Conditions: Ulcerative Colitis (UC)
Keywords: Upadacitinib (ABT-494) Moderately to Severely Active UC RINVOQ
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1302
Healthy volunteers: no

Brief summary:
This study was comprised of three substudies. The objective of Substudy 1 was to characterize the dose-response, efficacy, and safety of upadacitinib compared to placebo in inducing clinical remission to identify the induction dose of upadacitinib for further evaluation in Substudy 2. The objective of Substudy 2 was to evaluate the efficacy and safety of upadacitinib compared to placebo in inducing clinical remission in participants. The objective of Substudy 3 was to evaluate the efficacy and safety of upadacitinib compared to placebo in achieving clinical remission in participants who had a response following induction with upadacitinib.

Detailed description:
Substudy 1 was a Phase 2b dose-ranging study designed to evaluate the efficacy and safety of different oral doses of upadacitinib compared to placebo as 8-week induction therapy in participants with moderately to severely active UC. Approximately 250 participants were planned to be randomized 1:1:1:1:1 to the placebo group and 4 upadacitinib doses (7.5, 15, 30, and 45 mg). Randomization was stratified by previous biologic therapy use (yes/no), Baseline corticosteroid use (yes/no), and Baseline Adapted Mayo score (≤ 7 or \> 7). The study duration included a Screening Period of up to 5 weeks and an 8-week double-blind (DB) Induction Period. After all randomized participants completed the 8-week induction, a dose-selection analysis of efficacy and safety (selected laboratory parameters) of upadacitinib versus placebo was performed. Based on this dose-selection analysis, one induction dose (upadacitinib 45 mg) was identified for further evaluation in two Phase 3 induction studies, M14-234 Substudy 2 and M14-675 (NCT03653026). During the analysis period, 132 additional participants were randomized into Groups 3 and 4 of Substudy 1 (upadacitinib 30 mg and 45 mg dose groups; approximately 66 participants per dose group). The objectives of enrolling these additional participants were to avoid interrupting the study activities during the analysis period and to support a sufficient number of participants with clinical response to be re-randomized into the maintenance portion in Substudy 3. Substudy 1 main participants are defined as those first 250 randomized 250, and additional participants are defined as those who were randomized after the main participants.

Substudy 2 was a two-part Phase 3 dose-confirming study designed to evaluate the efficacy and safety of oral administration of upadacitinib 45 mg compared to placebo as induction therapy for up to 16 weeks in participants with moderately to severely active UC. Substudy 2 included a Screening Period of up to 5 weeks, Part 1, and Part 2. Part 1 was a randomized, DB, placebo-controlled 8-week induction period. Part 2 was an open-label, 8-week extended treatment period for clinical non-responders from Part 1 of Substudy 2. Part 1 was planned to enroll 462 subjects; actual enrollment was 474 subjects. Eligible participants were randomized in a 2:1 ratio to one of the two treatment groups (DB upadacitinib 45 mg or matching placebo) for 8 weeks. The randomization was stratified by bio-IR status (Biologic inadequate responders \[bio-IR\] vs Non-biologic-inadequate responders \[non-bio-IR\], corticosteroid use (yes or no), and Adapted Mayo score (≤ 7 or \> 7) at Baseline. Within bio-IR, the randomization was further stratified by number of prior biologic treatments (≤ 1 or \> 1). Within non-bio-IR, the randomization was further stratified by previous biologic use (yes or no). Part 2 was an open label, 8-week Extended Treatment Period for those who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1. All participants received upadacitinib 45 mg.

Substudy 3 was a Phase 3 maintenance study designed to evaluate the efficacy and safety of upadacitinib 15 and 30 mg once daily (QD) compared to placebo in achieving clinical remission per Adapted Mayo score in participants with moderately to severely active UC who achieved clinical response per Adapted Mayo score following induction therapy from Substudy 1, Substudy 2, or Study M14-675. A total of 1,046 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 entered Substudy 3, and 1,044 were treated with a blinded treatment assignment for up to 52 weeks. Substudy 3 included 4 cohorts. Cohort 1: 847 participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, and received upadacitinib 15, 30, or 45 mg QD. The treatment groups in Cohort 1 were Group 1: upadacitinib 15 mg QD; Group 2: upadacitinib 30 mg QD; and Group 3: placebo QD. Those who achieved clinical response and received upadacitinib 15 mg QD in Substudy 1 were re-randomized 1:1 to only receive upadacitinib 15 mg QD or placebo QD (treatment Group 1 or 3). Cohort 2: 104 participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3. Cohort 3: 75 participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 were re-randomized 1:1 and received blinded upadacitinib 30 mg QD or upadacitinib 15 mg QD in Substudy 3. Cohort 4: 20 participants who received double-blinded treatment of upadacitinib 7.5 mg QD for 8 weeks during Substudy 1 and achieved clinical response at Week 8 continued to receive blinded treatment of upadacitinib 7.5 mg QD in Substudy 3.

Arms:
arm 1: During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. arm 2: During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. arm 3: During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. arm 4: During the 8-week induction phase in Substudy 1, participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks. arm 5: During the 8-week induction phase in Substudy 1, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks. arm 6: During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks. arm 7: During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks. arm 8: Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were re-randomized and treated with a blinded treatment assignment (15 mg upadacitinib film-coated tablets once daily by mouth \[QD\], or 30 mg upadacitinib film-coated tablets QD, or placebo for upadacitinib film-coated tablets QD) for up to 52 weeks.

Interventions: intervention 1: Placebo intervention 2: Upadacitinib
Intervention descriptions: intervention 1: Film-coated tablet for oral administration intervention 2: Film-coated tablet for oral administration

Protocol document:
Prot_000.pdf: 
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


Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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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.


Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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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.


Upadacitinib
M14-234 Protocol Amendment 7
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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. 


Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
5
●
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.


Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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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).


Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
7
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).


Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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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.


Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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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.


Upadacitinib
M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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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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M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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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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M14-234 Protocol Amendment 7
EudraCT 2016-000641-31
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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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M14-234 Protocol Amendment 7
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.


Upadacitinib
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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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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39
●
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' 
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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 
in Substudy 3 who meet the criteria for loss of response after at least 4 weeks of follow up 


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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
Reference List
1.
Hanauer SB.  Update on the etiology, pathogenesis and diagnosis of ulcerative 
colitis.  Nat Clin Pract Gastroenterol Hepatol.  2004;1(1):26-31.
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

SAP_001.pdf: 
Upadacitinib (ABT-494)
M14-234 – Statistical Analysis Plan for Substudy 3
Version 4.0 – 20 May 2021
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Statistical Analysis Plan for Substudy 3
Study 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
Date:  20 May 2021
Version 4.0
NCT02819635


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................6
2.1
Objectives, and Hypotheses and Estimands...............................................6
2.2
Study Design Overview .............................................................................8
2.3
Treatment Assignment and Blinding .......................................................12
2.4
Sample Size Determination......................................................................13
3.0
Endpoints................................................................................13
3.1
Primary Endpoint.....................................................................................15
3.2
Secondary Endpoints ...............................................................................15
3.3
Additional Efficacy Endpoints.................................................................16
3.4
Safety Endpoints ......................................................................................19
4.0
Analysis Populations .............................................................19
5.0
Subject Disposition................................................................22
6.0
Study Drug Duration and Compliance................................23
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................23
7.1
Demographics and Baseline Characteristics............................................24
7.2
Medical History .......................................................................................25
7.3
Prior and Concomitant Medications ........................................................26
8.0
Efficacy Analyses...................................................................26
8.1
General Considerations............................................................................26
8.2
Handling of Potential Intercurrent Events ...............................................27
8.2.1
Premature Discontinuation of Study Drug...............................................27
8.2.2
UC-Related Rescue Medications .............................................................28
8.3
Handling of Missing Data........................................................................29
8.3.1
Categorical Endpoints..............................................................................30
8.3.2
Continuous Endpoints..............................................................................32
8.4
Primary Efficacy Endpoint and Analyses ................................................33
8.4.1
Primary Efficacy Endpoint ......................................................................33
8.4.2
Handling of Missing Data for the Primary Efficacy Endpoint ................34
8.4.3
Primary Efficacy Analysis .......................................................................34


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8.4.4
Additional Analyses of the Primary Efficacy Endpoint...........................34
8.5
Secondary Efficacy Analyses...................................................................35
8.5.1
Key Secondary Efficacy Analyses...........................................................35
8.5.2
Additional Analyses of the Secondary Efficacy Endpoints.....................35
8.6
Additional Efficacy Analyses ..................................................................35
8.7
Efficacy Subgroup Analyses....................................................................37
9.0
Safety Analyses ......................................................................38
9.1
General Considerations............................................................................38
9.2
Adverse Events ........................................................................................39
9.2.1
Treatment-Emergent Adverse Events ......................................................39
9.2.2
Adverse Event Overview .........................................................................40
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................41
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................42
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................42
9.2.6
Adverse Events of Special Interest ..........................................................42
9.3
Analysis of Laboratory Data....................................................................43
9.4
Analysis of Vital Signs ............................................................................45
10.0
Other Analyses.......................................................................46
11.0
Interim Analyses....................................................................46
11.1
Data Monitoring Committee....................................................................46
12.0
Overall Type-I Error Control ..............................................46
13.0
Version History......................................................................49
14.0
References...............................................................................51
List of Tables
Table 1.
Definition of ITT Populations..................................................................20
Table 2.
Definition of Safety Populations..............................................................22
Table 3.
SAP Version History Summary...............................................................49
Table B-1.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................54
Table C-1.
Criteria for Potentially Clinically Significant Vital Sign Values.............56


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Table D-1.
Random Seeds for NRI-C ........................................................................57
Table D-2.
Random Seeds for HMI ...........................................................................57
Table D-3.
Random Seeds for DBMI.........................................................................58
Table D-4.
Random Seeds for RTB-MI.....................................................................58
List of Figures
Figure 1.
Maintenance Study Schematic.................................................................11
Figure 2.
Graphical Multiple Testing Procedure for Primary and Ranked 
Secondary Efficacy Endpoints (ITT_A Population)................................48
List of Appendices
Appendix A.
Protocol Deviations..................................................................................53
Appendix B.
Definition of Adverse Events of Special Interest ....................................54
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............56
Appendix D.
Random Seeds..........................................................................................57
Appendix E.
Attributes of the Estimand for Primary and Ranked Secondary 
Endpoints .................................................................................................59


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Substudy 3 of 
upadacitinib Study 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.
Study M14-234 comprises 3 substudies:  a Phase 2b dose-ranging induction study 
(Substudy 1), a Phase 3 induction study (Substudy 2), and a Phase 3 maintenance study 
(Substudy 3).  Study M14-234 Substudy 3 examines the efficacy and safety of 
upadacitinib 30 mg once daily (QD) and 15 mg QD for maintenance therapy in subjects 
with moderate to severely active ulcerative colitis who achieved clinical response 
following induction therapy from Study M14-234 Substudy 1, Substudy 2, or 
Study M14-675 (Phase 3 induction study).  Throughout this SAP, "Induction Study" 
refers to one of the induction studies: Study M14-234 Substudy 1, Substudy 2, or 
Study M14-675, "Maintenance Study" is used interchangeably for Study M14-234 
Substudy 3, and "study" refers to Study M14-234.
The analyses of pharmacokinetic endpoints, pharmacodynamic biomarker endpoints and 
exploratory research and validation endpoints will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 13.0.


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2.0
Study Design and Objectives
2.1
Objectives, and Hypotheses and Estimands
The objective of the Maintenance Study is to evaluate efficacy and safety of upadacitinib 
15 mg QD and upadacitinib 30 mg QD compared to placebo in achieving clinical 
remission (per Adapted Mayo score) in subjects with moderately to severely active UC 
achieved clinical response per Adapted Mayo score following induction therapy from 
Study M14-234 Substudy 1, Substudy 2, or Study M14-675.
Primary Efficacy Objective
The primary efficacy objective of the Maintenance Study is to demonstrate efficacy based 
on a higher rate of clinical remission per Adapted Mayo score in the 52-week 
maintenance study treated with upadacitinib 15 mg QD or upadacitinib 30 mg QD when 
compared to placebo in subjects with moderately to severely active UC who achieved 
clinical response (per Adapted Mayo score) following induction therapy from the 
Induction Studies.  The primary efficacy objective will be assessed based on Intent-to-
Treat (ITT_A) population (See definition in Section 4.0).
Hypothesis corresponding to the primary efficacy objective and endpoint is:
●
The proportion of subjects achieving clinical remission per Adapted Mayo 
score treated with each upadacitinib dose group is greater than those treated 
with placebo at Week 52.
The estimand corresponding to the primary efficacy objective is defined as follows:
●
Difference in the percentage of subjects achieving clinical remission per 
Adapted Mayo score at Week 52 regardless of premature discontinuation of 
study drug and without use of UC-related rescue medications (See 
Section 8.2.2) in the upadacitinib 15 mg QD, upadacitinib 30 mg QD and 
placebo groups in the ITT_A population.


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Secondary Efficacy Objectives
The secondary efficacy objectives of the Maintenance Study are to demonstrate higher 
efficacy of treatment with upadacitinib 15 mg QD or upadacitinib 30 mg QD when 
compared to placebo with respect to the ranked secondary endpoints specified in 
Section 3.2; in subjects with moderately to severely active UC who achieved clinical 
response (per Adapted Mayo score) following induction therapy from the Induction 
Studies.  The secondary efficacy objectives will be assessed based on ITT_A population.
Hypotheses corresponding to the secondary efficacy objectives and endpoints are:
1.
For each of the ranked categorical secondary endpoints (Section 3.2), greater 
proportion of subjects with improvement for the endpoint is achieved with each 
upadacitinib dose group when compared to placebo;
2.
For each of the ranked continuous endpoints (Section 3.2), greater mean change 
from baseline for the endpoint is achieved with each upadacitinib dose group when 
compared to placebo.
The estimands corresponding to the secondary efficacy objectives are defined as follows: 
regardless of premature discontinuation of study drug and without use of UC-related 
rescue medications (See Section 8.2.2) in the upadacitinib 15 mg QD, upadacitinib 30 mg 
QD and placebo groups in the ITT_A population:
●
Difference in the percentage of subjects achieving endoscopic improvement at 
Week 52;
●
Difference in the percentage of subjects achieving clinical remission per 
Adapted Mayo score at Week 52 among subjects who achieved clinical 
remission at the end of the induction treatment in the Induction Study;
●
Difference in the percentage of subjects achieving clinical remission per 
Adapted Mayo score at Week 52 and corticosteroid free for ≥ 90 days 
immediately preceding Week 52 among subjects who achieved clinical 
remission at the end of the induction treatment in the Induction Study;


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●
Difference in the percentage of subjects achieving endoscopic improvement at 
Week 52 among subjects who achieved endoscopic improvement at the end of 
the induction treatment in the Induction Study;
●
Difference in the percentage of subjects achieving endoscopic remission at 
Week 52;
●
Difference in the percentage of subjects achieving clinical response per 
Adapted Mayo score at Week 52 among subjects who achieved clinical 
response at the end of the induction treatment in the Induction Study;
●
Difference in the percentage of subjects achieving histologic-endoscopic 
mucosal improvement at Week 52;
●
Difference in the mean change from Baseline in IBDQ total score at Week 52;
●
Difference in the percentage of subjects achieving mucosal healing at Week 52;
●
Difference in the percentage of subjects achieving no bowel urgency at 
Week 52;
●
Difference in the percentage of subjects achieving no abdominal pain at 
Week 52;
●
Difference in the mean change from Baseline in FACIT-F score at Week 52;
2.2
Study Design Overview
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of upadacitinib as maintenance therapy in subjects with 
moderately to severely active ulcerative colitis who had achieved a clinical response (per 
Adapted Mayo score) following induction treatment with upadacitinib.
Approximately 750 subjects who achieved clinical response after completion of induction 
treatment in the Induction Studies will be eligible to enter the Maintenance Study and 
treated with a blinded treatment assignment for up to 52 weeks.  The Baseline Visit 
(Week 0) of the Maintenance Study (thereafter referred to as Week 0) is completed on the 
same day as the final visit in the Induction Studies for subjects who are eligible. The 
maintenance treatment period is 44 weeks under the original Protocol, Protocol 
Amendment 1 and 2, and 52 weeks under Protocol Amendment 3 and after.


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The Maintenance Study consists of:
Cohort 1:  A total of approximately of 525 subjects will be enrolled in this cohort.
Approximately 500 subjects who achieved clinical response by Adapted Mayo score in 
the Induction Studies and received one of the following induction treatments will be 
enrolled in this cohort:
●
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 or 
Study M14-675 Part 1
●
Placebo QD in Study M14-234 Substudy 2 Part 1 or Study M14-675 Part 1, 
followed by upadacitinib 45 mg QD in the 8-week OL extended treatment 
period (Study M14-234 Substudy 2 Part 2 or Study M14-675 Part 2)
The above subjects will be re-randomized in a 1:1:1 ratio to one of the treatment groups in 
Cohort 1:
●
Group 1:  upadacitinib 15 mg QD
●
Group 2:  upadacitinib 30 mg QD
●
Group 3:  placebo QD
For subjects from Study M14-234 Substudy 2 or Study M14-675, the randomization will 
be stratified by Bio-IR status (Bio-IR or non-Bio-IR) at the Baseline of Study M14-234 
Substudy 2 or Study M14-675, clinical remission status at Week 0 (yes or no) and 
corticosteroid use at Week 0 (yes or no).  For subjects from Study M14-234 Substudy 1, 
the randomization will be stratified by previous biologic use (yes or no) at the Baseline of 
Study M14-234 Substudy 1 and dose received in Study M14-234 Substudy 1 (30 mg QD 
or 45 mg QD).
In addition, approximately 25 subjects who achieved clinical response and received 
double-blind induction treatment of upadacitinib 15 mg QD in Study M14-234 Substudy 1 
will be enrolled in this cohort.  These subjects will be re-randomized in a 1:1 ratio to 


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receive upadacitinib 15 mg QD or placebo QD (Treatment Group 1 or 3).  The 
randomization will be stratified by previous biologic use (yes or no) at the Baseline of 
Study M14-234 Substudy 1.
Cohort 2:  Approximately 60 subjects who received double-blind placebo QD induction 
treatment for 8 weeks in the Induction Studies and achieved clinical response by Adapted 
Mayo score will continue to receive blinded placebo QD in this cohort.
Cohort 3:  Approximately 150 subjects who received 8-week double-blind upadacitinib 
45 mg QD and 8-week open-label (OL) upadacitinib 45 mg QD in the OL extended 
treatment period (Study M14-234 Substudy 2 Part 2 or Study M14-675 Part 2) and 
achieved clinical response by Adapted Mayo score at Week 16 will be re-randomized in a 
1:1 ratio to receive blinded upadacitinib 30 mg QD or 15 mg QD in this cohort.  The 
randomization will be stratified by Bio-IR status (bio-IR or non-bio-IR) at the Baseline of 
Study M14-234 Substudy 2 or Study M14-675, clinical remission status at Week 0 (yes or 
no) and corticosteroid use at Week 0 (yes or no).
Cohort 4:  Approximately 15 subjects who received double-blind 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 this 
cohort.
The schematics of the Maintenance Study design are shown in Figure 1.


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Figure 1.
Maintenance Study Schematic
During the Maintenance Study, 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 long-term 
extension Study M14-533 and receive open-label upadacitinib.  Details regarding loss of 
response are described in Protocol Section 5.1.3.


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2.3
Treatment Assignment and Blinding
For subjects who are from Study M14-234 Substudy 2 or Study M14-675 and who are 
eligible to be re-randomized to one of the three treatment groups in Cohort 1 (upadacitinib 
15 mg QD, upadacitinib 30 mg QD, or placebo), the randomization will be stratified by 
Bio-IR status (Bio-IR or Non-Bio-IR) at the Baseline of Study M14-234 Substudy 2 or 
Study M14-675, clinical remission status at Week 0 (yes or no) and corticosteroid use at 
Week 0 (yes or no).  For subjects who are from Study M14-234 Substudy 1 and who 
received 15 mg, 30 mg or 45 mg QD, the randomization will be stratified by previous 
biologic use (yes or no) at the Baseline of Study M14-234 Substudy 1 and induction dose 
received.  For subjects who are eligible to be re-randomized to 1 of the 2 treatment groups 
in Cohort 3 (upadacitinib 15 mg QD and upadacitinib 30 mg QD), randomization will be 
stratified by Bio-IR status (Bio-IR or Non-Bio-IR) at the Baseline of Study M14-234 
Substudy 2 or Study M14-675, clinical remission status at Week 0 (yes or no) and 
corticosteroid use at Week 0 (yes or no).
The primary analysis will be performed after the first 450 subjects in the Maintenance 
Study Cohort 1 who were upadacitinib 45 mg QD induction responders have completed 
the Maintenance Study activities (i.e., completed Week 52 or prematurely discontinued 
prior to Week 52) and the database has been locked, for the purpose of regulatory 
submission.  This is the only and final analysis for the 52-week efficacy analyses.  
Treatment assignments for the Maintenance Study will be unblinded to AbbVie for 
statistical analyses.  Additional subjects in any cohort who have not completed the 
Maintenance Study at the time of database lock will be kept on the same blinded treatment 
until study completion.  The study sites and subjects will remain blinded to the 
maintenance treatment assignments until all subjects have completed the Maintenance 
Study.  Once all subjects have completed the Maintenance Study, the data collected from 
these subjects will be used to update the safety analysis only.


