 
blinded treatment assignment for up to 52 weeks.  During the COVID-19 pandemic, Investigators should 
make the best effort to complete the required endoscopies per protocol. Subjects who have missed the
Week 8 and/or Week 16 endoscopy when performing endoscopies are prohibited during COVID-19 
pandemic will not be eligible to enter Substudy 3.  The Baseline Visit of Substudy 3 is completed on the 
same day as the final visit in the Induction Phase (either at Week 8 or at Week 16) for subjects who are 
eligible.  
Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and 
≥30% from baseline, PLUS a decrease in RBS ≥1 or an absolute RBS ≤ 1.  The treatment assignment in 
Substudy 3 will depend on the treatment received in Substudies 1, 2, or Study M14-675, as detailed 
below.
Substudy 3 will have 4 cohorts:
Cohort 1:  Approximately 525 subjects who achieved clinical response in Study M14-234 Substudies 1, 
2 and received upadacitinib 45 mg, 30 mg or 15 mg QD, or in Study M14-675 will be re-randomized to 
one of the following treatment groups.
Treatment groups for Cohort 1:  
!
Group 1:  Upadacitinib 15 mg QD
!
Group 2:  Upadacitinib 30 mg QD
!
Group 3:  Placebo QD
The eligibility of entering Cohort 1 will be decided by the treatment (placebo or upadacitinib) and dose 
of upadacitinib received in the induction phase.
Cohort 2:  approximately 60 subjects who received double-blind placebo QD treatment for 8 weeks 
during Study M14-234 Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical 
response will continue to receive blinded placebo QD in Substudy 3.
Cohort 3:  approximately 150 upadacitinib 45 mg QD induction phase non-responders who received 
upadacitinib 45 mg during the Extended Treatment Period in Study M14-234 (Substudy 2, Part 2) and 
Study M14-675 (Part 2) and achieved clinical response at Week 16 will be re-randomized and receive 
blinded upadacitinib 30 mg QD or upadacitinib 15 mg QD in Study M14-234 (Substudy 3).
Cohort 4:  approximately 15 subjects who received double-blinded treatment of upadacitinib 7.5 mg for 
8 weeks during Study M14-234 (Substudy 1) and achieved clinical response will continue to receive 
blinded treatment of upadacitinib 7.5 mg QD in Substudy 3.
All subjects will be provided with an electronic diary (eDiary) at Screening in Study M14-234 or 
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 SFS and RBS 
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.

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Methodology (Continued):
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 Substudy 1, Substudy 2 
Part 1, or Study M14-675 Part 1); Week 44 in Substudy 3 (for subjects entering from Substudy 1), or 
Week 52/PD in Substudy 3 (for all subjects entering from Substudy 2 and Study M14-675), a full 
colonoscopy or flexible sigmoidoscopy, depending on the extent of disease at Screening, will be 
performed.
For subjects in Substudy 2 Part 2 or Study M14-675 Part 2, an endoscopy will be performed at Week 16.  
A flexible rectosigmoidoscopy is recommended at Week 16, 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 
Substudy 1 and Substudy 2 Part 1, Week 16 of Substudy 2 Part 2 and Week 44 (for subjects that enter 
from Substudy 1 prior to amendment approval) or Week 52 of Substudy 3 (for subjects that enter from 
Substudy 2 or Study M14-675).
However, for re-randomization into Substudy 3, the endoscopic subscore at Week 8 (Study M14-234 
Substudy 1, Substudy 2 Part 1 or Study M14-675 Part 1) or Week 16 (Substudy 2 Part 2 or 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 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 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.
Electronic patient reported outcomes (ePRO) instruments:  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), and Ulcerative Colitis 
Symptoms Questionnaire (UC-SQ; only in select sites during Substudy 1, but all subjects will complete 
this questionnaire during Substudy 2 and Study M14-675) and Patient Global Impression of Change 
(PGIC) and Patient Global Impression of Severity (PGIS) at some sites will be collected at specific visits 
throughout all three substudies.
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.

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Methodology (Continued):
Concomitant UC-Related Medications (Oral Corticosteroids, Antibiotics, Aminosalicylates, and/or 
Methotrexate):
All UC-related concomitant medications should be kept on stable doses in Substudy 1 and Substudy 2 
Parts 1 and 2.
For Substudy 3, at baseline (Week 8 or Week 16 of Study M14-234 Substudy 1, Substudy 2, and 
Study M14-675) subjects who are taking corticosteroid therapy will have their corticosteroid therapy 
tapered according to a proposed tapering schedule.  All subjects receiving UC-related antibiotics may 
discontinue treatment starting at Week 0 of Substudy 3 at the discretion of the investigator.  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.
Rescue Therapy:
At or after Week 4 in Substudy 3, subjects who demonstrate loss of response and require medical 
treatment but have not yet met the criteria to enter Study M14-533 Cohort 1, may receive rescue therapy.  
Rescue therapy should not be withheld even if subject does not meet the criteria for loss of response or 
before 4 weeks after entering Substudy 3 if in the opinion of the investigator, failure to prescribe them 
would compromise the subject's safety.  Rescue therapy may be provided in the form of initiation or 
increased dosage, at the investigator's discretion, of any allowed UC-related medications to treat new or 
worsening UC symptoms.  The allowed UC-related medications are locally acting, oral, or intravenous 
corticosteroids, aminosalicylates, MTX or UC-related antibiotics.
Diagnosis and Main Criteria for Inclusion/Exclusion:
The following Inclusion/Exclusion criteria are for subjects enrolled in both Substudies 1 and 2.
Main Inclusion:
1.
Male or female between 16 and 75 years of age at Baseline.
Subjects at 16 and 17 years of age 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 J) 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). 
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.

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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
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 red blood cell count [RBC] or higher on the current dosing regimen), 
injectable 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.
!
Biologic Agents for UC
Signs and symptoms of persistently active disease despite a history of any of the following:
o
at least one 6-week induction regimen of infliximab (≥ 5 mg/kg intravenous [IV] at 0, 2, 
and 6 weeks),
o
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 dose in countries where this 
dosing regimen is allowed] followed by one 40 mg SC dose at least 2 weeks apart),

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EudraCT 2016-000641-31
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
o
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),
o
at least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2, and 6 weeks), 
o
at least one induction regimen of ustekinumab, a single IV dose using weight-based dosing 
(260 mg for subjects with body weight ≤ 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 contraception criteria as stated in Section 5.2.4 of this protocol.
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-mercaptopurine 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 × upper limit of 
normal (ULN);
!
Estimated glomerular filtration rate 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 < 9 g/dL.

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M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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Investigational Product(s):
Upadacitinib (ABT-494)
Double-Blind Induction Doses –
Phase 2b (Substudy 1):
Upadacitinib 7.5 mg QD
Upadacitinib 15 mg QD
Upadacitinib 30 mg QD
Upadacitinib 45 mg QD
Double-Blind Induction Doses –
Phase 3 (Substudy 2 – Part 1):
Upadacitinib 45 mg QD
Open-Label Induction Doses –
Phase 3 (Substudy 2 – Part 2):
Upadacitinib 45 mg QD
Double-Blind Maintenance 
Doses – Phase 3 (Substudy 3)
Upadacitinib 7.5 mg QD
Upadacitinib 15 mg QD
Upadacitinib 30 mg QD
Mode of Administration:
Oral
Reference Therapy:
Matching Placebo
Dose(s):
N/A
Mode of Administration:
Oral
Duration of Treatment:  8 weeks to 16 weeks (as applicable) induction and 44 to 52 weeks 
maintenance for a total of up to 68 weeks
Criteria for Evaluation:
Efficacy:
Primary Endpoints:
The primary endpoint for Phase 2b Induction (Substudy 1) is the proportion of subjects who achieve 
clinical remission per Adapted Mayo score (defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1) 
at Week 8.  The primary endpoint for Phase 3 induction (Substudy 2) 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:  in Substudy 2, evidence of friability during 
endoscopy in subjects with otherwise "mild" endoscopic activity will confer an endoscopic subscore of 
2.
The primary endpoint for Phase 3 maintenance (Substudy 3) is the proportion of subjects who achieve 
clinical remission per Adapted Mayo score (definition same as definition in Substudy 2) at Week 52.
Substudy 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

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M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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Criteria for Evaluation (Continued):
Efficacy (Continued):
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
Substudy 3 Ranked Secondary Endpoints: 
1.
Proportion of subjects with endoscopic improvement at Week 52
2.
Proportion of subjects who maintain clinical remission per Adapted Mayo score at Week 52 among 
subjects who achieved clinical remission per Adapted Mayo score in Study M14-234 (Substudy 1 or 
2) or Study M14-675
3.
Proportion of subjects who achieved clinical remission at Week 52 per adapted Mayo score and 
were corticosteroid free for ≥ 90 days among subjects in clinical remission in the end of the 
induction treatment in Study M14-234 (Substudy 1 or 2) or Study M14-675
4.
Proportion of subjects with endoscopic improvement at Week 52 among subjects with endoscopic 
improvement in Study M14-234 (Substudy 1 or 2) or Study M14-675
5.
Proportion of subjects with endoscopic remission at Week 52
6.
Proportion of subjects maintain clinical response per Adapted Mayo score at Week 52
7.
Proportion of subjects with histologic-endoscopic mucosal improvement at Week 52
8.
Change from Baseline in IBDQ total score at Week 52
9.
Proportion of subjects with mucosal healing at Week 52
10. Proportion of subjects who reported no bowel urgency at Week 52
11. Proportion of subjects who reported no abdominal pain at Week 52
12. Change from Baseline in FACIT-F score at Week 52 
Pharmacokinetic:
Blood samples will be collected for measurement of upadacitinib plasma concentration at the following 
times:
Substudy 1:  Week 2, Week 4, Week 6, and Week 8/Premature Discontinuation (PD) 
Substudy 2 Part 1:  Week 2, Week 6, and Week 8/Premature Discontinuation (PD)  
Substudy 3:  Week 36, and Week 52/PD
Safety:
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, electrocardiogram, physical examination results, and clinical 
laboratory data will be assessed.

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M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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Criteria for Evaluation (Continued):
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.
Statistical Methods:
Efficacy:
For Substudy 1 (Phase 2b portion of the study), a total of 250 subjects will be equally allocated to 
four upadacitinib treatment groups and the placebo group, representing a randomization ratio of 
1:1:1:1:1.
The dose-response relationships using the most significant model in Multiple Comparison Procedure –
Modeling (MCP-Mod) among the 4 upadacitinib treatment groups and placebo group will be 
characterized for the primary endpoint clinical remission per Adapted Mayo score at Week 8.
For Substudy 2, a total of 462 subjects will be allocated to upadacitinib treatment group or placebo in a 
randomization ratio of 2:1.
For both Substudies 1 and 2, efficacy analysis will be based on intent-to-treat (ITT) analysis set.  The 
ITT analysis set for Substudy 1 includes all randomized subjects who received at least one dose of study 
drug from Substudy 1 (denoted as ITT1A) at the time of dose-selection analysis.  The ITT analysis set 
that includes all ITT1A subjects, plus all the additional subjects who were randomized to upadacitinib 
30 mg QD and 45 mg QD groups during the dose-selection period is denoted as ITT1B.  ITT1A is the 
primary analysis set of Substudy 1.  Primary analysis and ranked secondary analysis of Substudy 1 will 
be repeated using ITT1B.  The comparisons between treatment groups for the primary efficacy endpoint 
will be performed using the Cochran-Mantel-Haenszel (CMH) test and will be stratified by previous 
biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7).  The 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.
The ITT analysis set for Substudy 2 includes all randomized subjects who received at least one dose of 
study drug from Substudy 2 Part 1 (denoted as ITT2A).  The ITT analysis set that includes all subjects 
who received the open label upadacitinib induction dose of 45 mg QD from Substudy 2 Part 2 is denoted 
as ITT2B.  ITT2A is the primary analysis set of Substudy 2.  Primary analysis and ranked secondary 
analysis of Substudy 2 will be repeated using ITT2B.  The comparisons between treatment groups for 
the primary efficacy endpoint will be performed using the Cochran-Mantel-Haenszel (CMH) test and 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 a previous biologic use (yes or no).  Non-responder imputation incorporating 
multiple imputation to handle COVID-19 (NRI-C) method will be used for primary analysis.
For Substudy 3, efficacy analyses will be based on the ITT analysis set.

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Statistical Methods (Continued):
Efficacy (Continued):
A database lock and unblinded analysis will be conducted for the purpose of regulatory submission after 
the first 450 subjects in Substudy 3 Cohort 1 who were upadacitinib 45 mg QD induction responders 
have completed the maintenance study (i.e., completed Week 52 or prematurely discontinued prior to 
Week 52). This is the only and final analysis for the 52-week efficacy analyses.  AbbVie study team 
will be unblinded to the treatment assignment, study sites and subjects will remain blinded until all 
subjects complete the maintenance study. If there are additional subjects in any cohort who have not 
completed the maintenance study at the time of database lock, they will be kept on the same blinded 
treatment until study completion. Once all subjects have completed the maintenance study, the data 
collected from these subjects will be used to update the safety analysis only.
For Substudy 3, the following ITT analysis sets are defined:
!
ITT3:  All subjects who received at least 1 dose of study drug in the Substudy 3.
!
ITT3_A:  The subset of ITT3 who were the first 450 upadacitinib 45 mg QD 8-week induction 
responders and who were enrolled under the protocol for 52-week maintenance treatment 
period in Cohort 1. The ITT3_A is the primary analysis population in Cohort 1 for efficacy 
endpoints.
!
ITT3_B:  The subset of ITT3 in Cohort 3 who were upadacitinib 45 mg QD 16-week induction 
responders.
!
ITT3_C:  The subset of ITT3 who were enrolled under the original protocol, Amendment 1 or 2 
for 44-week maintenance treatment period.
!
ITT3_D: The subset of ITT3 who were upadacitinib 45 mg QD 8-week induction responders 
and who were enrolled under the protocol for 52-week maintenance treatment period in 
Cohort 1.
!
ITT3_E:  The subset of ITT3 who were placebo, upadacitinib 7.5 mg QD, 15 mg QD or 30 mg 
QD 8-week induction responders and who were enrolled under the protocol for 52-week 
maintenance treatment period.
Primary analysis and secondary analyses of Substudy 3 will be performed for ITT3_A, ITT3_B, ITT3_C 
and ITT3_E.
The comparison between treatment groups in ITT3_A population for the primary efficacy endpoint will 
be performed using the CMH test and will be stratified by previous bio-IR status (yes or no), clinical 
remission status at Week 0 (yes or no), and corticosteroid use at Week 0 (yes or no).  Non-responder 
imputation incorporating multiple imputation to handle COVID-19 (NRI-C) method will be used for the 
primary analysis.
Additional analyses are outlined in the protocol.
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.

