Clinical trial NCT03345836
Conditions: Crohn's Disease
Keywords: Upadacitinib Crohn's Disease Efficacy Safety
Sponsor: AbbVie
Start date: 2017-11-29; Completion date: 2021-08-11
Enrollment: 624 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the efficacy and safety of upadacitinib compared to placebo as induction therapy in participants with moderately and severely active Crohn's disease (CD).

Detailed description:

Arms: arm 1: Participants received upadacitinib matching placebo tablets, orally, once daily (QD) for 12 weeks during the Double-blind (DB) Induction Period. arm 2: Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the DB Induction Period. arm 3: Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the Open-label (OL) Induction Period. arm 4: Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks (until Week 24) during the Extended Treatment (ET) Period. Participants who received placebo in Part 1 and did not achieve clinical response at Week 12 were included in this group. arm 5: Participants received upadacitinib 30 mg tablets, orally, QD for 12 weeks (until Week 24) during the ET Period. Participants who received DB upadacitinib 45 mg in Part 1 and did not achieve clinical response at Week 12 were included in this group. arm 6: Participants received upadacitinib 30 mg tablets, orally, QD for 12 weeks (until Week 24) during the ET Period. Participants who received OL upadacitinib 45 mg during Part 2 and did not achieve clinical response at Week 12 were included in this group.
Interventions: intervention 1: Matching Placebo for Upadacitinib intervention 2: Upadacitinib
Intervention descriptions: intervention 1: Matching placebo tablets intervention 2: Upadacitinib tablets

Protocol documents:
Prot_000.pdf: 
Upadacitinib (ABT-494)
M14-431 Protocol Amendment 7
EudraCT 2017-001226-18
1
1.0
Title Page
Clinical Study Protocol M14-431
A Multicenter, Randomized, Double-Blind,
Placebo-Controlled Induction Study of the Efficacy 
and Safety of Upadacitinib (ABT-494) in Subjects 
with Moderately to Severely Active Crohn's Disease 
Who Have Inadequately Responded to or are 
Intolerant to Biologic Therapy
Incorporating Administrative Changes 1 and 2, and 
Amendments 1, 2, 3, 4, 5, 6, and 7
AbbVie Investigational
  Product:
Upadacitinib (ABT-494)
Date:
05 March 2021
Development Phase:
3
Study Design:
A randomized, double-blind, placebo-controlled induction study
EudraCT Number:
2017-001226-18
Investigators:
Multicenter Trial (Investigator information is on file at AbbVie)
Sponsor:
For Non-EU Countries, 
Excluding Japan: 
AbbVie 
1 North Waukegan Road 
Bldg. AP31-2 
North Chicago, IL 60064
For Japan:
AbbVie GK
3-1-21, Shibaura, Minato ku
Tokyo 108-0023, Japan
For EU Countries:* 
AbbVie Deutschland GmbH & Co. 
KG (AbbVie) 
Knollstrasse 50
67061 Ludwigshafen 
Germany
 
NCT03345836


Upadacitinib (ABT-494)
M14-431 Protocol Amendment 7
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Sponsor/Emergency 
  Contact:
AbbVie, Inc.
Immunology Development
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Cell:
Fax:
Email:
* 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 (ABT-494)
M14-431 Protocol Amendment 7
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
01 June 2017
Amendment 1
02 October 2017
Amendment 2
24 January 2018
Amendment 2.01 (Canada Only)
16 May 2018
Amendment 2.02 (Hungary Only)
06 June 2018
Amendment 3
24 August 2018
Administrative Change 1
19 September 2018
Amendment 3.01 (Canada Only)
11 October 2018
Amendment 3.02 (Hungary Only)
11 October 2018
Amendment 4
08 April 2019
Amendment 4.01 (Canada Only)
03 May 2019
Amendment 4.02 (Hungary Only)
08 May 2019
Amendment 4.03 (China Only)
01 May 2019
Amendment 5
29 April 2020
Administrative Change 2
11 June 2020
Amendment 5.01 (Canada Only)
23 June 2020
Amendment 5.02 (Hungary Only)
23 June 2020
Amendment 5.03 (China Only)
23 June 2020
Amendment 6
24 September 2020
Amendment 6.01 (Canada Only)
02 December 2020
Amendment 6.02 (Hungary Only)
30 November 2020
Amendment 6.03 (China Only)
19 November 2020
 


Upadacitinib (ABT-494)
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The purpose of this amendment is to:
●
Update Section 5.1, Section 5.2, Section 5.5.3, Section 5.6.1, and Section 8.2 to 
decrease the sample size of Part 2 from approximately 150 subjects to 
approximately 130 subjects, and consequently the total sample size from 645 to 
625 subjects.
Rationale:  An adequate number of subjects to be enrolled in the maintenance 
study will be achieved with a smaller sample size in Part 2.
●
Update Section 5.1 to increase the maximum percentage of subjects enrolled 
who have had inadequate response or intolerance to 3 or more biologics from 
30% to 35%.
Rationale:  To revise the maximum percentage of subjects with an inadequate 
response or intolerance to 3 or more biologics based on enrollment and 
updated study sample size.
●
Update Section 1.2, Synopsis.
Rationale:  To be consistent with Amendment 7 revisions.
●
Update Section 1.2, Synopsis to delete duplicated text for multiple testing 
procedure and overall type-1 error control from statistical methods.
Rationale:  To correct a typographical error.
●
Update Section 1.2, Synopsis to add text that details for handling of missing 
data due to COVID-19 will be described and documented in the statistical 
analysis plan.
Rationale:  To align with language in Section 8.1 for COVID-19 modifications 
for statistical and analytical plans.
●
Update Section 6.1.5 to revise safety team contact information.
Rationale:  To correct per current safety team contact information.
●
Update Section 8.1 to revise text to "extent" of missing data due to COVID-19.
Rationale:  To clarify the impact of missing data due to COVID-19 on the 
efficacy analysis.
●
Update Appendix B, to revise the protocol signatories.
Rationale:  To update due to personnel changes for this protocol amendment.
●
Remove Appendix K, Protocol Amendment List of Changes.
 


Upadacitinib (ABT-494)
M14-431 Protocol Amendment 7
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Rationale:  Appendix was removed from the AbbVie protocol template.
 


Upadacitinib (ABT-494)
M14-431 Protocol Amendment 7
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-431
Name of Study Drug:  Upadacitinib (ABT-494)
Phase of Development:  3
Name of Active Ingredient:  
Upadacitinib (ABT-494)
Date of Protocol Synopsis:  05 March 2021
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the 
Efficacy and Safety of Upadacitinib (ABT-494) in Subjects with Moderately to Severely Active Crohn's 
Disease Who Have Inadequately Responded to or are Intolerant to Biologic Therapy
Objective:  The objective of Study M14-431 is to evaluate the efficacy and safety of upadacitinib 
compared to placebo as induction therapy in subjects with moderately and severely active Crohn's 
disease (CD).
Investigators:  Multicenter  
Study Sites:  Approximately 400 sites worldwide.
Study Population:  Males and females between 18 and 75 years of age (or minimum age of adult 
consent according to local regulations) with a confirmed diagnosis of CD for at least 3 months and 
moderately to severely active CD who have inadequately responded to or are intolerant to biologic 
therapy. 
Moderately to severely active CD is defined by:

Average daily very soft or liquid stool frequency (SF) ≥ 4 AND/OR average daily abdominal 
pain (AP) score ≥ 2 (values represent the unweighted daily averages of the corresponding 
subscores from the Crohn's Disease Activity Index [CDAI]); and

Evidence of mucosal inflammation, defined as Simplified Endoscopic Score for CD (SES-CD) 
≥6 (≥ 4 for subjects with isolated ileal disease), excluding the presence of narrowing 
component.
Subjects must have had an inadequate response or intolerance to one or more biologic agents for CD 
(adalimumab, certolizumab, infliximab, ustekinumab and/or vedolizumab).  The study will allow 
enrollment of up to 35% of subjects who have demonstrated inadequate response or intolerance to 3 or 
more biologics.
Number of Subjects to be Enrolled:  Approximately 625 subjects worldwide.
Methodology:  Study M14-431 is a Phase 3, randomized, double-blind, placebo-controlled induction 
study to evaluate the efficacy and safety of upadacitinib, an orally administered Janus kinase 1 inhibitor, 
in adult subjects with moderately to severely active CD who have inadequately responded to or are 
intolerant to biologic therapy.
Subjects who consent and meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into this study, which encompasses 3 parts:  (Part 1) a randomized, double-blind, placebo-
controlled induction; (Part 2) an open-label, single-arm active induction; and (Part 3) an Extended 
Treatment Period for non-responders from Part 1 or Part 2.
 


Upadacitinib (ABT-494)
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Methodology (Continued):
Study visits may be impacted due to the coronavirus disease – 2019 (COVID-19) pandemic or any state 
of emergency or pandemic situation.  If visits cannot be conducted onsite due to travel restrictions or 
other pandemic-related reasons, phone or virtual visits, visits at alternative locations, or changes in the 
visit frequency and timing of study procedures, among others may be performed.  Additional details are 
provided in the subsequent sections.  Every effort should be made to ensure the safety of subjects and 
site staff, while maintaining the integrity of the study.
Part 1
In Part 1, subjects (n = 495) will be randomized in a 2:1 ratio to upadacitinib 45 mg once daily (QD) or 
matching placebo for 12 weeks.  The randomization will be stratified by baseline corticosteroid use (yes 
or no), endoscopic disease severity (SES-CD < 15 and ≥ 15), and number of prior biologic treatments 
(> 1 and ≤1).  The data collected from subjects from Part 1 will be used for the primary efficacy 
analysis. 
Visits during the study will occur at Baseline and Weeks 2, 4, 8, and 12/Premature Discontinuation (PD) 
to collect clinical, endoscopic, and laboratory assessments of disease activity. 
At Week 12, subjects achieving clinical response, defined as ≥ 30% decrease in average daily very soft 
or liquid SF and/or ≥30% decrease in average daily AP score (both not worse than Baseline) may be 
eligible to enter the 52-week, double-blind, maintenance portion of Study M14-430. 
All subjects who do not achieve clinical response at Week 12 will be able to enroll in Part 3 (Extended 
Treatment Period) and receive double-blind upadacitinib until Week 24/PD. 
Subjects are not eligible to enter Study M14-430 until the ileocolonoscopy procedure at Week 12 has 
been completed.  If the COVID-19 pandemic precludes a subject from undergoing an endoscopy, the 
subject can enroll in Study M14-430 if clinical response was achieved at Week 12.
Part 2
Part 2 is an open-label portion (open-label cohort) of this study.  Once enrollment in Part 1 is complete, 
approximately 130 subjects will be enrolled in Part 2 to receive open-label upadacitinib 45 mg QD for 
12 weeks.  The objective of Part 2 is to have a sufficient number of subjects with clinical response to be 
rerandomized in the double-blind, maintenance portion of Study M14-430, while minimizing 
unnecessary exposure to placebo.  The data collected from subjects from Part 2 will not be part of the 
primary efficacy analysis for this study, will use descriptive statistics, and will be reported separately in 
the clinical study report.
Visits during the study will occur at Baseline and Weeks 2, 4, 8, and 12/PD to collect clinical, 
endoscopic, and laboratory assessments of disease activity. 
At Week 12, subjects achieving clinical response may be eligible to enter Study M14-430.  Subjects who 
do not achieve clinical response at Week 12 will be eligible to participate in Part 3 (Extended Treatment 
Period) to receive open-label upadacitinib 30 mg QD until Week 24/PD.
Part 3
Part 3 is a 12-week Extended Treatment Period consisting of 3 cohorts of subjects who do not achieve 
clinical response at Week 12 in Part 1 or Part 2.  The objectives of Part 3 are to offer blinded 
upadacitinib induction treatment to placebo non-responders from Part 1 and to evaluate delayed clinical 
response to upadacitinib in subjects who did not initially respond to upadacitinib during Part 1 or Part 2.
 


Upadacitinib (ABT-494)
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Methodology (Continued):

Cohort 1:  Subjects who received placebo in Part 1 and did not achieve clinical response at 
Week 12 are eligible to receive double-blind induction treatment with upadacitinib 45 mg QD 
for 12 weeks (until Week 24). 

Cohort 2:  Subjects who received double-blind upadacitinib in Part 1 and did not achieve 
clinical response at Week 12 are eligible to receive double-blind upadacitinib 30 mg QD for 
12 weeks (until Week 24).

Cohort 3:  Subjects who received open-label upadacitinib during Part 2 and did not achieve 
clinical response at Week 12 are eligible to receive open-label upadacitinib 30 mg QD for 
12 weeks (until Week 24).
Subjects in Cohort 1 and 2 will remain blinded to treatment to avoid unmasking the treatment received 
during Part 1.  The data collected from subjects from Part 3 will not be part of the primary efficacy 
analysis for this study, will use descriptive statistics, and will be reported separately in the clinical study 
report.
Subjects are not eligible to enter in Part 3 until the Week 12 endoscopy has been completed.  If the 
COVID-19 pandemic precludes a subject from undergoing an endoscopy, and the subject has not 
achieved clinical response, the subject can enter Part 3 of Study M14-431.  Visits will occur at 
Weeks 16, 20 and 24/PD to collect clinical, endoscopic, and laboratory assessments of disease activity. 
During Part 3, subjects with persistent symptoms or worsening of CD may be discontinued at any time. 
At Week 24, subjects who achieve clinical response may be eligible to enter Study M14-430.  Subjects 
are not eligible to enter Study M14-430 until the ileocolonoscopy procedure at Week 24 for evaluation 
of mucosal inflammation has been completed.  If the COVID-19 pandemic precludes a subject from 
undergoing an endoscopy, the subject can enroll in Study M14-430 if clinical response was achieved at 
Week 24.  
Subjects who do not achieve clinical response at Week 24 will be discontinued from Study M14-431 and 
will receive standard of care treatment at the investigator's discretion.  Subjects who do not achieve 
clinical response at Week 24 and all subjects who prematurely discontinue the study will have a 
follow-up visit 30 days from the last dose of study drug to collect information on new or ongoing 
adverse events (AEs) and laboratory assessments.  Subjects will be discontinued from the study if they 
withdraw consent or if they are deemed unsuitable to continue for any reason by the investigator.
The duration of the study could be up to 33 weeks, including Screening Period (5 weeks), a 12-week 
double-blind or open-label cohort Induction Period (Part 1 and Part 2), a 12-week Extended Treatment 
Period (Part 3), and a 30-day follow-up for subjects who do not enroll into Study M14-430.
At the Screening Visit, all subjects will be provided with an electronic diary.  Subjects will be instructed 
and trained on how to record CD-related symptoms (including total and very soft and liquid number of 
stools and abdominal pain), general well-being and use of anti-diarrheals on a daily basis; and use of 
medications for endoscopy preparation throughout the study.  The very soft and liquid stools are defined 
as consistency Type 6 or Type 7 based on the Bristol Stool Chart. 
 


Upadacitinib (ABT-494)
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Methodology (Continued):
The diary will be reviewed by site personnel with the subject at each visit and for the assessment of the 
clinical endpoints.  At each Study Visit, routine physical examination including evaluation of vital signs, 
extra intestinal manifestations, and presence or absence of fistulas; calculation of CDAI score, average 
daily very soft or liquid SF and average daily AP (SF and AP entries from the most recent 7-day period 
prior to each study visit will be used); monitoring of AEs; reporting of concomitant medications and 
laboratory assessments will be performed.  The very soft or liquid SF and AP score values represent the 
unweighted daily averages of the corresponding subscores from the CDAI.  Additionally, subjects will 
complete quality of life (QoL), CD symptoms, symptoms impact on QoL, and work productivity 
questionnaires throughout the study.
Subjects will undergo a full colonoscopy (ileocolonoscopy) for evaluation of mucosal inflammation 
using the SES-CD.  All endoscopies will be centrally read to document eligibility at Screening and for 
Week 12 and 24/PD assessments.  Intestinal biopsies during the endoscopic evaluation will be collected 
for histologic assessment and exploratory research during endoscopy visits at Screening, Week 12, and 
Week 24/PD in approximately 200 subjects (intestinal biopsy substudy).
Optional blood samples will be collected for exploratory research at Baseline, Week 4, Week 12, and 
Week 24/PD.  Optional stool collections will be done at Baseline, Week 4 and Week 12 for exploratory 
evaluation of biomarkers in approximately 200 subjects (fecal biomarker substudy).
Concomitant CD-Related Medications (Antibiotics, Aminosalicylates, and/or Methotrexate) 
All subjects receiving a stable dose of CD-related antibiotics, aminosalicylates, or methotrexate (MTX) 
at Baseline should maintain their concomitant treatments without dose changes through the end of the 
study.  Initiating and/or changing doses of these medications are prohibited during the study.  Doses of 
CD-related antibiotics, aminosalicylates, or MTX may be decreased only in the event of safety or 
tolerability issues.
Concomitant Corticosteroids
Subjects who enter the study on oral corticosteroids are not allowed to change the corticosteroid dose 
during the first 4 weeks of the induction treatment period.  Dose may be decreased only for safety or 
tolerability issues.  Initiating locally acting (rectal or suppository) or systemic corticosteroids is 
prohibited during the induction treatment period.
At Week 4, subjects who are on prednisone (or oral equivalent) or oral budesonide must have their 
corticosteroid dose tapered, according to the tapering schedule.
Subjects who do not achieve clinical response at Week 12 in Part 1 or Part 2, and enter Part 3 without 
having completed the steroid taper should resume the corticosteroid taper at Week 16, according to the 
tapering schedule.
 


Upadacitinib (ABT-494)
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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Confirmed diagnosis of CD for at least 3 months prior to Baseline.  Appropriate documentation of 
biopsy results consistent with the diagnosis of CD, as determined by the investigator, must be 
available.
2.
SES-CD (excluding the presence of narrowing component) ≥ 6 (or ≥ 4 for subjects with isolated 
ileal disease), as confirmed by a central reader.
3.
Average daily very soft or liquid SF ≥ 4.0 AND/OR average daily AP score ≥ 2.0 at Baseline.
4.
Demonstrated an inadequate response or intolerance to one or more of the following biologic 
agents:

At least one 6-week induction regimen of infliximab (≥ 5 mg/kg intravenous [IV] at Baseline 
and Weeks 2, and 6), 

At least one 4-week induction regimen of adalimumab (one 160 mg subcutaneous [SC] dose at 
Baseline, followed by one 80 mg SC dose at Week 2 [or one 80 mg SC dose at Baseline, 
followed by one 40 mg SC dose at Week 2, in countries where this dosing regimen is 
approved]), 

At least one 4-week induction regimen of certolizumab pegol (400 mg SC at Baseline and 
Weeks 2, and 4), 

At least one 6-week induction regimen of vedolizumab (300 mg IV at Baseline and Weeks 2, 
and 6), 

At least one 8-week induction regimen of ustekinumab [260 mg (≤ 55 kg) or 390 mg (> 55 to 
≤85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at Week 8], 

Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit 
of the above biologics,

Intolerance to a biologic may include, but not limited to infusion-related reaction, rash, serum 
sickness, anaphylaxis, elevated liver enzymes, demyelination, congestive heart failure, 
infection.  Demonstration of intolerance requires no minimum dose or duration of use.
Main Exclusion:  
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
Concomitant Medications and Treatments 
2.
Subject on CD related antibiotics who: 

has not been on stable doses of these medications for at least 14 days prior to Baseline, or 

has discontinued these medications within 14 days of Baseline. 
3.
Subject on oral aminosalicylates who: 

has not been on stable doses of these medications for at least 14 days prior to Baseline, or

has discontinued these medications within 14 days of Baseline.
4.
Subject on corticosteroids who meet the following:

prednisone or equivalent dose > 30 mg/day; or

budesonide > 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.
 


Upadacitinib (ABT-494)
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
5.
Subject on MTX who:

has not been on the current course for ≥ 42 days prior to Baseline, and

has not been on a stable dose for ≥ 28 days prior to Baseline
CD Related
6.
Subject with the ongoing following known complications of CD: 

abscess (abdominal or peri-anal), 

symptomatic bowel strictures,

> 2 entire missing segments of the following 5 segments:  terminal ileum, right colon, 
transverse colon, sigmoid and left colon, and rectum,

fulminant colitis, 

toxic megacolon, 

or any other manifestation that might require surgery while enrolled in the study. 
7.
Subject with ostomy or ileoanal pouch
8.
Subject diagnosed with conditions that could interfere with drug absorption including but not 
limited to short gut or short bowel syndrome.
9.
Subject with surgical bowel resection within the past 3 months prior to Baseline, or a history of 
> 3 bowel resections 
Safety
10. Laboratory values meeting the following criteria within the Screening period prior to the first dose 
of study drug:

Serum aspartate transaminase (AST) or alanine transaminase (ALT) > 2.0 × upper limit of the 
reference range (ULN);

Total white blood cell count < 2500/µL;

Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal 
Disease (MDRD) formula < 30 mL/min/1.73 m2;

Hemoglobin < 9 g/dL;

Platelet count < 100,000/µL;

Absolute neutrophil count  < 1200/µL;

Absolute lymphocyte count < 750/µL.
Investigational Products:
Upadacitinib (ABT-494)
Doses:
Part 1:  upadacitinib 45 mg QD
Part 2:  upadacitinib 45 mg QD
Part 3:  upadacitinib 45 mg QD or upadacitinib 30 mg QD
Mode of Administration:
Oral
Reference Therapy:
Part 1:  placebo
Doses:
N/A
Mode of Administration:
Oral
 


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Duration of Treatment:  12 weeks for subjects achieving clinical response at Week 12; or 24 weeks for 
subjects who do not achieve clinical response at Week 12.
Criteria for Evaluation:
Endpoint Definitions:

Clinical remission per patient reported outcomes (PROs):  average daily very soft or liquid 
SF ≤ 2.8 AND average daily AP score ≤1.0 and both not greater than baseline 

Clinical remission per CDAI:  CDAI < 150

Enhanced Clinical Response:  ≥ 60% decrease in average daily very soft or liquid SF and/or 
≥35% decrease in average daily AP score and both not greater than baseline, or clinical 
remission 

Clinical response 100 (CR-100): Decrease of at least 100 points in CDAI from Baseline

Clinical response:  ≥ 30% decrease in average daily very soft or liquid SF and/or ≥ 30% 
decrease in average daily AP score and both not greater than baseline

Endoscopic remission:  SES-CD ≤ 4 and at least 2 point reduction from Baseline and no 
subscore > 1 in any individual variable, as scored by central reviewer 

Endoscopic response:  decrease in SES-CD > 50% from Baseline of the induction study (or for 
subjects with an SES-CD of 4 at Baseline, at least a 2-point reduction from Baseline), as scored 
by central reviewer
Efficacy:
The co-primary and ranked secondary endpoints will be analyzed separately for EU/EMA and US/FDA 
regulatory purposes.  These endpoints are specified separately for each set of analyses.
EU/EMA Endpoints
Co-primary Endpoints: 
1.
Proportion of subjects with clinical remission per PROs at Week 12, and 
2.
Proportion of subjects with endoscopic response at Week 12.
Ranked Secondary Endpoints: 
1.
Proportion of subjects with clinical remission per CDAI (CDAI < 150) at Week 12
2.
Proportion of subjects with clinical remission per PROs at Week 4
3.
Proportion of subjects with endoscopic remission at Week 12
4.
Proportion of subjects who discontinue corticosteroid use for CD and achieve clinical remission at 
Week 12, in subjects taking corticosteroids for CD at Baseline
5.
Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue at Week 12
6.
Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 12
7.
Proportion of subjects achieving CR-100 at Week 2
8.
Proportion of subjects achieving CR-100 at Week 12
9.
Proportion of subjects with hospitalizations due to CD at during the 12 week double-blind induction 
period
10. Proportion of subjects with resolution of extra-intestinal manifestation (EIM) at Week 12, in 
subjects with EIM at Baseline.
 


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Criteria for Evaluation (Continued):
US/FDA Endpoints
Co-primary Endpoints: 
1.
Proportion of subjects with clinical remission per CDAI (CDAI < 150) at Week 12, and 
2.
Proportion of subjects with endoscopic response at Week 12.
Ranked Secondary Endpoints:
1.
Proportion of subjects with clinical remission per PROs at Week 12
2.
Proportion of subjects with endoscopic remission at Week 12
3.
Proportion of subjects who discontinue corticosteroid use for CD and achieve clinical remission per 
CDAI at Week 12, in subjects taking corticosteroids for CD at Baseline
4.
Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue at Week 12
5.
Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 12
6.
Proportion of subjects achieving CR-100 at Week 2
7.
Proportion of subjects achieving CR-100 at Week 12
8.
Proportion of subjects with clinical remission per CDAI at Week 4 
9.
Proportion of subjects with hospitalizations due to CD at during the 12-week double-blind 
induction period
10. Proportion of subjects with resolution of extra-intestinal manifestation (EIM) at Week 12, in 
subjects with EIM at Baseline.
Additional endpoints are outlined in the protocol.
Pharmacokinetic:  Upadacitinib plasma concentrations will be determined from samples collected at 
each visit beginning at Week 2.  Blood samples at the Week 4 visit will be collected prior to dosing if 
possible.  For all other visits, blood samples will be collected at any time during the visit.
Safety:  Safety analyses will be performed on the safety set, which includes all subjects who receive at 
least one dose of study drug.  The incidence of AEs, changes in vital signs, physical examination results, 
and clinical laboratory data will be assessed throughout the study.  Electrocardiograms will be performed 
at screening, and at the end of each Part 1, 2, 3 of the study.  AEs and laboratory data, when available, 
will be graded as described in the National Cancer Institute Common Terminology Criteria for Adverse 
Events and summarized accordingly.
An external, independent Data Monitoring Committee will be responsible for monitoring unblinded 
safety data and alerting AbbVie to possible safety concerns related to the conduct of the study.
Exploratory Research Variables (Optional Serum, Whole Blood, Stool and Biopsy Samples):  
Prognostic, surrogate, predictive, and pharmacodynamic biomarker signatures may be investigated.  
Samples for different applications including, but not limited to, pharmacogenetic, epigenetic, 
transcriptomic, proteomic, metabolomic, metagenomic, and targeted investigations will be collected at 
various time points.  Optional serum and whole blood collections will be done at Baseline, Week 4, 
Week 12, and Week 24/PD for evaluation of biomarkers.  Optional stool collections will be done at 
Baseline, Week 4 and Week 12 for exploratory evaluation of biomarkers.  Biopsies include optional 
samples at Screening, Week 12, and Week 24/PD.  Assessments will include but may not be limited to 
nucleic acids, proteins, metabolites, or lipids.
 


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Statistical Methods:
Efficacy:  The co-primary endpoints are the proportion of subjects with clinical remission per PROs 
(EU/EMA) or clinical remission per CDAI (US/FDA) at Week 12 and the proportion of subjects with 
endoscopic response at Week 12.  This study will evaluate one induction dose of upadacitinib 45 mg 
QD.
Efficacy analysis will be based on all intent-to-treat (ITT) subjects.  The ITT analysis set includes all 
randomized subjects who have taken at least one dose of study drug in the double-blind induction period 
from Part 1.
The comparison between treatment groups on the co-primary efficacy endpoints will be performed using 
the Cochran-Mantel-Haenszel (CMH) test and will be stratified by Baseline corticosteroid use (yes or 
no), endoscopic disease severity (SES-CD < 15 and ≥ 15), and number of prior biologics used (> 1 and 
≤1).  Both of the co-primary efficacy endpoints will be tested at two-sided significance level of 0.05.  A 
CMH-based, two-sided 95% confidence interval for the difference between treatment groups will be 
calculated.  If the average daily SF or average daily AP score (EU/EMA) or CDAI (US/FDA) data at 
Week 12 are missing, the non-responder imputation approach will be applied for the clinical remission 
per PROs and clinical remission per CDAI endpoints, respectively.  Subjects who discontinue prior to 
Week 12 for any reason will be considered as "not-achieved" for clinical remission or endoscopic 
response endpoints.
A multiple testing procedure will be used to provide strong control of the type 1 error rate at
alpha = 0.05 (2-sided) across analyses with respect to the co-primary endpoints, and ranked secondary 
endpoints.  Specifically, testing will utilize a sequence of hypothesis testing for the co-primary endpoints 
followed by the ranked secondary endpoints, and will begin with testing co-primary endpoints using α of 
0.05 (2-sided).  If both co-primary endpoints achieve statistical significance, continued testing will 
follow a pre-specified weight of α allocation between individual hypotheses as well as between families 
of hypotheses.  The details of the testing procedure will be specified and documented in the statistical 
analysis plan (SAP).
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 SES-CD) 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 for missing data will be used for categorical 
secondary endpoints.
The extent of missing data due to COVID-19 will be monitored and appropriate analysis to handle these 
missing data may be performed; details will be included in the SAP.  Further details of the statistical 
analysis will be described and documented in the SAP.
 


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Statistical Methods (Continued):
Pharmacokinetic:  A non-linear mixed-effects modeling approach will be used to estimate the 
population central values and the empirical Bayesian estimates of the individual values for upadacitinib 
oral clearance and volume of distribution.  Additional parameters may be estimated if useful in the 
interpretation of the data.  Data from this study may be combined with data from other studies for the 
population pharmacokinetic analyses.
Safety:  AEs, laboratory data, and vital signs are the primary safety parameters in this study.  All safety 
comparisons will be performed between treatment groups using the safety set.  Treatment-emergent AEs 
are defined as events that begin or worsen either on or after the first dose of the study drug and within 
30 days after the last dose of the study drug for subjects who do not participate in Study M14-430, or 
within 30 days after the last dose of study drug in Study M14-431 or first dose of study drug in 
Study M14-430 if the subject enrolls in Study M14-430, whichever comes first.
An overview of treatment-emergent AEs, including AEs of special interest, AEs leading to death, AEs 
leading to PD, AEs by Medical Dictionary for Drug Regulatory Activities 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.  
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.  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.
 


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
6-MP
6-mercaptopurine
ADL
activities of daily living
AE
adverse event
AESI
adverse event of special interest
ALC
absolute lymphocyte count
ALT 
alanine transaminase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
ANC
absolute neutrophil count
AP
abdominal pain
AST
aspartate transaminase
AUC
area under the concentration-time curve
AZA
Azathioprine
BCG
Bacille Calmette-Guérin
BID
twice daily
BP
blood pressure
CAC
Cardiovascular Adjudication Committee
CD
Crohn's disease
CDAI
Crohn's Disease Activity Index
CD4, CD8
cluster of differentiation
CGC
common gamma-chain
CGHAS/IGHAS
Colonic and Ileal Global Histologic Disease Activity Score
CL/F
oral clearance
Cmax
maximum plasma concentration
CMH
Cochran-Mantel-Haenszel
Cmin
minimum plasma concentration
CNS
central nervous system
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase
CRP
C-reactive protein
CSS
Crohn's Symptoms Severity Questionnaire
 


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CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DTP
direct to patient
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EIM
extra-intestinal manifestations
EMA
European Medicines Agency
Emax
maximum effect
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
European Quality of Life 5 Dimensions 5 Levels
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FCP
fecal calprotectin
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
gp130
glycoprotein 130
HBc Ab 
hepatitis B core antibody
HBs Ab
hepatitis B surface antibody
HBs Ag
hepatitis B surface antigen
HBV
hepatitis B virus
Hct
Hematocrit
HCV
hepatitis C virus
HCV Ab
hepatitis C virus antibody
HDL-C
high density lipoprotein cholesterol
HIV
human immunodeficiency virus
HIV Ab
human immunodeficiency virus antibody
hs-CRP
high-sensitivity C-reactive protein
IBDQ
Inflammatory Bowel Disease Questionnaire
IC50
half maximal inhibitory concentration
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
 


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IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
IL
Interleukin
IL-6R
interleukin-6 receptor
IM
Intramuscular
INF-g
interferon gamma
INR
international normalized ratio
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
IV
Intravenous
JAK
Janus kinase
LDL-C
low density lipoprotein cholesterol
lncRNA
long non-coding RNA
MACE
major adverse cardiac event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
microRNA
MMRM
Mixed-Effect Model Repeated Measure
MTX
Methotrexate
NCI
National Cancer Institute
NK
natural killer
NMSC
nonmelanoma skin cancer
NOEL
no observed effect level
NRI
non-responder imputation
NSAIDs
nonsteroidal anti-inflammatory drugs
OC
observed cases
PCR
polymerase chain reaction
PD
premature discontinuation
PGIC
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
piRNA
piwi interacting RNA
PK
Pharmacokinetic
PPD
purified protein derivative
 


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PRO
patient reported outcome
QD
once daily
QoL
quality of life
QTcF
Fridericia's correction formula
RA
rheumatoid arthritis
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SES-CD
Simplified Endoscopic Score for Crohn's Disease
SF
stool frequency
SF-36
Short Form-36
SNP
single nucleotide polymorphisms
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
TNF
tumor necrosis factor
ULN
upper limit of normal
VAS
visual analog scale
V/F
volume of distribution
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment Questionnaire 
 


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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........................................16
2.0
Table of Contents...................................................................20
3.0
Introduction ...........................................................................25
3.1
Differences Statement..............................................................................30
3.2
Benefits and Risks....................................................................................30
4.0
Study Objective......................................................................32
5.0
Investigational Plan...............................................................32
5.1
Overall Study Design and Plan:  Description ..........................................32
5.2
Selection of Study Population..................................................................43
5.2.1
Inclusion Criteria .....................................................................................43
5.2.2
Exclusion Criteria ....................................................................................45
5.2.3
Prior and Concomitant Therapy...............................................................51
5.2.3.1
Prior Therapy ...........................................................................................51
5.2.3.2
Concomitant Therapy...............................................................................52
5.2.3.2.1
Concomitant CD-Related Medications (Antibiotics, 
Aminosalicylates, and/or Methotrexate)..................................................52
5.2.3.2.2
Concomitant Corticosteroids ...................................................................52
5.2.3.3
Prohibited Therapy...................................................................................53
5.2.4
Contraception Recommendations ............................................................56
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Exploratory 
Research, and Safety Assessments/Variables ..........................................59
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................59
5.3.1.1
Study Procedures .....................................................................................59
5.3.1.2
Collection and Handling of Optional Samples for Exploratory 
Research...................................................................................................85
5.3.1.2.1
Optional Samples for Histology Exploratory Research...........................86
5.3.2
Drug Concentration Measurements .........................................................86
5.3.2.1
Collection of Samples for Analysis .........................................................86
 


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5.3.2.2
Handling/Processing of Samples .............................................................87
5.3.2.3
Disposition of Samples ............................................................................87
5.3.2.4
Measurement Methods.............................................................................87
5.3.3
Efficacy Variables....................................................................................88
5.3.3.1
Part 1 Primary Variables..........................................................................88
5.3.3.2
Part 1 Secondary Variables......................................................................89
5.3.3.2.1
Ranked Secondary Variables ...................................................................89
5.3.3.2.2
Additional Efficacy Variables..................................................................90
5.3.3.3
Part 2 Variables........................................................................................93
5.3.3.4
Part 3 Variables........................................................................................93
5.3.4
Safety Variables.......................................................................................96
5.3.5
Pharmacokinetic Variables ......................................................................96
5.3.6
Optional Exploratory Research Variables ...............................................96
5.4
Removal of Subjects from Therapy or Assessment.................................97
5.4.1
Discontinuation of Individual Subjects....................................................97
5.4.2
Discontinuation of Entire Study...............................................................99
5.5
Treatments................................................................................................99
5.5.1
Treatments Administered.........................................................................99
5.5.2
Identity of Investigational Product.........................................................100
5.5.2.1
Packaging and Labeling.........................................................................100
5.5.2.2
Storage and Disposition of Study Drug(s) .............................................100
5.5.3
Method of Assigning Subjects to Treatment Groups.............................101
5.5.4
Selection and Timing of Dose for Each Subject....................................103
5.5.5
Blinding..................................................................................................104
5.5.5.1
Blinding of Investigational Product.......................................................104
5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)....................105
5.5.6
Treatment Compliance...........................................................................105
5.5.7
Drug Accountability...............................................................................106
5.6
Discussion and Justification of Study Design........................................107
5.6.1
Discussion of Study Design and Choice of Control Groups..................107
5.6.2
Appropriateness of Measurements.........................................................108
5.6.3
Suitability of Subject Population ...........................................................108
5.6.4
Selection of Doses in the Study .............................................................108
 


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6.0
Complaints ...........................................................................109
6.1
Medical Complaints...............................................................................109
6.1.1
Definitions..............................................................................................110
6.1.1.1
Adverse Event........................................................................................110
6.1.1.2
Serious Adverse Events .........................................................................111
6.1.1.3
Adverse Events of Special Interest ........................................................112
6.1.2
Adverse Event Severity..........................................................................113
6.1.3
Relationship to Study Drug....................................................................114
6.1.4
Adverse Event Collection Period...........................................................114
6.1.5
Adverse Event Reporting.......................................................................116
6.1.6
Pregnancy...............................................................................................117
6.1.7
Toxicity Management ............................................................................118
6.1.8
Data Monitoring Committee (DMC) .....................................................122
6.1.9
Cardiovascular Adjudication Committee (CAC)...................................122
6.2
Product Complaint .................................................................................123
6.2.1
Definition ...............................................................................................123
6.2.2
Reporting................................................................................................123
7.0
Protocol Deviations..............................................................124
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................125
8.1
Statistical and Analytical Plans..............................................................125
8.1.1
Datasets for Analysis .............................................................................125
8.1.1.1
Intent to Treat Analysis Set....................................................................125
8.1.1.2
Safety Analysis Set ................................................................................125
8.1.2
Definition of Missing Data Imputation..................................................126
8.1.3
Subject Disposition ................................................................................126
8.1.4
Demographics and Baseline Characteristics..........................................126
8.1.5
Prior and Concomitant Medications ......................................................127
8.1.6
Efficacy Analysis ...................................................................................127
8.1.6.1
Primary Efficacy Variables....................................................................127
8.1.6.2
Secondary Efficacy Variables................................................................128
8.1.7
Safety Analyses......................................................................................128
8.1.8
Pharmacokinetic and Exposure-Response Analyses .............................129
 


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8.2
Determination of Sample Size ...............................................................131
8.3
Randomization Methods ........................................................................132
9.0
Ethics.....................................................................................133
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................133
9.2
Ethical Conduct of the Study.................................................................133
9.3
Subject Information and Consent...........................................................134
9.3.1
Informed Consent Form and Explanatory Material ...............................135
9.3.2
Revision of the Consent Form and Explanatory Material .....................135
10.0
Source Documents and Case Report Form 
Completion ...........................................................................136
10.1
Source Documents .................................................................................136
10.2
Electronic Case Report Forms (eCRF) ..................................................136
10.3
Electronic Patient Reported Outcomes (ePRO).....................................137
11.0
Data Quality Assurance ......................................................139
12.0
Use of Information...............................................................139
13.0
Completion of the Study .....................................................141
14.0
Investigator's Agreement....................................................142
15.0
Reference List ......................................................................143
List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers....................................................................................................54
Table 2.
Clinical Laboratory Tests.........................................................................72
Table 3.
Minimum Laboratory Tests for Safety Evaluation ..................................74
Table 4.
Identity of Investigational Product.........................................................100
Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values..................................................................................120
List of Figures
Figure 1.
Study M14-431 Study Design – Part 1 and Part 2...................................35
Figure 2.
Study M14-431 Study Design – Part 3 ....................................................37
 