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2.4
Sample Size Determination
The sample size for the Maintenance Study is based on the expected proportion of 
subjects who achieve clinical remission per Adapted Mayo score at Week 52.  The 
assumptions of clinical remission rates were based on the historical data from other 
compounds with similar or different MOAs.  In vedolizumab Phase 3 UC study, the 
clinical remission rate was 16% in placebo group and 42% in treatment group.1  In 
tofacitinib Phase 3 UC study, the clinical remission rate was 11.1% in placebo group and 
40.6% in 10 mg BID treatment group.2  Considering the factors that may influence the 
clinical remission rate (e.g., differences in MOAs, patient population, and clinical 
remission definition), clinical remission rates are assumed to be 12% in the placebo group 
and 40% in the upadacitinib treatment group at Week 52.
Assuming clinical remission rate of 12% in the placebo group and 40% in one of the 
upadacitinib QD treatment groups 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 induction treatment in the Induction 
Studies is 50%, a total of approximately 450 subjects will be re-randomized to 
upadacitinib 15 mg QD or 30 mg QD treatment groups or placebo in a randomization ratio 
of 1:1:1 if they achieved clinical response from upadacitinib 45 mg QD in the Induction 
Studies.  The assumption of an average response rate of 50% in upadacitinib doses after 
induction is based on the Phase 2b results.
3.0
Endpoints
The induction baseline (thereafter referred to as Baseline) visit date is the date when the 
first dose of study drug is received during Induction Studies.  The baseline value for a 
variable is defined as the last non-missing value on or before the date of the first dose of 
study drug during Induction Studies. 


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The maintenance baseline visit date is on the same day as the final visit in the Induction 
Studies (thereafter referred to as Maintenance Baseline).  The maintenance baseline value 
for a variable is defined as the last non-missing value on or before the date of the first 
dose of study drug during Maintenance Study.
The terminologies and efficacy variables are defined as below:
●
Mayo Score
○
Full Mayo Score: composite score of UC disease activity based on the 
stool frequency subscore [SFS] (0 – 3), rectal bleeding subscore [RBS] 
(0 – 3), physician's global assessment [PGA] subscore (0 – 3) and 
endoscopic subscore (0 – 3).  This score ranges from 0 – 12 points with 
higher scores representing more severe disease.
○
Partial Mayo Score: Full Mayo score minus the endoscopic subscore.
○
Adapted Mayo Score: Full Mayo score minus the PGA subscore.
○
Partial Adapted Mayo Score: Adapted Mayo score minus the 
endoscopic subscore.
●
Clinical Remission 
○
per Full Mayo Score:  Full Mayo score ≤ 2 with no subscore > 1.
○
per Adapted Mayo Score:  Adapted Mayo score ≤ 2, with SFS ≤ 1 and 
not greater than baseline, RBS of 0, and endoscopic subscore ≤ 1.
○
per Partial Mayo Score:  Partial Mayo score ≤ 2, with no subscore > 1.
●
Clinical Response
○
per Full Mayo Score:  decrease in Full Mayo score of ≥ 3 points and 
≥30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute 
RBS ≤1.
○
per Adapted Mayo Score:  decrease in Adapted Mayo score ≥2 points 
and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute 
RBS ≤ 1.
○
per Partial Mayo Score:  decrease in Partial Mayo score ≥ 2 points and 
≥30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute 
RBS ≤1.


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○
per Partial Adapted Mayo Score:  decrease in Partial Adapted Mayo 
score ≥ 1 point and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or 
an absolute RBS ≤ 1.
●
Endoscopic Improvement: Endoscopic subscore of 0 or 1.
●
Endoscopic Remission: Endoscopic subscore of 0.
●
Histologic Improvement: decrease from Baseline in Geboes score.
●
Histologic Remission: Geboes score < 2.
●
Histologic Endoscopic Mucosal Improvement: Endoscopic subscore of 0 or 1 
and Geboes score ≤ 3.1.
●
Mucosal Healing: Endoscopic score of 0 and Geboes score < 2.0.
Note:  Evidence of friability during endoscopy in subjects with otherwise "mild" 
endoscopic activity will confer an endoscopic subscore of 2.
For subjects enrolled under the protocol with 44-week maintenance period, the efficacy 
endpoints at Week 52 will apply at Week 44, as applicable.
3.1
Primary Endpoint
The primary efficacy endpoint is the achievement of clinical remission per Adapted Mayo 
score at Week 52.
3.2
Secondary Endpoints
The ranked secondary efficacy endpoints under overall type I error control are as follows:
1.
The achievement of endoscopic improvement at Week 52;
2.
The achievement of clinical remission per Adapted Mayo score at Week 52 among 
subjects who achieved clinical remission at the end of the induction treatment in 
the Induction Study;
3.
The achievement of clinical remission per Adapted Mayo score at Week 52 and 
corticosteroid free for ≥ 90 days immediately preceding Week 52 among subjects 


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who achieved clinical remission at the end of the induction treatment in the 
Induction Study;
4.
The achievement of endoscopic improvement at Week 52 among subjects who 
achieved endoscopic improvement at the end of the induction treatment in the 
Induction Study;
5.
The achievement of endoscopic remission at Week 52;
6.
The achievement of clinical response per Adapted Mayo score at Week 52 among 
subjects who achieved clinical response at the end of the induction treatment in the 
Induction Study;
7.
The achievement of histologic-endoscopic mucosal improvement at Week 52;
8.
Change from Baseline in IBDQ total score at Week 52;
9.
The achievement of mucosal healing at Week 52;
10.
The achievement of no bowel urgency at Week 52;
11.
The achievement of no abdominal pain at Week 52;
12.
Change from Baseline in FACIT-F score at Week 52;
3.3
Additional Efficacy Endpoints
The following additional efficacy endpoints will be evaluated:
●
The achievement of clinical remission per Partial Mayo score and 
corticosteroid free over time among subjects taking corticosteroid at Baseline in 
the Induction Study;
●
The achievement of clinical remission per Adapted Mayo score and 
corticosteroid free at Week 52 among subjects taking corticosteroid at Baseline 
in the Induction Study;
●
The achievement of clinical remission per Adapted Mayo score at both 
Maintenance Baseline and Week 52, and corticosteroid free for ≥ 90 days 


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immediately preceding Week 52 among subjects taking corticosteroids at 
Baseline in the Induction Study; 
●
The achievement of SFS ≤ 1 (and not worse than Baseline), RBS = 1 at both 
Week 36 and Week 44, clinical remission per Adapted Mayo score at Week 52
and corticosteroid free for ≥ 90 days immediately preceding Week 52 among 
subjects taking corticosteroids at Baseline in the Induction Study;
●
The achievement of clinical remission per Full Mayo Score at Week 52;
●
The achievement of clinical remission per Partial Mayo score over time;
●
The achievement of clinical response per Partial Mayo score over time; 
●
The achievement of clinical remission per Adapted Mayo score over time;
●
The achievement of SFS = 0, RBS = 0 and endoscopic subscore = 0 over time;
●
The achievement of SFS = 0, RBS = 0 and endoscopic subscore ≤1 over time;
●
The achievement of SFS ≤ 1, RBS = 0 at Week 28 and clinical remission per 
Adapted Mayo score at Week 52;
●
The achievement of SFS ≤ 1, RBS = 0 at both Week 28 and Week 52; 
●
The achievement of SFS ≤ 1 over time; 
●
The achievement of RBS = 0 over time; 
●
Change from Baseline in Adapted Mayo score, Full Mayo score, Partial 
Adapted Mayo score, Partial Mayo score and Mayo subscores over time;
●
Change from Baseline in subject-reported stool frequency (absolute values) 
over time;
●
The achievement of histologic improvement at Week 52;
●
The achievement of histologic remission at Week 52;
●
The achievement of histologic remission at both Maintenance Baseline and 
Week 52.
●
Change from Baseline in histologic score over time; 
●
The achievement of corticosteroid free over time among subjects taking 
corticosteroids at Baseline in the Induction Study;
●
Change from Baseline in corticosteroid dose over time among subjects taking 
corticosteroids at Baseline in the Induction Study;
●
Change from Baseline in hs-CRP over time;


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The achievement of fecal calprotectin below 150 mg/kg over time;
●
Change from Baseline in fecal calprotectin over time;
●
The achievement of response in IBDQ Bowel Symptom domain at Week 52 
(increase of IBDQ bowel symptom domain score ≥ 6); 
●
The achievement of with IBDQ response (increase of IBDQ ≥ 16 from 
Baseline) over time;
●
The achievement of IBDQ remission (IBDQ total score ≥ 170) over time;
●
The achievement of response in IBDQ fatigue item at Week 52 (increase of 
IBDQ fatigue item score ≥ 1);
●
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;
●
Change from Baseline in UCEIS score over time;
●
Change from Baseline in EQ-5D-5L score over time;
●
Change from Baseline in WPAI scores over time;
●
Change from Baseline in SF-36 Physical Component Summary (PCS) and 
Mental Component Summary (MCS) components and domain scores over time;
●
Summary of PGIC improvement category over time;
●
Summary of PGIS severity category over time;
●
Change from Baseline in FACIT-F score over time;
●
Change from Baseline in UC-SQ score over time;
●
Incidence rate of UC-related hospitalizations through Week 52;
●
Incidence rate of UC-related surgeries through Week 52.
In addition, change from Maintenance Baseline 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.
The primary and ranked secondary endpoints will be summarized at Week 44 for subjects 
who enrolled under the protocol/protocol amendments with only 44-week maintenance 
period.


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3.4
Safety Endpoints
The following endpoints will be included in the safety analyses:
●
Treatment emergent adverse events (TEAEs);
●
Serious adverse events (SAEs);
●
Adverse events of special interest (AESIs);
●
Adverse events (AEs) leading to discontinuation of study drug;
●
Vital signs and laboratory tests.
4.0
Analysis Populations
Significant non-compliance was identified at an investigational site (original Investigator 
). There were 6 subjects enrolled at this site in the Induction Studies who 
continued into the Maintenance Study. As a result of this finding, efficacy data for these 
subjects will be excluded from the statistical analyses for the Maintenance Study.  Safety 
data for these subjects will be included in the safety analyses.
Intent-to-Treat (ITT) Populations
ITT population:  All subjects who received at least 1 dose of study drug in the 
Maintenance Study.
ITT_A population:  The subset of ITT population 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 ITT_A population is the primary 
analysis population in Cohort 1 for efficacy endpoints.
ITT_B population:  The subset of ITT population in Cohort 3 who were upadacitinib 
45 mg QD 16-week induction responders.
ITT_C population:  The subset of ITT population who were enrolled under the original 
protocol, Amendment 1 or 2 for 44-week maintenance treatment period.


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ITT_D population: The subset of ITT population 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.
ITT_E population:  The subset of ITT 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.
The above populations were annotated as ITT3, ITT3_A, ITT3_B, ITT3_C, ITT3_D and 
ITT3_E in the protocol.  The number "3" was included in the protocol to indicate the 
Substudy 3 but removed in this Substudy 3-specific SAP for simplicity.
For ITT populations, subjects will be included in the analysis according to the treatment 
groups that they are randomized to, as applicable.
Table 1.
Definition of ITT Populations
ITT_
Cohort
Induction
Maintenance
Study
Period
Dose
Protocol Type 
and Remarks
A
1
M14-234 Substudy 1
M14-234 Substudy 2 /M14-675
8-week
UPA 45 mg
52-week
First 450 
randomized
M14-234 Substudy 2 /M14-675
16-week
PBO/UPA 45 mg
B
3
M14-234 Substudy 2 /M14-675
16-week
UPA 45 mg/UPA 
45 mg
52-week
C
1, 2, 4
M14-234 Substudy 1
8-week
PBO, UPA 7.5, 
15, 30, 45 mg
44-week
D
1
M14-234 Substudy 1
M14-234 Substudy 2 /M14-675
8-week
UPA 45 mg
52-week
M14-234 Substudy 1
M14-234 Substudy 2 /M14-675
16-week
PBO/UPA 45 mg
E
1, 2, 4
M14-234 Substudy 1
M14-234 Substudy 2 /M14-675
8-week
PBO, UPA 7.5, 
15, 30 mg
52-week
A database lock and unblinded analysis will be conducted for the purpose of regulatory 
submission after subjects in the ITT_A population complete the Maintenance Study 


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(i.e., completed Week 52 or prematurely discontinued prior to Week 52).  Efficacy 
analysis for ITT_B, ITT_C and ITT_E population at this database lock will be conducted 
among subjects who have completed the protocol defined study period or have the 
potential to complete the protocol defined study period (i.e., at least 52 weeks/44 weeks 
for subjects enrolled under the protocol with 52-week/44-week maintenance period) but 
withdrawn from the study.
Safety Populations
SA population:  All subjects who received at least 1 dose of study drug in the 
Maintenance Study.
SA_A population:  The subset of SA population 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.
SA_B population:  The subset of SA population in Cohort 3 who were upadacitinib 
45 mg QD 16-week induction responders.
SA_C population:  The subset of SA population who were upadacitinib 45 mg QD 
8-week induction responders and who were enrolled under the protocol for 44- or 
52-week maintenance treatment period in Cohort 1.
SA_D population:  The subset of SA population who were placebo, upadacitinib 7.5 mg 
QD, 15mg QD or 30 mg QD 8-week induction responders and who were enrolled under 
the protocol for 44- or 52-week maintenance treatment period.
SA_UPA population (all upadacitinib safety analysis set): All subjects who received 
at least one dose of upadacitinib study drug in the Maintenance Study.


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Table 2.
Definition of Safety Populations
SA_
Cohort
Induction
Maintenance
Study
Period
Dose
Protocol Type
A
1
M14-234 Substudy 1
M14-234 Substudy 2 /M14-675
8-week
UPA 45 mg
52-week
First 450 
randomized
M14-234 Substudy 2 /M14-675
16-week
PBO/UPA 45 mg
B
3
M14-234 Substudy 2 /M14-675
16-week
UPA 45 mg/UPA 
45 mg
52-week
C
1
M14-234 Substudy 1
M14-234 Substudy 2 /M14-675
8-week
UPA 45 mg
44 or 52-week
M14-234 Substudy 2 /M14-675
16-week
PBO/UPA 45 mg
D
1, 2, 4
M14-234 Substudy 1
M14-234 Substudy 2 /M14-675
8-week
PBO, UPA 7.5, 
15, 30 mg
44 or 52-Week
UPA
Received at least one dose of UPA
For the safety populations, subjects are assigned to a treatment group based on the "as 
treated" treatment group, regardless of the treatment randomized.  The "as treated" will be 
determined by the most frequent dose regimen received in the analysis period.
5.0
Subject Disposition
For ITT_A, ITT_B, ITT_C, ITT_D and ITT_E populations, a summary of subject 
accountability will be provided where the number of subjects in each of the following 
categories will be summarized for each treatment group: 
●
Subjects randomized/enrolled; 
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who prematurely discontinued study drug;
●
Subjects who prematurely discontinued from study.
Number and percentage of subjects who discontinued study drug and who withdrew from 
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treatment group as well as for all treatment groups combined.  Subjects with multiple 
reasons for premature discontinuation will be counted once in the calculation of the 
number and percentage of total discontinuations.
In addition, the above subject disposition will be summarized for ITT population by each 
cohort, as well as for all subjects combined.
6.0
Study Drug Duration and Compliance
For the safety populations (SA_A, SA_B, SA_C and SA_D), duration of treatment will be 
summarized for each treatment group.  Duration of treatment is defined for each subject as 
last dose date minus first dose date + 1.  Duration of treatment will be summarized using 
the number of subjects treated, mean, standard deviation, median, minimum and 
maximum.  In addition, the number and percentage of subjects in each treatment duration 
interval (≥ 4 weeks, ≥8 weeks, ≥ 12 weeks, ≥ 20 weeks, ≥28 weeks, ≥ 36 weeks, 
≥44 weeks, ≥ 52 weeks) will be summarized.
Treatment compliance will be summarized for SA_A by treatment group.  Treatment 
compliance is defined as the number of tablets actually taken divided by the number of 
tablets that should have been taken.  Percent compliance will be summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics and Baseline characteristics will be summarized for the ITT_A, ITT_B, 
ITT_C and ITT_E populations overall and by treatment group.  Medical history, prior and 
concomitant medications will be summarized for the ITT_A population overall and by 
treatment group.  Categorical variables will be summarized with the number and 
percentage of subjects; percentages will be calculated based on the number of non-
missing observations.  Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean and standard deviation, median, minimum 
and maximum).


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7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include:
●
Sex (Male, Female)
●
Age Group 1 (< 18 year, ≥ 18 years - < 40 years, ≥ 40 years - < 65 years, 
≥65 years)
●
Age Group 2 (≤ median, > median)
●
Weight Group (≤ median, > median)
●
BMI Group (normal: < 25 kg/m2, overweight: ≥ 25 - 30 kg/m2, obese: 
≥30 kg/m2)
●
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
●
Race (White, Black/African American, American Indian/Alaska Native, Native 
Hawaiian or Other Pacific Islander, Asian, Other)
●
Region (US, ex-US)
●
Tobacco user (current, former, never, unknown)
●
Alcohol user (current, former, never, unknown)
Continuous baseline or disease characteristics variables include:
●
Disease duration (years)
●
Full Mayo score and its components (stool frequency subscore, rectal bleeding 
subscore, Physician Global Assessment, and endoscopy subscores)
●
Partial Mayo score
●
Adapted Mayo score
●
hs-CRP (mg/L)
●
Fecal Calprotectin (μg/g)
●
IBDQ total and domain score
●
Short Form 36 Health Survey (SF-36) and its components
●
European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)


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WPAI and its components
●
Ulcerative Colitis Symptoms Questionnaire (UC-SQ)
Categorical baseline or disease characteristics variables include:
●
Bio-IR status (Bio-IR, non-Bio-IR),
●
Prior exposure to biologic therapy (yes, no) for non-Bio-IR 
●
Number of prior biologic treatments (≤ 1 or > 1) for Bio-IR
●
Prior exposure to anti-TNF (yes, no)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Baseline aminosalicylates use (yes, no)
●
Baseline Adapted Mayo score (≤ 7, > 7)
●
Baseline Full Mayo score (≤ 9, > 9)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Disease duration Group 1 (≤ 3 years, > 3 years)
●
Disease duration Group 2 (≤ median, > median)
●
Disease extent (rectosigmoid, left-sided, extensive/pancolitis)
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group for the ITT_A population.  The system organ 
class (SOC) will be presented in alphabetical order, and the preferred terms will be 
presented in alphabetical order within each SOC.  Subjects reporting more than one 
condition/diagnosis will be counted only once in each row (SOC or preferred term).


