Conditions: Ulcerative Colitis (UC)
Keywords: ABBV-066 BI 655066
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1558
Healthy volunteers: no

Brief summary:
The objectives of Sub-Study 1 are to evaluate the efficacy, safety, and pharmacokinetics of risankizumab as induction treatment in subjects with moderately to severely active ulcerative colitis (UC), and to identify the appropriate induction dose of risankizumab for further evaluation in Sub-Study 2.

The objective of Sub-Study 2 is to evaluate the efficacy and safety of risankizumab compared to placebo in inducing clinical remission in subjects with moderately to severely active UC.

Detailed description:

Arms:
arm 1: Participants randomized to receive placebo for risankizumab administered by intravenous (IV) infusion. arm 2: Participants randomized to receive risankizumab 600mg administered by intravenous (IV) infusion. arm 3: Participants randomized to receive risankizumab 1200mg administered by intravenous (IV) infusion. arm 4: Participants randomized to receive risankizumab 1800mg administered by intravenous (IV) infusion. arm 5: Participants receive risankizumab 1800mg administered by intravenous (IV) infusion. arm 6: Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 180mg administered by subcutaneous (SC) injection in Induction 2. arm 7: Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 360mg administered by subcutaneous (SC) injection in Induction 2. arm 8: Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 1800mg administered by intravenous (IV) infusion in Induction 2. arm 9: Participants who received placebo with inadequate response in Induction 1 receive risankizumab 1800mg administered by intravenous (IV) infusion in Induction 2. arm 10: Participants randomized to receive placebo for risankizumab administered by intravenous (IV) infusion. arm 11: Participants randomized to receive risankizumab 1200mg administered by intravenous (IV) infusion. arm 12: Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 180mg administered by subcutaneous (SC) injection in Induction 2. arm 13: Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 360mg administered by subcutaneous (SC) injection in Induction 2. arm 14: Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 1200mg administered by intravenous (IV) infusion in Induction 2. arm 15: Participants who received placebo with inadequate response in Induction 1 randomized to receive risankizumab 1200mg administered by intravenous (IV) infusion in Induction 2.

Interventions: intervention 1: risankizumab IV intervention 2: placebo for risankizumab intervention 3: risankizumab SC
Intervention descriptions: intervention 1: risankizumab intravenous (IV) infusion intervention 2: placebo for risankizumab intervention 3: risankizumab subcutaneous (SC) injection

Protocol document:
Prot_000.pdf: 
Risankizumab
M16-067 Protocol Amendment 4 
EudraCT 2016-004677-40
1 
1.0
Title Page
Clinical Study Protocol M16-067
A Multicenter, Randomized, Double-Blind, Placebo 
Controlled Induction Study to Evaluate the Efficacy 
and Safety of Risankizumab in Subjects with 
Moderately to Severely Active Ulcerative Colitis
Incorporating Amendments 1, 2, 2.01 (Canada Only), 
2.02 (China Only), 2.03 (Germany Only) 3, 3.02 
(Ukraine and Surrounding Impacted Countries), and 
4 and Administrative Changes 5, 6, 7, 8, and 9
AbbVie Investigational 
  Product: 
Risankizumab
Date:
16 December 2022 
Development Phase:
2b/3 
Study Design: 
Randomized, Double-Blind, Placebo-Controlled Parallel Group 
Seamless design
EudraCT Number: 
2016-004677-40 
Investigator(s): 
Multicenter Study (Investigator information is on file at AbbVie) 
Sponsor:* 
For non-European 
countries excluding 
Japan:
AbbVie 
1 North Waukegan Road 
North Chicago, IL 60064 
USA
For European 
Countries: 
AbbVie Deutschland 
GmbH & Co KG
Knollstrasse 50
Ludwigshafen 67061 
Germany
Japan:
AbbVie GK
3-1-21 Shibaura,  
Minato-ku,  
Tokyo 108-0023,  
Japan
NCT03398148


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Sponsor/Emergency  
  Contact: 
AbbVie
Pharmaceutical Development
1 North Waukegan Road 
North Chicago, IL 60064 
USA
Office:
Mobile: 
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.


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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date  
Original
28 September 2017
Amendment 1
18 October 2017
Amendment 2
14 February 2018
Amendment 2.01 (Canada Only)
18 April 2018
Amendment 2.02 (China Only)
12 November 2018
Amendment 2.03 (Germany Only)
01 September 2020
Amendment 3
01 October 2020
Administrative Change 5
30 November 2020
Amendment 3.01 (France Only)
18 February 2021
Administrative Change 6
10 March 2021
Administrative Change 7
10 June 2021
Administrative Change 8
01 September 2021
Administrative Change 9
13 April 2022
Amendment 3.02 (Ukraine and Surrounding 
Impacted Countries Only)
09 May 2022
The purpose of this amendment is to: 
●
Updated Secondary Endpoints and Additional Endpoints for Sub-Study 2 
(Phase 3) in the synopsis and in Section 5.3.3
Rationale:  To ensure objective measures of endoscopic and histologic UC 
disease activity are prioritized and adjust the ranking of endpoints which 
include subjective outcomes and subpopulations as additional endpoints. 
●
Clarify in the synopsis and Section 5.1 that enrollment target has been met and 
enrollment is closed
Rationale:  For clarity. 
●
Clarified randomization stratification factors for Period 2 of Sub-Studies 1 
and 2 in Section 5.1, Section 5.3.3, and Section 8.3. 
Rationale:  For clarity.


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●
Added All Risankizumab safety analysis population for Sub-Study 2 
(SA2_ALL) which includes all subjects who received at least one dose of 
risankizumab any time during Sub-Study 2, and removed combined 
Sub-Study 1 and Sub-Study 2 All Risankizumab safety analysis set in 
Section 8.1.1. 
Rationale:  Clarified the safety analyses based on All Risankizumab are to be 
performed within Sub-Study2 and integrated safety analyses are defined in the 
Integrated Safety Analysis Plan (ISS SAP). 
●
Replaced NRI-C by NRI-MI to handle missing data in binary endpoints in 
Section 8.1.2. 
Rationale:  To replace NRI-C by NRI-MI to handle both missing due to Covid 
and missing due to geo-political conflict for binary endpoints 
●
Added RTB-MI approach to handle missing data in continuous endpoints in 
Section 8.1.2. 
Rationale:  Added per regulatory recommendation 
●
Added Tipping Point as sensitivity analysis for primary endpoint in 
Section 8.1.2. 
Rationale:  To evaluate the robustness of departures from the missing-at-
random (MAR) assumption in the primary analysis  
●
Updated the language of baseline summary in Section 8.1.4. 
Rationale: Language updated for clarity. 
●
Updated CMH test as the primary method for binary endpoints instead of M-N 
test in Section 8.1.6.1, Section 8.1.6.2, and synopsis 
Rationale:  The test was changed based on regulatory recommendation. 
●
Advanced Therapy-IR status (yes vs no), in replacement of "number of prior 
failed biologics (0, 1, >1)", will be used as a stratification factor in the CMH 
test in Section 8.1.6.1. 
Rationale:  Advanced Therapy-IR (yes vs no) is anticipated to have stronger 
association with the outcome of interest  
●
Updated multiple testing procedure language for Sub-Study 2 in Section 8.1.6. 
Rationale:  To incorporate the updates in endpoint ranking. 


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●
Added RTB-MI analysis method for secondary efficacy endpoints in 
Section 8.1.6.2
Rationale:  Added based on regulatory recommendations  
●
Clarified efficacy analysis methods for secondary endpoints in Section 8.1.6.2
Rationale:  Updated for clarity 
●
Removed the wording that safety analysis for All Risankizumab treated 
subjects in a population combining SS1 and SS2 In Section 8.1.7
Rationale:  Integrated safety analyses are defined in the Integrated Safety 
Analysis Plan (ISS SAP). 
Incorporate changes from Amendment 4.02 Ukraine and surrounding Impacted Countries 
●
Addition of language in the synopsis Section 1.2, Section 5.1 and 
Section 5.3.1.1, and Study Activities Table (Appendix C) to specify that 
clinical response at Week 12 and Week 24 can be calculated using the Partial 
Adapted Mayo Score. 
Rationale:  To allow subjects who cannot have endoscopy performed due to 
the geo-political conflict in Ukraine and surrounding impacted regions to be 
assessed for clinical response and continue in the maintenance study  
●
Addition of study procedure language in Section 5.3.1.1 and Section 9.2
Rationale:  To modify study visits/protocol-specified procedures impacted by 
the geo-political conflict in Ukraine and surrounding impacted regions, as 
necessary to ensure the safety of subjects, including use of a local lab, visit 
frequency, delays and interruptions of dosing, alternative methods of 
assessments, locations for data collection permitted by IRB/IEC 
●
Addition of language in Section 5.4.1
Rationale:  To ensure investigators explore acceptable mitigation strategies 
before discontinuing a subject due to the geo-political conflict in Ukraine and 
surrounding impacted regions 
●
Addition of protocol deviation language in Section 7.0
Rationale:  To clarify that deviations include deviations occurring due to the 
geo-political conflict in Ukraine and surrounding impacted regions. 


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●
Addition of language to address handling of missing data due to the geo-
political conflict in Ukraine and surrounding impacted regions in the statistical 
analysis plan in Section 8.1
Rationale:  To clarify handling of missing data due to the geo-political conflict 
in Ukraine and surrounding impacted regions and that modifications to the 
analysis for missing data due to the geo-political conflict in Ukraine and 
surrounding impacted regions will be incorporated into the statistical analysis 
plan
●
Addition of protocol modification language in Section 9.2
Rationale:  To clarify that AbbVie will modify the study protocol as necessary 
due to the geo-political conflict in Ukraine and surrounding impacted regions 
pandemic 
●
Addition of Study Subject Information and Informed Consent language in 
Section 9.3
Rationale:  To allow obtaining additional temporary verbal consent prior to 
obtaining signed and dated consent, in accordance with local regulations, in 
case of further adaptions or substantial changes in study conduct 
●
Addition of protocol modification language in Section 10.1
Rationale:  To clarify that due to the geo-political conflict in Ukraine and 
surrounding impacted regions, remote source data verification will be allowed 
if necessary
Incorporate changes from Administrative Changes 5, 6, 7, 8 and 9 
●
Update the physician contact in Section 6.1.5 of the protocol 
●
Remove the sentence "These samples are not applicable for China" from 
Section 5.3.1.1 Study Procedures- Clinical Laboratory Tests - Table 1
footnote "e," because it does not belong to this footnote 
●
Move the words "ADA, and nAb assays" to the correct part of the sentence at 
Section 5.3.1.1 Study Procedures- Clinical Laboratory Tests- Anaphylaxis 
Testing, to make the sentence more understandable 


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●
Remove the "X" for PGA at screening in Appendix C of the protocol, as 
collection of PGA assessment starts at baseline and is consistent with Full 
Mayo Score assessment at baseline.
●
Update the sponsor emergency contact on the title page 
●
Adapt the protocol to the recent civil law amendment in Japan, that has 
modified the legal age of adulthood from 20 to 18 years old 


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-067
Name of Study Drug:  Risankizumab
Phase of Development:  2b/3
Name of Active Ingredient:  Risankizumab
Date of Protocol Synopsis:  16 December 2022
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study to 
Evaluate the Efficacy and Safety of Risankizumab in Subjects with Moderately to Severely Active 
Ulcerative Colitis 
Objective:
Study M16-067 comprises two sub-studies:
The objective of Sub-Study 1 (Phase 2b induction) is to characterize the efficacy, safety, and 
pharmacokinetics of risankizumab as induction treatment in subjects with moderately to severely active 
ulcerative colitis (UC) and to identify the appropriate induction dose of risankizumab for further 
evaluation in Sub-Study 2 (Phase 3 induction).
At the time of this amendment, enrollment have been completed and all subjects in the double-blind, 
placebo-controlled portion of the study have completed induction.
The objective of Sub-Study 2 (Phase 3 induction) is to evaluate the efficacy and safety of risankizumab 
compared to placebo in inducing clinical remission in subjects with moderately to severely active UC.
Investigators:  Multicenter
Study Sites:  Approximately 400 sites worldwide
Study Population:
Males and females ≥ 18 and ≤ 80 years of age, or minimum age of adult consent according to local 
regulations, or aged 16 to < 18 year of age who meet the definition of Tanner stage 5 development where 
locally permitted with a diagnosis of moderately to severely active UC, defined as Adapted Mayo score 
of 5 – 9 points (using the Mayo scoring system, excluding Physician's Global Assessment) with an 
endoscopic subscore of 2 or 3 on screening endoscopy, confirmed by central review.
Sub-Study 1 enrolled subjects who have had an inadequate response or intolerance (IR) to prior biologic 
therapy (bio-IR).  Sub-Study 2 will enroll subjects who have had an inadequate response or intolerance 
to prior biologic therapy (bio-IR) and subjects who have not had an inadequate response or intolerance to 
prior biologic therapy (non-bio-IR).  The bio-IR enrollment will be approximately 541 subjects and the 
non-bio-IR enrollment will be approximately 425 subjects.
The bio-IR population is defined as subjects with documented intolerance or inadequate response to 
one or more of the approved biologics for UC (infliximab, adalimumab, golimumab, and/or 
vedolizumab) or tofacitinib.
The non-bio-IR population will include subjects who had an inadequate response or intolerance to 
conventional therapy.  Conventional therapy is defined as one or more of the following:  
aminosalicylates, oral locally acting steroids (e.g., budesonide, beclomethosone), systemic 
corticosteroids (prednisone or equivalent), or immunomodulators.  This population will also include 
subjects who have received biologic therapy or tofacitinib in the past but stopped therapy based on 
reasons other than inadequate response or intolerance (e.g., change in reimbursement coverage, well-
controlled disease).


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Number of Subjects to be Enrolled:
Approximately 1547 subjects in total:
•
240 subjects in Sub-Study 1, Phase 2b double-blind, placebo-controlled induction,
•
340 subjects in Sub-Study 1 enrolled during open-label (OL) dose selection period, and
•
approximately 966 subjects in Sub-Study 2 Phase 3 induction.
Methodology:
This Phase 2b/3 study has an operationally seamless design and comprises two sub-studies.  The purpose 
of this design is to seamlessly transition from the Phase 2b induction study to the Phase 3 induction 
study without enrollment pause.  Sub-Study 1 was designed as a Phase 2b dose finding study to evaluate 
the efficacy, safety, and PK of risankizumab as induction treatment to identify the appropriate induction 
dose of risankizumab for further evaluation in Sub-Study 2.  Sub-Study 2 is a Phase 3 induction study to 
evaluate the efficacy and safety of risankizumab versus placebo.
Sub-Study 1 (Phase 2b Induction):
Induction Period 1:
Subjects (n = 240) who met all of the inclusion criteria and none of the exclusion criteria were
randomized into the study in a 1:1:1:1 ratio to one of the following treatment groups:
•
Group 1:  Risankizumab 1800 mg IV Weeks 0, 4, 8 (n = 60)
•
Group 2: Risankizumab 1200 mg IV Weeks, 0, 4, 8 (n = 60)
•
Group 3:  Risankizumab 600 mg IV Weeks 0, 4, 8 (n = 60)
•
Group 4:  Placebo IV Weeks 0, 4, 8 (n = 60)
The randomization at baseline was stratified by baseline steroid use (yes vs no) and baseline Adapted 
Mayo score (≤ 7 vs > 7).  Endoscopy and evaluation of clinical response and remission will occur at 
Week 12.
Subjects in Sub-Study 1 who achieved clinical response per Adapted Mayo score (locally read Mayo 
endoscopic subscore) after completion of the 12-week Induction Period 1 were eligible to be enrolled 
into maintenance Study M16-066.  Clinical response is defined as a decrease from baseline in the 
Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, PLUS a decrease in rectal bleeding subscore 
(RBS) ≥ 1 or an absolute RBS ≤ 1.  Subjects who did not achieve clinical response at Week 12 were
eligible to receive blinded risankizumab treatment in Induction Period 2 as specified below.  Subjects 
were not eligible to enter Induction Period 2 until the Week 12 endoscopy has been completed.


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Methodology (Continued):
Sub-Study 1 (Phase 2b Induction) (Continued):
Induction Period 2:
At Week 12, subjects who did not achieve clinical response were be randomized by Interactive Response 
Technologies (IRT) to Induction Period 2, a double-blind, double-dummy 12-week treatment period to 
evaluate reinduction with risankizumab versus starting maintenance dosing on clinical response status. 
Subjects who received IV risankizumab induction were randomized 1:1:1 to:
•
Group 1:  1800 mg IV risankizumab Weeks 12, 16, 20
•
Group 2:  360 mg SC risankizumab Weeks 12, 20
•
Group 3:  180 mg SC risankizumab Weeks 12, 20
The randomization in Period 2 was stratified by baseline steroid use (yes vs no) and baseline Adapted 
Mayo score (≤ 7 vs > 7).
Subjects who received IV placebo induction treatment received: 
•
Group 4:  1800 mg IV risankizumab Weeks 12, 16, 20
Subjects randomized in Groups 1 and 4 received placebo SC and subjects randomized in Groups 2 and 3 
received placebo IV, in order to keep the blind.  The IV risankizumab dose or matching IV placebo were
given at Weeks 12, 16, and 20.  The SC risankizumab dose or matching SC placebo were given at 
Weeks 12, and 20.  At Week 24, subjects who received blinded risankizumab treatment during Induction 
Period 2 were reassessed and underwent a third endoscopy for evaluation of mucosal inflammation.  
Subjects who achieved clinical response per Adapted Mayo score (locally read Mayo endoscopic 
subscore) at Week 24 were eligible to enter into the maintenance Study M16-066.  Subjects without 
clinical response at Week 24, as well as all subjects who terminated the study early (including subjects 
who were eligible for but did not receive blinded risankizumab therapy during Induction Period 2), were
discontinued and have a follow-up call 140 days from the last dose of study drug to obtain information 
on any new or ongoing AEs.
Dose Selection Analysis:
After 240 subjects were randomized and completed the 12-week Induction Period 1, dose response and 
exposure response analysis for the key efficacy and safety variables were performed.  Based on this 
analysis, one induction dose of risankizumab has been identified (risankizumab selected dose) for 
evaluation in Sub-Study 2 (Phase 3 Induction).  The results of this analysis were reviewed and discussed 
with regulatory authorities, as applicable, prior to initiation of enrollment of subjects in Sub-Study 2. 
During the analysis period, additional subjects continued to be enrolled in the 1800 mg dosing group, on 
an open-label basis, to avoid interrupting the study activities during the analysis period and to generate a 
sufficient number of subjects with clinical response to be enrolled into the maintenance Study M16-066.  
The data collected from these additional subjects will not be included in the primary analysis but 
reported in the clinical study report.


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Methodology (Continued):
Sub-Study 2 (Phase 3 Induction):
Induction Period 1:
Approximately 966 subjects who meet all of the inclusion criteria and none of the exclusion criteria will 
be randomized into the double-blind 12-week study in a 2:1 ratio to one of the following treatment 
groups:
•
Group 1:  Risankizumab 1200 mg IV Weeks 0, 4, 8 (n = 644)
•
Group 2:  Placebo IV Weeks 0, 4, 8 (n = 322)
The randomization at baseline will be stratified by number of prior failed biologic treatments (0, 1 vs 
> 1), baseline steroid use (yes vs no), and baseline Adapted Mayo score (≤ 7 vs > 7).  Endoscopy and the 
primary analyses will occur at Week 12.  Subjects in Sub-Study 2 who achieve clinical response after 
completion of the 12-week Induction Period 1 will be enrolled into maintenance Study M16-066.  
Subjects who do not achieve clinical response per Adapted Mayo score (locally read Mayo endoscopic 
subscore) at Week 12 may be eligible to receive blinded risankizumab treatment in Induction Period 2 as 
specified below.  Subjects are not eligible to enter Induction Period 2 until the Week 12 endoscopy has 
been completed.
Induction Period 2: 
At Week 12, subjects who do not achieve clinical response will be randomized by IRT to Induction 
Period 2, a double-blind, double-dummy 12-week treatment period to evaluate reinduction with 
risankizumab versus starting maintenance dosing on clinical response status. 
Subjects who received IV risankizumab will be randomized 1:1:1 to:
•
Group 1:  1200 mg IV risankizumab Weeks 12, 16, and 20
•
Group 2:  360 mg SC risankizumab Weeks 12, and 20
•
Group 3:  180 mg SC risankizumab Weeks 12, and 20
The randomization in Period 2 will be stratified by number of prior failed biologic treatments (0, 1 vs 
> 1), baseline steroid use (yes vs no), and baseline Adapted Mayo score (≤ 7 vs > 7).
Subjects who received placebo induction treatment will receive:
•
Group 4:  1200 mg IV risankizumab Weeks 12, 16, and 20
Subjects randomized in Groups 1 and 4 will receive placebo SC and subjects randomized in Groups 2 
and 3 will received placebo IV, in order to keep the blind.  The IV risankizumab dose or matching IV 
placebo will be given at Weeks 12, 16, and 20.  The SC risankizumab dose or matching SC placebo will 
be given at Weeks 12, and 20.  At Week 24, subjects who receive blinded risankizumab during the 
Induction Period 2 will be reassessed and undergo a third endoscopy for evaluation of mucosal 
inflammation.  Subjects who achieve clinical response per Adapted Mayo score (locally read Mayo 
endoscopic subscore) at Week 24 may be eligible to enter into the maintenance Study M16-066.  
Subjects without clinical response at Week 24, as well as all subjects who terminate the study early 
(including subjects who are eligible for but do not receive blinded risankizumab therapy during 
Induction Period 2), will be discontinued and have a follow-up call 140 days from the last dose of study 
drug to obtain information on any new or ongoing AEs.
If endoscopy cannot be performed at Week 12 or 24 due to COVID-19 pandemic restrictions or geo-
political conflict in Ukraine and surrounding impacted regions, clinical response will be calculated using 
the Partial Adapted Mayo score and is defined as a decrease from Baseline in the Partial Adapted Mayo 


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score ≥ 1 points and ≥ 30% from Baseline, PLUS a decrease in rectal bleeding subscore (RBS) ≥ 1 or an 
absolute RBS ≤ 1.
Study Visits:
Study visits for clinical and safety assessments will be performed at Baseline, Weeks 4, 8, and 
12/Premature Discontinuation (PD).  For subjects entering Induction Period 2, additional study visits 
will occur at Weeks 16, 20, and 24/PD.  All subjects will be provided with a subject diary where they 
will record UC related symptoms, use of anti-diarrheals, and use of medications for endoscopy 
preparation.  Additionally, subjects will complete symptom, quality of life (QoL) and work productivity 
questionnaires throughout the study.  Clinical labs including, but not limited to, urinalysis, chemistry and 
hematology, high-sensitivity C-reactive protein (hs-CRP), serum risankizumab concentrations, and 
serum anti-drug antibody (ADA) levels will be collected throughout the study.  In addition, stool 
samples for calprotectin analysis will be collected and should be taken before starting bowel preparations 
for endoscopy.
Subjects will undergo endoscopies during screening and Week 12.  Subjects who enter Induction 
Period 2 will undergo an additional endoscopy at Week 24.  Endoscopies will be evaluated using the 
Mayo endoscopic subscore and the presence or absence of friability will be documented.  All 
endoscopies will be video recorded.  Videos from subjects with eligible Mayo endoscopic sub-scores 
during Screening and all videos from subjects at Week 12 and Week 24 will be sent to a central review 
vendor and scored as described in the central review charter.  In addition, the central reader will assess 
the endoscopy findings using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for additional 
exploratory analyses.  Biopsy samples for histologic assessment will be collected at each endoscopy 
visit.  Additional biopsies to confirm diagnosis (during Screening) or to rule out dysplasia/malignancy 
may be performed during the same time points as the endoscopy.  For subjects who consent, optional 
exploratory research samples may be taken during the study.
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.
Concomitant Aminosalicylates, Immunomodulators (Azathioprine [AZA], Mercaptopurine 
[6-MP], Methotrexate [MTX]), and/or UC-Related Antibiotics:
Subjects taking oral aminosalicylates, immunomodulators, and/or UC-related antibiotics at Baseline 
must continue these treatments for the duration of the study.  Initiating and/or increasing doses of oral 
aminosalicylates, immunomodulators, and/or UC-related antibiotics after Baseline is prohibited.  
Decreasing doses of oral aminosalicylates, immunomodulators, and/or UC-related antibiotics is 
prohibited during the study, except in the event of moderate-to-severe treatment related toxicities (e.g., 
leukopenia or elevated liver enzymes) in the opinion of the investigator.  However, UC-related 
antibiotics may be discontinued during Induction Period 2 at the discretion of the Investigator.
Note:  The duration of the study includes Induction Period 2.
Concomitant Corticosteroids:
Subjects taking oral corticosteroids at Baseline must continue their concomitant treatment at the Baseline 
dose for the duration of Induction Period 1.  Initiation and/or increasing doses of systemic and/or UC-
related corticosteroids after Baseline is prohibited.  Decreasing doses of oral corticosteroids is prohibited
during Induction Period 1, except in the event of moderate-to-severe treatment related toxicities in the 
opinion of the investigator.