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Figure 3.
Interpretation and Management of HBV Serologic Test Results ............70
Figure 4.
Adverse Event Collection ......................................................................115
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................147
Appendix B.
List of Protocol Signatories....................................................................149
Appendix C.
Study Activities......................................................................................150
Appendix D.
Latent TB Risk Factor Assessment Form Example...............................156
Appendix E.
Patient Reported Outcomes Descriptions ..............................................157
Appendix F.
Bristol Stool Chart .................................................................................161
Appendix G.
Corticosteroid Taper ..............................................................................162
Appendix H.
Standard Weights...................................................................................164
Appendix I.
Crohn's Disease Activity Index (CDAI) ................................................167
Appendix J.
Simple Endoscopic Score for Crohn's Disease (SES-CD34) 
Assessment.............................................................................................168
 


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3.0
Introduction
Crohn's disease (CD) encompasses a spectrum of clinical and pathological processes 
manifested by focal asymmetric, transmural, and occasionally granulomatous 
inflammation that can affect any segment of the gastrointestinal tract.1  The disease can 
affect persons of any age, and its onset is most common in the second and third decades.  
Females are affected slightly more than males, and the risk for disease is higher in some 
ethnic groups.2,3  In North America, the incidence of CD is estimated to be 3.1 to 
14.6 cases per 100,000 persons.  Prevalence rates range from 26 to 99 cases per 
100,000 persons.  In Europe, CD has an incidence of 0.7 to 9.8 cases per 100,000 persons 
and a prevalence rate of 8.3 to 214 cases per 100,000 persons.2
CD has been characterized by significant morbidity including abdominal pain, diarrhea, 
weight loss/malnutrition, a progressive nature that leads to complications such as fistulas, 
strictures and abscesses.  
Given that no known medical or surgical cure currently exists for CD, the therapeutic 
strategy is to reduce symptoms, improve quality of life (QoL), reduce endoscopic 
evidence of inflammation, and minimize short- and long-term toxicity and complications.3  
Currently, patients with moderate to severe disease who have failed aminosalicylates or 
topical treatments are usually treated with conventional pharmacologic interventions, 
which include corticosteroids and immunosuppressive agents such as azathioprine (AZA), 
6-mercaptopurine (6-MP), or methotrexate (MTX).1,4  Local or systemic corticosteroids 
may be used for induction of remission, but are not recommended as maintenance therapy, 
due to their side effect profile.5,6  Immunosuppressants are recommended for use as 
maintenance therapy; however, not all patients have a clinically meaningful response or a 
sustained response to these therapies.  Patients who do not respond to conventional 
therapies may be treated with biologics, such as anti-tumor necrosis factor (TNF) α 
therapies.1,4  However, approximately 40% of patients do not respond to their first 
biologic therapy (primary non-responders).7-11  Among patients who initially respond and 
continue to receive maintenance treatment for longer durations, approximately 38% 
 


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become non-responders after 6 months and approximately 50% become non-responders at 
1 year (secondary non-responders).8,10  Patients who initially respond to a first anti-TNF 
agent but then lose response tend to have lower response and remission rates to the second 
anti-TNF agent or other biologic therapies.10,12  Vedolizumab, an anti-integrin biologic, is 
associated with a relatively slower onset of action and the majority of subjects in the 
Phase 3 clinical induction (85%) and maintenance (68.6%) trials did not achieve 
remission.  Furthermore, vedolizumab treatment has not been associated with reduction of 
systemic signs of inflammation (such as C-reactive protein [CRP]).13  More recently, 
ustekinumab, which targets the p40 subunit shared by interleukin (IL)-23 and IL-12, 
demonstrated efficacy in three Phase 3 studies (UNITI-1, UNITI-2,14 and IM-UNITI15) in 
subjects with CD.  In UNITI-1 and UNITI-2, clinical remission rates at Week 8 were 
20.9% and 40.2%, respectively, compared with placebo (7.3% and 19.6%, respectively).  
After maintenance treatment, 53.1% of patients receiving ustekinumab achieved clinical 
remission, versus 35.9% of patients receiving placebo at Week 44.  The available 
treatment options may also be associated with some adverse events (AEs) that may limit 
the use or require close monitoring.  Therefore, there remains a medical need for 
additional therapeutic options in CD for patients with inadequate response to or 
intolerance to conventional therapies and anti-TNF α agents.
Rationale for Development of a JAK Inhibitor in CD
Inhibition of Janus kinase (JAK)-mediated pathways is a promising approach for the 
treatment of patients with CD.16  The JAK family is composed of 4 family members:  
JAK1, 2, 3, and Tyrosine kinase 2.  These cytoplasmic kinases are associated with 
membrane cytokine receptors such as common gamma-chain (CGC) receptors and the 
glycoprotein 130 (gp130) transmembrane proteins.17  Activation of JAK pathways 
initiates expression of survival factors, cytokines, chemokines, and other molecules that 
facilitate leukocyte cellular trafficking and cell proliferation which contribute to 
inflammatory and autoimmune disorders.18
In CD, the imbalance between anti-inflammatory and pro-inflammatory cytokines in the 
mucosal immune system is thought to play an important role.  Cells from the innate 
 


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mucosal immune system, i.e., TH1 or TH17, are over-activated and secrete various 
pro-inflammatory cytokines such as interferon gamma (INF-g), TNFα, IL-6, IL-1b, IL-12, 
IL-23.  These cytokines signal via JAK pathways.19
JAK3 and JAK1 are components of the CGC cytokine receptor complexes and blockade 
of either inhibits signaling by the inflammatory cytokines IL-2, -4, -7, -9, -15 and -21.20  
Cytokines such as IL-6 bind to gp130 and transduce its signal predominantly via JAK1.21  
Targeting the IL-6 receptor (IL-6R) is a promising approach given the fact that expression 
of IL-6 and soluble IL-6 receptors is elevated in patients with active CD.22  Thus, 
inhibition of JAK1 is expected to attenuate the signaling of IL-6 and other 
pro-inflammatory cytokines (i.e., IFN-g), that are involved in development of CD.
Tofacitinib, a pan-JAK inhibitor approved for use in rheumatoid arthritis (RA), failed to 
demonstrate the efficacy in two Phase 2 studies in CD.23  Filgotinib, a second generation 
JAK inhibitor, selective for JAK1, induced clinical remission in significantly more 
patients with active CD compared with placebo, however, did not demonstrate endoscopic 
improvement after a 10-week induction period.24
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 (WBC) counts, serum creatinine, total cholesterol, 
high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol 
(LDL-C) and liver transaminases (alanine transaminase [ALT], aspartate transaminase 
[AST]) and creatine phosphokinase (CPK).24,25
Upadacitinib is a novel selective JAK1 inhibitor being developed for the treatment of 
adult patients with CD.  In an in vitro setting, upadacitinib potently inhibits JAK1 activity, 
but to a lesser degree, inhibits the other isoforms, JAK2 and JAK3.  The enhanced 
selectivity of upadacitinib against JAK1 may offer an improved benefit-risk profile in 
patients with CD.  The clinical hypothesis is that upadacitinib should be effective in 
decreasing inflammation and damage associated with CD by interfering with JAK1-
mediated signaling pathways (i.e., IL-6) without causing excessive anemia due to its 
 


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reduced activity against JAK2 (half maximal inhibitory concentration [IC50] 120 nM), 
which is essential for erythropoietin signaling.  Upadacitinib is also less potent against 
JAK3 (IC50 2.3 µM), an important component of lymphocyte activation and function.  As 
such, treatment with upadacitinib, a selective JAK1 inhibitor with reduced JAK3 
inhibition, could result in a decreased risk for infection (including viral reactivation) 
and/or malignancy compared to less selective JAK inhibitors.
Additional information regarding the preclinical toxicology, metabolism, pharmacology, 
safety experience and indications under study with upadacitinib can be found in the 
current edition of the Investigator's Brochure.26
Upadacitinib has been evaluated in Phase 2 dose ranging placebo-controlled studies in 
subjects with moderately to severely active CD (Study M13-740; NCT02365649) and 
moderately to severely active RA (Study M13-537; NCT02066389 and 
Study M13-550; NCT01960855).  The 52-week data in subjects with CD from 
Study M13-740 suggest that upadacitinib may alleviate signs and symptoms of active CD 
and reduce mucosal inflammation.
In Study M13-740, 220 subjects were randomized to 4 twice daily (BID), 1 once daily 
(QD) dose regimens of upadacitinib immediate release capsules (3 mg BID, 6 mg BID, 
12 mg BID, 24 mg BID, and 24 mg QD), or to placebo.  As induction treatment, a 
statistically significant dose-response relationship was observed with upadacitinib for the 
co-primary endpoint of endoscopic remission.  A dose-response was not observed for the 
clinical remission co-primary endpoint; however, a new endpoint for potential use as 
primary in Phase 3 demonstrated a statistically significant dose-response relationship for 
clinical remission in the 6 mg BID and 24 mg BID dose groups compared to placebo.  
Endoscopic response was statistically significantly better in all upadacitinib dose groups 
except for 3 mg BID compared to placebo.  In the Extension Phase, subjects who achieved 
response and were re-randomized to the 12 mg BID group achieved statistically 
significant clinical remission and endoscopic outcomes compared to subjects in the 3 mg 
BID group at Week 52.
 


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Safety data from the induction portion of Study M13-740 were consistent with the profile 
observed in the Phase 3 RA studies.  The incidences of AEs in Study M13-740 were 
numerically higher in the upadacitinib dose groups, with no dose relationship.  Infections 
occurred with higher incidences in the upadacitinib groups than the placebo group, but 
also did not show dose-related increases.  The most frequently reported AEs (≥ 5%) in the 
upadacitinib treated subjects were headache, Crohn's disease, abdominal pain, fatigue, 
nasopharyngitis, urinary tract infection, upper respiratory tract infection, vomiting and 
pyrexia.  Upadacitinib continued to be generally well tolerated following re-
randomization of subjects at Week 16 to upadacitinib 3 mg BID, 6 mg BID, 12 mg BID, 
or 24 mg QD through Week 52 of the Extension Phase.  There were 5 subjects with non-
serious events of herpes zoster reactivation.  Two events of gastrointestinal perforation 
were reported in 2 subjects; 1 subject had worsening of CD and associated fistulization 
and abscess, and the other subject had a perforation in an area of fissuring ulcer.  Similar 
to the RA Phase 3 studies, increase in LDL-C and HDL-C, reductions in natural killer 
(NK) cells, slight decreases in red blood cell (RBC) counts, and asymptomatic and 
transient CPK elevations were observed.  No deaths were reported during the study.
All subjects who complete Study M13-740 are eligible to enroll in Study M14-327, a 
Phase 2, open-label extension study to evaluate the long-term safety and efficacy of 
upadacitinib.
Study M14-431 will evaluate one induction dose of upadacitinib (45 mg QD) of the once-
daily modified-release tablet formulation.  The selection of this dose was informed by the 
analysis of the 16-week safety, efficacy, and exposure-response Phase 2 data from 
Study M13-740.  In addition, all the currently available pharmacokinetic (PK), 
pharmacodynamic, safety, and efficacy data from upadacitinib studies were used to 
support the selection of this dose.  Upadacitinib 45 mg QD, dosed for up to 12 weeks, is 
expected to be efficacious with an acceptable safety profile, and upadacitinib 15 mg QD 
and 30 mg QD, dosed for up to 240 weeks as maintenance treatment, are expected to be 
efficacious with acceptable safety profiles.  
 


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In this study, subjects with moderately to severely active CD will be enrolled.  Moderate 
to severe active disease will be determined by evidence of active intestinal mucosal 
inflammation assessed by the Simplified Endoscopic Score for CD (SES-CD), confirmed 
by a central endoscopy reader; and the presence of signs and symptoms of the patient-
reported outcomes and Crohn's Disease Activity Index (CDAI) subcomponents of very 
soft/liquid stool frequency and abdominal pain.  This is supported by post-hoc analyses of 
the adalimumab studies, the Phase 2 risankizumab Study 1311.6 and upadacitinib 
Study M13-740, where the proposed inclusion criterion of very soft/liquid stool frequency 
and abdominal pain score was met by 85% to 92% of subjects with baseline CDAI 220 to 
450, respectively.
3.1
Differences Statement
This study is designed to evaluate the efficacy and safety of upadacitinib 45 mg QD 
versus placebo in subjects with moderately to severely active CD.  The primary difference 
between Study M14-431 and the prior Phase 2 study of upadacitinib in CD is that this 
study will test a QD oral formulation of upadacitinib and confirm the efficacy of 
upadacitinib in a larger CD population with inadequate response or intolerance to biologic 
therapies.  Additionally, some efficacy endpoint definitions in this study are different 
from Phase 2 to reflect the changing regulatory requirements for pivotal registrational 
studies for new agents for the treatment of CD.
3.2
Benefits and Risks
Although conventional and newer treatments such as biologic therapies have improved the 
standard of care for patients with CD, there remains a significant unmet medical need for 
patients with inadequate or loss of response to these agents, and efforts are ongoing to 
develop novel therapies.  
Clinical efficacy in targeting pro-inflammatory cytokines and downstream signaling 
pathways has been demonstrated in CD with second generation JAK inhibitors, including 
upadacitinib.  These drugs are also being studied for the treatment of patients with 
ulcerative colitis. 
 


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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 
pan-JAK inhibition, which are thought to be mediated by inhibition of JAK2 and JAK3 
signaling pathways.  
Adverse events (AEs) such as infections, herpes zoster reactivation, malignancies, and 
hematologic AEs have been observed with JAK inhibition.  By its selectivity for JAK1, 
upadacitinib may be able to decrease inflammation mediated by JAK1 signaling while 
having less inhibitory effect on JAK2 and JAK3.  This could potentially minimize some 
of the reported safety concerns with less 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 therapy.  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) and pulmonary embolism (PE) have been reported in patients receiving 
JAK inhibitors including upadacitinib.  In addition, no new safety signals have been 
identified in the Phase 2 (Study M13-740; NCT02365649) study of moderately to 
severely active CD with upadacitinib during 52 weeks of treatment.
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. 
 


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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. 
Taken together, the safety and efficacy data from upadacitinib studies to date show a 
favorable benefit:risk profile for upadacitinib and support the continued investigation of 
upadacitinib in patients with various autoimmune/inflammatory conditions.
AbbVie is conducting a Phase 3 study in subjects with CD based on the following 
supportive findings:  1) demonstrated clinical and endoscopic improvements in the 
induction treatment in a Phase 2 dose-ranging study; and 2) safety results were consistent 
with those known to be associated with JAK inhibition.  The current Phase 3 
Study M14-431 will further evaluate the benefit to risk profile of upadacitinib in CD 
subjects who have inadequately responded to, or are intolerant to, biologic therapies.
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.
4.0
Study Objective
The objective of Study M14-431 is to evaluate the efficacy and safety of upadacitinib 
compared to placebo as induction therapy in subjects with moderately and severely active 
CD.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
Study M14-431 is a Phase 3, randomized, double-blind, placebo-controlled induction 
study to evaluate the efficacy and safety of upadacitinib, an orally administered JAK1 
inhibitor in adult subjects with moderately to severely active CD who have inadequately 
responded to or are intolerant to biologic therapy.  The study will allow enrollment of up 
 


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to 35% of subjects who have demonstrated inadequate response or intolerance to 3 or 
more biologics.
The study will enroll approximately 625 subjects at approximately 400 study centers 
worldwide to meet scientific and regulatory objectives without enrolling an undue number 
of subjects in alignment with ethical considerations.  
This study will evaluate one induction dose of upadacitinib (45 mg QD) (Figure 1).
Subjects who consent and meet all of the inclusion criteria and none of the exclusion 
criteria will be enrolled into this study which encompasses three parts:  
●
Part 1:  a randomized, double-blind, placebo-controlled induction period, 
●
Part 2:  an open-label, single-arm active induction period, and 
●
Part 3:  an Extended Treatment Period for non-responders from Part 1 or 
Part 2.
Part 1
In Part 1, subjects (n = 495) will be randomized in a 2:1 ratio to upadacitinib 45 mg QD or 
matching placebo for 12 weeks (Figure 1).  The randomization will be stratified by 
baseline corticosteroid use (yes or no), endoscopic disease severity (SES-CD < 15 and 
≥15), and number of prior biologic treatments (> 1 and ≤ 1).  The data collected from 
subjects from Part 1 will be used for the primary efficacy analysis. 
Visits during the study will occur at Baseline and Weeks 2, 4, 8, and 12/Premature 
Discontinuation (PD) to collect clinical, endoscopic and laboratory assessments of disease 
activity. 
At Week 12, subjects achieving clinical response, defined as ≥ 30% decrease in average 
daily very soft or liquid stool frequency (SF) and/or ≥ 30% decrease in average daily 
abdominal pain (AP) score (both not worse than Baseline) may be eligible to enter the 
52-week, double-blind, maintenance portion of Study M14-430. 
 


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All subjects who do not achieve clinical response at Week 12 will be able to enroll in 
Part 3 (Extended Treatment Period) and receive double-blind upadacitinib until 
Week 24/PD.
Subjects are not eligible to enter Study M14-430 until the ileocolonoscopy procedure at 
Week 12 has been completed.  If the COVID-19 pandemic precludes a subject from 
undergoing an endoscopy, a subject can enroll in Study M14-430 if clinical response was 
achieved at Week 12.  
Part 2
Part 2 is an open-label portion (open-label cohort) of this study.  Once enrollment in 
Part 1 is complete, approximately 130 subjects will be enrolled in Part 2 to receive 
upadacitinib 45 mg QD for 12 weeks (Figure 1).  The objective of Part 2 is to have a 
sufficient number of subjects with clinical response to be re-randomized in the double-
blind maintenance portion of Study M14-430, while minimizing unnecessary exposure to 
placebo.  The data collected from subjects from Part 2 will not be part of the primary 
efficacy analysis for this study, will use descriptive statistics, and will be reported 
separately in the clinical study report.
Visits during the study will occur at Baseline and Weeks 2, 4, 8, and 12/PD to collect 
clinical, endoscopic and laboratory assessments of disease activity. 
At Week 12, subjects achieving clinical response may be eligible to enter Study M14-430 
(Figure 1).  Subjects who do not achieve clinical response at Week 12 will be able to 
participate in Part 3 (Extended Treatment Period) to receive open-label upadacitinib 
30 mg QD until Week 24/PD.
 


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Figure 1.
Study M14-431 Study Design – Part 1 and Part 2
QD = once daily; Rand = randomization
The study will allow the enrollment of up to 10% of subjects who received a JAK 
inhibitor prior to study entry if they have not had inadequate response or loss of response.
Part 3
Part 3 is a 12-week Extended Treatment Period consisting of 3 cohorts for subjects who 
do not achieve clinical response at Week 12 in Part 1 or Part 2 (Figure 2).  The objectives 
of Part 3 are to offer blinded upadacitinib induction treatment to placebo non-responders 
from Part 1 and to evaluate delayed clinical response to upadacitinib in subjects who did 
not initially respond to upadacitinib during Part 1 or Part 2.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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●
Cohort 1:  Subjects who received placebo in Part 1 and did not achieve clinical 
response at Week 12 are eligible to receive double-blind induction treatment 
with upadacitinib 45 mg QD for 12 weeks (until Week 24). 
●
Cohort 2:  Subjects who received double-blind upadacitinib in Part 1 and did 
not achieve clinical response at Week 12 are eligible to receive double-blind 
upadacitinib 30 mg QD for 12 weeks (until Week 24). 
●
Cohort 3:  Subjects who received open-label upadacitinib during Part 2 and did 
not achieve clinical response at Week 12 are eligible to receive open-label 
upadacitinib 30 mg QD for 12 weeks (until Week 24).
Subjects in Cohort 1 and 2 will remain blinded to treatment to avoid unmasking the 
treatment received during Part 1.  The data collected from subjects from Part 3 will not be 
part of the primary efficacy analysis, will use descriptive statistics, and will be reported 
separately in the clinical study report.
Subjects are not eligible to enter in Part 3 until the Week 12 endoscopy has been 
completed.  If the COVID-19 pandemic precludes a subject from undergoing an 
endoscopy, a subject can continue into Part 3.  Visits will occur at Weeks 16, 20 and 
24/PD to collect clinical, endoscopic and laboratory assessments of disease activity. 
During Part 3, subjects with persistent symptoms or worsening of CD may be 
discontinued at any time.
 


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Figure 2.
Study M14-431 Study Design – Part 3
DB = double-blind; NR = non-responders; OL = open-label; QD = once daily
At Week 24, subjects who achieve clinical response may be eligible to enter 
Study M14-430.  Subjects are not eligible to enter Study M14-430 until the 
ileocolonoscopy procedure at Week 24 for evaluation of mucosal inflammation has been 
completed.  If the COVID-19 pandemic precludes a subject from undergoing an 
endoscopy, a subject can enroll if clinical response was achieved at Week 24.  
Subjects who do not achieve clinical response at Week 24 will be discontinued from 
Study M14-431 and will receive standard of care treatment at the investigator's discretion.  
Subjects who do not achieve clinical response at Week 24 and all subjects who 
prematurely discontinue the study will have a follow-up visit 30 days from the last dose of 
study drug to collect information on new or ongoing AEs and laboratory assessments.  
Subjects will be discontinued from the study if they withdraw consent or if they are 
deemed unsuitable to continue for any reason by the investigator.
The duration of the study could be up to 33 weeks, including Screening Period (5 weeks), 
a 12-week double-blind or open-label cohort Induction Period (Part 1 or Part 2), a 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12-week Extended Treatment Period (Part 3), and a 30-day follow-up for subjects who do 
not enroll into Study M14-430.
At the Screening Visit, all subjects will be provided with an electronic diary.  Subjects 
will be instructed and trained on how to record CD-related symptoms (including total and 
very soft and liquid number of stools and abdominal pain), general well-being and use of 
anti-diarrheals on a daily basis; and use of medications for endoscopy preparation 
throughout the study.  The very soft and liquid stools are defined as consistency Type 6 or 
Type 7 based on the Bristol Stool Chart (Appendix F). 
The diary will be reviewed by site personnel with the subject at each visit and for the 
assessment of the clinical endpoints.  At each Study Visit, routine physical examination 
including evaluation of vital signs, extra-intestinal manifestations (EIMs), presence or 
absence of fistulas; calculation of CDAI score, total and average daily very soft or liquid 
SF and average daily AP (very soft or liquid SF and AP entries from the most recent 
7-day period prior to each study visit will be used); monitoring of AEs; concomitant 
medications and laboratory assessments will be performed.  The very soft or liquid SF and 
AP score values represent the unweighted daily averages of the corresponding subscores 
from the CDAI.  Additionally, subjects will complete QoL, CD symptoms, symptoms 
impact on QoL, and work productivity questionnaires throughout the study as indicated in 
Appendix C.
Clinical samples for urinalysis, chemistry and hematology, high sensitivity 
C-reactive protein (hs-CRP), plasma upadacitinib concentrations will be collected.  In 
addition, stool samples for calprotectin analysis will be collected and should be taken 
before starting bowel preparations for endoscopy.  
Subjects will undergo a full colonoscopy (ileocolonoscopy) for evaluation of mucosal 
inflammation using the SES-CD.  All endoscopies will be centrally read to document 
eligibility at Screening, and for Week 12 and 24/PD assessments.  Biopsy to confirm 
diagnosis (during Screening) or to rule out dysplasia/malignancy may be performed 
 


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during the same time points as the endoscopy.  Optional exploratory research samples 
may be taken during the study (see also Appendix C).
Screening Period
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and then undergo 
the screening procedures outlined in Appendix C.  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.
The length of time between Screening and the Baseline visit must allow time for 
endoscopy central reading and review of laboratory results.  The Screening period will be 
a minimum of 8 days.
Subjects who have been taking exclusionary medications prior to Screening or Baseline 
must complete the medication(s) washout within the duration described in the protocol 
Exclusion Criteria Section 5.2.2 prior to the Baseline Visit (i.e., 8-week washout of a 
biologic therapy).  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 from the last dose; 
(2) adalimumab, certolizumab, golimumab, or vedolizumab:  may be tested approximately 
6 weeks from the last dose; (3) ustekinumab:  may be tested approximately 8 weeks 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.
All subjects need to have their average daily very soft or liquid SF and average daily AP 
score calculated and meeting eligibility criteria before randomization at Baseline.
 


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Re-Screen
Subjects who initially screen fail for the study are permitted to re-screen once following 
re-consent.  For additional re-screenings, AbbVie Therapeutic Area Medical Director 
(TA MD) approval is required.  Laboratory values can be re-tested once during the 
re-screening period.  As appropriate, sites are encouraged to contact the AbbVie TA MD 
to confirm if subjects should or should not be re-screened.  All screening procedures with 
the possible exceptions noted below will be repeated during re-screening.  The subject 
must meet all of the inclusion criteria 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.  The re-screening period will be a minimum 
of 8 days, with the exception of subjects who are re-screened immediately after being 
screen failed and do not require a repeated endoscopy.  The minimum re-screening period 
for these subjects will be 4 days.
If the subject had a complete initial screening evaluation including the assessment of an 
Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB [tuberculosis] Gold In Tube 
test) and/or a purified protein derivative (PPD) test (or equivalent) (or both if required per 
local guidelines), chest x-ray and electrocardiogram (ECG), tests for hepatitis B virus 
(HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) and 
beta-D-glucan (Japan only), these tests will not be required to be repeated for re-screening 
provided the conditions noted in Section 5.2 are met, there are no changes in the subject's 
medical history that would warrant re-testing, and no more than 90 days have passed since 
the collection date of the assessment.  If a subject is being re-screened within 14 days 
(≤14 days have passed) from the collection date of the previous screening testing, it is not 
required to repeat Screening testing for chemistry, hematology, urinalysis, serum 
pregnancy, and Clostridium difficile provided that the subject's health status has not 
changed to warrant a repeat test.  
An endoscopy 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 45 days have passed between the 
previous screening endoscopy and Baseline.
 


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All subjects need to have their average daily very soft or liquid SF and average daily AP 
score calculated and meeting eligibility criteria before randomization at Baseline.
12-Week Induction Period – Part 1 and Part 2
This period will begin at the Baseline Visit and will end at the Week 12 Visit.  At the 
Baseline Visit, subjects who meet all of the inclusion criteria and none of the exclusion 
criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the study.  In 
Part 1, subjects will be randomized to a double-blind induction period.  In Part 2, subjects 
enrolled will receive open-label upadacitinib.  During this induction period, all subjects 
will visit the study site at Weeks 2, 4, 8, and 12/PD, and a ± 3-day window is permitted 
around scheduled study visits.  The last dose of study drug during this period is taken the 
day prior to the Week 12 visit.  
12-Week Extended Treatment Period – Part 3
This period will begin at Week 12 and will end at the Week 24 Visit.  At Week 12, 
subjects who do not achieve clinical response will enter Part 3.  Clinical response is 
defined as ≥ 30% decrease in average daily very soft or liquid SF and/or ≥ 30% decrease 
in average daily AP and both not greater than Baseline.  During this period, all subjects 
will visit the study site at Weeks 16, 20, and 24/PD.  A ± 3-day window is permitted 
around scheduled study visits.  The last dose of study drug during this period is taken the 
day prior to the Week 24 visit.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
Subjects may withdraw from the study completely (withdrawal of informed consent) for 
any reason at any time (refer to Section 5.4.1 for additional details).  If a subject 
prematurely discontinues study drug treatment and study participation (withdrawal of 
informed consent), the procedures outlined for the PD visit should be completed as soon 
as possible, preferably within 2 weeks of study drug discontinuation.  In addition, if the 
subject is willing, a 30-day follow-up visit (or telephone call if a visit is not possible) 
should occur to determine the occurrence or status of any new or ongoing AEs/serious 
 


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adverse events (SAEs).  Subjects who discontinue the study prematurely after 
randomization will not be replaced.  
Discontinuation of Study Drug and Continuation of Study Participation 
Subjects may discontinue study drug treatment but may choose to continue to participate 
in the study (refer to Section 5.4.1 for additional details).  Subjects who prematurely 
discontinue study drug should complete a PD visit as soon as possible, preferably within 
2 weeks.  Afterwards, subjects should follow the regular visit schedule as outlined in 
Appendix C, and adhere to all study procedures except for dispensing study drug and PK 
sample collection, and blood, stool and biopsy sample collection for optional exploratory 
research.  As the subject has discontinued study drug, all rescue and efficacy driven 
discontinuation criteria no longer apply.  If at any point a subject no longer wants to 
provide assessments (withdrawal of informed consent) following discontinuation of study 
drug, a second PD visit is not required.
Unscheduled Visits
Unscheduled Visits may occur when the subject is coming in for a medical visit for 
evaluation and assessment.  During Unscheduled Visits, blood samples will be obtained 
for the laboratory tests listed in Table 2 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.
Follow-Up Visit
A follow-up visit will occur approximately 30 days after the last dose of study drug to 
obtain information on any new or ongoing AE/SAEs and laboratory assessments. 
Subjects will complete the follow-up visit when they have either
●
Completed the final study visit and have not enrolled in Study M14-430 OR
 


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●
Prematurely discontinued study drug and study participation.
The follow-up visit is not applicable for subjects who discontinued study drug and 
continued study participation and completed at least one study visit at least 30 days after 
last study visit.
If a follow-up visit is not possible, a telephone call may be possible to collect information 
about new or ongoing AEs.
Study visits may be impacted due to the COVID-19 pandemic or any state of emergency 
or pandemic situation.  If visits cannot be conducted onsite due to travel restrictions or 
other pandemic-related reasons, phone or virtual visits, visits at alternative locations, or 
changes in the visit frequency and timing of study procedures, among others may be 
performed.  Additional details are provided in the subsequent sections.  Every effort 
should be made to ensure the safety of subjects and site staff, while maintaining the 
integrity of the study.
5.2
Selection of Study Population
It is anticipated that approximately 625 subjects with active moderately to severely active 
CD will be enrolled at approximately 400 sites worldwide.  
A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria and none of the exclusion criteria specified in this protocol.
5.2.1
Inclusion Criteria
1.
Male or female aged ≥ 18 and ≤ 75 years of age or minimum age of adult consent 
according to local regulations at Baseline.
2.
Confirmed diagnosis of CD for at least 3 months prior to Baseline.  Appropriate 
documentation of biopsy results consistent with the diagnosis of CD, as determined 
by the investigator, must be available.
 


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3.
SES-CD (excluding the presence of narrowing component) ≥ 6 (or ≥ 4 for subjects 
with isolated ileal disease), as confirmed by a central reader.
4.
Average daily very soft or liquid SF ≥ 4.0 AND/OR average daily AP score ≥ 2.0 
at Baseline.
5.
Demonstrated an inadequate response or intolerance to one or more of the 
following biologic agents as defined by:
●
At least one 6-week induction regimen of infliximab (≥ 5 mg/kg intravenous 
[IV] at Baseline and Weeks 2 and 6), 
●
At least one 4-week induction regimen of adalimumab (one 160 mg 
subcutaneous [SC] dose at Baseline, followed by one 80 mg SC dose at Week 2 
[or one 80 mg SC dose at Baseline, followed by one 40 mg SC dose at Week 2, 
in countries where this dosing regimen is approved]), 
●
At least one 4-week induction regimen of certolizumab pegol (400 mg SC at 
Baseline, and Weeks 2, and 4), 
●
At least one 6-week induction regimen of vedolizumab (300 mg IV at Baseline 
and Weeks 2, and 6), 
●
At least one 8-week induction regimen of ustekinumab [260 mg (≤ 55 kg) or 
390 mg (> 55 to ≤ 85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at 
Week 8], 
●
Recurrence of symptoms during scheduled maintenance dosing following prior 
clinical response to the above biologics, 
●
Intolerance to a biologic may include, but not limited to infusion-related 
reaction, rash, serum sickness, anaphylaxis, elevated liver enzymes, 
demyelination, congestive heart failure, infection.  Demonstration of 
intolerance requires no minimum dose or duration of use.
6.
Women of childbearing potential (refer to Section 5.2.4), must not have a positive 
serum pregnancy test at the Screening Visit and must have 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 a 
 


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borderline result and a serum pregnancy test ≥ 3 days later to document continued 
lack of a positive result.
7.
If female, subject must be either postmenopausal, OR permanently surgically 
sterile OR for women of childbearing potential practicing at least 
one protocol specified method of birth control (refer to Section 5.2.4), that is 
effective from Baseline Visit through at least 30 days after the last dose of study 
drug.
8.
Subject is judged to be in good health as determined by the principal investigator 
based upon the results of medical history, laboratory profile, physical examination, 
chest x-ray, and a 12-lead ECG performed during Screening.
9.
Subjects must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study-specific procedures and comply with the 
requirements of this study protocol.  In countries where the subject is 18 years-old 
but not of minimum adult age to consent according to local regulations, a subject's 
parent or guardian must be willing to provide written informed consent (e.g., Japan 
< 20 years old).
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
Concomitant Medications and Treatments
2.
Subject on CD-related antibiotics who: 
●
has not been on stable doses of these medications for at least 14 days prior to 
Baseline, or
 


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●
has discontinued these medications within 14 days of Baseline. 
3.
Subject on oral aminosalicylates who: 
●
has not been on stable doses of these medications for at least 14 days prior to 
Baseline, or
●
has discontinued these medications within 14 days of Baseline.
4.
Subject on corticosteroids who meet the following:
●
prednisone or equivalent dose > 30 mg/day; or
●
budesonide > 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.
5.
Subject on MTX who:
●
has not been on the current course for ≥ 42 days prior to Baseline, and
●
has not been on a stable dose for ≥ 28 days prior to Baseline
Medications and Treatments During the Screening Period
6.
Infection(s) requiring treatment with intravenous (IV) anti-infectives within 
30 days prior to the Baseline Visit or oral/intramuscular (IM) anti-infectives within 
14 days prior to the Baseline Visit.
7.
Subject requiring or receiving any parenteral nutrition and/or exclusive enteral 
nutrition.
8.
Subject who received oral or parenteral traditional Chinese medicines within 
30 days prior to Baseline.
9.
Subject who received any live vaccination within 30 days (or longer if required 
locally [e.g., 8 weeks for Japan]) prior to Baseline, or who is expected to need live 
vaccination during study participation including at least 30 days (longer if required 
locally [e.g, 8 weeks for Japan]) after the last dose of study drug.
 


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10.
Subject who received cyclosporine, tacrolimus, mycophenolate mofetil, or 
thalidomide within 30 days prior to Baseline.
11.
Subject who received azathioprine (AZA) or 6-mercaptopurine (6-MP) within 
10 days of Baseline.
12.
Subject who received fecal microbial transplantation within 30 days prior to 
Baseline. 
13.
Subject who received nonsteroidal anti-inflammatory drugs (NSAIDs) within 
7 days prior to Baseline, except topical NSAIDs and low dose aspirin for 
cardiovascular protection.
14.
Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong 
CYP3A inducers from Screening through the end of the study (refer to Table 1 for 
examples of commonly used strong CYP3A inhibitors and inducers).
Prior Medications and Treatments 
15.
Subject who received any of the following agents:
●
adalimumab, certolizumab, golimumab, infliximab, natalizumab, vedolizumab 
within 8 weeks prior to Baseline; or
●
ustekinumab within 12 weeks prior to Baseline.
○
Note:  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.
●
any investigational agent within 30 days or 5 half-lives prior to Baseline, 
whichever is longer, or is currently enrolled in another interventional study.
16.
Subject with previous exposure to a JAK inhibitor (e.g., tofacitinib, baricitinib, 
filgotinib) within 30 days from Baseline.
Note:  Subjects who received a JAK inhibitor prior to study entry may be enrolled 
if they have not had inadequate response or loss of response.
 