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7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name for the ITT_A 
population.  A prior medication is defined as any medication taken prior to the date of the 
first dose of study drug in the Induction Studies.  A concomitant medication is defined as 
any medication that started prior to the date of the first dose of study drug in the 
Maintenance Study and continued to be taken after the first dose of study drug or any 
medication that started on or after the date of the first dose of study drug, but not after the 
date of the last dose of study drug + 1 day.  The number and percentage of subjects taking 
medications will be summarized by generic drug name based on the World Health 
Organization (WHO) Drug Dictionary for both prior and concomitant medications.
8.0
Efficacy Analyses
8.1
General Considerations
The primary and secondary efficacy endpoints will be analyzed based on ITT_A 
population as defined in Section 4.0.  The primary and ranked secondary efficacy 
endpoints as specified in Section 3.1 and Section 3.2 will be tested with graphical 
multiplicity adjustment to ensure a strong control of family-wise type I error rate at 
significance level α= 0.05 (2-sided).
For analyses based on ITT_A population, unless otherwise specified, categorical variables 
will be analyzed using Cochran-Mantel-Haenszel (CMH) test, stratified by Bio-IR status 
(Bio-IR or Non-Bio-IR) at the Baseline of Induction Study, clinical remission status at 
Week 0 (yes or no), and corticosteroid use at Week 0 (yes or no).  Any subject who was 
randomized under the wrong stratum will be analyzed according to the actual stratum the 
subject belongs to.  Continuous variables collected longitudinally will be analyzed using 
Mixed-Effect Model Repeat Measurement (MMRM) model.  Continuous variables 
collected at only one post-baseline visit will be analyzed using an Analysis of Covariance 
(ANCOVA) model.  MMRM model includes the categorical fixed effects of treatment, 
visit and treatment-by-visit interaction, randomization stratification factors (Bio-IR status 
(Bio-IR or Non-Bio-IR) at the Baseline of the Induction Study, clinical remission status at 


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Week 0 (yes or no), and corticosteroid use at Week 0 (yes or no)), and the continuous 
fixed covariates of Baseline measurements. An unstructured variance covariance matrix 
(UN) will be used.  If the model cannot converge, autoregressive (1) covariance structure 
matrix will be used.  The parameter estimations are based on the method of restrictive 
maximum likelihood (REML).  The fixed effects will be used to report model-based 
means at corresponding visits.  ANCOVA model includes the categorical fixed effects of 
treatment, randomization stratification factors (Bio-IR status:  Bio-IR or Non-Bio-IR) at 
the Baseline of the Induction Study, clinical remission status at Week 0 (yes or no), and 
corticosteroid use at Week 0 (yes or no)), and the continuous fixed covariates of Baseline 
measurements.
8.2
Handling of Potential Intercurrent Events
Potential intercurrent events considered in the Induction Study include 1) premature 
discontinuation of study drug and 2) use of UC-related rescue medications defined in 
Section 8.2.2.  Intercurrent events will be handled using the following methods for the 
efficacy analysis:
8.2.1
Premature Discontinuation of Study Drug
If the subjects prematurely discontinued study drug but stayed in the study, data collected 
after premature discontinuation of study drug will be used, unless subjects received UC-
related medications satisfying one or more of the following criteria,
●
Usage of any biologics approved for UC (anti-TNF-α agents including 
infliximab, adalimumab, golimumab and biosimilars, vedolizumab and 
biosimilars, Ustekinumab and biosimilars)
●
Usage of any JAK inhibitors approved for UC (including but not limited to 
tofacitinib)
●
Usage of any total parenteral nutrition (TPN)
●
Usage of any cytapheresis treatment 
●
Any Initiation or dose escalation of immunosuppressant compared to Week 0 of 
the Maintenance Study


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●
Any initiation or dose escalation of antibiotics compared to Week 0 of the 
Maintenance Study
●
Any initiation or dose escalation of aminosalicylates compared to Week 0 of 
the Maintenance Study
●
Any initiation or dose escalation of corticosteroids (Definitions in 
Section 8.2.2)
●
Usage of investigational compounds
8.2.2
UC-Related Rescue Medications
The UC-related rescue medications intercurrent events during the study drug treatment 
period comprises of the following two intercurrent events,
1.
UC-Related corticosteroids intercurrent events are defined as follows:
●
subjects not on UC-related corticosteroids (systemic or locally acting 
corticosteroids for UC) at Baseline who initiated UC-related corticosteroids 
during the Maintenance Study;
●
subjects on UC-related systemic corticosteroids at Baseline who had dosages 
increased to greater than the prednisone equivalent dose of corticosteroid at 
Baseline, or initiation of any rectal corticosteroids during the Maintenance 
Study regardless of rectal corticosteroid dose;
●
subjects on UC-related rectal corticosteroids at Baseline who have dosages 
increased to greater than the dose taken at Baseline, or initiation of any new 
type of rectal or any systemic corticosteroids during the Maintenance Study.
●
if a subject enters the Maintenance Study without corticosteroids, threshold 
dose of corticosteroids for censoring will be compared to the Baseline dose of 
the Induction Study.  If subject enters the Maintenance Study with 
corticosteroids, threshold dose of corticosteroids for censoring will be 
compared to the dose at Baseline of the Induction Study or at baseline of the 
Maintenance Study, whichever of the two doses is higher.
2.
UC-related non-corticosteroid rescue medications include systemic or rectal use of 
aminosalicylates, antibiotics and methotrexate. The intercurrent events are defined 


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as subjects who have initiation or dose escalation of any of these medications 
compared to Week 0.
The time point of the UC-related rescue medications intercurrent event is defined as the 
date when one of the intercurrent events above occurs for a subject. For categorical
endpoints, subjects will be considered as "non-responder" at or after the occurrence of the 
UC-related rescue medication intercurrent event through the end of the Maintenance 
Study except for the As Observed (AO) analysis.  For continuous endpoints, all 
measurements from the date of UC-related rescue medications intercurrent event through 
the end of the Maintenance Study will not be used in the analysis except for the As 
Observed (AO) analysis.  Methods to handle visits after these intercurrent events are 
described in Section 8.3.2.
8.3
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the Maintenance Study, or missing due to COVID-19 infection or 
logistical restrictions.  Assessments on or after the date of UC-related rescue medication 
intercurrent event will be excluded from analyses, and methods to handle missing data 
will be applied for these visits.
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis and the interpretation 
of clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 
recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at 


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random (MAR) and the statistical models that require MAR assumption are appropriate.  
The intent is to provide reliable estimates of the treatment effects under the scenario 
without the impact of COVID-19 pandemic.
Handling of missing data for the efficacy analyses is described below.
8.3.1
Categorical Endpoints
For binary efficacy endpoints, missing data will be handled using the following 
approaches:
●
The primary approach for handling missing data will be Non-Responder 
Imputation while incorporating Multiple Imputation (MI) to handle missing 
data due to COVID-19 (NRI-C).
●
The NRI-C will categorize any subject who does not have an evaluation during 
a pre-specified visit window (either due to missing assessment or due to early 
withdrawal from the study) as a non-responder for the visit.  The only 
exception is that missing data due to COVID-19 infection or logistical 
restrictions related to the COVID-19 pandemic will be handled by Multiple 
Imputation (MI).  At each visit, subjects will be characterized as responders or 
non-responders based on MI imputed values if missing due to COVID-19; 
otherwise, subjects will be considered as non-responders for missing due to 
other reasons in the NRI-C approach.  In addition, at and after the UC-related 
rescue medications intercurrent event (see Section 8.2), subjects will be 
counted as non-responders.
●
A sensitivity analysis will use NRI with No special data handling for missing 
due to COVID-19 (NRI-NC).
●
NRI-NC will be performed in the same way as NRI-C without the exception 
above.  Missing due to COVID-19 infection or logistical restrictions will also 
be counted as non-responders.  Subjects at or after the occurrence of the UC-
related rescue medications intercurrent event will still be counted as non-
responders.  This is the same method as the "NRI" defined in the protocol.
●
Hybrid Multiple Imputation Method (HMI):  Sensitivity analysis will be 
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Subjects who discontinue study drug prior to Week 52 due to lack of efficacy 
or AEs and have no available measurements will be considered as "non-
responder" for clinical remission.  Subjects who discontinue for other reasons 
and have no available measurements, or subjects who has missing Week 52 
evaluations will be categorized according to the data from multiple imputations. 
In addition, at and after the UC-related rescue medications intercurrent event 
(see Section 8.2), subjects will be counted as non-responders.
●
As Observed (AO):  The AO analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the AO analysis for that visit.  AO will include all 
values collected in the study regardless the occurrence of UC-related rescue 
medication intercurrent event.
Details of Multiple Imputation (MI) for NRI-C and HMI:  Markov Chain Monte Carlo 
(MCMC) will be first applied to augment data into monotonic missing pattern, where 
applicable, and PROC MI will be used to generate 30 datasets using the regression 
method.  The variables to be included in the imputation model are:  treatment group, 
stratification factors (Bio-IR status (Bio-IR or Non-Bio-IR) at the Baseline of the 
Induction Study, clinical remission status at Week 0 (yes or no), and corticosteroid use at 
Week 0 (yes or no)), Baseline measurement, and if applicable, post-baseline 
measurements at each visit up to the end of the analysis period.  The random seed for 
MCMC and the random seed for PROC MI are specified in Appendix D.  The imputed 
post-baseline measurements will be rounded to the same precision as the observed data 
before the determination of responder status.  Subjects will be characterized as responders 
or non-responders based on MI imputed datasets.  Using the CMH model adjusted by 
stratification factors (Bio-IR status (Bio-IR or Non-Bio-IR) at the Baseline of the 
Induction Study, clinical remission status at Week 0 (yes or no), and corticosteroid use at 
Week 0 (yes or no)), the imputed endpoints will be analyzed using each of the 30 datasets.  
SAS PROC MIANALYZE will be used to generate the final treatment difference between 
each upadacitinib treatment group and placebo group and statistical inference of the risk 
difference, including hypothesis testing and 95% CI using Rubin's rule and 
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8.3.2
Continuous Endpoints
For continuous endpoints, missing data will be handled using the following approaches:
●
The primary approach is Multiple Imputation Incorporating Return-to-Baseline 
to Handle Visits After UC-related Rescue Medication Use (RTB-MI).  To 
assess the potential departures from the missing-at-random (MAR) assumption
for visits after the intercurrent event of UC-related rescue medication use (see 
section 8.2.2), the Return-to-Baseline (RTB)4,5 approach which assumes 
subjects received UC-related rescue medication will have a washout "return to 
baseline" of any potential treatment effect, will be performed as following:
○
Step 1: after setting data after the intercurrent event of UC-related rescue
medication use as missing, missing values due to all causes will first be 
imputed via MI under the MAR assumption.
○
Step 2: subject's efficacy assessments after the intercurrent event of UC-
related rescue medication will be assumed to have returned to baseline.
For each imputed dataset, missing change from baseline data due to the 
intercurrent event of UC-related rescue medication will be replaced by a 
value from a normal distribution (0, ), where  is the variance of 
change from baseline estimated from all observed values regardless of 
treatment groups, excluding those after UC-related rescue medication use.
○
Step 3: For each imputed dataset, the MMRM/ANCOVA model described 
in Section 8.1 will be applied to each completed set and the inference will 
be drawn using Rubin's combination rules (SAS proc MIANALYZE).
●
MMRM/ANCOVA:  Assuming any unobserved data (including the missing 
due to the intercurrent event of UC-related rescue medication use) can be 
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intercurrent event of UC-related rescue medication use will be performed as a 
sensitivity analysis.
●
Delta-Based Multiple Imputation (DBMI).6  A missing-not-at-random (MNAR) 
model that varies assumptions for data after the intercurrent event of UC-
related rescue medication use will be implemented through Delta-Based
Multiple Imputation (DBMI). The DBMI is two-dimensional, i.e., assumptions 
about the missing outcomes on the upadacitinib treatment groups and the 
placebo group are allowed to vary independently. After setting data after the 
intercurrent event of UC-related rescue medication use as missing, missing 
values due to all causes will first be imputed via MI under the MAR 
assumption, and then a shift parameter (i.e., delta) will be applied to the 
imputed values for the missing data due to UC-related rescue medication use. 
For each pair of deltas, the MMRM/ANCOVA model described in Section 8.1
will be applied to each completed set and the inference will be drawn using 
Rubin's combination rules (SAS proc MIANALYZE). For each endpoint to be 
analyzed, the analysis will be repeated for a range of delta values corresponding 
to 0 to ±100% of the unadjusted mean observed for all subjects.
●
As Observed (AO): The AO analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the AO analysis for that visit. AO will include all 
values collected in the study regardless the occurrence of UC-related rescue 
medication intercurrent event.
8.4
Primary Efficacy Endpoint and Analyses
8.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the achievement of clinical remission per Adapted Mayo 
score at Week 52.  The primary estimand is the difference in the percentage of subjects 
achieving clinical remission per Adapted Mayo score at Week 52 regardless of premature 
discontinuation of study drug and without use of UC-related rescue medications (See 
Section 8.2.2) in the upadacitinib 15 mg QD, upadacitinib 30 mg QD and placebo groups 
in the ITT_A population.  Details of the estimand definition are outlined in Appendix E.


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8.4.2
Handling of Missing Data for the Primary Efficacy Endpoint
The NRI-C will be the primary approach for missing data handling in the analyses of the 
primary efficacy endpoint.
The NRI-NC and HMI approaches will be used as sensitivity analyses.
8.4.3
Primary Efficacy Analysis
The primary analysis will compare the proportion of subjects achieving clinical remission 
in each upadacitinib treatment group and placebo group in the ITT_A population.  The 
difference between the treatment groups in the primary efficacy endpoint will be assessed 
using the CMH test and will be stratified Bio-IR status (Bio-IR or Non-Bio-IR) at the 
Baseline of the Induction Study, clinical remission status at Week 0 (yes or no), and 
corticosteroid use at Week 0 (yes or no).  A CMH based two-sided 95% confidence 
interval for the difference between treatment groups will be calculated.
8.4.4
Additional Analyses of the Primary Efficacy Endpoint
For the primary efficacy endpoint, the same CMH analysis as detailed in Section 8.1 will 
be repeated performed using As Observed (AO) data handling without any imputation as 
an additional analysis.  The analysis will be conducted on the ITT_A population who have 
the efficacy measurement at Week 52 visit.
For the primary efficacy endpoint, a supplementary analysis will be conducted to evaluate 
the potential impact of deviations.  In this analysis, subjects with deviations that could 
potentially impact the analysis of primary endpoint will be excluded.  The criteria will be 
fully defined in the classification plan and the Exclusion of subjects will be adjudicated by 
the therapeutic area medical director (TAMD) and reasons for the subjects to be excluded 
will be documented and finalized before the Maintenance Study database lock for the 
primary analysis.  Treatment difference between each upadacitinib treatment group and 
placebo with point estimate and 95% CI using NRI-C approach with the CMH method as 
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8.5
Secondary Efficacy Analyses
8.5.1
Key Secondary Efficacy Analyses
The key secondary endpoints are defined in Section 3.2.  The estimands corresponding to 
the secondary efficacy endpoints are defined in Section 2.1.  Details of the estimand 
definitions are outlined in Appendix E.  For ITT_A population, the key secondary efficacy 
endpoints will be analyzed by comparing each upadacitinib treatment group and placebo 
group.  The binary secondary endpoints will be analyzed by CMH and the corresponding 
analyses are defined in Section 8.3.1.  The NRI-C will be the primary approach for 
missing data handling in the analyses of binary secondary efficacy endpoints.  The NRI-
NC approach will be used as sensitivity analyses.
Continuous secondary endpoints will be analyzed by ANCOVA model with RTB-MI 
approach to handle the missing data due to UC-related rescue medication use as described
in Section 8.3.2.
8.5.2
Additional Analyses of the Secondary Efficacy Endpoints
The secondary efficacy endpoints will also be analyzed for ITT_A population using As 
Observed (AO) data handling without any imputation.  The binary endpoints and 
continuous endpoints will be analyzed by CMH and ANCOVA, respectively, and the 
corresponding analyses are specified in Section 8.1.
In addition, the continuous endpoints will be analyzed by ANCOVA (excluding data after 
rescue medication use) and DBMI method.  Details are specified in Section 8.3.2.
8.6
Additional Efficacy Analyses
Additional efficacy endpoints are defined in Section 3.3.
The estimands corresponding to the additional efficacy endpoints are defined for each of 
the binary additional endpoints as follows: difference in percentage of subjects achieving 
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UC-related rescue medications (See Section 8.2.2) in the upadacitinib 15 mg QD, 
upadacitinib 30 mg QD and placebo groups in the ITT_A population.
The estimands corresponding to the additional efficacy endpoints are defined for each of 
the continuous additional endpoints as follows: difference in mean change from baseline 
regardless of premature discontinuation of study drug and if subjects would not use UC-
related rescue medications (See Section 8.2.2) in the upadacitinib 15 mg QD, upadacitinib 
30 mg QD and placebo groups in the ITT_A population.
The estimands corresponding to UC-related hospitalization and surgery incidence rates is 
as follows: difference in the incidence rate through Week 52 regardless of premature 
discontinuation of study drug or use of UC-related rescue medications in the upadacitinib 
15 mg QD, upadacitinib 30 mg QD and placebo groups in the ITT_A population.
For ITT_A population, additional efficacy endpoints will be analyzed by comparing each 
upadacitinib treatment group and placebo group.  The binary endpoints and change from 
baseline continuous endpoints will be analyzed by CMH and RTB-MI with 
MMRM/ANCOVA, respectively, and the corresponding analyses are specified in 
Section 8.3.  Change from maintenance baseline continuous endpoints will be analyzed by 
ANCOVA.  The NRI-C approach will be used for missing data handling in the analyses of 
binary efficacy endpoints.  For incidence rate of UC-related hospitalization and surgery 
during the Maintenance Study, adjusted incidence rates will be used to compare the risk 
between each upadacitinib treatment group and placebo group.  Adjusted rates will be 
calculated as the number of subjects with the respective event divided by the time at risk.  
For subjects with an event during the Maintenance Study, time at risk is the patient-years 
(PYs) from Week 0 to the first event.  For subjects without event, time at risk is PYs from 
Week 0 to the end of 30-day follow up period.  Relative risk ratios of the incidence rates 
and confidence intervals will be calculated to evaluate the statistical significance of the 
difference between each upadacitinib treatment group and placebo group using z-score 
normal approximations.  For multi-level categorical endpoints PGIC and PGIS, 
percentage of each outcome category will be reported descriptively, and no statistical 
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For ITT_B, ITT_C and ITT_E populations, the primary and secondary endpoints 
(specified in Section 3.1 and Section 3.2) will be summarized and descriptive statistics 
will be provided.  The approaches of NRI-C and RTB-MI with MMRM/ANCOVA will 
be used for missing data handling in the analyses of binary and continuous efficacy 
endpoints, respectively.
8.7
Efficacy Subgroup Analyses
The following subgroup analyses will be conducted for the primary efficacy endpoint in 
the ITT_A population.  Treatment difference between each upadacitinib treatment group 
and placebo group with point estimate and 95% confidence interval using normal 
approximation will be presented.  The NRI-C approach will be used for missing data 
handling.  No p-value will be provided for subgroup analysis.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Bio-IR status (Bio-IR, Non-Bio-IR)
●
Baseline corticosteroid use (yes, no)
●
Baseline Adapted Mayo score (≤ 7, > 7)
●
Baseline Full Mayo score (≤ 9, > 9)
●
Prior exposure to anti-TNF (yes, no) for non-Bio-IR
●
Prior exposure to biologic therapy (yes, no) for non-Bio-IR
●
Baseline weight (≤ median, > median)
●
Presence of pancolitis at Baseline (yes, no)
●
Disease duration at Baseline (≤ median, > median)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Region (US versus non-US)
●
Baseline aminosalicylate use (yes, no)


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For a subgroup with the resulting categories that has fewer than 10% of the planned study 
size, subgroup analyses will not be presented for that category.
In addition, the following key secondary efficacy endpoints will be analyzed in the Bio-IR 
and non-Bio-IR subgroups in the ITT_A population.
●
The achievement of endoscopic improvement at Week 52;
●
The achievement of clinical remission per Adapted Mayo score at Week 52
among subjects who achieved clinical remission at the end of the induction 
treatment in the Induction Study;
●
The achievement of clinical remission per Adapted Mayo score at Week 52 and 
corticosteroid free for ≥ 90 days immediately preceding Week 52 among 
subjects who achieved clinical remission at the end of the induction treatment 
in the Induction Study;
●
The achievement of endoscopic improvement at Week 52 among subjects who 
achieved endoscopic improvement at the end of the induction treatment in the 
Induction Study;
●
The achievement of endoscopic remission at Week 52;
●
The achievement of clinical response per Adapted Mayo score at Week 52;
●
The achievement of histologic-endoscopic mucosal improvement at Week 52;
●
The achievement of mucosal healing at Week 52.
9.0
Safety Analyses
9.1
General Considerations
Safety analyses will be performed on the safety populations for SA_A population.  In 
addition, safety summaries will be provided on SA_B, SA_C, SA_D and SA_UPA 
populations.
The standard safety analyses will include reporting of adverse events (AEs), adverse 
events of special interest (AESIs), laboratory, and vital signs measurements.  Frequency 
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treatment-emergent adverse events (TEAEs) by system organ class (SOC) and by 
preferred term (PT) as in the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary will be provided by treatment group.  All continuous laboratory parameters and 
vital signs variables at each visit will also be summarized by treatment group.  Frequency 
tables of subjects meeting criteria for potentially clinically significant vital sign values 
and for potentially clinically significant laboratory values will be provided by treatment 
group.
The Baseline for the analysis of potentially clinically significant laboratory and vital sign 
values, and shift tables is the last available measurement before upadacitinib 
administration in the (Phase 2b) Induction Studies for subjects who received upadacitinib 
in the Phase 2b or Phase 3 Induction Studies; or the last available measurement before 
placebo administration in the (Phase 2b) Induction Studies for subjects who only received 
placebo in the Phase 2b or Phase 3 Induction Studies.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
The Treatment-Emergent Adverse Events (TEAEs) for SA (SA_A, SA_B, SA_C and 
SA_D) and SA_UPA populations are defined as follows.
SA (SA_A, SA_B, SA_C and SA_D) population:  TEAEs are defined as events that 
begin either on or after the first dose of the study drug in the Maintenance Study and


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●
within 30 days after the last dose administration of the study drug for subjects 
who do not participate in the long-term extension Study M14-533 or
●
until first dose of study drug in the Study M14-533 if the subject is enrolled 
into Study M14-533
SA_UPA population:  TEAEs are defined as events that begin either on or after the first 
dose of upadacitinib study drug in Maintenance Study and 
●
within 30 days after the last dose administration of the study drug for subjects 
who do not participate in the long-term extension Study M14-533 or
●
until first dose of study drug in the Study M14-533 if the subject is enrolled 
into Study M14-533
If an incomplete onset date was collected for an adverse event, the event will be assumed 
to be treatment-emergent unless there is other evidence that confirms that the event was 
not treatment-emergent (e.g., the event end date was prior to the study drug start date).  
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any TEAE related to study drug according to the investigator
●
Any severe TEAE
●
Any serious TEAE
●
Any TEAE leading to discontinuation of study drug
●
Any TEAE leading to death
●
TEAEs of Special Interest (as defined in Appendix B)
●
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○
Deaths occurring ≤ 30 days after last dose of study drug
○
Deaths occurring > 30 days after last dose of study drug
In addition, an overview of AEs per 100 patient-years of study exposure will be presented 
for the AE categories defined above.  The number of TEAEs reported, the total number of 
years of study drug exposure, and the TEAE rate per 100 patient-years will be presented.
For the SA_A and SA_C populations, 95% CI will be provided for the treatment 
differences between each upadacitinib group and placebo group. The treatment difference 
and 95% CI will be adjusted by the study size of the Phase 2b Induction Study and 
Induction Studies described by Sui et al.7
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by 
subject number and SOC and PT.  Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to investigational product will be reported.  The SOCs will be presented in 
alphabetical order, and the PTs will be presented in alphabetical order within each SOC.
For summary by maximum severity, if a subject has an AE with an unknown severity, 
then the subject will be counted in the severity category of unknown, even if the subject 
has another occurrence of the same event with a severity present.  The only exception is if 
the subject has another occurrence of the same AE with the most extreme severity –
severe.  In this case, the subject will be counted under the severe category.
For summary by maximum relationship to study drug, if a subject has an AE with an 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 


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same AE with a relationship assessment of "Reasonable Possibility."  In this case, the 
subject will be counted under the "Reasonable Possibility" category.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the upadacitinib overall.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
exposure in 100 patient-years, i.e.,
100 * (Number of TEAEs) / (Total Patient Years)
where total patient years is defined as the sum of the study drug exposure of all subjects, 
normalized by 365.25, and rounded to 1 decimal place.  Note that one event per preferred 
term per day per subject will be counted in the calculation of the number of AEs (i.e., a 
preferred term will not be counted twice on the same day for the same subject).
The TEAE rates per 100 patient-years of exposure will be provided for each AE category 
in the AE overview summary (defined in Section 9.2.2) and for TEAE summary by SOC 
and PT. 
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
9.2.6
Adverse Events of Special Interest
The AESI categories will be identified by the search criteria per Standard MedDRA 
Queries (SMQs)/Company MedDRA Queries (CMQs) specified in Appendix B.