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Statistical Methods (Continued):
Safety:
Safety analyses will be carried out using the safety analysis set in Substudies 1 to 3, which includes all 
subjects who receive at least one dose of study medication in each portion of the study, respectively.  
Incidence of adverse events, 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 and by 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
AD
Atopic dermatitis
AE
Adverse Event
ALC
Absolute Lymphocyte Count
ALT
Alanine Transaminase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AST
Aspartate Transaminase
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
CR
Clinical Remission

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CRA
Clinical Research Associate
CRF
Case Report Form
CRP
C-Reactive Protein
Cmin
Minimum Plasma Concentration During a Dosing Interval
CT
Computed Tomography
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
EIMs
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
Follicule-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
HCV
Hepatitis C Virus

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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
MMRM
Mixed Effect Repeated Measure 

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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
NRI-C
Non-Responder Imputation while incorporating Multiple Imputation (MI) to 
handle missing data due to COVID-19
NSAID
Non-Steroidal Anti-Inflammatory Drug
OC
Observed Cases
PCR
Polymerase Chain Reaction
PCS
Physical Component Summary
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

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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 .....................................................................................................6
1.3
List of Abbreviations and Definition of Terms........................................19
2.0
Table of Contents...................................................................24
3.0
Introduction ...........................................................................29
3.1
Differences Statement..............................................................................33
3.2
Benefits and Risks....................................................................................33
3.3
Safety Evaluations ...................................................................................35
4.0
Study Objective......................................................................35
5.0
Investigational Plan...............................................................37
5.1
Overall Study Design and Plan:  Description ..........................................37
5.1.1
Substudy 2................................................................................................41
5.1.2
Substudy 3................................................................................................44
5.2
Selection of Study Population..................................................................51
5.2.1
Inclusion Criteria .....................................................................................52
5.2.2
Exclusion Criteria ....................................................................................56
5.2.3
Prior and Concomitant Therapy...............................................................61
5.2.3.1
Prior Therapy ...........................................................................................61
5.2.3.2
Concomitant Therapy...............................................................................62
5.2.3.3
Prohibited Therapy...................................................................................64
5.2.3.4
Rescue Therapy........................................................................................67
5.2.4
Contraception Recommendations ............................................................68
5.3
Efficacy and Safety Assessments/Variables ............................................70
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................70
5.3.1.1
Study Procedures .....................................................................................71
5.3.1.2
Collection and Handling of Optional Samples for Exploratory 
Research and Validation Studies ...........................................................104
5.3.2
Drug Concentration Measurements .......................................................105
5.3.2.1
Collection of Samples for Analysis .......................................................105
5.3.2.2
Handling/Processing of Samples ...........................................................106

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5.3.2.3
Disposition of Samples ..........................................................................106
5.3.2.4
Measurement Methods...........................................................................106
5.3.3
Efficacy Variables..................................................................................107
5.3.3.1
Primary Variables ..................................................................................108
5.3.3.2
Secondary Variables ..............................................................................108
5.3.3.3
Additional Variables ..............................................................................110
5.3.4
Safety Variables.....................................................................................115
5.3.5
Pharmacokinetic Variables ....................................................................115
5.3.6
Exploratory Research Variables and Validation Studies.......................116
5.4
Removal of Subjects from Therapy or Assessment...............................116
5.4.1
Discontinuation of Individual Subjects..................................................116
5.4.2
Discontinuation of Entire Study.............................................................119
5.5
Treatments..............................................................................................120
5.5.1
Treatments Administered.......................................................................120
5.5.2
Identity of Investigational Product(s) ....................................................123
5.5.2.1
Packaging and Labeling.........................................................................123
5.5.2.2
Storage and Disposition of Study Drug .................................................123
5.5.3
Method of Assigning Subjects to Treatment Groups.............................124
5.5.4
Selection and Timing of Dose for Each Subject....................................126
5.5.5
Blinding..................................................................................................128
5.5.5.1
Blinding of Investigational Product.......................................................129
5.5.5.2
Blinding of Data for Independent Data Monitoring Committee 
(DMC)....................................................................................................129
5.5.6
Treatment Compliance...........................................................................129
5.5.7
Drug Accountability...............................................................................130
5.6
Discussion and Justification of Study Design........................................131
5.6.1
Discussion of Study Design and Choice of Control Groups..................131
5.6.2
Appropriateness of Measurements.........................................................133
5.6.3
Suitability of Subject Population ...........................................................133
5.6.4
Selection of Doses in the Study .............................................................133
6.0
Complaints ...........................................................................138
6.1
Medical Complaints...............................................................................138
6.1.1
Definitions..............................................................................................138

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6.1.1.1
Adverse Event........................................................................................138
6.1.1.2
Serious Adverse Events .........................................................................139
6.1.1.3
Adverse Events of Special Interest ........................................................141
6.1.2
Adverse Event Severity..........................................................................141
6.1.3
Relationship to Study Drug....................................................................142
6.1.4
Adverse Event Collection Period...........................................................143
6.1.5
Adverse Event Reporting.......................................................................144
6.1.6
Pregnancy...............................................................................................146
6.1.7
Toxicity Management ............................................................................147
6.1.8
Cardiovascular Adjudication Committee (CAC)...................................151
6.1.9
Data Monitoring Committee (DMC) .....................................................151
6.2
Product Complaint .................................................................................152
6.2.1
Definition ...............................................................................................152
6.2.2
Reporting................................................................................................153
7.0
Protocol Deviations..............................................................153
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................154
8.1
Statistical and Analytical Plans..............................................................154
8.1.1
Datasets for Analysis .............................................................................156
8.1.1.1
Intent-to-Treat Analysis Sets .................................................................156
8.1.1.2
Safety Analysis Set ................................................................................157
8.1.2
Subject Accountability...........................................................................157
8.1.3
Definition of Missing Data Imputation..................................................157
8.1.4
Demographics and Baseline Characteristics..........................................159
8.1.4.1
Baseline Characteristics.........................................................................159
8.1.4.2
Medical Histories...................................................................................159
8.1.4.3
Prior Therapy and Medications..............................................................159
8.1.4.4
Concomitant Medications ......................................................................159
8.1.5
Subject Disposition and Study Drug Exposure......................................160
8.1.5.1
Subject Disposition ................................................................................160
8.1.5.2
Study Drug Exposure.............................................................................160
8.1.6
Efficacy Analysis ...................................................................................161
8.1.6.1
Primary Efficacy Variables....................................................................161

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8.1.6.1.1
Analysis of Primary Endpoint................................................................161
8.1.6.2
Secondary Efficacy Variables................................................................163
8.1.7
Other Statistical Analyses of Efficacy ...................................................164
8.1.8
Safety Analysis ......................................................................................165
8.1.8.1
General Considerations..........................................................................165
8.1.8.2
Analysis of Adverse Events...................................................................166
8.1.8.2.1
Treatment-Emergent Adverse Events ....................................................166
8.1.8.2.2
Serious Adverse Events and Death ........................................................168
8.1.8.3
Analysis of Laboratory and Vital Sign Data..........................................168
8.1.9
Pharmacokinetic and Exposure-Response Analyses .............................168
8.2
Determination of Sample Size ...............................................................170
9.0
Ethics.....................................................................................172
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................172
9.2
Ethical Conduct of the Study .................................................................172
9.3
Subject Information and Consent...........................................................173
9.3.1
Informed Consent Form and Explanatory Material ...............................175
9.3.2
Revision of the Consent Form and Explanatory Material .....................175
10.0
Source Documents and Case Report Form 
Completion ...........................................................................176
10.1
Source Documents .................................................................................176
10.2
Case Report Forms.................................................................................176
10.3
Electronic Patient Reported Outcomes (ePRO).....................................177
11.0
Data Quality Assurance ......................................................179
12.0
Use of Information...............................................................179
13.0
Completion of the Study .....................................................180
14.0
Investigator's Agreement....................................................182
15.0
Reference List ......................................................................183
List of Tables
Table 1.
Clinical Laboratory Tests.........................................................................88
Table 2.
Corticosteroid Dose Taper .......................................................................94

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Table 3.
Treatments Administered.......................................................................122
Table 4.
Serious Adverse Events .........................................................................140
Table 5.
Toxicity Management Guidelines for Abnormal Lab Values................149
List of Figures
Figure 1.
Study M14-234 Overall Design Schematic .............................................40
Figure 2.
Study M14-234 Substudy 2 Schematic....................................................43
Figure 3.
Study M14-234 Substudy 3 Schematic....................................................46
Figure 4.
Interpretation and Management of HBV Serologic Test Results ............84
Figure 5.
Adverse Event Collection ......................................................................143
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................187
Appendix B.
List of Protocol Signatories....................................................................189
Appendix C.
Study Activities (Substudies 1 and 2, Parts 1 and 2) .............................190
Appendix D.
Study Activities (Substudies 1 and 2, Parts 1 and 2) Optional 
Samples for Exploratory Research and Validation Studies ...................198
Appendix E.
Study Activities (Substudy 3) ................................................................200
Appendix F.
Study Activities (Substudy 3) Optional Samples for Exploratory 
Research and Validation Studies ...........................................................205
Appendix G.
Patient Reported Outcomes Descriptions in Upadacitinib 
(ABT-494) UC Programs.......................................................................206
Appendix H.
Mayo Scoring System for Assessment of Ulcerative Colitis 
Activity ..................................................................................................210
Appendix I.
Screening/annual TB Risk Assessment Questionnaire Example...........211
Appendix J.
Tanner Staging Example........................................................................212
Appendix K.
Protocol Amendment:  List of Changes.................................................213

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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 amendment, Phase 2b interim results from this 
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 the 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 2b/3 study differs from other upadacitinib studies as it is the first to evaluate 
the efficacy, safety and pharmacokinetics of upadacitinib in subjects with 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 and biologic therapies.
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.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.
A detailed discussion of the pre-clinical and clinical toxicology, metabolism, 
pharmacology, and safety experience with upadacitinib can be found in the current 
Investigator's Brochure.
We propose to initiate a Phase 2b/3 study in UC subjects with multiple doses of 
upadacitinib 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 2b/3 Study M14-234 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, at the time of this amendment, the completed Phase 2b dose ranging 
part of this study (Study M14-234 Substudy 1) has demonstrated superior efficacy of 
upadacitinib with an acceptable safety profile compared to placebo in subjects with 

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moderately to severely active UC.  The benefit-risk profile of upadacitinib in Substudy 1 
of this study supports further evaluation of upadacitinib in Substudies 2 and 3 for subjects 
with UC.24
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 
Study M14-234 comprises 3 substudies. 
The objective of Substudy 1 (Phase 2b induction) was to characterize the dose-response, 
efficacy, and safety of upadacitinib compared to placebo in inducing clinical remission 
per Adapted Mayo score (using the Mayo Scoring System for Assessment of Ulcerative 
Colitis Activity, excluding Physician's Global Assessment [PGA]) in subjects with 
moderately to severely active UC in order to identify the induction dose of upadacitinib 
for further evaluation in Phase 3 studies including Substudy 2.
The population in Substudy 1 included subjects who had demonstrated inadequate 
response, loss of response, or intolerance to biologic therapy (biologic inadequate 
responders [bio-IR]) and subjects who had demonstrated inadequate response to, loss of 
response to, or intolerance to conventional therapy but had not failed biologic therapy 
(non-bio-IR).  Approximately 75% of subjects were bio-IR and 25% of subjects were non-
bio-IR in Substudy 1.  At the time of this amendment, Substudy 1 has closed and all 
subjects have completed the induction phase.

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Subjects in Substudy 1 who did not achieve clinical response after completion of the 
8-week induction treatment had the option to enroll into a separate AbbVie Study, Study 
M14-533, a Phase 3 multicenter, long-term extension study.
The primary objective of Substudy 2 (Phase 3 induction) is to evaluate the efficacy and 
safety of upadacitinib 45 mg QD compared to placebo in inducing clinical remission (per 
Adapted Mayo score) in subjects with moderately to severely active UC who are bio-IR or 
non-bio-IR.
The secondary objectives of Substudy 2 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.
Substudy 2 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 other than inadequate response, loss of response, or intolerance.  
Substudy 2 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. At the time of this amendment, Substudy 2 has closed and all subjects have 
completed the induction phase.
The primary objective of Substudy 3 (Phase 3 maintenance) is to evaluate the efficacy and 
safety of upadacitinib 30 mg QD and 15 mg QD compared to placebo in achieving clinical 

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remission (per Adapted Mayo score) in subjects with moderately to severely active UC 
who achieved clinical response (per Adapted Mayo score) following induction therapy 
from Study M14-234 Substudy 1, Substudy 2, or Study M14-675.  Study M14-675 is an 
induction study in patients with moderately to severely active UC.
The secondary objective of Substudy 3 is to evaluate the efficacy of upadacitinib 30 mg 
QD and 15 mg QD compared to placebo in the ranked secondary endpoints at Week 52 of 
achieving endoscopic improvement, maintaining clinical remission, corticosteroid free 
remission, maintaining endoscopic improvement, endoscopic remission, maintaining 
clinical response, mucosal healing, no bowel urgency, no abdominal pain, histologic-
endoscopic mucosal improvement, change in IBDQ total score and FACIT-F score.
Note:  For subjects who entered Substudy 3 from Study M14-234 Substudy 1, these 
subjects were only required to complete 44 weeks of maintenance therapy in Substudy 3.  
At the time of this amendment, if a subject from Substudy 1 is in Substudy 3 and has not 
yet completed the Week 44 Visit, they will be re-consented to extend treatment to 
Week 52 after approval for the amendment has been obtained for each respective site.  
Subjects entering Substudy 3 from Study M14-234 Substudy 2 or Study M14-675 will be 
required to complete 52 weeks in Substudy 3 if they do not withdraw prior.  At the time of 
this amendment, Substudy 3 has closed enrollment.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2b/3, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy, safety, and pharmacokinetics of upadacitinib as 
induction and maintenance therapy in subjects with moderately to severely active UC. 
The study comprises 3 substudies:  a Phase 2b dose-ranging induction substudy 
(Substudy 1), a Phase 3 dose-confirming induction substudy (Substudy 2), and a Phase 3 
maintenance substudy (Substudy 3). 

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The study is designed to enroll approximately 844 subjects in Substudy 1 and Substudy 2 
to meet scientific and regulatory objectives without enrolling an undue number of subjects 
in alignment with ethical considerations.  Therefore, if the target number of subjects has 
been enrolled, there is a possibility that additional subjects in screening will not be 
enrolled.
The study duration could be up to 77 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), a 52-week 
Maintenance Period, and a 30-day Follow-up Period.  For subjects who meet criteria for 
loss of response during the Maintenance Period (Substudy 3), the Week 52/PD Visit 
should be conducted.
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.
Substudy 1
At the time of this amendment, Substudy 1 has closed and all subjects in Substudy 1 have 
completed the 8-week induction phase.
Subjects (n = 250) who met eligibility criteria were randomized in a 1:1:1:1:1 ratio to one 
of the following double-blinded induction treatment arms:  
●
Group 1:  upadacitinib 7.5 mg QD (n = 50)
●
Group 2:  upadacitinib 15 mg QD (n = 50)
●
Group 3:  upadacitinib 30 mg QD (n = 50)

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●
Group 4:  upadacitinib 45 mg QD (n = 50)
●
Group 5:  Placebo QD (n = 50)
The population in Substudy 1 included subjects who demonstrated inadequate response to, 
loss of response to, or intolerance to biologic therapy (biologic inadequate responders 
[bio-IR]) and subjects who demonstrated inadequate response to, loss of response to, or 
intolerance to conventional therapy but had not failed biologic therapy (non-bio-IR).  
Approximately 75% of subjects enrolled were bio-IR and 25% of subjects were non-bio-
IR in Substudy 1.
After the 250 randomized subjects completed the 8-week induction, an analysis of 
efficacy and safety (selected laboratory parameters) of upadacitinib versus placebo was 
performed.  This analysis is referred to as dose-selection analysis thereafter.  Based on 
this analysis, one induction dose (upadacitinib 45 mg) was identified for further 
evaluation in Substudy 2 and Study M14-675.  The results of this analysis were reviewed 
and discussed with regulatory authorities, as applicable, prior to initiation of enrollment of 
subjects in Substudy 2 and/or Study M14-675.
During the analysis period, 132 additional subjects were randomized into Groups 3 and 4 
of Substudy 1 (upadacitinib 30 mg QD and 45 mg QD dose groups; approximately 
66 subjects per dose group).  The objectives of enrolling these additional subjects are to 
avoid interrupting the study activities during the analysis period and to support a 
sufficient number of subjects with clinical response to be re-randomized into the 
maintenance portion in Substudy 3.  The data collected from these subjects will be 
reported separately in the clinical study report.
Subjects in Substudy 1 who did not achieve clinical response after completion of the 
8-week induction treatment had the option to enroll into a separate AbbVie 
Study M14-533, a Phase 3 multicenter long-term extension study.  Clinical response is 
defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% 
from baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.

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Figure 1.
Study M14-234 Overall Design Schematic
Abbreviations:  SS1 = Substudy 1; SS2 = Substudy 2
Note:
132 additional subjects were randomized to upadacitinib 30 mg QD (~66 subjects) or upadacitinib 45 mg QD (~66 subjects) during the analysis for dose selection.

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5.1.1
Substudy 2
At the time of this amendment, Substudy 2 has closed enrollment.
Subjects 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 Substudy 2, which consists 
of two parts:  (Part 1) a randomized, double-blind, placebo-controlled 8-week induction 
study; (Part 2) an 8-week Extended Treatment Period for clinical non-responders from 
Part 1 of Substudy 2. 
In Substudy 2, the number of non-bio-IR subjects will be at least 25% and not exceed 
50% and will allow enrollment of up to 30% of subjects who have failed 3 or more 
biologics among bio-IR subjects.  In 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 other than inadequate response, loss of response, or intolerance.  
Substudy 2 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. 
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 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).