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Methodology (Continued):
Subjects who enter Induction Period 2 will be allowed to taper their oral corticosteroids at the discretion 
of the Investigator.  While stopping the taper is permitted, increasing doses above the Baseline dose is 
prohibited.
Dose Selection:
Sub-Study 2 (Phase 3 induction study) will evaluate IV risankizumab 1200 mg during induction.  The 
selection of doses was informed by the analysis of safety and efficacy data, as well as the dose-response 
and exposure-response relationships of efficacy from Sub-Study 1 (Phase 2b dose finding study).
Induction Period 2 will evaluate IV (1800 mg [Sub-Study 1] or 1200 mg [Sub-Study 2] Q4W) or SC 
(180 mg or 360 mg Q8W; maintenance dosing regimen) risankizumab.  The purpose of Induction 
Period 2 is to evaluate the efficacy and safety of re-induction of risankizumab versus starting 
maintenance regimen on clinical response status.  Data from the Phase 2 study in subjects with CD 
suggested that re-induction with 600 mg IV increased both clinical response and clinical remission in 
subjects with inadequate response at Week 12.  The selection of the SC doses is based on safety and 
efficacy data, as well as the exposure-response relationship, of the maintenance period during the 
Phase 2 study in subjects with CD that evaluated 180 mg SC risankizumab for maintenance.  A higher 
dose of 360 mg Q8W is proposed to provide exposures reasonably separated with 180 mg Q8w dose to 
characterize the exposure-response relationship during maintenance phase with a potential of 360 mg 
Q8w dose to maintain higher response compared to 180 mg Q8w dose.
Data Monitoring Committee (DMC):
An independent Data Monitoring Committee (DMC) will be assessing all potential safety signals and 
will be unblinded to treatment allocation.  The DMC will review unblinded safety data on a cohort level, 
at a minimum of 6-month intervals throughout the course of the study.  At the time of this amendment, 
the DMC has provided recommendation that the study may continue without modification and has 
endorsed the commencement of enrollment for 16 and 17 year old subjects.
For China only:  The first 12 subjects enrolled in China will be monitored at an individual subject level.  
Also, the initial 12 subjects enrolled in China will be monitored on site for 2 hours after completion of 
the infusion.  Once the DMC assesses the safety results of the initial 12 subjects with no safety concerns 
identified, all sites in China will be notified that subjects should be monitored as necessary after 
completion of the infusion.  In addition, 16 to < 18 year olds will not be enrolled in China until the DMC 
has reviewed the first 12 adult subjects enrolled in China and provided endorsement.
A separate DMC charter will be prepared outside of the protocol and will describe the roles and 
responsibilities of the DMC member, frequency and triggers of data reviews, and relevant safety data to 
be assessed.  The cardiac adjudication committee (CAC) and anaphylaxis adjudication committee (AAC) 
adjudicates blinded data and the DMC reviews the data in an unblinded manner.  Unblinded adjudicated 
cardio-cerebrovascular events and anaphylactic reactions will be presented to the DMC for review on a 
periodic basis.  Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.


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Diagnosis and Main Criteria for Inclusion/Exclusion:
The following Inclusion/Exclusion Criteria are for subjects enrolled in either Sub-Study 1 or 2, except 
where specified.
Main Inclusion:
1.
Males or females ≥ 18 and ≤ 80 years of age, or minimum age of adult consent according to local 
regulations at the Baseline Visit.  In addition, for Sub-Study 2 only:  Where locally permissible, 
subjects 16 to < 18 years of age who meet the definition of Tanner Stage 5 for development (refer to 
the Appendix G) at the Baseline Visit.
2.
Confirmed diagnosis of UC for at least 3 months prior to Baseline.  Appropriate documentation of 
biopsy results consistent with the diagnosis of UC or in the assessment of the Investigator, must be 
available.
3.
Active UC with an Adapted Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3 
(confirmed by central review).
4.
Demonstrated intolerance or inadequate response to one or more of the following categories of 
drugs:  aminosalicylates, oral locally acting steroids, systemic steroids (prednisone or equivalent), 
immunomodulators, and/or biologic therapies or tofacitinib.
•
Demonstration of intolerance requires no minimum dose or duration of use.
•
Inadequate response is defined as outlined below:
o
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide):
•
Signs and symptoms of persistently active disease, in the opinion of the Investigator, during a 
current or prior course of at least 4 weeks of treatment with 2.4 g/day mesalamine (2 g/day if 
controlled release), 4 g/day sulfasalazine, 1 g/day olsalazine, or 6.75 g/day balsalazide,
o
Oral locally acting steroids (e.g., budesonide, beclomethasone):
•
Signs and symptoms of persistently active disease, in the opinion of the Investigator, 
during or after a course of at least 4 weeks of treatment with 9 mg/day budesonide or 
5 mg/day beclomethasone,
OR
•
Inability to taper oral budesonide to at or below 6 mg/day without recurrent active 
disease, 
o
IV or Oral systemic steroids (prednisone or equivalent):
•
Signs and symptoms of persistently active disease, in the opinion of the Investigator, 
during or after tapering of at least one regimen consisting of a dose equivalent to 
prednisone ≥ 40 mg/day orally for 3 weeks or intravenously for 1 week,
OR
•
Inability to taper oral systemic steroids to at or below a dose equivalent to prednisone 
10 mg/day without recurrent active disease,


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
o
Immunomodulators:
•
Signs and symptoms of persistently active disease, in the opinion of the Investigator, 
during a current or prior course of at least 90 days of treatment with one or more of 
the following: 
o
AZA:  ≥ 2.0 mg/kg/day rounded to the nearest available tablet or half tablet 
formulation (≥ 1 mg/kg/day for subjects in Japan, Korea, Taiwan, Singapore, or 
China) (or a documented 6-TGN level of ≥230 pmol/8 × 108 RBC)
o
6-MP:  ≥ 1 mg/kg/day rounded to the nearest available tablet or half tablet 
formulation (≥ 0.6 mg/kg/day for subjects in Japan, Korea, Taiwan, Singapore, or 
China) (or a 6-TGN level of ≥230 pmol/8 × 108 RBC)
o
MTX:  ≥ 15 mg/week subcutaneous (SC) or intramuscular (IM)
•
Note:  Oral MTX use is allowed during the study, however prior or current 
use of oral MTX is not sufficient for inclusion into the study
o
Tacrolimus: (for Japan, Taiwan and other countries in Asia with local treatment 
guidelines that include tacrolimus) documented trough level 5 - 10 ng/mL
•
Biologic Therapies and tofacitinib for UC:  Signs and symptoms of persistently active 
disease despite a history of one or more of the following:
o
At least one 6-week induction regimen of infliximab (≥ 5 mg/kg intravenous [IV] 
at Weeks 0, 2, and 6),
o
At least one 4-week induction regimen of adalimumab (one 160 mg SC dose at 
Week 0, followed by one 80 mg SC dose at Week 2 [or one 80 mg SC dose at 
Week 0, followed by one 40 mg SC dose at Week 2, in countries where this 
dosing regimen is approved]),
o
At least one 4-week induction regimen of golimumab (200 mg SC at Week 0 and 
100 mg SC at Week 2),
o
At least one 6-week induction regimen of vedolizumab (300 mg IV at Weeks 0, 2, 
and 6), 
o
At least one 8-week induction regimen of tofacitinib (10 mg PO twice daily)
•
Recurrence of symptoms during scheduled maintenance dosing following prior 
clinical benefit of the above biologics
•
Note:  Subjects who discontinued biologics or tofacitinib for reasons other than 
inadequate response as defined above or intolerance (e.g., change of insurance) must 
meet the criteria for intolerance or inadequate response to aminosalicylates, oral 
locally acting steroids, systemic steroids (prednisone or equivalent), and/or 
immunomodulators as defined above


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
5.
If female, subject must meet the criteria as stated in Section 5.2.4 of this protocol Contraception 
Recommendations.  Females of childbearing potential must have a negative serum pregnancy test 
result during Screening, and a negative urine pregnancy at Baseline.  Females of non-childbearing 
potential (either postmenopausal or permanently surgically sterile as defined in Section 5.2.4) during 
Screening do not require pregnancy testing at Baseline. 
6.
Subject must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.  In Japan, if the subject is under the legal age of adulthood, a 
subject's parent or legal guardian must be willing to give written informed consent.
Main Exclusion:
1.
Subject with a current diagnosis of Crohn's disease (CD), IBD-unclassified (IBD-U) or a history of 
radiation colitis or ischemic colitis.
Concomitant Medications and Treatments 
2.
Subject on oral UC-related antibiotics who has not been on stable doses for greater than, or 
discontinued within, 14 days prior to Baseline.
3.
Subject on oral aminosalicylates who has not been on stable doses for greater than, or discontinued 
within, at least 14 days prior to Baseline.
4.
Subject taking oral corticosteroids:
•
Budesonide > 9 mg/day
•
Beclomethasone > 5 mg/day
•
Prednisone or equivalent > 20 mg/day
•
Or has not been on the current course for ≥ 14 days prior to Baseline and on a stable dose for 
≥ 7 days prior to Baseline
5.
Subject on immunomodulators (AZA, 6-MP, MTX) who:
•
Has not been on the course for ≥ 42 days prior to Baseline, and
•
Has not been on a stable dose for ≥ 35 days prior to Baseline
Medications and Treatments During the Screening Period
6.
Subject who received IV anti-infectives within 35 days prior to Baseline visit or oral anti-infectives 
(non-UC-related) within 14 days prior to the Baseline visit. This does not apply to TB prophylaxis.
7.
Subject who received any parenteral nutrition within 35 days prior to Baseline.
8.
Subject who received any live bacterial or viral vaccination within 35 days (8 weeks for Japan) prior 
to Baseline.
9.
Subject who received cyclosporine, tacrolimus, or mycophenolate mofetil within 35 days prior to 
Baseline.
10. Subject who received fecal microbial transplantation within 35 days prior to Baseline.


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M16-067 Protocol Amendment 4 
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
Prior Medications and Treatments 
11. Subject who received any:
•
approved biologic agent (e.g., infliximab, adalimumab, golimumab, vedolizumab) within 
8 weeks prior to Baseline or tofacitinib within 35 days prior to Baseline 
12. Subject with prior exposure to p40 inhibitors (e.g., ustekinumab [Stelara]) or p19 inhibitors 
(e.g., risankizumab).
13. Subject has been taking combination of two or more of the following oral budesonide, oral 
beclomethasone, and/or oral prednisone (or equivalent) simultaneously, with the exception of 
inhalers, within 14 days prior to Screening or during the Screening period.
14. Subject who received IV/intramuscular corticosteroids within 14 days prior to Screening or during 
the Screening period.
15. Subject who received therapeutic enema or suppository (i.e., rectal aminosalicylates/corticosteroids), 
other than required for endoscopy, within 14 days prior to Screening or during the Screening period.
16. Subject who received apheresis (e.g., Adacolumn apheresis) ≤ 60 days prior to Screening or during 
the Screening period.
17. Subject who has concomitant cannabis use either recreational or for medical reasons within 14 days 
prior to Baseline or any history of clinically significant drug, or alcohol abuse in the last 12 months.
UC Related
18. Extent of inflammatory disease limited to the rectum as assessed by screening endoscopy
19. Subject with currently known complications of UC such as:
•
fulminant colitis,
•
toxic megacolon,
•
previous colectomy (total or subtotal),
•
or any other manifestation that might require surgery while enrolled in the study.
20. Subject with ostomy or ileoanal pouch.
Safety
21. Subject who has a known hypersensitivity to risankizumab or the excipients of any of the study 
drugs or the ingredients of Chinese hamster ovary (CHO).
22. Subjects with the following chronic or active infections: 
•
Active, chronic, or recurrent infection that based on the Investigator's clinical assessment makes 
the subject unsuitable candidate for the study, 
•
Infection with C. difficile toxin as identified during Screening, 
•
Known infection with an intestinal pathogen  
•
Are infected with human immunodeficiency virus (HIV),


Risankizumab
M16-067 Protocol Amendment 4 
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
•
QuantiFERON®-TB test or Purified Protein Derivative (PPD) skin test, or both, according to 
local guidelines, will be performed during Screening.  QuantiFERON®-TB test is preferred for 
subjects who received BCG vaccination or were exposed to other Mycobacteria species.  
Subjects with a positive test result (or indeterminate results that have been repeated) may 
participate in the study if further work up (according to local practice/guidelines) establishes 
conclusively that the subject has no evidence of active tuberculosis.  Subjects with a history of 
active TB who have documented completion of a full course of anti-TB therapy may be allowed 
to enter the study after consultation with the AbbVie TA MD).  If latent TB is established, TB 
prophylaxis/treatment should be initiated and maintained according to local country 
guidelines.
•
Have active hepatitis B or hepatitis C defined as:
o
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;
o
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody 
(HCV Ab)
23. Subject with a previous history of dysplasia of the gastrointestinal tract or found to have dysplasia, 
other than completely removed low-grade dysplastic lesions, in any biopsy performed during the 
Screening endoscopy.
24. Subject with a known history of lymphoproliferative disease, including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or 
splenomegaly.
25. Subject with or history of malignancy other than a successfully treated non-metastatic cutaneous 
squamous cell or basal cell carcinoma or localized carcinoma in situ of the cervix.
26. Subject who has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, 
disorder or symptoms thereof.
27. Female subjects who is pregnant, breastfeeding, or is considering becoming pregnant during the 
study or for approximately 140 days after the last dose of study drug.
28. Subject who has any condition including any physical, psychological, or psychiatric condition, 
which in the opinion of the Investigator, would compromise the safety of the subject or the quality 
of the data and renders the subject an unsuitable candidate for the study.
29. Screening laboratory and other analyses show any of the following abnormal results:
•
Aspartate transaminase (AST), alanine transaminase (ALT) > 2 × upper limit of the reference 
range;
•
White blood cell (WBC) count < 3.0 × 109/L;
•
Total bilirubin ≥ 2 mg/dL; except for subjects with isolated elevation of indirect bilirubin 
relating to Gilbert syndrome;
•
Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal 
Disease (MDRD) formula < 30 ml/min/1.73 m2. 
•
Hemoglobin < 8 g/dL
•
Platelets < 100,000/µL


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M16-067 Protocol Amendment 4 
EudraCT 2016-004677-40
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
•
Positive serum pregnancy test at the Screening visit or positive urine pregnancy test at the 
Baseline visit.
30. No known active COVID-19 infection.  If a subject has signs/symptoms suggestive of COVID-19, 
they should undergo molecular (i.e., PCR) testing to rule out SARS-CoV-2 infection.
•
Subjects who do not meet COVID-19 eligibility criteria must be screen failed and may only 
rescreen after they meet the following criteria:
•
Symptomatic subjects:  At least 14 days have passed since recovery, defined as resolution of 
fever without use of antipyretics and improvement in symptoms
•
Asymptomatic subjects:  At least 14 days have passed since the first positive molecular (i.e., 
PCR) test result.
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.
Investigational Product:
Risankizumab
Doses:
Risankizumab 1800 mg IV Q4W
Risankizumab 1200 mg IV Q4W
Risankizumab 360 mg SC Q8W
Risankizumab 180 mg SC Q8W
Mode of Administration:
Risankizumab solution for infusion (IV)
Risankizumab solution for injection (SC)
Reference Therapy:
Placebo for Risankizumab
Dose:
Placebo:  N/A
Mode of Administration:
Placebo solution for infusion (IV)
Placebo solution for injection (SC)
Duration of Treatment:  12 to 24 weeks
The study will include a Screening period of approximately 35 days and a double blind induction period 
of 12 weeks.  All subjects who do not achieve clinical response at Week 12 will be eligible to receive 
blinded risankizumab treatment over a subsequent 12 week period.  There will be a follow up call 
140 days from the last dose of study drug to obtain information on any new or ongoing AEs for those 
subjects who do not enroll into Study M16-066 or discontinue from the study prematurely.
Criteria for Evaluation:
•
Clinical Remission per Adapted Mayo:  stool frequency subscore (SFS) ≤ 1 and not greater 
than baseline, rectal bleeding subscore (RBS) = 0, and endoscopic subscore ≤ 1 without the 
evidence of friability
•
Clinical Response per Adapted Mayo:  decrease from Baseline ≥ 2 points and ≥ 30%, PLUS a 
decrease in RBS ≥ 1 or an absolute RBS ≤ 1


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Criteria for Evaluation (Continued):
•
Clinical Response per Partial Adapted Mayo (without endoscopy):  decrease from Baseline 
≥ 1 points and ≥ 30%, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1
•
Clinical Remission per Full Mayo:  Full Mayo score ≤ 2 with no subscore > 1
•
Endoscopic Improvement:  endoscopy subscore of 0 or 1 without the evidence of friability
•
Endoscopic Remission:  endoscopic subscore = 0
•
Histologic Remission:  Geboes score of < 2.0
•
Histologic Endoscopic Mucosal Remission (HEMR): Endoscopy subscore of 0 and Geboes 
score < 2.0
•
Histologic Endoscopic Mucosal Improvement (HEMI): endoscopic subscore of 0 or 1 
without the evidence of friability and Geboes score ≤ 3.1
Note:  Evidence of friability during endoscopy in subjects with otherwise "mild" endoscopic activity will 
confer an endoscopic subscore of 2.
Efficacy (Risankizumab Versus Placebo):  The primary endpoint is the same for Sub-Studies 1 and 2.
Primary Endpoint:
The achievement of clinical remission per Adapted Mayo score at Week 12.
Sub-Study 1 Secondary Endpoints:
1.
The achievement of endoscopic improvement at Week 12
2.
The achievement of clinical remission per Full Mayo score (defined as a Full Mayo score ≤ 2 with 
no subscore > 1) at Week 12 in subjects with a Full Mayo score of 6 to 12 at Baseline
3.
The achievement of clinical response per Adapted Mayo score at Week 12
4.
The achievement of clinical response per Partial Adapted Mayo score at Week 4
5.
The achievement of endoscopic remission at Week 12
6.
Occurrence of subjects with hospitalizations through Week 12
7.
The achievement of HEMR at Week 12
8.
Change from Baseline to Week 12 in UC-Symptom Questionnaire (UC-SQ) 
9.
Change from Baseline to Week 12 in Inflammatory Bowel Disease Questionnaire (IBDQ)
10. Change from Baseline to Week 12 in Short Form-36
11. Change from Baseline to Week 12 in Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-Fatigue)
12. UC-related surgeries through Week 12
Sub-Study 2 Secondary Endpoints:
1.
The achievement of clinical response per Adapted Mayo score at Week 12
2.
The achievement of endoscopic improvement at Week 12
3.
The achievement of histologic endoscopic mucosal improvement (HEMI: Endoscopic subscore of 0 
or 1 without evidence of friability and Geboes score ≤ 3.1) at Week 12
4.
The achievement of endoscopic remission at Week 12
5.
The achievement of clinical response per Partial Adapted Mayo score at Week 4
6.
The achievement of no bowel urgency at Week 12


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Criteria for Evaluation (Continued):
Sub-Study 2 Secondary Endpoints (Continued):
7.
The achievement of no abdominal pain at Week 12
8.
The achievement of histologic endoscopic mucosal remission (HEMR: Endoscopy subscore of 0 and 
Geboes score < 2.0) at Week 12
9.
Change from Baseline to Week 12 in Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-Fatigue)
10. Change from Baseline to Week 12 in Inflammatory Bowel Disease Questionnaire (IBDQ) total score
11. Occurrence of UC-related hospitalizations through Week 12
12. The achievement of no nocturnal bowel movements at Week 12
13. The achievement of no tenesmus at Week 12
14. Change from Baseline to Week 12 in number of fecal incontinence episodes per week
15. Change from Baseline to Week 12 in number of days per week with sleep interrupted due to UC 
symptoms.
Pharmacokinetics (PK):
Serum risankizumab concentrations will be determined from samples collected just prior to dosing at 
Weeks 4, 8, and 12/PD, and at Week 24 for subjects who undergo blinded risankizumab treatment 
during Induction Period 2.
Additionally, intensive pharmacokinetic assessment was performed in 24 subjects in Sub-Study 1 after 
the 3rd induction dose (Weeks 8 to 12).  For Subjects who consented to the intensive pharmacokinetic 
assessment, in addition to the time points above, blood samples were collected at Week 8, immediately 
after completion of infusion and 2 hours post completion of infusion, and at Weeks 9, 10 and 11.  Refer 
to Appendix H for more details.  At the time of finalizing this amendment, intensive PK sub-study has 
been completed.
Immunogenicity:
Serum ADAs will be determined from samples collected just prior to dosing at Baseline and Weeks 4, 8, 
and 12/PD, and at Week 24 for subjects who undergo blinded risankizumab treatment during Induction 
Period 2.
Safety:
Incidence of adverse events (AEs), changes in vital signs, physical examination results, and clinical 
laboratory data will be assessed throughout the study.  
Exploratory Research (Optional):
Prognostic, surrogate, predictive and pharmacodynamics biomarkers signatures may be investigated.  
Samples for different applications, potentially including but not limited to pharmacogenetic, epigenetic, 
transcriptomic, proteomic, metabolomic, metagenomic, phenotypic, functional and targeted 
investigations will be collected at various time points.  Assessments may include but may not be limited 
to nucleic acids, proteins, metabolites, lipids, or peripheral blood mononuclear cells (PBMC).