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Treatment-emergent Adverse events of special interest will be summarized by SOC and 
PT and listing format.  Additionally, AESI rates per 100 patient years of exposure will be 
provided for each AESI category (Appendix B) in the AE overview summary.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol (e.g., hematology and clinical chemistry) 
will be summarized.
Analysis of Quantitative Laboratory Parameters
Each laboratory variable will be summarized for all time points with the number of non-
missing observations, mean and standard deviation, median, minimum and maximum.  
Mean change from Maintenance Baseline to each applicable post-baseline visit will be 
summarized for selected laboratory variables, with the number of observations, baseline 
mean, and visit mean.  The change from Maintenance Baseline mean, standard error, and 
95% confidence interval will be presented within each treatment group.
Treatment group differences between upadacitinib treatment group and placebo group for 
changes from Maintenance Baseline will be analyzed using a one-way Analysis of 
Variance (ANOVA) model with treatment as a fixed factor and 95% CI for treatment 
difference will be presented for selected laboratory parameters, for SA_A and SA_C 
population only.
Shift Table Analyses
Changes in laboratory parameters will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample.  A 
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be created.  A similar shift table will be provided to summarize shifts from Baseline to the 
final post-baseline value.
Potentially Clinically Significant Laboratory Values
The criteria for potentially clinically significant laboratory values will be determined by 
CTCAE criteria of Grade 3, Grade 4 and ≥ Grade 3, with a grade worsening compared to 
baseline.  Toxicity grading scale is based on National Cancer Institute Common Toxicity 
Criteria (NCI CTC) AE version 4.03.  The number and percentage of subjects meeting the 
criteria for potentially clinically significant laboratory values will be summarized by 
treatment group.  Listings will be provided to summarize subject-level laboratory data for 
subjects meeting the criteria.
Assessment of Liver Enzyme and Bilirubin Elevations
The liver-specific laboratory tests include the serum glutamic pyruvic transaminase 
(SGPT/ALT), serum glutamic-oxaloacetic transaminase (SGOT/AST), alkaline 
phosphatase (ALP), and total bilirubin (TBL).  The frequencies and percentages of 
subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
ALP ≥ 1.5 × ULN
●
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●
ALT and/or AST ≥ 3 × ULN and TBL ≥ 2 × ULN,
where ULN is the upper normal limit.  The maximum ratio relative to the ULN will be 
used to determine if subjects meet any of the criteria listed above.
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
●
ALT ≥ 2.5 × ULN, or
●
AST ≥ 2.5 × ULN, or
●
ALP ≥ 1.5 × ULN, or
●
TBL ≥ 1.5 × ULN.
In addition, eDISH plots will be created displaying post-baseline total bilirubin versus 
post-baseline ALT, in terms of the maximum ratio relative to the ULN (not necessarily 
concurrent).
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, body weight, 
respiratory rate and body temperature will be summarized.
Each vital sign variable will be summarized for all time points with the number of non-
missing observations, mean and standard deviation, median, minimum and maximum.  
Mean change from Maintenance Baseline to each applicable post-baseline visit will be 
summarized for each vital sign variable, with the number of observations, Baseline mean, 
and visit mean.  The change from Maintenance Baseline mean, standard error, and 
95% confidence interval will be presented within each treatment group.
Treatment group differences between upadacitinib treatment group and placebo group for 
changes from Maintenance Baseline will be analyzed using a one-way Analysis of 
Variance (ANOVA) with treatment as a fixed factor and 95% CI for treatment difference 
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Vital sign variables will be evaluated based on potentially clinically significant (PCS) 
criteria (Appendix C).  For each vital sign PCI criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized.  Listings 
will be provided to summarize subject-level vital sign data for subjects meeting PCI 
criteria.
10.0
Other Analyses
No other analyses are planned.
11.0
Interim Analyses
There are no planned efficacy interim analyses.
11.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study.  The primary responsibility of the DMC will be to protect the safety of 
the subjects participating in this study.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no multiplicity adjustment is 
needed.
12.0
Overall Type-I Error Control
The iterative graphical testing procedure is provided in Figure 2.  The overall type I error 
rate of the primary and ranked secondary endpoints for the two upadacitinib doses will be 
strongly controlled using such multiple testing procedure.8 Specifically, the testing will 
utilize the sequence of hypothesis testing for the primary endpoint followed by the ranked 
key secondary endpoints in the order as specified in Section 3.2, and will begin with 


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testing the primary endpoint using α of 0.025 for each upadacitinib dose compared to 
placebo.  Continued testing will follow a pre-specified weight of α allocation between the 
single hypothesis within the family, as well as between the families of hypotheses across 
the doses (denoted as node).
In the graph, the arrows specify the weight of α allocation between nodes.  Once a 
hypothesis is rejected (i.e., deemed the endpoint is significant) at its assigned significance 
level, its significance level will be allocated to the subsequent node.  If more than 
one arrow originates from a node, the significance level will be split between multiple 
subsequent nodes following the pre-specified weight.  The numbers on the arrows denote 
the weights.  For example, the weight 1 denotes 100% transfer of significance level to the 
next node, and the weight 1/2 denotes 50% and 50% splitting of significance level 
between the 2 nodes connected to it.
No multiplicity adjustment will be applied to additional efficacy endpoints listed in 
Section 3.3.  The analysis for additional efficacy endpoints will be performed at the 
nominal α level of 0.05 (two-sided) for each dose.


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Figure 2.
Graphical Multiple Testing Procedure for Primary and Ranked 
Secondary Efficacy Endpoints (ITT_A Population)


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13.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
18 July 2018
Original version
2.0
15 October 
2020
!
Revised the SAP per the latest SAP template.
!
The following changes have occurred in order to reflect changes in the 
protocol amendment and regulatory guideline.
!
Updated secondary endpoints: added histologic-endoscopic mucosal 
improvement, change from baseline in IBDQ total score and change 
from baseline in FACIT-F score; moved response in IBDQ Bowel 
Symptom domain and response in IBDQ fatigue item to other efficacy 
endpoints.
!
Updated the 3rd ranked secondary endpoint to clarify corticosteroid 
free for ≥ 90 days immediately preceding Week 52 and modified to 
"among subjects in clinical remission at the end of the induction 
treatment in the Induction Study.
!
Non-ranked secondary endpoints are now listed under Other Efficacy 
Endpoints.
!
Added NRI-C approach for handling missing data due to COVID-19.  
NRI-C will be used for the primary efficacy analysis and NRI-NC will 
be considered as sensitivity analysis.
!
Removed the Last Observation Carried Forward (LOCF) approach 
from the missing data imputation as LOCF potentially can result in a 
biased estimation of treatment effect and underestimate the variability.
!
Added the bio-IR and non-bio-IR subgroup analysis for the secondary 
endpoints: endoscopic improvement, maintaining clinical remission, 
maintaining clinical remission and corticosteroid free, maintaining
endoscopic improvement, clinical response, endoscopic remission, 
mucosal healing.
!
Remove subgroup analyses including Baseline immunosuppressant 
use (yes, no), Baseline Adapted Mayo Score (≤ median, > median), 
Baseline Full Mayo Score (≤ 1, > 1), Baseline hs-CRP (≤ median, 
> median), Baseline fecal calprotectin (≤ 150 mg/kg, > 150 mg/kg), 
Baseline fecal calprotectin (≤ median, > median), and Baseline 
albumin (≤ median, > median).
!
Added definitions of estimand for primary and key secondary 
endpoints.
!
Clarified the MI method to handle missing data due to COVID-19 and 
other reasons.
!
Added supplementary analysis for the primary endpoint to exclude 
subjects with deviations that could potentially impact the primary 
analysis.


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Table 3.
SAP Version History Summary (Continued)
Version
Date
Summary
3.0
10 May 2021
!
Removed incidence rate of UC-related hospitalization and surgeries 
through Week 52 from secondary endpoints in Section 3.2, and add 
both as additional efficacy endpoints in Section 3.3
!
Updated additional endpoints in Section 3.3: added clinical remission 
per Partial Mayo score and corticosteroid free over time among 
subjects taking corticosteroid at Baseline in the Induction Study, 
changed the evaluation of SFS and RBS from Week 40 and 48 to 
Week 36 and Week 44 in endpoint achievement of SFS ≤ 1 (and not 
worse than Baseline), RBS = 1 at both Week 36 and Week 44, clinical 
remission per Adapted Mayo score at Week 52 and corticosteroid free 
for ≥ 90 days immediately preceding Week 52 among subjects taking 
corticosteroids at Baseline in the Induction Study. 
!
Clarified the definition of ITT populations and scopes of analyses in 
data base lock for each ITT population in Section 4.0.
!
Clarified the subject disposition and compliance summary in 
Section 5.0 and Section 6.0, respectively
!
Specified the derivation of confidence interval for difference in 
proportions between treatment groups using NRI-C approach in 
Section 8.3.1 in response to a comment from FDA on December 10, 
2020.
!
Updated the potential intercurrent events in Section 8.2
!
Added DAMI as a sensitivity analysis for continuous key secondary 
endpoints to assess the impact of potential departures from the MAR 
assumption in Section 8.4
!
Clarified the analysis method of multi-level categorical endpoints 
PGIC and PGIS in Section 8.6.  The two endpoints will be reported 
only descriptively using AO approach.  Consequently, the random 
seeds of NRI-C for PGIC and PGIS has been removed from 
Table D-1.
!
Added Baseline aminosalicylate use (yes, no) as a subgroup analysis.
!
Clarified the baseline for safety analysis in Section 9.1.
!
Added risk difference and 95% CI for TEAE analysis of SA_A and 
SA_D populations in Section 9.2.
!
Clarified the interim analysis in Section 11.0.
!
Updated the type-I error control approach in Section 12.0


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Table 3.
SAP Version History Summary (Continued)
Version
Date
Summary
4.0
20 May 2021
!
Moved the MMRM model details from Section 8.1 to Section 8.3.2.
!
Amended the primary approach to handle missing data for continuous 
endpoint from protocol-specified MMRM to RTB-MI, per FDA 
recommendation.  The protocol-specified MMRM/ANCOVA 
methods will be a sensitivity analysis for ranked continuous secondary 
endpoints.  Details are included in Section 8.3.2, Section 8.5.1 and 
Section 8.6. 
!
Updated the name of DAMI to DBMI to match with existing literature 
in Section 8.3.2 and Section 8.5.2.
!
Fixed a typo in the multiple testing procedure graph for the primary 
and ranked secondary efficacy endpoints in Section 12.0.
!
Corrected the endpoints for which the DBMI approach is to be applied 
in Appendix table D-3.
!
Added random seeds for RTB-MI in Appendix table D-4.
14.0
References
1.
Feagan BG, Rutgeerts P, Sands BE, et al.  Vedolizumab as induction and 
maintenance therapy for ulcerative colitis.  N Engl J Med.  2013;369(8):699-710.
2.
Sandborn WJ, Su C, Sands BE, et al.  Tofacitinib as induction and maintenance 
therapy for ulcerative colitis.  N Engl J Med.  2017;376(18):1723-36.
3.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data:  a case 
study using agriculture industry codes.  J Am Stat Assoc.  1987;81:366-74.
4.
Kim Y, Wang Y, et al.  Statistical Review and Evaluations (NDA 209210).  FDA.  
Reference ID 4153028.  2017.
5.
Zhang Y, Zimmer Z, Xu L, et al.  Missing Data Imputation With Baseline 
Information in Longitudinal Clinical Trials.  Stat Biopharm Res.  2020;00:0 – 7.
6.
Cro S, Morris TP, Kenward MG, et al. Sensitivity analysis for clinical trials with 
missing continuous outcome data using controlled multiple imputation: A practical 
guide. Stat Med. 2020;39(21):2815-42.


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7.
Sui S, Jiao J, Sun Y, et al. Evaluation of alternative confidence intervals to address 
non-inferiority through the stratified difference between proportions.  Pharm Stat.
2020;1-17.
8.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.


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


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


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


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Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints
The criteria for Potentially Clinically Significant (PCS) criteria for vital sign findings are 
described in Table C-1.
Table C-1.
Criteria for Potentially Clinically Significant Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight (Adults)
High
> 7% increase from baseline
Low
> 7% decrease from baseline
Weight (Adolescents)
Low
> 7% decrease from baseline


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Appendix D.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 100000 at each 
attempt until convergence of model happens.
The missing Mayo subscores are imputed to calculate the Adapted Mayo score, Partial 
Mayo score, Partial Adapted Mayo score, and Full Mayo score.
Table D-1.
Random Seeds for NRI-C
Endpoints
Random Seed
MCMC Procedure
PROC MI
Rectal bleeding subscore (0, 1, 2, 3)
31481
32061
Stool frequency subscore (0, 1, 2, 3)
31482
32062
Endoscopic subscore (0, 1, 2, 3)
31483
32063
Physician's global assessment (0, 1, 2, 3)
31484
32064
Geboes grade score (0, 1, 2, 3, 4, 5)
31485
32065
Geboes Grade 3 subscore (3.1, 3.2, 3.3)
31486
32066
No bowel urgency (0, 1)
31487
32067
No abdominal pain (0, 1, 2, 3)
31488
32068
Fecal Calprotectin (< 150 mg/kg)
31489
32069
IBDQ response and remission in domain and total score
31490
32070
Table D-2.
Random Seeds for HMI
Endpoints
Random Seed
MCMC Procedure
PROC MI
Rectal bleeding subscore (0, 1, 2, 3)
31501
32501
Stool frequency subscore (0, 1, 2, 3)
31502
32502
Endoscopic subscore (0, 1, 2, 3)
31503
32503


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Table D-3.
Random Seeds for DBMI
Endpoints
Random Seed
PROC MI
Change from Baseline in IBDQ total score
32169
Change from Baseline in FACIT-F
32170
Table D-4.
Random Seeds for RTB-MI
Endpoints
Random Seed
PROC MI
Change from Baseline in IBDQ total score
33169
Change from Baseline in FACIT-F
33170


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Appendix E.
Attributes of the Estimand for Primary and Ranked Secondary 
Endpoints
Estimand
Attributes of the Estimand
Populatio
n
Endpoint
Treatment
Intercurrent 
Events
Statistical 
Summary
Primary
ITT_A 
population1
Achievement of clinical 
remission per Adapted 
Mayo score at Week 52
Upadacitinib 
15 mg QD vs. 
placebo
Upadacitinib 
30 mg QD vs. 
placebo
IE1:
premature 
discontinuation 
of study drug
IE2: Use of 
UC-related 
rescue 
medications
All data after 
IE1 will be 
used until 
initiation or 
dose escalation 
of UC-related 
medications
All subjects 
will be 
considered as 
non-responders 
at or after IE2
Difference 
in the 
percentage 
of subjects 
achieving 
clinical 
remission 
per Adapted 
Mayo score


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Estimand
Attributes of the Estimand
Populatio
n
Endpoint
Treatment
Intercurrent 
Events
Statistical 
Summary
Categorical 
Key 
Secondary
ITT_A 
population
Achievement of 
endoscopic 
improvement/endoscopic 
remission/HEMI/mucosa
l healing/no bowel 
urgency/no abdominal 
pain at Week 52,
clinical remission per 
Adapted Mayo 
score/clinical remission 
per Adapted Mayo score 
at Week 52 and 
corticosteroid free for 
≥90 days immediately 
preceding Week 52; 
among clinical remitters 
in the Induction Study
clinical response per 
Adapted Mayo score T 
Week 52 among clinical 
responders in the 
Induction Study
endoscopic improvement 
at Week 52 among 
endoscopic improvers in 
the Induction Study
Upadacitinib 
15 mg QD vs. 
placebo
Upadacitinib 
30 mg QD vs. 
placebo
IE1: premature 
discontinuation 
of study drug
IE2: Use of 
UC-related 
rescue 
medications
All data after 
IE1 will be 
used until 
initiation or 
dose escalation 
of UC-related 
medications
All subjects 
will be 
considered as 
non-responders 
at or after IE2
Difference 
in the 
percentage
of subjects 
achieving 
each 
categorical
secondary 
endpoint


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Estimand
Attributes of the Estimand
Populatio
n
Endpoint
Treatment
Intercurrent 
Events
Statistical 
Summary
Continuous 
Key 
Secondary
ITT_A 
population 
Change from Baseline in 
IBDQ total at Week 52
Change from Baseline in 
FACIT-F score at Week 
52 
Upadacitinib 
15 mg QD vs. 
placebo
Upadacitinib 
30 mg QD vs. 
placebo
IE1:
premature 
discontinuation 
of study drug
IE2: Use of 
UC-related 
rescue 
medications
All data after 
IE1 will be 
used until 
initiation or 
dose escalation 
of UC-related 
medications
All Data at or 
after IE2 will 
not be used
(will be set as 
missing and 
imputed by 
RTB)
Difference 
in the mean 
change 
from 
Baseline in 
IBDQ total 
score and 
FACIT-F 
score
1.
ITT_A population: subjects who were randomized and received at least one dose of study drug, and were the first 
450 upadacitinib 45 mg QD 8-week induction responders, and were enrolled under the protocol for 52 week 
maintenance treatment period in Cohort 1.
In addition, a supplementary analysis will be conducted in which all data at or after IE1 
and IE2 will be used for the primary and key binary secondary endpoints.  This 
supplementary analysis corresponded to the AO analysis specified in Section 8.3.1 will 
provide additional insights into the understanding of the treatment effect.


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Statistical Analysis Plan for Substudy 2
Study 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
Date:  13 November 2020
Version 5.0


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives, Hypotheses and Estimands .....................................................5
2.2
Study Design Overview .............................................................................7
2.3
Treatment Assignment and Blinding .......................................................10
2.4
Sample Size Determination......................................................................10
3.0
Endpoints................................................................................11
3.1
Primary Endpoint.....................................................................................12
3.2
Secondary Endpoints ...............................................................................12
3.3
Other Efficacy Endpoints.........................................................................13
3.4
Safety Endpoints ......................................................................................15
4.0
Analysis Populations .............................................................16
5.0
Subject Disposition................................................................17
6.0
Study Drug Duration and Compliance................................17
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................18
7.1
Demographics and Baseline Characteristics............................................18
7.2
Medical History .......................................................................................20
7.3
Prior and Concomitant Medications ........................................................20
8.0
Efficacy Analyses...................................................................20
8.1
General Considerations............................................................................20
8.2
Handling of Potential Intercurrent Events ...............................................21
8.2.1
Premature Discontinuation of Study Drug...............................................21
8.2.2
UC-Related Corticosteroids.....................................................................21
8.3
Handling of Missing Data........................................................................22
8.3.1
Categorical Endpoints..............................................................................23
8.3.2
Continuous Endpoints..............................................................................25
8.4
Primary Efficacy Endpoint and Analyses ................................................25
8.4.1
Primary Efficacy Endpoint ......................................................................25
8.4.2
Handling of Missing Data for the Primary Efficacy Endpoint ................26
8.4.3
Primary Efficacy Analysis .......................................................................26


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8.4.4
Additional Analyses of the Primary Efficacy Endpoint...........................26
8.5
Secondary Efficacy Analyses...................................................................27
8.5.1
Key Secondary Efficacy Analyses...........................................................27
8.5.2
Supportive Secondary Efficacy Analyses ................................................27
8.6
Additional Efficacy Analyses ..................................................................27
8.7
Efficacy Subgroup Analyses....................................................................28
9.0
Safety Analyses ......................................................................29
9.1
General Considerations............................................................................29
9.2
Adverse Events ........................................................................................30
9.2.1
Treatment-Emergent Adverse Events ......................................................30
9.2.2
Adverse Event Overview .........................................................................31
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................32
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................33
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................33
9.2.6
Adverse Events of Special Interest ..........................................................33
9.3
Analysis of Laboratory Data....................................................................34
9.4
Analysis of Vital Signs ............................................................................36
10.0
Other Analyses.......................................................................37
11.0
Interim Analyses....................................................................37
11.1
Data Monitoring Committee....................................................................37
12.0
Overall Type-I Error Control ..............................................37
13.0
Version History......................................................................39
14.0
References...............................................................................40
List of Tables
Table 1.
SAP Version History Summary...............................................................39
List of Figures
Figure 1.
Induction Study Schematic ........................................................................9


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List of Appendices
Appendix A.
Protocol Deviations..................................................................................41
Appendix B.
Definition of Adverse Events of Special Interest ....................................42
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints ...............44
Appendix D.
Random Seeds..........................................................................................45
Appendix E.
Attributes of the Estimand for Primary and Ranked Secondary 
Endpoints .................................................................................................47


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Substudy 2 of 
upadacitinib Study 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.
Study M14-234 comprises 3 substudies:  a Phase 2b dose-ranging induction study 
(Substudy 1), a Phase 3 induction study (Substudy 2), and a Phase 3 maintenance study 
(Substudy 3).  Study M14-234 Substudy 2 examines the efficacy and safety of 
upadacitinib 45 mg once daily (QD) for induction therapy in subjects with moderate to 
severely active ulcerative colitis.  Throughout this SAP, "Induction Study" is used 
interchangeably for Study M14-234 Substudy 2, "Maintenance Study" is used 
interchangeably for Study M14-234 Substudy 3, and "study" refers to Study M14-234.
The analyses of pharmacokinetic endpoints, pharmacodynamic biomarker endpoints and 
exploratory research and validation endpoints will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The objective of the Induction Study is to evaluate efficacy and safety of upadacitinib 
45 mg QD compared to placebo in inducing clinical remission (per Adapted Mayo score) 