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The following are the treatment groups for Part 1 of Substudy 2:
●
Group 1:  Upadacitinib 45 mg QD (blinded, n = 308)
●
Group 2:  Placebo QD (blinded, n = 154)
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 clinial 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 Substudy 2 Part 1 will be maintained as these subjects will be assessed 
simply as non-responders and moved to Substudy 2 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 will be eligible to enroll into 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 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 M14-533 (long-
term extension).

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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 
Substudy 2 Part 2 will be based on the local reader scoring.  Visits in Part 2 will occur at 
Week 10, 12, 14, and 16, and an endoscopy will be performed at Week 16.  Flexible 
sigmoidoscopy is recommended, however the use of colonoscopy or flexible 
sigmoidoscopy is in the investigator's discretion based on local practice.
Figure 2 shows the schematic for Substudy 2. 
Figure 2.
Study M14-234 Substudy 2 Schematic

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5.1.2
Substudy 3
Approximately 750 subjects who achieved clinical response per Adapted Mayo Score
after completion of induction treatment or Extended Treatment Period in Study M14-234 
Substudy 1, Substudy 2, or Study M14-675 will be eligible to enter Substudy 3 and 
treated with a blinded treatment assignment for up to 52 weeks. Subjects with missing 
Week 8 or/and Week 16 endoscopy during the period of COVID-19 pandemic will not be 
eligible to enter Substudy 3. Subjects who completed Study M14-675 will consent for 
Study M14-234 prior to entering Substudy 3.  The only eligibility checks required for a 
subject to enter Study M14-234 Substudy 3 from Study M14-675 is to consent to the 
Study M14-234 Substudy 3 and to have achieved clinical response at Week 8 or 16 of 
Study M14-675 and do not meet any study discontinuation criteria, meeting the Protocol 
listed inclusion and exclusion criteria for Study M14-234 is not required for these subjects 
at this point of transition.  The Baseline Visit of Substudy 3 is completed on the same day 
as the final visit in the Induction Phase (either at Week 8 or Week 16) for subjects who 
are eligible.
Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 
points and ≥ 30% from baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.  
The treatment assignment in Substudy 3 will depend on the treatment received in 
Substudies 1 and 2, or Study M14-675, as detailed below.
Substudy 3 will include 4 cohorts:
Cohort 1: 
Approximately 525 subjects who achieved clinical response in Study M14-234 
Substudies 1 and 2, or Study M14-675, and received 1 of the following treatments will be 
re-randomized in a 1:1:1 ratio to one of the treatment groups in Cohort 1:
●
Upadacitinib 30 mg QD or 45 mg QD in Study M14-234 Substudy 1
●
Upadacitinib 45 mg QD in Study M14-234 Substudy 2 Part 1 
●
Upadacitinib 45 mg QD in Study M14-675 Part 1

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●
Placebo QD in Study M14-234 Substudy 2 Part 1 followed by upadacitinib 
45 mg QD in Study M14-234 Substudy 2 Part 2
●
Placebo QD in Study M14-675 Part 1 followed by upadacitinib 45 mg QD in 
Part 2
Treatment groups in Cohort 1:
●
Group 1:  upadacitinib 15 mg QD
●
Group 2:  upadacitinib 30 mg QD
●
Group 3:  placebo QD
Subjects who achieved clinical response and received upadacitinib 15 mg QD in 
Study M14-234 Substudy 1 will be re-randomized 1:1 to only receive upadacitinib 15 mg 
QD or placebo QD (treatment Group 1 or 3). 
Cohort 2:  approximately 60 subjects who received double-blind placebo QD treatment 
for 8 weeks during Study M14-234 Substudy 1, Substudy 2 Part 1 or Study M14-675 
Part 1 and achieved clinical response will continue to receive blinded placebo QD in 
Substudy 3.
Cohort 3:  approximately 150 subjects who received upadacitinib 45 mg QD in induction 
phase and did not achieve clinical response - and received upadacitinib 45 mg in Extended 
Treatment in Study M14-234 (Substudy 2, Part 2) or Study M14-675 (Part 2) and 
achieved clinical response at Week 16 will be re-randomized 1:1 and receive blinded 
upadacitinib 30 mg QD or upadacitinib 15 mg QD in Study M14-234 (Substudy 3). 
Cohort 4:  approximately 15 subjects who received double-blinded treatment of 
upadacitinib 7.5 mg for 8 weeks during Study M14-234 (Substudy 1) and achieved 
clinical response will continue to receive blinded treatment of upadacitinib 7.5 mg QD in 
Substudy 3.  The schematic of Substudy 3 is shown in Figure 3.

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Figure 3.
Study M14-234 Substudy 3 Schematic
The rationale for re-randomizing only induction responders who received upadacitinib 15, 
30 or 45 mg QD from Substudy 1 is to ensure that no subject receives a dose during 
maintenance that is higher than what was received in the induction period. 
During Substudy 3, subjects who meet the criteria for initial loss of response after at least 
2 weeks of treatment and have a second confirmed loss of response on a consecutive visit 
at least 14 days later will have the option to enroll into Study M14-533 and receive open-
label upadacitinib.  Timely data entry regarding loss of response is required and should 
not be done retrospectively to ensure accurate calculations.

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Loss of response is defined as follows:
●
A subject who presents with an SFS and RBS score each at least 1 point greater 
than the end-of-induction value (Week 8 of Substudy 1, Substudy 2 Part 1, 
Study M14-675 Part 1 or Week 16 of Substudy 2 Part 2 or Study M14-675 Part 
2) on two consecutive visits at least 14 days apart, associated with the presence 
of signs or symptoms of progression of UC disease as assessed by the 
investigator.
For subjects with SFS or RBS ≥ 2.1 at the end-of-induction, loss of response is defined as:
●
An increase in either the SFS or RBS of at least 1 point greater than the end-of-
induction value on two consecutive visits at least 14 days apart and associated 
with the presence of signs or symptoms of progression of UC disease as 
assessed by the investigator.
Confirmation of loss of response may be performed at either the next scheduled visit or at 
an Unscheduled Visit.  For subjects who meet criteria for loss of response during the 
maintenance period (Substudy 3), the Week 52/PD Visit should be conducted.
The duration of the study could be up to 77 weeks, including Screening Period (5 weeks), 
an 8-week Double-Blind Induction Period, an 8-week Open-Label Extended Treatment 
Period (for eligible subjects), a 52-week Maintenance Period, and a 30-day Follow-Up 
Period.
Note: Subjects who entered Substudy 3 from Study M14-234 Substudy 1 were only 
required to complete 44 weeks of maintenance therapy in Substudy 3.  At the time of this 
amendment, if a subject from Substudy 1 is in Substudy 3 and has not yet completed the 
Week 44 Visit, they will be re-consented to extend treatment to Week 52 after approval 
for the amendment has been obtained for each respective site.  Subjects entering 
Substudy 3 from Study M14-234 Substudy 2 or from Study M14-675 will be required to 
complete 52 weeks in Substudy 3 if they do not withdraw or have loss of response prior.

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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 M14-234 or 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 Substudy 2 due to enrollment limits, these 
subjects may be moved to Study M14-675 for induction treatment if enrollment limits on 
that study have not been fulfilled.
8-Week Induction Period – Substudy 1 and Substudy 2 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 for the respective substudy 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.
8-Week Extended Treatment Period – Substudy 2 Part 2
The period will begin after the Week 8 endoscopy in Substudy 2, Part 1 and will end at 
the Week 16 Visit.  Substudy 1 subjects will not be eligible for this portion of the study.
At Week 8, subjects in Substudy 2, 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 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 
Part 2.  If the subject is a clinical non-responder at Week 16 the subject will discontinue 

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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.
52-Week Maintenance Period – Substudy 3
Subjects in Substudies 1 and 2 or Study M14-675 who achieved clinical response per 
Adapted Mayo Score after completion of the 8-Week Induction Period or the Week 16 
Visit of the Extended Treatment Period, if applicable, will be enrolled in Substudy 3.  
Subjects who completed Study M14-675 will consent for Study M14-234 prior to entering 
Substudy 3.  This period will begin at the Baseline (Week 0) Visit (Week 8 or Week 16 of 
Substudy 1, Substudy 2, or Study M14-675) and will end at the Week 52 Visit.  Treatment 
in Substudy 3 will depend on the treatment received in Substudies 1 and 2 or 
Study M14-675, as described in Section 5.1.  During this period of the study, subjects will 
visit the study site at Weeks 4, 8, 12, 20, 28, 36, 44, and 52.  A ± 3-day window is 
permitted around scheduled study visits up to and including Week 12.  Following 
completion of the Week 12 visit, a ± 7-day window is permitted around scheduled study 
visits.  The final dose of study drug is taken the day prior to the Week 52 Visit.
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 
Substudy 1 due to enrollment limits, these subjects may also be rescreened into 
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 

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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 the 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).
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 844 subjects (382 in Substudy 1 and approximately 
462 in Substudy 2) 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 750 subjects from Substudies 1, 2 or Study M14-675 
who achieve response per Adapted Mayo score following induction with upadacitinib will 
be re-randomized into Substudy 3 (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.

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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 J) at the screening 
Visit.
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 

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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
○
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-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-TGN level of 230 – 450 pmol/8 × 108
RBC or higher on the current dosing regimen), injectable 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 

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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 IV at 0, 
2, and 6 weeks),
●
at least one 4-week induction regimen of adalimumab (one 160 mg 
subcutaneous (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 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.

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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.
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.
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

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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. 
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;

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●
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).
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, 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. 

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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.
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 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 subjects who are hepatitis B core antibody (HBc Ab) 

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positive (+) subjects (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 (GI) dysplasia, other than completely removed low-
grade dysplastic lesion in any biopsy performed during or before the Screening 
endoscopy.
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 normal (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).

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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.
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 

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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
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.

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The AbbVie TA MD identified in Section 6.1.5 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):
Substudies 1 and 2
All UC-related concomitant medications should be kept on the stable dose in Substudies 1 
and 2.  Dose may be decrease or terminated in the event of moderate-to-severe 
treatmentrelated toxicity (e.g., leukopenia or elevated liver enzymes) in the opinion of the 
investigator.
Substudy 3
At Baseline of Substudy 3 (Week 8 or Week 16 of Study M14-234 Substudy 1, 
Substudy 2, and Study M14-675), subjects who are taking corticosteroid therapy will have 
their corticosteroid therapy tapered according to a proposed tapering schedule specified in 
Section 5.3.1.1 in the Protocol.  Subjects taking corticosteroids who have worsening of 
disease per the investigator's judgment after the steroid taper has been initiated may have 
their corticosteroid dose increased per the investigator's discretion during the study.  Use 
of inhaled or topical dermatologic corticosteroids is not restricted.
All subjects receiving UC-related antibiotics may discontinue treatment starting at Week 0 
of Substudy 3 at the discretion of the investigator. 
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.

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Changes in all concomitant medications will be assessed at each study visit from Baseline 
(Week 0) through Week 8/PD Visits in Substudies 1 and 2 or Study M14-675; through 
Week 16/PD Visits in the extended treatment periods of Substudy 2 or Study M14-675; 
and through Week 52/PD Visits in Substudy 3.  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.

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5.2.3.3
Prohibited Therapy
The following are prohibited medications during the study:
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, unless administered as rescue 

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therapy due to worsening of UC in Substudy 3.  (Initiating rectal or systemic 
corticosteroids use is prohibited during the induction and maintenance 
treatment period.  Rectal or systemic corticosteroids may be used as rescue 
therapy at the investigator's discretion for subjects as rescue therapy in 
Substudy 3; 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, unless administered as rescue therapy 
due to worsening of UC in Substudy 3
●
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.

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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:
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.
5.2.3.4
Rescue Therapy
At or after Week 4 in Substudy 3, subjects who demonstrate loss of response and require 
medical treatment but have not met the criteria to enter Study M14-533 Cohort 1, may 

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receive rescue therapy.  Rescue therapy may be provided in the form of initiation or 
increased dosage, at the investigator's discretion, of allowed UC-related medications to 
treat new or worsening UC symptoms.  The allowed UC-related medications are locally 
acting, oral, or intravenous corticosteroids, aminosalicylates, MTX or UC-related 
antibiotics.
Anti-diarrheals for control of diarrhea are not considered rescue treatment.  Azathioprine 
(AZA), 6-mercaptopurine (6-MP), cyclosporine, tacrolimus, and thalidomide are 
prohibited medications during the study and cannot be used as rescue treatment.  
Changes in UC-related concomitant medications should be documented in the appropriate 
eCRF.  Rescue therapy should not be withheld even if subject does not meet the criteria 
for loss of response or before 4 weeks after entering Substudy 3 if in the opinion of the 
investigator, failure to prescribe them would compromise the subject's safety.  Subjects 
may also be discontinued at any time based on the investigator's medical assessment.  
For subjects receiving corticosteroids as a rescue treatment, the investigator is encouraged 
to initiate tapering based on the subject clinical response status.
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:
●
Postmenopausal, age > 55 years with no menses for 12 or more months without 
an alternative medical cause.

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●
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).
○
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 

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[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 childbearing 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.
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.

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5.3.1.1
Study Procedures
The study procedures outlined in the Study Activities in Appendix C through Appendix F
are discussed in detail in this section, with the exception of exploratory research and 
validation studies (discussed in Section 5.3.1.2), drug concentration measurements 
(discussed in Section 5.3.2), the collection of prior and concomitant medication 
information (discussed in Section 5.2.3), and the collection of AE information (discussed 
in Section 6.1.1.1).  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 
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.  For US subjects only:  at the end of the induction period (Week 8 or Week 16 of 
Substudy 1, Substudy 2, or Section M14-675), the subject will sign and date a study 
specific IEC/IRB approved Informed Consent Form before Substudy 3 procedures are 
performed; a separate informed consent will be required for each subject in order to 
participate in the 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 biologic 
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 
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 (Substudies 1 and 2 or Study M14-675), 
Week 16 and Premature Discontinuation Visit (Substudy 2 or Study M14-675), Week 52 
and Premature Discontinuation Visit (Substudy 3) 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, 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-based 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) assessment, a symptom-
based physical examination will be performed.  The assessment of EIMs must be 
completed at all study visits.  Please refer to Appendix C and Appendix E.

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Height and Weight
For Subjects ≥ 18 years of age, height (with shoes off) will be measured at the Screening 
Visit of Study M14-234 Substudy 2 or Study M14-675.  For subjects 16 or 17 years of 
age, where locally permitted, height (with shoes off) will be measured at the Screening 
Visit of Study M14-234 Substudy 2, Week 8, Week 16 and if continuing into Substudy 3 
at Week 0 and Week 52/PD.  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 
tomography [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 

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(posterior-anterior and lateral views) (or normal CT Scan of the chest for subjects in 
Japan) within 90 days of Screening, provided all source documentation is available at the 
site, as outlined below and provided nothing has changed in the subject's medical history 
to warrant a repeat test.  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 CXR will be performed at Week 52/PD for subjects with a positive response to TB risk 
questionnaire Part 1 or for subjects with newly positive PPD and/or QuantiFERON-TB 
Gold Plus test after baseline.
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 CXR 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.

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12-Lead Electrocardiogram (ECG)
For all subjects, a resting 12-lead ECG will be performed at Screening and 
Week 8/Premature Discontinuation Visit in Substudy 1 and 2 or Study M14-675; 
Week 16 of the Extended Treatment Period of Substudy 2 or Study M14-675, and at 
Week 52/Premature Discontinuation in Substudy 3.  The ECG at Week 8 in Substudy 1, 
Substudy 2, or Study M14-675; or ECG at Week 16 of the Extended Treatment Period of 
Substudy 2 or Study M14-675 will serve as the baseline ECG for Substudy 3.  A 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.

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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 
prior, 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 I) and tested for TB infection by QuantiFERON-TB Gold Plus test.  The site 
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 has 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 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 

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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 
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.  

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●
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 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. 

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●
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 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 IGRA (such as T-SPOT TB test) may be substituted for the 
QuantiFERON-TB Gold Plus. 
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 CXR 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 study drug.