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17.
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.
18.
Subject received IV corticosteroids within 14 days prior to Screening or during the 
Screening Period.
19.
Subject has received therapeutic enema or suppository (i.e., rectal 
aminosalicylates/corticosteroids), other than required for endoscopy, within 
14 days prior to endoscopy used for Screening or during the Screening period.
20.
Subject who received apheresis (e.g., Adacolumn apheresis) within 60 days prior to 
Screening or during the Screening Period.
21.
Subject has cannabis use, either recreational or for medical reasons, within 14 days 
prior to Baseline or any history of clinically significant (per investigator's 
judgment) drug or alcohol abuse in the last 6 months.
22.
Subject who previously received stem cell transplantation (except for local stem 
cell therapy for complex perianal fistula). 
23.
Subject has been a previous recipient of an organ transplant which requires 
continued immunosuppression.
CD Related
24.
Subject with the following ongoing known complications of CD: 
●
abscess (abdominal or peri-anal), 
●
symptomatic bowel strictures,
●
> 2 entire missing segments of the following 5 segments:  terminal ileum, right 
colon, transverse colon, sigmoid and left colon, and rectum,
●
fulminant colitis, 
●
toxic megacolon, 
 


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●
or any other manifestation that might require surgery while enrolled in the 
study. 
25.
Subject with ostomy or ileoanal pouch.
26.
Subject diagnosed with conditions that could interfere with drug absorption 
including but not limited to short gut or short bowel syndrome.
27.
Subject with surgical bowel resection within the past 3 months prior to Baseline, or 
a history of > 3 bowel resections.
Safety
28.
Subject with positive Clostridium difficile (C. difficile) toxin stool assay during 
Screening.
29.
Any active, chronic or recurrent infection that, based on the investigator's clinical 
assessment, makes the subject an unsuitable candidate for the study, including 
hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated 
(even a single episode) herpes zoster, disseminated (even a single episode) herpes 
simplex, or HIV infection.  Active HBV, HCV and HIV are 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 hepatitis B core antibody (HBc Ab) positive (+) subjects; 
●
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV 
antibody (HCV Ab);
●
HIV:  confirmed positive anti-HIV antibody (HIV Ab) test;
●
Confirmed COVID-19: the Baseline visit must be at least 14 days from onset 
of signs/symptoms or positive SARS-CoV-2 test, symptomatic subjects must 
have recovered, defined as resolution of fever without use of anti-pyretics and 
improvement in symptoms;
●
Suspected COVID-19: subjects with signs/symptoms suggestive of 
COVID-19, known exposure, or high risk behavior should undergo molecular 
 


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(e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic 
for 14 days from a potential exposure.
30.
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB testing).
31.
History of any malignancy except for successfully treated nonmelanoma skin 
cancer (NMSC) or localized carcinoma in situ of the cervix. 
32.
Prior or current gastrointestinal dysplasia, other than completely removed low-
grade dysplastic lesions in any biopsy performed during or before the Screening 
endoscopy.
33.
History of gastrointestinal perforation (other than appendicitis or mechanical 
injury), diverticulitis or significantly increased risk for gastrointestinal perforation 
per investigator judgment.
34.
Female who is pregnant, breastfeeding, or is considering becoming pregnant during 
the study or within 30 days after the last dose of study drug.
35.
History of an allergic reaction or significant sensitivity to constituents of the study 
drug (and its excipients) and/or other products in the same.
36.
Laboratory values meeting the following criteria within the Screening period prior 
to the first dose of study drug:
●
Serum AST or ALT > 2.0 × upper limit of normal (ULN);
●
Total WBC count < 2500/µL;
●
Estimated glomerular filtration (eGFR) rate by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m2;
●
Hemoglobin < 9g/dL;
●
Platelet count < 100,000/µL;
●
Absolute neutrophil count (ANC) < 1200/µL;
●
Absolute lymphocyte count (ALC) < 750/µL.
37.
Any of the following cardiovascular conditions or thrombotic conditions:
 


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●
recent (within past 6 months) cerebrovascular accident, myocardial infarction, 
coronary stenting;
●
current uncontrolled hypertension as defined by a confirmed systolic blood 
pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg;
●
prior history of thrombotic events including deep venous thrombosis and 
pulmonary embolism;
●
known inherited conditions that predispose to hypercoagulability.
38.
History of clinically significant medical conditions or any other reason that in the 
opinion of the investigator would interfere with the subject's participation in this 
study or would make the subject an unsuitable candidate to receive study drug or 
would put the subject at risk by participating in the study.
39.
For Japan subjects only:  positive result of beta-D-glucan or 2 consecutive 
indeterminate results of beta-D-glucan during the Screening Period.
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 is receiving at the time of screening, 
and/or receives during the study, must be recorded along with the reason for use, date(s) 
of administration including start and end dates, and dosage information including dose, 
route and frequency on the appropriate electronic case report form (eCRF). 
If subjects have/had ever been treated with CD-related, including, but not limited to 
corticosteroid, immunosuppressants (AZA, 6-MP or MTX), aminosalicylates, CD-related 
antibiotics 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 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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5.2.3.2
Concomitant Therapy
Changes in all concomitant medications will be assessed at each study visit from Baseline 
through Week 12/PD and during Weeks 12 to 24/PD visits for subjects who participate in 
the Part 3.  Any changes will be documented in the source documents and captured on the
appropriate eCRF page.
5.2.3.2.1
Concomitant CD-Related Medications (Antibiotics, 
Aminosalicylates, and/or Methotrexate)
All subjects receiving a stable dose of CD-related antibiotics, aminosalicylates, or MTX at 
Baseline should maintain their concomitant treatments, without dose changes through the 
end of the study.  Initiating and/or changing doses of these medications are prohibited 
during the study.  Doses of CD-related antibiotics, aminosalicylates, or MTX may be 
decreased in the event of moderate-to-severe treatment related toxicities.
Setons are authorized as concomitant therapy in subjects with perianal fistulas and should 
be documented in the eCRF under concomitant medications.
5.2.3.2.2
Concomitant Corticosteroids
Subjects who enter the study on oral corticosteroids are not allowed to change the 
corticosteroid dose during the first 4 weeks of the induction treatment period.  Doses of 
corticosteroids may be decreased during the first 4 weeks only in the event of moderate-
to-severe treatment related toxicities.  At Week 4, subjects should have their 
corticosteroid dose reduced according to a tapering schedule described in Section 5.3.1.1
Study Procedures.
Subjects who do not achieve clinical response at Week 12 in Part 1 or Part 2, and enter 
Part 3 without having completed the steroid taper should resume the corticosteroid taper at 
Week 16, according to the tapering schedule.
 


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Initiating locally acting (rectal or suppository) or systemic corticosteroids for any reason 
is prohibited during the induction treatment period and will be considered a protocol 
deviation and must be discussed with the TA MD.
Use of inhaled or topical (except rectal or suppository) corticosteroids is not restricted.
Subjects may not be on both budesonide (for CD disease) and prednisone (or equivalent) 
simultaneously.
5.2.3.3
Prohibited Therapy
Biologic Therapies 
Subjects must have discontinued any biologic therapy prior to the first dose of study drug 
as specified in the washout procedures in Exclusion Criterion 15, Section 5.2.2.  For all 
other biologic therapies, contact the AbbVie TA MD for the washout period required prior 
to the first dose of study drug. 
Therapies including but not limited to the following biologic therapies are prohibited 
medications during the study: 
●
Adalimumab
●
Etanercept 
●
Infliximab
●
Abatacept
●
Anakinra
●
Rituximab
●
Natalizumab
●
Tocilizumab
●
Golimumab
●
Certolizumab
●
Ustekinumab
●
Belimumab
 


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●
Secukinumab
●
Vedolizumab
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors or strong CYP3A inducers is excluded 
from the Screening Visit through the end of the study.  The most common strong CYP3A 
inhibitors and inducers are listed in Table 1.
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Avasimibe
Carbamazepine
Phenytoin
Rifampin (rifampicin)
Rifapentine
St. John's Wort
CYP = cytochrome P450
Traditional Chinese Medicine
Oral and parenteral traditional Chinese medicine is not permitted during the study, and 
subjects must have discontinued traditional Chinese medicine at least 30 days prior to the 
first dose of study drug.
 


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Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 
5 half-lives of the drug (whichever is longer) prior to the first dose of study drug are 
excluded from participation in this study.  Investigational drugs are also prohibited during 
the study.
Vaccines
Although not mandated by the protocol, vaccines recommended by local guidelines 
should be considered.  It is recommended that subjects be up to date for recommended 
inactivated, toxoid or biosynthetic vaccines, such as injectable flu vaccine, pneumococcal, 
tetanus-diphtheria-acellular pertussis (Tdap), and herpes zoster (Shingrix, non-live, 
recombinant).  If the subject and investigator choose to administer live vaccines, these 
vaccinations must be completed (per local label) at least 30 days (or longer, if required 
locally [e.g., or 8 weeks in Japan]) before first dose of study drug with appropriate 
precautions and are not allowed during study participation including at least 30 days (or 
longer, if required locally) after last dose of oral study drug.  Live vaccines are NOT 
allowed during the study.  If the herpes zoster live attenuated vaccine (Zostavax) is to be 
administered, and there is no known history of primary varicella (chicken pox), 
pre-existing 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 herpes zoster vaccine should not be administered.
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;
 


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●
Oral polio vaccine;
●
Smallpox;
●
Yellow fever;
●
Bacille Calmette-Guérin (BCG);
●
Typhoid (oral)
Other medications prohibited during the study:
●
JAK inhibitors (e.g., tofacitinib [Xeljanz®])
●
Cyclosporine, tacrolimus, thalidomide, mycophenolate mofetil, AZA, or 6-MP.
●
NSAIDs (except topical NSAIDs and the use of low dose aspirin for 
cardiovascular protection).
●
Rectal therapy with any therapeutic enemas or suppositories, with the exception 
of those required for endoscopy.
●
Any parenteral nutrition and exclusive enteral nutrition.
●
Cytapheresis treatment (granulocytapheresis, etc.) (in Japan and China only).
●
Cannabis.
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding prohibited therapy.
5.2.4
Contraception Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.  
Postmenopausal is defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause; or
 


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●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND a follicle-stimulating hormone (FSH) level > 40 mIU/mL.
If the female subject is ≤ 55 years of age AND has had no menses for ≥ 12 months AND 
has no history of permanent surgical sterilization (defined above), FSH should be tested at 
Screening.
●
If FSH is not tested, it is assumed that the subject is of childbearing potential 
and protocol-specified contraception is required.
●
If the FSH is tested and the result is consistent with postmenopausal status, 
contraception is not required.
●
If the FSH is tested and the result is consistent with premenopausal status, 
contraception is required, and pregnancy testing requirements for females of 
childbearing potential must be followed (see Section 5.3.1.1, pregnancy test).
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following highly effective methods of birth control (for subjects in the US and where 
appropriate per local requirements:  must simultaneously use two of the following highly 
effective methods of birth control; or one of the following highly effective methods of 
birth control PLUS a barrier [condoms, diaphragm or cervical cap] with spermicide) that 
is effective from Study Day 1 (Baseline) (or earlier) through at least 30 days after the last 
dose of study drug:
●
Combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal, and injectable) associated with the inhibition of 
ovulation, initiated at least 30 days prior to Study Day 1 (Baseline).
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Day 1 (Baseline).
●
Bilateral tubal occlusion/ligation.
 


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●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success and is the sole sexual 
partner.
●
Intrauterine device.
●
Intrauterine hormone-releasing system.
●
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 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
If required per local practices, progesterone-only oral hormonal contraception where 
inhibition of ovulation is not the primary mode of action (initiated at least 1 month prior 
to Baseline), male or female condom with or without spermicide OR cap, diaphragm or 
sponge with spermicide should be used in addition to one of the highly effective birth 
control methods listed above (excluding true abstinence).
If during the course of the study a woman becomes surgically sterile or postmenopausal 
and complete documentation is available, contraceptive measures as defined above are no 
longer required.
Contraception recommendations related to use of concomitant therapies prescribed per 
standard of care should be based on the local label. 
It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy upadacitinib.
 


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5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Exploratory 
Research, 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.
5.3.1.1
Study Procedures
The study procedures outlined in Appendix C are discussed in detail in this section, with 
the exception of optional exploratory research (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, IEC/IRB approved, 
informed consent form for the study before any study procedures are performed or any 
medications are withheld from the subject in order to participate in this study.  Separate 
written consent will be required for each subject in order to participate in the optional 
exploratory research.  The separate written consent may be part of the main consent form.  
Subjects can withdraw informed consent at any time.
Details regarding how informed consent will be obtained and documented are provided in 
Section 9.3. 
 


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Due to the COVID-19 pandemic, any state of emergency or pandemic situation, 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 non-CD-related medical and surgical history, including history of alcohol and 
nicotine use, will be taken from each subject during the Screening Visit.  Additionally, a 
list of each subject's CD-related medical and surgical history will be recorded at 
Screening.  Information on prior aminosalicylate, corticosteroid, immunosuppressants 
(e.g., AZA, 6-MP, and MTX) use, biologics, CD-related antibiotics, or any other 
physician prescribed therapy for CD will be obtained as outlined in Section 5.2.3.1.  
Information for the Montreal classification for CD will be collected at Screening for all 
subjects.
History of herpes zoster, herpes zoster vaccination, and hepatitis B vaccination status will 
be recorded as part of the medical history.  An updated medical history will be obtained 
prior to study drug administration at Baseline, to ensure the subject is still eligible for 
enrollment.
A detailed medical history with respect to TB risk factors will be documented in the study 
source documentation.  This information will include Bacille Calmette-Guerin (BCG) 
vaccination, cohabitation with individuals who have had TB, and travel to, residence in, or 
work in TB endemic locations.
 


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TB Testing/TB Prophylaxis
The TB screening tests are diagnostic test results to be interpreted in the context of the 
subject's epidemiology, history, exam findings, etc., and it is the responsibility of the 
investigator to determine if a subject has previous, active, or latent TB.
At screening, all subjects will be assessed for evidence of increased risk for TB by a risk 
factor assessment form (Appendix D) and tested for TB infection by QuantiFERON-TB 
Gold test (or IGRA equivalent such as T-SPOT TB test).  The PPD Skin Test (also known 
as a TB Skin Test or Mantoux Test) should be utilized only when a QuantiFERON-TB 
Gold Test is not possible for any reason (unless both tests are required per local 
guidelines).  The site staff will complete the TB risk assessment form and enter the data 
into an appropriate eCRF. 
If a subject had a negative QuantiFERON-TB Gold (and/or PPD) test within 90 days prior 
to Screening and source documentation is available, the test does not need to be repeated, 
provided nothing has changed in the subject's medical history to warrant a repeat test.  
These cases may be discussed with the AbbVie TA MD.  The results of the TB test(s) will 
be retained at the site as the original source documentation.
Subjects with documentation of a prior positive result of QuantiFERON-TB Gold Test (or 
equivalent) or PPD may not repeat either test at Screening or during the study and should 
be considered positive.
TB Test
For regions that require both PPD and QuantiFERON-TB Gold testing, both will be 
performed.  A positive TB test is defined by local guidelines (for example, in some 
countries, both PPD and QuantiFERON-TB Gold are performed, and if either one is 
positive, the TB test is considered positive).
 


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In the absence of local guidelines defining a positive result when both PPD and 
QuantiFERON-TB Gold tests are performed, the TB test is considered positive if either 
one is positive.
If a site has the capacity to perform both PPD and QuantiFERON-TB Gold tests, and local 
guidelines require only one test to be performed, then the QuantiFERON-TB Gold is the 
preferred test.  If only a PPD is placed at screening, then the PPD will be the reference TB 
test to be used for the remainder of the program for that subject.  Similarly, if a subject 
enters the study with a QuantiFERON-TB Gold test alone or other IGRA (negative 
result), then any future TB test performed should be a QuantiFERON-TB Gold test.
If the QuantiFERON-TB Gold Test is NOT possible (or if both the QuantiFERON-TB 
Gold Test and the PPD are required per local guidelines):  the PPD will be performed 
according to standard clinical practice.  The TB Skin Test should be read by a licensed 
healthcare professional between 48 and 72 hours after administration.  A subject who does 
not return within 72 hours will need to be rescheduled for another skin test.  The reaction 
will be measured in millimeters (mm) of induration and induration ≥ 5 mm is considered a 
positive reaction. The absence of induration will be recorded as "0 mm" not "negative."  
Subjects who have had a prior positive PPD test or an ulcerating reaction to the TB Skin 
Test in the past should not be re-exposed and the TB Skin Test should be considered 
positive.
Subjects with a negative TB test and chest x-ray not suggestive of active TB or prior TB 
exposure may be enrolled.
If the QuantiFERON-TB Gold test is indeterminate, the site should repeat the test with 
another blood sample and/or perform a PPD test.  If the second QuantiFERON TB Gold 
test is also indeterminate or positive, the subject is considered to be positive for the 
purpose of the study.  If the second QuantiFERON-TB Gold test is negative, the subject is 
considered to be negative. 
 


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In cases where the Screening QuantiFERON-TB Gold 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 TB risk assessment form) and has no clinical suspicion of TB, the 
investigator may perform a repeat QuantiFERON-TB Gold test (or IGRA equivalent) at 
the local laboratory or 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 subject to be negative based on his/her clinical judgment.  If the repeat 
testing result is positive or indeterminate, the subject is considered to be positive.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent 
TB, including signs and symptoms and chest x-ray.  Subjects with no signs or symptoms 
and a chest x-ray 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.
Subjects with history of active TB may be enrolled if it has been adequately treated with 
no evidence of current active TB; subjects with inadequate documentation of treatment 
should be cleared by a TB specialist prior to enrollment.
TB Prophylaxis
At screening, if the subject has evidence of latent TB infection (no symptoms, positive TB 
test and the subject has a chest x-ray not suggestive of active TB), prophylactic treatment 
must be initiated at least 2 weeks prior to administration of study drug (or per local 
guidelines, whichever is longer).  At least 6 months of prophylaxis needs to be completed; 
however, the full course of prophylaxis does not need to be completed prior to the 
first dose of study drug.  If the investigator deems that it is necessary, consultation with a 
TB expert could be considered. 
In case of a subject at low risk for TB (i.e., no risk factors identified using the TB risk 
assessment form), no clinical suspicion of TB, who had a negative confirmatory repeat 
QuantiFERON-TB Gold test result available after initiation of isoniazid, then TB 
prophylaxis can be stopped.
 


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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 to 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.
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 and isoniazid should be initiated and 2 to 4 weeks 
later (per local guidelines), subject should be re-evaluated (unscheduled visit) for signs 
and symptoms of isoniazid toxicity.  
If the subject is experiencing signs or symptoms suspicious for 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.
Chest X-Ray 
Chest x-ray (posterior-anterior view and lateral view) is required (in Japan and China, a 
computerized tomography [CT] scan of the chest may be performed in lieu of a chest x-
ray, at the investigator's discretion) for all subjects at Screening to rule out the presence of 
TB or other clinically relevant findings.
The chest x-ray will not be required if the subject had a previous normal chest x-ray 
(posterior-anterior and lateral views) (or normal CT Scan of the chest) 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.
 


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Subjects can have a repeat chest x-ray at any time during the study as warranted based on 
the opinion of the investigator. 
A radiologist or pulmonologist must perform an assessment of the chest x-ray (or CT scan 
of the chest for subjects in Japan and China).  The principal investigator will indicate the 
clinical significance of any findings and will sign and date the report.  In the assessment 
of the chest x-ray (or CT scan of the chest for subjects in Japan and China) the principal 
investigator or their designee must indicate the presence or absence of (1) calcified 
granulomas, (2) pleural scarring/thickening, and (3) signs of active TB.  If the chest x-ray 
demonstrates changes suggestive of previous TB (e.g., calcified nodule, fibrotic scar, 
apical or basilar pleural thickening) or other findings that are clinically significant, the 
principal investigator should contact the AbbVie TA MD before enrolling the subject.
12-Lead Electrocardiogram (ECG) 
For all subjects, a resting 12-lead ECG will be performed as specified in Appendix C.  A 
qualified physician will interpret the clinical significance of any abnormal finding, sign, 
and date each ECG.  ECGs with QT interval corrected for heart rate using Fridericia's 
correction formula (QTcF) should be reported (or calculated) and documented in the 
source documents and later transcribed on to the appropriate eCRF if QTcF prolongation 
is observed.  A valid QTcF cannot be calculated in subjects who have a pacemaker or 
supraventricular or ventricular conduction abnormalities.  In cases of QTcF prolongation, 
the baseline QTcF will need to be entered into the appropriate eCRF for comparison as 
well.  In addition, any clinically significant findings will be documented in the source 
documents and later transcribed on to the appropriate eCRF.  Each signed original ECG 
will be monitored by the responsible site monitor and kept with subject's source 
documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided source documentation is available and provided 
nothing has changed in the subject's medical history to warrant a repeat ECG.  If there are 
 


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other findings that are clinically significant, the investigator must contact the AbbVie 
TA MD before enrolling the subject.
Subjects can have a repeat ECG at any time during the study as warranted based on the 
opinion of the investigator.
At Week 12 or Week 24, in the event this may not be performed due to the COVID-19 or 
any pandemic, the site should perform the 12-lead ECG at the next earliest feasible visit 
or arrange to have an alternative acceptable local facility perform the ECG.
Height and Weight
Height will be measured at the Screening Visit only (with shoes off).  Body weight will be 
measured at all scheduled visits, as specified in Appendix C.  All measurements will be 
recorded in metric units where applicable.
Vital Signs
Vital sign determinations of systolic and diastolic BP in sitting position, pulse rate, 
respiratory rate, and body temperature will be obtained at visits specified in Appendix C.  
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed 
before blood draws are performed.
Physical Examination 
A complete physical examination will be performed at Screening, Baseline, Week 12, and 
Week 24/PD as specified in Appendix C and must include an assessment of EIMs and 
fistulas.  The physical examination at the Baseline Visit will serve as the baseline physical 
examination for the entire study.  Physical examinations at all other visits (including 
unscheduled visits) are symptom based and should include the assessment of EIMs, and 
presence or absence of fistulas as part of calculating the CDAI.  The presence or absence 
of (1) arthritis/arthralgia, (2) iritis/uveitis, and (3) erythema nodosum, pyoderma 
gangrenosum, and aphthous stomatitis will be collected for the assessment of EIMs. 
 


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At Baseline, Week 12, and Week 24/PD, the number of fissures, draining and non-
draining enterocutaneous (perianal and abdominal) and rectovaginal fistulas should be 
recorded, including the number of fistulas draining upon gentle compression.  
Enterocutaneous fistulas will be considered draining when there is drainage upon gentle 
compression, and rectovaginal fistulas will be considered draining based on either 
presence of drainage on physical examination or presence of relevant symptoms 
(e.g., passage of rectal material or flatus from the vagina).  A complete examination of the 
presence and number of draining and non-draining fistulas during Screening or during the 
visit for endoscopy at Screening, Week 12, or Week 24/PD may be used for the Baseline, 
Week 12, or Week 24/PD visits, respectively, and does not need to be repeated at the 
respective visit.
Physical examination abnormalities noted by the investigator at Baseline prior to the 
first dose of study drug will be recorded in the subject's medical history; abnormalities 
noted after the first dose of study drug will be evaluated and documented by the 
investigator as to whether or not the abnormality is an AE (see Section 6.1.1.1 for AE 
definition).  All findings, whether related to an AE or part of each subject's medical 
history, will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed 
necessary by the investigator.
Pregnancy Test
A serum pregnancy test will be performed for all female subjects of childbearing potential 
at the Screening Visit.  The serum pregnancy test will be sent to and performed by the 
central laboratory.  If the serum pregnancy test is positive the subject is considered a 
screen failure.  If the serum pregnancy test is borderline, it should be repeated ≥3 days 
later to determine eligibility.  If the repeat serum pregnancy test is:
●
Positive, the subject is considered a screen failure;
●
Negative, the subject can be enrolled into the trial;
 


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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.
A urine pregnancy test will be performed for all female subjects of childbearing potential 
at the Baseline Visit prior to the first dose of study drug and at all subsequent visits.  More 
frequent pregnancy tests will be performed throughout the study if required per 
local/country requirements.
If the baseline urine pregnancy test performed at the site is negative, then dosing with 
study drug may begin.  
If the baseline or a postbaseline urine pregnancy test performed at the site is positive, 
dosing with study drug must be withheld and a serum pregnancy test is required.  The 
serum pregnancy test will be sent to and performed by the central laboratory.  If the serum
pregnancy test is negative, study drug may be started or resumed.  If the serum pregnancy 
test is positive, study drug must be permanently discontinued.  In the event a pregnancy 
test comes back borderline, a repeat test is required, as described above.
At each visit, the study staff should review the pregnancy avoidance recommendations 
with each female subject of childbearing potential and document this discussion in the 
subject's source records. 
If during the course of the study a woman becomes surgically sterile or postmenopausal 
and complete documentation as described in Section 5.2.4 is available, pregnancy testing 
is no longer requested.
A pregnant or breastfeeding woman will not be eligible for participation in the study or be 
allowed to continue study drug.
During the COVID-19 or any pandemic-related restrictions, urine pregnancy tests may be 
performed at the local laboratory or at home and confirmed by site staff via phone, 
 


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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 3.
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will trigger automatic reflex testing for core antibodies 
(HBc Ab) and surface antibodies (HBs Ab).
For a subject who has had an HBV vaccination (should document in the medical history), 
a positive test result for HBs Ab is expected, the HBV DNA PCR qualitative testing is not
required and the subject may be enrolled (Scenario B). 
A negative test result for HBc Ab does not require HBV DNA PCR qualitative testing 
and the subject may be enrolled (Scenarios A and B).  
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic reflex 
testing) (Scenarios C and D).
●
A positive result for HBV DNA or a result that exceeds detection sensitivity 
will be exclusionary.
 


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●
A subject with a negative result for HBV DNA may be enrolled.
Where mandated by local requirements, subjects with positive HBs Ab and/or positive 
HBc Ab and a negative HBV DNA PCR test at Screening, should have HBV DNA PCR 
test performed at 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+.  In cases where 
recurrence of HBV DNA is observed, the subject should be discontinued from the study.
Figure 3.
Interpretation and Management of HBV Serologic Test Results
DNA = deoxyribonucleic acid, HBV = hepatitis B virus, PCR = polymerase chain reaction
*
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.
**
In the event that the HBV DNA PCR cannot be performed due to the COVID-19 or any pandemic, perform the 
HBV DNA PCR at the next earliest feasible visit or arrange to have it completed by a local laboratory.
Hepatitis C
Blood samples for Hepatitis C serology will be obtained at the Screening Visit.  A 
positive HCV Ab will trigger an HCV RNA test.  A subject will not be eligible for study 
participation if test results indicate active Hepatitis C (HCV RNA detectable in any 
subject with anti HCV Ab).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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HIV
Subjects with HIV infection (positive HIV test result) are excluded from study 
participation.  HIV testing 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
Samples will be obtained for the clinical laboratory tests listed in Table 2 and at visits 
specified in Appendix C.  Unscheduled clinical labs may be obtained at any time during 
the study if deemed appropriate per the investigator's discretion.  A certified central 
laboratory will be utilized to process and provide results for the clinical laboratory tests.  
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing, and shipping of these samples.
Blood draws should be performed, as much as possible, only after all questionnaires, 
clinical assessments, and vital sign determinations are obtained.
For blood sampling, subjects should be fasting (a minimum 8-hour fast) whenever 
possible.  If a subject is not able to fast when necessary, the non-fasting status will be 
recorded in study source documentation.
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant, the investigator should apply the standard of care for medical 
evaluation and treatment per local guidelines:
●
The investigator will repeat the test to verify the out-of-range value.
 


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●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
A laboratory test value that requires a subject to be discontinued from study drug or 
requires a subject to receive treatment will be recorded as an AE.  Other laboratory 
abnormalities, including those which meet the toxicity management criteria outlined in 
Section 6.1.7, may be recorded as AEs at the discretion of the investigator.
Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistrya
Urinalysis
Other Laboratory Tests
Hematocrit
Hemoglobin
RBC count
WBC count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Reticulocyte count
Platelet count
BUN
Creatinine
Total bilirubin
ALT
AST
Alkaline phosphatase
CPK
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Inorganic phosphate
Uric acid
Cholesterol
LDL-C
HDL-C
Triglycerides 
Total protein
Albumin 
Glucose
eGFRb
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Microscopic 
examination, if 
needed
Serum pregnancy (bHCG) 
testc
FSHd
HBs Ag
HBs Ab
HBc Ab
HBV DNA PCR (reflex only)
HCV Ab
HCV RNA (reflex only)
HIV Ab
QuantiFERON-TB Golde
hs-CRP
International Normalized Ratio 
(INR) (reflex only)f
Lymphocyte Subsetsg
PK
Beta-D-glucan test (Japan 
only)
Local Lab Test:
Urine pregnancy testh
Stool Samples
C. difficile toxin
Fecal calprotectin
Additional Samples Collected (Optional)
Blood, serum, plasma, stool, and intestinal tissue samples for exploratory research,a biologic drug level.i
 


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Table 2.
Clinical Laboratory Tests (Continued)
ALT = alanine transaminase; AST = aspartate transaminase; bHCG = beta human chorionic gonadotropin; BUN = blood 
urea nitrogen; CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; eGFR = estimated glomerular filtration 
rate; FSH = follicle-stimulating hormone; HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B surface antibody; 
HBs Ag = hepatitis B surface antigen; HBV = hepatitis B virus; HCV Ab = hepatitis C virus antibody; HDL-C = high 
density lipoprotein cholesterol; HIV = human immunodeficiency virus; hs-CRP = high-sensitivity C-reactive protein; 
INR = international normalized ratio; LDL-C = low-density lipoprotein cholesterol; PCR = polymerase chain reaction; 
PK = pharmacokinetic; RBC = red blood cell; RNA = ribonucleic acid; TB = tuberculosis; WBC = white blood cell
a.
Minimum 8-hour fast for chemistry.  If a subject is not able to fast when necessary, the non-fasting status will be 
recorded in study source documentation.
b.
eGFR will be done at Screening only.
c.
A serum pregnancy test will be performed for all women of childbearing potential at the Screening Visit and if 
postbaseline urine pregnancy test turns positive.
d.
At Screening for female subjects ≤ 55 years old AND has had no menses for ≥ 12 months AND has no history of 
permanent surgical sterilization (defined in Section 5.2.4) an FSH should be tested.
e.
QuantiFERON-TB Gold is not needed if for some reason PPD is being performed.
f.
INR will only be measured if ALT and/or AST > 3 × ULN.
g.
Lymphocyte subsets include T (cluster of differentiation [CD]4+ and CD8+) cells, B (CD19+) cells, NK cells, and 
natural killer T (NKT) cells.
h.
A urine pregnancy test will be performed for all female subjects of childbearing potential at the Baseline Visit prior 
to the first dose of study drug and all subsequent visits.
i.
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 
from the last dose; (2) adalimumab, certolizumab, golimumab, or vedolizumab:  may be tested approximately 
6 weeks from the last dose; (3) ustekinumab:  may be tested approximately 8 weeks from the last dose.
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic or any state of emergency or pandemic situation prevent the subject from 
having blood drawn for laboratory testing at the study site, if possible, sites should 
arrange for subjects to have laboratory work done at a local laboratory, hospital, or other 
facility.  It is recommended to perform all scheduled tests in the protocol, except for 
hs-CRP, fecal calprotectin, PK, lymphocyte subsets, and optional samples for exploratory 
research which should not be collected.  Local laboratory results should be obtained along 
with reference ranges and kept within the subject's source documentation.  Local 
laboratory results should be reviewed by the investigator and documented in EDC as an 
unscheduled laboratory visit as soon as possible. 
 


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If it is not possible to perform all of the laboratory tests locally, the minimum laboratory 
tests presented below should be performed for safety evaluation.
Table 3.
Minimum Laboratory Tests for Safety Evaluation
Hematology
Clinical Chemistry
Urine
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, if applicable
Urinalysis, if applicable
ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood urea nitrogen; RBC = red blood cell; 
WBC = white blood cell
If laboratory samples cannot be obtained, study drug administration may be continued, 
under some requirements, as described in the Study Drug Dispensing/Administration 
section below. 
Other Laboratory Assessments
High-Sensitivity C-Reactive Protein (hs-CRP)
Blood samples for hs-CRP will be obtained as specified in Appendix C.  The hs-CRP 
results will remain blinded to the sponsor, investigator, study site personnel and the 
subject.  The hs-CRP test will be performed by the central lab.  
Local laboratory or site testing for hs-CRP is not allowed after Baseline.  Results of hs-
CRP may unblind the treatment assignment, and the results may be blunted in subjects 
taking a JAK inhibitor, thereby limiting clinical utility in the setting of a safety 
assessment or AE management.  Any local testing of hs-CRP or CRP during the placebo-
controlled portion of the study is therefore strongly discouraged and any local hs-CRP or 
 


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CRP tests reported to the investigator prior to the primary endpoint assessment will be 
recorded as protocol deviations.
Urinalysis
Dipstick urinalysis (macroscopic analysis) will be completed by the central laboratory at 
all required visits as listed in Appendix C.  A microscopic urinalysis will only be 
performed by the central laboratory if the dipstick urinalysis results are abnormal, where 
abnormal is defined as leukocytes, nitrite, ketone, protein, blood, or glucose value of 
greater than a trace.
Lymphocyte Subsets
Blood samples will be collected at specified visits (Appendix C) to assess lymphocyte 
subsets:  T (CD4+ and CD8+) cells, B (CD19+) cells, NK cells, and NKT cells.  These 
tests will be performed by the central lab.
Stool Samples 
Fecal Calprotectin (FCP)
FCP will be performed for all subjects as indicated in Appendix C.  Subjects will be asked 
to provide a stool sample, subjects will be sent home with instructions and a stool sample 
supplies.  All stool samples should be collected before any bowel preparation for 
endoscopy is started.  
The FCP results will remain blinded to the sponsor, investigator, study site personnel and 
the subject throughout the study.  Local laboratory or site testing for FCP is not allowed 
after Baseline.
The central laboratory will be utilized to process and provide results for these laboratory 
tests.
 


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Clostridium difficile Toxin
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.
If a second sample collection is needed due to unforeseen issues with the first sample 
(e.g., missing sample, stability issues, inadequate sample, etc.), all efforts must be made to 
ship the second sample to the central laboratory using dry ice.  On an exceptional basis, 
and after consultation with the AbbVie TA MD, this second sample may be sent to the 
local lab for testing.
Subjects who are positive for C. difficile toxin should be screen-failed; these subjects may 
be re-screened after completing the appropriate treatment.
Outcomes and Questionnaires
The following outcomes and questionnaires will be completed at the time points as 
indicated in Appendix C.  Refer to Appendix E for descriptions of Patient Reported 
Outcomes.  
●
Inflammatory Bowel Disease Questionnaire (IBDQ)
●
Work Productivity and Activity Impairment Questionnaire (WPAI)-CD
●
Crohn's Symptoms Severity Questionnaire (CSS)
●
Short Form-36 (SF-36)
●
European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
Patient Global Impression of Change (PGIC)
●
Patient Global Impression of Severity (PGI-S)
●
Bristol Stool Chart
 


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During the COVID-19 pandemic or any state of emergency or pandemic situation, when 
an onsite visit cannot be performed, all questionnaires except EQ-5D-5L scale are eligible 
for completion by phone or virtual interview.  Prior to the phone/virtual visit, 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 remotely.  The date and start and stop time of PRO data collection should be 
recorded along with the name of the person who collected the information, their role, and 
which questionnaires were completed.
Subject Diary
Subjects will be dispensed an electronic 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.  The diary will be reviewed 
by site personnel with the subject at each visit and collected at the Final/PD Visit, unless 
the subject continues into Study M14-430.
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.
Remote Visits Due to the COVID-19 or any Pandemic
If visits cannot be conducted onsite due to travel restrictions or other pandemic-related 
reasons, phone or virtual (remote) visits, or visits at alternative locations may be 
performed.  These visits should occur within 7 days of the planned date, if possible.  
During these visits, the following procedures should be performed:
●
Adverse event assessment
 


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●
Concomitant medications
●
Compliance to contraception (if applicable) 
●
Monthly pregnancy testing results (if applicable)
●
IP compliance/dosing and drug accountability
●
Confirm subject diary entries
●
Weight (may be performed by the subject or caregiver)
●
Vital signs (may be obtained by the subject or caregiver)
●
Questionnaires:  All questionnaires except EQ-5D-5L scale are eligible for 
completion by remote interview at all visits.  If there are time constraints to the 
remote visit, at a minimum, the following must be completed:  IBDQ, FACIT-
F, PGIC, PGIS.
Assessments that require physical examination (e.g., gentle compression of fistulas, etc.) 
should not be performed.
The site must keep records of all remote visits.
Study Drug Dispensing/Administration
Study drug will be dispensed to subjects at Baseline, Week 4, and Week 8 in Parts 1 
and 2.  Subjects that continue into Part 3 will have study drug dispensed at Week 12, 
Week 16, and Week 20.  
Study drug will be taken orally QD beginning at the Baseline visit, and should be taken at 
approximately the same time each day.  
Refer to Section 5.5 for additional information.
If a subject is unable to come to the study site for drug dispensation due to COVID-19 or 
any pandemic, 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.  
 


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DTP study drug shipments will be removed once the pandemic is considered to be 
resolved.
Study drug may be dispensed, and study drug administration may be continued if 
laboratory samples cannot be obtained, provided that all the following criteria are met:
1.
There is at least 1 post-baseline laboratory assessment,
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, 
3.
No longer than 6 weeks have passed from the last safety laboratory tests.
Crohn's Disease Activity Index (CDAI) 
Average daily very soft or liquid SF, average daily AP score, and well-being will be 
calculated from the subject diary.  During screening subjects will be instructed on how to 
calculate the number of very soft and liquid stools, including a visual depiction based on 
the Bristol Stool Chart.  Physical exam and appropriate laboratory values will be 
calculated at all study visits, except the 30-day follow-up visit, beginning at Baseline.  
The Screening period will be a minimum of 8 days to calculate the Baseline scores.
The CDAI scores must be calculated using a hematocrit (Hct) value from the same visit 
laboratory work.  The final CDAI for each visit will be calculated once the Hct value is 
received from the central lab.  If the Hct is missing due to technical issues (e.g., lost 
sample, clotted sample, etc.), the Hct value from the preceding visit may be used.
Instructions to calculate CDAI
●
To answer questions one (1) through three (3), entries from the 7 days prior 
to the visit should be used as recorded by the subject from the diary.
●
Diary entries should not be included in the 7 days evaluated prior to the visit if:  
(1) the day the subject received medication for bowel preparation prior to 
 


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endoscopy, (2) the day the subject underwent an endoscopy, and (3) 2 days 
following the endoscopy.  Diary entries, up to 14 days prior to the visit, will be 
used accordingly in order to provide the most recent data for 7 days prior to the 
respective study visit.  The 7 days do not need to be consecutive.
●
In question four (4), for the section regarding presence of anal fistulas and 
other fistulas, all fistulas detectable on physical examination (draining and non-
draining) should be captured on the CDAI and calculated into the CDAI score.
●
The evaluation for fever should include all the days that are taken into account 
for the calculation of the CDAI.
●
When completing question five (5) ("Taking 
Lomotil/Imodium/Loperamide/opiates for diarrhea, 0 = no, 1 = yes") on the 
CDAI, "no" should be answered if a subject is taking an opiate(s) solely for 
pain.  The use of these medications takes into account only the day of the 
scheduled visit and is only assessing their use as anti-diarrheals.
●
For question seven (7), Hct results from central laboratory will be used for the 
CDAI calculation.  If the Hct value contains more than one decimal point, the 
rounding will be allowed to the tenths decimal (e.g., Hct value 33.44 will be 
captured as 33.4, Hct value of 33.45 will be captured as 33.5).  The Hct values 
either prior to completing the calculation or at the subtotal box 7 of the CDAI 
should not be rounded to a whole number.
●
For question eight (8), the height obtained at Screening should be used when 
selecting the standard weight in Appendix H, and this standard weight should 
be used for calculating every CDAI throughout subject participation in the 
study. 
●
Standard height is calculated by using the height obtained at Screening (without 
shoes) adding 1 inch or 2.5 cm. 
●
If the body weight obtained at the time of assessment is not captured in 
kilograms (kg), then when converting into kg, rounding should occur using the 
second digit after the decimal (also known as the hundredth place) where if the 
number is 0 – 4, then keep the first digit after the decimal (also known as the 
tenth place) unchanged.  If the second digit after the decimal is 5 – 9, then 
round up the first digit after the decimal (e.g., 90.246 would be captured as 90.2 
and 97.687 would be captured as 97.7).
 