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in subjects with moderately to severely active UC who demonstrated inadequate response 
to, loss of response to, or intolerance to either biologic therapy (Bio-IR) or to 
conventional therapy (aminosalicylates, corticosteroids or immunosuppressants) but had 
not failed biologic therapy (non-Bio-IR).
Primary Efficacy Objective
The primary efficacy objective of the Induction Study is to demonstrate efficacy based on 
a higher rate of clinical remission per Adapted Mayo score after 8 weeks of treatment with 
upadacitinib 45 mg QD when compared to placebo in subjects with moderately to 
severely active UC who have demonstrated inadequate response, loss of response, or 
intolerance to oral aminosalicylates, immunosuppressants, corticosteroids, and/or biologic 
therapies.  The primary efficacy objective will be assessed based on Intent-to-Treat (ITT) 
population, which consists of all randomized subjects who have received at least one dose 
of double-blinded study drug.
Hypothesis corresponding to the primary efficacy objective and endpoint is:
●
The proportion of subjects achieving clinical remission per Adapted Mayo 
score treated with upadacitinib 45 mg QD is greater than those treated with 
placebo at Week 8.
The estimand corresponding to the primary efficacy objective is defined as follows:
●
Difference in the percentage of subjects achieving clinical remission per 
Adapted Mayo score at Week 8 regardless of premature discontinuation of 
study drug and without initiation or dose escalation of UC-related 
corticosteroids (See Section 8.2.2) in the upadacitinib 45 mg QD and placebo 
groups in the ITT population.
Secondary Efficacy Objectives
The secondary efficacy objectives of the Induction Study are to demonstrate higher 
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to the ranked secondary endpoints specified in Section 3.2. The ranked secondary 
efficacy objectives will be assessed based on ITT population.
Hypotheses corresponding to the secondary efficacy objectives and endpoints are:
1.
For each of the ranked binary secondary endpoints (Section 3.2), greater proportion 
of subjects with improvement for the endpoint is achieved with upadacitinib 45 
mg QD when compared to placebo;
2.
For each of the ranked continuous endpoints (Section 3.2), greater mean change 
from baseline for the endpoint is achieved with upadacitinib 45 mg QD when 
compared to placebo.
The estimands corresponding to the secondary efficacy objectives are defined for each of 
the binary ranked secondary endpoints as follows: difference in the percentage of subjects 
achieving binary endpoints regardless of premature discontinuation of study drug and 
without initiation or dose escalation of UC-related corticosteroids (See Section 8.2.2) in 
the upadacitinib 45 mg QD and placebo groups in the ITT population.
The estimands corresponding to the secondary efficacy objectives are defined for each of 
the continuous ranked secondary endpoints as follows: difference in the mean change 
from baseline regardless of premature discontinuation of study drug and if subjects would 
not initiate or escalate dose of UC-related corticosteroids (See Section 8.2.2) in the 
upadacitinib 45 mg QD and placebo groups in the ITT population.
2.2
Study Design Overview
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy, safety, and pharmacokinetics of upadacitinib as 
induction therapy in subjects with moderately to severely active UC who have been 
inadequate responders or intolerant to oral aminosalicylates, immunosuppressants, 
corticosteroids, and/or biologic therapies. 


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The number of enrolled non-biologic-inadequate responders (non-bio-IR) subjects will be 
at least 25% and not exceed 50%.  Among bio-IR subjects, the Induction Study will allow 
enrollment of up to 30% of subjects who have failed 3 or more biologics. Among non-
bio-IR subjects, it will allow enrollment of up to 20% subjects who could also have 
previous use of biologic therapy but discontinued based on reasons other than inadequate 
response, loss of response, or intolerance.  Subjects who have used a biologic up to 1 year 
and have discontinued for reasons other than inadequate response, loss of response, or 
intolerance (e.g., change of insurance/reimbursement, well-controlled disease, etc.) may 
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 Induction Study consists of:
1.
Screening period of up to a maximum of 35 days;
2.
Part 1:  a randomized, placebo-controlled 8-week double-blind (DB) induction 
period;
3.
Part 2:  an 8-week open-label (OL) extended treatment period for subjects who do 
not achieve clinical response at Week 8 of Part 1;
4.
30-day follow-up period.
The schematics of the Induction Study design are shown in Figure 1.


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Figure 1.
Induction Study Schematic
In Part 1, approximately 462 subjects will be enrolled.  Eligible subjects will be 
randomized in a 2:1 ratio to one of the two treatment groups (DB upadacitinib 45 mg QD 
or matching placebo) for 8 weeks.
●
Group 1:  Upadacitinib 45 mg QD (blinded, n = 308)
●
Group 2:  Placebo QD (blinded, n = 154)
Part 2 is an 8-week OL extended treatment period for subjects who did not achieve 
clinical response at Week 8 in Part 1.  The objectives of Part 2 are to offer upadacitinib 
induction treatment to placebo clinical non-responders from Part 1, and to evaluate 
delayed clinical response to upadacitinib in subjects who do not initially respond to 
upadacitinib during Part 1.
Subjects who achieve clinical response at Week 8 (Part 1) or Week 16 (Part 2) will be 
eligible to enroll into Study M14-234 Substudy 3 (Maintenance Study) following written 
informed consent.  Subjects who do not achieve clinical response at Week 16 will be 


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discontinued from the study and will not be eligible to enroll into the Maintenance Study.  
Subjects who discontinued will complete the 30-Day follow-up visit.
The data collected from subjects in Part 2 will be exploratory in nature and will not be 
part of the primary efficacy analysis for the Induction Study; only descriptive statistics 
will be provided for Part 2.
2.3
Treatment Assignment and Blinding
In Part 1, approximately 462 subjects will be randomized in a 2:1 ratio to DB upadacitinib 
45 mg QD or matching placebo for 8 weeks.  The randomization will be stratified by bio-
IR status (bio-IR vs. non-bio-IR), corticosteroid use (yes vs. no) and Adapted Mayo score 
(≤ 7 vs. > 7) at Baseline.  Within bio-IR, the randomization will be further stratified by 
number of prior biologic treatments (≤ 1 vs. > 1).  Within non-bio-IR, the randomization 
will be further stratified by previous biologic use (yes vs. no).
All eligible subjects entering Part 2 will receive OL upadacitinib 45 mg QD for an 
additional 8 weeks (until Week 16).
The primary analysis will be performed after all ongoing subjects have completed the
Induction Study activities and the database has been locked. Treatment assignments for 
the Induction Study will be unblinded to AbbVie for statistical analyses.  The study sites 
and subjects will remain blinded to the DB induction treatment assignments until all 
subjects have completed the Maintenance Study.
2.4
Sample Size Determination
For the Induction Study (Part 1), approximately 462 subjects are expected to be 
randomized to upadacitinib 45 mg QD or placebo in a randomization ratio of 2:1. The 
sample size for this study is based on the expected proportion of subjects who achieve 
clinical remission per Adapted Mayo score at Week 8. Based on the results from 
Phase 2b upadacitinib Study M14-234 (Substudy 1), the proportions of subjects achieving 
clinical remission per Adapted Mayo score in upadacitinib 45 mg QD group and placebo 


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group are 19.6% and 0%, respectively.  Considering the small sample size in Phase 2b
study and more stringent definition of primary endpoint used for Phase 3 studies, clinical 
remission rate is assumed to be 5% in the placebo group and 18% in the upadacitinib 
45 mg QD treatment group. Based on these assumptions, a sample size of 154 subjects in 
placebo and 308 subjects in upadacitinib dose will have > 95% power to detect the 13% 
treatment difference in the primary endpoint between upadacitinib 45 mg QD group and 
placebo group using two-sided Fisher's exact test at a 0.05 significant level.
3.0
Endpoints
The terminologies and efficacy variables are defined as below:
●
Mayo Score
○
Full Mayo Score: composite score of UC disease activity based on the 
stool frequency subscore [SFS] (0 – 3), rectal bleeding subscore [RBS] 
(0 – 3), physician's global assessment [PGA] subscore (0 – 3) and 
endoscopic subscore (0 – 3).  This score ranges from 0 – 12 points with 
higher scores representing more severe disease.
○
Partial Mayo Score: Full Mayo score minus the endoscopic subscore.
○
Adapted Mayo Score: Full Mayo score minus the PGA subscore.
○
Partial Adapted Mayo Score: Adapted Mayo score minus the 
endoscopic subscore.
●
Clinical Remission
○
per Full Mayo Score:  Full Mayo score ≤ 2 with no subscore > 1.
○
per Adapted Mayo Score:  Adapted Mayo score ≤ 2, with SFS ≤ 1 and 
not greater than baseline, RBS of 0, and endoscopic subscore ≤ 1.
○
per Partial Mayo Score:  Partial Mayo score ≤ 2, with no subscore > 1.
●
Clinical Response
○
per Full Mayo Score:  decrease in Full Mayo score of ≥ 3 points and 
≥30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS 
≤1.


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○
per Adapted Mayo Score:  decrease in Adapted Mayo score ≥2 points 
and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute 
RBS ≤ 1.
○
per Partial Mayo Score:  decrease in Partial Mayo score ≥ 2 points and 
≥30% from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS 
≤1.
○
per Partial Adapted Mayo Score:  decrease in Partial Adapted Mayo 
score ≥ 1 point and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or 
an absolute RBS ≤ 1.
●
Endoscopic Improvement: Endoscopic subscore of 0 or 1.
●
Endoscopic Remission: Endoscopic subscore of 0.
●
Histologic Improvement: decrease from Baseline in Geboes score.
●
Histologic Endoscopic Mucosal Improvement:  Endoscopic subscore of 0 or 
1 and Geboes score ≤ 3.1.
●
Mucosal Healing:  Endoscopic score of 0 and Geboes score < 2.0.
Note:  Evidence of friability during endoscopy in subjects with otherwise "mild" 
endoscopic activity will confer an endoscopic subscore of 2.
3.1
Primary Endpoint
The primary efficacy endpoint is the achievement of clinical remission per Adapted Mayo 
score at Week 8 in Part 1.
3.2
Secondary Endpoints
The ranked secondary efficacy endpoints for Part 1 under overall type I error control are 
as follows:
1.
The achievement of endoscopic improvement at Week 8;
2.
The achievement of endoscopic remission at Week 8;
3.
The achievement of clinical response per Adapted Mayo score at Week 8;


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4.
The achievement of clinical response per Partial Adapted Mayo score at Week 2;
5.
The achievement of histologic-endoscopic mucosal improvement at Week 8;
6.
The achievement of no bowel urgency at Week 8;
7.
The achievement of no abdominal pain at Week 8;
8.
The achievement of histologic improvement at Week 8;
9.
Change from Baseline in IBDQ total score at Week 8;
10.
The achievement of mucosal healing at Week 8;
11.
Change from Baseline in FACIT-F score at Week 8.
3.3
Other Efficacy Endpoints
The following additional efficacy endpoints will be evaluated for Part 1:
●
The achievement of response in IBDQ Bowel Symptom domain (defined as 
increase of IBDQ bowel symptom domain score ≥ 6 from Baseline) at Week 8;
●
The achievement of response in IBDQ fatigue item (defined as increase of 
IBDQ fatigue item score ≥ 1 from Baseline) at Week 8;
●
The achievement of SFS of 0, RBS of 0 and endoscopic subscore of 0 at 
Week 8;
●
The achievement of SFS of 0, RBS of 0 and endoscopic subscore of ≤1 at 
Week 8;
●
The achievement of clinical remission per Full Mayo score at Week 8;
●
Change in Full Mayo score from Baseline at Week 8;
●
The achievement of clinical remission per Partial Mayo score over time;
●
The achievement of clinical response per Partial Adapted Mayo score over 
time;
●
The achievement of clinical response per Partial Mayo score over time;
●
The achievement of SFS ≤ 1 over time;
●
The achievement of RBS of 0 over time;


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The achievement of Fecal calprotectin below 150 mg/kg over time;
●
Change from Baseline in fecal calprotectin over time;
●
Change from Baseline in hs-CRP over time;
●
Change from Baseline in Partial Adapted Mayo score, Partial Mayo score and 
SFS, RBS over time;
●
Change from Baseline in UCEIS score over time;
●
Change from Baseline in laboratory and nutritional parameters (e.g., 
hemoglobin, hematocrit, albumin, total protein concentration, and weight);
●
Change from Baseline in subject-reported stool frequency (absolute values)
over time;
●
Change from Baseline in IBDQ total and domain score over time;
●
Change from Baseline in individual IBDQ item under Bowel Symptom domain 
(for Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, and Q29) over time;
●
The achievement of IBDQ response (defined as increase of IBDQ total score 
≥16 from Baseline) over time;
●
The achievement of IBDQ remission (defined as IBDQ total score ≥ 170) over 
time;
●
Change from Baseline in EQ-5D-5L score over time;
●
Change from Baseline in WPAI scores over time;
●
Change from Baseline in SF-36 Physical Component Summary (PCS) and 
Mental Component Summary (MCS) components and domain scores over time;
●
Summary of PGIC improvement category over time;
●
Summary of PGIS severity category over time;
●
Change from Baseline in FACIT-F score over time;
●
Change from Baseline in UC-SQ score over time;
●
UC-related hospitalizations through Week 8;
●
UC-related surgeries through Week 8;
●
All-cause hospitalizations through Week 8;
●
All-cause surgeries through Week 8.


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The following additional efficacy endpoints will be evaluated for Part 2:
●
The achievement of clinical remission per Adapted Mayo score at Week 16;
●
The achievement of endoscopic improvement at Week 16;
●
The achievement of endoscopic remission at Week 16;
●
The achievement of clinical response per Adapted Mayo score at Week 16;
●
The achievement of clinical response per Partial Adapted Mayo score at 
Week 10;
●
The achievement of histologic-endoscopic mucosal improvement at Week 16;
●
The achievement of no bowel urgency at Week 16;
●
The achievement of no abdominal pain at Week 16;
●
The achievement of histologic improvement at Week 16;
●
Change from Baseline in IBDQ total score at Week 16;
●
The achievement of mucosal healing at Week 16;
●
Change from Baseline in FACIT-F score at Week 16.
3.4
Safety Endpoints
The following endpoints will be included in the safety analyses:
●
Treatment emergent adverse events (TEAEs);
●
Serious adverse events (SAEs);
●
Adverse events of special interest (AESIs);
●
Adverse events (AEs) leading to discontinuation of study drug;
●
Vital signs and laboratory tests.


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4.0
Analysis Populations
Significant non-compliance was identified at an investigational site (Investigator ID 
. As a result of this finding, efficacy data for the subjects enrolled at this 
investigational site will be excluded from the statistical analyses. Safety data for those 
subjects will be included in the statistical analyses. There was 1 subject enrolled at this 
site in the Induction Study.
Intent-to-Treat (ITT) Populations
The ITT population for the 8-week DB induction period (Part 1) (denoted by ITT1) 
includes all randomized subjects who received at least one dose of double-blinded study 
drug in Part 1.  The ITT1 population will be used for all efficacy and baseline analyses for 
Part 1.
The ITT population for the 8-week OL extended treatment period (Part 2) (denoted by 
ITT2) includes all subjects who received at least one dose of upadacitinib 45 mg QD in 
Part 2.
For ITT1 population, subjects will be included in the analysis according to the treatment 
groups that they are randomized to.
Safety Populations
The safety population for Part 1 (denoted by SA1) includes all randomized subjects who 
received at least one dose of study drug in Part 1.
The safety population for Part 2 (denoted by SA2) includes all subjects who received at 
least one dose of the upadacitinib 45 mg QD in Part 2.
The all upadacitinib treated safety population (denoted by SA-UPA) includes all subjects 
who received at least one dose of upadacitinib in Part 1 or Part 2.


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For the safety populations, subjects are assigned to a treatment group based on the "as 
treated" treatment group, regardless of the treatment randomized.  The "as treated" will be 
determined by the most frequent dose regimen received in the analysis period.
5.0
Subject Disposition
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects randomized in Part 1;
●
Subjects who took at least one dose of study drug (Part 1 and Part 2);
●
Subjects who completed protocol-specified treatment (Part 1 and Part 2);
●
Subjects who prematurely discontinued study drug (Part 1 and Part 2);
●
Subjects who prematurely discontinued from study.
Number and percentage of subjects who discontinued study drug and who withdrew from 
the study will be summarized by reason (primary reason and all reasons) for each 
treatment group within Part 1 and Part 2.  Subjects with multiple reasons for premature 
discontinuation will be counted once in the calculation of the number and percentage of 
total discontinuations.
6.0
Study Drug Duration and Compliance
For the safety populations (SA1 and SA2), duration of treatment will be summarized for 
each treatment group.  Duration of treatment is defined for each subject as last dose date 
minus first dose date + 1.  Duration of treatment will be summarized using the number of 
subjects treated, mean, standard deviation, median, minimum and maximum.  In addition, 
the number and percentage of subjects in each treatment duration interval (≥ 2 weeks, 
≥4 weeks, ≥ 6 weeks, ≥ 8 weeks) will be summarized.
Treatment compliance will be summarized for each treatment period by treatment group.  
Treatment compliance is defined as the number of tablets actually taken divided by the 
number of tablets that should have been taken.  Percent compliance will be summarized.


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7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, Baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the ITT1 population overall and by 
treatment group.  Categorical variables will be summarized with the number and 
percentage of subjects; percentages will be calculated based on the number of non-
missing observations.  Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean and standard deviation, median, minimum 
and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include:
●
Sex (Male, Female)
●
Age Group 1 (< 18 year, ≥ 18 years – < 40 years, ≥ 40 years – < 65 years, 
≥65 years)
●
Age Group 2 (≤ median, > median)
●
Weight Group (≤ median, > median)
●
BMI Group (normal: < 25 kg/m2, overweight: ≥ 25 – 30 kg/m2, obese: 
≥30 kg/m2)
●
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
●
Race (White, Black/African American, American Indian/Alaska Native, Native 
Hawaiian or Other Pacific Islander, Asian, Other)
●
Region (US, ex-US)
●
Tobacco user (current, former, never, unknown)
●
Alcohol user (current, former, never, unknown)
Continuous baseline or disease characteristics variables include:
●
Weight (kg)


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●
Height (cm)
●
BMI (kg/m2)
●
Disease duration (years)
●
Full Mayo score and its components (stool frequency, rectal bleeding, 
Physician Global Assessment, and endoscopy subscores)
●
Partial Mayo score
●
Adapted Mayo score
●
hs-CRP (mg/L)
●
Fecal Calprotectin (μg/g)
●
IBDQ total and domain score
●
Short Form 36 Health Survey (SF-36) and its components
●
European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
WPAI and its components
●
Ulcerative Colitis Symptoms Questionnaire (UC-SQ)
Categorical baseline or disease characteristics variables include:
●
Bio-IR status (Bio-IR, non-Bio-IR),
●
Prior exposure to biologic therapy (yes, no) for non-Bio-IR 
●
Number of prior biologic treatments (≤ 1 or > 1) for Bio-IR
●
Prior exposure to anti-TNF (yes, no)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Baseline aminosalicylates use (yes, no)
●
Baseline Adapted Mayo score (≤ 7, > 7)
●
Baseline Full Mayo score (≤ 9, > 9)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Disease duration Group 1 (≤ 3 years, > 3 years)
●
Disease duration Group 2 (≤ median, > median)


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Disease extent (rectosigmoid, left-sided, extensive/pancolitis)
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group.  The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC.  Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name (ITT1 population 
for prior medication; ITT1 and ITT2 populations for concomitant medications).  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug in Part 1.  A concomitant medication is defined as any medication that started prior 
to the date of the first dose of study drug and continued to be taken after the first dose of 
study drug or any medication that started on or after the date of the first dose of study 
drug, but not after the date of the last dose of study drug + 1 day.  The number and 
percentage of subjects taking medications will be summarized by generic drug name 
based on the World Health Organization (WHO) Drug Dictionary for both prior and 
concomitant medications.
8.0
Efficacy Analyses
8.1
General Considerations
The efficacy analyses for the 8-week DB induction period (Part 1) will be conducted in 
the ITT1 population.  The efficacy analyses for the 8-week OL extended treatment period 
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(2-sided).  "Baseline" refers to the last non-missing observation prior to the first 
administration of the study drug or prior to the randomization if no study drug is given.
The primary analysis will be performed after all ongoing subjects have completed the 
study activities up to Week 16 and the database has been locked.  This will be the only 
and final analysis for the primary and secondary efficacy endpoints as well as all other 
efficacy endpoints in the Induction Study.
Unless otherwise specified, categorical variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) test, stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline 
corticosteroid use (yes vs. no) and Baseline Adapted Mayo score (≤7 vs. > 7).  Any 
subject who was randomized under the wrong stratum will be analyzed according to the 
actual stratum the subject belongs to.  Continuous variables collected longitudinally will 
be analyzed using Mixed-Effect Model Repeat Measurement (MMRM) method.  
Continuous variables collected at only one post-baseline visit (such as Mayo score) will 
be analyzed using an Analysis of Covariance (ANCOVA) model.
8.2
Handling of Potential Intercurrent Events
Potential intercurrent events considered in the Induction Study include 1) premature 
discontinuation of study drug and 2) initiation or dose escalation of UC-related 
corticosteroids defined in Section 8.2.2. Intercurrent events will be handled using the 
following methods for the efficacy analysis:
8.2.1
Premature Discontinuation of Study Drug
Data collected will be used regardless of premature discontinuation of study drug.
8.2.2
UC-Related Corticosteroids
The UC-related corticosteroids intercurrent event is defined as follows.
●
subjects not on UC-related corticosteroids (systemic or locally acting 
corticosteroids for UC) at Baseline who initiated UC-related corticosteroids 
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subjects on UC-related systemic corticosteroids at Baseline who have dosages 
increased to greater than the prednisone equivalent dose of corticosteroid taken
at Baseline, or initiation of any rectal corticosteroids during the Induction Study 
regardless of rectal corticosteroid dose;
●
subjects on UC-related rectal corticosteroids at Baseline who have dosages 
increased to greater than the dose taken at Baseline, or initiation of any new 
type of rectal or any systemic corticosteroids during the Induction Study.
The time point of the UC-related corticosteroids intercurrent event is defined as the date 
when one of the scenarios above occurs for a subject.  As such, subjects will be 
considered as "non-responder" for binary endpoints at or after the occurrence of the UC-
related corticosteroids intercurrent event through the end of the Induction Study.  For 
continuous endpoints, all measurements at or after the occurrence of the UC-related 
corticosteroids intercurrent event through the end of the Induction Study will not be used 
in the analysis.
8.3
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the Induction Study, or missing due to COVID-19 infection or 
logistical restrictions.
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis and the interpretation 
of clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 
recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 


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of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate.  
The intent is to provide reliable estimates of the treatment effects under the scenario 
without the impact of COVID-19 pandemic.
Handling of missing data for the efficacy analyses is described below.
8.3.1
Categorical Endpoints
For binary efficacy endpoints, missing data will be handled using the following 
approaches:
●
The primary approach for handling missing data in the analysis of binary
endpoints will use Non-Responder Imputation while incorporating Multiple 
Imputation (MI) to handle missing data due to COVID-19 (NRI-C).
The NRI-C will categorize any subject who does not have an evaluation during 
a pre-specified visit window (either due to missing assessment or due to early 
withdrawal from the study) as a non-responder for the visit.  The only 
exception is that missing data due to COVID-19 infection or logistical 
restrictions related to the COVID-19 pandemic will be handled by Multiple 
Imputation (MI).  At each visit, subjects will be characterized as responders or 
non-responders based on MI imputed values if missing due to COVID-19; 
otherwise, subjects will be considered as non-responders for missing due to 
other reasons in the NRI-C approach. In addition, at or after the occurrence of
the UC-related corticosteroids intercurrent event (see Section 8.2), subjects 
will be counted as non-responders.
●
A sensitivity analysis for categorical endpoints will use NRI with No special 
data handling for missing due to COVID-19 (NRI-NC).
NRI-NC will be performed in the same way as NRI-C without the exception
above. Missing due to COVID-19 infection or logistical restrictions will also 
be counted as non-responders.  Subjects at or after the occurrence of the UC-
related corticosteroids intercurrent event will still be counted as non-
responders.  This is the same method as the "NRI" defined in the protocol.