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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.
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.
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;

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●
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 enrollment. 
●
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 
at least one year, without an alternate medical reason for amenorrhea and a FSH level 
> 40 IU/L).
In Substudy 1 and 2, women of childbearing potential will have a urine pregnancy test 
performed locally by designated study personnel at Baseline and all subsequent visits.  In 
Substudy 3, women of childbearing potential will have a urine pregnancy test performed 
locally by designated study personnel at all visits and monthly at home between scheduled 
study visits.  The results of the monthly at home tests will be communicated to the site by 
the subject and documented in the source documents. 
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 is identified at end of study 
visit, pregnancy must be reported to AbbVie as outlined in Section 6.1.6.

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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.  
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 4.
●
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 

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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.
Figure 4.
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 

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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).
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.

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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.
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 E.  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.

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Lymphocyte Subsets (TBNK)
Blood samples will be collected at Baseline, Week 8 and Premature Discontinuation in 
Substudy 1 or in Substudy 2 and at Week 16/Premature Discontinuation of the Extended 
Treatment Period of Substudy 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 Immunoglobulin 
M (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.

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Table 1.
Clinical Laboratory Tests (Continued)
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.
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 the investigator 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.

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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:
During Substudy 2 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.
During Substudy 3 drug may be dispensed if the following criteria are met:
1.
There is at least 1 post-Week 0 lab assessment
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

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AND
3.
No longer than 12 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 E.  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.
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.

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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 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. difficle treatment.
Outcomes and Questionnaires
The following outcomes and questionnaires will be completed at the time points indicated 
in Appendix C and Appendix E.  However, please ensure questionnaires are always 
completed prior to obtaining blood samples.  Refer to Appendix G for descriptions of 
Patient Reported Outcomes (PRO).
●
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
●
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 and not in 
Substudy 1)
●
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 

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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/video 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.
Corticosteroid Taper
At Baseline of Substudy 3 (Week 8 or Week 16), subjects who are taking corticosteroid 
therapy at Baseline of Substudy 1 or 2 or Study M14-675 will have their corticosteroid 
dose tapered according to the following proposed schedule or based on investigators' 
discretion:

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Table 2.
Corticosteroid Dose Taper
Dose
Rate
Oral Prednisone (or equivalent)
> 10 mg/day 
≤ 10 mg/day
5 mg/day/week
2.5 mg/day/week
Oral Budesonide
≤ 9 mg/day
3 mg/day/week
Oral budesonide-MMX
(e.g., Cortiment, eUceris)
Discontinue
Oral beclomethasone
Discontinue
If a subject should experience worsening of disease during the corticosteroid taper, the 
subject may have their corticosteroid dose increased, per the investigator's discretion 
during the study.  Subjects in whom the maximum steroid dose equivalent exceeds the 
dose used at Baseline will be considered non-responders and will be censored for efficacy 
assessments from that point forward through the end of the study.  These subjects will 
continue to be evaluated in the safety analysis set.
Subject Diary
Subjects will be dispensed an electronic diary (eDiary) at Screening in Study M14-234 or 
Study M14-675 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.

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Study Drug Dispensing/Administration
Study drug will be dispensed to subjects at the time points indicated in Appendix C and 
Appendix E.  No study medication will be dispensed at Week 52 in Substudy 3.
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 than when the visit is set to occur, the time of the last 2 doses 
will be documented in the eCRF and pharmacokinetic (PK) samples drawn at the visit.
Refer to Section 5.5 for additional information.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Study 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:
During Substudy 2 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.

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During Substudy 3 drug may be dispensed if the following criteria are met:
1.
There is at least 1 post-Week 0 lab assessment
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 12 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; 
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.

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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 E.
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 SFS, RBS, and PGA 
subscores of the Mayo score are described in Appendix H. 
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 E.  There will be a window of 7 days prior to the scheduled 
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 

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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 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 (Substudies 1 and 2), Week 16 (Substudy 2), and Week 44 in Substudy 3 (for 
subjects entering from Substudy 1), or Week 52/PD (Substudy 3) Endoscopy:  The 
Week 8 and Week 52/PD endoscopies may be either a full colonoscopy or a flexible 
sigmoidoscopy depending on the extent of the disease at Screening Endoscopy should be 
performed up to the segment where a clear demarcation of inflammation is observed.  For 
subjects that entered Substudy 2 Part 2, an endoscopy will be performed at 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 

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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.  For subjects that 
reach and complete the Week 52 endoscopy for Substudy 3 of Study M14-234, the local 
endoscopy reading will be utilized to determine the status of clinical remission for the 
purpose of treatment assignment in Study M14-533.  The central reader's assessment will 
be used for the Mayo scores used in all efficacy endpoint assessments.  For subjects who 
discontinue during the maintenance period (Substudy 3), an endoscopy will not be 
performed if the subject discontinues the study prior to the Week 28 Visit.
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 Substudy 2 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 an Endoscopy required at Substudy 3 Week 52 is not able to be scheduled at the study 
site in the required protocol window due to COVID-19, then this may be performed 
–2 weeks and +4 weeks from the planned visit and can be completed at a different 
hospital/facility.  The investigator should evaluate the benefits-risks for continuing the 
subject in the study before the division of window extension.
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 5.1.2.

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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 
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 –

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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 
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 E.  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: 

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1.
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.  
2.
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.
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).
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 Visit 
and complete the procedures outlined for the PD Visit in Appendix C through Appendix F
as soon as possible after the last dose of study drug and preferably prior to the 
administration of any new therapies.

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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.
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, collection of 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.

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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. 
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]

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●
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.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetics assay of upadacitinib and possibly other concomitant 
medications will be collected at the following times:
●
Substudy 1:  Week 2, Week 4, Week 6, and Week 8/PD
●
Substudy 2 Part 1:  Week 2, Week 6, and Week 8/PD 
●
Substudy 3:  Week 36 and Week 52/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. 

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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.
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.

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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
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 score = 0 and Geboes score < 2

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5.3.3.1
Primary Variables
The primary endpoint for Phase 2b Induction (Substudy 1) is the proportion of subjects 
who achieve clinical remission per Adapted Mayo score (defined as SFS ≤ 1, RBS of 0, 
and endoscopic subscore ≤ 1) at Week 8.  
The primary endpoint for Phase 3 Induction (Substudy 2) 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:  in 
Substudy 2, evidence of friability during endoscopy in subjects with otherwise "mild" 
endoscopic activity will confer an endoscopic subscore of 2.
The primary endpoint for Phase 3 maintenance (Substudy 3) is the proportion of subjects 
who achieve clinical remission per Adapted Mayo score (definition same as definition in 
Substudy 2) at Week 52.
5.3.3.2
Secondary Variables
Ranked secondary efficacy variables for Phase 2b induction (Substudy 1) are as follows:
1.
Proportion of subjects with endoscopic improvement (defined as an endoscopic 
subscore ≤ 1) at Week 8 
2.
Proportion of subjects achieving clinical remission per Full Mayo score (defined as 
a Full Mayo score ≤ 2 with no subscore > 1) at Week 8
3.
Proportion of subjects achieving clinical response per Adapted Mayo score 
(defined as 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) at Week 8
4.
Proportion of subjects achieving clinical response per Partial Mayo score (using the 
Mayo Scoring System for Assessment of Ulcerative Colitis Activity, excluding 
endoscopic subscore; clinical response defined as decrease from baseline in the 

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Partial Mayo score ≥ 2 points and ≥ 30% from baseline, PLUS a decrease in rectal 
bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1) at Week 2
5.
Change in Full Mayo score from Baseline to Week 8
6.
Proportion of subjects with endoscopic remission (defined as an endoscopic 
subscore of 0) at Week 8
7.
Proportion of subjects who achieved histologic improvement (defined as decrease 
from baseline in Geboes score) at Week 8 
Ranked secondary efficacy variables for Phase 3 induction (Substudy 2) 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
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

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Ranked secondary efficacy variables for Phase 3 Maintenance (Substudy 3) are as follows 
at Week 52 (for subjects who enrolled under the protocol with 44-week maintenance 
period, these will apply at Week 44, as applicable):
1.
Proportion of subjects with endoscopic improvement 
2.
Proportion of subjects who maintain clinical remission per Adapted Mayo score 
among subjects who achieved clinical remission per Adapted Mayo score in 
Study M14-234 (Substudy 1 or 2) or Study M14-675
3.
Propotion of subjects who achieved clinical remission at Week 52 per adapted 
Mayo score and were corticosteroid free for ≥ 90 days among subjects in clinical 
remission in the end of the induction treatment in Study M14-234 (Substudy 1 or 2) 
or Study M14-675.
4.
Proportion of subjects with endoscopic improvement among subjects with 
endoscopic improvement in Study M14-234 (Substudy 1 or 2) or Study M14-675
5.
Proportion of subjects with endoscopic remission
6.
Proportion of subjects maintain clinical response per Adapted Mayo score 
7.
Proportion of subjects with histologic-endoscopic mucosal improvement 
8.
Change from Baseline in IBDQ total score
9.
Proportion of subjects with mucosal healing
10.
Proportion of subjects who reported no bowel urgency
11.
Proportion of subjects who reported no abdominal pain
12.
Change from Baseline in FACIT-F score
5.3.3.3
Additional Variables
In Substudies 1 and 2, additional efficacy variables are as follows and will be evaluated.

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●
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 subjects achieving clinical response per Partial Adapted Mayo 
score over time
●
Proportion of subjects achieving clinical response per Partial Mayo score over 
time.
●
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.

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●
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 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 PGIC category over time. 
●
Proportion of subjects by PGIS category over time.
●
Change from Baseline in FACIT-F score over time.  
●
Change from Baseline in 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
In Substudy 3, additional efficacy variables are as follows and will be evaluated:
●
Proportion of subjects who discontinued corticosteroid use, remained 
corticosteroid free for ≥ 90 days immediately before Week 52 and achieved 
clinical remission per Adapted Mayo score in subjects taking steroids at 
Baseline (of induction)
●
Proportion of subjects achieving response in IBDQ Bowel Symptom domain at 
Week 52 (increase of IBDQ bowel symptom domain score ≥ 6) 

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●
Proportion of subjects achieving response in IBDQ fatigue item at Week 52 
(increase of IBDQ fatigue item score ≥ 1)
●
Proportion of subjects who are taking corticosteroids at Baseline (of induction) 
and are steroid-free over time.
●
Proportion of subjects who are taking corticosteroid at Baseline (of induction) 
and are steroid free at Week 52
●
Proportion of subjects who discontinued corticosteroid use and achieved 
clinical remission per Adapted Mayo score at Week 52 in subjects taking 
steroids at Baseline (of induction)
●
Proportion of subjects achieving clinical remission per Full Mayo Score 
(defined as a full Mayo score ≤ 2 with no sub-score > 1) at Week 52
●
Proportion of subjects who discontinued corticosteroid use and achieved 
clinical remission per Partial Mayo Score over time in subjects taking steroids 
at baseline (of induction)
●
Proportion of subjects who discontinued corticosteroid use of ≥ 90 days 
immediately before Week 52 and achieved clinical remission at Weeks 0 and 
Week 52 of Substudy 3, in subjects who were taking steroids at Baseline (of 
induction)
●
Proportion of subjects who discontinued corticosteroid use of ≥ 90 days 
immediately before Week 52 and achieved a SFS ≤ 1 (and not worse than 
Baseline of induction) and RBS = 1 at Weeks 36 and 44 and clinical remission 
at Week 52, in subjects who were taking steroids at baseline (of induction)
●
Proportion of subjects achieving clinical remission per Partial Mayo score over 
time.
●
Proportion of subjects with SFS of 0, RBS of 0 and endoscopic subscore of 0 at 
Week 52
●
Proportion of subjects with SFS of 0, RBS of 0 and endoscopic subscore of 
≤1 at Week 52
●
Proportion of subjects with SFS ≤ 1, RBS = 0 at Week 28 and clinical 
remission per adapted Mayo score at Week 52
●
Proportion of subjects with SFS ≤ 1, RBS = 0 at Week 28 and Week 52

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●
Proportion of subjects with SFS of 0, RBS of 0, and endoscopic subscore of 0 
over time.  
●
Proportion of subjects achieving clinical response per Partial Mayo score over 
time.
●
Proportion of subjects with SFS ≤ 1 over time. 
●
Proportion of subjects with RBS of 0 over time.
●
Proportion of subjects with fecal calprotectin below 150 mg/kg over time.
●
Change from Baseline in hs-CRP over time.
●
Change from Baseline in fecal calprotectin over time
●
Change from Baseline in corticosteroid dose over time.
●
Change from Baseline in Adapted Mayo score, Partial Adapted Mayo score, 
Full Mayo score, Partial Mayo score and Mayo subscores over time.
●
Change from Baseline in UCEIS score over time.
●
Proportion of subjects with histologic improvement at Week 52
●
Proportion of subjects with histologic remission at Week 52
●
Proportion of subjects with histologic remission (defined as Geboes score < 2) 
at Weeks 8, or Week 16, and Week 52.
●
Change from Baseline in histologic 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 score over time.

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●
Change from Baseline in WPAI scores over time.
●
Change from Baseline in SF-36 PCS, MCS components and domain scores 
over time.
●
Proportion of subjects by PGIC category over time.
●
Proportion of subjects by PGIS category over time.
●
Change from Baseline in UC-SQ score over time.
●
Health care resource utilization (all-cause and UC-related hospitalizations and 
surgeries) during the study.
●
Incidence rate of UC-related hospitalizations.
●
Incidence rate of UC-related surgeries.
In addition, change from Week 0 of Substudy 3 will be summarized for hs-CRP, fecal 
calprotectin, IBDQ total and domain score, EQ-5D-5L score, FACIT-F score, and other 
PRO endpoints, as applicable.
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
and Appendix E.  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. 

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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.
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.  Toxicity management criteria for events of serious 
infections, malignancy, cardiovascular events, gastrointestinal perforation, ECG 
abnormality, and select laboratory abnormalities are described in Section 6.1.7 Toxicity 
Management. 
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.

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●
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.
●
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 
mechnical 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 outlined in the Study Activities daily, 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. 

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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 
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 and 
Appendix E.
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 and Appendix E for details on how to handle 
study activities/procedures.