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Statistical Methods:
Sample Size Determination:
Sub-Study 1:
For Sub-Study 1 (Phase 2b portion of the study), a total of 240 subjects were equally randomized with 
1:1:1:1 ratio to three risankizumab treatment groups (600 mg, 1200 mg and 1800 mg IV Q4W) and the 
placebo group.  Assuming clinical remission rate of 7% in the placebo arm and maximum of 25% in at 
least one of the risankizumab treatment groups at Week 12, a sample size of 60 subjects per treatment 
group is sufficient to test for the presence of a dose response signal with an average power of 
approximately 87% at 5% level of significance (one-sided), via modeling using Multiple comparison 
procedure and modeling (MCP-Mod) approach.
Sub-Study 2:
For Sub-Study 2, a total of 966 subjects will be allocated to risankizumab 1200 mg IV dose or placebo in 
a randomization ratio of 2:1.  The sample size has been re-assessed after analyzing the combined PK, 
safety and efficacy results from Sub-Study 1.  It is determined to provide adequate powers for the 
primary endpoint and selected ranked secondary endpoints and adequate responders to meet the sample 
size requirement for Study M16-066.  Assuming clinical remission rate of 6% in the placebo arm and 
16% of the risankizumab treatment arm at Week 12, a sample size of 644:322 subjects per arm will 
provide at least 90% power to detect the 10% treatment difference in the primary endpoint using 
two sided Miettinen and Nurminen test at a 0.05 significant level.
Analysis Sets:
For both Sub-Studies 1 and 2, efficacy analysis will be based on Intent-to-Treat (ITT) population and 
Safety analysis will be based on safety population.  The ITT and safety populations for each sub-study 
are defined in the protocol Section 8.1.1. Subjects who received treatment in Induction Period 2 after 
Week 12 in both Sub-Study 1 and Sub-Study 2 will be analyzed separately for exploratory purpose.
Sub-Study 1:
The dose response modeling between risankizumab treatment groups and placebo on the primary 
efficacy endpoint clinical remission rate at Week 12 was performed using MCP-Mod approach in the 
ITT1A population.
The pairwise comparison between each risankizumab treatment group and placebo was performed using 
the 2-sided Cochran-Mantel-Haenszel (CMH) test and stratified by baseline corticosteroid use (yes vs 
no) and baseline Adapted Mayo score (≤ 7 vs > 7).
Non-responder imputation method (NRI) was used for the primary endpoint as the primary imputation 
method.
Continuous secondary efficacy endpoints were analyzed using a Mixed-Effect Model Repeated 
Measures (MMRM) method as the primary analysis.
Categorical secondary efficacy endpoints were analyzed using CMH controlling for stratification 
variables. NRI was used as the primary imputation method except for occurrence of hospitalization and 
UC-related surgeries, of which as observed data were used. 
Sub-Study 2:
All efficacy comparisons between risankizumab and placebo will be based on corresponding ITT 
Population.


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Statistical Methods (Continued):
Analysis Sets (Continued):
The comparisons between [each] risankizumab treatment group and placebo for the primary efficacy 
endpoint clinical remission rate at Week 12 will be performed using 2-sided Cochran-Mantel-Haenszel 
(CMH) test and will be stratified by Advanced Therapy-IR status (yes vs no), baseline corticosteroid use 
(yes vs no), and baseline Adapted Mayo score (≤ 7 vs > 7).  Non-responder imputation while 
incorporating multiple imputation to handle missing data due to COVID-19 or geo-political conflict in 
Ukraine and surrounding impacted regions (NRI-MI) will be used for the primary efficacy endpoint as 
the primary imputation method.
Continuous secondary efficacy variables will be analyzed using RTB-MI as defined in Section 8.1.2 with 
MMRM (for endpoints with more than one post-baseline visits) or with ANCOVA (for endpoints with 
one post-baseline visit) models.
Categorical secondary efficacy endpoints will be analyzed using CMH test controlling for stratification 
variables.  NRI-MI will be used except for occurrence of UC-related hospitalization, of which AO data 
will be used.
Pharmacokinetics and Immunogenicity:
Serum risankizumab concentrations will be summarized at each time point for each dosing regimen 
using descriptive statistics.  Population pharmacokinetic analyses combining the data from this study and 
other studies may be performed.  Relationships between risankizumab exposures and efficacy and safety 
variables of interest may be explored.
ADA incidence will be summarized by cohort and study visits.  ADA titers will be tabulated for each 
subject at the respective study visits.  The effect of ADA on risankizumab pharmacokinetics, efficacy 
and/or safety variable(s) and/or any additional analyses will be explored.
Safety:
Treatment Emergent Adverse events (TEAEs), laboratory data and vital signs are the primary safety 
parameters in this study.  All safety comparisons will be performed between treatment groups based on 
the corresponding safety population.  TEAEs for each induction period are defined in protocol 
Section 8.1.7.
An overview of TEAEs, including TEAEs of special interest such as serious infection, malignancies, 
major adverse cardiovascular events, systemic hypersensitivity reactions/infusion reactions, TEAEs 
leading to death and TEAEs leading to premature discontinuation (see details in the SAP), TEAEs by 
Medical Dictionary for Drug Regulatory Activities (MedDRA version 18.1 or later) preferred term and 
system organ class, TEAEs by maximum relationship to study drug, and TEAEs by maximum severity 
will be summarized by number and percentage.  Treatment group differences in the overall incidence of 
TEAEs will be assessed with Fisher's exact test for each preferred term.
Changes in laboratory data will be described using statistical characteristics and compared between-
treatment groups will be performed using a one-way Analysis of Variance (ANOVA).  In addition, shift 
tables and listings will be provided for abnormal values, whereby the normal range of the analyzing 
laboratory will be used.  Vital signs will be analyzed similarly.
* 
Pinheiro J, Bornkamp B, Bretz F.  Design and analysis of dose-finding studies combining multiple comparisons 
and modeling procedures.  J Biopharm Stat.  2006;16(5):639-56.
Bretz F, Pinheiro JC, Branson M.  Combining multiple comparisons and modeling techniques in dose-response 
studies.  Biometrics.  2005;61(3):738-48.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations 
6-MP
Mercaptopurine
AAC
Anaphylaxis Adjudication Committee
ADA
Anti-Drug Antibody
AE
Adverse Event
ALT
Alanine Transaminase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AST
Aspartate Transaminase
ANC
Absolute Neutrophil Count
AUC
Area under the plasma concentration-time curve
BID
Twice daily
BMI
Body Mass Index
BP
Blood pressure
BUN
Blood Urea Nitrogen
CAC
Cardiac Adjudication Committee
CD
Crohn's Disease
CDC
Centers for Disease Control and Prevention
CD4, CD8
Cluster of Differentiation
CGC
Common Gamma-Chain
CHF
Congestive Heart Failure
CI
Confidence Interval
Cmax
Maximum Observed Plasma Concentration
CMH 
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease - 2019
CPK
Creatine Phosphokinase
CR
Clinical Remission
CRF
Case Report Form
CRP
C-Reactive Protein
Cmin
Minimum Plasma Concentration During a Dosing Interval
CXR
Chest X-Ray
CYP3A
Cytochrome P450 3A


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DMARD
Disease-Modifying Anti-Rheumatic Drug
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC 
Electronic Data Capture
EIM
Extra-Intestinal Manifestations
Epro
Electronic Patient Reported Outcomes
EQ-5D
EuroQoL-5D
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue
FDA
US Food and Drug Administration
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
HCV Ab
Hepatitis C Virus Antibody
HDL
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
HRUQ
Health Resource Utilization Questionnaire
hsCRP
High-Sensitivity C-Reactive Protein
IBDQ
Inflammatory Bowel Disease Questionnaire
IC
Indeterminate Colitis
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
IL
Interleukin
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
JAK
Janus Activated Kinase
LDL
Low Density Lipoprotein


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LFT
Enter LFT definition
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Effect Repeated Measure 
MTX
Methotrexate
NK
Natural Killer Cells
NOAEL
No Observable Adverse Effect Level
NRI
Non-Responder Imputation
NRI-MI
Non-Responder Imputation while incorporating multiple imputation to 
handle missing data due to COVID-19 or geo-political conflict in Ukraine 
and surrounding impacted regions 
NSAID
Non-Steroidal Anti-Inflammatory Drug
NYHA
New York Heart Association
OC
Observed Cases
PD
Premature Discontinuation
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PE
Physical Examination
PG
Pharmacogenetic
PK
Pharmacokinetic
PPD
Purified Protein Derivative
QTc
QT Interval Corrected for Heart Rate
QTcF
QT Interval Corrected for Heart Rate by Fridericia's Formula
RA
Rheumatoid Arthritis
RAVE®
EDC System from Medidata
RBC
Red Blood Cell Count
RNA
Ribonucleic Acid
RBS
Rectal Bleeding Subscore
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SDP
Study designated physician
SFS
Stool Frequency Subscore
STAT
Signal Transduction Activators of Transcription
TB
Tuberculosis
TEAE
Treatment-Emergent Adverse Event
Tmax
Time to Maximum Observed Plasma Concentration


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TNF
Tumor Necrosis Factor
TPN
Total Parenteral Nutrition
Tyk2
Tyrosine Kinase 2
UC
Ulcerative Colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity
ULN
Upper Limit of Normal
WBC
White Blood cell Count
WPAI
Work Productivity and 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 ..................................................................................................... 8
1.3
List of Abbreviations and Definition of Terms ........................................ 24
2.0
Table of Contents...................................................................28
3.0
Introduction ...........................................................................33
3.1
Differences Statement .............................................................................. 35
3.2
Benefits and Risks .................................................................................... 35
4.0
Study Objective......................................................................38
5.0
Investigational Plan...............................................................39
5.1
Overall Study Design and Plan:  Description .......................................... 39
5.2
Selection of Study Population .................................................................. 53
5.2.1
Inclusion Criteria ..................................................................................... 53
5.2.2
Exclusion Criteria .................................................................................... 56
5.2.3
Prior and Concomitant Therapy ............................................................... 62
5.2.3.1
Prior Therapy ........................................................................................... 62
5.2.3.2
Concomitant Therapy ............................................................................... 62
5.2.3.3
Prohibited Therapy ................................................................................... 64
5.2.4
Contraception Recommendations and Pregnancy Testing....................... 66
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Optional 
Exploratory Research and Safety Assessments/Variables ....................... 67
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................ 67
5.3.1.1
Study Procedures ..................................................................................... 67
5.3.1.2
Collection and Handling of Optional Exploratory Research 
Samples .................................................................................................... 84
5.3.2
Drug Concentration Measurements ......................................................... 85
5.3.2.1
Collection of Samples for Analysis ......................................................... 85
5.3.2.2
Handling/Processing of Samples ............................................................. 85
5.3.2.3
Disposition of Samples ............................................................................ 85
5.3.2.4
Measurement Methods ............................................................................. 86
5.3.3
Efficacy Variables .................................................................................... 86


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5.3.3.1
Primary Variable ...................................................................................... 87
5.3.3.2
Secondary Variable .................................................................................. 87
5.3.4
Safety Variables ....................................................................................... 91
5.3.5
Pharmacokinetic Variables ...................................................................... 91
5.3.6
Optional Exploratory Research Variables ............................................... 91
5.4
Removal of Subjects from Therapy or Assessment ................................. 92
5.4.1
Discontinuation of Individual Subjects .................................................... 92
5.4.2
Discontinuation of Entire Study ............................................................... 94
5.5
Treatments ................................................................................................ 95
5.5.1
Treatments Administered ......................................................................... 95
5.5.2
Identity of Investigational Product(s) ...................................................... 96
5.5.2.1
Packaging and Labeling ........................................................................... 96
5.5.2.2
Storage and Disposition of Study Drug ................................................... 97
5.5.2.3
Preparation/Reconstitution of Dosage Form ............................................ 97
5.5.3
Method of Assigning Subjects to Treatment Groups ............................... 97
5.5.4
Selection and Timing of Dose for Each Subject ...................................... 99
5.5.5
Blinding .................................................................................................... 99
5.5.5.1
Blinding of Investigational Product ......................................................... 99
5.5.5.2
Data Monitoring Committee (DMC) ..................................................... 100
5.5.6
Treatment Compliance ........................................................................... 101
5.5.7
Drug Accountability ............................................................................... 101
5.6
Discussion and Justification of Study Design ........................................ 102
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 102
5.6.2
Appropriateness of Measurements ......................................................... 103
5.6.3
Suitability of Subject Population ........................................................... 103
5.6.4
Selection of Doses in the Study ............................................................. 103
6.0
Complaints ...........................................................................106
6.1
Medical Complaints ............................................................................... 106
6.1.1
Definitions .............................................................................................. 107
6.1.1.1
Adverse Event ........................................................................................ 107
6.1.1.2
Serious Adverse Events ......................................................................... 108
6.1.1.3
Areas of Safety Interest .......................................................................... 109
6.1.2
Adverse Event Severity .......................................................................... 111


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6.1.3
Relationship to Study Drug .................................................................... 112
6.1.3.1
Lack of Efficacy or Worsening of Disease ............................................ 113
6.1.4
Adverse Event Collection Period ........................................................... 113
6.1.5
Adverse Event Reporting ....................................................................... 113
6.1.5.1
Adverse Events Commonly Associated with Study Population ............ 115
6.1.6
Pregnancy ............................................................................................... 116
6.1.7
Cardiac Adjudication Committee .......................................................... 116
6.1.8
Anaphylaxis Adjudication Committee ................................................... 117
6.2
Product Complaint ................................................................................. 117
6.2.1
Definition ............................................................................................... 117
6.2.2
Reporting ................................................................................................ 117
7.0
Protocol Deviations..............................................................118
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................118
8.1
Statistical and Analytical Plans .............................................................. 118
8.1.1
Datasets for Analysis ............................................................................. 119
8.1.1.1
Intent-to-Treat Population ...................................................................... 119
8.1.1.2
Safety Population ................................................................................... 120
8.1.2
Definition of Missing Data Imputation .................................................. 121
8.1.3
Subject Disposition ................................................................................ 122
8.1.4
Demographics and Baseline Characteristics .......................................... 123
8.1.5
Prior and Concomitant Medications ...................................................... 123
8.1.6
Efficacy Analysis ................................................................................... 124
8.1.6.1
Primary Efficacy Variables .................................................................... 124
8.1.6.1.1
Analysis of Primary Endpoint ................................................................ 124
8.1.6.2
Secondary Efficacy Variables ................................................................ 126
8.1.7
Safety Analysis ...................................................................................... 127
8.1.8
Analysis of Optional Exploratory Variables .......................................... 128
8.1.9
Analysis of Pharmacokinetic and Pharmacodynamic Variables............ 129
8.2
Determination of Sample Size ............................................................... 130
8.3
Randomization Methods ........................................................................ 132
9.0
Ethics .....................................................................................133


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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 ............................... 136
9.3.2
Revision of the Consent Form and Explanatory Material ..................... 136
10.0
Source Documents and Case Report Form 
Completion ...........................................................................137
10.1
Source Documents ................................................................................. 137
10.2
Case Report Forms ................................................................................. 137
10.3
Electronic Patient Reported Outcomes (ePRO) ..................................... 138
11.0
Data Quality Assurance ......................................................140
12.0
Use of Information...............................................................140
13.0
Completion of the Study .....................................................142
14.0
Investigator's Agreement....................................................143
15.0
Reference List ......................................................................144
List of Tables
Table 1.
Clinical Laboratory Tests ......................................................................... 73
Table 2.
Identity of Investigational Product ........................................................... 96
Table 3.
Common Events Associated with UC .................................................... 116
List of Figures
Figure 1.
Induction Period 1 of Study M16-067 Sub-Study 1* (Phase 2b) ............ 44
Figure 2.
Induction Period 2 of Study M16-067 (Sub-Study 1 and 
Sub-Study 2) ............................................................................................ 46
Figure 3.
Induction Period 1 of Study M16-067 Sub-Study 2 (Phase 3) ................ 49
Figure 4.
Adverse Event Collection ...................................................................... 113
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator .......................................... 147


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Appendix B.
List of Protocol Signatories.................................................................... 149
Appendix C.
Study Activities Sub-Study 1 and Sub-Study 2 ..................................... 150
Appendix D.
Study Activities ...................................................................................... 155
Appendix E.
Script for Collection of Mayo Scores for Use in Study M16-067* ....... 157
Appendix F.
Clinical Criteria for Diagnosing Anaphylaxis ....................................... 162
Appendix G.
Tanner Stage 5 for Development* ......................................................... 164
Appendix H.
Optional Intensive PK Subjects ............................................................. 167


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


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Corticosteroids are used in patients with more severe symptoms but are not useful for 
longer term therapy.6  The frequency and severity of corticosteroid toxicities are 
significant, including infections, emotional and psychiatric disturbances, skin injury, and 
metabolic bone disease.  Corticosteroids are not effective for the maintenance of 
remission and the UC practice guidelines from the American College of Gastroenterology 
and the European Crohn's and Colitis Organization recommend against chronic steroid 
treatment.7  Patients with moderate to severe symptoms may derive some benefits from 
immunomodulatory agents (azathioprine [AZA], mercaptopurine [6-MP], or methotrexate 
[MTX]), however, up to 17% of patients on these agents experience adverse events severe 
enough to necessitate drug withdrawal.8  Adverse events (AEs) include idiosyncratic flu 
like reactions, bone marrow suppression, hepatotoxicity, pancreatitis, infections and 
malignancies.9,10  Despite these therapies, approximately 15% of ulcerative colitis patients 
experience a severe clinical course, and 30% of these patients require removal of the 
colon/rectum, to eliminate the source of the inflammatory process.  This procedure is 
accompanied by significant morbidity.12 Biological agents targeting specific 
immunological pathways have been evaluated for their therapeutic effect in treating 
patients with UC.  Anti-tumor necrosis factor (TNF) agents were the first biologics to be 
used for IBD.  Infliximab, adalimumab, and golimumab are successfully being used for 
the treatment of UC.  Vedolizumab, an anti-adhesion therapy, has also been approved for 
the treatment of UC.  Recently, tofacitinib, an oral Janus kinase (JAK) inhibitor, has been 
approved for the treatment of UC. 
Anti-TNF therapies are an effective treatment for patients who are steroid refractory or 
steroid dependent, who had inadequate response to a thiopurine, or who are intolerant to 
these medications.  Potential risks with anti-TNF therapies include infusion or injection 
site reactions, serious infections, lymphoma, heart failure, lupus-like syndromes, and 
demyelinating conditions.13  Despite the beneficial results achieved with the available 
biologic agents, only 17% to 45% of patients who receive them are able to achieve 
clinical remission.14-17  Thus, there remains a clear medical need for additional therapeutic 
options in UC for patients with inadequate response to or intolerance to conventional 
therapies and biologic therapies. 


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Risankizumab is a fully humanized mAb of the IgG1 subclass directed towards IL-23p19.  
The antibody has been engineered to reduce Fcγ receptor and complement binding and 
potential charge heterogeneity.  Risankizumab binds with high affinity to human IL-23 
and inhibits IL-23 stimulated IL-17 production at inhibitory concentration (IC) 50 
concentrations below 10 pM, as compared with 167 pM for ustekinumab in the same 
system.  Risankizumab does not affect IL-12 at a maximum tested concentration (33 nM) 
and it does not inhibit IL-12 stimulated IFN-γ production.
3.1
Differences Statement
The primary difference of this Phase 2b/3 study from other risankizumab studies is that it 
is the first to evaluate the efficacy, pharmacokinetics and safety of risankizumab in 
subjects with moderately to severely active UC.  Additionally, the Phase 2b portion of this 
study will test a higher dosing of 1800 mg.  Also, the endpoints in this study are different 
to reflect the changing regulatory requirements for pivotal registrational studies for new 
agents for the treatment of UC. 
3.2
Benefits and Risks
Despite the availability of various UC therapies, including biologic therapies such as anti-
TNFs, many patients still do not respond adequately to these treatments, or gradually lose 
response over time.  Thus, there remains a clear medical need for additional therapeutic 
options in UC for patients with inadequate response to or intolerance to conventional 
therapies and biologic therapies. 
Data suggest that altered immune regulation at the epithelial barrier leads to an 
overproduction of inflammatory cytokines, tissue destruction, and aberrant tissue repair in 
UC.  Among the cytokines implicated in UC pathogenesis, data at the genetic, human 
biology and clinical level strongly implicate IL-23 in this disease.18,19  The preclinical and 
clinical profiles of risankizumab suggest that it may have the potential to address unmet 
medical need in UC.  