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visit will be excluded from the AO analysis for that visit. AO will include all 
values collected in the study.
8.3.2
Continuous Endpoints
For continuous endpoints, missing data will be handled using Mixed-Effect Model Repeat 
Measurement (MMRM).
The MMRM will be conducted using mixed model including observed measurements at 
all visits, except that measurements at or after the occurrence of UC-related 
corticosteroids intercurrent event will be excluded (see Section 8.2.2).  The mixed model 
includes the categorical fixed effects of treatment, visit and treatment-by-visit interaction, 
randomization stratification factors (bio-IR status [bio-IR vs. non-bio-IR], Baseline 
corticosteroid use [yes vs. no] and Baseline Adapted Mayo score [≤7 vs. > 7]), and the 
continuous fixed covariates of Baseline measurements.  An unstructured variance 
covariance matrix (UN) will be used.  If the model cannot converge, an autoregressive (1) 
covariance structure matrix will be used.  The parameter estimations are based on the 
method of restrictive maximum likelihood (REML).  The fixed effects will be used to 
report model-based means at corresponding visits.
8.4
Primary Efficacy Endpoint and Analyses
8.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the achievement of clinical remission per Adapted Mayo 
score at Week 8. The primary estimand is the difference in the percentage of subjects 
achieving clinical remission per Adapted Mayo score at Week 8 regardless of premature 
discontinuation of study drug and without initiation or dose escalation of UC-related 
corticosteroids (See Section 8.2.2) in the upadacitinib 45 mg QD and placebo groups in 
the ITT population.  Details of the estimand definitions are outlined in Appendix E.


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8.4.2
Handling of Missing Data for the Primary Efficacy Endpoint
The NRI-C will be the primary approach for missing data handling in the analyses of the 
primary efficacy endpoint.
The NRI-NC and HMI approaches will be used as sensitivity analyses.
8.4.3
Primary Efficacy Analysis
The primary analysis will compare the proportion of subjects achieving clinical remission 
in upadacitinib treatment group and placebo group in the ITT1 population.  The difference
between the treatment groups in the primary efficacy endpoint will be assessed using the 
CMH test and will be stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline 
corticosteroid use (yes vs. no) and Baseline Adapted Mayo score (≤7 vs. > 7).  A CMH 
based two-sided 95% confidence interval for the difference between treatment groups will 
be calculated.
8.4.4
Additional Analyses of the Primary Efficacy Endpoint
For the primary efficacy endpoint, the same CMH analysis as detailed in Section 8.1 will 
be performed using As Observed (AO) data handling without any imputation as an 
additional analysis. The analysis will be conducted on the ITT1 population who have the 
efficacy measurement at Week 8 visit.
For the primary efficacy endpoint, a supplementary analysis will be conducted to evaluate 
the potential impact of deviations. In this analysis, subjects with deviations that could 
potentially impact the analysis of primary endpoint will be excluded.  The criteria will be 
fully defined in the classification plan. Exclusion of subjects will be adjudicated by the 
therapeutic area medical director (TAMD) and reasons for the subjects to be excluded will 
be documented and finalized before the Induction Study database lock for the primary 
analysis.  Treatment difference between upadacitinib 45 mg QD and placebo with point 
estimate and 95% CI will be presented using NRI-C approach with the CMH method as 
detailed in Section 8.1.


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8.5
Secondary Efficacy Analyses
8.5.1
Key Secondary Efficacy Analyses
The key secondary endpoints are defined in Section 3.2. The estimands corresponding to 
the secondary efficacy endpoints are defined in Section 2.1.  Details of the estimand 
definitions are outlined in Appendix E.  For ITT1 Population, secondary efficacy 
endpoints in Part 1 will be analyzed by comparing upadacitinib treatment group and 
placebo group.  The binary secondary endpoints will be analyzed by CMH and the 
corresponding analyses are specified in Section 8.3.1.  The NRI-C will be the primary 
approach for missing data handling in the analyses of binary secondary efficacy 
endpoints.  The NRI-NC approach will be used as sensitivity analyses.
The continuous secondary endpoints will be analyzed by MMRM and the corresponding 
analyses are specified in Section 8.3.2.
8.5.2
Supportive Secondary Efficacy Analyses
The secondary efficacy endpoints will also be analyzed for ITT1 population using As 
Observed (AO) data handling without any imputation.  The categorical endpoints and 
continuous endpoints will be analyzed by CMH and MMRM, respectively, and the 
corresponding analyses are specified in Section 8.1.
8.6
Additional Efficacy Analyses
Additional efficacy endpoints are defined in Section 3.3. The estimands corresponding to 
the additional efficacy endpoints are defined for each of the binary additional endpoints as 
follows: difference in the percentage of subjects achieving binary endpoints; regardless of 
premature discontinuation of study drug and without initiation or dose escalation of UC-
related corticosteroids (See Section 8.2.2) in the upadacitinib 45 mg QD and placebo 
groups in the ITT population.  The estimands corresponding to the additional efficacy 
endpoints are defined for each of the continuous additional endpoints as follows:  
difference in the mean change from baseline regardless of premature discontinuation of 
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(See Section 8.2.2) in the upadacitinib 45 mg QD and placebo groups in the ITT 
population.  For ITT1 Population, additional efficacy endpoints in Part 1 will be analyzed 
by comparing upadacitinib treatment group and placebo group.  The categorical endpoints 
and continuous endpoints will be analyzed by CMH and MMRM (or ANCOVA), 
respectively, and the corresponding analyses are specified in Section 8.2.  The NRI-C 
approach will be used for missing data handling in the analyses of categorical efficacy 
endpoints.
For ITT2 population, descriptive statistics will be provided for additional efficacy 
endpoints in Part 2.  The NRI-C approach will be used for missing data handling in the 
analyses of categorical efficacy endpoints.
8.7
Efficacy Subgroup Analyses
The following subgroup analyses will be conducted for the primary efficacy endpoint in 
the ITT1 population.  Treatment difference between upadacitinib treatment group and 
placebo group with point estimate and 95% confidence interval using normal 
approximation will be presented.  The NRI-C approach will be used for missing data 
handling.  No p-value will be provided for subgroup analysis.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Bio-IR status (Bio-IR, non-Bio-IR)
●
Baseline corticosteroid use (yes, no)
●
Baseline Adapted Mayo score (≤ 7, > 7)
●
Baseline Full Mayo score (≤ 9, > 9)
●
Prior exposure to anti-TNF (yes, no) for non-Bio-IR
●
Prior exposure to biologic therapy (yes, no) for non-Bio-IR
●
Baseline weight (≤median, > median)
●
Presence of pancolitis at Baseline (yes, no)
●
Disease duration at Baseline (≤ median, > median)


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Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L)
●
Region (US versus non-US)
In addition, the following key secondary efficacy endpoints will be analyzed in the Bio-IR 
and non-Bio-IR subgroups in the ITT1 population.
●
Endoscopic remission at Week 8
●
Endoscopic improvement at Week 8
●
Clinical response per adapted Mayo score at Week 8
9.0
Safety Analyses
9.1
General Considerations
Safety analyses will be performed on the safety populations in the 8-week DB induction 
period (Part 1, SA1 population) and the 8-week OL extended treatment period (Part 2, 
SA2 population).  In addition, safety summaries will be provided on the all upadacitinib 
treated safety population (SA-UPA).
The standard safety analyses will include reporting of adverse events (AEs), adverse 
events of special interest (AESIs), laboratory, and vital signs measurements.  Frequency 
tables and exposure adjusted event rate per 100 patient-years tables of subjects with 
treatment-emergent adverse events (TEAEs) by system organ class (SOC) and by 
preferred term (PT) as in the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary will be provided by treatment group.  All continuous laboratory parameters and 
vital signs variables at each visit will also be summarized by treatment group.  Frequency 
tables of subjects meeting criteria for potentially clinically important vital sign values and 
for potentially clinically important laboratory values will be provided by treatment group.
The Baseline for safety analysis will be treatment dependent.  For SA1 population, 
laboratory and vital signs measurements, the Baseline value is defined as the last available 
measurement before study drug administration for each subject.  For SA2 and SA-UPA 


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populations, the Baseline value is defined as the last available measurement before 
first dose of upadacitinib.
Missing safety data will not be imputed.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
The Treatment-Emergent Adverse Events (TEAEs) for SA1, SA2 and the SA-UPA 
populations are defined as follows.
Part 1 (SA1 population):  TEAEs for Part 1 are defined as events that begin either on or 
after the first dose of the study drug in Part 1 and
●
until first dose of study drug in Part 2 if the subject is enrolled into Part 2 or
●
until first dose of study drug in the Maintenance Study if the subject is enrolled 
into the Maintenance Study or 
●
within 30 days after the last dose administration of the study drug for subjects 
who are not enrolled in Part 2 and do not participate in the Maintenance Study.
Part 2 (SA2 population):  TEAEs for Part 2 are defined as events that begin either on or 
after the first dose of OL upadacitinib study drug in Part 2 and


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until first dose of study drug in the Maintenance Study if the subject is enrolled 
into the Maintenance Study or
●
within 30 days after the last dose administration of the study drug for subjects 
who do not participate in the Maintenance Study.
SA–UPA population:  TEAEs are defined as events that begin either on or after the first 
dose of upadacitinib study drug in either Part 1 or Part 2 and
●
until first dose of study drug in the Maintenance Study if the subject is enrolled 
into the Maintenance Study or
●
within 30 days after the last dose administration of the study drug in Part 1 for 
subjects who are not enrolled in Part 2 and do not participate in the 
Maintenance Study or
●
within 30 days after the last dose of the study drug in Part 2 for subjects who 
are enrolled in Part 2 and do not participate in the Maintenance Study.
If an incomplete onset date was collected for an adverse event, the event will be assumed 
to be treatment-emergent unless there is other evidence that confirms that the event was 
not treatment-emergent (e.g., the event end date was prior to the study drug start date).  
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any TEAE related to study drug according to the investigator
●
Any severe TEAE
●
Any serious TEAE
●
Any TEAE leading to discontinuation of study drug
●
Any TEAE leading to death


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TEAEs of Special Interest (as defined in Appendix B)
●
All deaths
○
Deaths occurring ≤ 30 days after last dose of study drug
○
Deaths occurring > 30 days after last dose of study drug
In addition, an overview of AEs per 100 patient-years of study exposure will be presented 
for the AE categories defined above. The number of TEAEs reported, the total number of 
years of study drug exposure, and the TEAE rate per 100 patient-years will be presented.
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by 
subject number and SOC and PT.  Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to investigational product will be reported.  The SOCs will be presented in 
alphabetical order, and the PTs will be presented in alphabetical order within each SOC.
For summary by maximum severity, if a subject has an AE with an unknown severity, 
then the subject will be counted in the severity category of unknown, even if the subject 
has another occurrence of the same event with a severity present.  The only exception is if 
the subject has another occurrence of the same AE with the most extreme severity –
severe.  In this case, the subject will be counted under the severe category.
For summary by maximum relationship to study drug, if a subject has an AE with an 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 
same AE with a relationship assessment of "Reasonable Possibility."  In this case, the 
subject will be counted under the "Reasonable Possibility" category.


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In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the upadacitinib 45 mg QD treatment group.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
exposure in 100 patient-years, i.e.,
100 * (Number of TEAEs) / (Total Patient Years)
where total patient years is defined as the sum of the study drug exposure of all subjects, 
normalized by 365.25, and rounded to 1 decimal place.  Note that one event per preferred 
term per day per subject will be counted in the calculation of the number of AEs (i.e., a 
preferred term will not be counted twice on the same day for the same subject).
The TEAE rates per 100 patient-years of exposure will be provided for each AE category 
in the AE overview summary (defined in Section 9.2.2) and for TEAE summary by SOC 
and PT. 
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
9.2.6
Adverse Events of Special Interest
The AESI categories will be identified by the search criteria per Standard MedDRA 
Queries (SMQs)/Company MedDRA Queries (CMQs) specified in Appendix B.
Treatment-emergent Adverse events of special interest will be summarized by SOC and 
PT and listing format. Additionally, AESI rates per 100 patient years of exposure will be 
provided for each AESI category (Appendix B) in the AE overview summary.


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9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol (e.g., hematology and clinical chemistry) 
will be summarized.
Analysis of Quantitative Laboratory Parameters
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from Baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from Baseline 
within each treatment group.
For SA1 population, treatment group differences between upadacitinib treatment group 
and placebo group for changes from Baseline will be analyzed using a one-way Analysis 
of Variance (ANOVA) model with treatment as a fixed factor and 95% CI for treatment 
difference will be presented for selected laboratory parameters.
Shift Table Analyses
Changes in laboratory parameters will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample.  A 
shift table from Baseline to minimum and maximum value (based on normal range) will 
be created.  A similar shift table will be provided to summarize shifts from Baseline to the 
final post-baseline value.


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Potentially Clinically Significant Laboratory Values
The criteria for potentially clinically significant laboratory values will be determined by 
CTCAE criteria of Grade 3, Grade 4 and ≥ Grade 3, with a grade worsening compared to 
baseline.  Toxicity grading scale is based on National Cancer Institute Common Toxicity 
Criteria (NCI CTC) AE version 4.03.  The number and percentage of subjects meeting the 
criteria for potentially clinically significant laboratory values will be summarized by 
treatment group.  Listings will be provided to summarize subject-level laboratory data for 
subjects meeting the criteria.
Assessment of Liver Elevations
The liver-specific laboratory tests include the serum glutamic pyruvic transaminase 
(SGPT/ALT), serum glutamic-oxaloacetic transaminase (SGOT/AST), alkaline 
phosphatase (ALP), and total bilirubin (TBL).  The frequencies and percentages of 
subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
ALP ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and TBL ≥ 2 × ULN,


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where ULN is the upper normal limit.  The maximum ratio relative to the ULN will be 
used to determine if subjects meet any of the criteria listed above.
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
●
ALT ≥ 2.5 × ULN, or
●
AST ≥ 2.5 × ULN, or
●
ALP ≥ 1.5 × ULN, or
●
TBL ≥ 1.5 × ULN.
In addition, eDISH plots will be created displaying post-baseline total bilirubin versus 
post-baseline ALT, in terms of the maximum ratio relative to the ULN (not necessarily 
concurrent).
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, body weight, 
respiratory rate and body temperature will be summarized.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from Baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
Baseline mean, and visit mean.  The change from Baseline mean, standard error, and 
95% confidence interval will be presented for the mean change from Baseline within each 
treatment group.
For SA1 population, treatment group differences between upadacitinib treatment group 
and placebo group for changes from Baseline will be analyzed using a one-way Analysis 
of Variance (ANOVA) with treatment as a fixed factor and 95% CI for treatment 
difference will be presented for each vital sign variable.


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Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C).  For each vital sign PCI criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized.  Listings 
will be provided to summarize subject-level vital sign data for subjects meeting PCI 
criteria.
10.0
Other Analyses
No other analyses are planned.
11.0
Interim Analyses
There will be no efficacy interim analyses planned for the Induction Study.
11.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study.  The primary responsibility of the DMC will be to protect the safety of 
the subjects participating in this study.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no multiplicity adjustment is 
needed.
12.0
Overall Type-I Error Control
The overall type I error rate of the primary and the ranked secondary endpoints will be 
strongly controlled using the fixed-sequence multiple testing procedure.1  Specifically, the 
testing will utilize the endpoint sequence of the primary and ranked secondary endpoints 
in the order as specified in Section 3.1 and Section 3.2 at the α level of 0.05 (two-sided).


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No multiplicity adjustment will be applied to the additional efficacy endpoints listed in 
Section 3.3.  The analysis for additional efficacy endpoints will be performed at the 
nominal α level of 0.05 (two-sided).
Since there are no efficacy analyses for early stopping planned for the DMC review, no α
spending is needed due to the DMC review.


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


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Table 1.
SAP Version History Summary (Continued)
Version
Date
Summary
4.0
05 November 2020
!
Added supplementary analysis for the primary endpoint to exclude 
subjects with deviations that could potentially impact the primary 
analysis.
5.0
13 November 2020
!
Added exclusion of subjects from efficacy analysis due to site 
non-compliance. 
14.0
References
1.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.


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


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


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


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCI) criteria for vital sign findings are 
described in Table C-1.
Table C-1.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight (Adults)
High
> 7% increase from baseline
Low
> 7% decrease from baseline
Weight (Adolescents)
Low
> 7% decrease from baseline


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


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Table D-2.
Random Seeds for HMI
Endpoints
Random Seed
MCMC Procedure
PROC MI
Rectal bleeding subscore (0, 1, 2, 3)
21501
22501
Stool frequency subscore (0, 1, 2, 3)
21502
22502
Endoscopic subscore (0, 1, 2, 3)
NA
22503
Note:
The MCMC procedure is not applicable for imputation of endoscopic subscore, which is collected at Baseline 
and Week 8 only for the primary efficacy endpoint.


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


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analysis corresponded to the AO analysis specified in Section 8.3.1 will provide 
additional insights into the understanding of the treatment effect.