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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 
investigator 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.
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 

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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.
5.5.1
Treatments Administered
In Substudy 1, subjects were assigned to 1 of 5 groups and received 2 tablets of study 
drug QD as shown in Table 3.  In Substudy 2, all subjects will receive 1 tablet QD.  In 
Part 1 of Substudy 2, subjects will be assigned to 1 of 2 groups and will receive 1 tablet of 
upadacitinib 45 mg QD or matching placebo QD, while in Part 2 of Substudy 2, subjects 
will receive 1 tablet open-label upadacitinib 45 mg QD as shown in Table 3.
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 on the study for the duration of the COVID-19 
pandemic and will be removed once the pandemic is considered to be resolved.
For subjects from Study M14-234 Substudy 2 and Study M14-675:
●
Subjects from Study M14-234 Substudy 2 Part 1 and Study M14-675 Part 1 
who received upadacitinib 45 mg and achieved clinical response will be re-
randomized to 1 of 3 groups in Cohort 1 (upadacitinib 15 mg, 30 mg or 
placebo) and will receive 1 tablet of study drug QD.  Subjects from Study M14-
234 Substudy 2 Part 2 and Study M14-675 Part 2 who received placebo in Part 
1 and upadacitinib in Part 2 and achieved clinical response will be re-

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randomized to 1 of the 3 groups in Cohort 1 and will receive 1 tablet of study 
drug QD
●
Subjects from Study M14-234 Substudy 2 part 1 and Study M14-675 Part 1 
who received placebo and achieved clinical response will continue to receive 
placebo in Cohort 2.
●
Subject from Study M14-234 Substudy 2 Part 2 and Study M14-675 Part 2 who 
received upadacitinib in Part 1 and upadacitinib in Part 2 and achieved clinical 
response will be re-randomized to 1 of the 2 groups in Cohort 3 (15 mg or 30 
mg) and will receive 1 tablet of study drug QD.
In Substudy 3, all subjects will receive 1 tablet QD.  
For subjects from Study M14-234 Substudy 1:
●
Subjects who received upadacitinib 30 mg or 45 mg and achieved clinical 
response in Substudy 1 will be re-randomized to 1 of 3 groups in Cohort 1 
(upadacitinib 15 mg, 30 mg, or placebo) and will receive 1 tablet of study drug 
QD as shown in Table 3.
●
Subjects on upadacitinib 15 mg and achieved clinical response in Substudy 1 
will be re-randomized to one of 2 groups in Cohort 1 (upadacitinib 15 mg or 
placebo), as shown in Table 3.  Subjects on upadacitinib 7.5 mg or placebo and 
achieved clinical response in Substudy 1 will continue to receive the same 
treatment in Substudy 3 but will change from 2 tablets QD to 1 tablet QD.  
Placebo subjects will be in Cohort 2 and 7.5 mg subjects will be in Cohort 4.
For subjects from Study M14-234 Substudy 2 and Study M14-675:
●
Subjects from Study M14-234 Substudy 2 Part 1 and Study M14-675 Part 1 
who received upadacitinib 45 mg and achieved clinical response will be re-
randomized to 1 of 3 groups in Cohort 1 (upadacitinib 15 mg, 30 mg or 
placebo) and will receive 1 tablet of study drug QD.  Subjects from Study M14-
234 Substudy 2 Part 2 and Study M14-675 Part 2 who received placebo in Part 
1 and upadacitinib in Part 2 and achieved clinical response will be re-

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randomized to 1 of the 3 groups in Cohort 1 and will receive 1 tablet of study 
drug QD
●
Subjects from Study M14-234 Substudy 2 part 1 and Study M14-675 Part 1 
who received placebo and achieved clinical response will continue to receive 
placebo in Cohort 2.
●
Subject from Study M14-234 Substudy 2 Part 2 and Study M14-675 Part 2 who 
received upadacitinib in Part 1 and upadacitinib in Part 2 and achieved clinical 
response will be re-randomized to 1 of the 2 groups in Cohort 3 (15 mg or 30 
mg) and will receive 1 tablet of study drug QD.
Table 3.
Treatments Administered
Substudies
Treatment
Treatment Administered
Double-Blind Induction 
Doses – Phase 2b 
(Substudy 1):
Upadacitinib 7.5 mg 
Upadacitinib 15 mg
Upadacitinib 30 mg
Upadacitinib 45 mg
Placebo
Upadacitinib 7.5 mg QD + Placebo QD
Upadacitinib 15 mg QD + Placebo QD
Upadacitinib 30 mg QD + Placebo QD
Upadacitinib 30 mg QD + Upadacitinib 
15 mg QD
Matching Placebo (2 tablets) QD
Double-Blind Induction 
Doses – Phase 3 
(Substudy 2 – Part 1):
Upadacitinib 45 mg QD
Placebo
Upadacitinib 45 mg QD
Matching Placebo QD
Open-Label Induction 
Doses – Phase 3 
(Substudy 2 – Part 2):
Upadacitinib 45 mg  
Upadacitinib 45 mg QD
Double-Blind Maintenance 
Doses – Phase 3 
(Substudy 3 – Cohort 1)
Upadacitinib 15 mg
Upadacitinib 30 mg
Placebo
Upadacitinib 15 mg QD
Upadacitinib 30 mg QD
Matching Placebo QD
Double-Blind Maintenance 
Doses – Phase 3 
(Substudy 3 – Cohort 2)
Placebo
Matching Placebo QD
Double-Blind Maintenance 
Doses – Phase 3 
(Substudy 3 – Cohort 3)
Upadacitinib 15 mg
Upadacitinib 30 mg
Upadacitinib 15 mg QD
Upadacitinib 30 mg QD
Double-Blind Maintenance 
Doses – Phase 3 
(Substudy 3 – Cohort 4)
Upadacitinib 7.5 mg 
Upadacitinib 7.5 mg QD

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5.5.2
Identity of Investigational Product(s)
Investigational 
Product
Upadacitinib
Mode of 
Administration
Oral
Oral
Oral
Oral
Oral
Dosage Form
Film-coated 
tablet
Film-coated 
tablet
Film-coated 
tablet
Film-coated 
tablet
Film-coated 
tablet
Strength (mg)
7.5
15
30
45
Matching 
placebo
Manufacturer
AbbVie
AbbVie
AbbVie
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 

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destroyed on site according to local procedures or regulations or returned to the 
destruction depot.  Upon receipt of study drugs the site will acknowledge receipt within 
the IRT system.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be centrally randomized using a web -based IRT.
All subjects will be assigned a unique identification number by the IRT at the Screening
Visit.  In Substudy 1 (Phase 2b, 8-week induction), 250 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 1:1:1:1:1 ratio to receive one of five treatment groups at 
Baseline (Week 0) in a double-blind manner (upadacitinib 7.5 mg QD, 15 mg QD, 30 mg 
QD, 45 mg QD, or placebo QD).  Randomization will be stratified by previous biologic 
use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 or > 7).
In Substudy 2, 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 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). 
After completion of the respective induction treatment period (8-weeks or Extended 
Treatment Period Week 16), approximately 750 subjects in Substudies 1 and 2 who 
received either placebo or upadacitinib 7.5, 15, 30, or 45 mg QD in Substudy 1 and those 
who received either placebo or upadacitinib 45 mg QD in Substudy 2 or Study M14-675
and achieved response (defined as a decrease from baseline in the Adapted Mayo score 
≥2 points and ≥ 30% from baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1) 
where the Week 8 or Week 16 endoscopic subscore is determined based on local reader's 
assessment, will be eligible to enroll in Substudy 3 (Phase 3 52 week maintenance).

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Substudy 3 will include 4 cohorts.  Treatment assignment in Substudy 3 will depend on 
the treatment received in Substudies 1 and 2 or Study M14-675, as described in 
Section 5.1.2.  For subjects who are eligible to be re-randomized to 1 of the 3 treatment 
groups in Cohort 1, randomization will be stratified by prior treatment failure (bio-IR or 
non-bio-IR), clinical remission status at Week 0 of Substudy 3 (yes or no), dose received 
in Induction Phase (only applicable to subjects from Substudy 1) and corticosteroid use at 
Week 0 of Substudy 3 (yes or no).  For subject who are eligible to be re-randomized to 1 
of the 2 treatment groups in Cohort 3, randomization will be stratified by prior treatment
failure (bio-IR or non-bio-IR), clinical remission status at Week 0 of Substudy 3 (yes or 
no), and corticosteroid use at Week 0 (yes or no) of Substudy 3.
Subjects in Substudy 3 who meet the criteria for initial loss of response after at least 
2 weeks of follow-up and have a second confirmed loss of response on a consecutive visit 
(unscheduled or next scheduled visit) at least 14 days later will have the option to enroll 
into a separate AbbVie study (Study M14-533) and receive open-label upadacitinib 
therapy starting from 15 mg.  Loss of response is defined as a subject who presents with 
either:
●
an SFS and RBS score each at least 1 point greater than the end-of-induction 
value (Week 0 of Substudy 3 or the end of induction for either Study M14-234 
or Study M14-675) on 2 consecutive visits at least 14 days apart;
OR
For subjects who had an SFS or RBS ≥2.1 at the end of induction:
●
either an SFS or an RBS at least 1 point greater than the end-of-induction value 
(Week 0 of Substudy 3 or the end of induction for either Study M14-234 or 
Study M14-675) on two consecutive visits at least 14 days apart, associated 
with the presence of signs or symptoms of progression of UC disease as 
assessed by the investigator.

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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 5.5.  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 in Substudies 1 and 2 will be randomly assigned to receive one of the treatment 
groups at Baseline by the IRT system as described in Section 5.5.3. 
Substudy 1:
●
Upadacitinib 7.5 mg QD
●
Upadacitinib 15 mg QD
●
Upadacitinib 30 mg QD
●
Upadacitinib 45 mg QD
●
Placebo QD
Substudy 2 (Part 1):
●
Upadacitinib 45 mg QD
●
Placebo QD
Substudy 2 (Part 2) – Extended Treatment Period:
●
Upadacitinib 45 mg QD

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Substudy 3:
For subject from Study M14-234 Substudy 1
●
Subjects who received upadacitinib 30 mg or 45 mg and achieved clinical 
response in Substudy 1 will be re-randomized to one of 3 groups in Cohort 1 
(upadacitinib 15 mg, 30 mg, or placebo) and will receive 1 tablet of study drug 
QD as shown in Table 3.
●
Subjects on upadacitinib 15 mg and achieved clinical response in Substudy 1 
will be re-randomized to one of 2 groups in Cohort 1 (upadacitinib 15 mg or 
placebo), as shown in Table 3.
●
Subjects on upadacitinib 7.5 mg or placebo and achieved clinical response in 
Substudy 1 will continue to receive the same treatment in Substudy 3, but will 
change from 2 tablets QD to 1 tablet QD.  Placebo subjects will be in Cohort 2 
and 7.5 mg subjects will be in Cohort 4.
For subjects from Study M14-234 Substudy 2 and Study M14-675
●
Subjects from Study M14-234 Substudy 2 part 1 and Study M14-675 part 1 
who received upadacitinib 45 mg and achieved clinical response will be re-
randomized to one of 3 groups in Cohort 1 (upadacitinib 15 mg, 30 mg or 
placebo) and will receive 1 tablet of study drug QD.  Subjects from 
Study M14-234 Substudy 2 part 2 and Study M14-675 part 2 who received 
placebo in part 1 and upadacitinib in part 2 and achieved clinical response will 
be re-randomized to one of the 3 groups in Cohort 1 and will receive 1 tablet of 
study drug QD
●
Subjects from Study M14-234 Substudy 2 Part 1 and Study M14-675 part 1 
who received placebo and achieved clinical response will continue to receive 
placebo in Cohort 2.
●
Subject from Study M14-234 Substudy 2 part 2 and Study M14-675 part 2 who 
received upadacitinib in part 1 and upadacitinib in part 2 and achieved clinical 
response will be re-randomized to one of the 2 groups in Cohort 3 (15 mg or 30 
mg) and will receive 1 tablet of study drug QD

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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) of Substudy 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 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 

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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 (DMC)
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.
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.

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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 
returned to the destruction depot.  A copy of the destruction methodology should be 
maintained at the site's facility.

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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 2b/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 3 substudies.  Substudy 1 is a Phase 2b dose-ranging study designed 
to evaluate the efficacy and safety of repeated once daily oral administration of different 
dose levels of upadacitinib compared with placebo as induction therapy for 8 weeks.  
Substudy 2 is a Phase 3 dose-confirming study designed to evaluate the efficacy and 
safety of repeated once daily oral administration of upadacitinib 45 mg QD, identified 
from Substudy 1.  In Substudy 2, Part 1, upadacitinib 45 mg QD is compared with 
placebo as induction therapy for 8 weeks.  Substudy 2, 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.  Substudy 3 is a Phase 3 study designed to evaluate 
the efficacy and safety of oral administration of 2 dose levels of upadacitinib 30 mg QD 
and 15 mg QD compared with placebo as maintenance therapy for 44 or 52 weeks in 
subjects who achieved clinical response following induction with upadacitinib in 
Substudy 1, Substudy 2, or Study M14-675.  Each substudy will have an individual 
statistical analysis plan.  
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 Substudy 1 who do not 
achieve clinical response after completion of the 8-week induction treatment and subjects 
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will have the option to enroll into a separate Phase 3 multicenter long-term extension 
study (Study M14-533) Cohort 1 and receive oral upadacitinib therapy. 
Subjects who complete 52-week treatment in Substudy 3 will enter Cohort 2 in 
Study M14-533.
Data from Phase 2b and Phase 3 portions of the study will be analyzed separately 
(i.e., operational seamless) for the efficacy endpoints and will not be combined for 
statistical inference.  For clinical operational efficiency, AbbVie proposes to conduct this 
seamless Phase 2b/3 study.  The operational seamless design is proposed to allow for 
statistical simplicity where the Type I error controlled is well known. 
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 
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 
(Substudy 2), 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 upadacitinib 
45 mg QD will be provided for an additional 8 weeks.  In the maintenance phase 
(Substudy 3), subjects will have 2/3 chance to be randomized to receive upadacitinib 
15 mg or 30 mg QD therapy in Cohort 1, placebo responders (Cohort 2) will continue to 

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receive placebo, all patients in Cohort 3 and 4 will receive active drug treatment.  If 
patients have loss of response during the maintenance phase, subjects can be enrolled into 
the open label cohort in long term extension Study M14-533 and receive open label 
upadacitinib 15 mg QD and possibly with dose escalation to 30 mg QD.  Additionally, 
during the maintenance phase subjects can receive rescue therapy including locally acting, 
oral or intravenous corticosteroids, aminosalicylates, MTX or antibiotics.  
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 studies.  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.
5.6.4
Selection of Doses in the Study
AbbVie aims to study four doses of upadacitinib using the once-daily formulation in 
Substudy 1 (upadacitinib 7.5 mg QD, 15 mg QD, 30 mg QD and 45 mg QD), one 

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induction dose in Substudy 2 (upadacitinib 45 mg QD), and two doses in the Phase 3 
maintenance Substudy 3 (upadacitinib 15 mg QD and 30 mg QD).
Dose Selection Rationale for Substudy 1
The selection of the doses was informed by the exposure-response relationship 
characterized in Phase 2 studies in RA, the published results for the Phase 2b study of the 
JAK inhibitor tofacitinib in UC,22 and the safety margins relative to the highest doses 
evaluated in healthy subjects and in subjects with RA and to the preclinical toxicology no 
observable adverse effect level (NOAEL) exposures.
Exposure-response analysis of two Phase 2 studies in RA using the immediate-release 
formulations (doses from 3 mg BID to 18 mg BID and 24 mg QD) indicated that 6 mg 
BID dose approaches the plateau of efficacy in RA, and increasing the dose to 12 mg BID
appears to result in some incremental efficacy benefit, particularly in the more refractory 
subjects with inadequate response or intolerance to anti-TNF biologic therapy.  A 
bioavailability study has demonstrated that 15 mg QD and 30 mg QD regimens of the
once-daily formulation provide equivalent daily AUC and comparable Cmax, and Cmin to 
6 mg BID and 12 mg BID, respectively, of the immediate-release capsule formulation 
used in Phase 2 studies in RA.  
It is expected that a dose higher than the efficacious dose in RA may be needed to induce 
clinical remission in UC.  This is supported by the published data from tofacitinib 
Phase 2b study22 in UC and the dose selection for tofacitinib Phase 3 study.  The 45 mg 
dose of upadacitinib in Substudy 1 is expected to be comparable or better than the 15 mg 
BID dose of tofacitinib (a dose higher than the optimal dose in RA) which appeared to be 
already at the plateau, at least for remission.  The highest dose in Substudy 1 (45 mg QD) 
is predicted to provide exposures comparable to (or slightly above) the NOAEL exposures 
from the preclinical toxicology studies as well as the highest exposures that were 
previously evaluated and found to be safe and well tolerated in healthy volunteers in 
Phase 1 and in subjects with RA in Phase 2.

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The lowest dose in Substudy 1, 7.5 mg once-daily, is predicted to be sub-optimal based on 
the Phase 2 studies in RA, the likelihood that induction of remission in UC would require 
higher doses than the efficacious doses in RA, and based on the tofacitinib dose ranging 
study in UC, where 3 mg BID (a dose lower than the efficacious RA dose) was sub-
efficacious in UC.  Evaluating the 7.5 mg QD dose in Substudy 1 aims to ensure that the 
minimally efficacious dose is characterized. 
Dose Selection Rationale for Substudy 2
The results from the Substudy 1 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 sub-populations, 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 

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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 
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).
Dose selection Rationale for Substudy 3
Substudy 3 will evaluate upadacitinib 15 mg QD and 30 mg QD for maintenance of 
response, which is the same dosing regimen currently being evaluated in the upadacitinib 
Phase 3 CD program.  Using a upadacitinib lower maintenance dose than the induction 
dose is expected to provide a more favorable long-term safety profile compared to 
maintaining subjects on the dose used in induction. 