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●
The subtotal of box 8 should not be rounded to a whole number.
The calculation of the CDAI score is in Appendix I.
Endoscopy
An endoscopy (ileocolonoscopy) will be performed as specified in Appendix C.  It is 
expected that all subjects who remain in the study through at least Week 8 will have a 
Week 12/PD endoscopy in Part 1 or Part 2.  For subjects entering Part 3, it is expected 
that all subjects who remain in the study through at least Week 20 will have a 
Week 24/PD endoscopy.  An endoscopy performed before the Screening visit, 
independently of the study, may be used as the Screening endoscopy, with the approval of 
the AbbVie TA MD, if the following conditions are met:
1.
Biopsy confirmation of the diagnosis is available according to section "Biopsy 
During Endoscopy" below, as applicable. 
2.
The endoscopy took place within 45 days prior to Baseline visit.
3.
The endoscopy was recorded in a video format as the endoscopic eligibility will be 
determined by the central reviewers.
The same endoscopist, where possible, should perform all endoscopies.  In addition, 
where possible, the investigator or sub-investigator should be the endoscopist for the 
study.  
During the COVID-19 or any pandemic, the Week 12 and Week 24 endoscopies may be 
performed within 7 days of the planned date if travel restrictions or other pandemic-
related reasons impact scheduling.  If the endoscopy cannot be performed at the study site, 
it can be completed at a different hospital/facility. 
If the COVID-19 or any pandemic precludes a subject from undergoing an endoscopy at:
 


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●
Week 12 or Week 24 and clinical response was achieved, the subject can enroll 
in Study M14-430.
●
Week 12 and clinical response was not achieved, the subject can enter Part 3 of 
Study M14-431.
All ileocolonoscopies will be performed and recorded at the site in a video format.  Sites 
should also perform the SES-CD assessment and record the findings on the SES-CD score 
sheet Appendix J and in the appropriate eCRF.
All endoscopies will be reviewed by a central reviewer who is blinded.  
There will be a window of 7 days prior to the scheduled visit to conduct the endoscopy, 
with the exception of the screening endoscopy.  This window may be extended as 
necessary after consultation with the AbbVie TA MD in case of external, not subject-
related circumstances (e.g., scheduling conflict).
The endoscopies performed at the time points described above will be used to provide the 
endoscopy subscores to calculate the SES-CD.  All attempts should be made by the 
endoscopist to explore all segments of the colon and terminal ileum, including intubation 
of the terminal ileum, at every endoscopy visit.  The endoscopy subscores by segment will 
be noted in the subject's source documents and in the database but the central reviewer's 
endoscopy subscore will be used for the efficacy analyses.
Biopsy During Endoscopy
Appropriate documentation of biopsy results consistent with the diagnosis of CD, 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.  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.
 


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If any biopsy sample(s) are obtained, it should also be recorded on the video.
Any biopsy sample(s) will be collected from the respective bowel segment during the 
withdrawal of the endoscope and after sufficient recording for the central reader to 
calculate the SES-CD.
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 Screening 
endoscopy or endoscopy performed within 45 days prior to Baseline visit.  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.
Subjects who consent to participate in the substudy to collect intestinal biopsies for 
histologic assessment and exploratory research will have samples collected at Screening, 
Week 12/PD in Part 1 and Part 2, and Week 24/PD in Part 3, as described in 
Section 5.3.1.2.1 and the laboratory manual. 
Corticosteroid Taper
Subjects who enter the study on oral corticosteroids are not allowed to change the 
corticosteroid dose during the first 4 weeks of the induction treatment period.  Doses of 
corticosteroids may be decreased during the first 4 weeks only in the event of moderate-
to-severe treatment related toxicities. 
 


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At Week 4, subjects who are on prednisone (or oral equivalent) or oral budesonide must 
have their corticosteroid dose tapered according to the proposed schedule in Appendix G.  
Subjects who enter the study on oral budesonide MMX® (e.g., Cortiment®, Uceris®) or 
oral beclomethasone must discontinue their corticosteroid at Week 4.
During Part 1 or Part 2, if a subject is unable to tolerate the corticosteroid taper, the 
subject may have the taper stopped or their corticosteroid dose increased prior to 
Week 10, per the investigator's discretion, up to the dose used at Baseline.  Initiating 
locally acting (rectal or suppository) or systemic corticosteroids is prohibited during 
Part 1 or Part 2.  Increasing the corticosteroid dose is not allowed at Week 10 through 
Week 12.
Subjects who do not achieve clinical response at Week 12 and enter in Part 3 and have not 
completed the corticosteroid taper, must resume and proceed with the taper at Week 16, 
following the schedule in Appendix G.  During Part 3, if a subject is unable to tolerate the 
corticosteroid taper, the subject may have the taper stopped or their corticosteroid dose 
increased prior to Week 22, per the investigator's discretion, up to the dose used at 
Baseline.  Increasing the corticosteroid dose is not allowed at Week 22 through Week 24.  
Initiating locally acting (rectal or suppository) or systemic corticosteroids is prohibited 
during Part 3.  
Optional Home Healthcare Service Due to the COVID-19 Pandemic or a State of 
Emergency or Pandemic Situation
Subjects may be offered the option of home healthcare visits provided by a study nurse or 
third-party vendor.  Study procedures conducted in the home setting may include vital 
signs, weight, physical examination, safety assessments, compliance to ePRO entries, 
study medication and contraception, pregnancy test, ECG, blood/stool/urine sample 
collection, if applicable.  This option can only be offered in countries and sites that 
comply with local regulatory and IRB/IEC requirements for home care.  Any pre-requisite 
submissions or notifications to the site IRB/IEC and local competent health authority 
 


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should be made, and approvals must be obtained prior to implementation.  The 
investigator should be available via phone call if a consultation is necessary.
Finally, it is recommended that medical personnel entering a subject's home adhere to 
local health regulations during the pandemic, such as the use of Personal Protective 
Equipment (PPE), as required.
Sites may perform home healthcare visits after the following requirements are met:
1.
Confirmation that the subjects study safety assessments have been reviewed by the 
principal investigator and that home assessment is appropriate.
2.
Confirmation that the subject's written consent to home healthcare has been 
obtained.  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. 
5.3.1.2
Collection and Handling of Optional Samples for 
Exploratory Research
Subjects will have the option to provide samples for exploratory research.  Subjects may 
still participate in the main study even if they decide not to participate in this optional 
exploratory research.  The procedures for obtaining and documenting informed consent 
are discussed in Section 9.3.
AbbVie (or people or companies working with AbbVie) will store the exploratory 
research 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 CD and related conditions continues, but for no longer than 20 years after 
study completion.
The following samples will be collected according to Appendix C from each subject who 
consents to provide samples for exploratory research:
 


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●
Blood samples for pharmacogenetic and epigenetic analyses (DNA)
●
Blood samples for transcriptomic and/or epigenetic analyses (RNA) if possible
●
Serum and plasma samples for systemic analyses including, but not limited to, 
proteomics and metabolomics
●
Stool samples for biomarker analyses including but not limited to proteomics 
and microbiota analysis in approximately 200 subjects (fecal biomarker 
substudy).
Samples will be shipped to AbbVie or a designated laboratory for analyses or long-term 
storage.  Instructions for the preparation and shipment of the samples will be provided in 
the laboratory manual.
5.3.1.2.1
Optional Samples for Histology Exploratory Research
Optional intestinal biopsy samples for histopathology and biological investigations, 
including but not limited to, transcriptomic analyses and immunohistochemistry may be 
evaluated in approximately 200 subjects (intestinal biopsy substudy).  Samples will be 
collected according to Appendix C.
Instructions for the preparation and shipment of the samples will be provided in the 
laboratory manual.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for assay of upadacitinib will be collected at each visit beginning at 
Week 2.  On the Week 4 visit day, if possible, subjects should take the oral study drug 
dose at the clinic after collecting the PK blood sample, except if the subjects regularly 
take the study drug dose at night.  Those subjects who regularly take the oral study drug 
dose at night should continue to take oral study drug according to their normal schedule.  
For all other visits, subjects can take the oral study drug dose on visit days at their regular 
schedule and not necessarily at the clinic.
 


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For all PK samples, the date and accurate time of the PK sample collection will be 
recorded on the lab requisition form.  The date and accurate time of the last two study 
drug doses will be recorded on the eCRF to the nearest minute.
Blood samples for the screening of prior biologics treatment (infliximab, natalizumab, 
adalimumab, certolizumab, golimumab, vedolizumab, or ustekinumab) may be collected 
at the discretion of the investigator according to Appendix C.
5.3.2.2
Handling/Processing of Samples
Detailed instructions for the handling and processing of plasma and serum samples will be 
provided by the central laboratory.  The plasma samples will be shipped to the central 
laboratory.  Upadacitinib plasma concentration will be determined at AbbVie.
Instructions for the preparation and shipment of samples will be provided in the laboratory 
manual.  The serum samples for biologics testing will be shipped to the central lab.
5.3.2.3
Disposition of Samples
The frozen plasma samples for upadacitinib assays and samples for biologics testing will 
be packed in dry ice sufficient to last during transportation and shipped from the study site 
to the central laboratory according to instructions in the central laboratory Lab Manual.  
An inventory of the samples included will accompany the package.
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.
Serum levels of biologics will be determined under the supervision of the drug analysis 
department at AbbVie.
 


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5.3.3
Efficacy Variables
The following endpoint definitions apply to the efficacy variables described below:  
●
Clinical remission per PROs:  average daily very soft or liquid SF ≤ 2.8 AND 
average daily AP score ≤1.0 and both not greater than Baseline 
●
Clinical remission per CDAI:  CDAI < 150
●
Enhanced Clinical Response:  ≥ 60% decrease in average daily very soft or 
liquid SF and/or ≥35% decrease in average daily AP score and both not greater 
than baseline, or clinical remission 
●
Clinical response 100 (CR-100): decrease of at least 100 points in CDAI from 
Baseline
●
Clinical response:  ≥ 30% decrease in average daily very soft or liquid SF 
and/or ≥ 30% decrease in average daily AP score and both not greater than 
Baseline 
●
Endoscopic remission:  SES-CD ≤ 4 and at least 2 point reduction from 
Baseline and no subscore > 1 in any individual variable, as scored by central 
reviewer 
●
Endoscopic response:  decrease in SES-CD > 50% from Baseline of the 
induction study (or for subjects with an SES-CD of 4 at Baseline, at least a 
2 point reduction from Baseline), as scored by central reviewer
5.3.3.1
Part 1 Primary Variables
The co-primary and ranked secondary endpoints will be analyzed separately for EU/EMA 
and US/FDA regulatory purposes.  The endpoints are specified separately for each set of 
analyses. 
Co-primary endpoints for EU/EMA regulatory purposes:
1.
Proportion of subjects with clinical remission per PROs at Week 12, and
2.
Proportion of subjects with endoscopic response at Week 12.
 


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Co-primary endpoints for US/FDA regulatory purposes:
1.
Proportion of subjects with clinical remission per CDAI at Week 12, and
2.
Proportion of subjects with endoscopic response at Week 12.
5.3.3.2
Part 1 Secondary Variables
5.3.3.2.1
Ranked Secondary Variables
The ranked secondary endpoints for EU/EMA regulatory purposes are as follows:  
1.
Proportion of subjects with clinical remission per CDAI (CDAI < 150) at Week 12
2.
Proportion of subjects with clinical remission per PROs at Week 4
3.
Proportion of subjects with endoscopic remission at Week 12
4.
Proportion of subjects who discontinue corticosteroid use for CD and achieve 
clinical remission per PROs at Week 12, in subjects taking corticosteroids for CD 
at Baseline
5.
Change from Baseline in FACIT-F at Week 12
6.
Change from Baseline in IBDQ at Week 12
7.
Proportion of subjects achieving CR-100 at Week 2
8.
Proportion of subjects achieving CR-100 at Week 12
9.
Proportion of subjects with hospitalizations due to CD during the 12 week double-
blind induction period
10.
Proportion of subjects with resolution of EIMs at Week 12, in subjects with EIMs 
at Baseline.
The ranked secondary endpoints for US/FDA regulatory purposes are as follows:
1.
Proportion of subjects with clinical remission per PROs at Week 12
 


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2.
Proportion of subjects with endoscopic remission at Week 12
3.
Proportion of subjects who discontinue corticosteroid use for CD and achieve 
clinical remission per CDAI at Week 12, in subjects taking corticosteroids for CD 
at Baseline
4.
Change from Baseline in FACIT-F at Week 12
5.
Change from Baseline in IBDQ at Week 12
6.
Proportion of subjects achieving CR-100 at Week 2
7.
Proportion of subjects achieving CR-100 at Week 12
8.
Proportion of subjects with clinical remission per CDAI at Week 4 
9.
Proportion of subjects with hospitalizations due to CD at during the 12-week 
double-blind induction period
10.
Proportion of subjects with resolution of extra-intestinal manifestation (EIM) at 
Week 12, in subjects with EIM at Baseline.
5.3.3.2.2
Additional Efficacy Variables
Non-ranked endpoints are as follows:
●
Proportion of subjects:
○
with clinical remission per PROs over time
○
with clinical remission per CDAI (CDAI < 150) over time
○
with enhanced clinical response over time
○
with clinical response over time
○
with CR-100 over time
○
with clinical remission per PROs and endoscopic remission at Week 12
○
with clinical remission per CDAI and endoscopic remission at Week 12
○
with enhanced clinical response and endoscopic response at Week 12
 


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○
who discontinue corticosteroid use for CD and achieve endoscopic 
remission at Week 12, in subjects taking corticosteroids for CD at Baseline
○
who discontinue corticosteroid use for CD and achieve enhanced clinical 
response at Week 12, in subjects taking corticosteroids for CD at Baseline
○
who discontinue corticosteroid use for CD and achieve endoscopic 
response at Week 12, in subjects taking corticosteroids for CD at Baseline
○
who discontinue corticosteroid use for CD at Week 12, in subjects taking 
corticosteroids for CD at Baseline
○
with ≥ 50% reduction in the corticosteroid dose for CD from Baseline at 
Week 12, in subjects taking corticosteroids for CD at Baseline
○
with hospitalizations during the 12 week double-blind induction period 
○
undergoing CD-related surgeries during the 12 week double-blind 
induction period
○
decrease in SES-CD > 50% from Baseline of the induction study or 
endoscopic remission at Week 12, as scored by central reviewer
○
with SES-CD ≤ 2 at Week 12
○
with SES-CD ulcerated surface subscore of 0 at Week 12 in subjects with 
SES-CD ulcerated surface subscore ≥ 1 at Baseline, as scored by a central 
reviewer
○
with SES-CD ulcerated surface subscore ≤ 1 in each segment at Week 12 
in subjects with a SES-CD ulcerated surface subscore ≥ 2 at Baseline, as 
scored by a central reviewer
○
with endoscopic remission at Week 12 among subjects with SES-CD 
subscore of 3 in the narrowing component at Week 12, which was not 
present at Baseline
○
with endoscopic response at Week 12 among subjects with SES-CD 
subscore of 3 in the narrowing component at Week 12, which was not 
present at Baseline
○
with endoscopic response or endoscopic remission at Week 12 among 
subjects with SES-CD subscore of 3 in the narrowing component at 
Week 12, which was not present at Baseline 
 


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○
with endoscopic remission at Week 12 among subjects with SES-CD 
narrowing component subscore between 0 and 2 in all intestinal segments 
at Baseline
○
with endoscopic response at Week 12 among subjects with SES-CD 
narrowing component subscore between 0 and 2 in all intestinal segments 
at Baseline
○
with endoscopic response or endoscopic remission at Week 12 among 
subjects with SES-CD narrowing component subscore between 0 and 2 in 
all intestinal segments at Baseline
○
achieving Colonic and Ileal Global Histologic Disease Activity Score 
(CGHAS/IGHAS) histologic remission (defined as CGHAS/IGHAS score 
≤ 3 in those with abnormal histology at Baseline) at Week 12
○
without draining fistulas at Week 12 in subjects with draining fistulas at 
Baseline
○
with ≥ 50% reduction in draining fistulas at Week 12, in subjects with 
draining fistulas at Baseline
○
with at least 50% decrease in the number of days with very soft or liquid 
stools (Type 6 or 7, per Bristol Stool Chart) during the last 7 days at 
Week 12
○
with IBDQ remission (IBDQ > 170 points) over time 
○
with IBDQ response (increase in IBDQ > 16 points from Baseline) over 
time 
○
achieving response in IBDQ fatigue item (increase of IBDQ fatigue item 
score ≥ 1) over time.
○
achieving response in IBDQ Bowel Symptom domain (increase of IBDQ 
bowel symptom domain score ≥ 8) at Week 12
●
Change from Baseline in:
○
IBDQ over time
○
individual IBDQ domain scores (bowel, emotional, social, systemic) over 
time
○
individual IBDQ item under Bowel Symptom domain (for Q1, Q5, Q9, 
Q13, Q17, Q20, Q22, Q24, Q26, and Q29) over time
 


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○
WPAI-CD over time
○
EQ-5D-5L over time
○
SF-36 over time
○
CSS over time
○
FCP over time 
○
hs-CRP over time
○
average daily AP score over time
○
average daily very soft or liquid SF over time
○
average daily total SF over time
○
CDAI over time
○
SES-CD at Week 12
○
mean CGHAS/IGHAS at Week 12 among subjects with abnormal 
histology at Baseline
5.3.3.3
Part 2 Variables
Same efficacy endpoints as those listed in Part 1 (Section 5.3.3.1 and Section 5.3.3.2) are 
considered for Part 2 of the study.  All the Part 2 efficacy endpoints are considered 
additional endpoints and ranking of the endpoints is not applicable for Part 2.
5.3.3.4
Part 3 Variables
●
Proportion of subjects:
○
with clinical remission per PROs over time
○
with clinical remission per CDAI (CDAI < 150) over time
○
with enhanced clinical response over time
○
with clinical response over time
○
with endoscopic remission at Week 24
○
with clinical remission per PROs and endoscopic remission at Week 24
○
with clinical remission per CDAI and endoscopic remission at Week 24
○
with enhanced clinical response and endoscopic response at Week 24
 


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○
who discontinue corticosteroid use for CD and achieve clinical remission 
per PROs at Week 24, in subjects taking corticosteroids for CD at Week 12
○
who discontinue corticosteroid use for CD and achieve clinical remission 
per CDAI at Week 24, in subjects taking corticosteroids for CD at 
Week 12.
○
who discontinue corticosteroid use for CD and achieve endoscopic 
remission at Week 24, in subjects taking corticosteroids for CD at Week 12
○
who discontinue corticosteroid use for CD and achieve enhanced clinical 
response at Week 24, in subjects taking corticosteroids for CD at Week 12
○
who discontinue corticosteroid use for CD and achieve endoscopic 
response at Week 24, in subjects taking corticosteroids for CD at Week 12
○
who discontinue corticosteroid use for CD at Week 24, in subjects taking 
corticosteroids for CD at Week 12
○
with ≥50% reduction in the corticosteroid dose for CD from Baseline at 
Week 24, in subjects taking corticosteroids for CD at Week 12
○
with hospitalizations due to CD during Part 3 
○
with hospitalizations during Part 3 
○
undergoing CD-related surgeries during Part 3
○
with resolution of EIMs at Week 24, in subjects with EIMs at Baseline or 
Week 12 
○
decrease in SES-CD > 50% from Baseline of the induction study or 
endoscopic remission at Week 24, as scored by central reviewer
○
with SES-CD ≤ 2 at Week 24
○
with SES-CD ulcerated surface subscore of 0 at Week 24 in subjects with 
SES-CD ulcerated surface subscore ≥ 1 at Baseline, as scored by a central 
reviewer
○
with SES-CD ulcerated surface subscore ≤ 1 in each segment at Week 24 
in subjects with a SES-CD ulcerated surface subscore ≥ 2 at Baseline, as 
scored by a central reviewer
○
achieving (CGHAS/IGHAS) histologic remission (defined as 
CGHAS/IGHAS score ≤ 3 in those with abnormal histology at Baseline) at 
Week 24
 


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○
with ≥ 50% reduction in draining fistulas at Week 24, in subjects with 
draining fistulas at Baseline 
○
without draining fistulas at Week 24 in subjects with draining fistulas at 
Baseline or Week 12
○
with at least 50% decrease in the number of days with very soft or liquid 
stools (Type 6 or 7, per Bristol Stool Chart) during the last 7 days at 
Week 24.
●
Change from Baseline in:
○
IBDQ over time
○
WPAI-CD over time
○
EQ-5D-5L over time
○
CSS at Week 24
○
FACIT-F at Week 24
○
SF-36 at Week 24
○
FCP over time 
○
hs-CRP over time
○
average daily AP score over time
○
average daily very soft/liquid SF over time
○
average daily total SF over time
○
CDAI over time
○
SES-CD at Week 24
○
mean CGHAS/IGHAS at Week 24 among subjects with abnormal 
histology at Baseline
●
Time to: 
○
clinical response
○
enhanced clinical response
○
clinical remission
 


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5.3.4
Safety Variables
Safety analyses will be performed on all subjects who receive at least one dose of study 
drug.  Incidence of AEs, changes in vital signs, physical examination results, and clinical 
laboratory data will be assessed throughout the study.
5.3.5
Pharmacokinetic Variables
Plasma upadacitinib concentrations will be obtained at the times indicated in Appendix C.  
A non-linear mixed-effects modeling approach will be used to estimate the population 
central values and the empirical Bayesian estimates of the individual values of 
upadacitinib oral clearance (CL/F) and volume of distribution (V/F).  Additional 
parameters may be estimated if useful in the interpretation of the data.  
5.3.6
Optional Exploratory Research Variables
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.  The samples may be analyzed as 
part of a multi-study assessment of factors influencing the subjects' response to the study 
drug (or drugs of the same or similar class) or the development and progression of the 
subjects' disease or related conditions.  The samples may be analyzed for genetic factors 
contributing to the subject's response to study treatment, in terms of pharmacokinetics, 
tolerability, and safety.  Such genetic factors may include genes for drug metabolizing 
enzymes, drug transport proteins, genes within the target pathway, or other genes believed 
to be related to drug response.  Genomic testing and analysis may involve (but is not 
limited to) sequencing of single nucleotide polymorphisms (SNPs), whole exomes, whole 
genomes and epigenetics.  RNA testing and analysis may involve (but not limited to) 
sequencing and expression of all classes (i.e., microRNA [miRNA], long non-coding 
RNA [lncRNA], piwi interacting RNA [piRNA] etc.) of RNA.  The samples may also be 
used to develop new diagnostic tests, therapies, research methods or technologies.  The 
results from these analyses are exploratory in nature and may not be included with the 
study report.
 


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects can request to be discontinued from participating in the study at any time for any 
reason including but not limited to disease progression or lack of response to treatment.  
The investigator may discontinue any subject's participation for any reason, including but 
not limited to disease progression, lack of response to treatment, an AE, safety concerns, 
or failure to comply with the protocol.  See Section 6.1.7 for toxicity management criteria.
Subjects will have study drug discontinued immediately if any of the following occur:
●
Clinically significant abnormal laboratory results or AEs, which rule out 
continuation of the study drug, as determined by the investigator or the AbbVie 
TA MD.
●
Serious infections (e.g., sepsis), which would put the subject at risk for 
continued participation in the trial as determined by the investigator.
●
The investigator believes it is in the best interest of the subject, including 
subjects with no improvement to study drug at Week 12 for whom the 
investigator believes it is not in the best interest of the subject to enter in the 
Extended Treatment Period.
●
The subject requests withdrawal from the study.
●
Inclusion or exclusion criteria violation was noted after the subject started study 
drug, when continuation of the study drug would place the subject at risk as 
determined by the AbbVie 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 drug.
●
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix.
 


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●
Subject is significantly non-compliant with study procedures, which would put 
the subject at risk for continued participation in the trial as determined by the 
investigator or the AbbVie TA MD.
●
Subject develops a gastrointestinal perforation (other than appendicitis or 
mechanical injury).
●
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus or non-
cardiac, nonneurologic arterial thrombosis.  See Section 6.1.7 Toxicity 
Management.
During the COVID-19 pandemic or any state of emergency or pandemic situation, it has 
been necessary to employ mitigation strategies to enable the investigator to ensure subject 
safety and continuity of care.  The investigator should contact the AbbVie TA MD before 
discontinuing a subject from the study for a reason other than "planned per protocol," to 
ensure all acceptable mitigation steps have been explored.
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment or study participation should complete a PD 
visit as described in Section 5.1.  
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study drug or study participation.  The information 
will be recorded on the appropriate eCRF page.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of study drug, the subject will be treated in accordance with the investigator's best clinical 
judgment irrespective of whether the subject decides to continue participation in the study.
Lost to Follow-Up
For subjects that are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent.
 


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5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Study drug will be taken orally QD, beginning on Day 1 (Baseline), and should be taken 
at approximately the same time each day.  The study drug can be taken with or without 
food.  Subjects will continue their stable background CD therapy, if allowed per protocol.  
AbbVie will not supply any background CD therapy taken during the course of the study.  
Study drug may be shipped from the study site directly to the study subject's home if all of 
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., paper copies of PROs, 
urine pregnancy tests).  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 pandemic-
 


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related social distancing, this may be provided by the courier after delivery.  
Documentation of the shipment is to be retained by the clinical site. 
●
AbbVie will not receive subject identifying information related to these 
shipments as the site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug and for obtaining consent to provide delivery information to the 
courier and documenting this consent in source documents.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 4.
Table 4.
Identity of Investigational Product
Investigational Product
Dosage Form
Strength
Route of 
Administration
Upadacitinib 
Film-coated tablet
45 mg
Oral
Matching placebo 
Film-coated tablet
NA
Oral
Upadacitinib 
Film-coated tablet
30 mg
Oral
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 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(s)
Study drugs must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  
The investigational products are for investigational use only and are to be used only 
 


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within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or destroyed as appropriate.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be assigned a unique identification number by the IRT at the Screening 
visit and will keep the same unique subject identification number throughout the study.  
Subjects who meet all of the inclusion criteria and none of the exclusion criteria defined in 
Section 5.2.1 and Section 5.2.2 will be centrally randomized.
The IRT will assign a randomization number that will encode the subject's treatment 
group assignment according to the randomization schedule generated by the Statistics 
Department at AbbVie.
IRT will provide the appropriate medication kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Section 5.5.  
Returned study drug should not be re-dispensed to any subject.
In Part 1, subjects (n = 495) will be randomized in a 2:1 ratio to upadacitinib 45 mg QD or 
matching placebo for 12 weeks (Figure 1).  The randomization will be stratified by 
baseline corticosteroid use (yes or no), endoscopic disease severity (SES-CD < 15 and 
≥15), and number of prior biologic treatments (> 1 and ≤ 1).  
At Week 12, subjects achieving clinical response, defined as ≥ 30% decrease in average 
daily very soft or liquid SF and/or ≥ 30% decrease in average daily AP score (both not 
worse than Baseline) may be eligible to enter the 52-week double-blind maintenance 
portion of Study M14-430.
Part 2 is an open-label portion of this study.  Once enrollment in Part 1 is complete, 
approximately 130 subjects will be enrolled to receive upadacitinib 45 mg QD for 
12 weeks (Figure 1).  The objective of Part 2 is to have a sufficient number of subjects 
with clinical response to be re-randomized in the double-blind maintenance portion of 
 


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Study M14-430, while minimizing unnecessary exposure to placebo.  At Week 12, 
subjects achieving clinical response may be eligible to enter Study M14-430.  
Subjects who do not achieve clinical response at Week 12 in Part 1 or Part 2 will be able 
to participate in Part 3 (Extended Treatment Period) and receive upadacitinib for 12 weeks 
until Week 24/PD.  The objectives of Part 3 are to offer blinded upadacitinib induction 
treatment to placebo non-responders from Part 1 and to evaluate a delayed clinical 
response to upadacitinib in subjects who did not initially respond to upadacitinib during 
Part 1 or Part 2.  Part 3 consists of 3 cohorts, and the treatment assignment will depend on 
the treatment received in Part 1 or Part 2, as follows:
●
Cohort 1:  Subjects who received placebo in Part 1 and did not achieve clinical 
response at Week 12 are eligible to receive double-blind induction treatment 
with upadacitinib 45 mg QD. 
●
Cohort 2:  Subjects who received double-blind upadacitinib in Part 1 and did 
not achieve clinical response at Week 12 are eligible to receive double-blind 
upadacitinib 30 mg QD. 
●
Cohort 3:  Subjects who received open-label upadacitinib during Part 2 and did 
not achieve clinical response at Week 12 are eligible to receive open-label
upadacitinib 30 mg QD.
Subjects in Cohort 1 and 2 will remain blinded to treatment to avoid unmasking the 
treatment received during Part 1.  Subjects are not eligible to enter in Part 3 until the 
Week 12 endoscopy has been completed.  If the COVID-19 pandemic precludes a subject 
from undergoing an endoscopy, the subject can continue in Part 3.
At Week 24, subjects who achieve clinical response may be eligible to enter 
Study M14-430.  Subjects are not eligible to enter Study M14-430 until the 
ileocolonoscopy procedure at Week 24 for evaluation of mucosal inflammation has been 
completed.  If the COVID-19 pandemic precludes a subject from undergoing an 
endoscopy, the subject can enroll in Study M14-430 if clinical response was achieved at 
Week 24.
 


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Subjects who do not achieve clinical response at Week 24 will be discontinued from 
Study M14-431 and will receive standard of care treatment at the investigator's discretion.  
Subjects who do not achieve clinical response at Week 24 and all subjects who 
prematurely discontinue the study will have a follow-up visit 30 days from the last dose of 
study drug to collect information on new or ongoing AEs and laboratory assessments.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.5.1.
On dosing days that occur on study visit days, subjects should follow the regular dosing 
schedule (refer to Section 5.3.2.1 regarding Week 4 visit).
Each subject's dosing schedule should be closely monitored by the site at each study visit.  
This will ensure that all subjects enrolled into the study maintain their original dosing 
schedule beginning with the first dose of study drug (Baseline/Day 1).
If a subject should forget to take their upadacitinib (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.  
For elective and emergency surgeries, the following rules apply:
●
If the subject must undergo emergency surgery, the study drug should be 
interrupted at the time of the surgery.  After emergency surgery, allow 
reintroduction of study drug once the physician has examined the surgical site 
and determined that it has healed and there is no sign of infection.
●
Elective surgery will not be allowed during the study until the primary endpoint 
has been assessed.  If the subject undergoes elective surgery, the study drug 
should be interrupted 1 week prior to the planned surgery.  Reintroduction of 
study drug is allowed once the physician has examined the surgical site and 
determined that it has healed and there is no sign of infection.
 


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5.5.5
Blinding
All AbbVie personnel with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie Drug Supply Management Team), the investigator, study 
site personnel, and the subject will remain blinded to each subject's treatment throughout 
the study and until that data is locked and analyzed as part of the planned analysis.  In 
order to maintain the blind, the upadacitinib tablets and placebo tablets provided for the 
study will be identical in appearance.  The IRT will provide access to unblinded subject 
treatment information in the case of medical emergency.
In the event of a medical situation that requires unblinding of the study drug assignment, 
the investigator is requested to contact the AbbVie TA MD prior to breaking the blind.  
However, if an urgent therapeutic intervention is necessary which warrants breaking the 
blind prior to contacting the AbbVie TA MD, the investigator can directly access the IRT 
system to break the blind without AbbVie notification or agreement.  Unblinding is 
available in the IRT system via the Unblind Subject transaction, which is available only to 
the investigator.  If the IRT system is unavailable, unblinding may occur by contacting 
EndPoint technical support via either phone (preferred) or email 
(support@endpointclinical.com).  For country-specific phone numbers, please see the 
following website:  http://www.endpointclinical.com/help-desk/.
In the event that the blind is broken before notification to the AbbVie TA MD, we request 
that the AbbVie TA MD be notified within 24 hours of the blind being broken.  The date 
and reason that the blind was broken must be conveyed to AbbVie and recorded on the 
appropriate eCRF.
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.
 


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5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)
An external DMC comprised of persons independent of AbbVie and with relevant 
expertise in their field will review unblinded safety data from the ongoing study.  The 
primary responsibility of the DMC will be to protect the safety of the subjects 
participating in this study.
A separate DMC charter will be prepared outside of the protocol and will describe the 
roles and responsibilities of the DMC members, frequency and triggers of data reviews, 
relevant safety data to be assessed, and communication with and recommendations to 
AbbVie as well as relevant competent authorities, if necessary.
An independent committee of physician experts in cardiovascular adjudication will be 
utilized to assess cardiovascular AEs and embolic and thrombotic events (non-cardiac, 
non-central nervous system) in a blinded manner as defined by the cardiovascular 
adjudication committee (CAC) charter.
Communications from the DMC to the Study Teams and CAC will not contain 
information that could potentially unblind the team to subject treatment assignments.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subjects will be instructed to return all drug containers (even if empty) to the study site 
personnel at each clinic 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 
 


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documented on the source documents as per "best recollection" before completing on the 
applicable eCRF page.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt or similar document and by registering the arrival of drug through the 
IRT.  The original Proof of Receipt Note and the IRT confirmation sheet will be kept in 
the site files as a record of what was received.
In addition, an IRT will be used to document investigational product accountability 
including but not limited to date received, the lot number, kit number(s), date dispensed, 
subject number, and the identification of the person dispensing the drug.
All empty/used study drug packaging will be inventoried by the site.  Empty/used study 
drug packaging should be returned by the subject at each visit for accountability and 
compliance purposes and new packaging issued as necessary.  
Site staff will complete study drug accountability via IRT, by using source documents, 
and by visually inspecting the packaging whenever possible.  After drug accountability 
has been completed, used packaging and unused study drug will be destroyed on site 
according to local procedures or regulations or returned to the destruction depot (for those 
sites that do not meet AbbVie's documentation requirements for on-site destruction).  The 
use of a third party vendor for drug destruction must be pre-approved by AbbVie.  For 
sites performing on-site drug destruction or using a third party vendor for drug 
destruction, a copy of the destruction methodology and date of destruction should be 
maintained at the site's facility.
During the COVID-19 or any pandemic, if a visit is completed virtually, study drug 
accountability can be conducted remotely with the subject.  Any kits that are accounted 
for remotely should be retained by the subject and when the subject is then able to 
 


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complete an onsite visit, they should return all kits for verification of the drug 
accountability by the site staff.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Upadacitinib is a novel, orally administered JAK1 inhibitor being developed for the 
treatment of adult patients with inflammatory diseases and may provide improved clinical 
benefit to CD patients.  The proposed study is a Phase 3, randomized, double-blind, 
placebo-controlled induction study to evaluate the efficacy and safety of upadacitinib in 
adult subjects with a confirmed diagnosis of CD for at least 3 months and moderately to 
severely active CD who have inadequately responded to or are intolerant to biologic 
therapy.  This study will evaluate one induction dose of upadacitinib 45 mg QD.
In Part 1, subjects (n = 495) will be randomized in a 2:1 ratio to 45 mg upadacitinib QD or 
matching placebo for 12 weeks.  The randomization will be stratified by baseline 
corticosteroid use (yes or no), endoscopic disease severity (SES-CD < 15 and ≥ 15), and 
number of prior biologic treatments (> 1 and ≤ 1).  At this time, a 12-week placebo-
controlled study is necessary for registrational purposes.  A comparative study utilizing 
placebo provides an unbiased assessment of the efficacy and safety profile of 
upadacitinib.  
Part 2 is an open-label portion (open-label cohort) of this study.  Once enrollment in 
Part 1 is complete, approximately 130 subjects will be enrolled to receive upadacitinib 
45 mg QD for 12 weeks.  The objective of Part 2 is to have a sufficient number of subjects 
with clinical response to be re-randomized in the double-blind maintenance portion of 
Study M14-430, while minimizing unnecessary exposure to placebo. 
To ensure all subjects are given the opportunity to receive potentially efficacious therapy, 
all subjects in Part 1 or Part 2 who do not achieve clinical response after 12 weeks will be 
able to enroll in Part 3, an Extended Treatment Period for 12 weeks.  Part 3 consists of 
3 cohorts.  The first objective of Part 3 is to offer blinded upadacitinib induction treatment 
 


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to placebo non-responders from Part 1.  In the upadacitinib Phase 2 Study M13-740, some 
subjects achieved clinical remission between Week 12 and Week 16 with upadacitinib 
6 mg BID, 24 mg BID and 24 mg QD.  This study will also evaluate delayed clinical 
response to upadacitinib in subjects who did not initially respond to upadacitinib 45 mg 
QD during Part 1 or Part 2.  In Part 3, these subjects will receive upadacitinib 30 mg QD 
for an additional 12 weeks.
The study was designed to enroll 625 subjects to meet scientific and regulatory objectives, 
without enrolling an undue number of subjects in alignment with ethical considerations.  
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 CD.  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 CD.
5.6.3
Suitability of Subject Population
Adult male and female subjects between 18 to 75 years of age (or minimum age of adult 
consent according to local regulations) with moderately to severely active CD, 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 
subjects with a history of inadequate response or intolerance to biologic therapy.
5.6.4
Selection of Doses in the Study
This study will evaluate one induction dose of upadacitinib (45 mg QD) (Figure 1).  The 
selection of this dose was informed by the analysis of the 16-week safety, efficacy and 
exposure-response data of Phase 2 CD Study M13-740, which evaluated 5 induction 
doses of upadacitinib using the immediate-release formulation (3, 6, 12 or 24 mg BID or 
24 mg QD) versus placebo.  In addition, all of the currently available PK, 
pharmacodynamic, safety, and efficacy data from upadacitinib studies were used to 
 


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support the selection of this dose.  The induction phase results from Study M13-740 
demonstrated the clinical and endoscopic efficacy of upadacitinib compared to placebo 
with doses of 6 mg BID and higher.  
Upadacitinib dose of 45 mg QD using the once-daily formulation provides equivalent 
daily area under the concentration-time curve (AUC) and comparable maximum plasma 
concentration (Cmax) and minimum plasma concentration (Cmin) to 18 mg BID dose using 
the immediate-release formulation.  In the CD Phase 2 study, the dose of 12 mg BID and 
higher were shown to approach the plateau of efficacy for clinical endpoints while 
increasing the dose to 24 mg BID provided additional efficacy benefit particularly for the 
endoscopic endpoints.  Therefore, 45 mg QD regimen using the once-daily formulation 
(equivalent to 18 mg BID immediate-release) is predicted to provide the optimal balance 
between maximizing efficacy while limiting the effects on laboratory parameters 
(e.g., decreases in hemoglobin and NK cells).  Upadacitinib 45 mg QD, dosed for up to 
12 weeks is expected to be efficacious with an acceptable safety profile and upadacitinib 
15 mg QD and 30 mg QD, dosed for up to 240 weeks as maintenance treatment, are 
expected to be efficacious with acceptable safety profiles.  
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For AEs, please refer to Sections 6.1
through 6.1.9.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of AEs on 
a routine basis throughout the study.  The investigator will assess and record any AE in 
 


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detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drug, and 
any action(s) taken.  For serious AEs considered as having "no reasonable possibility" of 
being associated with study drug, the investigator will provide an "Other" cause of the 
event.  For AEs to be considered intermittent, the events must be of similar nature and 
severity.  AEs, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All AEs will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an AE.  Worsening in 
severity of a reported AE should be reported as a new AE.  Laboratory abnormalities and 
changes in vital signs are considered to be AEs only if they result in discontinuation from 
the study, necessitate therapeutic medical intervention, and/or if the investigator considers 
them to be AEs.
An elective surgery/procedure scheduled to occur during the study will not be considered 
an AE if the surgery/procedure is being performed for a pre-existing condition or 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 
 


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planned), then the deterioration of the condition for which the elective surgery/procedure 
is being done will be considered an AE.
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as a serious 
adverse event (SAE) within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially
interferes with the activities of daily living (ADL) of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
 


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate eCRF.
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 cardiac event [MACE]);
●
Anemia;
●
Neutropenia;
●
Lymphopenia;
●
Renal dysfunction;
 


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●
Hepatic disorder;
●
Elevated CPK;
●
Adjudicated embolic and thrombotic events (non-cardiac, non-central nervous 
system [CNS]).
6.1.2
Adverse Event Severity
When criteria are available, events should be graded as described in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03, which can be accessed at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40.
If no grading criteria are provided for the reported event, then the event should be graded 
as mild, moderate, or severe per the investigator's judgment.
Mild (Grade 1)
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
Moderate (Grade 2)
Minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL
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
Grade 4
Life-threatening consequences; urgent intervention 
indicated.  
Grade 5
Death related to AE
Use the following guidelines when entering the severity grading criteria into the electronic 
data capture (EDC) system:  Grade 1 as Mild; Grade 2 as Moderate; and Grade 3 to 5 as 
severe.
 