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At the time of this amendment, study results from Sub-Study 1 (Phase 2b) became 
available.  The primary endpoint was clinical remission per Adapted Mayo Score at 
Week 12.  In pairwise comparisons, all risankizumab doses (600 mg IV, 1200 mg IV, 
1800 mg IV) achieved higher clinical remission rates compared to placebo, with both the 
1200 mg and 1800 mg groups achieving nominal p-values < 0.1.  All risankizumab arms 
achieved higher response rates on selected clinical and endoscopic secondary endpoints 
compared to placebo.  No new safety-risks were identified and the overall safety profile 
was consistent with the known safety profile of risankizumab. 
Though there are no serious adverse drug reactions known to be associated with 
risankizumab therapy, risks of participating in this study include risk of infections and 
risks related to the study specific procedures of blood sampling, infusion and injection of 
study drug, and endoscopy with biopsy. 
Blood sampling, intravenous (IV) infusions and subcutaneous (SC) injections can cause 
local bruising, inflammation, and pain.  Endoscopy and biopsy, although generally well 
tolerated, can be associated with diarrhea, abdominal pain, and in more severe cases, 
perforation, bleeding, effects from anesthetic medications, and infection. 
Local reactions to IV or SC administered biologic therapies are uncommon, and are 
usually limited to redness, swelling or induration at the injection site.  Manifestations of 
systemic hypersensitivity reactions include anaphylaxis, pruritus, hypotension, and 
respiratory distress.  Both local and systemic hypersensitivity reactions are readily 
detectable, transient in nature, and manageable with standard medical treatment.  Subjects 
will be closely monitored during drug administration.  An independent anaphylaxis 
adjudication committee (AAC) will be adjudicating observed systemic hypersensitivity 
and anaphylactic events.  The committee will remain blinded to treatment allocation.
As with any immune modulating agent, risankizumab has the potential to impair immune 
function resulting in a risk of infection.  This will be addressed by clinical monitoring for 
adverse events (AEs) during the treatment and follow up periods.  Subjects with positive 
screening for M. Tuberculosis (TB) (skin/interferon-gamma release assay [IGRA] test 


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positive) will be further worked up for signs and symptoms of active TB (e.g., chest x-ray 
[CXR]).  Subjects with active TB will be excluded from enrolling in the study.  Subjects 
with latent TB will be allowed to enroll in line with local guidelines.  If latent TB is 
established, TB prophylaxis/treatment should be initiated and maintained according to 
local country guidelines.  Subjects with current signs or symptoms of infection or history 
of serious infection will not be included in the study. 
The role of IL-23 in tumor immunity is not well established at this time, but an increased 
risk of cancer from an IL-23 antagonist, though considered small, cannot be excluded. 
Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators.  Therefore, though there is no known DILI risk 
with risankizumab, this study requires timely detection, evaluation, and follow-up of 
laboratory alterations of selected liver laboratory parameters to ensure subjects' safety.
An independent Data Monitoring Committee (DMC) will be assessing all potential safety 
signals and will be unblinded to treatment allocation.  The DMC will review unblinded 
safety data on a cohort level, at a minimum of 6-month intervals throughout the course of 
the study.  As of the time of this amendment, the DMC has provided recommendation that 
the study may continue without modification and has endorsed the commencement of 
enrollment of 16 – 17 year old subjects.  A patient information card with information of 
the symptoms and signs of hypersensitivity reactions, infusion related reactions as well as 
late stage reactions will be provided to the patients at Screening so that any such events 
once occurred will be reported immediately by the patients to the investigator.   
Increases in major adverse cardiovascular events (MACE) including myocardial 
infarction, cerebrovascular accident, and cardiovascular death have been reported in drugs 
with similar mechanism of action to risankizumab (e.g., p40 inhibitors).  However, the 
incidence of MACE has not been observed in longer term studies.  While the likelihood of 
increased MACE is small, all suspected cardiovascular events (serious or nonserious) 
observed in this study will be adjudicated by an independent adjudication committee.  An 
independent cardiac adjudication committee (CAC) will be adjudicating observed cardio- 


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and cerebro-vascular events and will remain blinded to treatment allocation.  In addition, 
an independent anaphylaxis adjudication committee (AAC) will be adjudicating observed 
potential anaphylactic events and will remain blinded to treatment allocation.
As discussed above, at the time of this amendment, data from Sub-Study 1 and Phase 2b 
dose ranging part of this study has demonstrated efficacy of risankizumab with an 
acceptable safety profile compared to placebo in subjects with moderately to severely 
active UC.  The benefit-risk profile of risankizumab in Sub-Study 1 supports further 
evaluation of risankizumab in Sub-Study 2 for subjects with UC. 
In view of the COVID-19 pandemic, the benefit-risk profile of various 
immunomodulatory therapies on COVID-19 is being evaluated based on real world and 
clinical trial data.  At this time, the effects of risankizumab on the course of COVID-19 
are not well defined. 
4.0
Study Objective
Study M16-067 comprises two sub-studies. 
●
The objective of Sub-Study 1 (Phase 2b induction) was to characterize the 
efficacy, safety, and pharmacokinetics of risankizumab as induction treatment 
in subjects with moderately to severely active UC and to identify the 
appropriate induction dose of risankizumab for further evaluation in 
Substudy 2 (Phase 3 induction).  At the time of this amendment, the double-
blind, placebo-controlled portion of Sub-Study 1 has been completed.
●
The objective of Sub-Study 2 (Phase 3 induction) is to evaluate the efficacy 
and safety of risankizumab compared to placebo in inducing clinical remission 
in subjects with moderately to severely active UC.


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5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2b/3, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy and safety of risankizumab as induction therapy in adult 
subjects with moderately to severely active UC, defined as Adapted Mayo score of 5 – 
9 points (using the Mayo scoring system, excluding Physician's Global Assessment) with 
an endoscopic subscore of 2 or 3 on screening endoscopy, confirmed by central review. 
This study comprises 2 sub-studies:  a Phase 2b dose-ranging induction sub-study 
(Sub-Study 1) and a Phase 3 induction sub-study (Sub-Study 2).  Sub-Study 1 enrolled 
subjects who have had an inadequate response or intolerance (IR) to prior biologic therapy 
(bio-IR).  Sub-Study 2 will enroll subjects who have had an inadequate response or 
intolerance to prior biologic therapy (bio-IR) and subjects who have not had an inadequate 
response or intolerance to prior biologic therapy (non-bio-IR).  The bio-IR enrollment in 
Sub-Study 2 will be approximately 541 subjects and the non-bio-IR enrollment will be 
approximately 425 subjects. At the time of this amendment the enrollment target has 
already been met and enrollment is closed
The bio-IR population is defined as subjects with documented intolerance or inadequate 
response to one or more of the approved biologics for UC (infliximab, adalimumab, 
golimumab, and/or vedolizumab) or tofacitinib. 
The non-bio-IR population will include subjects who had an inadequate response or 
intolerance to conventional therapy.  Conventional therapy is defined as one or more of 
the following:  aminosalicylates, oral locally acting steroids (e.g., budesonide, 
beclomethosone), systemic corticosteroids (prednisone or equivalent), or 
immunomodulators.  This population will also include subjects who have received 
biologic therapy or tofacitinib in the past but stopped therapy based on reasons other than 
inadequate response or intolerance (e.g., change in reimbursement coverage, well-
controlled disease). 


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This Phase 2b/3 study has an operationally seamless design and comprises 
two sub-studies.  The purpose of this design is to seamlessly transition from the Phase 2b 
induction study to the Phase 3 induction study without enrollment pause.  Sub-Study 1 
was designed as a Phase 2b dose finding study and will evaluate the efficacy, safety, and 
PK of risankizumab as induction treatment to identify the appropriate induction dose of 
risankizumab for further evaluation in Sub-Study 2.  At the time of this amendment, 
240 subjects were randomized and completed Week 12 treatment in Sub-Study 1, and the 
dose selection analysis was conducted.  During analysis of Sub-Study 1, subjects could 
continue to enroll in the highest dosing arm (risankizumab 1800 mg IV Weeks 0, 4, 8) on 
an open-label basis.
Once an induction dose has been selected, Sub-Study 2 will begin enrollment.  Sub-
Study 2 is a Phase 3 induction study to evaluate the efficacy and safety of risankizumab 
versus placebo.  Approximately 966 subjects will be randomized in the double-blind 
portion of Sub-Study 2. 
The study is designed to enroll a total of approximately 1547 subjects to meet scientific 
and regulatory objectives without enrolling an undue number of subjects in alignment 
with ethical considerations.  Therefore, if the target number of subjects has been enrolled, 
there is a possibility that additional subjects in screening will not be enrolled.
The study duration may be up to 45 weeks, including a Screening period of approximately 
35 days, a 12-week Induction Period 1, a 12-week Induction Period 2 for those subjects 
who do not achieve clinical response at Week 12, and a 140 day follow-up period from 
the last dose of study drug. 
Visits for clinical evaluation will occur at Baseline, Weeks 4, 8, and 12/PD.  Subjects, 
who do not achieve clinical response at Week 12 will be offered blinded induction therapy 
with risankizumab in Induction Period 2 with additional visits at Weeks 16 and 20 and 
evaluation for clinical response at Week 24. 


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At the study visit indicated in Appendix C, all subjects will be provided with a subject 
diary where they will record UC related symptoms throughout the study, use of anti-
diarrheals, and use of medications for endoscopy preparation.  Subjects will also be 
dispensed the patient information card at Screening.  Additionally, subjects will complete 
symptom, quality of life (QoL) and work productivity questionnaires throughout the study 
as indicated in Appendix C.  Clinical labs including, but not limited to, urinalysis, 
chemistry and hematology, high sensitivity C-reactive protein (hs-CRP), serum 
risankizumab concentrations, and serum anti-drug antibody (ADA) levels may be 
collected.  In addition, stool samples for calprotectin analysis will be collected and should 
be taken before starting bowel preparations for endoscopy.  Endoscopies will be evaluated 
using the Mayo endoscopic subscore and the presence or absence of friability will be 
documented.  All endoscopies will be video recorded.  Videos from subjects with eligible 
Mayo endoscopic subscores during Screening and all videos from subjects at Week 12 
and 24 will be sent to a central review vendor and scored as described in the central 
review charter.  In addition, the central reader will assess the endoscopy findings using the 
Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scoring system for additional 
exploratory analyses.  Biopsy to confirm diagnosis (during Screening) or to rule out 
dysplasia/malignancy may be performed during the same time points as the endoscopy.  
Two mandatory biopsy samples will be taken during each study endoscopy for 
histopathological scoring.  The same mandatory histopathological biopsy samples 
collected for the main study may be used for exploratory research if subjects provide 
additional consent for exploratory research.  In addition, two additional biopsies may be 
taken from subjects who consent to participate in the optional RNA biopsies substudy. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the Study.  As of the time of this amendment, the DMC has provided 
recommendation that the study may continue without modification and has endorsed the 
commencement of enrollment of 16 – 17 year old subjects. 


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Screening Period 
Approximately 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 
undergo the screening procedures as outlined in Appendix C.  Once written informed 
consent is obtained, subjects will undergo screening procedures. 
The length of time between Screening and the Baseline visit must allow time for 
endoscopy central reading and lab results. 
Laboratory values that are exclusionary 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 the previous result was never obtained. 
Clinical laboratory assessments as specified in Appendix C will only need to be repeated 
at Baseline if the time between Screening and Baseline is > 14 days, or if the subject's 
health status has changed to warrant a repeat test.
All subjects need to have their average daily Stool Frequency sub-score, average daily 
Rectal Bleeding sub-score, and Adapted Mayo Score calculated and meet eligibility 
criteria before randomization at Baseline.
Sub-Study 1:  Phase 2b Induction Study: 
At the time of this amendment, Sub-Study 1 has closed and all subjects have completed 
the 12-week double-blind, placebo-controlled induction period. 
Sub-Study 1 Induction Period 1: 
Subjects (n = 240) who met eligibility criteria were randomized in a 1:1:1:1 ratio to one of 
the following double-blinded induction treatment groups (Figure 1):
●
Group 1:  Risankizumab 1800 mg IV Weeks 0, 4, 8 (n = 60) 


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●
Group 2:  Risankizumab 1200 mg IV Weeks, 0, 4, 8 (n = 60) 
●
Group 3:  Risankizumab 600 mg IV Weeks 0, 4, 8 (n = 60) 
●
Group 4:  Placebo IV Weeks 0, 4, 8 (n = 60) 
Randomization at Baseline was stratified by baseline steroid use (yes vs no) and baseline 
Adapted Mayo score (≤ 7 vs > 7).  Endoscopy and evaluation of clinical response and 
remission will occur at Week 12.
After the 240 randomized subjects completed the 12-week Induction Period 1, dose 
response and exposure response analysis for the key efficacy and safety variables were
performed.  This analysis is referred to as dose-selection analysis hereafter.  Based on this 
planned analysis, one induction dose of risankizumab will be identified (risankizumab 
selected dose) for evaluation in Sub-Study 2 (Phase 3 Induction). 
Subjects in Sub-Study 1 who achieved clinical response per Adapted Mayo score (locally 
read Mayo endoscopic subscore) after completion of the 12-week Induction Period 1 were
enrolled into maintenance Study M16-066.  Clinical response is defined as a decrease 
from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, PLUS a 
decrease in rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1.
Subjects who did not achieve clinical response at Week 12, were eligible to receive 
blinded risankizumab treatment in Induction Period 2 as specified below.  Subjects were
not eligible to enter Induction Period 2 until the Week 12 endoscopy had been completed.


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Figure 1. 
Induction Period 1 of Study M16-067 Sub-Study 1* (Phase 2b) 
DC = discontinue; IR = subjects with inadequate clinical response; IV = intravenous; R = subjects with clinical 
response; SS-1 = Sub-Study 1
* 
DBL for Study M16-067 Sub-Study 1 occurs after first randomized 240 subjects complete 12 weeks assessment.  
After 240 subjects have been enrolled and before the dose has been selected for Sub-Study 2, additional subjects 
will continue to be enrolled into Sub-Study 1, where they will be assigned to the risankizumab 1800 mg IV Wks 0, 
4 and 8 dosing group.
Sub-Study 1 Induction Period 2: 
At Week 12, subjects who did not achieve clinical response were randomized by 
Interactive Response Technologies (IRT) to Induction Period 2, a double-blind, double-
dummy 12-week treatment period to evaluate reinduction with risankizumab versus 
starting maintenance dosing on clinical response status (Figure 2).
Subjects who received IV risankizumab induction were randomized 1:1:1 to: 
●
Group 1:  Risankizumab 1800 mg IV Weeks 12, 16, 20 
●
Group 2:  Risankizumab 360 mg SC Weeks 12, 20 
●
Group 3:  Risankizumab 180 mg SC Weeks 12, 20 
The randomization in Period 2 was stratified by baseline steroid use (yes vs no) and 
baseline Adapted Mayo score (≤ 7 vs > 7).


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Subjects who received IV placebo induction treatment received: 
●
Group 4:  risankizumab 1800 mg IV Weeks 12, 16, 20 
Subjects randomized in Groups 1 and 4 received placebo SC and subjects randomized in 
Groups 2 and 3 received placebo IV, in order to keep the blind.  The IV risankizumab 
dose or matching IV placebo were given at Weeks 12, 16, and 20.  The SC risankizumab 
dose or matching SC placebo were given at Weeks 12, and 20.  At Week 24, subjects who 
received blinded risankizumab treatment during Induction Period 2 were reassessed and 
underwent a third endoscopy for evaluation of mucosal inflammation.  Subjects who 
achieved clinical response per Adapted Mayo score (locally read Mayo endoscopic 
subscore) at Week 24 were eligible to enter into the maintenance Study M16-066.  
Subjects without clinical response at Week 24, as well as all subjects who terminated the 
study early (including subjects who were eligible for but do not receive blinded 
risankizumab therapy during Induction Period 2), were discontinued and had a follow-up 
call 140 days from the last dose of study drug to obtain information on any new or 
ongoing AEs. 


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Figure 2. 
Induction Period 2 of Study M16-067 (Sub-Study 1 and 
Sub-Study 2) 
DC = discontinue; RZB = risankizumab; IR = subjects with inadequate response; IV = intravenous; Plb = placebo; 
R = subjects with clinical response; RR = re-randomize; SC = subcutaneous
* 
Subjects who enter from Study M16-067 Sub-Study 1 will receive risankizumab 1800 mg IV.  Subjects who enter 
from Study M16-067 Sub-Study 2 will receive 1200 mg risankizumab IV.
Dose Selection Analysis:
After all 240 randomized subjects completed the 12-week Induction Period 1, dose 
response and exposure response analysis for the key efficacy and safety variables were
performed.  Based on this planned analysis, one dose of risankizumab will be identified 
for further evaluation in Sub-Study 2.  During this analysis, Sub-Study 1 enrolled 
additional subjects in the risankizumab 1800 mg IV Weeks 0, 4 and 8 dosing group, on an 
open-label basis.  The objectives of enrolling these additional subjects are to avoid 
interrupting the study activities during the analysis period and to support a sufficient 
number of subjects with clinical response to be enrolled into the maintenance 
Study M16-066.  The data collected from these additional subjects were not included in 


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the primary analysis of the 240 subjects and will be reported separately as exploratory 
analysis in the clinical study report. 
At the time of this amendment, dose selection enrollment has been closed, 340 subjects 
were enrolled and received risankizumab 1800 mg IV and all subjects have completed the 
12-week double-blind, placebo-controlled induction period. 
Subjects follow the same study design described for Sub-Study 1 above (i.e., study visits 
and subject flow through Induction Period 1 and Induction Period 2).  In addition, for 
subjects where endoscopy cannot be performed at Week 12 or Week 24 due to COVID-19 
pandemic restrictions or geo-political conflict in Ukraine and surrounding impacted 
regions, clinical response will be calculated using Partial Adapted Mayo score (decrease 
from baseline in the Partial Adapted Mayo score ≥ 1 points and ≥ 30% from baseline, 
PLUS a decrease in rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1).  Subjects 
who have missing endoscopy due to COVID-19 or geo-political conflict in Ukraine and 
surrounding impacted regions and achieve clinical response per Partial Adapted Mayo 
score will be eligible for Study M16-066 Sub-Study 3. 
Sub-Study 2:  Phase 3 Induction
Sub-Study 2 Induction Period 1: 
Once the dose selection analysis in Sub-Study 1 is completed, subjects (n = 966) who 
meet all of the inclusion criteria and none of the exclusion criteria will be enrolled into the 
double-blind 12-week study and randomized in a 2:1 ratio to one of the following 
treatment groups (Figure 3):
●
Group 1:  Risankizumab 1200 mg Weeks 0, 4, 8 (n = 644) 
●
Group 2:  Placebo IV Weeks 0, 4, 8 (n = 322) 
Sub-Study 2 will enroll approximately 541 bio-IR subjects.


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The randomization at Baseline will be stratified by number of prior failed biologics (0, 1 
vs > 1), baseline steroid use (yes vs no), and baseline Adapted Mayo score (≤ 7 vs > 7).  
Endoscopy and efficacy evaluation will occur at Week 12. 
Subjects in Sub-Study 2 who achieve clinical response per Adapted Mayo score (locally 
read Mayo endoscopic subscore) after completion of the 12-week Induction Period 1 will 
be enrolled into maintenance Study M16-066.  Subjects who do not achieve clinical 
response at Week 12, may be eligible to enter a blinded risankizumab treatment in 
Induction Period 2 as specified below. 
Subjects are not eligible to enter Induction Period 2 until the Week 12 endoscopy has been 
completed, except in case of COVID-19 pandemic restrictions or geo-political conflict in 
Ukraine and surrounding impacted regions. 
If endoscopy cannot be performed at Week 12 due to COVID-19 pandemic restrictions or 
geo-political conflict in Ukraine and surrounding impacted regions, clinical response will 
be calculated using the Partial Adapted Mayo score. 
Subjects with missing endoscopy due to COVID-19 pandemic restrictions or geo-political 
conflict in Ukraine and surrounding impacted regions and achieve clinical response per 
Partial Adapted Mayo score at Week 12 may be eligible to enroll in Study M16-066 
Sub-Study 3.  Subjects who do not achieve clinical response at Week 12, may be eligible 
to enter a blinded risankizumab treatment in Induction Period 2 as specified below. 


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Figure 3. 
Induction Period 1 of Study M16-067 Sub-Study 2 (Phase 3) 
DC = discontinue; IR = subjects with inadequate clinical response; R = subjects with clinical response; 
SS-2 = Sub-Study 2
Sub-Study 2 Induction Period 2: 
At Week 12, subjects who do not achieve clinical response will be randomized by 
Interactive Response Technologies (IRT) to Induction Period 2, a double-blind, double-
dummy 12-week treatment period to evaluate reinduction with risankizumab versus 
starting maintenance dosing on clinical response status (Figure 2).
Subjects who received IV risankizumab will be randomized 1:1:1 to: 
●
Group 1:  Risankizumab 1200 mg IV Weeks 12, 16, and 20 
●
Group 2:  Risankizumab 360 mg SC Weeks 12, and 20 
●
Group 3:  Risankizumab 180 mg SC Weeks 12, and 20 
The randomization in Period 2 will be stratified by number of prior failed biologics (0, 1 
vs > 1), baseline steroid use (yes vs no), and baseline Adapted Mayo score (≤ 7 vs > 7).
Subjects who received placebo induction treatment will receive:
●
Group 4:  Risankizumab 1200 mg IV Weeks 12, 16, and 20 


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Subjects randomized in Groups 1 and 4 will receive placebo SC and subjects randomized 
in Groups 2 and 3 will received placebo IV, in order to keep the blind.  The IV 
risankizumab dose or matching IV placebo will be given at Weeks 12, 16, and 20.  The 
SC risankizumab dose or matching SC placebo will be given at Weeks 12, and 20.  At 
Week 24, subjects who receive blinded risankizumab during the Induction Period 2 will 
be reassessed and undergo a third endoscopy for evaluation of mucosal inflammation.  
Subjects who achieve clinical response per Adapted Mayo score (locally read Mayo 
endoscopic subscore) at Week 24 may be eligible to enter into the maintenance 
Study M16-066. 
If endoscopy cannot be performed at Week 24 due to COVID-19 pandemic restrictions or 
geo-political conflict in Ukraine and surrounding impacted regions, clinical response will 
be calculated using the Partial Adapted Mayo score.  Subjects with missing endoscopy 
due to COVID-19 pandemic restrictions or geo-political conflict in Ukraine and 
surrounding impacted regions who achieve clinical response per Partial Adapted Mayo 
score at Week 24 may be eligible to enroll into maintenance Study M16-066 Sub-Study 3. 
Subjects without clinical response at Week 24, as well as all subjects who terminate the 
study early (including subjects who are eligible for but do not receive blinded 
risankizumab therapy during Induction Period 2), will be discontinued and have a 
follow-up call 140 days from the last dose of study drug to obtain information on any new 
or ongoing AEs. 
Concomitant Aminosalicylates, Corticosteroids, Immunomodulators (Azathioprine 
[AZA], Mercaptopurine [6-MP], Methotrexate [MTX]), and/or UC-Related 
Antibiotics
Subjects in Sub-Studies 1 & 2 taking aminosalicylates, immunomodulators, and/or UC-
related antibiotics at Baseline must continue their concomitant treatment for the duration 
of the study.  Initiating and/or increasing doses of aminosalicylates, immunomodulators, 
and/or UC-related antibiotics after Baseline is prohibited.  Decreasing doses of 
aminosalicylates, immunomodulators, and/or UC-related antibiotics is prohibited during 


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the study, except in the event of moderate-to-severe treatment related toxicities (e.g., 
leukopenia or elevated liver enzymes) in the opinion of the investigator.  UC-related 
antibiotics may be discontinued in Induction Period 2 at the discretion of the Investigator. 
Note:  the duration of the study includes Induction Period 2. 
Concomitant Corticosteroids (Sub-Studies 1 & 2)
Subjects in Sub-studies 1 & 2 taking oral corticosteroids at Baseline must continue their 
concomitant treatment at the Baseline dose for the duration of Induction Period 1.  
Initiation and/or increasing doses of systemic and/or UC related corticosteroids 
prohibited.  Decreasing doses of corticosteroids is prohibited during Induction Period 1, 
except in the event of moderate-to-severe treatment related toxicities in the opinion of the 
investigator. 
Subjects who receive blinded therapy in Induction Period 2 during Weeks 12 to 24 will be 
allowed to taper their corticosteroids at the discretion of the Investigator.  While stopping 
the taper and/or increasing the dose back to baseline level is permitted, increasing doses 
above the Baseline dose is prohibited. 
Follow-Up Period/Premature Discontinuation (PD)
Subjects in Sub-Studies 1 & 2 may discontinue treatment at any time during the study 
participation (Section 5.4).  Subjects who end study participation early will have a PD 
visit and complete the procedures outlined for the PD visit in Appendix C as soon as 
possible after the last dose of study drug and preferably prior to the administration of any 
new therapies.
Subjects who discontinue the study or subjects who complete the Week 12/Week 24 visit 
and do not roll-over into Study M16-066 will have a follow-up call 140 days from the last 
dose of study drug to obtain information on any new or ongoing AEs. 