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Both the 15 and 30 mg ER QD doses have been proven to be efficacious in the UC 
induction study.  Furthermore, the proposed maintenance doses of 15 mg QD and 30 mg 
QD using the ER formulation provide equivalent daily area under the plasma 
concentration-time curve (AUC) and comparable maximum plasma concentration (Cmax) 
and trough (plasma) concentration measured at the end of a dosing interval (Ctrough) to the 
IR formulation of upadacitinib 6 mg BID and 12 mg BID used in CD Phase 2 
Study M13-740.  The upadacitinib 6 mg BID and 12 mg BID doses in the Phase 2 study 
showed statistically significantly better endoscopic response at Week 12/16 compared to 
placebo.  Following induction with upadacitinib 45 mg QD, doses of upadacitinib 15 mg 
QD and 30 mg QD are therefore expected to maintain efficacy while providing better 
long-term safety than higher doses.
The efficacy and safety data from the extension phase of the ongoing Phase 2 
Study M13-740 also support the selection of upadacitinib 15 mg QD and 30 mg QD as the 
maintenance regimen.  In the 36-week extension period, dose-dependent clinical and 
endoscopic improvements were observed at Week 52.  Among subjects who received 
upadacitinib 6 mg BID (exposures equivalent to 15 mg ER QD) and 12 mg BID 
(exposures equivalent to 30 mg ER QD) and achieved clinical response at Week 16, 43% 
and 52% of subjects achieved modified clinical remission at Week 52, and 21% and 24% 
of subjects achieved endoscopic remission at Week 52, respectively.  The safety profile 
observed during the extension phase was consistent with that reported during the 
induction phase, and no new safety signal was identified with the longer term upadacitinib 
treatment.  These results support the selection of the equivalent doses of 15 and 30 mg ER 
QD formulation as the maintenance doses in the Phase 3 program. 
The upadacitinib 15 mg QD and 30 mg QD doses are being evaluated in the Phase 3 RA 
clinical program.  The RA program is currently evaluating > 4600 subjects, of which 
approximately 3700 are expected to receive upadacitinib.  Periodic blinded analyses of 
cumulative safety data and parallel Data Monitoring Committee evaluation of unblinded 
safety data have not shown any unexpected adverse event.

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6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.  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 
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), 

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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 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.

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Table 4.
Serious Adverse Events
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).
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.

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6.1.1.3
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study (see detailed 
toxicity management in Section 6.1.7):
●
Serious infections, 
●
opportunistic infections, 
●
herpes zoster, 
●
Active TB;
●
Malignancy (all types);
●
Adjudicated gastrointestinal perforations;
●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE]);
●
Anemia;
●
Neutropenia;
●
Lymphopenia;
●
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 (CTCAE26) 
version 4.03, 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. 

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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:
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.

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●
Heart failure;
●
Cerebral vascular accident and transient ischemic attack.
In case of a reported AE of herpes zoster, or a non-cardiac, non-CNS embolic or 
thrombotic event, the respective Supplemental AE eCRF should be completed.
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of 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

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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.
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, stillbirth or congenital anomaly is considered a serious adverse event and must 
be reported to AbbVie within 24 hours of the site becoming aware of the event.

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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 
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 

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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.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change 
considered clinically significant and with reasonable possibility of relationship to study 
drug.
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 5, 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 5, the repeat testing must occur as soon as 
possible.

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Table 5.
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 5.
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 5.
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.  
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 is responsible for 
monitoring safety data and alerting AbbVie to possible safety concerns related to the 
conduct of the study.  The DMC will review safety data of the first 60 enrolled subjects in 
Substudy 1 of AbbVie Study M14-234 through 8 weeks of treatment to determine if there 
are any significant safety concerns that would warrant any study action as outlined in the 
DMC charter.  Thereafter, 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. 

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For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 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 

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in subjects with moderately to severely active UC in order to identify one induction dose 
of upadacitinib for further evaluation in Substudy 2 (Phase 3 induction).
The objective of the statistical analyses of Substudy 2 (Phase 3 induction) 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.
The objective of the statistical analyses of Substudy 3 (Phase 3 maintenance) is to 
evaluate the efficacy and safety of upadacitinib compared to placebo in subjects with 
moderately to severely active UC who had a clinical response (per Adapted Mayo score) 
following induction with upadacitinib.
A database lock and unblinded analysis will be conducted for the purpose of regulatory 
submission after the first 450 subjects in Substudy 3 Cohort 1 who were upadacitinib 
45 mg QD induction responders have completed the maintenance study (i.e., completed 
Week 52 or prematurely discontinued prior to Week 52). This is the only and final 
analysis for the 52-week efficacy analyses. AbbVie study team will be unblinded to the 
treatment assignment, study sites and subjects will remain blinded until all subjects 
complete the maintenance study. If there are additional subjects in any cohort who have 
not completed the maintenance study at the time of database lock, they will be kept on the 
same blinded treatment until study completion. Once all subjects have completed the 
maintenance study, the data collected from these subjects will be used to update the safety 
analysis only.
Complete, specific details of the statistical analyses will be described and fully 
documented in the Statistical Analysis Plan (SAP) of each substudy.  The SAP will be 
finalized prior to the corresponding database lock for each substudy.

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8.1.1
Datasets for Analysis 
8.1.1.1
Intent-to-Treat Analysis Sets
The intent-to-treat (ITT) analysis set for Substudy 1 includes all randomized subjects who 
received at least 1 dose of study drug from Substudy 1 (denoted as ITT1A) at the time of 
dose-selection analysis.  The ITT analysis set that includes all ITT1A subjects, plus all the 
additional subjects who were randomized to upadacitinib 30 mg and 45 mg groups during 
the dose-selection period is denoted as ITT1B. 
The ITT analysis set for Substudy 2 includes all randomized subjects who received at 
least one dose of double-blinded study drug from Substudy 2 (denoted as ITT2A).  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 ITT2B.
For Substudy 3, the following ITT analysis sets are defined:  
●
ITT3:  All subjects who received at least 1 dose of study drug in the 
Substudy 3.
●
ITT3_A:  The subset of ITT3 who were the first 450 upadacitinib 45 mg QD 
8-week induction responders and who were enrolled under the protocol for 
52-week maintenance treatment period in Cohort 1. The ITT3_A is the primary 
analysis population in Cohort 1 for efficacy endpoints.
●
ITT3_B:  The subset of ITT3 in Cohort 3 who were upadacitinib 45 mg QD 
16-week induction responders.
●
ITT3_C:  The subset of ITT3 who were enrolled under the original protocol, 
Amendment 1 or 2 for 44-week maintenance treatment period.
●
ITT3_D: The subset of ITT3 who were upadacitinib 45 mg QD 8-week 
induction responders and who were enrolled under the protocol for 52-week 
maintenance treatment period in Cohort 1.  
●
ITT3_E:  The subset of ITT3 who were placebo, upadacitinib 7.5 mg QD, 
15 mg QD or 30 mg QD 8-week induction responders and who were enrolled 
under the protocol for 52-week maintenance treatment period.

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Primary analysis and secondary analyses of Substudy 3 will be performed for ITT3_A, 
ITT3_B, ITT3_C and ITT3_E. 
For the ITT analysis sets, subjects are assigned to a treatment group based on the 
randomization or re-randomization schedule, regardless of the treatment actually received.  
The efficacy analysis in each substudy will be based on the corresponding ITT analysis 
set.
8.1.1.2
Safety Analysis Set
The safety analysis set in each substudy consists of all subjects who received at least 
one dose of study medication in each portion 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 Substudy 1 to 3 will be 
carried out using the corresponding safety analysis set.  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/re-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, as well as for all subjects combined, in each 
substudy.
8.1.3
Definition of Missing Data Imputation
Missing data will be imputed using one or more of the following methods:
Non-Responder Imputation (NRI):  In NRI analyses, subjects who prematurely 
discontinue the study prior to efficacy assessment at Week 8 of Substudy 1 or Substudy 2 
Part 1, Week 16 of Substudy 2 Part 2, and Week 44 or Week 52 of Substudy 3 will be 
considered non-responders with respect to the efficacy endpoint.

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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 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). At each visit, subjects will be characterized as 
responders or non-responders based on MI imputed values if missing due to COVID-19; 
otherwise, subjects will be considered as non-responders for missing due to other reasons 
in the NRI-C approach.
For continuous endpoints, missing data will be handled using Mixed-Effect Model Repeat 
Measurement (MMRM). 
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 (not taken at Baseline) or who 
have dosages of these medications increased to greater than the dose taken at Baseline
during Substudy 1 or Study 2, or UC-related rescue medications are used during 
Substudy 3 will be considered a failure for categorical efficacy endpoints, and for non-
categorical assessments will have the last values carried forward from that time point 

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through the end of the substudy for Substudy 1 and will be handled by MMRM for 
Substudy 2 and Substudy 3.
8.1.4
Demographics and Baseline Characteristics
Baseline demographics and characteristics will be summarized for ITT analysis sets in 
each substudy.
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 sets in each substudy.  No statistical test will be 
performed.
8.1.4.4
Concomitant Medications
Concomitant drugs will be summarized for the ITT analysis sets in each substudy.  
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 

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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.
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 
substudy.  Number of subjects of Substudy 1 and 2 or Study M14-675 that enter 
Substudy 3 will also be summarized by treatment group.  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 substudy 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 

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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 rate at significance level alpha = 0.05 (2-sided) within each substudy (Substudies 2 
and 3).  The details of the testing procedure will be specified and documented in the SAP.
8.1.6.1
Primary Efficacy Variables
The primary endpoint for Phase 2b Induction (Substudy 1) is the proportion of subjects 
who achieve clinical remission per Adapted Mayo score (defined as SFS ≤ 1, RBS of 0, 
and endoscopic subscore ≤ 1) at Week 8.
The primary endpoint for Phase 3 induction (Substudy 2) 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. 
The primary endpoint for Phase 3 maintenance (Substudy 3) is the proportion of subjects 
who achieve clinical remission per Adapted Mayo score at Week 52 (for subjects who 
enrolled under the protocol with 44-week maintenance period, these will apply at 
Week 44, as applicable).
8.1.6.1.1
Analysis of Primary Endpoint
Substudy 1
The comparisons between an upadacitinib treatment group and placebo on the primary 
efficacy endpoint will be performed using Multiple Comparison Procedure – Modeling 

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(MCP-Mod) approach in the ITT1A analysis set.  Subjects with missing primary endpoint 
data at Week 8 will be classified as "not achieved" (NRI method) for the primary 
endpoint.
The dose-response relationships among the four upadacitinib treatment groups and 
placebo group will be characterized for the primary endpoint at Week 8 using the MCP-
Mod approach.  The following models will be considered:  log-linear, Emax, exponential, 
logistic and sigEmax.  The MCPMod approach for trial analysis stage consists of two main 
steps:  MCP and Mod step.  The MCP step focuses on establishing evidence for a drug 
effect across the doses, i.e., detecting a statistically significant dose response signal for the 
clinical endpoint and patient population investigated in the study.  This step will typically 
be performed using an efficient test for trend, adjusting for the fact that multiple candidate 
dose response models are being considered.  If a statistically significant dose response 
signal has been established at significance level of 0.05 using two-sided test, one proceeds 
with determining a reference set of significant dose response models by discarding the 
non-significant models from the initial candidate set.  The response function will be the 
log odds (logit) of the proportion of subjects with endoscopic/clinical remission.  The 
fitted curve will be shown graphically with confidence intervals for each dose.  Estimates 
of the treatment differences in the response function and associated 95% confidences for 
each active dose against placebo will be calculated from the model.  These results will be 
back-transformed to give point estimates of the difference in proportions and associated 
95% confidence intervals.  The pairwise comparison between the treatment groups will be 
performed using the Cochran-Mantel-Haenszel (CMH) test and will be stratified by 
previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤7 
and > 7).
Primary analysis of Substudy 1 will be repeated using ITT1B population.  
Substudy 2
The primary analysis will compare the subjects in upadacitinib treatment group and 
placebo group in the ITT2A analysis set.  The difference between the treatment groups in 

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the primary efficacy endpoint will be assessed using the 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 Non-responder imputation incorporating multiple imputation to 
handle COVID-19 (NRI-C) method will be used for primary analysis.
Primary efficacy endpoint will be summarized descriptively for the ITT2B population.
Subgroup (characterized by the varying inclusion and exclusion criteria) analysis for the 
primary endpoint, clinical remission per Adapted Mayo score, will be conducted.
Substudy 3
The primary analysis will compare the subjects in upadacitinib treatment groups and 
placebo group in the ITT3_A analysis set.  The difference between the treatment groups in 
the primary efficacy endpoint will be assessed using the CMH test and will be stratified 
by previous bio-IR status (yes or no), clinical remission status at Week 0 (yes or no), and 
cortecorsteroid use at Week 0 (yes or no).  NRI-C will be used for the primary analysis.
The efficacy analyses, as applicable, will also be performed for the subset of the ITT 
population who only completed to Week 44 per protocol.
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 
for stratification variables.  NRI-C for missing data will be used for categorical 
secondary endpoints.  
The primary analysis and ranked secondary analysis in each substudy will be repeated in 
the ITT analysis sets as defined in Section 8.1.1, as appropriate.

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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 status (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)
For Substudy 3, the primary endpoint will also be analysed from 
●
Baseline aminosalicylate use (yes, no)
In addition, the following key secondary endpoints will be analyzed in bio-IR and non-
bio-IR subgroup.
Induction Phase 
●
Endoscopic remission at Week 8
●
Endoscopic improvement at Week 8
●
Clinical response per adapted Mayo score at Week 8

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Maintenance Phase 
●
Endoscopic improvement at Week 52
●
Proportion of subjects who maintain clinical remission per Adapted Mayo score 
at Week 52 among subjects who achieved clinical remission per Adapted Mayo 
score in Study M14-234 (Substudy 1 or 2) or Study M14-675
●
Propotion of subjects who achieved clinical remission at Week 52 per adapted 
Mayo score and were corticosteroid free for ≥90 days among subjects in 
clinical remission in the end of the induction treatment in Study M14-234 
(Substudy 1 or 2) or Study M14-675.
●
Proportion of subjects with endoscopic improvement at Week 52 among 
subjects with endoscopic improvement in Study M14-234 (Substudy 1 or 2) or 
Study M14-675
●
Maintain Clinical response per adapted Mayo score at Week 52
●
Endoscopic remission at Week 52
●
Mucosal healing at Week 52
8.1.8
Safety Analysis
8.1.8.1
General Considerations
Safety analysis in Substudies 1 to 3 will be carried out using the corresponding safety 
analysis set.  For the safety analysis of the entire study (Substudy 1, Substudy 2, and 
Substudy 3), all treated subjects will be included.  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 AEs are defined as events that begin or worsen either on or after the 
first dose of the study medication and within 30 days after the last dose of the study 
medication.  AEs will be summarized for each substudy and through the entire study.  An 
overview of treatment-emergent AEs, including AEs of special interest such as adverse 
events leading to death and adverse events leading to early termination (see details in the 
SAP), AEs by Medical Dictionary for Regulatory Activities (MedDRA) preferred term 

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and system organ class, AEs by maximum relationship to study drug, and AEs by 
maximum severity will be summarized by number and percentage.
Changes in laboratory data will be described using statistical characteristics and 
comparison between treatment groups will be performed using a one-way Analysis of 
Variance (ANOVA).  In addition, shift tables and listings will be provided for abnormal 
values, whereby the normal range of the analyzing laboratory will be used.  Vital signs 
will be analyzed similarly.
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 
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 

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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.
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.

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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 in continuous laboratory and vital sign parameters will be 
summarized by treatment group.  Treatment group differences between each of the 
upadacitinib dosing groups and the placebo group 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.
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.