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6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:
Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is sufficient evidence 
(information) to suggest a causal relationship.
No Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is insufficient
evidence (information) to suggest a causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the SAE.
6.1.4
Adverse Event Collection Period
All AEs reported from the time of study drug administration until 30 days following 
discontinuation of study drug administration have elapsed will be collected, whether 
solicited or spontaneously reported by the subject.  Subjects who discontinue study drug 
treatment but continue to participate in the study will have SAEs and nonserious AEs 
collected for the remainder of study participation.  In addition, SAEs and protocol-related 
nonserious AEs will be collected from the time the subject signed the study-specific 
informed consent.
AE information will be collected as shown in Figure 4.
 




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COVID-19 related supplemental eCRFs should be completed: 
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form
6.1.5
Adverse Event Reporting
In the event of an SAE, whether associated with study drug or not, the investigator will 
notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the 
SAE by entering the SAE data into the EDC system.  SAEs that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the SAE.
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660
For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Office:
(833) 942-2226
Email:
SafetyManagement_Immunology@abbvie.com
For any subject safety concerns, please contact the physician listed below:
 


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Primary Therapeutic Area Medical Director:
AbbVie, Inc.
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Cell:
Fax:
Email:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  +1 (973) 784-6402
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the upadacitinib Investigator's Brochure. 
In Japan, the principal investigator will provide documentation of all SAEs to the Director 
of the investigative site and the Sponsor.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued from study drug (Section 5.4.1).
 


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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 AE.  However, the medical outcome of 
an elective or spontaneous abortion, stillbirth, or congenital anomaly is considered an 
SAE and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
6.1.7
Toxicity Management
The toxicity management of the AEs including AEs of special interest consists of safety 
monitoring (review of AEs on an ongoing basis, and periodical/ad hoc review of safety 
issues by a safety DMC), interruption of study drug dosing with appropriate clinical 
management if applicable, and discontinuation of the subjects from study drug.  The 
management of specific AEs and laboratory parameters is described below.
For subjects who discontinued study drug but continued study participation and are on 
standard of care therapies, these toxicity management requirements do not apply 
(including alerts from the central lab) and any intolerability to standard of care therapies 
should be managed by the prescribing physician.
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection.  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 
resumed once the infection has been successfully treated.  Subjects who develop active 
TB must be discontinued from study drug.
Herpes zoster:  If a subject develops herpes zoster, consider temporarily interrupting 
study drug until the episode resolves.
 


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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 gastrointestinal perforation is confirmed (other than 
appendicitis or mechanical injury), the subject must be discontinued from study drug.
Cardiovascular Events (MACE):  Subjects presenting with potential cardiovascular 
events should be appropriately assessed and carefully monitored.  These events will be 
reviewed and adjudicated by an independent Cardiovascular Adjudication Committee 
(CAC) in a blinded manner.
Thrombosis Events:  Subjects who develop symptoms of thrombosis should be promptly 
evaluated and treated appropriately.  If the diagnosis of deep vein thrombosis, pulmonary 
embolus or noncardiac, nonneurologic arterial thrombosis is confirmed, the subject must 
be discontinued from study drug.
COVID-19:  Interrupt study drug in subjects with a confirmed diagnosis of COVID-19.  
Consider interrupting study drug in subjects with signs and/or symptoms and suspicion of 
COVID-19.  The COVID-19 eCRF form must be completed.
Malignancy:  Subjects who develop malignancy or high grade colonic dysplasia, other 
than NMSC or carcinoma in situ of the cervix must be discontinued from study drug.  
Information including histopathological results should be queried for the confirmation of 
the diagnosis.  Periodic skin examination is recommended for subjects who are at 
increased risk for skin cancer.
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 following any local guidelines.  Specific toxicity 
management guidelines for abnormal laboratory values are described in Table 5 and may 
 


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require an appropriate supplemental eCRF to be completed.  All abnormal laboratory tests 
that are considered clinically significant by the investigator will be followed to 
satisfactory resolution.  If a repeat test is required per Table 5, the repeat testing must 
occur as soon as possible.
Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values
Laboratory 
Parameter
Toxicity Management Guideline
Hemoglobin

If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by repeat testing 
with a new sample.

If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative 
etiology, interrupt study drug dosing and confirm by repeat testing with new 
sample. 

If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative etiology is 
known, 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.
ANC

If confirmed < 1000/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 rechallenge is expected to be safe for the subject.  Study 
drug should be discontinued if no alternative etiology can be found.
ALC

If confirmed < 500/μL by repeat testing with new sample, interrupt study drug 
dosing until ALC returns to normal reference range or its baseline value.
Total WBC 
count

If confirmed < 2000/μL by repeat testing with new sample, interrupt study drug 
dosing until WBC count returns to normal reference range or its baseline value.
Platelet count

If confirmed < 50,000/μL by repeat testing with new sample, interrupt study 
drug dosing until platelet count returns to normal reference range or its baseline 
value.
 


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Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory 
Parameter
Toxicity Management Guideline
AST or ALT

Interrupt study drug 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.
o
Interrupt study drug if confirmed ALT or AST > 3 × ULN by 
repeat testing with new sample along with new appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5% increase from Baseline).

Interrupt study drug if confirmed ALT or AST > 8 × ULN by repeat testing with 
new sample. 

Interrupt study drug if confirmed ALT or AST > 5 × ULN by repeat testing with 
new sample for more than 2 weeks.
Subjects with positive HBc Ab (irrespective of HBs Ab status) and negative HBV 
DNA at screening who develop the following laboratory findings should have HBV 
DNA by PCR performed within 1 week (based on initial elevated value):
o
ALT > 5 × ULN OR
o
ALT/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 1 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.  The 
investigator should contact the AbbVie TA MD to discuss the management of a 
subject when an alternative etiology has been determined.  The alternative etiology 
should be documented appropriately in the eCRF; study drug should be discontinued 
if no alternative etiology can be found and ALT or AST elevations persist.  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 
rechallenge is expected to be safe.
For any confirmed ALT or AST elevations > 3 ULN, complete supplemental hepatic 
eCRF.
 


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Table 5.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory 
Parameter
Toxicity Management Guideline
Serum 
Creatinine

If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the test for 
serum creatinine (with subject in a 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 scenarios, complete supplemental renal 
eCRF.
CPK

If any confirmed CPK value ≥ 4 × ULN (if symptomatic or asymptomatic).

If confirmed CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis 
or rhabdomyolysis, interrupt study drug and contact AbbVie TA MD.
For the above CPK elevation scenarios, complete supplemental CPK eCRF.
6.1.8
Data Monitoring Committee (DMC)
An external, independent DMC will be responsible for monitoring unblinded safety data 
and alerting AbbVie to possible safety concerns related to the conduct of the study.  See 
Section 5.5.5.2 for details.
6.1.9
Cardiovascular Adjudication Committee (CAC)
An independent committee of physician experts in cardiac adjudication will be utilized to 
assess cardiovascular AEs and embolic and thrombotic events (non-cardiac, non-CNS) in 
a blinded manner as defined by the CAC charter.  The events that are adjudicated and the 
adjudication process will be detailed in the CAC Charter.  Dedicated eCRFs will be used 
for events of myocardial infarction-unstable angina, stroke-transient ischemic attack, and 
death.  In addition, the site may be contacted for additional source documentation for 
relevant events.
 


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6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (e.g., 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 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with AEs 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.
 




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●
Subject who received wrong treatment or incorrect dose;
●
Subject who received excluded or prohibited concomitant treatment.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objective of the statistical analysis of Study M14-431 is to evaluate the efficacy and 
safety of an upadacitinib 45-mg QD induction dose versus placebo in subjects with 
moderately and severely active CD.
The extent of missing data due to COVID-19 will be monitored and appropriate analysis 
to handle these missing data may be performed; details will be included in the SAP.  
Further details of the statistical analysis will be described and documented in the 
Statistical Analysis Plan (SAP).
8.1.1
Datasets for Analysis
8.1.1.1
Intent to Treat Analysis Set
The intent-to-treat (ITT) analysis set includes all randomized subjects who have received 
at least one dose of study drug in the double-blind induction period from Part 1.  The ITT 
subjects will be analyzed as randomized.  The ITT set is the primary population for 
efficacy analysis.  All analyses of efficacy endpoints will be performed using the ITT 
analysis set. 
8.1.1.2
Safety Analysis Set
The safety analysis set consists of all subjects who received at least one dose of the study 
drug.  Similarly, safety analysis set (Part 1), safety analysis set (Part 2), and safety 
analysis set (Part 3) consist of subjects who received at least one dose of the study drug, 
enrolled in Part 1, Part 2, and Part 3 respectively.  The safety analysis set and safety 
analysis sets (Part 1, Part 2 and Part 3) will be analyzed as treated, according to treatment 
 


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the subject actually received.  The safety analysis set and safety analysis sets (Part 1, 
Part 2 and Part 3) will be used for safety analysis.
8.1.2
Definition of Missing Data Imputation
Missing data will be imputed using one or more of the following methods:
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 
approach, all missing values will be considered as 'Not Achieved.'
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.
8.1.3
Subject Disposition
The number and percentage of subjects who are enrolled, randomized, and received at 
least one dose of study drug, the number of subjects who completed the study and the 
number of subjects who prematurely discontinued and the reason for premature 
discontinuation will 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").
8.1.4
Demographics and Baseline Characteristics
Demographics and baseline characteristics of the study subjects will be summarized using 
descriptive statistics.  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 
 


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in each category for each treatment group, as well as for all subjects combined.  The 
P-value will be provided to assess the comparability of the treatment groups for Part 1. 
8.1.5
Prior and Concomitant Medications
Prior therapy and medications will include all therapies and medications administered 
prior to the date of the first dose of study drug.  Prior therapy and medication will be 
summarized for the ITT analysis set.  No statistical test will be performed. 
Concomitant medications will be summarized using the World Health Organization Drug 
Dictionary with frequencies and percentages for each treatment group.  No statistical test 
will be performed.
8.1.6
Efficacy Analysis
The co-primary and ranked secondary endpoints will be analyzed separately for EU/EMA
and US/FDA regulatory purposes; these endpoints are specified in Section 5.3.3
separately for each set of analyses.
8.1.6.1
Primary Efficacy Variables
The co-primary endpoints are the proportion of subjects with clinical remission per PROs 
(EU/EMA) and per CDAI (US/FDA) at Week 12 and proportion of subjects with 
endoscopic response at Week 12 for the ITT population in Part 1.
The comparison between treatment groups on the co-primary efficacy endpoints will be 
performed using the Cochran-Mantel-Haenszel (CMH) test and will be stratified by 
Baseline corticosteroid use (yes or no), endoscopic disease severity (SES-CD < 15 and 
≥15), and number of prior biologics used (> 1 and ≤ 1).  Both of the co-primary efficacy 
endpoints will be tested at two-sided significance level of 0.05.  A CMH based two-sided 
95% confidence interval for the difference between treatment groups will be calculated.  
If the average daily very soft or liquid SF or average daily AP score (EU/EMA) or CDAI 
(US/FDA) data at Week 12 are missing, the NRI approach will be applied for the clinical 
remission per PROs and clinical remission per CDAI endpoints, respectively.  Subjects 
 


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who discontinue prior to Week 12 for any reason will be considered as "not-achieved" for 
clinical remission or endoscopic response endpoints.
8.1.6.2
Secondary Efficacy Variables
A multiple testing procedure will be used to provide strong control of the type 1 error rate 
at alpha = 0.05 (2-sided) across analyses with respect to the co-primary endpoints, and 
ranked secondary endpoints as specified in Section 5.3.3.  Specifically, testing will utilize 
a sequence of hypothesis testing for the co-primary endpoints followed by the ranked 
secondary endpoints, and will begin with testing co-primary endpoints using α of 0.05 
(2-sided).  If both co-primary endpoints achieve statistical significance, continued testing 
will follow a pre specified weight of α allocation between individual hypotheses as well as 
between families of hypotheses.  The details of the testing procedure will be specified and 
documented in the SAP.
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 
SES-CD) 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 for missing data will be used for categorical secondary 
endpoints.
8.1.7
Safety Analyses
Safety analyses will be performed on safety analysis sets (Part 1, Part 2 and Part 3), as 
defined in Section 8.1.1.2.  Incidence of AEs, changes in vital signs, physical examination 
results, and clinical laboratory data will be assessed throughout the study.  ECGs will be 
performed at screening and at the end of each Part 1, 2, 3 of the study.  AEs and 
laboratory data when available will be graded as described in the NCI CTCAE, and 
summarized accordingly.
 


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AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent AEs are defined as events that begin or worsen either on or after the 
first dose of the study drug and within 30 days after the last dose of the study drug for 
subjects who do not participate in Study M14-430, or within 30 days after the last dose of 
the study drug in Study M14-431 or first dose of study drug in Study M14-430 if the 
subject enrolls in Study M14-430, whichever comes first.
An overview of treatment-emergent AEs, including AEs leading to death, AEs leading to 
premature discontinuation, AEs by MedDRA preferred term and system organ class, AEs 
by maximum relationship to study drug, AEs by maximum severity and AEs of special 
interest will be summarized by number and percentage.
Changes from Baseline in continuous laboratory and vital sign parameters will be 
summarized by treatment group.  Treatment group differences between upadacitinib and 
placebo groups for changes from Baseline may be analyzed using a one-way ANOVA.  
Vital signs and laboratory data will be described by statistical characteristics and 
frequency of abnormal values.  In addition, shift tables and listings will be provided for 
abnormal values, whereby the normal range of the analyzing laboratory will be used.  
Analysis details will be specified in the SAP.
8.1.8
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.
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 
 


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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 estimate 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, 
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.
 


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Relationships between upadacitinib exposure and clinical observations (primary efficacy 
variable) will be explored.  Exposure-response relationships for 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, maximum effect [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 CD, rather than in the 
CSR.
Additional analyses will be performed if useful and appropriate.
8.2
Determination of Sample Size
The co-primary endpoints are the proportion of subjects with clinical remission per PROs 
(EU/EMA) and per CDAI (US/FDA) at Week 12 and the proportion of subjects who 
achieve endoscopic response at Week 12. 
Sample size calculation is based on the maximum sample size needed to detect treatment 
difference for each of the co-primary endpoints.  The assumptions used were based on the 
16-week clinical and endoscopic data from the upadacitinib Phase 2 CD Study M13-740.  
For EU/EMA regulatory purposes:  Assuming a rate of 12% for clinical remission per 
PROs in the placebo group and 29% in the upadacitinib group at Week 12, a total sample 
size of 495 subjects randomized in a 2:1 ratio (330 subjects in the upadacitinib group and 
165 subjects in the placebo group) will be adequate to detect at least a 17% treatment 
difference in clinical remission rates at Week 12 between the treatment groups using 
Fisher's exact test with at least 95% power at a 0.05 two-sided significant level.  
For US/FDA regulatory purposes:  Assuming a rate of 20% for clinical remission per 
CDAI in the placebo group and 40% in the upadacitinib group at Week 12, the same 
 


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sample size of 495 subjects will be adequate to detect at least a 20% treatment difference 
in clinical remission rates at Week 12 between the treatment groups using Fisher's exact 
test with at least 95% power at a 0.05 two-sided significant level.  
Assuming an endoscopic response rate of 10% in the placebo group and 25% in the 
upadacitinib group at Week 12, this sample size will be adequate to detect at least a 15% 
treatment difference in endoscopic response rates at Week 12 between the treatment 
groups using Fisher's exact test with at least 95% power at a 0.05 two-sided significant 
level.  
The objective of Part 2 is to have a sufficient number of subjects with clinical response to 
be re-randomized in the double-blind maintenance portion of Study M14-430.  A total of
130 subjects enrolled in Part 2 would provide adequate number of subjects achieving 
clinical response to be re-randomized to the maintenance portion of Study M14-430.  
8.3
Randomization Methods
A total of 495 subjects will be randomized in Part 1 of the study in a 2:1 ratio to 
upadacitinib 45 mg QD or matching placebo (330 subjects for upadacitinib 45 mg dose 
group and 165 for placebo group).  Randomization will be stratified by baseline 
corticosteroid use (yes or no), endoscopic disease severity (SES-CD < 15 and ≥ 15), and 
number of prior biologic treatments (> 1 and ≤ 1).
Subjects enroll into Part 3 from Part 2 of the study in an open-label manner.  Subjects 
enrolling in Part 3 from Part 1 are assigned either upadacitinib 45 mg QD or upadacitinib 
30 mg QD depending on the randomized treatment received in Part 1 (placebo or 
upadacitinib 45 mg) in a blinded fashion.
 


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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 International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
GCP and all other applicable regulatory requirements.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies, as required by 
local regulations.  During the conduct of the study, the investigator should promptly 
provide written reports (e.g., ICH Expedited Reports, and any additional reports required 
by local regulations) to the IEC/IRB of any changes that affect the conduct of the study 
and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
 


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have their origin in the Declaration of Helsinki.  Responsibilities of the clinical 
investigator are specified in Appendix A.
In the event a state of emergency due to the COVID-19 or any pandemic leads 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 
laboratory instead of a central laboratory), and shipping investigational product and/or 
supplies DTP to ensure continuity of treatment where allowed.  In all cases, these 
alternative measures must be allowed by local regulations and permitted by IRB/IEC.  
Investigators should notify AbbVie if any urgent safety measures are taken to protect the 
subjects against any immediate hazard.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent will be given to the subject and the original will be placed in the 
subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent.
 


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Samples for exploratory research will only be collected and tested after the subject has 
voluntarily signed and dated the separate written consent for exploratory research, 
approved by an IRB/IEC, after the nature of the testing has been explained and the subject 
has had an opportunity to ask questions.  The separate written consent may be part of the 
main consent form.  If the subject does not consent to the exploratory research, it will not 
impact the subject's participation in the study.
In the event a subject withdraws from the main study, optional exploratory research 
samples will continue to be stored and analyzed unless the subject specifically withdraws 
consent for the optional samples.  If consent is withdrawn for the optional sampling, the 
subject must inform their study doctor, and once AbbVie is informed, the optional 
samples will be destroyed.  However, if the subject withdraws his/her consent and the 
samples have already been tested, those results will still remain as part of the overall 
research data.
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 on the 
appropriate source documents.  The Investigator Awareness Date (SAE eCRF) may serve 
as the source for this data point.  This AE 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 or any pandemic, remote monitoring of data may be employed if 
allowed by the local regulatory authority, IRB/IEC, and the study site.
10.2
Electronic Case Report Forms (eCRF)
eCRFs must be completed for each subject screened/enrolled in this study.  These forms 
will be used to transmit information collected during the study to AbbVie and regulatory 
authorities, as applicable.  The CRF data for this study are being collected with an EDC 
system called Rave® provided by the technology vendor Medidata Solutions Incorporated, 
NY, USA.  The EDC system and the study-specific eCRFs will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the 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 two electronic devices; 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 
study.  This access will be available for the duration of the study to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO system will be archived 
on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media.
The ePRO data will be collected by the following methods:
Diary Based
The ePRO data (number of total and liquid or very soft stools, stool consistency per 
Bristol Stool Chart, use of medications used for endoscopy preparation, if an endoscopy 
was performed, AP, and general well-being) will be collected electronically via a 
handheld device into which the subject will record the required pieces of information on a 
daily basis.  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 
investigational site staff will be able to access all uploaded subject entered data via a 
password protected website, up until the generation, receipt and confirmation of the study 
archive.
Tablet Based
The ePRO data (IBDQ, CSS, EQ-5D-5L, WPAI-CD, SF-36, FACIT-F, PGI-S, and PGIC) 
will be collected electronically via an onsite device at visits specified in Appendix C.  The 
electronic device will be programmed to allow data entry once per day per study subject.  
 


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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.
Due to the COVID-19 or any pandemic, subject visits may be conducted via phone or 
video conference.  PROs are eligible for completion by interview at the visits specified in 
Appendix C.  In this situation, 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 may share 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 time of PRO data collection should be 
recorded along with the name of the person who collected the information.
11.0
Data Quality Assurance
To ensure data integrity and subject safety, a study monitor will, throughout the study, 
verify that all subjects signed agreement of informed consent prior to any study-specific 
procedures being conducted.  The study monitor will confirm that the investigator is 
conducting the study in compliance with the protocol, GCP and applicable regulations, 
and verify that the information reported in the eCRF is complete, accurate, and supported 
by information in source documents.
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 
 


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information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
upadacitinib.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any exploratory research 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 from this study may be 
used in scientific publications or presented at medical conventions.  Exploratory research 
 


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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 
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 Guidance 
on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.
 


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for upadacitinib.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Induction Study of the Efficacy and Safety of Upadacitinib 
(ABT-494) in Subjects with Moderately to Severely Active Crohn's 
Disease Who Have Inadequately Responded to or are Intolerant to 
Biologic Therapy
Protocol Date:
05 March 2021
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
1.
Hanauer SB, Sandborn W; Practice Parameters Committee of the American 
College of Gastroenterology.  Management of Crohn's disease in adults.  Am J 
Gastroenterol.  2001;96(3):635-43.
2.
Loftus EV Jr.  Clinical epidemiology of inflammatory bowel disease:  incidence, 
prevalence, and environmental influences.  Gastroenterology.  
2004;126(6):1504-17.
3.
Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of 
American College of Gastroenterology.  Management of Crohn's disease in adults.  
Am J Gastroenterol.  2009;104(2):465-83.
4.
Dignass A, Van Assche G, Lindsay JO, et al; European Crohn's and Colitis 
Organisation (ECCO).  The second European evidence-based Consensus on the 
diagnosis and management of Crohn's disease:  current management.  J Crohns 
Colitis.  2010;4(1):28-62.  Erratum in:  J Crohn's Colitis.  2010;4(3):353.
5.
Irving PM, Gearry RB, Sparrow MP, et al.  Review article:  appropriate use of 
corticosteroids in Crohn's disease.  Aliment Pharmacol Ther.  2007;26(3):313-29.  
6.
Rutgeerts PJ.  Review article:  the limitations of corticosteroid therapy in Crohn's 
disease.  Aliment Pharmacol Ther.  2001;15(10):1515-25.
7.
Targan SR, Hanauer SB, van Deventer SJ, et al.  A short-term study of chimeric 
monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease.  
N Engl J Med.  1997;337(15):1029-35.
8.
Hanauer SB, Feagan BG, Lichtenstein GR, et al; ACCENT I Study Group.  
Maintenance infliximab for Crohn's disease:  the ACCENT I randomised trial.  
Lancet.  2002;359(9317):1541-9.
9.
Hanauer SB, Sandborn WJ, Rutgeerts P, et al.  Human anti-tumor necrosis factor 
monoclonal antibody (adalimumab) in Crohn's disease:  the CLASSIC-I trial.  
Gastroenterology.  2006;130(2):323-33.
 


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10.
Colombel JF, Sandborn WJ, Rutgeerts P, et al.  Adalimumab for maintenance of 
clinical response and remission in patients with Crohn's disease:  the CHARM trial.  
Gastroenterology.  2007;132(1):52-65.
11.
Sandborn WJ, Feagan BG, Stoinov S, et al; PRECISE 1 Study Investigators.  
Certolizumab pegol for the treatment of Crohn's disease.  N Engl J Med.  
2007;357(3):228-38.
12.
Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al; PRECISE 2 Study 
Investigators.  Maintenance therapy with certolizumab pegol for Crohn's disease.  
N Engl J Med.  2007;357(3):239-50.  Erratum in:  N Engl J Med.  
2007;357(13):1357.
13.
Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEMINI 2 Study Group.  
Vedolizumab as induction and maintenance therapy for Crohn's disease.  N Engl J 
Med.  2013;369(8):711-21.
14.
Feagan B, Gasink C, Lang Y, et al.  A multicenter, double-blind, placebo-
controlled Ph3 study of ustekinumab, a human monoclonal antibody to 
IL-12/23P40, in patients with moderately-severely active Crohn's disease who are 
naive or not refractory to anti-TNFa:  UNITI-2.  23rd United European 
Gastroenterology Week (UEGW), Barcelona, 24 – 28 Oct 2015.  United Eur 
Gastroenterol J.  2015;3(6):563-4, Abstr OP054-LB4.
15.
Sandborn W, Feagan BG, Gasink C, et al.  A phase 3 randomized, multicenter, 
double-blind, placebo-controlled study of ustekinumab maintenance therapy in 
moderate-severe Crohn's disease patients:  Results from IM-UNITI.  
Gastroenterology.  2016;150 (4 Suppl 1):S157–8.
16.
Neurath MF.  Cytokines in inflammatory bowel disease.  Nat Rev Immunol.  
2014 May;14(5):329-42.
17.
Murray PJ.  The JAK-STAT signaling pathway:  input and output integration.  
J Immunol.  2007;178(5):2623-9.
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O'Shea JJ, Holland SM, Staudt LM.  JAKs and STATs in immunity, 
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19.
Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK.  Role of 
cytokines in inflammatory bowel disease.  World J Gastroenterol.  
2008;14(27):4280-8.
20.
Ghoreschi K, Laurence A, O'Shea JJ.  Janus kinases in immune cell signaling.  
Immunol Rev.  2009;228(1):273-87.
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Guschin D, Rogers N, Briscoe J, et al.  A major role for the protein tyrosine kinase 
JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.  
EMBO J.  1995;14(7):1421-9.
22.
Hosokawa T, Kusugami K, Ina K, et al.  Interleukin-6 and soluble interleukin-6 
receptor in the colonic mucosa of inflammatory bowel disease.  J Gastroenterol 
Hepatol.  1999;14(10):987-96.
23.
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.
24.
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, randomised, placebo-controlled trial.  Lancet.  
2017;389(10066):266-75.
25.
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.
26.
AbbVie.  ABT-494 Investigator Brochure Edition 11.  18 August 2020.
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.
 


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29.
Reilly M. Work Productivity and Activity Impairment Questionnaire (WPAI).  
Reilly Associates.  2002.
30.
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.
31.
Ware JE Jr.  SF-36 health survey update.  Spine (Phila Pa 1976).  
2000;25(24):3130-9.
32.
Janssen MF, Pickard AS, Golicki D, et al.  Measurement properties of the EQ-5D-
5L compared to the EQ-5D-3L across eight patient groups:  a multi-country study.  
Qual Life Res.  2013;22(7):1717-27.
33.
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.
34.
Daperno M, D'Haens G, Van Assche G, et al. Development and validation of a 
new, simplified endoscopic activity score for Crohn's disease:  the SES-CD.  
Gastrointest Endosc.  2004;60(4):505-12.
 


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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 Development, Immunology
Clinical Program Development
Clinical Pharmacology and Pharmacometrics
Statistics
Medical Writing
 


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Appendix C.
Study Activities
Activity
Part 1 – 12-Week Double-Blind Induction
Part 2 – Open-Label Single-Arm Induction
Part 3 – Extended 
Treatment Period
Premature 
Discontinuation 
Visit
Unscheduled 
Visitb
30-Day 
Follow-Up 
Visit
Screeninga
Baseline
Week 
2
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Informed Consent
X
Inclusion/Exclusionc
X
X
Medical/Surgical Historyc
X
X
Prior and Concomitant 
Medicationsc,#
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examd,+ and 
Vital Signse,#
X
X
X
X
X
X
X
X
X
X
X
Endoscopyf,+ and SES-CD
X
X
X
X
Biopsyg,+
X
X
X
X
12-Lead ECGh,+
X
X
X
X
Latent TB Risk Factor 
Assessment Form
X
PPD Skin Test or 
QuantiFERON-TB Gold 
Testi
X
Chest X-rayj
X
FSHk
X
HBV, HCV and HIV 
Screeningl
X
HBV Periodic 
Screeningm,+
X
X
 


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Activity
Part 1 – 12-Week Double-Blind Induction
Part 2 – Open-Label Single-Arm Induction
Part 3 – Extended 
Treatment Period
Premature 
Discontinuation 
Visit
Unscheduled 
Visitb
30-Day 
Follow-Up 
Visit
Screeninga
Baseline
Week 
2
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
C. difficile toxin
X
Blood Chemistry and 
Hematologyn,o,ab,+
X
X
X
X
X
X
X
X
X
X
X
X
hs-CRP=
X
X
X
X
X
X
X
X
X
X
X
Urinalysiso,p,ab,+
X
X
X
X
Pregnancy Testq,ab,+
X
X
X
X
X
X
X
X
X
X
X
Upadacitinib Plasma 
Concentrationr,=
X
X
X
X
X
X
X
X
Stool Sample (FCP)s,=
X
X
X
X
X
X
Lymphocyte Subsets=
X
X
X
X
X
X
CDAI=
Xt
X
X
X
X
X
X
X
X
X
Patient Questionnaires:#
IBDQ
EQ-5D-5L 
WPAI
SF-36
FACIT-F
CSS
X
X
X
X
X
PGI-S#
X
X
X
X
X
X
X
X
PGIC#
X
X
X
X
X
X
X
AE Assessmentu,#
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensing/
Administrationab
X
X
X
Xv
X
X
 


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Activity
Part 1 – 12-Week Double-Blind Induction
Part 2 – Open-Label Single-Arm Induction
Part 3 – Extended 
Treatment Period
Premature 
Discontinuation 
Visit
Unscheduled 
Visitb
30-Day 
Follow-Up 
Visit
Screeninga
Baseline
Week 
2
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Dispense Subject Diary
X
Subject Diary Revieww,#
X
X
X
X
X
X
X
X
X
X
Optional biologic drug 
levelx,=
X
Optional 
Pharmacogeneticy,=
X
Optional Epigeneticy,=
X
X
X
X
X
Optional Serum and 
Plasmay,=
X
X
X
X
X
Optional mRNAy,=
X
X
X
X
X
Optional Stool 
Proteomicy,z,=
X
X
X
Optional Stool 
Microbiotay,z,=
X
X
X
Optional Intestinal 
Biopsyaa,=
X
X
X
X
CDAI = Crohn's Disease Activity Index; CSS = Crohn's Symptoms Severity Questionnaire; ECG = electrocardiogram; EQ-5D-5L = European Quality of Life 5 Dimensions 5 
Levels; FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue; FCP = fecal calprotectin; hs-CRP = high-sensitivity C-reactive protein; IBDQ = Inflammatory 
Bowel Disease Questionnaire; PGIC = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; SES-CD = Simplified Endoscopic Score for Crohn's 
disease; SF-36 = Short Form-36; PD = premature discontinuation; WPAI = Work Productivity and Activity Impairment Questionnaire
a.
The Screening Period will be a minimum of 8 days but no more than 35 days prior to Baseline Visit.  Baseline Visit date will serve as the reference for all subsequent visits.  
A ± 3-day window is permitted around scheduled study visits.
b.
Visits to retest a lab will not be 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.
 


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c.
Update inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information to assure subject eligibility.  All subjects need to have their average daily 
very soft or liquid SF and average daily AP score calculated and meeting eligibility criteria before randomization at Baseline.
d.
Physical examinations are full physical examinations performed at Screening, Baseline, and Week 12; and Week 24/PD if the subject undergoes Part 3.  Physical 
examinations at all other visits are symptom-based but should include an assessment of EIMs and presence or absence of cutaneous fistulas, as part of calculating the CDAI.  
During the full physical examination, all subjects will be assessed for presence and number of draining and non-draining enterocutaneous (perianal and abdominal) and 
rectovaginal fistulas at Baseline, Week 12, and Week 24/PD.  If the assessment of presence and number of draining and non-draining fistulas were performed during 
Screening or the visit for endoscopy, this may be used for the respective Baseline, Week 12 or Week 24/PD visits.
e.
Blood pressure, pulse rate, temperature, respiratory rate and weight should be performed before blood draws are performed.  Height will be measured at Screening only (with 
shoes off).
f.
Ileocolonoscopies will be used to calculate the SES-CD.  The Screening ileocolonoscopy should be done during the Screening Period or within 45 days of the Baseline Visit, 
if video recorded.  Endoscopic evaluations using SES-CD confirmed by central reader will be done at Screening.  Patients who complete at least 8 weeks in Part 1 and Part 2 
or at least 20 weeks in Part 3 will be required to have an endoscopy.  Where COVID-19 or any pandemic affects Week 12 or Week 24 endoscopy, a ± 7-day window is 
permitted.
g.
Biopsy may be done when performing the endoscopy.  At Screening, biopsy to confirm CD diagnosis must be done when performing the endoscopy if appropriate 
documentation for confirmation of the diagnosis does not exist.  Biopsies to rule out dysplasia and colon cancer may be taken at the investigator's discretion.  Optional 
intestinal biopsy samples for histopathology and biological investigations, including but not limited to, transcriptomic analyses and immunohistochemistry may be evaluated 
in approximately 200 subjects (intestinal biopsy substudy).
h.
Subjects with normal ECG within 90 days of Screening would not require a repeat ECG, if documentation is available.  Subjects can have a repeat ECG at any time during the 
study as warranted based on the opinion of the investigator.
i.
PPD skin test is to be read 48 to 72 hours after placement.  Subjects with negative QuantiFERON TB Gold test and/or PPD test within 90 days of Screening will not require a 
repeat test (documentation must be available).  In case of positive PPD/positive or repeat indeterminate IGRA testing, in the absence of active TB, the subject may participate 
in the study after initiation of latent TB treatment (regimen according to local practice/guidelines). 
j.
Chest x-ray includes posterior-anterior view and lateral view.  Subjects can have a chest x-ray anytime during the study as warranted based on the opinion of the investigator.  
In Japan and China, a CT scan of the chest may be performed in lieu of a chest x-ray, at the investigator's discretion.
k.
FSH should be tested at Screening if the female subject is ≤ 55 years of age AND has had no menses ≥ 12 months AND has no history of permanent surgical sterilization 
(Refer to Section 5.2.4).
l.
Subjects will be tested for the presence of HBV and HCV at Screening.  A positive result for HBs Ag or hepatitis C (HCV RNA detectable in any subject with anti-HCV Ab) 
will be exclusionary.  For subjects who are negative for both HBs Ag and HBs Ab but are positive for HBc Ab, HBV DNA PCR will be performed and any result that meets 
or exceeds detection sensitivity will be exclusionary.  HIV testing will be performed at the central laboratory, unless prohibited by local regulations.  The central lab will 
report the HIV test results directly to the sites.  AbbVie will not receive results from the HIV testing and not be made aware of any positive result. 
 


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m.
For Japan or countries who mandate periodic screening for HBV:  subjects with positive HBs Ab and/or positive HBc Ab and a negative HBV DNA PCR test result at 
Screening should have HBV DNA PCR test performed at 12 and 24 weeks; 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.
n.
Laboratory tests performed during the Screening Period can be repeated in case the abnormalities are considered to be transient by the investigator.
o.
Minimum 8-hour fast for chemistry.  If a subject is not able to fast, the non-fasting status will be recorded in study source documentation.  Urinalysis, chemistry and 
hematology may be collected at other scheduled and unscheduled visits than indicated in the table in case of repeat test for toxicity management criteria or if they are 
warranted by the investigator.
p.
Urinalysis will be completed by the central lab at the required visits.  A microscopic analysis will be performed in the event the dipstick results show leukocytes, nitrite, 
protein, ketones, or blood greater than negative or glucose greater than normal. 
q.
Serum pregnancy test will be performed on all women of childbearing potential at Screening.  Urine pregnancy test will be performed locally at the Baseline Visit prior to the 
first dose of study drug and at all subsequent visits, including the 30-day follow-up visit for all women of childbearing potential (refer to Section 5.2.4).  If any urine 
pregnancy test is positive, a serum pregnancy test will be performed by the central laboratory.  If serum pregnancy test comes back borderline, a repeat test is necessary 
(pregnancy is an exclusion criterion).  If still borderline ≥ 3 days later, this will be considered documentation of continued lack of a positive result and the subject can be 
enrolled into the study in absence of clinical suspicion of pregnancy or other pathological cause of borderline result.  If a pregnancy is identified, the pregnancy must be 
reported to AbbVie.
r.
At the Week 4 visit, PK samples should be collected prior to dosing if possible and the subjects should take the study drug dose at the clinic after collecting the PK blood 
sample.  However, if the subject normally takes the study drug dose at a time that is after the time of the scheduled study visit, the subject should follow the regular dosing 
schedule and the PK sample should be collected at any time during the visit.  At Week 16 and Week 20 visits, PK samples will not be collected from subjects in Part 3 
Cohort 3, who received open-label upadacitinib in Part 2.  For all other visits, PK samples should be collected at any time during the visit and the subject should follow the 
regular dosing schedule.
s.
A stool sample will be collected at each time point indicated for FCP.  For the visit that endoscopy will be conducted, stool sample should be collected prior to bowel prep.  
Subjects will be asked to provide a stool sample at the visit, if possible, or the site will give instructions and a stool sample supply kit.
t.
Diary information collected during Screening will serve to calculate Baseline CDAI.
u.
Collection of SAEs begins the day the subject signs the informed consent form.
v.
Only for subjects continuing into Part 3.
w.
Diary review includes a review of ePRO data (number of total and liquid or very soft stools, stool consistency per Bristol Stool Chart (Appendix F), use of medications used 
for endoscopy preparation, if an endoscopy was performed, AP, and general well-being).
 