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Re-Screen
Subjects in Sub-Studies 1 & 2 who initially screen fail for the study may be permitted to 
re-screen following re-consent.  The subject must meet all the inclusion and none of the 
exclusion criteria at the time of re-screening in order to qualify for the study.  There is no 
minimum period of time a subject must wait to re-screen for the study, unless a subject 
has a positive COVID-19 molecular (i.e., PCR) test per Exclusion Criterion 30. 
If the subject had a complete initial screening evaluation including the TB test, 
Hepatitis B virus (HBV), Hepatitis C virus (HCV), human immunodeficiency virus (HIV) 
and electrocardiogram (ECG), these tests will not be required to be repeated for re-
screening provided the conditions noted in Section 5.3.1.1 are met and no more than 
90 days have passed.
If a subject is being rescreened within 14 days (≤ 14 days have passed) from the collection 
date of the previous screening laboratory testing, repeat laboratory testing for 
chemistry/hematology, urinalysis, serum pregnancy, and C. difficile are not required 
unless, in the opinion of the Investigator, the subject's health status has changed. 
If a subject is being rescreened more than 14 days (> 14 days have passed) from the 
collection date of the previous screening laboratory testing then chemistry/hematology, 
urinalysis, serum pregnancy, and C. difficile should be repeated during rescreening. 
An endoscopy with biopsy will not be required to be repeated for re-screening provided 
the conditions noted in Section 5.3.1.1 are met and the endoscopy is within 45 days of the 
Baseline visit.  All other screening procedures will be repeated unless otherwise stated 
above.  Sites may contact the AbbVie TA MD if there are questions on if subjects should 
or should not be re-screened. 
All subjects need to have their average daily Stool Frequency sub-score, average daily 
Rectal Bleeding sub-score, and Adapted Mayo score calculated in order to verify 
eligibility criteria before randomization at Baseline.


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5.2
Selection of Study Population
It is anticipated that approximately 1547 subjects with active moderate to severe UC will 
be enrolled at approximately 400 sites worldwide. 
Both bio-IR and non-bio-IR subjects will be included.  The bio-IR population will be 
approximately 1122 subjects and the non-bio-IR population will be approximately 
425 subjects.
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.
Males or females ≥ 18 and ≤ 80 years of age, or minimum age of adult consent 
according to local regulations at the Baseline Visit.  Sub-Study 2 only:  Where 
locally permissible, subjects 16 to < 18 years of age who meet the definition of 
Tanner Stage 5 for development (refer to Appendix G) at the Baseline Visit.
2.
Confirmed diagnosis of UC for at least 3 months prior to Baseline.  Appropriate 
documentation of biopsy results consistent with the diagnosis of UC or in the 
assessment of the Investigator, must be available.
3.
Active UC with an Adapted Mayo score of 5 to 9 points and endoscopic subscore 
of 2 to 3 (confirmed by central review). 
4.
Demonstrated intolerance or inadequate response to one or more of the following 
categories of drugs:  aminosalicylates, oral locally acting steroids, systemic 
steroids (prednisone or equivalent), immunomodulators, and/or biologic therapies 
●
Demonstration of intolerance requires no minimum dose or duration of use. 
●
Inadequate response is defined as outlined below: 
○
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, 
balsalazide):
●
Signs and symptoms of persistently active disease, in the opinion of the 
Investigator, during a current or prior course of at least 4 weeks of 


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treatment with 2.4 g/day mesalamine (2 g/day if controlled release), 
4 g/day sulfasalazine, 1 g/day olsalazine, or 6.75 g/day balsalazide, 
○
Oral locally acting steroids (e.g., budesonide, beclomethasone): 
●
Signs and symptoms of persistently active disease in the opinion of the 
Investigator, during or after a course of at least 4 weeks of treatment 
with 9 mg/day budesonide or 5 mg/day beclomethasone, 
or 
●
Inability to taper oral budesonide to at or below 6 mg/day without 
recurrent active disease, 
○
IV or Oral systemic steroids (prednisone or equivalent): 
●
Signs and symptoms of persistently active disease in the opinion of the 
Investigator, during or after tapering of at least one regimen consisting 
of a dose equivalent to prednisone ≥ 40 mg/day orally for 3 weeks or 
intravenously for 1 week, 
or 
●
Inability to taper oral systemic steroids at or below a dose equivalent to 
prednisone 10 mg/day without recurrent active disease,
○
Immunomodulators: 
●
Signs and symptoms of persistently active disease in the opinion of the 
Investigator, during a current or prior course of at least 90 days of 
treatment with one or more of the following: 
○
AZA:  ≥ 2.0 mg/kg/day rounded to the nearest available tablet or 
half tablet formulation (≥ 1 mg/kg/day for subjects in Japan, Korea, 
Taiwan, Singapore, or China) (or a documented 6-TGN level of 
≥ 230 pmol/8 × 108 RBC)
○
6-MP:  ≥ 1 mg/kg/day rounded to the nearest available tablet or half 
tablet formulation (≥ 0.6 mg/kg/day for subjects in Japan, Korea, 
Taiwan, Singapore, or China) (or a 6 TGN level of ≥ 230 pmol/8 × 
108 RBC)
○
MTX:  ≥ 15 mg/week subcutaneous (SC) or intramuscular (IM)


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●
Note:  Oral MTX use is allowed during the study, however 
prior or current use of oral MTX is not sufficient for inclusion 
into the study 
○
Tacrolimus: (for Japan, Taiwan and other countries in Asia with 
local treatment guidelines that include tacrolimus) documented 
trough level 5 - 10 ng/mL 
○
Biologic therapies and tofacitinib for UC: 
○
Signs and symptoms of persistently active disease despite a history of one 
or more of the following: 
●
At least one 6-week induction regimen of infliximab (≥ 5 mg/kg 
intravenous [IV] at Weeks 0, 2, and 6), 
●
At least one 4-week induction regimen of adalimumab (one 160 mg SC 
dose at Week 0, followed by one 80 mg SC dose at Week 2 [or 
one 80 mg SC dose at Week 0, 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 golimumab (200 mg SC at 
Week 0 and 100 mg SC at Week 2), 
●
At least one 6-week induction regimen of vedolizumab (300 mg IV at 
Weeks 0, 2, and 6), 
●
At least one 8-week induction regimen of tofacitinib (10 mg PO twice 
daily) 
●
OR
○
Recurrence of symptoms during scheduled maintenance dosing following 
prior clinical benefit of the above biologics 
●
Note:  Subjects who discontinued biologics or tofacitinib for reasons 
other than inadequate response as defined above or intolerance 
(e.g., change of insurance) must meet the criteria for intolerance or 
inadequate response to aminosalicylates, oral locally acting steroids, 
systemic steroids (prednisone or equivalent), and/or 
immunomodulators as defined above 
5.
If female, subject must meet the criteria as stated in Section 5.2.4 of this protocol 
Contraception Recommendations.  Females of childbearing potential must have a 


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negative serum pregnancy test result during Screening, and a negative urine 
pregnancy at Baseline.  Females of non-childbearing potential (either 
postmenopausal or permanently surgically sterile as defined in Section 5.2.4) 
during Screening do not require pregnancy testing at Baseline. 
Note:  Subjects with borderline serum pregnancy test at Screening must have a 
serum pregnancy test ≥ 3 days later to document continued lack of a positive 
result.
6.
Subject must be able and willing to give written informed consent and to comply 
with the requirements of this study protocol.  In Japan, if the subject is under the 
legal age of adulthood, a subject's parent or legal guardian must be willing to give 
written informed consent. 
Rationale for Inclusion Criteria
1 – 4 
To select the adequate subject population with a disease status 
representative of the target population for evaluation 
5 
The impact of risankizumab on pregnancy and reproduction is unknown  
6 
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Subject with a current diagnosis of Crohn's disease (CD) or IBD-unclassified 
(IBD-U) or a history of radiation colitis or ischemic colitis.
Concomitant Medications and Treatments  
2.
Subject on oral UC-related antibiotics who has not been on stable doses for greater 
than, or discontinued within, 14 days prior to Baseline. 
3.
Subject on oral aminosalicylates who has not been on stable doses for greater than, 
or discontinued within, at least 14 days prior to Baseline. 


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4.
Subject taking oral corticosteroids: 
●
Budesonide > 9 mg/day 
●
Beclomethasone > 5 mg/day
●
Prednisone or equivalent > 20 mg/day 
●
Or has not been on the current course for ≥ 14 days prior to Baseline and on a 
stable dose for ≥ 7 days prior to Baseline
5.
Subject on immunomodulators (AZA, 6-MP, MTX) who: 
●
Has not been on the course for ≥ 42 days prior to Baseline, and
●
Has not been on a stable dose for ≥ 35 days prior to Baseline
Medications and Treatments During the Screening Period 
6.
Subject who received IV anti-infectives within 35 days prior to Baseline visit or 
oral anti-infectives (non-UC-related) within 14 days prior to the Baseline visit.  
This does not apply to TB prophylaxis. 
7.
Subject who received any parenteral nutrition within 35 days prior to Baseline. 
8.
Subject who received any live bacterial or viral vaccination within 35 days 
(8 weeks for Japan) prior to Baseline.
9.
Subject who received cyclosporine, tacrolimus, or mycophenolate mofetil within 
35 days prior to Baseline. 
10.
Subject who received fecal microbial transplantation within 35 days prior to 
Baseline.
Prior Medications and Treatments 
11.
Subject who received any: 
●
approved biologic agent (e.g., infliximab, adalimumab, golimumab, 
vedolizumab) within 8 weeks prior to Baseline. 
●
tofacitinib within 35 days prior to Baseline 


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●
any investigational agent or procedure within 35 days or 5 half-lives prior to 
the Baseline, whichever is longer or 
●
subject who is currently enrolled in another interventional clinical study 
12.
Subject with prior exposure to p40 inhibitors (e.g., ustekinumab [Stelara]) or p19 
inhibitors (e.g., risankizumab). 
13.
Subject has been taking combination of two or more of the following oral 
budesonide, oral beclomethasone, and/or oral prednisone (or equivalent) 
simultaneously, with the exception of inhalers, within 14 days prior to Screening 
or during the Screening period. 
14.
Subject who received IV/intramuscular corticosteroids within 14 days prior to 
Screening or during the Screening period. 
15.
Subject who received therapeutic enema or suppository (i.e., rectal 
aminosalicylates/corticosteroids), other than required for endoscopy, within 
14 days prior to Screening or during the Screening period. 
16.
Subject who received apheresis (e.g., Adacolumn apheresis) ≤ 60 days prior to 
Screening or during the Screening period. 
17.
Subject who has concomitant cannabis use either recreational or for medical 
reasons within 14 days prior to Baseline or any history of clinically significant 
drug, or alcohol abuse in the last 12 months. 
UC Related
18.
Extent of inflammatory disease limited to the rectum as assessed by screening 
endoscopy. 
19.
Subject with currently known complications of UC such as: 
●
fulminant colitis,
●
toxic megacolon, 
●
previous colectomy (total or subtotal), 


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●
or any other manifestation that might require surgery while enrolled in the 
study. 
20.
Subject with ostomy or ileoanal pouch. 
Safety
21.
Subject who has a known hypersensitivity to risankizumab or the excipients of any 
of the study drugs or the ingredients of Chinese hamster ovary (CHO). 
22.
Subjects with the following chronic or active infections:  
●
Active, chronic, or recurrent infection that based on the Investigator's clinical 
assessment makes the subject unsuitable candidate for the study,  
●
Infection with C. difficile toxin as identified during Screening,  
●
Known infection with an intestinal pathogen   
●
Are infected with human immunodeficiency virus (HIV),  
●
QuantiFERON®-TB test or Purified Protein Derivative (PPD) skin test, or 
both, according to local guidelines, will be performed during Screening.  
QuantiFERON®-TB test is preferred for subjects who received BCG 
vaccination or were exposed to other Mycobacteria species.  Subjects with a 
positive test result (or indeterminate results that have been repeated) may 
participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that the subject has no evidence 
of active tuberculosis.  Subjects with a history of active TB who have 
documented completion of a full course of anti-TB therapy may be allowed to 
enter the study after consultation with the AbbVie TA MD.  If latent TB is 
established, TB prophylaxis/treatment should be initiated and maintained 
according to local country guidelines, 
●
Have active hepatitis B or hepatitis C 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; 


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○
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-
HCV antibody (HCV Ab)
23.
Subject with a previous history of dysplasia of the gastrointestinal tract or found to 
have dysplasia, other than completely removed low-grade dysplastic lesions, in 
any biopsy performed during the Screening endoscopy. 
24.
Subject with a known history of lymphoproliferative disease, including 
lymphoma, or signs and symptoms suggestive of possible lymphoproliferative 
disease, such as lymphadenopathy and/or splenomegaly. 
25.
Subject with history of malignancy other than a successfully treated non-
metastatic cutaneous squamous cell or basal cell carcinoma or localized carcinoma 
in situ of the cervix. 
26.
Subject who has severe, progressive, or uncontrolled renal, hepatic, hematological, 
endocrine, disorder or symptoms thereof. 
27.
Female subjects who is pregnant, breastfeeding, or is considering becoming 
pregnant during the study or for approximately 140 days after the last dose of 
study drug. 
28.
Subject who has any condition, including any physical, psychological, or 
psychiatric condition, which in the opinion of the Investigator, would compromise 
the safety of the subject or the quality of the data and renders the subject an 
unsuitable candidate for the study. 
29.
Screening laboratory and other analyses show any of the following abnormal 
results:
●
Aspartate transaminase (AST), alanine transaminase (ALT) > 2 × upper limit 
of the reference range;
●
White blood cell (WBC) count < 3.0 × 109/L;
●
Total bilirubin ≥ 2 mg/dL; except for subjects with isolated elevation of 
indirect bilirubin relating to Gilbert's syndrome; 


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●
Estimated glomerular filtration rate by simplified 4-variable Modification of 
Diet in Renal Disease (MDRD) formula < 30 ml/min/1.73 m2.  
●
Hemoglobin < 8 g/dL 
●
Platelets < 100,000/µL 
●
Positive serum pregnancy test at the Screening visit or positive urine 
pregnancy test at the Baseline visit.
●
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 the previous result was never 
obtained. 
30.
No known active COVID-19 infection.  If a subject has signs/symptoms 
suggestive of COVID-19, they should undergo molecular (i.e., PCR) testing to 
rule out SARS-CoV-2 infection. 
Subjects who do not meet COVID-19 eligibility criteria must be screen failed and 
may only rescreen after they meet the following COVID-19 criteria:
●
Symptomatic subjects:  At least 14 days have passed since recovery, defined as 
resolution of fever without use of antipyretics and improvement in symptoms 
●
Asymptomatic subjects:  At least 14 days have passed since the first positive 
molecular (i.e., PCR) test result
Rationale for Exclusion Criteria
1 
To avoid medical conditions that may compromise the ability to identify 
subjects with the correct diagnosis or to interpret medical importance of 
clinical results
2 – 17 
To avoid bias for the evaluation of efficacy and safety by concomitant use 
of other medications or treatments and to ensure the safety of the subject 
18 – 20 
To avoid complications of UC that may compromise the evaluations of 
efficacy and safety
21 – 30 
To ensure the safety of the subject and or others 


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5.2.3
Prior and Concomitant Therapy
5.2.3.1
Prior Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject has received within 35 days prior to 
Baseline, is receiving at the time of enrollment, or receives during the study, must be 
recorded along with the reason for use, date(s) of administration including start and end 
dates, and dosage information including dose, route and frequency in source documents 
and the (electronic case report forms) eCRFs.
Ulcerative colitis disease specific medications (including but not limited to 
corticosteroids, aminosalicylates, immunosuppressant agents, and UC-related antibiotics) 
that the subject has received within 90 days of Baseline should be recorded on the 
appropriate page of the eCRF and should include the dates of administration and dosages.  
In addition, if a subject has ever received AZA, 6-MP, or MTX (oral or IM/SC), the 
duration of therapy, maximum dose, reason for use and reason(s) for termination of 
treatment will also be recorded in the appropriate eCRF. 
For all subjects with a history of biologic use for inflammatory bowel disease, the history 
of biologic use for inflammatory bowel disease, the history of previous use (including the 
names of biologic therapy used, duration of therapy, the highest known dose taken, reason 
for use and reason[s] for termination of treatment) of the biologic agent will be recorded 
in the appropriate eCRF. 
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding concomitant or prior therapy(ies). 
5.2.3.2
Concomitant Therapy
Subjects taking oral aminosalicylates, immunomodulators, and/or UC-related antibiotics 
at Baseline must continue their concomitant treatment for the duration of the study.  


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Initiating and/or increasing doses of oral aminosalicylates, immunomodulators, and/or 
UC-related antibiotics after Baseline is prohibited.  Decreasing doses of oral 
aminosalicylates, immunomodulators, and/or UC-related antibiotics is prohibited during 
the study, except in the event of moderate-to-severe treatment related toxicities in the 
opinion of the investigator.  UC-related antibiotics may be discontinued in the blinded 
Induction Period 2 at the discretion of the Investigator.  Rectal aminosalicylates are 
prohibited from 14 days prior to the screening period and for the entire duration of the 
study. 
Note:  the duration of the study includes the Induction Period 2. 
Concomitant Corticosteroids 
Subjects taking oral corticosteroids at Baseline must continue their concomitant treatment 
at the Baseline dose for the duration of Induction Period 1.  Initiation and/or increasing 
doses of systemic and/or UC related corticosteroids after Baseline is prohibited.  
Decreasing doses of oral corticosteroids is prohibited during Induction Period 1, except in 
the event of moderate-to-severe treatment related toxicities and after discussion with the 
AbbVie TA MD.
Subjects who receive blinded therapy in Induction Period 2 during Weeks 12 to 24 will be 
allowed to taper their corticosteroids at the discretion of the Investigator.  While stopping 
the taper is permitted, increasing doses above the Baseline dose is prohibited. 
Subjects may not be on both budesonide and prednisone (or equivalent) simultaneously, 
with exception of inhalers within 14 days prior to Screening. 
Rectal corticosteroids are prohibited from 14 days prior to the screening period and for the 
entire duration of the study. 
Changes in all concomitant medications will be assessed at each study visit from Baseline 
through Week 12/PD and during Weeks 12 to 24 visits for subjects who participate in the 


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blinded Induction Period 2.  Any changes will be documented in the source documents 
and captured on the appropriate eCRF page. 
Subjects should not be routinely pre-medicated prior to infusion of study drug.  If in the 
Investigator's judgment the subject requires pre-medication based on prior medical history 
or symptoms with prior infusions of study drug in the current study, pre-medication with 
diphenhydramine hydrochloride and acetaminophen (or equivalents) is permitted.  
Individual dosage, timing, and route of administration would be determined by the 
Investigator.  Any pre-medications administered must be recorded on the appropriate 
eCRF.
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding concomitant or prior therapy(ies). 
5.2.3.3
Prohibited Therapy
The following are prohibited medications during the study: 
●
All biologic therapy with a potential therapeutic impact on the disease being 
studied including but not limited to the following: 
○
Etanercept (Enbrel®);
○
Abatacept (Orencia®);
○
Anakinra (Kineret®);
○
Rituximab (Rituxan®);
○
Natalizumab (Tysabri®);
○
Tocilizumab (Actemra®);
○
Ustekinumab (Stelara®);
○
Belimumab (Benlysta®);
○
Infliximab (Remicade®);
○
Certolizumab pegol (Cimzia®);
○
Golimumab (Simponi®);
○
Adalimumab (Humira®) 


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○
Vedolizumab (Entyvio®);
○
Tofacitinib (Xeljanz®);
●
Investigational agents (e.g., baracitinib, filgotinib) 
●
Live or attenuated vaccines are NOT allowed during the study and for 
140 days after the last dose of study drug.  Examples of such vaccines include 
but are not limited to the following:
○
live attenuated influenza
○
herpes zoster, (e.g., Zostavax®) 
○
rotavirus 
○
varicella (chicken pox)
○
measles-mumps-rubella (MMR) or measles mumps rubella varicella 
(MMRV)
○
oral polio vaccine (OPV) 
○
smallpox
○
yellow fever 
○
Bacille Calmette-Guérin (BCG)
○
oral typhoid 
●
Oral or systemic cyclosporine, tacrolimus, or mycophenolate mofetil 
●
Concomitant cannabis use either recreational or for medical reasons.
●
Rectal therapy with any therapeutic enemas or suppositories (i.e., rectal 
aminosalicylates/corticosteroids), with the exception of those required for 
endoscopy, is prohibited during the study. 
●
Apheresis (e.g., Adacolumn apheresis) 
●
Any parenteral nutrition. 
●
Any fecal microbial transplant 
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding prohibited therapy. 


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5.2.4
Contraception Recommendations and Pregnancy Testing
If female, subject must be either postmenopausal defined as: 
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L.
○
or,
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
○
or for women of childbearing potential (WOCBP): 
○
Practicing at least one of the following methods of birth control, on 
Baseline (or earlier) through at least 140 days after the last dose of study 
drug. 
○
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal, injectable) associated with the inhibition of 
ovulation, initiated at least 1 month prior to Baseline. 
○
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation initiated at least 1 month prior to 
Baseline.
○
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure). 
○
Vasectomized partner(s), (the vasectomized partner should have received 
medical assessment of the surgical success and is the sole sexual partner of 
the trial participant)
○
Intrauterine device (IUD).
○
Intrauterine hormone-releasing system (IUS).
○
True abstinence, refraining from heterosexual intercourse when this is in 
line with the preferred and usual lifestyle of the subject.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable.