ABT-494
M14-234 – Statistical Analysis Plan for Substudy 1
Version 1.0 – 20 Nov 2017
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1.0
Title Page
Statistical Analysis Plan for Substudy 1
Study M14-234
A Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study to Evaluate the Safety and 
Efficacy of ABT-494 for Induction and Maintenance 
Therapy in Subjects with Moderately to Severely 
Active Ulcerative Colitis
Date:  20 Nov 2017
Version 1.0


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................4
4.0
Study Objectives, Design and Procedures............................4
4.1
Objectives .............................................................................................. 4
4.2
Design Diagram ..................................................................................... 5
4.3
Sample Size............................................................................................ 7
4.4
Substudy 1 Double-Blind Analysis ......................................................... 8
4.5
Derived, Defined and Transformed Variables ......................................... 8
5.0
Analysis Populations .............................................................9
5.1
Definition for Analysis Populations ........................................................ 9
5.2
Variables Used for Stratification of Randomization .............................. 10
6.0
Analysis Conventions .......................................................... 10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............17
7.1
Demographic and Baseline Characteristics ........................................... 17
7.2
Medical History.................................................................................... 19
7.3
Previous Treatment and Concomitant Medications ............................... 20
8.0
Patient Disposition............................................................... 20
9.0
Study Drug Exposure and Compliance.............................. 21
10.0
Efficacy Analysis .................................................................21
10.1
General Considerations......................................................................... 21
10.2
Primary Efficacy Analyses ................................................................... 22
10.3
Secondary Efficacy Analyses ............................................................... 24
10.4
Handling of Multiplicity....................................................................... 28
10.5
Efficacy Subgroup Analysis ................................................................. 28
11.0
Safety Analysis.....................................................................29
11.1
General Considerations......................................................................... 29
11.2
Analysis of Adverse Events.................................................................. 29
11.2.1
Treatment-Emergent Adverse Events.................................................... 29
11.2.2
Adverse Events of Special Interest........................................................ 31


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11.3
Analysis of Laboratory Data................................................................. 34
11.3.1
Assessment of Liver Elevation ............................................................. 34
11.4
Analysis of Vital Signs and Weight ...................................................... 35
12.0
Summary of Changes .......................................................... 36
12.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP ................................................................................... 37
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .................................................................. 37
13.0
Appendix.............................................................................. 37
14.0
References............................................................................37
List of Tables
Table 1.
Visit Windows for Analysis of Partial Mayo Score, HCRU, 
Laboratory Parameters and Vital Signs for Substudy 1 ......................... 12
Table 2.
Visit Windows for Analysis of Mayo Score, ECG, Fasting Lipids 
and Lymphocyte Subset for Substudy 1................................................ 12
Table 3.
Visit Windows for Analysis of hs-CRP and Patient Questionnaires 
(IBDQ, SF-36, etc.) for Substudy 1....................................................... 12
Table 4.
Visit Windows for Analysis of Fecal Calprotectin for Substudy 1......... 13
Table 5.
Equivalent Steroid Dose ....................................................................... 13
Table 6.
AESI with SMQs/CMQs/PTs Searches................................................. 33
Table 7.
Criteria for Potentially Clinically Significant Vital Sign Findings ......... 36
List of Figures
Figure 1.
Study Design Schematic (Substudy 1) .................................................... 7


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis to be completed by 
the AbbVie Clinical Statistics Department for the Substudy 1 of Protocol M14-234 
Amendment 2 dated 10 October 2017.  It provides details to further elaborate statistical 
methods as outlined in the protocol and describes analysis conventions to guide the 
statistical programming work.
This is the first version of the SAP for Substudy 1 of Protocol M14-234.
This analysis plan describes the primary and secondary efficacy analyses as well as the 
safety analysis for the Phase 2b dose-ranging induction substudy of Study M14-234 
(Substudy 1).  The statistical analyses presented in this SAP represent the analyses for 
Substudy 1 described in protocol Section 8.1 "Statistical and Analytical Plans" and are the 
final analyses of the Phase 2b dose-ranging portion of the study.
This document describes the analysis of data, with the exception of pharmacokinetic data 
and data from the optional exploratory research/validation studies which will be analyzed 
separately.  It takes into account ICH Guidelines E3 and E9.
Unless noted otherwise, all analyses will be performed using SAS version 9.4 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
Study M14-234 comprises three Substudies:
●
The objective of Substudy 1 (Phase 2b induction) is to characterize the dose-
response, efficacy, and safety of ABT-494 compared to placebo in inducing 
clinical remission (using the Mayo Scoring System for Assessment of 
Ulcerative Colitis Activity, excluding Physician's Global Assessment [Adapted 
Mayo score]) in subjects with moderately to severely active ulcerative colitis 


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in order to identify the induction dose of ABT-494 for further evaluation in 
Phase 3 studies including Substudy 2.
●
The objective of Substudy 2 (Phase 3 induction) is to evaluate the efficacy and 
safety of ABT-494 compared to placebo in inducing clinical remission (per 
Adapted Mayo score) in subjects with moderately to severely active ulcerative 
colitis.
●
The objective of Substudy 3 (Phase 3 maintenance) is to evaluate the efficacy 
and safety of ABT-494 compared to placebo in achieving clinical remission 
(per Adapted Mayo score) in subjects with moderately to severely active 
ulcerative colitis who had a response (per Adapted Mayo score) following 
induction with ABT-494 in either Substudy 1 or Substudy 2.
4.2
Design Diagram
Substudy 1 of Protocol M14-234 is a Phase 2b, dose-ranging, multicenter, randomized, 
double-blind, placebo-controlled study designed to evaluate the efficacy, safety, and 
pharmacokinetics of ABT-494 as induction therapy in adult subjects with moderately to 
severely active UC who have been inadequate responders or intolerant to 
immunosuppressants, corticosteroids, and/or biologic therapies. 
The study will allow enrollment of approximately 75% of subjects with a history of
inadequate response or intolerance to biologic therapies in Substudy 1.  Approximately 
350 subjects will be enrolled in Substudy 1. 
Substudy 2 of Protocol M14-234 is the Phase 3 induction proportion of Study M14-234 
that is designed to evaluate the efficacy and safety of ABT-494 dose A as identified in 
Substudy 1 compared to placebo in inducing clinical remission (per Adapted Mayo score) 
in subjects with moderately to severely active ulcerative colitis.  Approximately 
705 subjects will be enrolled in Substudy 2.
Substudy 3 of Protocol M14-234 is the Phase 3 maintenance proportion of 
Study M14-234 that is designed to evaluate the efficacy and safety of ABT-494 compared 
to placebo in achieving clinical remission (per Adapted Mayo score) in subjects with 


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moderately to severely active ulcerative colitis who had a response (per Adapted Mayo 
score) following induction with ABT-494.  Approximately 450 subjects will be enrolled 
in Substudy 3.
Substudy 1 is designed to enroll approximately 350 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
The duration of Substudy 1 could be up to 14 weeks, including a Screening Period of up 
to 5 weeks, an 8-week double-blind induction period, and a 30-day follow-up period.  
Substudy 1
Subjects (n = 250) who meet eligibility criteria will be randomized in a 1:1:1:1:1 ratio to 
one of the following double-blinded induction treatment arms:  7.5 mg QD, 15 mg QD, 
30 mg QD, 45 mg QD, or placebo QD. 
Once the 250 randomized subjects have completed 8-week induction, an analysis of 
efficacy and safety (selected laboratory parameters) of ABT-494 versus placebo will be 
performed.  This analysis is referred to as dose-selection analysis thereafter.  Based on 
this planned analysis, one induction dose of ABT-494 (Dose A) will be identified for 
further evaluation in Substudy 2 of Protocol M14-234.  In addition, the doses to be 
evaluated in Substudy 3 may be modified based on this analysis.  The results of this 
analysis will be reviewed and discussed with regulatory authorities, as applicable, prior to 
initiation of enrollment of subjects in Substudy 2.
During the analysis period, approximately 100 additional subjects will continue to be 
randomized in Substudy 1 to receive one of the following treatments: 30 mg QD or 
45 mg QD.  There will be 50 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 


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into the maintenance portion in Substudy 3.  The data collected from these subjects will 
be reported separately in the final clinical study report.
Subjects in Substudy 1 who do not achieve clinical response after completion of the 
8-week induction treatment will have the option to enroll into a separate AbbVie 
Study M14-533, a Phase 3 multicenter open-label study, and receive oral ABT-494 
therapy.  Clinical response is defined as a decrease from baseline in the Adapted Mayo 
score ≥ 2 points and ≥ 30% from baseline, PLUS a decrease in rectal bleeding subscore 
(RBS) ≥ 1 or an absolute RBS ≤ 1.
The schematic of the study design for Substudy 1 is shown in Figure 1.
Figure 1.
Study Design Schematic (Substudy 1)
Study procedures can be found in Section 5.3.1.1 and Appendix C of the protocol.
4.3
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 


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clinical remission rate of 12% in the placebo arm and maximum of 30% in at least one of 
the ABT-494 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 MCP-Mod (Multiple comparison procedure and modeling) 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, Emax, exponential, logistic and sigEmax models 
pre-specified as likely candidates to characterize the dose-response for ABT-494 for the 
primary endpoint of clinical remission per Adapted Mayo score. 
4.4
Substudy 1 Double-Blind Analysis
An analysis of the double-blind portion of Substudy 1 for primary endpoint and secondary 
efficacy variables as well as safety data collected from Baseline through double-blind 
Week 8 will be performed after the last subject in the ITT1A population (Section 5.1 for 
definition) completes the 8-week double-blind Substudy 1.  A database lock will be 
performed and any discrepant data will be clarified before the lock.
4.5
Derived, Defined and Transformed Variables
The following defined variables will be used:
●
Full Mayo Score
○
Full Mayo Score is defined as the composite score of UC disease activity 
based on the subscores of stool frequency (0 – 3), rectal bleeding (0 – 3), 
physician's global assessment (0 – 3) and endoscopy (0 – 3).  This score 
ranges from 0 – 12 points with higher scores representing more severe 
disease (also see Section 6.0 for the rules for calculation of rectal bleeding 
and stool frequency subscores).  A description of the Mayo Scoring System 
can be found in Appendix H of the protocol.
○
Clinical Response per Full Mayo Score is defined as a decrease in Full 
Mayo Score of ≥ 3 points and ≥ 30% from Baseline, PLUS a decrease in 
the rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1.


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○
Clinical Remission per Full Mayo Score is defined as Full Mayo Score ≤ 2 
with no subscore > 1.
●
Partial Mayo Score
○
Partial Mayo Score is defined as the composite score of UC disease 
activity based on the subscores of stool frequency, rectal bleeding, and 
physician's global assessment and DOES NOT include the endoscopy 
subscore.  This score ranges from 0 – 9 points (also see Section 6.0 for the
rules for calculation of rectal bleeding and stool frequency subscores).
○
Response per Partial Mayo Score is defined as a decrease in Partial Mayo 
Score ≥ 2 points and ≥ 30% from Baseline, PLUS a decrease in RBS ≥ 1 or 
an absolute RBS of 0 or 1.
○
Remission per Partial Mayo Score is defined as Partial Mayo Score ≤ 2, 
with no subscore > 1. 
●
Adapted Mayo Score
○
Adapted Mayo Score is defined as Full Mayo Score minus the Physician's 
Global Assessment (PGA) subscore.  This score ranges from 0 – 9 points.
○
Remission per Adapted Mayo Score is defined as an Adapted Mayo Score 
≤ 2, with stool frequency subscore ≤ 1, RBS of 0, and endoscopic subscore 
≤ 1.
○
Response per Adapted Mayo Score is defined as a decrease in the Adapted 
Mayo Score ≥ 2 points and ≥ 30% from baseline, PLUS a decrease in RBS 
≥ 1 or an absolute RBS ≤ 1.
●
Endoscopic Remission:  Endoscopic subscore of 0
●
Endoscopic Improvement: endoscopy subscore of 0 or 1
5.0
Analysis Populations
5.1
Definition for Analysis Populations
The following populations will be used for analyses in Substudy 1:
The intent-to-treat (ITT) analysis set for Substudy 1 includes all randomized subjects who 
received at least one dose of study drug from Substudy 1 at the time of dose-selection 


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analysis, denoted as ITT1A.  The ITT analysis set that includes all ITT1A subjects, plus 
all the additional subjects who were randomized to ABT-494 30 mg and 45 mg groups 
during the dose-selection analysis period is denoted as ITT1B. 
The safety analysis set in Substudy 1 consists of all subjects who received at least 
one dose of study medication in the study.  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 will be carried out using the safety 
analysis set.
5.2
Variables Used for Stratification of Randomization
In Substudy 1 (Phase 2b 8 week induction), 250 subjects who meet all the inclusion and 
none of the exclusion criteria defined in the protocol (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 (ABT-494 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 and > 7).
6.0
Analysis Conventions
Definition of Baseline 
The Baseline visit date for Substudy 1 is the date when the first dose of study drug is 
received and referred to as Day 1 or Week 0.  The Baseline value for a variable is defined 
as the last non-missing value on or before the date of the first dose of study drug.
Definition of Final Observation
Final Observation in the 8-week Substudy 1 is defined as the last non missing observation 
collected within 30 days following the last dose of study drug for subjects who are not re-
randomized into Substudy 3 or enrolled into Study M14-533, and on or before the day of 
the first dose of study drug in Substudy 3 or Study M14-533 for subjects who are re-
randomized into Substudy 3 or enrolled into Study M14-533.  Of note, the efficacy, 


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laboratory, and vital sign evaluations performed on the day of the first dose of study drug 
in Substudy 3 or Study M14-533 for Substudy 1 subjects will be included in the efficacy 
and safety analyses for Substudy 1.  AEs with onset on the date of the first dose of 
Substudy 3 or Study M14-533 will be attributed to Substudy 3 or Study M14-533, 
respectively.
Definition of Study Drug Exposure
Study drug exposure during Substudy 1 is measured as follows:
Study drug exposure = (date of last dose of study drug – date of first dose of study drug 
+ 1 day).
Definition of Rx Days (Days Relative to the First Dose of Study Drug)
Rx Days are calculated for each time point of interest and it provides a quantitative 
measure of days between the event and the first dose date.  That is, the Rx Day is 
calculated as the event date minus the date of first dose of study drug plus 1.  The Rx Day 
will be a negative value when the time point of interest is prior to the date of first dose of 
study drug, and the Rx Day will be a positive value when the time point of interest is after 
the first dose date.  By this calculation algorithm the first dose day is Rx Day 1, while the 
day prior to the date of first dose is defined as Rx Day –1 (there is no Rx Day 0).  
Rx Days are used to map actual study visits to the protocol specified study visits.
Definition of Analysis Windows
Since subjects do not always adhere to the study visit schedule, the following rules will be 
applied to assign actual visits to protocol-specified visits including early termination 
visits.  For each study visit mentioned in the protocol, a nominal or target day will be 
selected to represent the corresponding visit along with a window around the target day.  
Windows will be selected in a non-overlapping fashion so that a date collected on the 
CRF does not correspond to multiple visit windows.  Moreover, windows will not discard 
any Post-Baseline measurement recorded on the CRF.  If a subject had two or more actual 
visits in one visit window, the visit closest to the schedule visit will be used as the study 


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visit for that window.  If two visits are equidistant from the target, then the later visit will 
be used for reporting.  If more than one assessment is collected on the same day, then the 
average of those assessments will be used in analyses.
Table 1.
Visit Windows for Analysis of Partial Mayo Score, HCRU, 
Laboratory Parameters and Vital Signs for Substudy 1
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Week 0
1a
≤ 1
Week 2
15
2 – 22
Week 4
29
23 – 36
Week 6
43
37 – 50
Week 8
57
51 – 71b
Rx Day A = date of visit – date of first study drug in Substudy 1 + 1.  
a.
Day of first dose of study drug in Substudy 1.
b.
Rx Day 71 or the date of the first dose of Substudy 3/Study M14-533, whichever is earlier.
Table 2.
Visit Windows for Analysis of Mayo Score, ECG, Fasting Lipids 
and Lymphocyte Subset for Substudy 1
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Week 0
1a
≤ 1
Week 8
57
2 – 71b
Rx Day = date of visit – date of first study drug in Substudy 1 + 1.  
a.
Day of first dose of study drug in Substudy 1.
b.
Rx Day 71 or the date of the first dose of Substudy 3/Study M14-533, whichever earlier.
Table 3.
Visit Windows for Analysis of hs-CRP and Patient Questionnaires 
(IBDQ, SF-36, etc.) for Substudy 1
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Week 0
1a
≤ 1
Week 2
15
2 – 22
Week 4
29
23 – 43
Week 8
57
44 – 71b
Rx Day = date of visit – date of first study drug in Substudy 1 + 1.  
a.
Day of first dose of study drug in Substudy 1.
b.
Rx Day 71 or the date of the first dose of Substudy 3/Study M14-533, whichever earlier.


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Table 4.
Visit Windows for Analysis of Fecal Calprotectin for Substudy 1
Scheduled Week
Nominal Day
Time Window (Rx Day Range)
Week 0
1a
≤ 1
Week 2
15
2 – 36
Week 8
57
37 – 71b
Rx Day = date of visit – date of first study drug in Substudy 1 + 1.  
a.
Day of first dose of study drug in Substudy 1.
b.
Rx Day 71 or the date of the first dose of Substudy 3/Study M14-533, whichever earlier.
Rules for Efficacy Assessment Based on Concomitant Treatment
Subjects in whom the maximum steroid dose exceeds the dose used at Baseline will be 
considered non-responders and will be censored for efficacy assessments (i.e., they will be 
considered non-responders for categorical endpoints and will have Baseline values carried 
forward for non-categorical assessments) from that point forward through the end of the 
study.  These subjects will continue to be evaluated in the safety analysis set.
The equivalent steroid dose will be determined based on Table 5:
Table 5.
Equivalent Steroid Dose
Corticosteroid
Equivalent Dose (mg)
Cortisone
25
Hydrocortisone
20
Prednisone
5
Prednisolone
5
Triamcinolone
4.0
Methylprednisolone
4.0
Betamethasone
0.75
Dexamethasone
0.75
Budesonide
1
Beclomethasone
5
Subjects in whom the following UC-related medications (oral aminosalicylates, systemic 
corticosteroids, and MTX) that were not being taken at Baseline and are initiated during 


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the study or who have dosages of these medications increased to greater than the dose 
taken at Baseline will be censored for efficacy assessments (i.e., will be considered non-
responders for categorical endpoints and will have the last values carried forward for non-
categorical assessments) from that point through the end of the study.  These subjects will 
continue to be evaluated in the safety analysis set.
Definition of Missing Data Imputation
The following imputation methods will be used to impute missing values in the efficacy 
analyses.  In addition, an observed case analysis will be performed.
Non-Responder Imputation (NRI)
The NRI approach is used for binary efficacy variables.  These variables can take values 
of 'Achieved' or 'Not Achieved' or may be missing for any reason including 
discontinuation from study.  According to the NRI imputation approach, all missing 
values will be considered as 'Not Achieved.' 
Last Observation Carried Forward (LOCF)
For all variables (categorical variables and continuous variables), the following rules will 
be used for the LOCF approach:
1.
Baseline and Pre-Baseline values will not be used to impute the missing 
Post-Baseline values.
2.
Missing values after Study Day 1 will be imputed using the latest non-missing 
values after Day 1 and prior to the missing value.  If there are no non-missing 
values after Baseline, then the LOCF value will be missing.
Hybrid Multiple Imputation Method
Primary endpoint of clinical remission will be analyzed using hybrid multiple imputation 
method.  Subjects who discontinue prior to Week 8 due to lack of efficacy or AEs will be 


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considered as "not achieved" for clinical remission.  Subjects who discontinue for other 
reasons will be categorized according to multiple imputations. 
Mixed-Effect Model Repeated Measure (MMRM)
The MMRM model will be used for continuous efficacy variables with longitudinal data 
as the primary analysis.  The MMRM model includes the baseline values as covariate; 
randomization stratification factors, treatment, time point and treatment-by-time point 
interaction as fixed effects; and subjects within treatment as random effect.  An 
unstructured (co)variance structure will be used to model the within subject error.  The 
comparison at a time point will be the contrast between treatments at that time point.  
Satterthwaite's approximation will be used to estimate denominator degrees of freedom.  
Observed Case (OC)
Observed case analysis will be performed such that missing values will not be imputed.  
Imputation of Missing Dates
For Baseline, efficacy, and safety parameters, if the day and/or month are missing, the 
following conventions will be used to impute the missing dates:
●
01 for missing start day
●
End of month for missing end day
●
January 1st for missing start month
●
December 31st for missing end month
In case of partially missing AE start and stop dates, the dates will be imputed by 
comparing to first dose date of study medication so that the corresponding AEs will be
made treatment-emergent whenever possible.  If the start date of an AE is partially 
missing and the month is the same as the start date of a new therapy, the AE will be made 
treatment emergent to the new therapy.


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In case of missing or partially missing study drug dosing dates, the dates will not be 
imputed.  Subjects will be treated as not receiving dose on that date.
Rules for Calculation of Stool Frequency Subscore and Rectal Bleeding Subscore
The diary entries on the days the subjects take endoscopy preparation medications, the 
day of endoscopy procedure, and 2 days after endoscopy procedure will be excluded.  If a 
subject takes an antidiarrheal on a day, the stool frequency subscore is considered as 3 for 
that day.  For the calculation of the stool frequency subscore and the rectal bleeding 
subscore at each visit, the most recent consecutive 3-day period prior to the study visit 
will be used.
If diary entries from the 3 consecutive days prior to the visit are not available, the average 
of the entries from the most recent 3 non-consecutive days will be utilized.  If less than 
3 days of diary data are available, stool frequency and rectal bleeding subscores will be 
considered missing.
Rounding to one decimal place will be applied to the calculation above for the subscores, 
Adapted Mayo Score, Partial Mayo Score and Full Mayo Score.
The last day of the days used for stool frequency and rectal bleeding subscore calculation 
will be used to decide the actual visits that should be assigned to the Mayo Score and 
Partial Mayo Score data.
Definition of Prior Medications
Prior medications include all medications with an end date before the first study drug dose 
date, and the medications with start date prior to the first dose date but end date missing.
Definition of Medication Use at Baseline
Medications are considered to be used at Baseline if the medication start date is on or 
before the first study drug dose date and the medication end date is on or after the 


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first dose date.  All medications with a start date after the first dose date or an end date 
before the first dose date are excluded.
Definition of Concomitant Medications
Concomitant medications include medications with a start date prior to the Baseline date 
which are continuing after Baseline and all medications with a start date between the 
Baseline date and last study drug administration + 1 day.  All medications with an end 
date prior to the first dose date are excluded.
If the start date is completely missing for a medication and if the stop date is before the 
baseline date, it is considered previous medication and not further evaluated.  In addition 
to start date being completely missing, if the stop date is also completely missing or the 
stop date is on or after the baseline date, it will also be considered as a concomitant 
medication.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
For the subjects in ITT1A and safety analysis sets, demographic information and Baseline
values will be summarized by descriptive statistics.  Categorical data will be summarized 
by number and percent; and quantitative data will be presented by n, mean, standard 
deviation, minimum value, median, and maximum value.
In general, continuous variables will be analyzed using analysis of variance (using SAS 
procedure 'PROC GLM') with treatment group as factor.  Categorical variable will be 
analyzed using chi-square test or Fisher's exact test if ≥ 20% of the cells have expected 
cell count < 5.
The following demographic and Baseline values will be summarized.