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x.
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 from the last dose; (2) adalimumab, certolizumab, golimumab, or vedolizumab:  may be tested approximately 6 weeks 
from the last dose; (3) ustekinumab:  may be tested approximately 8 weeks from the last dose.
y.
Only if subject provides written consent to collect the samples; if the informed consent form is not signed, no samples can be collected.
z.
Optional stool samples for proteomic and microbiota analyses may be evaluated in approximately 200 subjects (fecal biomarker substudy).
aa.
If subject provides written consent, intestinal biopsy samples for histology and exploratory analyses will be collected in approximately 200 subjects as a substudy; if the 
informed consent form is not signed, no intestinal biopsy can be collected.  Biopsies will be obtained at Screening and at the Week 12 endoscopy; and at Week 24/PD, if the 
subject participates in Part 3.
ab.
During the COVID-19 or any pandemic, when a lab test cannot be collected per protocol, the administration and dispensing of study drug should occur if the investigator feels 
it is safe to continue study drug based on the remote visit, at least one post-Baseline lab test is available and no longer than 6 weeks have passed since the last safety lab tests.  
A local laboratory can be utilized when it is not feasible to use the central laboratory.
#
Study activity that can be performed by phone/virtually within a ± 7-day window when an onsite study visit is not possible due to COVID-19 or any pandemic, if allowed by 
local regulations.  This is applicable for all visits, except Screening and Baseline visits, which must be completed at the study site.  Physical examination that requires 
palpation should not be performed.  Patient questionnaire EQ-5D-5L is not eligible to be performed by phone/virtually.
+
Study activity that can be performed at a local facility when an onsite study visit is not possible due to COVID-19 or any pandemic, if allowed by local regulations.  This is 
applicable for all visits, except Screening and Baseline visits, which must be completed at the study site.
=
Study activity should not be performed by phone/virtually or at a local facility, when an onsite study visit is not possible due to COVID-19 or any pandemic.  Screening and 
Baseline visit procedures must be completed at the study site.
 


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Appendix D.
Latent TB Risk Factor Assessment Form Example
1.
Have you or an immediate family member or other close contact ever been 
diagnosed or treated for tuberculosis?
2.
Have you lived in or had prolonged travels to countries in the following regions:
●
Sub-Saharan Africa
●
India
●
China
●
Mexico
●
Southeast Asia or Micronesia
●
The former Soviet Union
3.
Have you lived or worked in a prison, homeless shelter, immigration center, or 
nursing home?
4.
Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:
●
Chronic Cough
●
Production of Sputum
●
Blood-Streaked Sputum
●
Unexplained Weight Loss
●
Fever
●
Fatigue/Tiredness
●
Night Sweats
●
Shortness of Breath
From:  http://www mayoclinic.com/health/tuberculosis/DS00372/DSECTION=risk-factors
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf
 


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Appendix E.
Patient Reported Outcomes Descriptions
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 – 70, 5 to 35, 12 to 84, 
and 5 to 35, respectively.27,28
WPAI-CD – Work Productivity and Activity Impairment Questionnaire-Crohn's 
Disease
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:  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; 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 CD on work and 10 = severe impact of CD while 
at work); 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 activity impairment 
(i.e., activities other than paid work like work around house, cleaning, shopping, traveling, 
studying), recorded and scored in same way as presenteeism.  Higher numbers indicate 
greater impairment and less productivity.29
 


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CSS – Crohn's Symptoms Severity Questionnaire
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.30,31
EQ-5D – European Quality of Life 5 Dimensions
The EQ-5D-5L is a standardized non-disease specific instrument for describing and 
valuing health-related quality of life.  The EQ-5D 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 
 


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dimension.  As a measure of health status, it provides a descriptive profile and can be used 
to generate a single index value for health status, where full health is equal to 1 and death 
is equal to 0.  The VAS records the subject's assessment of his/her own health along a 
vertical 20 cm line, which has health state scores between 0 and 100.32
FACIT-F – Functional Assessment of Chronic Illness Therapy-Fatigue
The Functional Assessment of Chronic Illness Therapy system is a collection of quality of 
life (QoL) questionnaires targeted to the management of cancer and other chronic 
illnesses.  The 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-F 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.33
PGIC – Patient Global Impression of Change
The PGIC is a self-administered instrument that assesses change in the overall symptoms 
due to Crohn's disease.  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."
PGI-S – Patient Global Impression of Severity
The PGI-S is a self-administered instrument that assesses the severity of the overall 
symptoms due to Crohn's disease.  The PGI-S 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."
 


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HCRU – Health Care Resource Use
Health Care Resource use data on number of Hospitalization and surgeries will be 
collected through subject Administration module SAE supplemental Page.
 


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Appendix F.
Bristol Stool Chart
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix G.
Corticosteroid Taper
Beginning at Week 4, all subjects will undergo the mandatory taper schedule outlined below, in which all subjects continuing in the 
study will have corticosteroid discontinued no later than Week 11.  For subjects entering the study on a corticosteroid dose that is in 
between two specific levels in taper schedule, the dose beginning at Baseline will be rounded up to the closest higher dose.
Baseline Dose
Prednisone or Prednisolone Dose Change at Each Study Week
Wk 4
Wk 5
Wk 6
Wk 7
Wk 8
Wk 9
Wk 10
Wk 11
Wk 12
30 mg/day
25 mg
20 mg
15 mg
10 mg 
7.5 mg
5 mg
2.5 mg
Discontinue
0
25 mg/day
20 mg
15 mg
10 mg 
7.5 mg
5 mg
2.5 mg
Discontinue
0
0
20 mg/day
15 mg
10 mg 
7.5 mg
5 mg
2.5 mg
Discontinue
0
0
0
15 mg/day
10 mg 
7.5 mg
5 mg
2.5 mg
Discontinue
0
0
0
0
10 mg/day
7.5 mg
5 mg
2.5 mg
Discontinue
0
0
0
0
0
7.5 mg/day
5 mg
2.5 mg
Discontinue
0
0
0
0
0
0
5 mg/day
2.5 mg
Discontinue
0
0
0
0
0
0
0
2.5 mg/day
Discontinue
0
0
0
0
0
0
0
0
Baseline Dose
Budesonide Dose Change at Each Study Week
Wk 4
Wk 5
Wk 6
Wk 7
Wk 8
Wk 9
Wk 10
Wk 11
Wk 12
9 mg/day
6 mg
6 mg
3 mg
3 mg
Discontinue
0
0
0
0
6 mg/day
3 mg
3 mg
Discontinue
0
0
0
0
0
0
3 mg/day
Discontinue
0
0
0
0
0
0
0
0
 


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Baseline Dose
Methylprednisolone Dose Change at Each Study Week
Wk 4
Wk 5
Wk 6
Wk 7
Wk 8
Wk 9
Wk 10
Wk 11
Wk 12
24 mg/day
20 mg
16 mg
12 mg
8 mg 
6 mg
4 mg
2 mg
Discontinue
0
20 mg/day
16 mg
12 mg
8 mg 
6 mg
4 mg
2 mg
Discontinue
0
0
16 mg/day
12 mg
8 mg 
6 mg
4 mg
2 mg
Discontinue
0
0
0
12 mg/day
8 mg 
6 mg
4 mg
2 mg
Discontinue
0
0
0
0
8 mg/day
6 mg
4 mg
2 mg
Discontinue
0
0
0
0
0
6 mg/day
4 mg
2 mg
Discontinue
0
0
0
0
0
0
4 mg/day
2 mg
Discontinue
0
0
0
0
0
0
0
2 mg/day
Discontinue
0
0
0
0
0
0
0
0
Baseline Dose
Hydrocortisone Dose Change at Each Study Week
Wk 4
Wk 5
Wk 6
Wk 7
Wk 8
Wk 9
Wk 10
Wk 11
Wk 12
120 mg/day
100 mg
80 mg
60 mg
40 mg 
30 mg
20 mg
10 mg
Discontinue
0
100 mg/day
80 mg
60 mg
40 mg 
30 mg
20 mg
10 mg
Discontinue
0
0
80 mg/day
60 mg
40 mg 
30 mg
20 mg
10 mg
Discontinue
0
0
0
60 mg/day
40 mg 
30 mg
20 mg
10 mg
Discontinue
0
0
0
0
40 mg/day
30 mg
20 mg
10 mg
Discontinue
0
0
0
0
0
30 mg/day
20 mg
10 mg
Discontinue
0
0
0
0
0
0
20 mg/day
10 mg
Discontinue
0
0
0
0
0
0
0
10 mg/day
Discontinue
0
0
0
0
0
0
0
0
 


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Appendix H.
Standard Weights
Standard Height and Weight Tables – Use to Calculate CDAI Score
Standard Height cm 
(Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women) 
kg (Pounds)
121.9 (48.0)
40.8 (89.9)
123.2 (48.5)
41.3 (91.0)
124.5 (49.0)
41.8 (92.1)
125.7 (49.5)
42.3 (93.3)
127.0 (50.0)
42.8 (94.4)
128.3 (50.5)
43.4 (95.6)
129.5 (51.0)
43.9 (96.8)
130.8 (51.5)
44.4 (98.0)
132.1 (52.0)
55.5 (122.4)
45.0 (99.2)
133.4 (52.5)
55.7 (122.7)
45.5 (100.4)
134.6 (53.0)
55.8 (123.1)
46.1 (101.6)
135.9 (53.5)
56.0 (123.5)
46.6 (102.8)
137.2 (54.0)
56.2 (123.9)
47.2 (104.1)
138.4 (54.5)
56.4 (124.4)
47.8 (105.3)
139.7 (55.0)
56.7 (124.9)
48.3 (106.6)
141.0 (55.5)
56.9 (125.5)
48.9 (107.9)
142.2 (56.0)
57.2 (126.1)
49.5 (109.1)
143.5 (56.5)
57.4 (126.7)
50.1 (110.4)
144.8 (57.0)
57.7 (127.3)
50.7 (111.7)
146.1 (57.5)
58.1 (128.0)
51.3 (113.0)
147.3 (58.0)
58.4 (128.7)
52.2 (115.0)
148.6 (58.5)
58.7 (129.5)
52.6 (116.0)
149.9 (59.0)
59.1 (130.3)
53.1 (117.0)
151.1 (59.5)
59.5 (131.1)
53.6 (118.3)
152.4 (60.0)
59.9 (132.0)
54.2 (119.5)
153.7 (60.5)
60.3 (132.9)
54.8 (120.8)
154.9 (61.0)
60.7 (133.8)
55.3 (122.0)
156.2 (61.5)
61.1 (134.8)
56.0 (123.5)
157.5 (62.0)
61.7 (136.0)
56.7 (125.0)
158.8 (62.5)
62.1 (137.0)
57.4 (126.5)
 


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Standard Height cm 
(Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women) 
kg (Pounds)
160.0 (63.0)
62.6 (138.0)
58.0 (128.0)
161.3 (63.5)
63.0 (139.0)
58.7 (129.5)
162.6 (64.0)
63.5 (140.0)
59.4 (131.0)
163.8 (64.5)
64.1 (141.3)
60.1 (132.5)
165.1 (65.0)
64.6 (142.5)
60.8 (134.0)
166.4 (65.5)
65.2 (143.8)
61.4 (135.5)
167.6 (66.0)
65.8 (145.0)
62.1 (137.0)
168.9 (66.5)
66.4 (146.5)
62.8 (138.5)
170.2 (67.0)
67.1 (148.0)
63.5 (140.0)
171.5 (67.5)
67.8 (149.5)
64.2 (141.5)
172.7 (68.0)
68.5 (151.0)
64.9 (143.0)
174.0 (68.5)
69.2 (152.5)
65.5 (144.5)
175.3 (69.0)
69.8 (154.0)
66.2 (146.0)
176.5 (69.5)
70.5 (155.5)
66.9 (147.5)
177.8 (70.0)
71.2 (157.0)
67.6 (149.0)
179.1 (70.5)
71.9 (158.5)
68.3 (150.5)
180.3 (71.0)
72.6 (160.0)
68.9 (152.0)
181.6 (71.5)
73.4 (161.8)
69.6 (153.5)
182.9 (72.0)
74.1 (163.5)
70.3 (155.0)
184.2 (72.5)
75.0 (165.3)
71.2 (156.9)
185.4 (73.0)
75.7 (167.0)
71.9 (158.5)
186.7 (73.5)
76.6 (169.0)
72.6 (160.2)
188.0 (74.0)
77.5 (171.0)
73.4 (161.8)
189.2 (74.5)
78.4 (172.8)
74.1 (163.4)
190.5 (75.0)
79.1 (174.5)
74.9 (165.1)
191.8 (75.5)
80.2 (176.8)
75.6 (166.8)
193.0 (76.0)
81.2 (179.0)
76.4 (168.4)
194.3 (76.5)
82.0 (180.8)
77.2 (170.1)
195.6 (77.0)
82.9 (182.9)
77.9 (171.8)
196.9 (77.5)
83.9 (185.0)
78.7 (173.5)
198.1 (78.0)
84.9 (187.2)
79.5 (175.2)
199.4 (78.5)
85.9 (189.4)
80.3 (177.0)
 


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Standard Height cm 
(Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women) 
kg (Pounds)
200.7 (79.0)
86.9 (191.6)
81.0 (178.7)
201.9 (79.5)
87.9 (193.9)
81.8 (180.5)
203.2 (80.0)
89.0 (196.2)
82.6 (182.2)
204.5 (80.5)
90.0 (198.6)
*Standard height is calculated using
actual height obtained at screening 
(without shoes) plus 1 inch or 2.5 cm
205.7 (81.0)
91.1 (200.9)
*Indoor clothing weighing 5 pounds for 
men and 3 pounds for women
207.0 (81.5)
92.2 (203.3)
*Centimeters × 0.3937 = inches
208.3 (82.0)
93.3 (205.8)
*Pounds × 0.4535 = kilograms
 


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Appendix I.
Crohn's Disease Activity Index (CDAI)
Factor
Subtotal
1.
Number of liquid or very soft stools 
(Record the frequency per day)
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
2
2.
Abdominal pain rating:
0 = none, 1 = mild, 2 = moderate, 
3 = severe
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
5
3.
General well-being:
0 = generally well, 1 = slightly
underpar, 2 = poor, 3 = very poor,
4 = terrible
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
7
4.
Number of 6 listed categories the
subject now has
Check all items that apply:
☐Arthritis/arthralgia
☐Iritis/uveitis
☐Erythema nodosum/pyoderma
gangrenosum/aphthous
stomatitis
☐Fissure, abscess and/or anal
fistula (draining/non-
draining)
☐Other cutaneous fistula
(draining/non-draining) Fistula
☐Fever over 100°F (37.8°C)
during past week
_________________________________ 
_________________________________
Record "0" if no categories checked
×
20
5.
Taking Lomotil/Imodium/
Loperamide/opiates for diarrhea
0 = no, 1 = yes
________
×
30
6.
Abdominal mass
0 = none, 2 = questionable,
5 = defined
________
×
10
7.
Hematocrit:  ___.__
Male:  (47 – hematocrit) =
Female:  (42 – hematocrit) =
Subtotal
If hematocrit > normal, enter "0"
×
6
8.
Body weight:  ___.__(kg)
Standard weight:  ___.__(kg)
100 × [1 – (Body wt/Standard wt)] =
Percent below standard weight:  ______
If body wt > std. wt, enter "0"
×
1
Total
NOTE:
At Baseline, subjects will be instructed on how to calculate the number of very soft and liquid stools, 
including a visual depiction.
 


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Appendix J.
Simple Endoscopic Score for Crohn's Disease (SES-CD34) 
Assessment
Rectum
Sigmoid 
and Left 
Colon
Transverse 
Colon
Right 
Colon
Ileum
Total
Size of Ulcers 
Enter:
0 if none
1 if aphthous ulcers (Ø 0.1 to 
0.5 cm)
2 if large ulcers (Ø 0.5 to 2 cm)
3 if very large ulcers (Ø > 2 cm)
Ulcerated Surface
Enter:
0 if none
1 if < 10%
2 if 10% – 30%
3 if > 30%
Affected Surface
Enter:
0 if unaffected segments
1 if < 50%
2 if 50% – 75%
3 if > 75%
Presence of Narrowing
Enter:
0 if none
1 if single, can be passed
2 if multiple, can be passed
3 if cannot be passed
TOTAL =
 

SAP_001.pdf: 
Upadacitinib (ABT-494)
M14-431 – Statistical Analysis Plan
Version 5.0 – 15 November 2021
1
Statistical Analysis Plan for Study M14-431
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Induction Study of the Efficacy 
and Safety of Upadacitinib (ABT-494) in Subjects 
with Moderately to Severely Active Crohn's Disease 
Who Have Inadequately Responded to or are 
Intolerant to Biologic Therapy
Date:  15 November 2021
Version 5.0
NCT03345836


Upadacitinib (ABT-494)
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Version 5.0 – 15 November 2021
2
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 .............................................................................8
2.3
Treatment Assignment and Blinding .......................................................13
2.4
Sample Size Determination......................................................................14
3.0
Endpoints................................................................................15
3.1
Co-Primary Endpoints .............................................................................16
3.2
Secondary Endpoints ...............................................................................16
3.3
Other Efficacy Endpoints.........................................................................18
3.3.1
Other Endpoints for Part 1 .......................................................................18
3.3.2
Other Endpoints for Part 2 .......................................................................21
3.3.3
Other Endpoints for Part 3 .......................................................................21
3.4
Safety Endpoints ......................................................................................24
4.0
Analysis Populations .............................................................24
5.0
Subject Disposition................................................................26
6.0
Study Drug Duration and Compliance................................26
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................27
7.1
Demographics and Baseline Characteristics............................................27
7.2
Medical History .......................................................................................29
7.3
Prior and Concomitant Medications ........................................................30
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints..............................30
8.1
Intercurrent Event 1 (IE1): Premature Discontinuation of Study 
Drug .........................................................................................................31
8.2
Intercurrent Event 2 (IE2): CD-Related Corticosteroids .........................32
9.0
Efficacy Analyses...................................................................33
9.1
General Considerations............................................................................33
9.2
Handling of Missing Data........................................................................35
9.2.1
Categorical Endpoints..............................................................................36


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9.2.2
Continuous Endpoints..............................................................................38
9.2.3
Additional Analyses.................................................................................39
9.3
Co-Primary Efficacy Endpoints and Analyses ........................................41
9.3.1
Co-Primary Efficacy Endpoints...............................................................41
9.3.2
Primary Analysis of Co-Primary Efficacy Endpoints..............................41
9.3.3
Sensitivity and Supplementary Analyses of the Co-Primary 
Efficacy Endpoints...................................................................................43
9.3.4
Additional Analyses of the Co-Primary Efficacy Endpoints...................44
9.4
Secondary Efficacy Analyses...................................................................44
9.4.1
Main Analyses of Ranked Secondary Efficacy Endpoints ......................44
9.4.2
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints...................................................................................48
9.5
Additional Efficacy Analyses ..................................................................48
9.6
Efficacy Subgroup Analyses....................................................................49
10.0
Safety Analyses ......................................................................51
10.1
General Considerations............................................................................51
10.2
Adverse Events ........................................................................................52
10.2.1
Treatment-Emergent Adverse Events ......................................................52
10.2.2
Adverse Event Overview .........................................................................53
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................54
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................54
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................55
10.2.6
Adverse Events of Special Interest ..........................................................56
10.3
Analysis of Laboratory Data....................................................................56
10.4
Analysis of Vital Signs ............................................................................58
11.0
Interim Analyses....................................................................59
11.1
Data Monitoring Committee....................................................................59
12.0
Overall Type-I Error Control ..............................................59
13.0
Version History......................................................................63
14.0
References...............................................................................65


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List of Tables
Table 1.
Summary of the Estimand Attributes of the Co-Primary Efficacy 
Endpoints .................................................................................................42
Table 2.
Summary of the Estimand Attributes of the Key Secondary 
Efficacy Endpoints...................................................................................46
Table 3.
Subgroups for Efficacy Analysis .............................................................50
Table 4.
SAP Version History Summary...............................................................63
List of Figures
Figure 1.
Study M14-431 Study Design – Part 1 and Part 2...................................10
Figure 2.
Study M14-431 Study Design – Part 3 ....................................................12
Figure 3.
Graphical Multiple Testing Procedure for Co-Primary and Ranked 
Secondary Endpoints for EU/EMA..........................................................61
Figure 4.
Graphical Multiple Testing Procedure for Co-Primary and Ranked 
Secondary Endpoints for US/FDA Graphical Multiple Testing 
Procedure for Co-Primary and Ranked Secondary Endpoints for 
US/FDA ...................................................................................................62
List of Appendices
Appendix A.
Protocol Deviations..................................................................................67
Appendix B.
Definition of Adverse Events of Special Interest ....................................68
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints ...............71
Appendix D.
Crohn's Disease Activity Index (CDAI) ..................................................72
Appendix E.
Simple Endoscopic Score – CD (SES-CD)..............................................77
Appendix F.
Patient Reported Outcomes Questionnaires Descriptions .......................79
Appendix G.
Extra-Intestinal Manifestations (EIMs) ...................................................84
Appendix H.
Cronh's Disease Location Per SES-CD....................................................85
Appendix I.
Random Seeds..........................................................................................86
Appendix J.
Geographic Region ..................................................................................87


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for upadacitinib 
(ABT-494) Study M14-431, A Multicenter, Randomized, Double-Blind, Placebo 
Controlled Induction Study of the Efficacy and Safety of Upadacitinib (ABT-494) in 
Subjects with Moderately to Severely Active Crohn's Disease Who Have Inadequately 
Responded to or are Intolerant to Biologic Therapy.
The analyses of pharmacokinetics/pharmacodynamic endpoints, pharmacogenetic 
endpoints, and selected biomarkers will be analyzed separately and are not described 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 previous SAP versions.  Details are 
outlined in Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The objective of Study M14-431 is to evaluate the efficacy and safety of upadacitinib 
compared to placebo as induction therapy in subjects with moderately and severely active 
Crohn's Disease (CD).
Primary Efficacy Objective
For EU/EMA regulatory purposes, the primary efficacy objective of Study M14-431 is to 
evaluate the efficacy based on higher rates of clinical remission per patient reported 
outcomes (PROs) of very soft or liquid stool frequency and abdominal pain score, and 


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endoscopic response after 12 weeks of treatment with upadacitinib 45 mg once daily (QD) 
compared to placebo as induction therapy in subjects with moderately and severely active 
CD who have inadequately responded to or are intolerant to biologic therapy during the 
12-week double-blind induction period (Part 1).
Hypotheses corresponding to the primary efficacy objectives and endpoints are:
●
The proportion of subjects achieving clinical remission per PROs at Week 12 
treated with upadacitinib 45 mg QD is greater than that treated with placebo, 
and
●
The proportion of subjects achieving endoscopic response at Week 12 treated 
with upadacitinib 45 mg QD is greater than that treated with placebo.
For US/FDA regulatory purposes, the primary efficacy objective of Study M14-431 is to 
evaluate the efficacy based on higher rates of clinical remission per Crohn's Disease 
Activity Index (CDAI) and endoscopic response after 12 weeks of treatment with 
upadacitinib 45 mg QD compared to placebo as induction therapy in subjects with 
moderately and severely active CD who have inadequately responded to or are intolerant 
to biologic therapy during the 12-week double-blind induction period (Part 1).
Hypotheses corresponding to the primary efficacy objectives and endpoints are:
●
The proportion of subjects achieving clinical remission per CDAI at Week 12 
treated with upadacitinib 45 mg QD is greater than that treated with placebo, 
and
●
The proportion of subjects achieving endoscopic response at Week 12 treated 
with upadacitinib 45 mg QD is greater than that treated with placebo.
The primary efficacy objectives 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.
The estimands corresponding to the primary efficacy objectives are defined as follows:


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●
The difference in the proportion of subjects achieving clinical remission per 
PROs  at Week 12 regardless of premature discontinuation of study drug but 
before initiation of CD-related confounding medications (See Section 8.1), and 
without initiation or dose escalation of CD-related corticosteroids (See
Section 8.2) in the upadacitinib 45 mg QD and placebo groups in the 
ITT population (EU/EMA regulatory purposes).
●
The difference in the proportion of subjects achieving clinical remission per 
CDAI at Week 12 regardless of premature discontinuation of study drug but 
before initiation of CD-related confounding medications (See Section 8.1), and 
without initiation or dose escalation of CD-related corticosteroids (See 
Section 8.2) in the upadacitinib 45 mg QD and placebo groups in the 
ITT population (US/FDA regulatory purposes).
●
The difference in the proportion of subjects achieving endoscopic response at 
Week 12 regardless of premature discontinuation of study drug but before 
initiation of CD-related confounding medications (See Section 8.1), and 
without initiation or dose escalation of CD-related corticosteroids (See 
Section 8.2) in the upadacitinib 45 mg QD and placebo groups in the 
ITT population.
Secondary Efficacy Objectives
The secondary efficacy objectives of the Study M14-431 are to demonstrate higher 
efficacy of treatment with upadacitinib 45 mg QD when compared to placebo during the 
12-week double-blind induction period (Part 1) with respect to the ranked secondary 
endpoints specified in Section 3.2 in subjects with moderately and severely active CD 
who have inadequately responded to or are intolerant to biologic therapy.  The secondary 
efficacy objectives will be assessed based on ITT population.
Hypotheses corresponding to the ranked secondary efficacy objectives and endpoints are: 
for each of the ranked secondary endpoints except occurrence of hospitalizations due to 
CD during Part 1 (Section 3.2), greater proportion of subjects with improvement 
(or greater mean change from Baseline for continuous endpoints) is achieved with 
upadacitinib 45 mg QD group when compared to that of placebo.  Hypothesis 


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corresponding to occurrence of hospitalizations due to CD during Part 1 is:  smaller 
proportion of subjects experience at least one occurrence of hospitalizations due to CD
during Part 1 with upadacitinib 45 mg QD group when compared to that of placebo.
The estimands corresponding to the secondary efficacy objectives are defined for each of 
the binary ranked secondary endpoints except occurrence of hospitalizations due to CD
during Part 1 as follows:  The difference in the proportion of subjects achieving binary 
endpoints regardless of premature discontinuation of study drug but before initiation of 
CD-related confounding medications (See Section 8.1), and without initiation or dose 
escalation of CD-related corticosteroids (See Section 8.2) in the upadacitinib 45 mg QD 
and placebo groups in the ITT population.
The estimand corresponding to the secondary objective for occurrence of hospitalizations 
due to CD during Part 1 is as follows: The difference in the proportion of subjects with at 
least one occurrence of hospitalization due to CD during Part 1 regardless of premature 
discontinuation of study drug (See Section 8.1), and regardless of initiation or dose 
escalation of CD-related corticosteroids (See Section 8.2) 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:  the difference in the mean change 
from baseline regardless of premature discontinuation of study drug but before initiation 
of CD-related confounding medications (See Section 8.1), and without initiation or dose 
escalation of CD-related corticosteroids (See Section 8.2) in the upadacitinib 45 mg QD 
and placebo groups in the ITT population.
2.2
Study Design Overview
This is a Phase 3, randomized, double-blind, placebo-controlled induction study to 
evaluate the efficacy and safety of upadacitinib, an orally administered JAK1 inhibitor in 
adult subjects with moderately to severely active CD who have inadequately responded to 


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or are intolerant to biologic therapy.  This study will enroll approximately 645 subjects at 
approximately 400 study centers worldwide.
The biologics approved for the treatment of CD include adalimumab, certolizumab, 
infliximab, ustekinumab and vedolizumab.  The study will allow enrollment of 
approximately 30% subjects who have had inadequate response or intolerance to 3 or 
more biologics.  The study will allow the enrollment of up to 10% of subjects who 
received a JAK inhibitor prior to study entry if they have not had inadequate response or 
loss of response.
The duration of the study could be up to 33 weeks and consists of the following parts:
1.
Screening period of up to a maximum of 35 days
2.
Part 1:  a randomized, double-blind, placebo-controlled 12-week induction
3.
Part 2:  an open-label, single-arm active 12-week induction
4.
Part 3:  a 12-week Extended Treatment Period for subjects who do not achieve 
clinical response at Week 12 of Part 1 or Part 2 
5.
30-day follow up period for subjects who do not enroll into Study M14-430
The schematics of the overall study design are shown in Figure 1 (Part 1 and Part 2) and 
Figure 2 (Part 3).


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Figure 1.
Study M14-431 Study Design – Part 1 and Part 2
QD = once daily; Rand = randomization
Part 1
In Part 1, subjects (n = 495) will be randomized in a 2:1 ratio to upadacitinib 45 mg QD or 
matching placebo for 12 weeks (Figure 1).  Centralized randomization will be 
implemented in the study.  The randomization will be stratified by baseline corticosteroid 
use (yes or no), endoscopic disease severity (Simplified Endoscopic Score for Crohn's 
Disease [SES-CD] < 15 or ≥ 15), and number of prior biologic treatments (> 1 or ≤ 1).  
The data collected from subjects from Part 1 will be used for the primary efficacy 
analysis.
Visits during the study will occur at Baseline and Weeks 2, 4, 8, and 
12/Premature Discontinuation (PD) to collect clinical, endoscopic and laboratory 
assessments of disease activity.
At Week 12, subjects achieving clinical response, defined as ≥ 30% decrease in average 
daily very soft or liquid stool frequency (SF) and/or ≥ 30% decrease in average daily 


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abdominal pain (AP) score (both not worse than Baseline) may be eligible to enter the 
52-week, double-blind, maintenance portion of Study M14-430.
All subjects who do not achieve clinical response at Week 12 will be able to enroll in 
Part 3 (Extended Treatment Period) to receive a double-blind regimen with upadacitinib 
until Week 24/PD.
Subjects are not eligible to enter Study M14-430 until the ileocolonoscopy procedure at 
Week 12 has been completed.  If the Coronavirus 2019 disease (COVID-19) pandemic 
precludes a subject from undergoing an endoscopy, a subject can enroll in Study M14-430 
if clinical response was achieved at Week 12.
Part 2
Part 2 is an open-label portion (open-label cohort) of this study.  Once enrollment in 
Part 1 is complete, approximately 130 subjects will be enrolled to receive upadacitinib 
45 mg QD for 12 weeks (Figure 1).  The objective of Part 2 is to have a sufficient number 
of subjects with clinical response to be re-randomized in the double-blind maintenance 
portion of Study M14-430, while minimizing unnecessary exposure to placebo.  The data 
collected from subjects from Part 2 will not be part of the primary efficacy analysis for 
this study and will be reported separately in the clinical study report.
Visits during the study will occur at Baseline and Weeks 2, 4, 8, and 12/PD to collect 
clinical, endoscopic and laboratory assessments of disease activity.
At Week 12, subjects achieving clinical response may be eligible to enter Study M14-430 
(Figure 1).  Subjects who do not achieve clinical response at Week 12 will be able to 
participate in Part 3 (Extended Treatment Period) to receive open-label upadacitinib 
30 mg QD until Week 24/PD.


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Figure 2.
Study M14-431 Study Design – Part 3
DB = double-blind; OL = open-label; NR = non-responders; QD = once-daily
Part 3
Part 3 is a 12-week Extended Treatment Period consisting of 3 cohorts for subjects who 
do not achieve clinical response at Week 12 in Part 1 or Part 2 (Figure 2).  The objectives 
of Part 3 are to offer blinded upadacitinib induction treatment to placebo non-responders 
from Part 1 and to evaluate a delayed clinical response to upadacitinib in subjects who did 
not initially respond to upadacitinib during Part 1 or Part 2.
●
Cohort 1:  Subjects who received double-blind placebo in Part 1 and did not 
achieve clinical response at Week 12 are eligible to receive double-blind 
induction treatment with upadacitinib 45 mg QD for 12 weeks (until Week 24).
●
Cohort 2:  Subjects who received double-blind upadacitinib in Part 1 and did 
not achieve clinical response at Week 12 are eligible to receive double-blind 
upadacitinib 30 mg QD for 12 weeks (until Week 24). 
●
Cohort 3:  Subjects who received open-label upadacitinib during Part 2 and did 
not achieve clinical response at Week 12 are eligible to receive open-label 
upadacitinib 30 mg QD for 12 weeks (until Week 24).


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Subjects in Cohort 1 and 2 will remain blinded to treatment to avoid unmasking the 
treatment received during Part 1.  The data collected from subjects from Part 3 will not be 
part of the primary efficacy analysis and will be reported separately in the clinical study 
report.
Subjects are not eligible to enter in Part 3 until the Week 12 endoscopy has been 
completed.  If the COVID-19 pandemic precludes a subject from undergoing an 
endoscopy, a subject can continue into Part 3.  Visits will occur at Weeks 16, 20 and 
24/PD to collect clinical, endoscopic and laboratory assessments of disease activity.
During Part 3, subjects with persistent symptoms or worsening of CD may be 
discontinued at any time.
At Week 24, subjects who achieve clinical response may be eligible to enter 
Study M14-430.  Subjects are not eligible to enter Study M14-430 until the 
ileo-colonoscopy procedure at Week 24 for evaluation of mucosal inflammation has been 
completed.  If the COVID-19 pandemic precludes a subject from undergoing an 
endoscopy, a subject can enroll if clinical response was achieved at Week 24.
Subjects who do not achieve clinical response at Week 24 will be discontinued from 
Study M14-431 and will receive standard of care treatment at investigator's discretion.  
Subjects who do not achieve clinical response at Week 24 and all subjects who 
prematurely discontinue the study will have a follow-up visit 30 days from the last dose of 
study drug to collect information on new or ongoing AEs and laboratory assessments.  
Subjects will be discontinued from the study if they withdraw consent or if they are 
deemed unsuitable to continue for any reason by the investigator.
2.3
Treatment Assignment and Blinding
At Baseline, 495 subjects will be randomized in a 2:1 ratio to upadacitinib 45 mg QD or 
matching placebo.  The randomization will be stratified by baseline corticosteroid use 
(yes or no), endoscopic disease severity (SES-CD < 15 or ≥ 15) and number of prior 
biologics with prior inadequate response or intolerance (> 1 or ≤ 1).


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Subjects who received placebo during Part 1 and did not achieve clinical response at 
Week 12 are eligible to enroll in Cohort 1 of Part 3 to receive double-blind induction 
treatment with upadacitinib 45 mg QD for 12 weeks (until Week 24).
Subjects who received upadacitinib during Part 1 and did not achieve clinical response at 
Week 12 are eligible to enroll in Cohort 2 of Part 3 to receive double-blind treatment with 
upadacitinib 30 mg QD for 12 weeks (until Week 24).
Subjects who received upadacitinib during Part 2 and did not achieve clinical response at 
Week 12 are eligible to enroll in Cohort 3 of Part 3 to receive open-label treatment with 
upadacitinib 30 mg QD for 12 weeks (until Week 24).
Subjects in Cohort 1 and Cohort 2 of Part 3 will remain blinded to treatment to avoid 
unmasking the treatment received during Part 1.
2.4
Sample Size Determination
The co-primary endpoints are achievement of clinical remission per PROs (EU/EMA) or 
per CDAI (US/FDA) at Week 12 and achievement of endoscopic response at Week 12.  
Sample size calculation is based on the maximum sample size needed to detect treatment 
difference for each of the co-primary endpoints.  The proposed assumptions were 
informed by the results of the 16-week clinical and endoscopic data of upadacitinib 
Phase 2 CD Study M13-740.
For EU/EMA regulatory purposes:  Assuming a rate of 12% for clinical remission per 
PROs in the placebo group and 29% in the upadacitinib group at Week 12, a total sample 
size of 495 subjects randomized in a 2:1 ratio (330 subjects in the upadacitinib group and 
165 subjects in the placebo group) will be adequate to detect at least a 17% treatment 
difference in clinical remission per PROs rates at Week 12 between the treatment groups 
using Fisher's exact test with at least 95% power at a 0.05 two-sided significant level.
For US/FDA regulatory purposes:  Assuming a rate of 20% for clinical remission per 
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sample size of 495 subjects will be adequate to detect at least a 20% treatment difference 
in clinical remission per CDAI rates at Week 12 between the treatment groups using 
Fisher's exact test with at least 95% power at a 0.05 two-sided significant level.
Assuming an endoscopic response rate of 10% in the placebo group and 25% in the 
upadacitinib group at Week 12, this sample size will be adequate to detect at least a 15% 
treatment difference in endoscopic response rates at Week 12 between the treatment 
groups using Fisher's exact test with at least 95% power at a 0.05 two-sided significant 
level.
In Part 2, assuming a Week 12 clinical response rate of approximately 52% among the 
subjects treated with upadacitinib 45 mg QD, an additional 150 subjects enrolled in Part 2 
would provide adequate number of subjects achieving clinical response to be re-
randomized to the maintenance portion of Study M14-430.
3.0
Endpoints
The following endpoint definitions apply to the efficacy variables described below:
●
Clinical remission per PROs:  average daily very soft or liquid SF ≤ 2.8 AND 
average daily AP score ≤ 1.0 and both not greater than baseline 
●
Clinical remission per CDAI:  CDAI < 150
●
Enhanced Clinical Response:  ≥ 60% decrease in average daily very soft or 
liquid SF and/or ≥ 35% decrease in average daily AP score and both not greater 
than baseline, or clinical remission per PROs
●
Clinical response 100 (CR-100):  decrease of at least 100 points in CDAI from 
Baseline
●
Clinical response per PROs:  ≥30% decrease in average daily very soft or 
liquid SF and/or ≥ 30% decrease in average daily AP score and both not greater 
than Baseline 
●
Endoscopic remission:  SES-CD ≤ 4 and at least 2 point reduction from 
Baseline and no subscore > 1 in any individual variable, as scored by central 
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●
Endoscopic response:  decrease in SES-CD > 50% from Baseline of the 
induction study (or for subjects with an SES-CD of 4 at Baseline of the 
induction study, at least a 2 point reduction from Baseline), as scored by central 
reviewer
Details of CDAI, SES-CD and PRO questionnaires are provided in Appendix D, 
Appendix E and Appendix F respectively.
3.1
Co-Primary Endpoints
Co-primary endpoints for EU/EMA regulatory purposes:
1.
Achievement of clinical remission per PROs at Week 12, and
2.
Achievement of endoscopic response at Week 12.
Co-primary endpoints for US/FDA regulatory purposes:
1.
Achievement of clinical remission per CDAI at Week 12, and
2.
Achievement of endoscopic response at Week 12.
3.2
Secondary Endpoints
The ranked secondary endpoints for EU/EMA regulatory purposes are as follows:
Group 1A_E:
1.
Achievement of clinical remission per CDAI at Week 12
2.
Achievement of clinical remission per PROs at Week 4
3.
Achievement of endoscopic remission at Week 12
4.
Discontinuation of corticosteroid use for CD and achievement of clinical remission 
per PROs at Week 12 (population:  ITT subjects taking corticosteroids for CD at 
Baseline)


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5.
Change from Baseline in Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-F) total score at Week 12
6.
Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) total 
score at Week 12
Group 1B_E:
7.
Achievement of CR-100 at Week 2
8.
Achievement of CR-100 at Week 12
9.
Occurrence of hospitalizations due to CD during Part 1
10.
Achievement of resolution of extra-intestinal manifestations (EIMs) at Week 12 
(population: ITT subjects with EIMs at Baseline) (see Appendix G)
The ranked secondary endpoints for US/FDA regulatory purposes are as follows:
Group 1A_F:
1.
Achievement of clinical remission per PROs at Week 12
2.
Achievement of endoscopic remission at Week 12
3.
Discontinuation of corticosteroid use for CD and achievement of clinical remission 
per CDAI at Week 12, in subjects taking corticosteroids for CD at Baseline 
4.
Change from Baseline in FACIT-F total score at Week 12
5.
Change from Baseline in IBDQ total score at Week 12
Group 1B_F:
6.
Achievement of CR-100 at Week 2
7.
Achievement of CR-100 at Week 12
8.
Achievement of clinical remission per CDAI at Week 4