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5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Optional 
Exploratory Research and Safety Assessments/Variables
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 the optional exploratory research (discussed in Section 5.3.2.1 and 
Appendix D), pharmacokinetics and pharmacodynamics (discussed in Section 5.3.2), and 
the collection of AE information (discussed in Section 6.1.4).  All study data will be 
recorded in source documents and on the appropriate eCRFs. 
Study visits may be impacted by changes in local regulations due to the COVID-19 
pandemic or geo-political conflict in Ukraine and surrounding impacted regions.  This 
may include changes such as phone or virtual visits, visits at alternative locations, or 
changes in the visit frequency and timing of study procedures, among others.  Every effort 
should be made to ensure the safety of subjects and site staff, while maintaining the 
integrity of the study. 
Informed Consent
At the Screening visit, the subject will sign and date a study specific, Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) approved, informed consent form 
before any study procedures are performed or any medications are withheld from the 
subject in order to participate in this study.  A separate informed consent will be required 
for each subject in order to participate in the optional exploratory research.  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 or the geo-political conflict in Ukraine and surrounding 
impacted regions, modifications to the protocol may be necessary.  Subjects should be 
informed of the changes to the conduct of the study relevant to their participation (e.g., 
cancellation of visits, change in laboratory testing site, etc.).  Documentation of this 
notification or verbal consent should be maintained at the site as required per local 
regulatory requirements.  A signed and dated informed consent form should be obtained 
from the subject afterwards as soon as possible. 
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at both Screening and Baseline visits.
Medical and Surgical History
A complete medical and surgical history, including UC-onset date, history of UC 
medication use, and history of alcohol and tobacco use will be obtained from each subject 
at the Screening Visit.  An updated medical history will be obtained prior to study drug 
administration at Baseline, to ensure the subject is still eligible for enrollment, and 
updated as necessary. 
Information on prior therapy for UC use will be obtained as outlined in Section 5.2.3.1. 
A detailed medical history with respect to TB exposure will be documented.  This 
information will include BCG vaccination, cohabitation with individuals who have had 
TB, and residence or work in TB endemic locations.  Subjects with a documented history 
of active TB who have documented completion of a full course of anti-TB therapy may be 
allowed to enter the study after consultation with the AbbVie TA MD.  TB history and 
anti-TB therapy needs to be documented in the source documents and eCRFs.  Physical 
Examination.


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Physical Examination 
A physical examination including evaluation of extra-intestinal manifestations (EIMs) 
will be performed at the designated study visits as specified in Appendix C. 
A full physical examination will be performed as outlined in Appendix C and must 
include an assessment of EIMs.  Symptom-based physical examinations will be performed 
at all other visits.
The physical examination at the Baseline Visit will serve as the Baseline physical 
examination for the entire study.  Abnormalities noted after the Baseline Visit and first 
dose of study drug will be evaluated and documented by the Investigator as to whether or 
not these are adverse events.  All findings whether related to an adverse event or part of 
each subject's medical history will be captured on the appropriate eCRF page. 
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate, respiratory rate, and body temperature will be obtained at each visit 
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.
Blood pressure, pulse rate, respiratory rate and weight should be measured before blood 
draws are performed.
TB Testing
All subjects will be tested for TB by either the QuantiFERON-TB Gold Test (or 
equivalent) or a TB Skin Test (PPD), or both, according to local guidelines, as specified in 
Appendix C. 


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For subjects treated with corticosteroids (equivalent to Prednisone 5 mg or above – with 
ongoing treatment or treatment within 1 month prior to TB screening), an 
Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold In-Tube test) must be 
performed during the Screening Period for all subjects including those with a prior history 
of Bacille Calmette-Guérin (BCG) administration or who were exposed to other 
Mycobacterial species.
For subjects NOT treated with corticosteroids (equivalent to Prednisone 5 mg or above – 
with ongoing treatment or treatment within 1 month prior to TB screening), a PPD skin 
test (alternatively, also known as tuberculin skin test) must be placed, or alternatively an 
Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold In-Tube test or 
T-SPOT TB test) must be performed during the Screening Period for all subjects.  IRGA 
is preferred for subjects with a prior history of Bacille Calmette-Guérin (BCG) 
administration or who were exposed to other Mycobacteria species. 
If PPD and/or the QuantiFERON®-TB Gold test (or IGRA equivalent) is positive, or if 
there is a repeat indeterminate (note:  the first indeterminate results must be repeated) 
QuantiFERON®-TB Gold test (or IGRA equivalent) upon retesting, subjects may 
participate in the study if further work up (according to local practice/guidelines) 
establishes conclusively that the patient has no evidence of active tuberculosis.  If active 
TB is diagnosed, the subject may not enroll in the study.  If presence of latent tuberculosis 
is established, then tuberculosis prophylaxis should be pursued according to clinical 
judgment of Investigator and local country guidelines.  It is also necessary to report the 
latent TB or positive TB testing in the source documents and eCRFs.  
●
QuantiFERON®-TB Gold Test is the preferred method which will be analyzed 
by the central laboratory (QuantiFERON test is preferred over TB Skin Test).  
However, if other IGRA equivalent tests are used, these may be performed by 
a certified local laboratory at the Investigator's discretion. 
●
If the QuantiFERON®-TB Gold Test is NOT possible (or if both the 
QuantiFERON®-TB Gold Test and the PPD Skin Test are required per local 


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guidelines) the PPD Skin Test will be performed according to standard clinical 
practice.  
○
The PPD 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 an ulcerating reaction to the TB Skin Test in the past 
should not be re-exposed and should not be tested by a PPD skin test. 
●
In the case of a tuberculosis-related AE, a supplemental eCRF that provides 
additional information should be completed by the Investigator or designee. 
If a CXR or other diagnostic tests are required to be performed to assess TB per local 
guidelines, this information will also be captured on the appropriate eCRF. 
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed during Screening as specified in Appendix C.  
A qualified physician will interpret the clinical significance of any abnormal finding, sign, 
and date each ECG.  ECG findings, including 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 clinical research associate 
(CRA) 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.  If there are 
other findings that are clinically significant, the Investigator must bring this to the 
attention of the AbbVie TA MD before the subject can be enrolled. 
Subjects can have a repeat ECG at any time during the study as warranted, based on the 
opinion of the Investigator. 


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Clinical Laboratory Tests 
Blood samples will be obtained for the laboratory tests listed in Table 1.  Blood draws 
should be performed, as much as possible, after vital signs, efficacy assessments and 
questionnaires (IBDQ, etc.) are obtained during a visit.  Blood draws should be performed 
before study drug administration. 
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  All abnormal laboratory tests that are considered clinically significant by 
the Investigator will be followed to a satisfactory resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing and shipping of these samples. 
For serum chemistry tests, it is preferred that the subject has fasted (8 hours, except for 
water) prior to sample collection, however it is not required.  It must be recorded whether 
the subject has fasted or not at the time of collection in the laboratory request, source 
document, and eCRF. 
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic or the geo-political conflict in Ukraine and surrounding impacted regions 
prevent the subject from having blood drawn for laboratory testing at the study site, if 
possible, arrange for subjects to have laboratory work done at a local lab, hospital, or 
other facility.  Local lab results should be obtained along with reference ranges and kept 
within the subjects' source documentation.  Local lab results should be reviewed by the 
investigator as soon as possible. 
If laboratory samples cannot be obtained, study drug administration may be continued 
provided the investigator has reviewed all prior laboratory results and confirms and 
discusses with the subject that there is no safety concern for the subject to continue use of 
the study drug in the absence of current labs. 


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Table 1. 
Clinical Laboratory Tests 
Hematology
Clinical Chemistrya
Screening Blood Tests
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
WBC Differential
Platelets
General:
Sodium
Potassium
Chloride
Bicarbonate (CO2) 
Urea (BUN)
Creatinine
Glucose
Additional Chemistry Tests:
Calcium
Phosphate
Total Protein
Albumin
Aspartate aminotransferase 
(AST)
Alanine aminotransferase (ALT)
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
(GGT/γ-GT)
Bilirubin Total and Direct
Lipid Panel:
Cholesterol (total, LDL, and 
HDL)
Triglycerides
Additional Calculations:
eGFR by simplified 4-MDRD 
(estimated by CKD-EPI 
formula; for Japan)c 
HBsAg
anti-HBs Ab
anti-HBc Ab
HBV DNA PCR reflex only
anti-HCV Ab
HCV RNA reflex only
QuantiFERON-TB Gold or PPD 
Test
HIV-1 and HIV-2 
Urinalysisb
Leukocyte esterase
Nitrite
pH
Protein
Blood 
Specific Gravity 
Ketones
Glucose
Bilirubin
Other Laboratory Tests:
Serum pregnancy (bHCG) test
Urine pregnancy test (Local)
Optional:  FSH, if needed to 
confirm postmenopausal 
status
Tryptasee,f
Histaminee,f
Biopsy
Histopathology scoring
Biomarkers:
High-Sensitivity C-Reactive 
Protein (hs-CRP)
Optional Biomarkers:
Blood, tissue and stool will be 
collected for optional 
exploratory research in 
countries/sites that allow it
Stool Samples:
C. difficile toxin
Fecal calprotectin (FCP)
PK/Immunogenicity:
Serum risankizumab
Serum anti-drug antibodies 
(ADA)e
Serum neutralizing antibodies 
(nAb)
Coagulation
INRd
a.
It is preferred that the subject has fasted (8 hours, except for water) prior to sample collection, however it is not 
required.
b.
A microscopic analysis will be performed by the central laboratory in the event the dipstick results listed show 
leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.


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Table 1. 
Clinical Laboratory Tests (Continued) 
c.
Calculated by the central laboratory.
d.
INR test only drawn if ALT or AST > 3 × ULN (upper limit of normal) and Total Bilirubin ≤ 2 × ULN.  Please 
refer to Section 5.4.1 for further information.
e.
To be done with the occurrence of a suspected anaphylactic reaction.  Refer to anaphylaxis testing Section 5.3.1.1
below.  For ADA these samples are collected in addition to those specified in Appendix C. 
f. 
Tryptase and histamine will not be taken in China.
Hepatitis B Testing
All subjects will be tested for the presence of the HBV at Screening.  A positive result for 
the Hepatitis B surface antigen (HBs Ag) will be exclusionary.  Samples that are negative 
for HBs Ag will be tested for surface antibodies (HBs Ab) and core antibodies (HBc Ab 
Total).  Subjects with HBs Ag (–), HBs Ab (–), and HBc Ab Total (+) require PCR 
qualitative testing for HBV DNA.  Any HBV DNA PCR result that meets or exceeds 
detection sensitivity will be exclusionary.
Subjects with a negative HBs Ag test and tests showing the results below do not require 
HBV DNA PCR qualitative testing:
●
HBc Ab Total (–) and HBs Ab (–) 
●
HBc Ab Total (–) and HBs Ab (+) 
●
HBc Ab Total (+) and HBs Ab (+) 
For Japan and China only:  for subjects with HBs Ab (+) and/or HBc Ab (+) at Screening, 
the HBV-DNA PCR test should be performed again at Week 12 and Week 24.  In cases 
where the recurrence of HBV-DNA is observed, the subject should be discontinued from 
the study drug.  Retesting at Week 12 and Week 24 is not necessary for subjects that have 
a history of HBV vaccine and are HBs Ab (+). 


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Hepatitis C Testing
All subjects will be tested for the presence of the hepatitis C Virus (HCV) antibody at 
Screening.  Subjects with positive HCV antibody will have an HCV RNA test.  If the 
HCV RNA is positive then the subject will be excluded.
HIV
Subjects with a known history of HIV infection are excluded from study participation.  
HIV testing will be conducted as part of the infection screening at the Screening visit.  
The Investigator must discuss any local reporting requirements to local health agencies 
with the subject.  The site will report these 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 be referred for clinical care promptly.  A subject will not be eligible for study 
participation if test results indicate a positive HIV infection.  AbbVie will not receive 
results from the testing.  This testing is to be done at the central lab.
Anaphylaxis Testing 
In the event of a suspected systemic post-dose hypersensitivity reaction, a serum 
risankizumab, ADA, and neutralizing antibody (nAb) sample should be collected once 
within 24 hours of the reaction. 
In addition to serum risankizumab, ADA, and nAb assays, in all countries except in China 
blood tests to be conducted in the event of a systemic hypersensitivity reaction are: 
●
Tryptase:  Optimally, measurement needs to be obtained from 15 minutes to 
3 hours of symptom onset, and no later than 6 hours (as tryptase may remain 
elevated for 6 or more hours after the onset and therefore may still be 
informative if obtained after 3 hours); it is also requested to collect a follow-up 
tryptase level a minimum of 2 weeks after the recorded event or at the next 
study visit. 


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●
Plasma histamine:  optimally, within 5 to 15 minutes of the onset of 
symptoms, and no later than 1 hour. 
Stool Samples Collected:
If the investigator has a reasonable suspicion of a gastrointestinal infection they should 
ensure this has been excluded prior to screening the subject. 
Fecal Calprotectin (FCP)
Fecal calprotectin will be performed for all subjects as indicated in Appendix C.  If 
subjects are unable to provide a sample at the site visit, subjects will be sent home with a 
stool sample supply kit and the site will give instructions to assist with collection 
procedures.  If the fecal calprotectin sample is collected during the Screening period it 
may be used as the Baseline All stool samples should be collected before any bowel 
preparation for endoscopy is started and returned to the site within 3 days of collection. 
The FCP results will remain blinded to Investigator, study site personnel and the subject 
throughout the study. 
The central laboratory will be utilized to process and provide results for these laboratory 
tests.  In order to maintain the study blind, local laboratory testing for FCP for routine 
subject monitoring should not be performed. 
C. Difficile Stool Testing
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 laboratory manual provided by the central laboratory. 
Subjects who are positive for C. difficile toxin may be treated appropriately and 
re-screened.


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Urinalysis
Dipstick urinalysis will be completed by the sites 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. 
Pregnancy Testing
A serum pregnancy test will be performed for all female subjects of childbearing potential 
during Screening. 
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 to determine eligibility ≥ 3 days later.  
If the repeat serum pregnancy test is:
●
Positive, the subject is considered a screen failure; 
●
Negative, the subject can be enrolled into the study; 
●
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 (unless prohibited locally) in the absence of clinical suspicion of 
pregnancy and other pathological causes of borderline results.
A urine pregnancy test will be performed for all WOCBP as indicated in Appendix C, 
prior to study drug administration.  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 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.  If the serum pregnancy test is positive, 


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study drug must be withheld and the subject must be discontinued from the 
study.  In the event a pregnancy test result is borderline, a repeat test is 
required. 
●
If a urine pregnancy test post-baseline is positive, study drug will be 
temporarily discontinued 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 restarted.  If the serum 
pregnancy test is positive, study drug will be permanently discontinued. 
A pregnant or breastfeeding female will not be eligible for participation or continuation in 
this study or be allowed to continue study drug. 
High-Sensitivity C-Reactive Protein (hs-CRP)
Blood samples for hs-CRP will be obtained per Appendix C.  The hs-CRP results will 
remain blinded to Investigator, study site personnel and the subject. 
Blood draws should be performed, as much as possible, after all efficacy assessments, 
questionnaires (IBDQ, etc.), and vital sign determinations are obtained and before study 
drug administration during a visit.  Local laboratory or site testing for hs-CRP is not 
allowed.
Full Mayo Score, Adapted Mayo Score, Adapted Partial Mayo Score 
Data from the subject diaries will be collected in order to calculate Full Mayo Score, 
Adapted Mayo Score, and Adapted Partial Mayo Score at the time points indicated in 
Appendix C. 
Detailed information about Full Mayo Score, Adapted Mayo Score, and Adapted Partial 
Mayo Score can be found in Appendix E. 
Whenever possible, the same physician (Investigator or Sub-Investigator) should 
determine the Physician's Global Assessment (PGA) subscore for an individual subject 
through the duration for the study.  The directions for capturing the stool frequency 


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subscore, rectal bleeding subscore, and PGA subscores of the Full Mayo Score, Adapted 
Mayo Score, and Adapted Partial Mayo Score are described in Appendix F. 
Endoscopy
An endoscopy will be performed on the following visits: 
●
During Screening* 
●
Week 12/PD
●
Week 24 (subjects in Induction Period 2 only) 
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.  It is expected that all subjects who remain in the study through at least Week 8 will 
have a Week 12/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: 
●
biopsy confirmation of the diagnosis is available according to section "Biopsy 
During Endoscopy" below, as applicable. 
●
the endoscopy took place within 45 days prior to Baseline visit. 
●
the endoscopy was recorded in a video format as the endoscopic eligibility will 
be determined by the central reviewers.
A full colonoscopy will be performed at Screening unless the subject underwent a full 
colonoscopy within 12 months prior to Screening.  There must be appropriate 
documentation available to confirm the diagnosis, extent of disease, and to exclude 
dysplasia and colon cancer.  If this is available, the screening endoscopy may be either a 
full colonoscopy or a flexible sigmoidoscopy.  All other endoscopies may be flexible 
sigmoidoscopies or colonoscopies at the discretion of the investigator. 


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All endoscopies will be performed and recorded at the site in a video format.  Videos from 
subjects with eligible Mayo endoscopic sub-scores during Screening and all videos from 
subjects at Week 12 and Week 24 will be sent to a central review vendor and scored as 
described in the central review charter.  Endoscopies will be evaluated using the Mayo 
endoscopic subscore.  The Mayo endoscopic subscore, including the presence or absence 
of friability will be documented by the endoscopist at the site and maintained in the 
subject's source documents.  If, in the assessment of the site endoscopist, the Screening 
endoscopy does not indicate an endoscopy subscore of 2 or 3 or the extent of 
inflammation is limited to the rectum, per eligibility requirements, the subject should be 
screen-failed and the video should not be sent for central reading.  In addition to the Mayo 
endoscopy subscore, the central reader will assess the endoscopy findings using the 
Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scoring system for additional 
exploratory analyses. 
Endoscopies completed at Week 12 and Week 24, for those subjects who undergo blinded 
therapy in Induction Period 2, will use the local reader results to evaluate clinical response 
for enrollment in maintenance Study M16-066, as well as for stratification based on 
clinical remission for maintenance Study M16-066. 
There will be a window of ± 7 days to conduct the endoscopy. 
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic or the geo-political conflict in Ukraine and surrounding impacted regions 
prevent the subject from performing endoscopy at the study site at Week 12 or Week 24, 
if possible, arrange for subjects to have endoscopy done at an alternate facility.  The 
endoscopist at the alternate facility should be trained using the study training materials.  
Endoscopy score should be read by an endoscopist already trained on the protocol 
requirements at the study site.
Every effort should be made to conduct endoscopy at Week 12 or Week 24, however, if 
endoscopy cannot be performed due to the COVID-19 pandemic restrictions or the 


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geo-political conflict in Ukraine and surrounding impacted regions, clinical response will 
be calculated using the Partial Adapted Mayo score.
Biopsy During Endoscopy
The following biopsies should be obtained during the study: 
Biopsy for histopathology Scoring:  All subjects will have two biopsies taken from an 
area of the rectosigmoid segment of the colon that represents the general degree of 
mucosal inflammation for histopathological scoring at each visit with endoscopy.  The 
same histopathological biopsy samples collected for the main study may be used for 
exploratory research (Section 5.3.1.2) only if subjects provide additional consent. 
Optional biopsy for RNA analysis:  subjects who consent to participate in the optional 
RNA biopsies sub-study, will have two additional biopsies taken from an area of the 
rectosigmoid colon that represents the general inflammation in the segment at each visit 
with endoscopic procedures. 
Histopathology scoring and RNA analysis biopsies, will be sent to the central laboratory 
for further analysis, except in China.  The central laboratory chosen for this study will 
provide instructions regarding the collection, processing and shipping of these samples.
Additionally, appropriate documentation of biopsy results consistent with the diagnosis of 
UC, in the assessment of the Investigator, must be available in order to confirm the 
subject's eligibility for the study.  If this documentation is not available, a diagnostic 
biopsy from the most affected observed area of the colon must be performed during the 
Screening endoscopy and read by a qualified local pathologist and the results reviewed by 
the Investigator. 
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. 
The signed pathology report will be monitored by the responsible Clinical Research 
Associate (CRA) 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. 
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 M16-066. 
Completion will be reinforced during study visits as necessary. 
Outcomes and Questionnaires
Subjects will be asked to complete the following electronic questionnaires/outcomes at the 
time points indicated in Appendix C. 
●
IBDQ – Inflammatory Bowel disease Questionnaire


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●
WPAI-UC – Work Productivity and Activity Impairment Questionnaire 
Ulcerative Colitis
●
FACIT-F – Functional Assessment of Chronic Illness Therapy-Fatigue 
●
EQ-5D-5L – European Quality of Life 5 Dimensions 
●
SF-36 – Short Form 36 
●
PGIC – Patient Global Impression of Change 
●
PGIS – Patient Global Impression of Severity
●
UC-SQ – UC-Symptom Questionnaire
Due to the COVID-19 pandemic and any local restrictions or the geo-political conflict in 
Ukraine and surrounding impacted regions, sites may administer PRO instruments over 
the phone as needed.  Sites may read the PRO questions and response options to the 
subject and record the subject's responses.  Sites may 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 who collected the information. 
Study Drug Dispensing/Administration
Intravenous and SC study drug will be administered to all subjects on-site.  For WOCBP 
subjects, the urine pregnancy test needs to be negative prior to receiving study drug.  The 
site will be provided administration instructions.  If an anaphylactic reaction or other 
serious allergic reaction occurs, administration of study drug should be discontinued 
immediately, appropriate laboratory testing samples drawn and appropriate therapy 
initiated.  The patient should be assessed for the presence of discontinuation criteria in 
Section 5.4.1. 
Study drug kits are assigned by the IRT following the subjects randomized treatment 
schedule.  (Refer to Section 5.5 for additional information). 


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Interruption/Discontinuation of Study Drug Due to COVID-19 or Geo-Political 
Conflict in Ukraine and Surrounding Impacted Regions
Continuation of study drug dosing due to a subject with COVID-19 must be discussed 
with the AbbVie medical contact, along with the possibility of premature discontinuation 
from the study drug dosing period.  Follow subsequent protocol Section 5.4.1 for subjects 
who discontinued study drug. 
Delays in study drug dosing due to the geo-political conflict in Ukraine and surrounding 
impacted regions must be discussed with the sponsor medical contact, along with the 
possibility of premature discontinuation from study drug.  The investigator should contact 
the sponsor medical contact before discontinuing a subject from the study for a reason 
other than described in the protocol to ensure all acceptable mitigation steps have been 
explored. 
5.3.1.2
Collection and Handling of Optional Exploratory Research 
Samples
Subjects will have the option to provide samples for exploratory research.  Subjects may 
still participate in the study even if they decide not to participate in the 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 optional samples in 
a secure storage space with adequate measures to protect confidentiality.  The samples 
will be retained while research on risankizumab (or drugs of this class) or UC and related 
conditions continues, but for no longer than 20 years after study completion. 
The following samples will be collected according to Appendix D from each subject who 
consents to provide samples: 
●
DNA samples for pharmacogenetic or epigenetic analyses
●
RNA samples for transcriptomic and/or epigenetic analyses 


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●
Serum and plasma samples for systemic analyses including, but not limited to 
proteomics and metabolomics
●
Stool samples for investigations including, but not limited to, proteomics, 
metabolomics, transcriptomics and metagenomics
●
Intestinal biopsies for pathological and biological investigations, including but 
not limited to transcriptomic and immunohistochemical analyses.
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. 
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Serum risankizumab concentrations, ADA, and neutralizing antibodies (nAb) will be 
determined from blood collected by venipuncture just prior to dosing as indicated in 
Appendix C.  The time that each blood sample is collected will be recorded to the nearest 
minute in the source document and on the central lab requisition form. 
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood/serum samples and subsequent preparation 
and storage of the samples for the assays will be provided by the central laboratory, 
AbbVie, or its designee. 
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment. 
5.3.2.3
Disposition of Samples
Frozen samples will be packed in dry ice (pellet form) sufficient to last 3 days during 
transport.  Samples will be shipped pursuant to instructions from the onsite CRA.  An 
inventory of the samples will be included in the package for shipment.  Arrangements will 
be made with the central lab for the transfer of samples.