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Population PK analyses will be performed using the actual sampling time relative to 
dosing.  PK models will be built using a non-linear mixed-effects modeling approach with 
NONMEM software (Version 7, or a higher version).  The structure of the starting PK 
model will be based on the PK analysis of data from previous studies.  The CL/F and V/F 
of upadacitinib will be the PK parameters of major interest in the analyses.  If necessary, 
other parameters, including the parameters describing absorption characteristics, may be 
fixed if useful in the analysis.
The evaluation criteria described below will be used to examine the performance of 
different models.
1.
The objective function of the best model is significantly smaller than the alternative 
model(s).
2.
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept and 
a slope of one) than the alternative model(s).
3.
Visual inspection of model fits, standard errors of model parameters and change in 
inter-subject and intra-subject error.
Once an appropriate base PK model (including inter- and intra-subject error structure) is 
developed, empirical Bayesian estimates of individual model parameters will be 
calculated by the posterior conditional estimation technique using non-linear mixed-
effects modeling.  The relationship between these conditional estimates CL/F and V/F 
values with only potentially physiologically relevant or clinically meaningful covariates 
(such as subject age, sex, body weight, concomitant medications, laboratory markers of 
hepatic of renal function, etc.) will be explored using stepwise forward selection method, 
or another suitable regression/smoothing method at a significance level of 0.05.  After 
identification of all relevant covariates, a stepwise backward elimination of covariates 
from the full model will be employed to evaluate the significance (at P < 0.005, 

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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 Substudy 1 (Phase 2b portion of the study), a total of 250 subjects will be equally 
allocated to four treatment groups and the placebo group, representing a randomization 
ratio of 1:1:1:1:1.  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 a 
clinical remission rate of 12% in the placebo arm and a maximum of 30% in at least one
of the upadacitinib QD treatment arms at Week 8, a sample size of 50 subjects per 
treatment group is sufficient to test for the presence of a dose response signal, to select the 
best dose response model for the observed data out of a pre-specified set of candidate 
models, and to estimate target doses of interest (e.g., the minimum effective dose, MED) 
via modeling using the MCP-Mod approach.  This approach provides an average power of 
68% to detect a dose effect at 5% level of significance (two-sided) with the log linear, 

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Emax, exponential, logistic and sigEmax models pre-specified as likely candidates to 
characterize the dose-response for upadacitinib for the primary endpoint of clinical 
remission per Adapted Mayo score. 
For Substudy 2 (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.
For Substudy 3, the sample size is based on the expected proportion of subjects who 
achieve clinical remission per Adapted Mayo score at Week 52.  Assuming clinical 
remission rate of 12% in the placebo arm and 40% in one of the upadacitinib QD 
treatment arms at Week 52, a sample size of 150 subjects in placebo and 150 subjects in 
each of the upadacitinib 15 mg QD and 30 mg QD treatment groups will have 
> 95% power to detect the 28% treatment difference in the primary endpoint between an 
upadacitinib dose and placebo using two-sided Fisher's exact test at a 0.025 significant 
level with multiplicity adjustment.  Under the assumption that average response rate in 
upadacitinib doses at the end of Substudies 1 and 2 is 50%, a total of approximately 
450 subjects will be re-randomized according to the following:  subjects will be allocated 
to upadacitinib 15 mg QD or 30 mg QD treatment groups or placebo in a randomization 
ratio of 1:1:1 if they achieved a response from upadacitinib 45 mg QD in Substudy 1 and 
the upadacitinib 45 mg QD in Substudy 2 or Study M14-675.  The assumption of an 
average response rate of 50% in upadacitinib doses after induction is based on the 
Phase 2b results.

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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 (Substudy 1 or 2 or Study M14-675), subjects 
who will continue into 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, 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, SF-36, PGIC, PGIS, FACIT-F, WPAI, EQ-5D-5L, UC-SQ [UC-
SQ only in select sites during Substudy 1]) 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 
Study to Evaluate the Safety and Efficacy of Upadacitinib 
(ABT-494) for Induction and Maintenance Therapy in Subjects 
with Moderately to Severely Active Ulcerative Colitis
Protocol Date:
10 May 2021
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)

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15.0
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2.
Molodecky NA, Soon IS, Rabi DM, et al.  Increasing incidence and prevalence of 
the inflammatory bowel diseases with time, based on systematic review.  
Gastroenterology.  2012;142(1):46-54.e42; quiz e30.
3.
Sandler RS, Everhart JE, Donowitz M, et al.  The burden of selected digestive 
diseases in the United States.  Gastroenterology.  2002;122(5):1500-11.
4.
Dignass A, Eliakim R, Magro F, et al.  Second European evidence-based consensus 
on the diagnosis and management of ulcerative colitis part 1:  definitions and 
diagnosis.  J Crohn's Colitis.  2012;6(10):965-90.
5.
Rutter M, Saunders B, Wilkinson K, et al.  Severity of inflammation is a risk factor 
for colorectal neoplasia in ulcerative colitis.  Gastroenterology.  
2004;126(2):451-9.
6.
Truelove SC, Witts LJ.  Cortisone and corticotrophin in ulcerative colitis.  
Br Med J.  1959;1(5119):387-94.
7.
Kornbluth A, Sachar DB; Practice Parameters Committee of the American College 
of Gastroenterology.  Ulcerative colitis practice guidelines in adults:  American 
College of Gastroenterology, Practice Parameters Committee.  Am J Gastroenterol.  
2010;105(3):501-23; quiz 524.
8.
Beaugerie L, Brousse N, Bouvier AM, et al.  Lymphoproliferative disorders in 
patients receiving thiopurines for inflammatory bowel disease:  a prospective 
observational cohort study.  Lancet.  2009;374(9701):1617-25.
9.
Aratari A, Papi C, Clemente V, et al.  Colectomy rate in acute severe ulcerative 
colitis in the infliximab era.  Dig Liver Dis.  2008;40(10):821-6.
10.
Turner D, Walsh CM, Steinhart AH, et al.  Response to corticosteroids in severe 
ulcerative colitis:  a systematic review of the literature and a meta-regression.  Clin 
Gastroenterol Hepatol.  2007;5(1):103-10.

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11.
Sandborn WJ.  State-of-the-art:  immunosuppression and biologic therapy.  Dig 
Dis.  2010;28(3):536-42.
12.
Rutgeerts P, Sandborn W, Feagan B, et al.  Infliximab for induction and 
maintenance therapy for ulcerative colitis.  N Engl J Med.  2005;353(23):2462-76.
13.
Sandborn WJ, van Assche G, Reinisch W, et al.  Adalimumab induces and 
maintains clinical remission in patients with moderate-to-severe ulcerative colitis.  
Gastroenterology.  2012;142(2):257-65.
14.
Feagan B, Greenberg G, Wild G, et al.  Treatment of ulcerative colitis with a 
humanized antibody to the alpha4beta7 integrin.  N Engl J Med.  
2005;352(24):2499-507.
15.
Sandborn W, Feagan B, Marano C, et al.  Subcutaneous golimumab induces 
clinical response and remission in patients with moderate-to-severe ulcerative 
colitis.  Gastroenterology.  2014;146(1):85-95; quiz e14-5.
16.
O'Shea JJ, Holland SM, Staudt LM.  JAKs and STATs in immunity, 
immunodeficiency, and cancer.  N Engl J Med.  2013;368(2):161-70.
17.
Sandborn WJ, Chinyu S, Sands BE, et al.  Tofacitinib as induction and 
maintenance therapy for ulcerative colitis.  New Engl J Med.  
2017;376(18):1723-36.
18.
Vermeire S, Schreiber S, Petryka R, et al.  Clinical remission in patients with 
moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study):  
results from a phase 2, double-blind, randomized, placebo-controlled trial.  Lancet.  
2017;389(10066):266-75.
19.
Fleischmann R, Kremer J, Cush J, et al; ORAL Solo Investigators.  Placebo-
controlled trial of tofacitinib monotherapy in rheumatoid arthritis.  N Engl J Med.  
2012;367(6):495-507.
20.
AbbVie.  ABT-494 Investigator's Brochure Edition 6.1.  12 May 2016.
21.
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 EQ5D5L 
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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+
Study activity that can be performed at a local centre when an onsite study visit is not possible due to COVID-19, if allowed by local regulations. This is applicable for the 
following Substudy 2 visits:  Week 2, 4, 6, 8, 10, 12, 14, 16, PD and 30 day Follow up.  All screening and Baseline visit procedures must be completed at the study site.
=
Study activity that cannot be performed by phone/virtually or at a local centre when an onsite study visit is not possible due to COVID-19.  All screening and Baseline visit 
procedures must be completed at the study site.
a.
The Screening period will be a maximum of 35 days. The Baseline Visit can be scheduled and a subject randomized at any point during this period once all eligibility criteria 
have been met.
b.
The Baseline Visit date will serve as the reference for all subsequent visits.  A ± 3-day window is permitted around all study visits.  Where COVID-19 affects an onsite 
scheduled Visit a ± 7-day window is permitted for all visits after the Baseline visit.
c.
At Week 8 of Substudy 2 Part 1, if a subject is a non-responder, Week 8 will be used as the Baseline Visit for Substudy 2 Part 2.
d.
Visits for dispensing new study drug in case of temperature excursion, loss or damage or visits to retest a lab are not considered an Unscheduled Visit.  Unscheduled visits 
according to this table are for purposes when the subject is coming in for a visit for evaluation and assessment.
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 or Study M14-533, this will not be required until the subject completes the UC program.  The home pregnancy test results will be reported at this visit 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 Substudy 2 Part 1, physical examinations performed at Screening, Baseline, Week 8/PD and Substudy 2 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, height (with shoes off) will be measured at 
Substudy 2 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 Substudy 2 Part 2 endoscopy will be performed at Week 16, for this a flexible sigmoidoscopy is recommended at 
Week 16, however, the use of flexible sigmoidoscopy or colonoscopy will be based on the investigator's discretion per local practice.  

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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 
Substudy 2 Part 2, if applicable or for Substudy 3.  For subjects who enter Substudy 2 Part 2, Week 16 ECG will serve as the baseline ECG for Substudy 3.
l.
Chest x-ray includes posterior-anterior 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 test.  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. 
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 Substudy 1 and Substudy 2 Part 1urine pregnancy test will be performed at 
the site at Baseline and at Weeks 2, 4, 6, 8 and PD Visits and in Substudy 2 Part 2 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 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 in Substudy 1 or 2 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.

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t.
Stool sample will be collected at each time point indicated.  For the visit that endoscopy will be conducted, stool sample should be collected prior to 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 procedures.  The Week 8 PK sample will be the Baseline PK sample for 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 Substudy 2 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.  PGIC will not be collected at 
Baseline; UC-SQ = UC Symptoms Questionnaire. PGIS = Patient Global Impression of Severity will only be collected from subjects in Substudy 2 (Parts 1 and 2) and 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 
healthcare 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.
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 due to 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 Substudy 2 Part 2, investigational product will be dispensed at this visit.  This is not applicable for Substudy 1 subjects or subjects in Substudy 2 Part 1 
who are responders and moving into Substudy 3 at Week 8.

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Appendix E.
Study Activities (Substudy 3)
Activity
Baseline 
of 
Substudy 
3a
Week 
4
Week 
8
Week 
12
Week 
20
Week 
28
Week 
36
Week 
44
Week 52/ 
Premature 
Discontinuation 
Visit
Unscheduled 
Visitb
30-Day 
Follow-
Upc
Informed Consent
Xd
Prior and Concomitant 
Medications#
X
X
X
X
X
X
X
X
X
X
Physical Exame,+
X
X
X
X
X
X
X
X
X
X
Vital Signsf,#
Xf
X
X
X
X
X
X
X
Xf
X
Schedule Endoscopy#
X
Endoscopy/Biopsyg,+
X
X
12-Lead ECG+
X
X
Chest X-Rayh,+
X
Chemistry and 
Hematologyi,+
X
X
X
X
X
X
X
X
X
X
Lipid Testi,+
X
X
X
Urinalysisj,+
X
X
X
X
X
X
X
X
X
X
Pregnancy Testk,+
X
X
X
X
X
X
X
X
X
X

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Activity
Baseline 
of 
Substudy 
3a
Week 
4
Week 
8
Week 
12
Week 
20
Week 
28
Week 
36
Week 
44
Week 52/ 
Premature 
Discontinuation 
Visit
Unscheduled 
Visitb
30-Day 
Follow-
Upc
Review and document 
continued compliance with 
pregnancy avoidance 
recommendations in the 
source records with 
females of childbearing 
potential#
X
X
X
X
X
X
X
X
X
X
X
hs-CRP=
X
X
X
X
X
X
X
X
X
X
Latent TB Risk Assessment 
Form#
X
X
PPD Skin Test or 
QuantiFERON-TB Gold 
Plus Testl,+
Xm
Provide Stool Kitn,#
X
X
X
X
Stool Sample (Fecal 
calprotectin)n,=
X
X
X
X
X
Upadacitinib Concentration 
(PK assay)o,=
X
X
X
HBV DNA PCR (For 
Japan subjects only)p,+
X
X
X
X
X
X
X

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Activity
Baseline 
of 
Substudy 
3a
Week 
4
Week 
8
Week 
12
Week 
20
Week 
28
Week 
36
Week 
44
Week 52/ 
Premature 
Discontinuation 
Visit
Unscheduled 
Visitb
30-Day 
Follow-
Upc
Reminder:  Samples for 
exploratory research and 
validation studies (Optional 
– see Appendix F)=
X
X
X
X
X
Mayo Score#
X
X
Partial Mayo Score#
X
X
X
X
X
X
X
X
X
X
Patient Questionnaires:  
IBDQ, SF-36, EQ-5D-5L, 
WPAI, PGIC, FACIT-F, 
UC-SQ, PGISq,#
X
X
Monitor Adverse Eventsr,#
X
X
X
X
X
X
X
X
X
X
X
Daily Diary Reviews,#
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensing/ 
Administrationt,u,#
X
X
X
X
X
X
X
X
EQ-5D-5L = European Quality of Life 5 Dimensions 5 Levels; FACIT F = Functional Assessment of Chronic Illness Therapy – Fatigue; IBDQ = Inflammatory Bowel Disease 
Questionnaire; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; SF-36 = Short-Form 36; UC-SQ = Ulcerative Colitis Symptoms 
Questionnaire; WPAI = Work Productivity and Activity Impairment
#
Study activity that can be performed by phone/virtually when an onsite study visit is not possible due to COVID-19, if allowed by local regulations.  This is applicable for all 
Substudy 3 visits.
+
Study activity that can be performed at a local centre when an onsite study visit is not possible due to COVID-19, if allowed by local regulations.  This is applicable for all 
Substudy 3 visits.
=
Study activity that cannot be performed by phone/virtually or at a local centre when an onsite study visit is not possible due to COVID-19. This is applicable for all 
Substudy 3 visits.

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a.
Subjects in Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 who achieved response after completion of the 8-week induction treatment will be enrolled into 
Substudy 3.  The Baseline Visit for Substudy 3 corresponds to the Week 8 Visit in Substudy 1 or Substudy 2 and serves as the reference for all subsequent visits.  Subjects in 
Substudy 2 Part 2 or Study M14-675 Part 2 who achieved response after completion of the Extended Treatment Period (Week 16) will be enrolled into Substudy 3 and the 
Baseline Visit for Substudy 3 corresponds to the Week 16 Visit and serves as the reference for all subsequent visits except for PK.  The PK sample collected at Week 8 of 
induction will be the baseline for Substudy 3.  A ± 3-day window is permitted around scheduled study visits up to and included Week 12.  Following completion of the 
Week 12 visit, a ±7-day window is permitted around scheduled study visits.  Where COVID-19 affects an onsite scheduled Visit a ± 7-day window is permitted for all visits 
after the Baseline visit.
b.
Visits for dispensing new study drug in case of temperature excursion, loss or damage are not considered an Unscheduled Visit.
c.
Subjects who do not continue into the Study M14-533 will be contacted 30 days following study drug discontinuation for an assessment of any new or ongoing AEs. The 
home pregnancy test results will be reported at this visit 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 only for 30 days or later and is dependent upon what 
phase of the study the subject was at when discontinuing study drug.  A + 3 day window is allowed up to Week 12 (30 - 33 days after last dose of study drug) and a + 7 day 
window is allowed after Week 12 (30 to 37 days after last dose of study drug).
d.
For US subjects only:  subjects will be enrolled into Substudy 3 only after written informed consent is obtained.  For subjects entering Study M14-234, Substudy 3 from 
Study M14-675, a new consent will be required.
e.
Physical examinations performed at Baseline, Week 52 and 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. 
f.
For Subjects 16 or 17 years of age at the time of screening, height (with shoes off) will be measured at Substudy 3 Week 0 and Week 52.
g.
Subjects will undergo an endoscopy (colonoscopy or flexible sigmoidoscopy, depending on the extent of disease at Screening in Substudy 1 or 2) with biopsy for histologic 
assessment at Baseline and at Week 52/PD.  The local endoscopy reading will be utilized to determine the status of clinical remission for the purpose of treatment assignment 
in Study M14-533.  During all endoscopies, up to 3 sets of biopsies will be taken (see Section 5.3.1.1 for details about biopsy sampling).  For subjects who discontinue during 
the maintenance period (Substudy 3), an endoscopy will not be performed if the subject discontinues the study prior to the Week 28 Visit.  Where COVID-19 affects the 
Week 52 endoscopy a –2 week and +4 week window is permitted.
h.
A CXR will be performed at Week 52/PD for subjects with a positive response to TB risk questionnaire, Part 1 questions or for subjects with newly positive PPD and/or 
QuantiFERON-TB Gold Plus test after baseline.
i.
It is requested to have a minimum of 8 hours fasting before chemistry or lipid test.
j.
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.