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9.
Occurrence of hospitalizations due to CD during Part 1
10.
Achievement of with resolution of EIMs at Week 12 (population: ITT subjects with 
EIMs at Baseline) (see Appendix G)
3.3
Other Efficacy Endpoints
3.3.1
Other Endpoints for Part 1
●
Achievement of:
○
clinical remission per PROs at Week 2, Week 4, Week 8 and Week 12
○
clinical remission per CDAI at Week 2, Week 4, Week 8 and Week 12
○
enhanced clinical response at Week 2, Week 4, Week 8 and Week 12
○
clinical response at Week 2, Week 4, Week 8 and Week 12
○
CR-100 at Week 2, Week 4, Week 8 and Week 12
○
clinical remission per PROs and endoscopic remission at Week 12
○
clinical remission per CDAI and endoscopic remission at Week 12
○
enhanced clinical response and endoscopic response at Week 12
○
corticosteroid use discontinuation for CD and endoscopic remission at 
Week 12 (population: ITT subjects taking corticosteroids for CD at 
Baseline)
○
corticosteroid use discontinuation for CD and enhanced clinical response at 
Week 12 (population: ITT subjects taking corticosteroids for CD at 
Baseline)
○
corticosteroid use discontinuation for CD and endoscopic response at 
Week 12 (population: ITT subjects taking corticosteroids for CD at 
Baseline)
○
corticosteroid use discontinuation for CD at Week 12 
(population: ITT subjects taking corticosteroids for CD at Baseline)
○
≥ 50% reduction in the corticosteroid dose for CD from Baseline at 
Week 12 (population: ITT subjects taking corticosteroids for CD at 
Baseline)


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○
decrease in SES-CD > 50% from Baseline or endoscopic remission at 
Week 12, as scored by central reviewer
○
SES-CD ≤ 2 at Week 12
○
SES-CD ulcerated surface subscore of 0 at Week 12 in subjects with 
SES-CD ulcerated surface subscore ≥ 1 at Baseline, as scored by a central 
reviewer
○
SES-CD ulcerated surface subscore ≤ 1 in each segment at Week 12 in 
subjects with a SES-CD ulcerated surface subscore ≥ 2 at Baseline, as 
scored by a central reviewer
○
endoscopic response at Week 12 among subjects with SES-CD subscore of 
3 in the narrowing component at Week 12, which was not present at 
Baseline
○
endoscopic remission at Week 12 among subjects with SES-CD narrowing 
component subscore between 0 and 2 in all intestinal segments at Baseline
○
endoscopic response at Week 12 among subjects with SES-CD narrowing 
component subscore between 0 and 2 in all intestinal segments at Baseline
○
endoscopic response or endoscopic remission at Week 12 among subjects 
with SES-CD narrowing component subscore between 0 and 2 in all 
intestinal segments at Baseline
○
Colonic and Ileal Global Histologic Disease Activity Score 
(CGHAS/IGHAS) histologic remission (defined as CGHAS/IGHAS score 
≤ 2) at Week 12 in subjects with abnormal histology at Baseline
○
≥ 50% reduction in draining fistulas at Week 12 (population: ITT subjects 
with draining fistulas at Baseline) 
○
resolution of draining fistulas at Week 12 (population: ITT subjects with 
draining fistulas at Baseline)
○
at least 50% decrease from Baseline in the number of days with very soft 
or liquid stools (Type 6 or 7, per Bristol Stool Chart) during the last 7 days 
at Week 12
○
IBDQ remission (IBDQ > 170 points) at Week 4, Week 12 
○
IBDQ response (increase in IBDQ > 16 points from Baseline) at Week 4, 
Week 12


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○
response in IBDQ fatigue item (increase of IBDQ fatigue item score ≥1) at 
Week 4, Week 12
○
response in IBDQ Bowel Symptom domain (increase of IBDQ bowel 
symptom domain score ≥ 8) at Week 12
○
increase in FACIT-Fatigue total score from baseline ≥7 at Week 12
○
increase in FACIT-Fatigue total score from baseline ≥9 at Week 12
○
increase in FACIT-Fatigue total score from baseline ≥11 at Week 12
○
resolution of EIMs at Week 2, Week 4, Week 8 and Week 12 
(population: ITT subjects with EIMs at Baseline)
●
Occurrence of:
○
hospitalizations during the 12-Week Double-Blind Induction Period 
(Part 1)
○
CD-related surgeries during the 12-Week Double-Blind Induction Period 
(Part 1)
●
Change from Baseline in:
○
IBDQ at Week 4, Week 12
○
individual IBDQ domain scores (bowel, emotional, social, systemic) at 
Week 4, Week 12
○
individual IBDQ item under Bowel Symptom domain (for Q1, Q5, Q9, 
Q13, Q17, Q20, Q22, Q24, Q26, and Q29) at Week 4, Week 12
○
Work Productivity and Activity Impairment Questionnaire-Crohn's Disease 
(WPAI-CD) at Week 4, Week 12
○
European Quality of Life 5 Dimensions 5 level version (EQ-5D-5L) at 
Week 4, Week 12
○
Short Form-36 (SF-36) at Week 4, Week 12
○
Crohn's Symptoms Severity Questionnaire (CSS) at Week 4, Week 12
○
fecal calprotectin (FCP) at Week 4, Week 12
○
high sensitivity C-reactive protein (hs-CRP) at Week 2, Week 4, Week 8 
and Week 12
○
average daily AP score at Week 2, Week 4, Week 8 and Week 12
○
average daily very soft/liquid SF at Week 2, Week 4, Week 8 and Week 12


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○
average daily total SF at Week 2, Week 4, Week 8 and Week 12
○
CDAI at Week 2, Week 4, Week 8 and Week 12
○
SES-CD at Week 12
○
CGHAS/IGHAS at Week 12 among subjects with abnormal histology at 
Baseline
○
FACIT-F at Week 4 and Week 12
3.3.2
Other Endpoints for Part 2
Same efficacy endpoints as those listed in Part 1 (Section 3.1 and Section 3.2) are 
considered for Part 2 of the study.  All the Part 2 efficacy endpoints are considered other 
endpoints and ranking of the endpoints is not applicable for Part 2.
3.3.3
Other Endpoints for Part 3
●
Achievement of:
○
clinical remission per PROs at Week 16, Week 20 and Week 24
○
clinical remission per CDAI at Week 16, Week 20 and Week 24
○
enhanced clinical response at Week 16, Week 20 and Week 24
○
clinical response at Week 16, Week 20 and Week 24
○
CR-100 at Week 16, Week 20 and Week 24
○
Endoscopic response at Week 24
○
endoscopic remission at Week 24
○
clinical remission per PROs and endoscopic remission at Week 24
○
clinical remission per CDAI and endoscopic remission at Week 24
○
enhanced clinical response and endoscopic response at Week 24
○
corticosteroid use discontinuation for CD and clinical remission per PROs 
at Week 24 (population: ITT subjects taking corticosteroids for CD at 
Week 12)
○
corticosteroid use discontinuation for CD and clinical remission per CDAI 
at Week 24 (population: ITT subjects taking corticosteroids for CD at 
Week 12)


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○
corticosteroid use discontinuation for CD and endoscopic remission at 
Week 24 (population: ITT subjects taking corticosteroids for CD at 
Week 12)
○
corticosteroid use discontinuation for CD and enhanced clinical response at 
Week 24 (population: ITT subjects taking corticosteroids for CD at 
Week 12)
○
corticosteroid use discontinuation for CD at Week 24 
(population: ITT subjects taking corticosteroids for CD at Week 12)
○
corticosteroid use discontinuation for CD and endoscopic response at 
Week 24 (population: ITT subjects taking corticosteroids for CD at 
Week 12)
○
≥ 50% reduction in the corticosteroid dose for CD from Baseline at 
Week 24 (population: ITT subjects taking corticosteroids for CD at 
Week 12)
○
resolution of EIMs at Week 24 (population: ITT subjects with EIMs at 
Baseline or Week 12)
○
decrease in SES-CD > 50% from Baseline or endoscopic remission at 
Week 24, as scored by central reviewer
○
SES-CD ≤ 2 at Week 24
○
SES-CD ulcerated surface subscore of 0 at Week 24 in subjects with 
SES-CD ulcerated surface subscore ≥ 1 at Baseline, as scored by a central 
reviewer
○
SES-CD ulcerated surface subscore ≤ 1 in each segment at Week 24 in 
subjects with a SES-CD ulcerated surface subscore ≥ 2 at Baseline, as 
scored by a central reviewer
○
CGHAS/IGHAS histologic remission (defined as CGHAS/IGHAS score 
≤2) at Week 24 in subjects with abnormal histology at Baseline
○
≥ 50% reduction in draining fistulas at Week 24 (population: ITT subjects 
with draining fistulas at Baseline) 
○
resolution of draining fistulas at Week 24 (population: ITT subjects with 
draining fistulas at Baseline or Week 12)


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○
at least 50% decrease in the number of days with very soft or liquid stools 
(Type 6 or 7, per Bristol Stool Chart) during the last 7 days at Week 24.
●
Occurrence of:
○
hospitalizations due to CD during Part 3
○
hospitalizations during Part 3
○
CD-related surgeries during Part 3
●
Change from Baseline in:
○
IBDQ at Week 24
○
WPAI-CD at Week 24
○
EQ-5D-5L at Week 24
○
CSS at Week 24
○
FACIT-F at Week 24
○
SF-36 at Week 24
○
FCP at Week 16, Week 24
○
hs-CRP at Week 16, Week 20 and Week 24
○
average daily AP score at Week 16, Week 20 and Week 24
○
average daily very soft/liquid SF at Week 16, Week 20 and Week 24
○
average daily total SF at Week 16, Week 20 and Week 24
○
CDAI at Week 16, Week 20 and Week 24
○
SES-CD at Week 24
○
CGHAS/IGHAS at Week 24 among subjects with abnormal histology at 
Baseline
●
Time to: 
○
clinical response
○
enhanced clinical response
○
clinical remission per PROs 
○
clinical remission per CDAI
○
CR-100


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3.4
Safety Endpoints
The following endpoints will be included in the safety analyses:
●
Treatment emergent adverse events;
●
Serious adverse events;
●
Adverse events of special interest;
●
Adverse events leading to discontinuation of study drug;
●
Vital signs and laboratory tests.
4.0
Analysis Populations
The following population sets will be used for the analyses.
Intent-to-Treat (ITT) Populations
The ITT population for the 12-week double blind induction period (Part 1) (denoted by 
ITT1) includes all randomized subjects who received at least one dose of double-blind 
study drug during Part 1.  The ITT1 population will be used for all efficacy and baseline 
analyses for Part 1.
For ITT1 population, subjects will be included in the analysis according to the treatment 
groups that they were randomized to.
The ITT population for the 12-week open-label induction period (Part 2) (denoted by 
ITT2) includes all subjects who have received at least one dose of study drug in Part 2.  
The ITT2 population will be used for all efficacy and baseline analyses for Part 2.
The ITT population 3 (ITT3) includes all subjects who have received at least one dose of 
study drug in the Part 3.


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Per-Protocol Population
The Per-Protocol (PP) population represents a subset of the ITT population, consisting of 
subjects that did not have a major protocol deviation.  Major protocol deviations leading 
to exclusion from the PP population will be identified prior to database lock.
For PP population, subjects will be included in the analysis according to the treatment 
groups that they were randomized to.
Safety Populations
The safety population for Part 1 (denoted by SA1) includes all subjects who received at 
least one dose of the 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 study drug in Part 2.
The safety population for Part 3 (denoted by SA3) includes all subjects who received at 
least one dose of the study drug in Part 3.
The safety population for subjects who receive upadacitinib in Part 1 or Part2 and enrolled 
in Part 3 (denoted by SA4) is a subset of SA3 which includes Cohort 2/Cohort 3 of SA3, 
defined as subjects who received upadacitinib in Part 1 or Part 2 and received at least one 
dose of study drug in Part 3.
The all upadacitinib safety population (SA-UPA) includes all subjects who received at 
least one dose of upadacitinib in Part 1 or Part 2 or Part 3.
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.


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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 for Part 1, 
for overall for Part 2 and for each cohort for Part 3:
●
Subjects randomized in Part 1;
●
Subjects who took at least one dose of study drug (Part 1, Part 2 and Part 3);
●
Subjects who completed protocol-specified treatment (Part 1, Part 2 and 
Part 3);
●
Subjects who prematurely discontinued study drug (Part 1, Part 2 and Part 3);
●
Subjects who prematurely discontinued from study (Part 1, Part 2 and Part 3).
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, for overall for Part 2 and for each cohort within Part 3.  
Subjects with multiple reasons for premature discontinuation will be counted once in the 
calculation of the number and percentage of total discontinuations.
In addition, subjects who reported at least one of the protocol deviation categories 
(Appendix A) will be summarized for each treatment group.
6.0
Study Drug Duration and Compliance
For the safety populations (SA1, SA2 and SA3), duration of treatment will be summarized 
for each treatment group for Part 1 (SA1), for overall for Part 2 (SA2) and for each cohort 
for Part 3 (SA3).  Duration of treatment is defined for each subject as last dose date minus 
first dose date + 1.  Duration of treatment will be summarized for each treatment group 
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, ≥ 10 weeks, ≥ 12 weeks) will be 
summarized.


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Treatment compliance will be summarized by treatment group in Part 1, for overall in 
Part 2 and by cohort in Part 3.  Treatment compliance is defined as the number of tablets 
actually taken divided by the number of tablets that should have been taken.  Percent 
compliance will be summarized.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the ITT1 population overall and by 
treatment group, and overall for ITT2.  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, standard deviation, median, 
minimum, and maximum).
7.1
Demographics and Baseline Characteristics
Demographic/vital Signs
●
Sex (Male, Female)
●
Age (Years)
●
Age Category (≥18 years - < 40 years, ≥40 years - < 65 years, ≥65 years)
●
Ethnicity (Hispanic/Latino, Non-Hispanic/Latino)
●
Race category (White, Black or African American, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, Asian, Multiple)
●
Geographic Region category 1 (US, ex-US)
●
Geographic Region category 2 (as defined in Appendix J)
●
Tobacco/Nicotine Use (currently smokes, ex-smoker, never smoked, unknown)
●
Alcohol use (current drinker, former drinker, non-drinker, unknown)
●
Body weight (kg) – overall and by sex
●
Body Mass Index (BMI, kg/m2)


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●
BMI category
○
Underweight [< 18.5 kg/m2]
○
Normal [≥ 18.5 and < 25 kg/m2]
○
Overweight [≥ 25 and < 30 kg/m2]
○
Obese [≥ 30 kg/m2]
●
Body temperature (°C)
●
Height (cm)
●
Pulse (bpm)
●
Systolic and diastolic blood pressure (mmHg)
Patient Reported Outcome Questionnaires at Baseline
●
IBDQ total and domain scores
●
WPAI-CD - 4 sub-scores
●
CSS
●
FACIT-F and its components
●
EQ-5D-5L - Index score and VAS
●
SF-36 - 8 domain scores, PCS and MCS
Other Baseline Characteristics
●
CDAI
●
Average Daily very soft or liquid SF
●
Average Daily AP score
●
SES-CD
●
SES-CD category (< 15, ≥ 15)
●
Crohn's Disease Duration (years)
●
Crohn's Disease Duration category (≤ 5 years, > 5 years)
●
CGHAS/IGHAS Score
●
Baseline CD-related corticosteroid use (yes, no)


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●
Baseline CD-related immunosuppressant use (yes, no)
●
Baseline CD-related aminosalicylates use (yes, no)
●
Prior biologic use/failure history
○
Prior biologic failure history (≤ 1, 2, > 3)
○
Prior failure to anti-TNF agent (yes, no)
○
Prior vedolizumab/natalizumab failure (yes, no)
○
Prior ustekinumab failure (yes, no)
●
hs-CRP (mg/L)
●
hs-CRP category (< 5, ≥ 5 mg/L)
●
FCP (µg/g)
●
FCP category (≤ 250 µg/g, > 250 µg/g)
●
Draining fistulas (yes, no)
●
Non-draining fistulas (yes, no)
●
Anal fissures (yes, no)
●
CD Location Per SES-CD (ileal, ileocolonic, colonic; Appendix H)
●
EIM (yes, no)
In addition, clinical tests at baseline such as TB test, pregnancy test and electrocardiogram 
assessment will be summarized.  Crohn's Disease history (Montreal classification) and 
Crohn's Disease surgical history will be summarized separately as well.
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 (SOC) and preferred term 
(PT)] will be summarized overall and by treatment group.  The 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 PT).


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7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name 
(ITT1 and ITT2 population for prior medications; ITT1, ITT2 and ITT3 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 Part1 or Part 2.
A concomitant medication for Part 1/Part 2 is defined as any medication other than study 
drug that (1) was started prior to the first dose study drug in Part 1/Part 2 and continued to 
be taken after the first dose of study drug in Part 1/Part 2, or (2) was started after the first 
dose of study drug in Part 1/Part 2, but (i) prior to the first dose of study drug in Part 3 (if 
applicable), or (ii) prior to the first dose of study drug of M14-430 (if applicable), or 
(iii) within the last dose + 30 days, whichever is earlier.
A concomitant medication for Part 3 is defined as any medication other than study drug 
that (1) was started prior to the first dose of study drug in Part 3 and continued to be taken 
after the first dose of study drug in Part 3 or (2) was started after the first dose of study 
drug in Part 3, but (i) prior to first dose of M14-430 (if applicable), or 
(ii) last dose + 30 days, whichever is earlier.
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
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
Potential intercurrent events considered in the Study M14-431 include 1) premature 
discontinuation of study drug and 2) initiation or dose escalation of 
CD-related corticosteroids defined in Section 8.2.  As suggested by Qu et al. (2021), a 
mix of strategies will be used to handle different intercurrent events for the efficacy 
analysis.


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8.1
Intercurrent Event 1 (IE1): Premature Discontinuation of 
Study Drug
Following the intent-to-treaty (ITT) principle, a treatment policy strategy will be used to 
handle the IE1.  Data collected on/after premature discontinuation of study drug will be 
used for all efficacy endpoints.
The only exception is when data are collected on/after the date subjects switching to other 
treatment for CD, which will be handled as follows:
●
Binary endpoints other than the occurrence of hospitalization and/or the 
occurrence of CD-related surgery endpoints: A composite strategy will be 
used in the efficacy analysis: the subject will be considered as non-responders 
at all visits on/after the initiation of other CD-related confounding medications.
●
Binary endpoints regarding the occurrence of hospitalization and/or the 
occurrence of CD-related surgery endpoints: A treatment policy strategy 
will be used regardless.
●
Continuous endpoints: A hypothetical strategy will be used in the efficacy 
analysis.  Data collected on/after the initiation of other CD-related confounding 
medications will not be used in the analysis.  Efficacy analysis will be handled 
by using corresponding statistical models (e.g., the Mixed-Effect Model 
Repeated Measurement [MMRM] model).
The CD-related confounding medications include:
●
Biologics approved for CD (Adalimumab, Certolizumab, Infliximab, 
Ustekinumab, Vedolizumab, Natalizumab)
●
Any investigational compound
●
Systemic corticosteroids or locally acting steroids, rectal corticosteroid
●
Immunosuppressants (azathioprine, mercaptopurine, methotrexate, tacrolimus, 
cyclosporine)


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8.2
Intercurrent Event 2 (IE2): CD-Related Corticosteroids
The CD-related corticosteroids intercurrent event is defined as follows.
In Part 1/Part 2:
1.
subjects not on CD-related corticosteroids (systemic or oral locally acting 
corticosteroids for CD) at baseline which are then initiated during Part 1/Part 2
2.
a) subjects on CD-related corticosteroids at baseline who have dosages increased 
to greater than the prednisone equivalent dose taken at baseline until Week 10 or
b) subjects with any dose increase in CD-related corticosteroids between Week 10 
and Week 12
3.
subjects not on rectal corticosteroid at baseline who initiated rectal corticosteroids 
during Part 1/Part 2, regardless of rectal corticosteroid dose
4.
subjects on rectal corticosteroids at baseline who have the dosage increased to 
greater than the dose taken at baseline during Part 1/Part 2;
5.
subjects on rectal corticosteroids at baseline and initiated different rectal 
corticosteroids during Part 1/Part 2, regardless of rectal corticosteroid dose
In Part 3:
1.
subjects not on CD-related corticosteroids (systemic or oral locally acting 
corticosteroids for CD) at baseline which are then initiated during Part 3
2.
a) subjects on CD-related corticosteroids at baseline who have dosages increased 
to greater than the prednisone equivalent dose taken at baseline and Week 12 until 
Week 22 or
b) subjects with any dose increase in CD-related corticosteroids between Week 22 
and Week 24


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3.
subjects not on any rectal corticosteroid at baseline and during Part 1/Part 2 who 
initiated rectal corticosteroids during Part 3, regardless of rectal corticosteroid 
dose
4.
subjects on rectal corticosteroids at baseline or during Part 1/Part 2 who have 
dosage increased to greater than the dose taken at baseline during Part 3;
5.
subjects on rectal corticosteroids at baseline or during Part 1/Part 2, and initiated 
different rectal corticosteroids during Part 3, regardless of rectal corticosteroid 
dose
The time point of the CD-related corticosteroids intercurrent event is defined as the date 
when one of the scenarios above occurs for a subject.
Binary endpoints other than the occurrence of hospitalization and/or the occurrence 
of CD-related surgery endpoints:  A composite strategy will be used in the efficacy 
analysis: the subject will be considered as non-responders at all visits on/after the 
initiation of CD-related corticosteroids.
Binary endpoints regarding the occurrence of hospitalization and/or the occurrence 
of CD-related surgery endpoints:  A treatment policy strategy will be used regardless.
Continuous endpoints:  A hypothetical strategy will be used in the efficacy analysis. 
Data collected on/after the initiation of CD-related corticosteroids will not be used in the 
analysis.  Efficacy analysis will be handled by using corresponding statistical models 
(e.g., the Mixed-Effect Model Repeated Measurement [MMRM] model).
9.0
Efficacy Analyses
9.1
General Considerations
The primary and secondary efficacy endpoints as specified in Section 3.0 will be analyzed 
based on ITT1 for Part 1.  The difference between treatment groups for the primary and 
secondary efficacy endpoints will be tested with graphical multiplicity adjustment1 to 


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ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 
(2-sided) (see Section 12.0).  Analyses of other efficacy endpoints for Part 1 will be 
performed using ITT1 at significance level alpha = 0.05 (2-sided) without multiplicity 
adjustment.
No statistical comparisons will be performed for Part 2 and Part 3.  For all efficacy 
endpoints, the descriptive statistics will be provided by treatment group for Part 1, for 
overall for Part 2 and by cohort for Part 3.  The statistics include number of observations, 
mean, standard deviation, 95% CI, minimum, median, and maximum for continuous 
variables, and number, percent and two-sided 95% CI for discrete variables.  And number 
of subjects with missing data due to COVID-19 pandemic will be summarized for primary 
and secondary efficacy endpoints.
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the actual stratum the subject belongs to.
The Primary Analysis will be performed after all enrolled subjects have completed Part 1, 
Part 2 and Part 3, and the database has been locked.  This will be the only and final 
efficacy analysis.
"Baseline" refers to the last non-missing observation prior to the first administration of 
study drug in Part 1 or Part 2 or prior to the randomization if no study drug is given.
Analysis of Categorical Variables:
For categorical variables, frequencies and percentages will be reported for each treatment 
group in Part 1, for overall for Part 2 and for each cohort in Part 3.  Comparison of 
upadacitinib group and placebo group will be performed using the Cochran Mantel-
Haenszel (CMH) test adjusting for stratification factors (baseline steroid use (Yes, No), 
endoscopic disease severity (SES-CD < 15, ≥15) and number of prior biologics with prior 
inadequate response or intolerance (≤1, > 1)).  If there is a stratum for a treatment group 
that has no subject in it, a value of 0.1 will be added to all cells in the corresponding table 
in order to prevent dividing by 0, as suggested in Greenland and Robins (1985).2  Point 


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estimates and 95% confidence intervals (CI) for the difference in proportions between 
upadacitinib group and placebo group will be provided.  Construction of CI for the 
common risk difference will be based on the Mantel-Haenszel estimate adjusting for 
stratification factors.
For endpoints with small sample size (such as resolution draining fistulas at Week 12 in 
subjects with draining fistulas at Baseline) or small number of responders (e.g., 
occurrence of CD-related hospitalizations during Part 1), comparison of upadacitinib 
group and placebo group will be performed using the Chi-Square test 
(or Fisher's exact test if more than 20% of the cells have expected counts of less than 5).
Analysis of Continuous Variables:
For continuous variables, the model based mean and standard error will be provided.  The 
mean value of the variable at baseline and each scheduled visit will also be presented for 
each treatment group.  Continuous variables collected longitudinally will be using a 
Mixed-Effect Model Repeated Measurement (MMRM) model.  Continuous efficacy 
variables which are collected at only one post-baseline visit (such as SES-CD) will be 
analyzed using an Analysis of Covariance (ANCOVA) model.  Point estimates and 95% 
CIs of mean change from baseline within each treatment group, and the difference 
between upadacitinib group and placebo group will be provided.
9.2
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the clinical trials, or missing due to COVID-19 infection or logistic 
restrictions during the pandemic. Assessments on or after any intercurrent event will be 
handled as specified in Section 8.0.
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.  For example, some scheduled visits may be missed due to 
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or canceled due to healthcare resource constraints during the pandemic.  Impacted visits 
due to COVID-19 will be recorded in the database.  The probability of having missed 
visits and missing data due to COVID-19 infection or logistical restrictions related to the 
COVID-19 pandemic can be reasonably assumed to be unrelated to the unobserved 
values.  Therefore, for the purpose of statistical analysis, it is reasonable to assume that 
these missing data are missing at random (MAR) and the statistical models that require 
MAR assumption are appropriate.  The intent is to provide reliable estimates of the 
treatment effects under the scenario without the impact of COVID-19 pandemic.
Missing data for the efficacy analyses will be handled using the methods described below.
9.2.1
Categorical Endpoints
For binary efficacy endpoints other than the occurrence of hospitalization and the 
occurrence of CD-related surgery, 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 (NRI) 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 restriction will be handled by 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 CD-related corticosteroids intercurrent event 
(see Section 8.2) and on/after the date of initiation of CD-related 
confounding medications after premature discontinuation of study drug
(see Section 8.1), subjects will be considered as non-responders and will 
not be imputed by MI.


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●
A sensitivity analysis for binary 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 
restriction will also be counted as non-responders.  Subjects on or after the 
occurrence of the CD-related corticosteroids intercurrent event and on/after 
the date of initiation of CD-related confounding medications after 
premature discontinuation of study drug will still be considered as 
non-responders.  This is the same method as "NRI" as defined in the 
protocol.
●
Details on MI method in NRI-C are described below:
○
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.  If the binary 
endpoints are derived from the continuous variables, PROC MI will be 
applied to the continuous variables.  The variables to be included in the 
imputation model are:  treatment group, randomization stratification factors 
(baseline steroid use (Yes, No), endoscopic disease severity 
(SES-CD < 15, ≥ 15) and number of prior biologics with inadequate 
response or intolerance (≤1, > 1)), age, gender, weight, baseline 
measurement (if applicable) and 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 I.  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 
data.  Using the CMH model adjusted by randomization stratification 
factors, the endpoints will be analyzed using each of the 30 imputed 
datasets.  SAS PROC MIANALYZE will be used to generate the final 
inferences of the risk difference between upadacitinib group and placebo 
group, using Rubin's rule3.  Note that measurements will be set to missing 
for 1) at or after the occurrence of the CD-related corticosteroids 
intercurrent event 2) on/after the date of initiation of CD-related 
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before applying MI.  After the MI imputation, an NRI override will be 
implemented for missing values 1) missing values due to reasons other 
than COVID-19 infection or logistic reasons, or 2) at or after the 
occurrence of the CD-related corticosteroids intercurrent event or 
3) on/after the date of initiation of CD-related confounding medications 
after premature discontinuation of study drug, that is, regardless of 
MI imputed values, subjects satisfying 1) or 2) or 3) will be considered as 
"non-responder" for binary efficacy endpoints.
For binary efficacy endpoints regarding the occurrence of hospitalization and the 
occurrence of CD-related surgeries, missing data will be handled using the following 
approaches.
●
As observed analysis (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.
9.2.2
Continuous Endpoints
For continuous efficacy endpoints where Mixed-Effect Model Repeat Measurement 
(MMRM) analysis or Analysis of Covariance (ANCOVA) is performed, missing data will
be handled using the following approaches.
●
MMRM:  The repeat measurement analysis will be conducted using a mixed 
model including observed measurements at all post-baseline visits up to the end 
of the analysis period.  The mixed model includes the categorical fixed effects 
of treatment, visit and treatment-by-visit interaction, stratification factors at 
randomization, and the continuous fixed covariates of baseline measurement.  
An unstructured variance covariance matrix will be used.  If the model cannot 
converge, an appropriate variance-covariance structure matrix (e.g., 
autoregressive or compound symmetry) will be used.  Parameter estimation is 
based on the method of restrictive maximum likelihood (REML).  MMRM will 


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be the primary approach in the analysis of continuous variables with repeated 
measurements.
●
ANCOVA: For continuous efficacy variables that are collected at only one 
post-baseline visit (such as SES-CD), ANCOVA will be used. The model 
includes the categorical fixed effects of treatment, stratification factors at 
randomization, and the continuous fixed covariates of baseline and 
measurement.
9.2.3
Additional Analyses
In addition, As Observed (AO) and tipping point analysis will be performed as 
supplementary and sensitivity analyses, if appropriate, for categorical or continuous 
endpoints.
●
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.
●
Tipping Point Analysis for Binary Endpoints
The tipping point analyses are two-dimensional, i.e., assumptions about the 
missing outcomes on each of the upadacitinib group and the placebo group can 
vary independently. The response rate among those subjects with missing 
response is assumed to be p0 for placebo group and p1 for upadacitinib group, 
and the response rate p0 and p1 systematically vary from 0% to 100% by every 
10% respectively. Given a set of (p0, p1), the subjects with missing response 
will be randomly assigned as responders or non-responders using binomial 
distribution to generate 30 imputed datasets, and the same CMH method used 
for the primary analysis will be performed on each of the imputed datasets to 
obtain the results for each comparison between the upadacitinib group versus 
the placebo group. SAS PROC MIANALYZE will be used to generate the 
final inferences of the risk difference between upadacitinib group and placebo 
group, using Rubin's rule.3
If one pair of (p0, p1) is found to reverse the study result interpretation in 
terms of p-value larger than 0.05, then the (p0, p1) is identified as the tipping 


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point. The results for a grid of (p0, p1) combinations are provided in tabular 
format. Note that missing data 1) on or after the occurrence of the CD-related 
corticosteroids intercurrent event or 2) on/after the date of initiation of CD-
related confounding medications after premature discontinuation of study drug 
will be considered as non-responders and will not be imputed in the tipping 
point analysis.
●
Tipping Point Analysis for Continuous Endpoints
The tipping point analyses are two-dimensional, i.e., assumptions about the 
missing outcomes on each of the upadacitinib group and the placebo group can 
vary independently. In addition, the focus is on scenarios where missing 
outcomes on upadacitinib are worse than the imputed values on upadacitinib, 
while missing outcomes on placebo are better than the imputed values on 
placebo. Missing values are first imputed via MI under MAR assumption, and 
then a shift parameter is applied to the imputed values (a different shift 
parameter may be specified for each treatment group). This is implemented by 
PROC MI using the MNAR statement. The imputation uses a two-step 
approach, augmentation step using MCMC and imputation step using 
Monotone Regression. The MNAR statement is applied in the imputation 
step. The number of imputed datasets is 30.
In cases where the shifted values are smaller than the minimum or larger than 
the maximum value of the endpoint, (i.e., out of range), the minimum or 
maximum value of the endpoint is used in further analysis steps. For each pair 
of shift parameters, the same MMRM/ANCOVA method used for the primary 
analysis will be performed on each of the imputed datasets to obtain the results 
for each upadacitinib treatment group versus the placebo group comparison. 
These results will be aggregated using Rubin's rule.3
●
If a pair of shift parameters is found to reverse the study result interpretation in 
terms of p-value larger than 0.05, then the pair of shift parameters is identified 
as the tipping point.


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9.3
Co-Primary Efficacy Endpoints and Analyses
9.3.1
Co-Primary Efficacy Endpoints
The co-primary endpoints for the primary analysis of efficacy are:
For EU/EMA regulatory purposes:
●
Achievement of clinical remission per PROs at Week 12, and
●
Achievement of endoscopic response at Week 12
For US/FDA regulatory purposes:
●
Achievement of clinical remission per CDAI at Week 12, and
●
Achievement of endoscopic response at Week 12
9.3.2
Primary Analysis of Co-Primary Efficacy Endpoints
The attributes of the estimands corresponding to the co-primary efficacy endpoints are 
summarized in Table 1.
The co-primary endpoints will be analyzed between upadacitinib group and placebo group 
using the CMH test, stratified by the randomization factors (baseline steroid use 
(Yes, No), endoscopic disease severity (SES-CD < 15, ≥ 15) and number of prior 
biologics with prior inadequate response or intolerance (≤1, > 1)) based on ITT1.


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Table 1.
Summary of the Estimand Attributes of the Co-Primary Efficacy 
Endpoints
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Intercurrent Events
Statistical 
Summary
Co-Primary 1a
Upadacitinib 
45 mg QD 
vs. placebo
Achievement 
of clinical 
remission 
per PROs at 
Week 12 (for 
EU/EMA)
ITT1 
population 
(Subjects who 
were 
randomized 
and received 
at least one 
dose of study 
drug in Part1) 
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of 
CD-related 
corticosteroids
All data after IE1 will 
be used until initiation 
of CD-related 
confounding 
medications
All subjects will be 
considered as 
non-responders at or 
after IE2
Difference 
in the 
proportion 
of subjects 
achieving 
clinical 
remission 
per PROs
Co-Primary 1b
Upadacitinib 
45 mg QD 
vs. placebo
Achievement 
of clinical 
remission 
per CDAI at 
Week 12 (for 
US/FDA)
ITT1 
population 
(Subjects who 
were 
randomized 
and received 
at least one 
dose of study 
drug in Part1)
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of 
CD-related 
corticosteroids
All data after IE1 will 
be used until initiation 
of CD-related 
confounding 
medications
All subjects will be 
considered as 
non-responders at or 
after IE2
Difference 
in the
proportion 
of subjects 
achieving 
clinical 
remission 
per CDAI


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Table 1.
Summary of the Estimand Attributes of the Co-Primary Efficacy 
Endpoints (Continued)
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Intercurrent Events
Statistical 
Summary
Co-Primary2
Upadacitinib 
45 mg QD 
vs. placebo
Achievement 
of endoscopic 
response at 
Week 12
ITT1 
population 
(Subjects who 
were 
randomized 
and received 
at least one 
dose of study 
drug in Part1)
IE1: premature 
discontinuation of 
study drug 
IE2: Initiation or dose 
escalation of 
CD-related 
corticosteroids
All data after IE1 will 
be used until initiation 
of CD-related 
confounding 
medications
All subjects will be 
considered as 
non-responders at or 
after IE2
Difference 
in the
proportion 
of subjects 
achieving 
endoscopic 
response
Both of the co-primary efficacy endpoints (EU/EMA:  1a and 2, US/FDA: 1b and 2 as 
specified in Table 1 above) will be tested at two-sided significance level of 0.05.  
A CMH based two-sided 95% CI for the difference between treatment groups will be 
constructed.
The NRI-C approach for handling missing data will be used for main analysis for the 
co-primary endpoints.
9.3.3
Sensitivity and Supplementary Analyses of the Co-Primary 
Efficacy Endpoints
Sensitivity analyses of the primary analysis of the co-primary efficacy endpoints are 
NRI-NC and tipping point analysis.


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In addition, sensitivity analyses which are based on "9-2 approach" (as detailed in 
Appendix D) to calculate CDAI score and average daily SF/AP will be performed on 
primary endpoints:
●
Achievement of clinical remission per PROs at Week 12 (for EU/EMA 
regulatory purposes)
●
Achievement of clinical remission per CDAI at Week 12 (for US/FDA 
regulatory purposes)
A supplementary analysis of the co-primary endpoints corresponded to the AO analysis 
specified in Section 9.2 will be performed in which all data after IE1 and IE2 will be used.  
CMH analysis as detailed in Section 9.1 will be repeated using 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 12 visit.
9.3.4
Additional Analyses of the Co-Primary Efficacy Endpoints
NRI-C analysis for the co-primary endpoints will also be conducted on the PP population.  
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 9.1 and 
Section 9.2.
9.4
Secondary Efficacy Analyses
9.4.1
Main Analyses of Ranked Secondary Efficacy Endpoints
The attributes of the estimands corresponding to the ranked secondary efficacy endpoints 
are summarized in Table 2.


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In general, continuous secondary efficacy variables with repeated measurements will be 
analyzed using a MMRM model including factors for treatment group, visit, visit by 
treatment interaction, and stratification variables.  The MMRM analysis is considered 
primary for inferential purposes.  Continuous secondary efficacy variables which are 
collected at only one post-baseline visit (such as SES-CD) will be analyzed using 
ANCOVA approach.
Categorical secondary efficacy variables will be analyzed using the CMH test controlling 
for stratification factors (baseline steroid use (Yes, No), endoscopic disease severity 
(SES-CD < 15, ≥ 15) and number of prior biologics with prior inadequate response or 
intolerance (≤1, > 1)).  A CMH based two-sided 95% CI for the difference between 
treatment groups will be constructed.  NRI-C method for missing data will be used for 
categorical secondary endpoints except occurrence of hospitalizations due to CD during 
Part 1.  The endpoints of "Occurrence of hospitalization due to CD during Part 1" will be 
analyzed using Chi-square test (or Fisher's exact test if ≥ 20% of the cells have expected 
cell count < 5).
The NRI-C method will be the primary approach for missing data handling for categorical 
secondary endpoints except hospitalization due to CD during Part 1.  The endpoint of 
"Occurrence of hospitalization due to CD during Part 1" will be analyzed based on the 
observed data using AO approach only.