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5.3.2.4
Measurement Methods
Serum concentrations of risankizumab and relative titers of risankizumab ADA will be 
determined using validated methods under the supervision of the Bioanalysis department 
at AbbVie.  Any additional analytes may be analyzed using non-validated methods.
Serum samples collected for risankizumab and risankizumab ADA and risankizumab nAb 
analysis may be used for future assay development or validation activities. 
The nAb samples upon request may be used for the analysis of neutralizing anti-drug 
antibodies in a validated assay. 
5.3.3
Efficacy Variables
Endpoints definition (Substudy 1 & 2): 
●
Clinical Remission per Adapted Mayo:  stool frequency subscore (SFS) ≤ 1, 
and not greater than baseline, rectal bleeding subscore (RBS) = 0, and 
endoscopic subscore ≤ 1 without the evidence of friability
●
Clinical Response per Adapted Mayo:  decrease from Baseline ≥ 2 points 
and ≥ 30%, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1
●
Clinical Response per Partial Adapted Mayo (without endoscopy):  
decrease from Baseline ≥ 1 points and ≥ 30%, PLUS a decrease in RBS ≥ 1 or 
an absolute RBS ≤ 1
●
Clinical Remission per Full Mayo:  Full Mayo score ≤ 2 with no 
subscore > 1 
●
Endoscopic Improvement:  endoscopy subscore of 0 or 1 without the 
evidence of friability
●
Endoscopic Remission: endoscopic subscore = 0
●
Histologic Remission:  Geboes score of < 2.0
●
Histologic Endoscopic Mucosal Remission (HEMR): Endoscopy subscore 
of 0 and Geboes score < 2.0 
●
Histologic Endoscopic Mucosal Improvement (HEMI): endoscopic 
subscore of 0 or 1 without the evidence of friability and Geboes score ≤ 3.1 


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Note:  Evidence of friability during endoscopy in subjects with otherwise 
"mild" endoscopic activity will confer an endoscopic subscore of 2. 
5.3.3.1
Primary Variable
The achievement of clinical remission per Adapted Mayo score at Week 12.
5.3.3.2
Secondary Variable
Secondary Endpoints for Sub-Study 1 (Phase 2b): 
1.
The achievement of endoscopic improvement at Week 12
2.
The achievement ofclinical remission per Full Mayo score at Week 12 in subjects 
with a Full Mayo score of 6 to 12 at Baseline 
3.
The achievement of clinical response per Adapted Mayo score at Week 12
4.
The achievement of clinical response per Partial Adapted Mayo score at Week 4
5.
The achievement of endoscopic remission at Week 12
6.
Occurrence of hospitalizations through Week 12 
7.
The achievement of HEMR at Week 12
8.
Change from Baseline to Week 12 in UC-Symptom Questionnaire (UC-SQ) 
9.
Change from Baseline to Week 12 in Inflammatory Bowel Disease Questionnaire 
(IBDQ) 
10.
Change from Baseline to Week 12 in Short Form-36  
11.
Change from Baseline to Week 12 in Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-Fatigue)   
12.
UC-related surgeries through Week 12


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Secondary Endpoints for Sub-Study 2 (Phase 3) 
1.
The achievement of clinical response per Adapted Mayo score at Week 12
2.
The achievement of endoscopic improvement at Week 12
3.
The achievement of histologic endoscopic mucosal improvement (HEMI) at 
Week 12 
4.
The achievement of endoscopic remission at Week 12
5.
The achievement of clinical response per Partial Adapted Mayo score at Week 4
6.
The achievement of no bowel urgency at Week 12 
7.
The achievement of no abdominal pain at Week 12 
8.
The achievement of histologic endoscopic mucosal remission (HEMR) at Week 12 
9.
Change from Baseline to Week 12 in Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-Fatigue) 
10.
Change from Baseline to Week 12 in Inflammatory Bowel Disease Questionnaire 
(IBDQ) total score
11.
Occurrence of UC-related hospitalizations through Week 12 
12.
The achievement of no nocturnal bowel movements at Week 12
13.
The achievement of no tenesmus at Week 12
14.
Change from Baseline to Week 12 in number of fecal incontinence episodes per 
week
15.
Change from Baseline to Week 12 in number of days per week with sleep 
interrupted due to UC symptoms. 


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Additional Endpoints for Sub-study 2: 
Induction Period 1
●
The achievement of SFS = 0, RBS = 0, and endoscopic subscore = 0 at 
Week 12 
●
The achievement of SFS ≤ 1 at Week 4, Week 8, Week 12 respectively
●
The achievement of RBS = 0  at Week 4, Week 8, Week 12 respectively
●
The achievement of clinical response per Partial Adapted Mayo score at 
Week 8, Week 12 respectively
●
Change from Baseline to Week 12 in Full Mayo score 
●
Change from Baseline in SFS at Week 4, Week 8, Week 12 respectively
●
Change from Baseline in RBS  at Week 4, Week 8, Week 12 respectively
●
Change from Baseline in hs-CRP at Week 4, Week 8, Week 12 respectively 
●
Change from Baseline in FCP at Week 4, Week 12 respectively
●
Change from Baseline to Week 12 in UCEIS 
●
The achievement of histologic remission at Week 12
●
Change from Baseline to Week 12 in European Quality of Life 5 Dimensions 
(EQ-5D-5L) 
●
Change from Baseline to Week 12 in Work Productivity and Impairment 
Questionnaire – UC (WPAI-UC) 
●
Change from Baseline to Week 12 in UC-SQ
●
The achievement of IBDQ remission (IBDQ total score ≥ 170) at Week 12
●
The achievement of IBDQ response (increase of IBDQ ≥ 16 from Baseline) at 
Week 12
●
Time to clinical response per Partial Adapted Mayo
●
Change from baseline in PGIS at Week 4, Week 8, Week 12 respectively
●
PGIC at Week 4, Week 8, Week 12 respectively
●
UC-related surgeries through Week 12
●
The achievement of clinical response per Adapted Mayo score at Week 12 in 
subjects with pancolitis at Baseline


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●
Change from Baseline to Week 12 in Short Form-36 (SF-36) 
●
The achievement of clinical remission per Full Mayo score at Week 12 in 
subjects with a Full Mayo score of 6 to 12 at Baseline 
Induction Period 2
●
The achievement of clinical remission per Adapted Mayo at Week 24
●
The achievement of clinical remission per Full Mayo score at Week 24 in
subjects with a Full Mayo score of 6 to 12 at Baseline 
●
The achievement of clinical response per Adapted Mayo score at Week 24
●
The achievement of no abdominal pain at Week 24 
●
The achievement of no bowel urgency at Week 24 
●
The achievement of endoscopic remission at Week 24
●
The achievement of endoscopic improvement at Week 24
●
Change from Baseline to Week 24 in Inflammatory Bowel Disease
Questionnaire (IBDQ) total score
●
Change from Baseline to Week 24 in Functional Assessment of Chronic 
Illness Therapy-Fatigue (FACIT-Fatigue) 
●
The achievement of histologic endoscopic mucosal improvement at Week 24 
●
The achievement of no nocturnal bowel movements at Week 24
●
The achievement of no tenesmus at Week 24
●
Change from Baseline to Week 24 in number of fecal incontinence episodes 
per week
●
Change from Baseline to Week 24 in number of days per week with sleep 
interrupted due to UC symptoms 
●
The achievement of clinical response per Adapted Mayo score at Week 24 in
subjects with pancolitis at Baseline
●
Occurrence of UC-related hospitalizations through Week 24 
●
Change from Baseline to Week 24 in Short Form-36 (SF-36) 
●
The achievement of SFS ≤ 1 at Week 16, Week 20, Week 24 respectively
●
The achievement of RBS = 0 at Week 16, Week 20, Week 24 respectively


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●
Change from Baseline in Partial Adapted Mayo score at Week 16, Week 20, 
Week 24 respectively
●
Change from Baseline in SFS at Week 16, Week 20, Week 24 respectively
●
Change from Baseline in RBS at Week 16, Week 20, Week 24 respectively 
●
Change from Baseline in hs-CRP at Week 24
●
Change from Baseline in FCP at Week 24
●
Time to clinical response per Partial Adapted Mayo
●
Change from baseline in PGIS at Week 16, Week 20, Week 24 respectively 
●
PGIC at Week 16, Week 20, Week 24 respectively 
5.3.4
Safety Variables
Incidence of adverse events, changes in vital signs, electrocardiogram, physical 
examination results, and clinical laboratory data will be assessed throughout the study. 
5.3.5
Pharmacokinetic Variables
Serum risankizumab concentrations will be determined during the treatment period as 
outlined in Appendix C.  Serum risankizumab concentrations will be summarized at each 
time point for each dosing regimen using descriptive statistics.  As appropriate, population 
pharmacokinetic analysis analyses combining the data from this study and other studies 
may be performed.  Relationships between risankizumab exposures and efficacy and 
safety variables of interest may be explored and/or any additional analyses may be 
performed.
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.  Biomarker assessments may be 
used to assess and generate prognostic, predictive, pharmacodynamic, or surrogate 


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biomarker signatures.  These assessments may be explored in the context of UC or related 
conditions and/or risankizumab or drugs of similar classes. 
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. 
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
A subject may withdraw from the study at any time.  The Investigator may discontinue 
any subject's participation for any reason, including an adverse event, safety concerns or 
failure to comply with the protocol. 
Subjects will be withdrawn from the study immediately if any one of the following 
occurs:
●
Clinically significant abnormal laboratory result(s) or adverse event(s), 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 
Induction Period 2.
●
The subject requests withdrawal from the study. 
●
The subject experiences a severe systemic hypersensitivity infusion/injection 
reaction or anaphylaxis. 
●
Inclusion and exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study would place the subject at risk as 
determined by the AbbVie Therapeutic Area Medical Director.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie 
Therapeutic Area Medical Director.
●
The subject becomes pregnant while on study drug. 


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●
Subject has a malignancy, except for localized non-melanoma skin cancer.  
Discontinuation for carcinoma in-situ of the cervix is at the discretion of the 
Investigator. 
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial, as determined by the 
Investigator, in consultation with the AbbVie Therapeutic Area Medical 
Director.
●
Occurrence of following hepatic test abnormalities considered by the 
Investigator to be related to study drug (retesting for ALT, AST, and TBL may 
be needed to confirm): 
○
Confirmed ALT or AST > 8 × Upper Limit of Normal (ULN) 
○
Confirmed ALT or AST > 5 × ULN for more than 2 weeks 
○
Confirmed ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5) 
○
Confirmed ALT or AST > 3 × ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%)
If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the Premature Discontinuation Visit must be 
completed within 2 weeks of the last dose of study drug, and preferably prior to the 
initiation of another therapy.  However, these procedures should not interfere with the 
initiation of any new treatments or therapeutic modalities that the Investigator feels are 
necessary to treat the subject's condition.  Following discontinuation of the study drug, the 
subject will be treated in accordance with the Investigator's best clinical judgment.
A final visit will occur for all subjects, approximately 140 days after the last dose of study 
medication to determine the status of any ongoing AEs/SAEs or the occurrence of any 
new AEs/SAEs, except for those who are rolled over to the Study M16-066. 
All attempts must be made to determine the date of the last dose of study drug and the 
primary reason for premature discontinuation.  The information will be recorded on the 
appropriate eCRF page.


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For subjects that are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent and documented in the subject's source 
documentation. 
Subjects who discontinue the study prematurely will not be replaced. 
During the COVID-19 pandemic or the geo-political conflict in Ukraine and surrounding 
impacted regions, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  This may include alternative 
methods for assessments (e.g., phone contacts or virtual site visits), alternative locations 
for data collection (e.g., use of a local lab instead of a central lab).  In all cases, these 
alternative measures must be allowed by local regulations and permitted by IRB/IEC. 
The investigator should contact the sponsor medical contact before discontinuing a subject 
from the study for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored. 
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. 


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5.5
Treatments
5.5.1
Treatments Administered
Sub-Study 1
Each dose of blinded study drug (1800 mg risankizumab, 1200 mg risankizumab, 600 mg 
risankizumab, or placebo) was administered intravenously to subjects during Induction 
Period 1.  Blinded risankizumab or placebo were administered intravenously at the 
Baseline visit, Week 4, and Week 8.  Subjects who did not achieve clinical response at 
Week 12 were eligible for Induction Period 2 with blinded risankizumab. 
During Induction Period 2, each dose of blinded study drug (1800 mg risankizumab, 
360 mg risankizumab or 180 mg risankizumab) was administered both intravenously and 
subcutaneously.  Blinded risankizumab was administered either intravenously at 
Weeks 12, 16 and 20 or subcutaneously at Weeks 12 and 20. 
Subjects who were enrolled during the dose selection period were assigned to the 
1800 mg risankizumab arm. 
Sub-Study 2
Each dose of blinded study drug (risankizumab 1200 mg or placebo) will be administered 
intravenously for approximately 2 hours to the subject during Induction Period 1 at the 
Baseline, Week 4 and Week 8 visits. 
Subjects who do not achieve clinical response at Week 12 will be eligible for Induction 
Period 2 with blinded risankizumab.  Each dose of blinded study drug (risankizumab 
1200 mg, 360 mg risankizumab or 180 mg risankizumab) will be administered either 
intravenously at Weeks 12, 16 and 20 (risankizumab 1200 mg) or subcutaneously at 
Weeks 12 and 20 (risankizumab 360 mg or 180 mg).  In order to keep the blind, subjects 
allocated to intravenous risankizumab will receive matching placebo subcutaneously at 
Week 12 and 20, and subjects allocated to subcutaneous risankizumab will receive 
matching placebo intravenously at Weeks 12, 16 and 20. 


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If the 1200 mg dose is discontinued due to any reason, subjects will continue to enroll into 
the study and be randomized to 600 mg risankizumab, or placebo at 2:1 ratio.  In this case, 
the randomization ratio and sample size may be further updated in an amendment to the 
protocol.  In addition, for subjects already randomized and for future randomization, 
600 mg will be administered during Induction Period 2. 
5.5.2
Identity of Investigational Product(s)
The individual study drug information is presented in Table 2. 
Table 2. 
Identity of Investigational Product 
Study Drug
Strength
Route of 
Administration
Manufacturer
Risankizumab 
(ABBV-066)
90 mg/mL
IV
Boehringer Ingelheim Pharma 
GmbH & Co. KG
Placebo for 
Risankizumab 
(ABBV-066)
NA
IV
Boehringer-Ingelheim Pharma 
GmbH & Co. KG
Risankizumab 
(ABBV-066)
90 mg/mL
SC
Boehringer-Ingelheim Pharma 
GmbH & Co. KG
Placebo for 
risankizumab 
(ABBV-066)
NA
SC
Boehringer-Ingelheim Pharma 
GmbH & Co. KG
AbbVie will not provide 5% dextrose to be used as a diluent for administration for 
risankizumab or placebo and it should be sourced locally from approved marketed 
products from various commercial manufacturers depending on availability. 
5.5.2.1
Packaging and Labeling
Blinded risankizumab or placebo will be provided as one (1) vial per carton or 
one (1) prefilled syringe per carton to accommodate the study design. 
Each kit label will contain a unique kit number.  This kit number is assigned to a subject 
via IRT and encodes the appropriate study drug to be dispensed at the subjects 
corresponding study visit.  Each kit will be labeled as required per country requirements.  


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Labels must remain affixed to the kits.  All blank spaces on the label will be completed by 
site staff prior to dispensing to the subjects. 
5.5.2.2
Storage and Disposition of Study Drug
Study drug must be kept protected from light in their original packaging, in a refrigerator 
between 2° to 8°C (36° to 46°F).  Study drug must not be frozen at any time. 
The investigational products are for investigational use only and are to be used only 
within 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.  A temperature log must be 
maintained for documentation.  
The refrigerator temperature must be recorded each business day.  Malfunctions or 
temperature excursions must be reported to the Sponsor immediately.  Sites are 
responsible to report site temperature excursions into the AbbVie Temperature Excursion 
Management System (ATEMS).  Study drug should be quarantined and not dispensed 
until AbbVie or ATEMS deems the drug as acceptable. 
Upon receipt of the study drugs, the site will acknowledge receipt within the IRT system. 
5.5.2.3
Preparation/Reconstitution of Dosage Form
Administration Instructions and Dose Preparation Instructions will be provided as 
separate documents outside of this protocol.  Dose preparation will be performed by a 
licensed unblinded pharmacist or qualified designee, as appropriate. 
5.5.3
Method of Assigning Subjects to Treatment Groups
In Sub-Study 1 (Phase 2b induction), 240 subjects who met all the inclusion and none of 
the exclusion criteria defined in Section 5.2.1 and Section 5.2.2 were centrally 
randomized in a 1:1:1:1 ratio to receive one of four treatment groups at Baseline in a 
double-blind manner during the Induction Period 1 of the study. 


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After 240 randomized subjects completed the 12-week induction period, a dose-selection 
analysis was performed.  During the analysis period additional subjects were enrolled into 
Group 1 – risankizumab 1800 mg IV Wks 0, 4 and 8 of Sub-Study 1 in an open-label 
fashion. 
Randomization at Baseline for Sub-Study 1 was stratified by baseline steroid use (yes vs 
no), and baseline Adapted Mayo score (≤ 7 vs > 7).
In Sub-Study 2 (Phase 3 induction), approximately 966 adult subjects who meet all of the 
inclusion criteria and none of the exclusion criteria as defined in Section 5.2.1 and 
Section 5.2.2 will be centrally randomized in a 2:1 ratio to receive one of two treatment 
groups at Baseline in a double-blind manner during Induction Period 1 of the study. 
Randomization at Baseline for Sub-Study 2 will be stratified by number of prior failed 
biologics (0, 1 vs > 1), baseline steroid use (yes vs no), and baseline Adapted Mayo score 
(≤ 7 vs > 7).
At Week 12, subjects who do not achieve clinical response (in both Sub-Studies 1 and 2) 
will be eligible for Induction Period 2 where subjects receiving blinded IV risankizumab 
will be re-randomized 1:1:1 to receive blinded risankizumab in one of three groups and 
subjects who are receiving blinded placebo will receive blinded IV risankizumab as 
summarized in Section 5.5. 
Randomization in Period 2 of Sub-Study 1 and 2 will be stratified by the same factors as 
in Period 1 of Sub-Study 1 and 2 respectively. 
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 medication should not be re-dispensed to any subject. 


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All subjects will keep the same unique subject identification number throughout the study. 
5.5.4
Selection and Timing of Dose for Each Subject
Subject will be administered study drug at the clinical site as outlined in Section 5.5.1. 
5.5.5
Blinding
All AbbVie personnel with direct oversight of the conduct and management of the study 
(with the exception of AbbVie's Drug Supply Management Team) as well as the 
Investigator, blinded study site personnel (with the exception of the unblinded site staff) 
and the subject will remain blinded to each subject's treatment throughout the study.  The 
IRT will provide access to blinded subject treatment information in the case of medical 
emergency.
In the event of a medical emergency in which the Investigator believes that knowledge of 
study drug treatment is required, reasonable efforts must be made to contact the AbbVie 
TA MD (see Section 6.1.5) prior to breaking the blind, as long as it does not compromise 
subject safety.  However, if an urgent therapeutic intervention is necessary which warrants 
breaking the blind prior to contacting AbbVie TA MD, the Investigator can directly 
access the IRT system to break the blind without AbbVie agreement.  In the event that the 
blind is broken before notification to AbbVie TA MD, it is requested that the AbbVie TA 
MD be notified within 24 hours of the blind being broken.  Also, the date and reason that 
the blind was broken must be recorded in the source documents and eCRF, as applicable. 
5.5.5.1
Blinding of Investigational Product
In order to maintain the blind, it is necessary to have unblinded site staff (unblinded 
licensed pharmacist or qualified designee) to prepare the IV solutions and blind the doses.  
Study personnel who administer the infusions to the subjects must remain blinded. 
The Administration Instructions and Dose Preparation Instructions are to be checked for 
the staff requirements for all activities concerning handling of study kits, including IRT 
transactions.