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Continuous Variables:
●
Age (years)
●
Body weight (kg)
●
Height (cm)
●
Body Mass Index (kg/m2)
●
Blood Pressure (systolic/diastolic) (mmHg)
●
Pulse (bpm)
●
Respiratory Rate (RPM)
●
Temperature (°C)
●
IBDQ score
●
Full Mayo score and its components (stool frequency, rectal bleeding, PGA, 
and endoscopy subscores)
●
Partial Mayo score
●
Adapted Mayo score
●
hs-CRP (mg/L)
●
Fecal Calprotectin (μg/g)
●
Albumin (g/L)
●
Short Form 36 Health Survey (SF-36) and its components
●
European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
WPAI and its components
●
Ulcerative Colitis Symptoms Questionnaire (UC-SQ)
●
Disease duration
Categorical Variables:
●
Sex (male, female)
●
Race
●
Ethnicity
●
Baseline corticosteroid use (yes, no)


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Baseline immunosuppressant use (yes, no)
●
Baseline aminosalicylates use (yes, no)
●
Baseline anti-TNF use (yes, no)
●
Baseline biologics use (yes, no)
●
Baseline hs-CRP (≤ 5 mg/L and > 5 mg/L) 
●
Disease duration (≤ 3 years, > 3 years)
●
Tobacco use (user, ex-user, never used, unknown)
●
Alcohol use (drinker, ex-drinker, non-drinker, unknown)
●
Disease extent (rectosigmoid, left-sided, extensive/pancolitis)
●
Region (US, ex-US)
7.2
Medical History
The following medical history will be presented for ITT1A and safety analysis sets.
Medical and Surgical History:  A complete medical and surgical history (which includes 
CD-onset date), history of tobacco and alcohol use, and TB history will be obtained from 
each subject during the Screening period.  Medical history will be summarized using body 
system and condition/diagnosis by treatment group.  No statistical tests will be performed.
Chest X-Ray Results:  Number and percent of subjects with presence or absence of 
finding for the previous TB infection, calcified granulomas, Pleural scarring/thickening, 
and other findings will be presented by treatment group.  No statistical tests will be 
performed.
TB Test Results:  Results of PPD skin test, QuantiFERON-TB Gold test reported at 
screening visit will be summarized.  Induration will be summarized descriptively using n, 
mean, standard deviation, minimum values, median, and maximum values.  The 
frequency distribution of induration ≥ 5 and < 5 will be provided.  QuantiFERON-TB 
tests will be described as positive or negative.  Indeterminate QuantiFERON-TB test 
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the final assessment will be considered positive.  If the second QuantiFERON-TB test is 
negative, the final assessment will be considered negative.  No statistical tests will be 
performed. 
TB Prophylaxis:  History of use of TB Prophylaxis or initiation of TB prophylaxis will 
be summarized.
ECG Results:  ECG results at screening will be presented as frequency distribution 
showing results as Normal, Abnormal (Not clinically significant), Abnormal (Clinically 
significant) and Unable to evaluate/missing.  No statistical tests will be performed.
7.3
Previous Treatment and Concomitant Medications
Based on generic medication names, these categories of medications used by subjects 
before and during the study will be summarized by number and percent for ITT1A and 
safety analysis sets for the treatment groups.  No statistical tests will be performed.
The number and percent of subjects using corticosteroid, immunosuppressant, 
aminosalicylates, anti-TNF or biologics within past 90 days prior to the Baseline, and at 
the Baseline will be tabulated. In addition, the number and percent of subjects using 
UC-related antibiotics at Baseline, and biologic therapies at any time prior to Baseline 
will be tabulated.
8.0
Patient Disposition
Subject disposition will be presented for subjects in the ITT1A and safety analysis sets 
using the following information by treatment group:
●
Number and percent of subjects in various analysis sets by treatment group and 
by investigator and/or site number
●
Number and percent of subjects completing double-blind induction period and 
discontinuing on or before Week 8 visit of Substudy 1
●
Subject disposition including the number and percent of subjects who 
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Summary of protocol deviations will be provided.
9.0
Study Drug Exposure and Compliance
Study drug exposure and compliance will be summarized using the mean, standard 
deviation, minimum, median, and maximum.  Exposure to study drug will be summarized 
by treatment group.
Compliance is defined as the number of capsules taken (i.e., the difference between the 
number of capsules dispensed and the number of capsules returned) divided by the 
number of capsules a subject is supposed to take each day times the length of time that the 
subject was in the Treatment Phase of the study (i.e., Final/Discontinuation Visit date 
during Treatment Phase – Day 1 [Baseline] Visit date + 1).  Subjects with missing data for 
the number of capsules returned will be excluded from the summary.
10.0
Efficacy Analysis
10.1
General Considerations
All statistical tests will be two-sided with the significance level of 0.05.  Descriptive 
statistics will be provided.  These include the number of observations, mean, standard 
deviation, minimum, median, and maximum for continuous variables; and number and 
percent for discrete variables.  The analysis will be performed using SAS® (SAS Institute 
Inc., Cary, NC, USA).
Efficacy analyses will be performed based on ITT1A analysis set.  The primary analysis 
and ranked secondary analysis will be repeated in the ITT1B analysis set and results will 
be reported separately in the final clinical study report.
Dose Response Modeling
Other than estimating the relative treatment effect of the investigational compound 
ABT-494 to placebo, one important goal of this Phase 2b substudy is to establish 


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dose-response relationship to facilitate the dose selection for Phase 3 substudies.  Multiple 
Comparison Procedure and dose-response Modeling (MCP-Mod) with a pre-defined 
group of candidates dose response curves will be tested against flat dose-response curve to 
best characterize the dose-response relationship.
Steps of MCP-Mod:
1.
Choose a candidate set of S models.
2.
Compute the optimum contrast for each model.
3.
Use contrast test to find the significant T models while preserving FWER.
4.
Use AIC criteria to find the most significant model from the significant T models 
found from Step 3.
5.
Use the model found from Step 4 to fit observed data from the study and make 
inference (e.g., to find Minimum Effective Dose (MED) or the dose achieving 
certain amount of maximum effect), or use all significant models to make inference 
about the weighted target dose of interest.
ADDPLAN or R will be used to evaluate different dose-response models and to make 
dose recommendation. 
10.2
Primary Efficacy Analyses
This section provides the details of the primary efficacy analysis for Substudy 1.
Primary Efficacy Endpoint:
Proportion of subjects who achieve clinical remission per Adapted Mayo score (defined as 
stool frequency subscore (SFS) ≤ 1, rectal bleeding subscore (RBS) of 0, and endoscopic 
subscore ≤ 1) at Week 8.


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Analysis Data Set for the Primary Efficacy Analysis:
The primary efficacy analysis will use the ITT1A analysis data set.
Imputation Method Used for the Primary Efficacy Analysis:
The primary efficacy analysis will use the NRI method to impute the missing values at 
Week 8 for Substudy 1.  
Statistical Method of the Primary Efficacy Analysis:
The comparisons between an ABT-494 treatment group and placebo on the primary 
efficacy endpoint will be performed using MCP-Mod approach in the ITT1A analysis set.  
The dose-response relationships among the four ABT-494 treatment groups and placebo 
group will be characterized for the primary endpoint at Week 8 using MCPMod approach.  
The following models will be considered:  log-linear, Emax, exponential, logistic and 
sigEmax, Quadratic.  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.  


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The pairwise comparisons for the difference in proportions of subjects between the 
treatment groups and placebo group 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).  Additionally, the 
CMH-based 95% confidence interval for the difference in proportions will be provided.  
Sensitivity Analyses for the Primary Efficacy Endpoint:
●
Hybrid multiple imputation method, as described in Section 6.0, will be to 
impute missing data.
●
The last observation carried forward (LOCF) method will be used to impute 
missing data.
●
Analysis of the primary endpoint will be conducted excluding the ITT1A 
subjects who did not meet inclusion/exclusion criteria. 
As a sensitivity analysis, the clinical remission endpoint will also be summarized using 
the worst rectal bleeding subscore instead of the average rectal bleeding subscore.  For 
this analysis, the rectal bleeding subscore will be calculated as the worst score during the 
most recent consecutive 3-day period prior to the study visit.  If diary entries from the 
3 consecutive days prior to the visit are not available, the worst value of the entries from 
the most recent 3 non-consecutive days will be utilized.  If less than 3 days of diary data 
are available, rectal bleeding subscore will be considered missing.
In addition, an exploratory analysis of clinical remission at Week 8 will be conducted 
using the definition of stool frequency subscore (SFS) ≤ 1, rectal bleeding subscore (RBS) 
of 0, and endoscopic subscore of 0.
10.3
Secondary Efficacy Analyses
For the analysis purpose, the secondary efficacy endpoints are divided into two groups:  
(1) ranked secondary endpoints and (2) additional, non-ranked endpoints.  The 
second group includes all other additional secondary variables.  All analyses of 
secondary endpoints will be performed using the ITT1A analysis set of Substudy 1.


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Ranked secondary efficacy variables (ranked hierarchically in decreasing order) for 
Substudy 1 are:
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 
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 
The additional, non-ranked endpoints include:
●
Proportion of subjects who achieve clinical remission per Adapted Mayo score 
over time.
●
Proportion of subjects achieving clinical remission per Partial Mayo score over 
time.


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●
Proportion of subjects achieving clinical remission defined as stool frequency 
subscore ≤ 1, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1 with 
absence of friability over time.
●
Proportion of subjects achieving clinical remission defined as stool frequency 
subscore of 0, rectal bleeding subscore 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 stool frequency subscore ≤ 1 over time. 
●
Proportion of subjects with rectal bleeding subscore of 0 over time. 
●
Proportion of subjects with fecal calprotectin below 150 mg/kg over time.
●
Proportion of subjects with IBDQ response (increase of IBDQ ≥ 16 from 
Baseline) over time.
●
Change from Baseline in hs-CRP over time.
●
Change from Baseline in fecal calprotectin over time
●
Change from Baseline in 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 remission (defined as Geboes score < 2) 
at Weeks 8 and 44.
●
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 score 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 PCS, MCS components and domain scores 
over time.
●
Change in PGIC score over time. 


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Change from Baseline in FACIT-F score over time.  
●
Change from Baseline in UC-SQ score over time
●
Health care resource utilization (UC-related hospitalizations and surgeries) 
during the study.
For categorical efficacy endpoints, the pairwise comparisons for the difference in 
proportions of subjects between treatment groups and placebo group will be analyzed 
using the CMH test adjusted for previous biologic use, baseline corticosteroid use and 
baseline Adapted Mayo score (≤ 7 and > 7).  Additionally, the CMH based two-sided 95% 
confidence interval (CI) for the difference in the proportions between the treatment groups 
and placebo group will be provided.
The non-responder imputation will be used for subjects with missing data at the endpoint 
evaluated.  The last observation carried forward (LOCF) method will also be used as the 
sensitivity analyses for the secondary endpoints.
Continuous secondary efficacy variables will be analyzed using an Analysis of 
Covariance (ANCOVA) model including factors for treatment group and stratification 
variables.  Baseline values will be used as a covariate in the ANCOVA models.  
Both last observation carried forward (LOCF) and observed case (OC) analyses will be 
used for continuous endpoints when conducting ANCOVA analysis.  The LOCF analysis 
is considered primary for inferential purposes.  HCRU will be analyzed as observed only.
Continuous secondary efficacy variables with repeated measurements will also be 
analyzed using a Mixed Effect Model Repeated Measurement (MMRM).  The baseline 
values to be included in MMRM are sex, age, disease duration, Baseline IMM use, 
Baseline hs-CRP.  The comparison at a time point will be the contrast between treatments 
at that time point. 
For HCRU, the number and percentage of hospitalizations and surgeries (all-cause and 
UC-related) will be calculated for each treatment group and placebo group.  Differences 


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in the risk of hospitalization and surgeries will be compared between treatment groups and 
placebo group using Chi-square test. 
10.4
Handling of Multiplicity
Substudy 1 is the Phase 2b randomized, placebo-controlled dose ranging study.  The MCP 
step in MCPMod approach will typically be performed using an efficient test for trend, 
adjusting for the fact that multiple candidate dose response models are being considered.  
Pairwise comparisons between treatment groups and placebo group for the primary, the 
ranked secondary and non-ranked secondary efficacy variables will be analyzed at the 
nominal α level of 0.05 (two-sided).  No multiplicity adjustment will be performed for 
Substudy 1.
10.5
Efficacy Subgroup Analysis
The subgroups listed below will be used in subgroup analyses of the primary endpoint.  
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Baseline Adapted Mayo Score (≤ 7, > 7)
●
Baseline Adapted Mayo Score (≤ median, > median)
●
Baseline Full Mayo Score (≤ 9, > 9)
●
Baseline Full Mayo Score (≤ median, > median)
●
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)


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Baseline hs-CRP (≤ median, > median)
●
Baseline Albumin (≤ median, > median)
●
Region (US versus non-US)
11.0
Safety Analysis
11.1
General Considerations
All safety comparisons will be performed between treatment groups and placebo group 
using the ITT1A and safety analysis sets.  The safety variable will be summarized by 
treatment according to the treatment a subject actually received.  The differences between 
treatment groups and placebo in safety parameters will be evaluated using two-sided tests 
at the significance level of 0.05.  
Unless otherwise specified, the treatment group differences in continuous safety variables 
(e.g., change from baseline to final observation on laboratory tests) will be assessed using 
an ANOVA model with the term of treatment, and the treatment group differences in 
categorical safety variables will be evaluated using a Fisher's exact test.
Missing safety data will not be imputed.
11.2
Analysis of Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
clinical study report.
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs during Substudy 1 are defined as events that begin or worsen 
either on or after the first dose of the study medication in Substudy 1 and within 30 days 
after the last dose of the study medication in Substudy 1 for subjects who discontinued 
Substudy 1 and are not enrolled into Substudy 3 or Study M14-533, or events that begin 
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the first dose of the study medication in Substudy 3 or Study M14-533.  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, AEs by MedDRA preferred term 
and system organ class, AEs by maximum relationship to study drug, and AEs by 
maximum severity will be summarized by number and percentage.  Treatment group 
differences (each ABT-494 dose group versus placebo group, as well as ABT-494 dose 
groups combined versus placebo group) in the overall incidence of treatment emergent 
AEs will be assessed with Fisher's exact test for each preferred term for Substudy 1.
The number and percent of subjects experiencing treatment-emergent adverse events will 
be summarized for the following adverse event categories.  Comparisons of the percent of 
subjects experiencing an adverse event between treatment groups and placebo will be 
performed using Fisher's exact tests.  Only P values < 0.100 when rounded to three digits 
will be presented.
●
Any treatment-emergent adverse event.
●
Any treatment-emergent adverse event that was rated as possibly related to 
study drug by the investigator (Reasonable Possibility).
●
Any treatment-emergent severe adverse event.
●
Any treatment-emergent serious adverse event.
●
Any treatment-emergent adverse event leading to discontinuation of study 
drug.
●
Any treatment-emergent adverse event leading to death.
●
Any treatment-emergent adverse event of special interest.
Treatment-emergent adverse events will be summarized as follows:
●
Grouped by System Organ Class and Preferred Term.
●
A by-subject listing will be provided.
●
Grouped by System Organ Class, Preferred Term and Severity.
●
Grouped by System Organ Class, Preferred Term and Relationship to Study 
Drug.


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●
Grouped by System Organ Class and Preferred Term with subject numbers.
In treatment-emergent AE tables, a subject who reports more than 
one treatment-emergent AE in different system organ classes will be counted only once in 
the overall total.  A subject who reports two or more different preferred terms which are in 
the same SOC will be counted only once in the SOC total.  A subject who reports more 
than one treatment AE with the same preferred term will be counted only once for that 
preferred term using the most extreme incident (i.e., most "severe" for the severity tables 
and most "related" for the relationship tables).
Adverse events will also be summarized by maximum severity.  If a subject has an 
adverse event with unknown severity, then the subject will be counted in the severity 
category of "unknown," even if the subject has another occurrence of the same adverse 
event with a severity present.  The only exception is if the subject has another occurrence 
of the same adverse event with the most extreme severity – "Severe."  In this case, the 
subject will be counted under the "Severe" category.
Adverse events will also be summarized by maximum relationship to study, as assessed 
by the investigator.  If a subject has an adverse event with unknown relationship, then the 
subject will be counted in the relationship category of "unknown," even if the subject has 
another occurrence of the same adverse event with a relationship present.  The only 
exception is if the subject has another occurrence of the same adverse event with a 
relationship assessment of "Reasonable Possibility."  In this case, the subject will be 
counted under the "Reasonable Possibility" category, respectively.
Incidence rates per 100 patient years of exposure to study drug will be presented for AE 
overviews and for AEs by SOC and preferred term where the number of events will be 
used as the numerator.
11.2.2
Adverse Events of Special Interest
The Adverse Events of Special Interest (AESI) categories will be summarized and 
presented by treatment group and overall using primary MedDRA system organ classes 


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(SOCs) and preferred terms (PTs).  The AESI categories will be identified by the 
following search criteria per Standard MedDRA Queries (SMQs)/Company MedDRA 
Queries (CMQs) in Table 6 below.


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Table 6.
AESI with SMQs/CMQs/PTs Searches
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection
CMQ
"Opportunistic Infection"
Malignancy
SMQ
Narrow
"Malignancies"
Confirmed Malignancy
SMQ
"Malignant tumours"
Non-Melanoma Skin Cancer (NMSC)
SMQ
Broad
Skin Malignant tumours (Broad 
SMQ) removing Melanoma CMQ
Confirmed Malignancy excluding NMSC
Confirmed Malignancy Narrow 
SMQ and removing NMSC output
Lymphoma
SMQ
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders"
Gastrointestinal Perforations
SMQ
Narrow
"Gastrointestinal Perforation"
Anemia
CMQ
"Non-Hemolytic and Non-
Aplastic Anemias"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia (Veliparib Product 
Specific)"
Herpes Zoster
CMQ
"Herpes Zoster"
Creatine Phosphokinase (CPK) Elevation
PT
Search only for the PT of "Blood 
creatine phosphokinase increased"
Renal Dysfunction
SMQ
Narrow
"Acute Renal, Failure"
Tuberculosis
CMQ
"Tuberculosis"
Adjudicated Cardiovascular Events:
MACE (Fatal and Non-fatal)
Undetermined/Unknown Cause of Deaths
Other Cardiovascular events*
Venous Thromboembolic Events*,**
Other Venous Thrombosis*
Arterial Thromboembolic Events*
Output from 
CAC
*
Non-fatal events.
**
Include deep vein thrombosis (DVT) and pulmonary embolism (PE).


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Version 1.0 – 20 Nov 2017
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Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
11.3
Analysis of Laboratory Data
Changes from Baseline in continuous laboratory parameters will be summarized by n, 
mean, standard deviation, minimum value, median, and maximum value for each 
treatment group.  The mean change from Baseline will be compared between treatment 
groups and placebo at each time point using the ANOVA model with treatment as a 
factor.  The differences between treatment groups and placebo for mean changes from 
Baseline will be summarized using the mean, standard error, 95% confidence interval, and 
P value for the between-group difference.
Cross (Shift) tables from Baseline to the final value according to the normal range will be 
provided for each hematology, clinical chemistry parameter and urinalysis parameter 
except for the microscopic examination.
For selected laboratory parameter with Common Toxicity Criteria (CTC) a listing of all 
subjects with any laboratory determinations meeting CTC Version 3.0 (or later) of 
Grade ≥ 3 will be provided.  For hemoglobin, an additional list will also be provided 
based on CTC Version 3.0 (or later) of Grade ≥ 2.  For each of these subjects, the whole 
course of the parameter will be listed.  For subjects with laboratory values with CTC ≥ 3, 
all of the laboratory parameters for those subjects will be listed.
11.3.1
Assessment of Liver Elevation
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.


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Version 1.0 – 20 Nov 2017
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For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
A listing of potentially clinically significant liver elevations based on criteria specified 
above will be provided.  For each of these subjects, the whole course of the respective 
parameter will be listed.
11.4
Analysis of Vital Signs and Weight
The following vital signs are measured at every visit during the study.
●
Body Weight (kg)
●
Blood Pressure (Systolic/Diastolic) (mmHg)
●
Pulse (bpm)
●
Respiratory Rate (RPM)
●
Temperature (°C)


ABT-494
M14-234 – Statistical Analysis Plan for Substudy 1
Version 1.0 – 20 Nov 2017
36
Changes from Baseline in vital sign values will be summarized by n, mean, standard 
deviation, minimum value, median, and maximum value for each treatment group.  The 
mean change from Baseline will be compared between treatment groups and placebo at 
each time point using the ANOVA model with treatment as a factor.  The differences 
between treatment groups and placebo for mean changes from Baseline will be 
summarized using the mean, standard error, 95% confidence interval, and P-value for the 
between-group difference.
In additional, incidence of potential clinically significant results will be summarized.
The criteria for potentially clinically significant vital sign findings are presented in 
Table 7.
Table 7.
Criteria for Potentially Clinically Significant Vital Sign Findings
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 15 mmHg from Baseline
High
Value ≥ 105 mmHg and increase ≥ 15 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Respiratory Rate
Low
< 10 rpm
High
> 24 rpm
Body temperature
High
> 39.0°C (102.3°F)
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
12.0
Summary of Changes
This is the first version of the SAP.


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Version 1.0 – 20 Nov 2017
37
12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
The statistical analyses include in this SAP reflect the latest version of protocol.
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP
This is the first version of the SAP.
13.0
Appendix
None.
14.0
References
None.