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Table 2.
Summary of the Estimand Attributes of the Key Secondary Efficacy 
Endpoints
Attributes of the Estimand
Treatment
Endpoint
Population
Handling 
Intercurrent 
Events
Statistical 
Summary
Categorical 
Key Secondary 
except 
occurrence of 
hospitalizations 
due to CD 
during Part 1
Upadacitinib 
45 mg QD 
vs. placebo
Achievement of 
clinical 
remission per 
CDAI 
(EU/EMA) or 
per PROs 
(US/FDA) at 
Week 12, 
endoscopic 
remission at 
Week 12, 
discontinuation 
of 
corticosteroid 
use for CD and 
achievement of 
clinical 
remission per 
PROs 
(EU/EMA) or 
per CDAI 
(US/FDA) at 
Week 12, CR-
100 at Week 12, 
resolution of 
EIM at 
Week 12,
clinical 
remission per 
PROs 
(EU/EMA) or 
per CDAI 
(US/FDA) at 
Week 4,
CR-100 at 
Week 2
ITT1 
population 
(Subjects 
who were 
randomized 
and received 
at least one 
dose of 
study drug in 
Part1)
IE1: premature 
discontinuation 
of study drug
IE2: Initiation or 
dose escalation 
of CD-related 
corticosteroids
All data after IE1 
will be used until 
initiation of 
CD-related 
confounding 
medications
All subjects will 
be considered as 
non-responders 
at or after IE2
Difference in 
the proportion 
of subjects 
achieving each 
binary 
secondary 
endpoint


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Table 2.
Summary of the Estimand Attributes of the Key Secondary Efficacy 
Endpoints (Continued)
Attributes of the Estimand
Treatment
Endpoint
Population
Handling 
Intercurrent 
Events
Statistical 
Summary
Occurrence of 
hospitalizations 
due to CD 
during Part 1
Upadacitinib 
45 mg QD 
vs. placebo
Occurrence of 
hospitalizations 
due to CD 
during Part 1
ITT1 
population 
(Subjects 
who were 
randomized 
and received 
at least one 
dose of 
study drug 
in Part 1)
IE1: premature 
discontinuation 
of study drug
IE2: Initiation or 
dose escalation 
of CD-related 
corticosteroids
All data will be 
used regardless 
of IE
Difference in 
the proportion 
of subjects 
with 
occurrence of 
hospitalizations 
due to CD 
during Part 1  
Continuous 
Key Secondary
Upadacitinib 
45 mg QD 
vs. placebo
Change from 
Baseline in 
FACIT-F, 
IBDQ at 
Week 12
ITT1 
population 
(Subjects 
who were 
randomized 
and received 
at least one 
dose of 
study drug 
in Part 1)
IE1: premature 
discontinuation 
of study drug
IE2: Initiation or 
dose escalation 
of CD-related 
corticosteroids
All data after IE1 
will be used until 
initiation of CD-
related 
confounding 
medications
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


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9.4.2
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints
For categorical key secondary endpoints except occurrence of hospitalizations due to CD 
during Part 1, sensitivity analyses of the of the main analyses of are NRI-NC, and tipping 
point analysis.  NRI-NC and tipping point analysis will be performed for all categorical 
key secondary endpoints except occurrence of hospitalizations due to CD during Part 1.
For continuous key secondary endpoints, sensitivity analysis of the of the main analysis is 
tipping point analysis.
A supplementary analysis of categorical key secondary endpoints except occurrence of 
hospitalizations due to CD during Part 1 corresponded to the AO analysis specified in 
Section 9.2 will be performed in which all data after IE1 and IE2 will be used.  
CMH analysis as detailed in Section 9.1 will be repeated using AO data handling without 
any imputation as an additional analysis.  The analyses will be conducted on the 
ITT1 population who have the efficacy measurement at corresponding visit for the 
endpoint.
9.5
Additional Efficacy Analyses
Part 1
Other efficacy endpoints will be analyzed similarly as the secondary efficacy endpoints as 
described in Section 9.4.  No multiplicity adjustment will be considered.
Part 2 and Part 3
Only descriptive statistics will be provided for the Part 2 and Part 3 endpoints specified in 
Section 3.3.  The analyses for Part 2 will be performed using ITT2, and the analyses for 
Part 3 will be performed using the ITT3 by cohort.  Categorical endpoints will be 
summarized by number, percent and two-sided 95% CI; and continuous endpoints will be 
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maximum value; and time to response endpoints will be summarized by n, number of 
events, and the 25%, 50%, 75% percentiles of time (in days).
A programming error from the ediary vendor was identified in the total number of daily 
stools question on patient ediaries that does not allow the transaction to progress if the 
answer 0 to question 1, "How many stools in total have you had in the last 24 hours from 
last record until now?" The vendor has confirmed the issue was only present in languages 
that are translated from right to left. For this program, that includes Hebrew and Arabic in 
Israel and Egypt, respectively.
Since data from total stool frequency is only applicable to non-ranked additional efficacy 
endpoints, a sensitivity analysis will be performed for the additional efficacy endpoint of 
change from Baseline in average daily total stool frequency at all scheduled visits, by 
excluding subjects from Egypt and Israel.
9.6
Efficacy Subgroup Analyses
To evaluate the consistency of the efficacy over demographic and other baseline 
characteristics, subgroup analysis will be performed for the co-primary endpoints for the 
subgroups listed in Table 3 below using ITT1.
For subgroup analysis, point estimate and 95% CI for each treatment group as well as
point estimate and 95% CI for treatment differences between upadacitinib group and 
placebo group will be presented.  No p-value will be provided.  If, for a subgroup factor 
except age, sex and race (Table 3), any of the resulting categories has fewer than 10% of 
the planned study size, subgroup analyses will not be presented for that category.


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Table 3.
Subgroups for Efficacy Analysis
Subgroup Factor
Categories
Sex
Age
Age
Male, Female
≤ median, > median
≥18 years - < 40 years, ≥40 years -
< 65 years, ≥65 years
Race
Race
White, non-White
White, Black or African American, American 
Indian or Alaska Native, Native Hawaiian or 
Other Pacific Islander, Asian, Multiple
Baseline fecal calprotectin
Baseline CD-related Steroids Use
Baseline CD-related immunosuppressant use
Baseline CD-related aminosalicylate use
Baseline CD-related antibiotic use
Baseline hs-CRP
Baseline CDAI
Baseline very soft/liquid SF 
Baseline AP score
Baseline SES-CD
Crohn's Disease Location at Baseline
Body Weight
BMI
≤ 250 µg/g, > 250 µg/g
Yes, No
Yes, No
Yes, No
Yes, No
≤ 5 mg/L, > 5 mg/L
≤ 300, > 300
≤ median, > median
≤ median, > median
< 15, ≥15
Colonic only, Ileal only, Ileal-colonic
≤ median, > median
Underweight [< 18.5 kg/m2], Normal [≥ 18.5 
and < 25 kg/m2], Overweight [≥ 25 and 
< 30 kg/m2], Obese [≥ 30 kg/m2]
Disease Duration
≤ 5 years, > 5 years
Geographic Region
North America, Western Europe, 
South/Central America, Eastern Europe, Asia, 
Other
Number of Prior Biologics Failed
≤1, > 1
Prior TNF Failure
1, > 1
Prior Ustekinumab Failure
Yes or No
Prior Vedolizumab/Natalizumab Failure 
Yes or No


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10.0
Safety Analyses
10.1
General Considerations
Safety analyses will be performed on the safety population for Part 1 (SA1) and 
SA-UPA population as defined in Section 4.0.  In addition, safety summaries will be 
performed on the safety analysis set for Part 2 (SA2) and Part 3 (SA3).
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 the Part 1/Part 2 
laboratory and vital signs measurements, the baseline value is defined as the last available 
measurement before study drug administration for all subjects.  Starting from the Part 3, 
the baseline value for subjects initially randomized to upadacitinib will remain the same.  
However, the baseline value for subjects initially randomized to placebo will be redefined 
as the last available measurement before first dose of upadacitinib administration in 
Part 3.
For the safety analysis, subjects are assigned to a treatment group based on the treatment 
actually received, regardless of the treatment randomized.
Missing safety data will not be imputed.


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10.2
Adverse Events
AEs will be summarized and presented using primary MedDRA SOCs and 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 AEs 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.
10.2.1
Treatment-Emergent Adverse Events
Part 1 (SA1 population) /Part 2 (SA2 population):  TEAEs for Part 1/Part 2 are defined 
as events that begin either on or after the first dose of the study drug in Part 1/Part 2 and 
until (i) the first dose of study drug in the Study M14-430 (if applicable), or (ii) until first 
dose of study drug in Part 3 (if applicable), or (iii) within 30 days after the last dose 
administration of the study drug in Part 1/Part 2, whichever is earlier.
Part 3 (SA3 population):  TEAEs for Part 3 are defined as events that begin either on or 
after the first dose of the study medication in the Part 3 and until (i) first dose of study 
drug in the Study M14-430 (if applicable), or (ii) within 30 days after the last dose of the 
study drug in the Part 3, whichever is earlier.  
All Upadacitinib (SA-UPA population):  TEAEs for "All Upadacitinib" are defined as 
events that begin either on or after the first dose of upadacitinib and (i) until first dose of 
study drug in the Study M14-430 (if applicable), or (ii) within 30 days after the last dose 
of upadacitinib in the study, whichever is earlier.
24-Week Upadacitinib (SA4 population):  TEAEs for "24-Week Upadacitinib" (SA4) 
are defined as events that begin either on or after the first dose of upadacitinib and until 
(i) first dose of study drug in the Study M14-430 (if applicable), or (ii) within 30 days 
after the last dose of upadacitinib in the study, whichever is earlier.


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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.  For Part 1, the risk difference and 95% CI between upadacitinib group and 
placebo group will be presented.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any TEAE related to COVID-19
●
Any TEAE that was rated as related to study drug by the investigator.
●
Any severe TEAE
●
Any serious TEAE.
●
Any TEAE leading to discontinuation of study drug.
●
Any TEAE leading to death.
●
Treatment-emergent AESI (Appendix B).
●
All deaths
○
Deaths occurring ≤ 30 days after last dose of study drug
○
Deaths occurring > 30 days after last dose of study drug
○
Deaths related to COVID-19
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.


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10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
TEAEs 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 AEs will be counted once for each subject for calculating percentages, 
unless stated otherwise.  In addition, if the same AE 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.
In addition, TEAEs will be summarized by PT and sorted by decreasing frequency for the 
upadacitinib 45 mg QD treatment group.
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
TEAEs will be summarized by event rate per 100 subject years, defined as
Years
Patient
Total
TEAEs
of
Number

100


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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 10.2.2) and for TEAE summary by SOC 
and PT.
The study drug exposure for each safety population is defined in the table below.
Safety Population
Scenario
Study Drug Exposure Definition
SA1, SA2
Enrolls in Study M14-430 or Part 3 
at the end of Part 1/Part 2
Last dose date in Part 1/Part 2 -
1st dose date in Part 1/Part 2 + 1
Does not participate in the 
Study M14-430 or Part 3
SA3
Enrolls in Study M14-430 
Last dose date in Part 3 - 1st dose 
date in Part 3 + 1
Does not participate in the 
Study M14-430
SA4
Enrolls in Study M14-430 
Last dose date in Study M14-431 -
1st dose date in Part 1/Part 2 + 1
Does not participate in the 
Study M14-430 
SA-UPA
Enrolls in Study M14-430
Last dose date of upadacitinib in 
Study M14-431 - 1st dose date in 
upadacitinib in M14-431 + 1
Does not participate in the 
Study M14-430
10.2.5
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.


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10.2.6
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 AESIs 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.
10.3
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 at baseline) with 
the number of non-missing observations, mean, 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% CI will 
be presented for the mean change from Baseline within each treatment group.
For SA1 population, treatment group differences between upadacitinib 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.


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Shift Table Analyses
Changes in laboratory parameters will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample.  A 
shift table from baseline to minimum and maximum value (based on normal range) will 
be created.  A similar shift table will be provided to summarize shifts from baseline to the 
final post-baseline value.
Potentially Clinically Significant Laboratory Values
The criteria for potentially clinically significant laboratory values will be determined by 
CTCAE criteria of Grade 3, Grade 4 and ≥ Grade 3, with a grade worsening compared to 
baseline.  Toxicity grading scale is based on National Cancer Institute Common Toxicity 
Criteria (NCI CTC) AE version 4.03.  The number and percentage of subjects meeting the 
criteria for potentially clinically significant laboratory values will be summarized by 
treatment group.  Listings of subject-level laboratory data will be provided 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


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●
AST > 10 × ULN
●
AST > 20 × ULN
●
TBL > 2 × ULN
●
ALP > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 1.5 × ULN
●
ALT and/or AST > 3 × ULN and TBL > 2 × ULN
where ULN is the upper normal limit.  The maximum ratio relative to the ULN will be 
used to determine if subjects meet any of the criteria listed above.
A listing of possible Hy's Law cases, defined as those meeting the following criteria will 
also be provided:
●
ALT and/or AST > 3 × ULN and 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).
10.4
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% CI will be presented for the mean change from Baseline within each treatment group.
For SA1 population, treatment group differences between upadacitinib group and placebo 
group for changes from Baseline will be analyzed using a one-way Analysis of Variance 


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(ANOVA) with treatment as a fixed factor and 95% CI for treatment difference will be 
presented for each vital sign variable.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C).  For each vital sign PCI criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized.  Listings 
will be provided to summarize subject-level vital sign data for subjects meeting 
PCI criteria.
11.0
Interim Analyses
There will be no efficacy interim analyses planned for this 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 alpha adjustment is needed.
12.0
Overall Type-I Error Control
The overall type I error rate of the co-primary and ranked secondary endpoints will be 
strongly controlled using a fixed sequence multiple-testing procedure1 as well as Holm 
procedure5 as described below.  Specifically, the testing will utilize the sequence of 
hypothesis testing for the co-primary endpoints followed by a set of ranked key secondary 
endpoints (Group 1A_E for EU/EMA, Group 1A_F for US/FDA) in the order as specified 
in Section 3.2, and will begin with testing each of the co-primary endpoints using 
two-sided α of 0.05.  If both of the co-primary endpoints are statistically significant at 


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two-sided 0.05 level of significance, the Group 1A (Group 1A_E for EU/EMA, 
Group 1A_F for US/FDA) ranked secondary endpoints will be tested at two-sided α of 
0.05 in the order specified in Section 3.2.  If the co-primary endpoints and the Group 1A 
(Group 1A_E for EU/EMA, Group 1A_F for US/FDA) ranked secondary endpoints are 
statistically significant at two-sided 0.05 level of significance, the Group 1B (Group 1B_E 
for EU/EMA, Group 1B_F for US/FDA) ranked secondary endpoints will be tested using 
the Holm procedure at two-sided α of 0.05.  The graphs for the testing procedures are 
provided in Figure 3 (for EU/EMA regulatory purpose) and Figure 4 (for US/FDA 
regulatory purpose).


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Figure 3.
Graphical Multiple Testing Procedure for Co-Primary and Ranked 
Secondary Endpoints for EU/EMA


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Figure 4.
Graphical Multiple Testing Procedure for Co-Primary and Ranked 
Secondary Endpoints for US/FDA Graphical Multiple Testing 
Procedure for Co-Primary and Ranked Secondary Endpoints for 
US/FDA


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13.0
Version History
Table 4.
SAP Version History Summary
Version
Date
Summary
1.0
05 Oct 2017
Original version
2.0
29 Jan 2018

Clarification provided on Part 1 efficacy endpoints; specified Part 2 
and Part 3 efficacy endpoints (Section 4.3).

Modified the graphical testing procedure to incorporate 
Holm procedure for the Group 1B endpoints in place of 
Hochberg procedure (Section 4.6).

Race and Region subgroup categories added.  Details and clarification 
added for subgroup analyses (Section 5.2).

Specified the primary analysis for inference purposes for the 
continuous secondary efficacy endpoints (Section 6.3).
3.0
28 Jan 2021

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 study design based on protocol amendments to reduce the 
number of subjects planned for open-label induction Part 2 
(from 360 to 150)
o
Updated co-primary endpoint and ranked secondary endpoints to 
address agency requests and reflect updates in protocol 
amendments
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

Added definitions of estimand for primary and key secondary 
endpoints.


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Table 4.
SAP Version History Summary (Continued)
Version
Date
Summary
4.0
23 Jul 2021

Add premature withdrawal from the study as an intercurrent event.

Replace Pattern Mixture Model (PMM) with tipping point analysis as 
the sensitivity analyses for all primary and key secondary endpoints.

Update the cutoff of CGHAS/IGHAS histology remission endpoint 
(defined as CGHAS/IGHAS score ≤ 2) where cutoff is updated from 
"≤3" to "≤ 2" to align with published literature
(Section 3.3.1/ Section 3.3.2).

Update criteria of liver function assessment from "≥" to ">" 
(Section 10.3).

Add and define SA4 population (Section 4.0) and corresponding TEAE 
for the safety analysis (Section 10.2.1) in subjects who took 
upadacitinib in both 12-Week Induction Period and Extended 
Treatment Period

Add three Other Efficacy Endpoints (Section 3.3) on clinically 
meaningful improvements in FACIT-F

Add details of calculation of total patient year in the exposure adjusted 
AE analysis (Section 10.2.4)

Delete "endoscopic remission at Week 12 among subjects with 
SES-CD subscore of 3 in the narrowing component at Week 12, which 
was not present at Baseline" (result in 0% remission rate) and 
"endoscopic remission or endoscopic response at Week 12 among 
subjects with SES-CD subscore of 3 in the narrowing component at 
Week 12, which was not present at Baseline" as they are not applicable 
by definition

Replace ANCOVA-C with ANCOVA as ANCOVA is valid under 
MAR missingness (Section 9.2.2)

Corrected typo on the TEAE definition for SA-UPA population 
(update "40 days" to "30 days," Section 10.2.1)


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Table 4.
SAP Version History Summary (Continued)
Version
Date
Summary
5.0
15 Nov 2021

Based on FDA guidance (E9(R1) addendum Revision 1, May 2021), 
removed study withdrawal from the scope of intercurrent events 
(Section 2.1, Section 8.0, Section 9.3.2 Table 1, Section 9.4.1 Table 2)

Added a sensitivity analysis to the primary endpoints in Section 9.3.3
per agency request, and provide details on derivation of total 
CDAI score, average daily SF/AP (Section 3.0, Appendix D)

Add five Other Efficacy Endpoints (Section 3.3.1, Section 3.3.3) on in 
(1) change in FACIT-F at Week 4 and Week 12; (2) resolution of EIM 
at Week 2, Week 4, Week 8 and Week 12; (3) achievement of CR-100 
at Week 16, Week 20 and Week 24; (4) time to CR-100; (5) 
achievement of endoscopic response at Week 24. 

Provided more clarity that baseline characteristics will also be 
summarized for ITT2 (Section 7.0) 

Clarified intercurrent event handling strategies (Section 8.1 and
Section 8.2)

Updated the category for Race to adhere with CDISC controlled 
terminology, and corrected a typo in the Baseline SES-CD variable 
(update "≤15, > 15" to "< 15, ≥15") in subgroup analysis (Section 7.1, 
Section 9.6 Table 3)

Provided more clarity on the concomitant medication definition 
(Section 7.3)

Provided more clarity on the scope of summary statistics for the 
Extended Treatment Period (Section 9.1)

Provided more clarity on handling premature discontinuation of study 
drug intercurrent event in NRI-C analysis (Section 9.2.1)

Provided more clarity on the analyses for time to response endpoints 
(Section 9.5)

Add sensitivity analyses on additional efficacy endpoint of change 
from Baseline in average daily total stool frequency (Section 9.5).

Provided more clarity on the TEAE definition, and also the scope of 
AE overview (Section 10.2.1, Section 10.2.2)
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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2.
Greenland S, Robins JM.  Estimation of a common effect parameter from sparse 
follow-up data.  Biometrics.  1985;41(1):55-68.
3.
Rubin DB.  Multiple imputation for nonresponse in surveys.  John Wiley & Sons, 
Inc.  1987.
4.
Hedeker D, Gibbons RD.  Application of random-effects pattern-mixture models 
for missing data in longitudinal studies.  Psychol Methods.  1997;2(1):64-78.
5.
Holm S.  A simple sequentially rejective multiple test procedure.  Scand J Stat.  
1979;6:65-70.
6.
Qu Y, Shurzinske L, Sethuraman S.  Defining estimands using a mix of strategies 
to handle intercurrent events in clinical trials.  Pharm Stat. 2021;20(2):314-23.


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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
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 Infections excluding 
Tuberculosis and Herpes Zoster
CMQ
"Opportunistic Infection 
excluding tuberculosis 
and herpes zoster"
Active Tuberculosis
CMQ
"Active Tuberculosis"
Herpes Zoster
CMQ
"Herpes Zoster"
Adjudicated Gastrointestinal 
Perforations
Based on 
adjudicated results 
(per GI 
Perforation 
charter) of events 
identified by the 
"Gastrointestinal 
Perforation" SMQ 
Narrow search
Anemia
CMQ
"Non-Hemolytic and 
Non-Aplastic Anemias"
Neutropenia
CMQ
"Hematological Toxicity 
– Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity 
– Lymphopenia"
Creatine Phosphokinase (CPK) 
Elevations
PT
Search for the PT of 
"Blood creatine 
phosphokinase 
increased."
Hepatic Disorders
SMQ
Narrow
"Drug Related Hepatic 
Disorders –
Comprehensive Search"
Renal Dysfunction
SMQ
Narrow
"Acute Renal Failure"
Malignancies (all types)
SMQ
"Malignant tumors"


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AESI
Type of 
MedDRA Query
Broad or 
Narrow Search
SMQ/CMQ Search 
Criteria
Malignancies excluding 
non-melanoma skin cancer (NMSC)
SMQ
Narrow
Malignant Tumors SMQ 
(Narrow) removing 
NMSC output
NMSC
SMQ
Narrow
Skin Malignant tumors 
(Narrow SMQ) 
removing Melanoma 
CMQ
Lymphoma
SMQ
"Malignant 
Lymphomas"
Adjudicated Cardiovascular Events
Output from 
CACa
MACE*
Cardiovascular Death
Non-fatal Myocardial 
Infarction
Non-fatal Stroke
Other Cardiovascular Events
Undetermined/Unknown Cause
of Death
Adjudicated Thrombotic Events
Output from 
CACa
VTE**
Deep Vein Thrombosis
Pulmonary Embolism
Other Venous Thrombosis
Arterial Thromboembolic
Events (non-cardiac, 
non-neurologic)
CAC = Cardiovascular Adjudication Committee; CMQ = company MedDRA query; PT = preferred term; 
SMQ = standard MedDRA query
*
MACE:  Major Adverse Cardiovascular Events, defined as cardiovascular death, non-fatal myocardial infarction 
and non-fatal stroke.
**
VTE:  Venous thromboembolic events, defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) 
(fatal and non-fatal).
a.
Reviewed and adjudicated by an independent Cardiovascular Adjudication Committee in a blinded manner.


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Table B-2.
Exposure-Adjusted Rate Analyses for AESI
Analysis
EAER*
EAIR**
Cumulative Inc. Prop.
AESI (Section 10.2.6)
Serious Infections
X
X
X
Opportunistic 
Infections excluding 
Tuberculosis and 
Herpes Zoster
X
X
X
Active Tuberculosis
X
X
X
Herpes Zoster
X
X
X
Adjudicated 
Gastrointestinal 
Perforations
X
X
Anemia
X
X
X
Neutropenia
X
X
X
Lymphopenia
X
X
X
Creatine Phosphokinase 
(CPK) Elevations
X
X
Hepatic Disorders
X
X
Renal Dysfunction
X
X
Malignancies
X
X
Malignancies excluding 
Non-Melanoma Skin 
Cancer (NMSC)
X
X
NMSC
X
X
Lymphoma
X
X
Adjudicated 
Cardiovascular Events
X
X
Adjudicated 
Thrombotic Events
X
X
*
EAER: Exposure-adjusted event rate.
**
EAIR:  Exposure-adjusted incidence rate.


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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 
High
> 7% increase from baseline
Low
> 7% decrease from baseline


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Appendix D.
Crohn's Disease Activity Index (CDAI)
The Crohn's Disease Activity Index (CDAI) is a composite instrument that includes 
patient symptoms evaluated over 7 days (abdominal pain, stool frequency and general 
well-being), as well as physical and laboratory findings.  These items are scored 
individually, weighted, and do not contribute equally to the overall score.  The CDAI is 
derived from summing up the weighted individual scores of eight items as outlined below:


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Factor
Subtotal
1.
Number of liquid or very soft stools 
(Record the frequency per day)
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
2
2.
Abdominal pain rating:
0 = none, 1 = mild, 2 = moderate,
3 = severe
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
5
3.
General well-being:
0 = generally well, 1 = slightly 
underpar, 2 = poor, 3 = very poor, 
4 = terrible
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
7
4.
Number of 6 listed categories the 
subject now has
Check all items that apply:
☐
Arthritis/arthralgia
☐
Iritis/uveitis
☐
Erythema nodosum/pyoderma 
gangrenosum/aphthous 
stomatitis
☐
Fissure, abscess and/or anal 
fistula (draining/non-draining)
☐
Other cutaneous fistula 
(draining/non-draining) Fistula
☐
Fever over 100°F (37.8°C) 
during past week
_________________________________ 
_________________________________
Record "0" if no categories checked
×
20
5.
Taking Lomotil/Imodium/
Loperamide/opiates for diarrhea
0 = no, 1 = yes
________
×
30
6.
Abdominal mass
0 = none, 2 = questionable,
5 = defined
________
×
10
7.
Hematocrit:  ___.__
Male:  (47 – hematocrit) =
Female:  (42 – hematocrit) =
Subtotal
If hematocrit > normal, enter "0"
×
6
8.
Body weight:  ___.__(kg)
Standard weight:  ___.__(kg)
100 × [1 – (Body wt/Standard wt)] =
Percent below standard weight:  ______
If body wt > std. wt, enter "0"
×
1
Total
Higher CDAI scores indicate more severe disease.  For the calculation of CDAI and 
components (daily stool frequency, abdominal pain score and general well-being) at each 
visit, the following rules will be applied:


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1.
Identify the visit date with CDAI components that are collected, and set it as the 
CDAI calculation date.
2.
Calculate the subtotal scores from the component 1-3 (liquid or very soft stool 
frequency, abdominal pain score and general well-being) as follows:
a.
"14-4 approach"
i.
Select the diary data from 14 days prior to the CDAI calculation date, 
and set the data from the 4 days (the day prior to, on the day of and two 
days after the endoscopy date) to missing;
ii.
Take non-missing diary data from 7 most recent days from step i. If
there are multiple entries on the same day for the eDiary component, use 
the worst result (larger number);
iii.
If there are non-missing diary data from 7 days, the subtotal score is 
calculated as the sum of the 7-day scores, and multiplying the factor for 
the corresponding component as listed in the table above;
iv.
If there are non-missing diary data from less than 7 days but greater than 
3 days (4, 5, 6 days), the subtotal score is calculated as average of the 
dairy data and times 7, and multiplying the factor for the corresponding 
component as listed in the table above;
v.
If there are only less than 4 days of non-missing diary data available, the 
subtotal score will be set to missing.
b. "9-2 approach"
i.
Select the diary data from 9 days prior to the CDAI calculation date, and 
set the data from the 2 days (the day prior to, and on the day of the 
endoscopy date) to missing;
ii.
Take non-missing diary data from 7 most recent days from step i. If 
there are multiple entries on the same day for the eDiary component, use 
the worst result (larger number);


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iii.
If there are non-missing diary data from 7 days, the subtotal score is 
calculated as the sum of the 7-day scores, and multiplying the factor for 
the corresponding component as listed in the table above;
iv.
If there are non-missing diary data from less than 7 days but greater than 
3 days (4, 5, 6 days) OR from 3 consecutive days, the subtotal score is 
calculated as average of the dairy data and times 7, and multiplying the 
factor for the corresponding component as listed in the table above;
v.
If there are non-missing diary data from 3 non-consecutive days OR less 
than 3 days of non-missing diary data available, the subtotal score will 
be set to missing.
c.
Average daily SF/AP will be determined in the same way as described above to 
derive PROs-related endpoints (for example, clinical remission per PROs); 
d. The "14-4 approach" will be used to calculated CDAI, average daily SF/AP at 
each CDAI date. Sensitivity analyses which are based on "9-2 approach" to 
calculate CDAI and SF/AP will be performed on primary endpoints (Clinical 
Remission per CDAI at Week 12, Clinical Remission per PROs at Week 12).
3.
Subtotal scores for components 4-6 (Number of 6 listed categories, usage of 
Lomotil/Imodium/Loperamide/opiates for diarrhea and abdominal mass) will be 
determined using the data collected on the CDAI calculation date and the 
corresponding formula in the table above;
4.
Subtotal score for component 7 (Hematocrit) is calculated as follows:
a.
Identify the Hematocrit (%) value form the same visit as the CDAI calculation 
date, use the Hematocrit that is closest to the CDAI calculation date;
b. Hematocrit values obtained from previous visits can be used.
c.
The subtotal score for Hematocrit is calculated using the formula in the table 
above. If Hematocrit value is greater or equal to 47% for male subjects (greater 
or equal to 42% for female subjects), the subtotal score is set to 0.


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5.
Subtotal score for component 8 (percentage below standard weight) is calculated as 
follows:
a.
Standard weight is calculated based on height obtained at screening, sex and 
study protocol Appendix H;
b. Body weight is based on the measurement obtained on the CDAI calculation 
data, or previous visits if the measurement is missing.
c.
The subtotal score for percentage below standard weight is calculated using the 
formula in the table above. 
6.
CDAI score is calculated as the sum of subtotal scores of 8 components, and the 
total CDAI score will be rounded to 1 decimal. If any of the subtotal scores are 
missing, the CDAI score will be missing.


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Appendix E.
Simple Endoscopic Score – CD (SES-CD)
SES-CD is calculated based the sum of individual segment values for four endoscopic 
variables (presence and size of ulcers, ulcerated surface, affected surface and presence of 
narrowing).  Each variable in each segment be scored 0 to 3 resulting in SES-CD values 
ranging from 0 to 56 with higher scores indicating more severe disease.


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SES-CD Scoring:
Rectum
Sigmoid and 
Left Colon
Transverse 
Colon
Right 
Colon
Ileum
Total
Size of Ulcers 
Enter:
0 if none
1 if aphthous ulcers (Ø 0.1 to 0.5 cm)
2 if large ulcers (Ø 0.5 to 2 cm)
3 if very large ulcers (Ø > 2 cm)
Ulcerated Surface
Enter:
0 if none
1 if < 10%
2 if 10% – 30%
3 if > 30%
Affected Surface
Enter:
0 if unaffected segments
1 if < 50%
2 if 50% – 75%
3 if > 75%
Presence of Narrowing
Enter:
0 if none
1 if single, can be passed
2 if multiple, can be passed
3 if cannot be passed
TOTAL =


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Appendix F.
Patient Reported Outcomes Questionnaires Descriptions
IBDQ – Inflammatory Bowel Disease Questionnaire
The IBDQ is a 32-item (ranges 1 – 7) self-report questionnaire for patients with IBD to 
evaluate the patient reported outcomes across 4 dimensions:  bowel symptoms (loose 
stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social 
function (work attendance, need to cancel social events), and emotional function (anger, 
depression, irritability).  The IBDQ total Score ranges from 32 to 224 with a higher score 
indicating better outcome.  
The derivation of the IBDQ total score and the four IBDQ domain scores are as follows:
Domain Scores:
S1. BOWEL SYMPTOM: Q1 + Q5 + Q9 + Q13 + Q17 + Q20 + Q22 + Q24 + 
Q26 + Q29
[score ranges from 10 - 70],


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S2. SOCIAL FUNCTION: Q4 + Q8 + Q12 + Q16 + Q28
[score ranges from 5 - 35],
S3. SYSTEMIC SYMPTOM: Q2 + Q6 + Q10 + Q14 + Q18
[score ranges from 5 - 35],
S4. EMOTIONAL FUNCTION: Q3 + Q7 + Q11 + Q15 + Q19 + Q21 + Q23 + 
Q25 + Q27 + Q30 + Q31 + Q32
[score ranges from 12 - 84].
Total Score:
IBDQ Total Score = SUM of (bowel symptom domain score, social function domain 
score, systemic symptom domain score, emotional function domain score).
The following convention applies to IBDQ:
When not more than 20% of items in a domain of IBDQ were missing, it was substituted 
with the mean values from the items completed in the particular domain; otherwise, they 
were treated as missing.  The 20% threshold in each domain is:  bowel symptom domain:  
2 items, systemic symptom domain:  1 item, social function domain:  1 item, emotional 
function domain:  2 items.  If any of the 4 domain scores is missing, the total IBDQ score 
will be set to missing.
WPAI-CD – Work Productivity and Activity Impairment Questionnaire-Crohn's 
Disease
The WPAI assesses the impact of the condition on work productivity losses and 
impairment in daily activity.  WPAI has six items covering four domains:  Absenteeism 
(work time missed), measured as the number of hours missed from work in the past 
7 days due to a condition related problem.  Scores are expressed as impairment 
percentages, adjusting for hours actually worked according to the WPAI scoring 
algorithm; 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 


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(where, 0 = no effect of CD on work and 10 = severe impact of CD while at work); 
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 activity impairment (i.e., activities other 
than paid work like work around house, cleaning, shopping, traveling, studying), recorded 
and scored in same way as presenteeism.  Higher numbers indicate greater impairment 
and less productivity. 
CSS – Crohn's Symptoms Severity Questionnaire
The CSS questionnaire is a 14-item assessment of both GI and non-GI CD symptoms 
using a 7-day recall period.  The 14 items assess the frequency or intensity of each 
individual symptom by utilizing a 5-point Likert-type scale.  An assessment of an 
individual items frequency and intensity is measured as follows: 
●
Frequency:  1 = Never, 2 = Rarely, 3 = Sometimes; 4 = Often, 5 = Always
●
Intensity:  1 = Not at all, 2 = A little bit; 3 = Somewhat; 4 = Quite a bit; 
5 = Very much
An overall symptom score is calculated by combining ratings from the 14 individual items 
(possible scores range from 14 to 70) with higher scores indicating greater symptom 
frequency or intensity. 
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. 


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EQ-5D – European Quality of Life 5 Dimensions
The EQ-5D-5L is a standardized non-disease specific instrument for describing and 
valuing health-related quality of life.  The EQ-5D consists of 5 dimensions:  mobility, 
self-care, usual activity, pain/discomfort, and anxiety/depression.  Each dimension has 
5 levels:  no problem, slight problem, moderate problem, severe problem or unable to do 
the activity.  It also contains a Visual Analogue Scale (VAS).  Subjects are asked to 
indicate the level that describes their current level of function or experience for each 
dimension.  As a measure of health status, it provides a descriptive profile and can be used 
to generate a single index value for health status, where full health is equal to 1 and death 
is equal to 0.  The VAS records the subject's assessment of his/her own health along a 
vertical 20 cm line, which has health state scores between 0 and 100. 
FACIT-F – Functional Assessment of Chronic Illness Therapy-Fatigue
The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system is a 
comprehensive compilation of questions that measure health related quality of life in 
patients with cancer and other chronic diseases (www.facit.org).  The FACIT-F scale is a 
symptom-specific subscale of FACIT and is composed of 13 fatigue-related questions as 
follows.  The response to each question is as follows: 0=Not at all, 1=A little bit, 
2=Somewhat, 3=Quite a bit, 4=Very much.
1.
I feel fatigued
2.
I feel weak all over
3.
I feel listless ("washed out")
4.
I feel tired
5.
I have trouble starting things because I am tired
6.
I have trouble finishing things because I am tired
7.
I have energy
8.
I am able to do my usual activities


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9.
I need to sleep during the day
10.
I am too tired to eat
11.
I need help doing my usual activities
12.
I am frustrated by being too tired to do the things I want to do
13.
I have to limit my social activity because I am tired
In order to have higher values representing lower level of fatigue, all of the items, except 
for item 7 "I have energy" and item 8 "I am able to do my usual activities," are assigned 
reversed scores: reversed score = 4 – raw score.  The total FACIT-F score will then be 
calculated as follows: 
●
FACIT-F score = 13[Sum of answered-item scores / Number of items 
answered]
The score ranges from 0 to 52, 52 being the lowest level of fatigue. 
When there are missing data, provided that more than 50% of the items 
(i.e., at least 7 of 13 items) were answered in FACIT-F questionnaire, the total score will 
not be deemed as missing but be calculated as the mean response for all the 
non-missing-value items.  If less than 50% of the items were answered, the total score will 
have a missing value.


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Appendix G.
Extra-Intestinal Manifestations (EIMs)
The following 16 items consist of evaluation of EIM, each of the item will be evaluated 
based on a binary response (Yes/No).  Subjects with any EIM at baseline will be included 
in the analysis of resolution of EIMs, only if none of the EIMs are presented (all 16 items 
with outcome of "No") will be considered as "achievement of resolution of EIMs."
1. Peripheral arthropathy
9. Oral aphthous ulcers
2. Axial arthropathy (including sacroiliitis or 
ankylosing spondylitis)
10. Primary sclerosing cholangitis
3. Episcleritis
11. Autoimmune hepatitis
4. Uveitis
12. Venous thromboembolism
5. Iritis
13. Chronic obstructive pulmonary disease
6. Erythema nodosum
14. Bronchiectasis
7. Pyoderma gangrenosum
15. Nephrolithiasis
8. Sweet's syndrome
16. Anemia


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Appendix H.
Cronh's Disease Location Per SES-CD
For isolated ileal disease in the analysis using SES-CD:  Patients who have SES-CD = 0 
in all segments other than ileum are considered to have isolated ileitis.
For ileocolonic disease in the analysis using SES-CD:  Patients who have SES-CD 
different than 0 in the ileum and at least one of the colonic segments.
For colonic disease in the analysis using SES-CD:  Patients who have SES-CD = 0 in the 
ileum and SES-CD different than 0 in at least one of the colonic segments.


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Appendix I.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 100000 at each 
attempt until convergence of model happens.
Table I-1.
Random Seeds for NRI-C
Variables
Random Seed
MCMC Procedure
PROC MI
CDAI
14431
24431
SES-CD (for 20 individual variables)
N/A
24432
SF 
14441
24441
AP score
14451
24451
EIM
N/A
24452
IBDQ total score
14461
24461
FACIT-F
14471
24471
CGHAS
14491
24491


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Appendix J.
Geographic Region
Below table lists the countries/regions considered for each geographic region.
Geographic Region
Countries/Regions
Asia
Japan (JPN), China (CHN), Malaysia (MYS), South Korea (KOR), 
Taiwan (TWN)
Eastern Europe
Bosnia and Herzegovina (BIH), Croatia (HRV), Czech Republic (CZE), 
Estonia (EST), Hungary (HUN), Lithuania (LTU), Poland (POL), 
Romania (ROU), Russia (RUS), Serbia (SRB), Slovakia (SVK), 
Slovenia (SVN), Turkey (TUR)
North America
Canada (CAN), United States (USA), Puerto Rico (PRI)
Other
Australia (AUS), Egypt (EGY), Israel (ISR), South Africa (ZAF)
South/Central America
Argentina (ARG), Brazil (BRA), Chile (CHL), Mexico (MEX)
Western Europe 
Austria (AUT), Belgium (BEL), Denmark (DNK), France (FRA), 
Germany (DEU), Greece (GRC), Ireland (IRL), Italy (ITA), 
Netherlands (NLD), Norway (NOR), Portugal (PRT), Spain (ESP), 
Switzerland (CHE), Sweden (SWE), United Kingdom (GBR)