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k.
Urine pregnancy test will be performed at Baseline and all subsequent visits for all women of child bearing potential.  In home urine pregnancy test will be completed at 
Weeks 16, 24, 32, 40, 48 and the 30-Day Follow-up Visit.  The results of the monthly at home tests will be communicated to the site.  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.
l.
QuantiFERON-TB Gold Plus test is to be carried out annually from the date of the original test carried out at screening.  For subjects with premature discontinuation if the 
Premature Discontinuation visit is ≤ 12 weeks from the prior TB test and no new known exposure of risk identified then the TB test does not need to be repeated.  If the 
Premature Discontinuation visit is > 12 weeks from the prior TB test, the TB test will be repeated at the Premature Discontinuation visit.
m.
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 
subsequent annual TB follow-up tests are not required.
n.
Stool sample will be collected at each time point indicated.  For the visit where endoscopy will be conducted, stool sample should be collected prior to 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.
o.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.  The PK sample drawn at Week 8 of Induction will be the 
baseline PK sample for Substudy 3.
p.
For Japan subjects only:  Subjects with positive HBs Ab and/or positive HBc Ab results at Screening in Substudy 1 or 2 should have HBV-DNA PCR test performed at 
Weeks 4, 12, 20, 28, 36, 44, and 52/PD in Substudy 3; 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.  HBV testing is done every 12 weeks where required.
q.
IBDQ, SF-36, EQ-5D-5L, WPAI, FACIT F, PGIC, UC-SQ will only be collected from subjects at select sites for subjects entering from Substudy 1, for subjects entering 
from Substudy 2 or Study M14-675, this will be completed at all sites; PGIS = Patient Global Impression of Severity will only be collected from subjects at select sites.
r.
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 HCRU form of AE collection in EDC.
s.
Subjects will continue to use the diary dispensed to them at Screening of Study M14-234 Substudy 1 or Substudy 2 or Study M14-675.  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. 
t.
Study drug will be dispensed for once daily oral intake and should be taken at the same time each day, when possible.
u.
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-Week 0 lab test AND (2) The investigator feels it is safe to continue based on prior labs and a phone/video call AND (3) No longer 
than 12 weeks have passed from the last safety lab tests.

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Appendix F.
Study Activities (Substudy 3) Optional Samples for Exploratory Research and Validation Studies
Activity
Baseline of 
Substudy 3 
Week 
4
Week 
8
Week 
12
Week 
20
Week 
28
Week 
36
Week 44
Week 52/ 
Premature 
Discontinuation 
Visit
Unscheduled 
Visit
30-Day 
Follow-
Up
Epigenetic samplesa
X
X
X
X
X
Transcriptomic and 
epigenetic samplesa,b
X
X
X
X
X
Plasma samples for 
proteomic and targeted 
protein investigationsa,b
X
X
X
X
X
Serum samples for 
proteomic and targeted 
protein investigationsa,b
X
X
X
X
X
Tissue biopsy samples 
for transcriptomic, 
epigenetic, and 
exploratory research
X
a.
Based on the value of the different technologies, samples may also be used to assess other biomarker signatures, including but not limited to metabolomics, lipidomics, and 
other approaches.
b.
Preferably collected while subjects are in a fasting condition.
Note:
Collections to be performed only if subject provides written consent to collect the exploratory research/validation studies samples; if the consent is not signed, 
no samples can be collected.

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Appendix G.
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 

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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
PGIC – Patient Global Impression of Change
The PGIC is a self-administered instrument that assesses change in the overall symptoms 
due to UC.  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

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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 
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.

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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 H.
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 -234 Substudy 2 and Substudy 3, evidence of friability during endoscopy in subjects with 
otherwise "mild" endoscopic activity will confer an endoscopic subscore of 2.

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Appendix I.
Screening/annual TB Risk Assessment Questionnaire 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 J.
Tanner Staging Example
Boys
Girls

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Appendix K.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.2  Synopsis
Subsection Objective(s):
Fifth paragraph previously read:
At the time of this amendment, Substudy 2 has closed enrollment.
Has been changed to read:
At the time of this amendment, Substudy 2 has closed enrollment and all subjects have 
completed the induction phase.
Section 1.2  Synopsis
Subsection Objective(s):
Last paragraph
Add:  new last sentence
At the time of this amendment, Substudy 3 has closed enrollment.
Section 1.2  Synopsis
Subsection Criteria for Evaluation:
Heading "Efficacy:"
Subheading "Substudy 3 Ranked Secondary Endpoints:"
Delete:  item 13 and 14
13. Incidence rate of UC-related hospitalizations through Week 52
14. Incidence rate of UC-related surgeries through Week 52

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Section 1.2  Synopsis
Subsection Statistical Methods:
Heading "Efficacy:"
Fifth paragraph, last sentence previously read:
The 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.
Has been changed to read:
Non-responder imputation incorporating multiple imputation to handle COVID-19 (NRI-
C) method will be used for primary analysis.
Section 1.2  Synopsis
Subsection Statistical Methods:
Heading "Efficacy:"
Eighth and ninth paragraph previously read:
Primary analysis and ranked secondary analyses of Substudy 3 will be performed for the following 
populations:
!
The ITT analysis set includes all re-randomized subjects in Cohort 1 who received at least one dose 
in Substudy 3 and achieved clinical response from upadacitinib 45 mg QD in Substudies 1 and/or 
2, and upadacitinib 45 mg QD in Study M14-675, denoted as ITT31.  Subjects in the ITT31 
analysis set who enrolled under protocol with 52-week maintenance period is defined as ITT31A.  
The primary analysis for Substudy 3 will be based on ITT31A population.  Subjects in the ITT31 
analysis set who enrolled under protocol with 44-week maintenance period is defined as ITT31B.
!
The ITT analysis set includes all re-randomized subjects in Cohort 1 who received at least one dose 
in Substudy 3 and achieved clinical response from upadacitinib doses groups of 15 mg QD or 30
mg QD in Substudy 1, are denoted as ITT31C and ITT31D for subjects re-randomized for 44-week 
or 52-week maintenance, respectively.
!
The ITT analysis set includes all subjects in Cohort 2 who received at least one dose in Substudy 3, 
denoted as ITT32.
!
The ITT analysis set includes all re-randomized subjects in Cohort 3 who received at least one dose 
in Substudy 3, denoted as ITT33.
!
The ITT analysis set includes all subjects in Cohort 4 who received at least one dose in Substudy 3, 
denoted as ITT34.

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The comparison between treatment groups in ITT31A population for the primary efficacy endpoint will be 
performed using the CMH test and will be stratified by previous bio-IR status (yes or no), clinical remission 
status at Week 0 (yes or no), and corticosteroid use at Week 0 (yes or no).  The NRI method will be used for 
the primary analysis.
Has been changed to read:
For Substudy 3, the following ITT analysis sets are defined:  
!
ITT3:  All subjects who received at least 1 dose of study drug in the Substudy 3.
!
ITT3_A:  The subset of ITT3 who were the first 450 upadacitinib 45 mg QD 8-week induction 
responders and who were enrolled under the protocol for 52-week maintenance treatment period in 
Cohort 1. The ITT3_A is the primary analysis population in Cohort 1 for efficacy endpoints.
!
ITT3_B:  The subset of ITT3 in Cohort 3 who were upadacitinib 45 mg QD 16-week induction
responders.
!
ITT3_C:  The subset of ITT3 who were enrolled under the original protocol, Amendment 1 or 2 for 
44-week maintenance treatment period.
!
ITT3_D: The subset of ITT3 who were upadacitinib 45 mg QD 8-week induction responders and 
who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1.
!
ITT3_E:  The subset of ITT3 who were placebo, upadacitinib 7.5 mg QD, 15 mg QD or 30 mg QD 
8-week induction responders and who were enrolled under the protocol for 52-week maintenance
treatment period.
Primary analysis and secondary analyses of Substudy 3 will be performed for ITT3_A, ITT3_B, ITT3_C 
and ITT3_E. 
The comparison between treatment groups in ITT3_A population for the primary efficacy endpoint will be 
performed using the CMH test and will be stratified by previous bio-IR status (yes or no), clinical remission 
status at Week 0 (yes or no), and corticosteroid use at Week 0 (yes or no).  Non-responder imputation 
incorporating multiple imputation to handle COVID-19 (NRI-C) method will be used for the primary 
analysis.
Section 1.3  List of Abbreviations and Definition of Terms
Add:
NRI-C
Non-Responder Imputation while incorporating Multiple Imputation (MI) to 
handle missing data due to COVID-19

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Section 4.0  Study Objective
Seventh paragraph
Add:  new last sentence
At the time of this amendment, Substudy 2 has closed and all subjects have completed the 
induction phase.
Section 4.0  Study Objective
Ninth paragraph previously read:
The secondary objective of Substudy 3 is to evaluate the efficacy of upadacitinib 30 mg 
QD and 15 mg QD compared to placebo in the ranked secondary endpoints at Week 52 of 
achieving endoscopic improvement, maintaining clinical remission, corticosteroid free 
remission, maintaining endoscopic improvement, endoscopic remission, maintaining 
clinical response, mucosal healing, no bowel urgency, no abdominal pain, histologic-
endoscopic mucosal improvement, change in IBDQ total score and FACIT-F score, UC-
related hospitalizations, UC-related surgeries.
Has been changed to read:
The secondary objective of Substudy 3 is to evaluate the efficacy of upadacitinib 30 mg 
QD and 15 mg QD compared to placebo in the ranked secondary endpoints at Week 52 of 
achieving endoscopic improvement, maintaining clinical remission, corticosteroid free 
remission, maintaining endoscopic improvement, endoscopic remission, maintaining 
clinical response, mucosal healing, no bowel urgency, no abdominal pain, histologic-
endoscopic mucosal improvement, change in IBDQ total score and FACIT-F score.
Section 4.0  Study Objective
Last paragraph
Add:  new last sentence
At the time of this amendment, Substudy 3 has closed enrollment.

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Section 5.3.3.2  Secondary Variables
Last paragraph
Delete:  item 13 and 14
13. Incidence rate of UC-related hospitalizations
14. Incidence rate of UC-related surgeries
Section 5.3.3.3  Additional Variables
Second paragraph previously read:
In Substudy 3, additional efficacy variables are as follows and will be evaluated at 
Week 52:
Has been changed to read:
In Substudy 3, additional efficacy variables are as follows and will be evaluated:
Section 5.3.3.3  Additional Variables
Second paragraph, eighth bullet previously read:
Proportion of subjects who discontinued corticosteroid use and achieved clinical 
remission over time in subjects taking steroids at baseline (of induction)
Has been changed to read:
Proportion of subjects who discontinued corticosteroid use and achieved clinical 
remission per Partial Mayo Score over time in subjects taking steroids at baseline (of 
induction)
Section 5.3.3.3  Additional Variables
Second paragraph, tenth and eleventh bullet previously read:
●
Proportion of subjects who discontinued corticosteroid use of ≥ 90 days 
immediately before Week 52 and achieved a SFS ≤ 1 ( and not worse than 

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The ITT analysis set includes all subjects in Cohort 4 who received at least one dose in 
Substudy 3, denoted as ITT34.
Has been changed to read:
For Substudy 3, the following ITT analysis sets are defined:  
●
ITT3:  All subjects who received at least 1 dose of study drug in the 
Substudy 3.
●
ITT3_A:  The subset of ITT3 who were the first 450 upadacitinib 45 mg QD 
8-week induction responders and who were enrolled under the protocol for 
52-week maintenance treatment period in Cohort 1. The ITT3_A is the primary 
analysis population in Cohort 1 for efficacy endpoints.
●
ITT3_B:  The subset of ITT3 in Cohort 3 who were upadacitinib 45 mg QD 
16-week induction responders.
●
ITT3_C:  The subset of ITT3 who were enrolled under the original protocol, 
Amendment 1 or 2 for 44-week maintenance treatment period.
●
ITT3_D: The subset of ITT3 who were upadacitinib 45 mg QD 8-week 
induction responders and who were enrolled under the protocol for 52-week 
maintenance treatment period in Cohort 1.  
●
ITT3_E:  The subset of ITT3 who were placebo, upadacitinib 7.5 mg QD, 
15 mg QD or 30 mg QD 8-week induction responders and who were enrolled 
under the protocol for 52-week maintenance treatment period.
Primary analysis and secondary analyses of Substudy 3 will be performed for ITT3_A, 
ITT3_B, ITT3_C and ITT3_E. 
Section 8.1.3 Definition of Missing Data Imputation
Fourth paragraph previously read:
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.

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Has been changed to read:
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 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). At each visit, subjects will be characterized as 
responders or non-responders based on MI imputed values if missing due to COVID-19; 
otherwise, subjects will be considered as non-responders for missing due to other reasons 
in the NRI-C approach.
For continuous endpoints, missing data will be handled using Mixed-Effect Model Repeat 
Measurement (MMRM). 
Section 8.1.3  Definition of Missing Data Imputation
Add:  new last paragraph
Subjects in whom UC-related corticosteroids are initiated (not taken at Baseline) or who 
have dosages of these medications increased to greater than the dose taken at Baseline
during Substudy 1 or Study 2, or UC-related rescue medications are used during 
Substudy 3 will be considered a failure for categorical efficacy endpoints, and for non-
categorical assessments will have the last values carried forward from that time point 
through the end of the substudy for Substudy 1 and will be handled by MMRM for 
Substudy 2 and Substudy 3.
Section 8.1.6.1  Primary Efficacy Variables
Last paragraph previously read:
The primary endpoint for Phase 3 maintenance (Substudy 3) is the proportion of subjects 
who achieve clinical remission per Adapted Mayo score at Week 44 or 52.

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Has been changed to read:
The primary endpoint for Phase 3 maintenance (Substudy 3) is the proportion of subjects 
who achieve clinical remission per Adapted Mayo score at Week 52 (for subjects who 
enrolled under the protocol with 44-week maintenance period, these will apply at 
Week 44, as applicable).
Section 8.1.6.1.1  Analysis of Primary Endpoint
Subsection Substudy 2
First paragraph, last sentence previously read:
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.
Has been changed to read:
The Non-responder imputation incorporating multiple imputation to handle COVID-19
(NRI-C) method will be used for primary analysis.
Section 8.1.6.1.1  Analysis of Primary Endpoint
Subsection Substudy 3
First paragraph previously read:
The primary analysis will compare the subjects in upadacitinib treatment groups and 
placebo group in the ITT31A analysis set.  The difference between the treatment groups in 
the primary efficacy endpoint will be assessed using the CMH test and will be stratified 
by previous bio-IR status (yes or no), clinical remission status at Week 0 (yes or no), and 
cortecorsteroid use at Week 0 (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 the primary analysis.

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Has been changed to read:
The primary analysis will compare the subjects in upadacitinib treatment groups and 
placebo group in the ITT3_A analysis set.  The difference between the treatment groups in 
the primary efficacy endpoint will be assessed using the CMH test and will be stratified 
by previous bio-IR status (yes or no), clinical remission status at Week 0 (yes or no), and 
cortecorsteroid use at Week 0 (yes or no).  NRI-C will be used for the primary analysis.
Section 8.1.6.2  Secondary Efficacy Variables
Second paragraph, last sentence previously read:
NRI for missing data will be used for categorical secondary endpoints.  
Has been changed to read:
NRI-C for missing data will be used for categorical secondary endpoints.  
Section 8.1.7  Other Statistical Analyses of Efficacy
Add:  new second paragraph and bullet list
For Substudy 3, the primary endpoint will also be analysed from 
●
Baseline aminosalicylate use (yes, no)
Section 8.1.8.3  Analysis of Laboratory and Vital Sign Data
First paragraph, first sentence previously read:
Changes from Baseline to minimum value, maximum value and final values in continuous 
laboratory and vital sign parameters will be summarized by treatment group.
Has been changed to read:
Changes from Baseline in continuous laboratory and vital sign parameters will be 
summarized by treatment group.

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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