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5.5.5.2
Data Monitoring Committee (DMC)
An external independent DMC will review unblinded safety data on a cohort level, at a 
minimum of 6-month intervals throughout the course of the study launch. 
A separate DMC charter will be approved by AbbVie and the DMC members before the 
first subject is enrolled into the study.  The DMC charter will describe the composition of 
the DMC, the roles and responsibilities of the DMC members, frequency and triggers of 
data reviews, relevant safety data to be assessed, meeting occasions, and communication 
with AbbVie as well as relevant competent authorities, if necessary.  The DMC is 
responsible for monitoring safety data, alerting AbbVie to possible safety concerns related 
to the conduct of the study, and recommending appropriate actions for study conduct and 
management.
At the time of this amendment, the DMC has provided recommendation that the study 
may continue without modification and has endorsed the commencement of enrollment of 
16 – 17 year old subjects.  A patient information card with information of the symptoms 
and signs of hypersensitivity reactions, infusion related reactions as well as late stage 
reactions will be provided to the patients at Screening so that any such events once 
occurred will be reported immediately by the patients to the investigator.
For China only:  The first 12 subjects enrolled in China will be monitored at an individual 
subject level.  Also, the initial 12 subjects enrolled in China will be monitored on site for 
2 hours after completion of the infusion.  Once the DMC assess the safety results of the 
initial 12 subjects with no safety concerns identified, all sites in China will be notified that 
subjects should be monitored as necessary after completion of the infusion.  In addition, 
16 to < 18 year olds will not be enrolled in China until the DMC has reviewed the 
first 12 adult subjects enrolled in China and provided endorsement. 
The DMC will review safety data at a minimum of 6-month intervals throughout the 
course of the study.  The DMC will determine if more frequent DMC meetings are 
required based on review of the accumulating safety data.  In addition, ad-hoc DMC 


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meetings will be scheduled in the event of any significant safety concerns.  Based on these 
reviews, the DMC will make recommendations, as appropriate, regarding the conduct and 
management of the study. 
The DMC reviews the data in an unblinded manner, including adjudicated cardio-
cerebrovascular events and anaphylactic reactions.
Communications from the DMC to the Study Teams 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. 
5.5.7
Drug Accountability
The Investigator or designee will verify that study drug supplies are received intact, at the 
appropriate temperature, and in the correct amounts from the depot.  This will be 
documented by signing and dating the Proof of Receipt (POR) or similar document and by 
registering the arrival of drug through the IRT.  The original POR and the IRT 
confirmation sheet will be kept in the site files as a record of what was received.
In addition 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.  Site staff will complete study drug 
accountability via IRT by using source documents, and by visually inspecting the 
packaging whenever possible. 
After drug accountability and monitor reconciliation has been completed, used packaging 
and unused study drug will be destroyed on site according to local procedures or 


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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.
Site monitors will reconcile the site's processes, source documents, IRT or site 
accountability records, and destruction records to assure site compliance. 
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Risankizumab is a selective anti IL-23 inhibitor that may provide an improved clinical 
benefit to risk profile in UC patients.  The proposed study is a Phase 2b/3, randomized, 
double-blind, placebo-controlled study to evaluate the safety and efficacy of risankizumab 
compared to placebo in subjects with moderately to severely active UC who have had 
inadequate response or intolerance to immunosuppressants, corticosteroids and/or biologic 
therapies and tofacitinib. 
The study comprises 2 sub-studies with a 12 week induction period.  Sub-Study 1 is a 
Phase 2b dose-ranging study designed to evaluate the efficacy, pharmacokinetics, and 
safety of three different risankizumab doses (IV, 600 mg, 1200 mg, or 1800 mg, Q4W) 
versus placebo.  Sub-Study 2 is a Phase 3 study designed to evaluate the efficacy and 
safety of risankizumab (IV, 1200 mg Q4W) versus placebo.  For subjects not in clinical 
response at Week 12 in either Sub-Study 1 or Sub-Study 2, an optional blinded Induction 
Period 2 (IV, 1800 mg [Sub-Study 1] or 1200 mg [Sub-Study 2], Q4W; SC 360 mg, 
Q8W; SC 180 mg, Q8W) for an additional 12 weeks will be offered.  Subjects with 
clinical response at the end of Induction Period 1 or Induction Period 2 can enter 
maintenance Study M16-066 for an additional 52 weeks of treatment, with additional OL 
treatment with risankizumab being offered through approval. 


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At this time, a placebo-controlled study is necessary for registrational purposes.  A 
comparative study utilizing a placebo control design provides an unbiased assessment of 
the efficacy and safety profile of risankizumab. 
For clinical operational efficiency, AbbVie proposes to conduct this operationally 
seamless Phase 2b/3 study.  Data from Phase 2b and Phase 3 portions of the study will be 
analyzed separately (i.e., operational seamless) for the efficacy endpoints and will not be 
combined for statistical inference.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, endoscopy-related and laboratory procedures will be utilized 
in this study.  All efficacy measurements in this study are standard for assessing disease 
activity in subjects with Ulcerative colitis.  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 subjects with moderately to severely active UC. 
5.6.3
Suitability of Subject Population
Adult male and female subjects, and 16 to 17 years old where locally permitted, with 
moderately to severely active UC who meet all of the inclusion criteria and none of the 
exclusion criteria are eligible for enrollment in this study.  The specific population chosen 
was based on the unmet medical need of those subjects with a history of inadequate 
response or intolerance to biologic therapies. 
5.6.4
Selection of Doses in the Study
Sub-Study 1: 
Sub-Study 1 is a Phase 2b dose finding study.  Doses (600 mg, 1200 mg, and 1800 mg) of 
IV risankizumab given every 4 weeks (Q4W) were informed by the analysis of the safety 
and efficacy data, as well as the exposure-response relationship of efficacy, of a Phase 2 
study in subjects with Crohn's disease (CD). 


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Results from the placebo controlled Study 1311.6 in subjects with CD that evaluated 
200 mg and 600 mg IV doses of risankizumab at Weeks 0, 4, 8 for induction suggests 
increasing trend of clinical response and remission (for both CDAI and PRO-2 based 
measures) at Week 12 with increasing risankizumab dose and exposure, indicating a 
potential for further improvement in proportion of subjects with response and remission at 
higher doses.  Preliminary model predictions suggest further incremental benefit in CDAI 
remission in subjects with CD at 1200 mg IV Q4w dose compared to 600 mg IV Q4w 
dose.  In subjects with UC, given the higher inflammatory burden, protein loss through 
ulcers, and increased proteolytic activity compared to subjects with CD, an 1800 mg dose 
will also be tested.
The evaluation of higher doses (1200 mg and 1800 mg IV Q4w) will facilitate a more 
robust characterization of the dose-response and exposure-response relationship for UC 
related efficacy endpoints.  Inclusion of doses up to 1800 mg IV in this study is further 
supported by the safety results from the 12 week blinded induction period in 
Study 1311.6.  The safety profile of the 600 mg risankizumab group compared favorably 
with the placebo group and no overall safety concerns were identified which would 
preclude evaluation of IV induction doses higher than 600 mg risankizumab in patients 
with UC.  Furthermore, truncated preliminary results from an ongoing heathy volunteer 
study (Study 1311.16) in six Japanese subjects suggest that a single IV dose of 1200 mg 
Risankizumab was safe and well tolerated up to 4 weeks post-dosing.  Preliminary safety 
and tolerability data from another planned heathy volunteer study in Japanese and 
Caucasian subjects (six subjects each) will also be available following a single dose of 
1800 mg IV risankizumab prior to initiating this study.  Finally, the projected steady state 
exposures for the 1800 mg IV risankizumab Q4w regimen in subjects with UC are 
covered by safety margins of ~1 and ~2.3 for Cmax and AUC0-28 days respectively (relative 
to NOAEL identified in the 26 week GLP toxicology study). 
Sub-Study 2: 
Sub-Study 2 (Phase 3 induction study) will evaluate IV risankizumab 1200 mg during 
induction.  The selection of this dose was informed by the analysis of safety and efficacy 


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data, as well as the exposure-response relationship of efficacy from Sub-Study 1 
(Phase 2b dose finding study) where risankizumab doses of 1800 mg IV, 1200 mg IV, and 
600 mg IV were evaluated.  All three risankizumab doses achieved higher clinical 
remission rates per Adapted Mayo Score (primary endpoint) at Week 12 compared to 
placebo; both the 1200 mg and 1800 mg groups achieved nominal P-values < 0.1 
(two-sided) based on pairwise comparisons.  All three risankizumab dose groups also 
achieved higher response rates compared to placebo for other selected endoscopic, clinical 
and composite endpoints.  Exposure-response analyses predicted greater efficacy for key 
endpoints (clinical remission, clinical response, and endoscopic remission) with higher 
risankizumab exposures and both doses of 1200 mg and 1800 mg are expected to provide 
better efficacy than 600 mg for subjects with UC during the induction period.  While 
incremental efficacy is predicted with doses increasing from 1200 mg to 1800 mg, the 
magnitude of the difference is modest and 1800 mg is not expected to provide clinically 
meaningful benefit beyond 1200 mg for induction.  No new safety risks were identified 
and the overall safety findings were consistent with the known safety profile of 
risankizumab. 
Induction Period 2:
Induction Period 2 will evaluate IV (1800 mg [Sub-Study 1] or 1200 mg [Sub-Study 2] 
Q4W) or SC (180 mg or 360 mg Q8W; maintenance dosing regimen) risankizumab.  The 
purpose of Induction Period 2 is to evaluate the efficacy and safety of re-induction of 
risankizumab versus starting maintenance regimen on clinical response status.  Data from 
the Phase 2 study in subjects with CD suggested that re-induction with 600 mg IV 
increased both clinical response and clinical remission in subjects with inadequate 
response at Week 12.  The selection of the SC doses is informed by the analysis of the 
safety and efficacy data, as well as the exposure-response relationship of efficacy, of the 
maintenance period during the Phase 2 study in subjects with CD that evaluated 180 mg 
SC risankizumab for maintenance.  A higher dose of 360 mg Q8W is proposed to provide 
exposures reasonably separated with 180 mg Q8w dose to characterize the exposure-


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response relationship during maintenance phase with a potential of 360 mg Q8w dose to 
maintain higher response compared to 180 mg Q8w dose. 
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. 
The investigational product in this study contains: 
●
Biologic compound(s)  
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.  For product complaints, please refer to Section 6.2. 
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide another cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion. 


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6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product. 
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the investigator considers them to be adverse events. 
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event. 
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
events (including capture of specific signs/symptoms of infection and testing results). 
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 


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protocol and above.  The following COVID-19 related supplemental eCRFs should be 
completed:
●
COVID-19 Supplemental Signs/Symptoms 
●
COVID-19 Status Form 
If a subject has a confirmed or suspected COVID-19 infection and study drug was 
interrupted, the investigator should contact the sponsor emergency medical contact listed 
above before reintroducing study drug. 
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject. 
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly 
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  
Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.1.3
Areas of Safety Interest
Additional information may be collected for the following events. 
Hepatic Events
In the case of any of the following AEs, the appropriate supplemental eCRFs should be 
completed:
●
Discontinuation or interruption of study drug due to a hepatic related AE 
●
A hepatic related SAE
●
A subject experiencing an ALT/AST > 8 × ULN 
●
A subject experiencing an ALT/AST > 3 × ULN in conjunction with a total 
bilirubin > 2 × ULN. 


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Systemic Hypersensitivity/Anaphylactic Reactions
Therapeutic protein products, such as biologics, may elicit a range of acute effects, from 
symptomatic discomfort to sudden, fatal reactions that have often been grouped as 
'infusion reactions' in the past.  Although the term implies a certain temporal relationship, 
infusion reactions are otherwise not well defined and may encompass a wide range of 
clinical events, including anaphylaxis and other event that may not be directly related to 
antibody responses, such as cytokine release syndrome. 
In the event of a suspected systemic hypersensitivity/anaphylactic reaction, in addition to 
the standard AE eCRF, a supplemental eCRF should also be completed by the site.  The 
clinical criterion for diagnosing anaphylaxis is provided in Appendix F for reference; 
symptoms of anaphylactic reaction usually occur within 24 hours after exposure to an 
allergen.  These are guidelines that are used to help diagnose anaphylaxis.  The 
investigator is encouraged to report any suspected reactions. 
All intravenous and subcutaneous doses of risankizumab will be administered by study-
site personnel under the direction of the Investigator.  Subjects will be monitored 
throughout the study for signs and symptoms suggestive of hypersensitivity reactions 
including allergic reactions and anaphylaxis.  A medical person qualified in the treatment 
of acute hypersensitivity reactions must be present during the infusions.  All appropriate 
medical support measures (e.g., diphenhydramine, steroids, epinephrine, oxygen) for the 
treatment of suspected hypersensitivity reactions should be available for immediate use in 
the event that a suspected hypersensitivity reaction occurs.  Subjects who manifest any 
new signs or symptoms during the infusion should be monitored for appropriate resolution 
prior to leaving the site.  Subjects are encouraged to report any symptoms related to a 
possible infusion related reactions or local injection site reaction or late phase reactions to 
the site any time during the study.  A patient information card listing the symptoms of 
these reactions will be provided to the participants. 


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Cardiac Events/Procedures
In the case of any of the following reported MACE, the appropriate supplemental eCRFs 
should be completed: 
●
Cardiac events;
●
Myocardial infarction or unstable angina; 
●
Cerebral vascular accident and transient ischemic attack;
●
Cardiovascular procedures
Tuberculosis (TB)
In the case of any positive TB test or diagnosis of active TB, the appropriate supplemental 
eCRFs should be completed. 
6.1.2
Adverse Event Severity
When criteria are available, events should be graded as described in the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03,20
which can be accessed at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. 
If no specific criteria are provided to grade for the reported event, the event should be 
graded as follows: 
Mild 
(Grade 1)
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate 
(Grade 2)
Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)
Severe 
(Grade 3)
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL
Severe 
(Grade 4)
Life-threatening consequences; urgent intervention indicated. 


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Severe 
(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
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug: 
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event 
biologic plausibility, clinical judgment and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a 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 serious adverse 
event.




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


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Phone:  +1 (973) 784-6402
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines and Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow up report, the RSI in 
place at the time of occurrence of the suspected Serious Adverse Reaction will be used to 
assess expectedness.
In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor. 
6.1.5.1
Adverse Events Commonly Associated with Study 
Population
Certain events are anticipated to occur in the study population as known consequences of 
UC (e.g., as symptoms or due to disease progression) independent of drug exposure.  
These events are listed in Table 3.  These AEs are considered expected for reporting 
purposes for this protocol.  Although exempt from expedited reporting to certain Health 
Authorities and ECs/IRBs as individual cases, if any of these events meets seriousness 
criteria, it must be reported to AbbVie within 24 hours of the site being made aware of the 
SAE (as defined in Section 6.1.5).
Events commonly associated with UC population hence considered expected for 
reporting. 


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Table 3. 
Common Events Associated with UC
Abscesses
•
Anal abscess
•
Rectal abscess
•
Perirectal abscess
Others
•
Anal fissure
•
Ulcerative colitis
•
Ulcerative colitis aggravated
•
Colitis
•
Megacolon
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 24 hours 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).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.1.7
Cardiac Adjudication Committee
The independent external CAC will be adjudicating all observed cardio- and cerebro-
vascular events and will remain blinded to treatment allocation.  The events that are 
adjudicated and the adjudication process will be detailed in the Adjudication Committee
Charter.  Dedicated eCRFs will be used for events of MI-unstable angina, stroke-TIA, 
death and CHF.  In addition, the site may be contacted for additional source 
documentation for relevant events. 


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6.1.8
Anaphylaxis Adjudication Committee
The independent external AAC will be adjudicating observed suspected anaphylactic 
reactions and will remain blinded to treatment allocation.  The events that are adjudicated 
and the adjudication process will be detailed in the Adjudication Committee Charter.  A 
supplemental eCRF will be used to collect information pertinent to the events.  In 
addition, the site may be contacted for additional source documentation for relevant 
events.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product. 
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues. 
Any information available to help in the determination of causality to the events outlined 
directly above should be captured. 
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis. 


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Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return. 
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified), 
including those that may be due to the COVID-19 pandemic or geo-political conflict in 
Ukraine and surrounding impacted regions, after a subject has been enrolled, the principal 
investigator is responsible for notifying Independent Ethics Committee (IEC)/Independent 
Review Board (IRB) regulatory authorities (as applicable), and AbbVie. 
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study. 
In Japan, the Investigator will record all protocol deviations in the appropriate medical 
records at site.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objective of the statistical analyses of Sub-Study 1 (Phase 2b induction) was to 
characterize the pharmacokinetics, dose-response, efficacy, and safety of risankizumab 
compared to placebo in subjects with moderately to severely active ulcerative colitis in 


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order to identify one induction dose of risankizumab for further evaluation in Sub-Study 2 
(Phase 3 induction). 
The objective of the statistical analyses of Sub-Study 2 (Phase 3 induction) is to evaluate 
the efficacy and safety of the induction dose of risankizumab 1200 mg IV compared to 
placebo in subjects with moderately to severely active ulcerative colitis.
Statistical analysis for demographics (where collection is allowed) and baseline 
characteristics, prior and concomitant medications, and the key efficacy endpoints and 
safety endpoints are included in this section.  More specific details of the statistical
analyses for the key efficacy and safety endpoints to address the primary and secondary 
objectives will be further described and fully documented in the Statistical Analysis Plan 
(SAP) of each sub-study. 
The impact of missing data due to COVID-19 or geo-political conflict in Ukraine and 
surrounding impacted regions will be monitored and detailed approaches for handling 
missing data due to COVID-19 infection or logistical restriction or geo-political conflict 
in Ukraine and surrounding impacted regions will be described in the SAP. 
8.1.1
Datasets for Analysis
8.1.1.1
Intent-to-Treat Population
Sub-Study 1 – Induction Period 1:  The Intent-to-Treat (ITT) Population for Induction 
Period 1 in Sub-Study 1 includes all randomized subjects who received at least one dose 
of study drug during Induction Period 1 in Sub-Study 1 (denoted as ITT1A) at the time of 
dose-selection analysis.  The set of all the additional subjects who enrolled into 
risankizumab 1800 mg IV treatment group after 240 subjects were randomized during the 
dose-selection period is denoted as ITT1B.  The ITT for Induction Period 1 in 
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Sub-Study 2 – Induction Period 1:  The ITT for Induction Period 1 in Sub-Study 2 
includes all randomized subjects who received at least one dose of study drug from 
Induction Period 1 in Sub-Study 2 (denoted as ITT2). 
For the ITT in Induction Period 1 in each sub-study, subjects will be analyzed in a 
treatment group based on the randomization or re-randomization schedule, regardless of 
the treatment actually received.  The demographic (where collection is allowed)/baseline 
and efficacy analyses for Induction Period 1 in each sub-study will be based on the 
corresponding ITT.
Sub-Study 1 and Sub-Study 2 Induction Period 2:
Subjects who received at least one dose of risankizumab during Induction Period 2 in both 
Sub-Study 1 (denoted as ITT1_P2) and Sub-Study 2 (denoted as ITT2_P2) will be 
analyzed separately for exploratory purpose.  More details will be specified in the SAP of 
each sub-study.  
8.1.1.2
Safety Population
For the safety population in each sub-study, subjects will be analyzed in a treatment group 
based on the treatment actually received.  The safety analysis in each sub-study will be 
based on the corresponding safety population. 
Sub-Study 1 – Induction Period 1
The Safety Population for Induction Period 1 in Sub-Study 1 includes all subjects who 
receive at least one dose of study drug during Induction Period 1 in Sub-Study 1 (denoted 
as SAS1A) at the time of dose-selection analysis.  The set of all the additional subjects 
who enrolled into risankizumab 1800 mg IV treatment group after 240 subjects were 
randomized during the dose-selection period is denoted as SAS1B.  The Safety Population 
for Induction Period 1 in Sub-Study 1 will be denoted SAS1 and will be the combination 
of SAS1A and SAS1B. 


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Sub-Study 2 – Induction Period 1
The Safety Population for Induction Period 1 in Sub-Study 2 includes all subjects who 
received at least one dose of study drug during Induction Period 1 in Sub-Study 2 
(denoted as SA2). 
Sub-Study 1 and Sub-Study 2 Induction Period 2:
Subjects who received at least one dose of risankizumab during the Induction Period 2 
after Week 12 in both Sub-Study 1 (denoted as SA1_P2) and Sub-Study 2 (denoted as 
SA2_P2) will be analyzed separately for exploratory purpose. 
Sub-Study 2 – All Risankizumab:
SA2_ALL includes all subjects who received at least one dose of risankizumab any time 
during the Sub-Study 2. 
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):  Subjects who prematurely discontinue the study prior 
to efficacy assessment or with missing values at Week 12 or Week 24 in Induction 
Period 2 will be considered non-responders for the categorical efficacy endpoints.
Non-Responder Imputation while incorporating Multiple Imputation (MI) to handle 
missing data due to COVID-19 or geo-political conflict in Ukraine and surrounding 
impacted regions (NRI-MI):  Subjects who do not have an evaluation at a scheduled 
assessment visit (either due to missing assessment or due to early withdrawal from the 
study) will be considered as non-responders for the visit.  The only exception is that 
missing data due to COVID-19 infection or logistical restrictions related to the COVID-19 
pandemic or due to geo-political conflict in Ukraine and surrounding impacted regions 
will be handled by MI. 


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Observed Cases (OC):  No impute values for missing evaluations, and thus a subject who 
did not have an evaluation on a scheduled visit will be excluded from the OC analysis for 
that visit.
Multiple Imputation Incorporating Return-to-Baseline (RTB-MI) to handle missing data 
in the analysis of continuous endpoints: to handle the potential departures from the 
missing-at-random (MAR) assumption for visits after intercurrent events, the Return-to-
Baseline (RTB) approach, which assumes subjects with intercurrent events will have a 
washout "return to baseline" of any potential treatment effect, will be performed. 
As Observed (AO): The AO analysis will not impute values for missing evaluations, and
thus a subject who does not have an evaluation on a scheduled visit will be excluded from
the AO analysis for that visit.  AO will include all values collected in the study regardless
of intercurrent events.
Tipping Point analysis will be performed as sensitivity analysis for the primary endpoint 
in Sub-Study 2 to handle the potential departures from the missing-at-random (MAR) 
assumption. 
More details about missing data imputation will be specified in SAP of each sub-study. 
8.1.3
Subject Disposition
The number and percentage of subjects who are enrolled, randomized, who received at 
least one dose of study drug, who completed the study treatment, and who prematurely 
discontinued, will be summarized overall and for each investigational site by treatment 
group, as well as for all subjects combined, for each Induction Period in each sub-study. 
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 based on corresponding ITT for each Induction Period in each 
sub-study.  Subjects may have multiple reasons for prematurely discontinuing study drug, 
but will be counted no more than once for the total ("Any Reason"). 


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8.1.4
Demographics and Baseline Characteristics
Demographics (where collection is allowed) and baseline characteristics will be 
summarized using descriptive statistics by treatment group for the corresponding ITT for 
each Induction Period in each sub-study. 
Baseline information of each treatment group in each sub-study will be summarized with 
respect to demographic and baseline variables such as age, gender, race, ethnicity, height, 
weight, BMI, duration of disease, vital signs (blood pressure, heart rate, and temperature), 
and planned efficacy assessments such as Adapted Mayo Score, Full Mayo Score, Partial 
Adapted Mayo Score, hs-CRP, etc.
Summary statistics for continuous variables will include the number of observations, 
mean, standard deviation, median, and range for each treatment group, in each sub-study.  
For other categorical or discrete variables, frequencies and percentages will be computed 
in each category for each treatment group, as well as for all subjects combined.
8.1.5
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 
tabulated by treatment group for corresponding ITT for each Induction Period in each sub-
study.  No statistical test will be performed.
Concomitant drugs will be summarized with frequencies and percentages by treatment 
group for corresponding ITT in each sub-study using the World Health Organization 
(WHO) Drug Dictionary.  
A subject who reports two or more uses of the same concomitant medication will be 
counted only once within each generic name.  A subject with concomitant medications 
with more than one generic name will be counted only once in the overall total. 


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8.1.6
Efficacy Analysis
All analyses for the primary and secondary efficacy endpoints will be based on 
corresponding ITT in each sub-study as defined in Section 8.1.1.1. 
In order to control the family-wise type I error rate at a significance alpha level of 0.05 
(2-sided) in Sub-Study 2, a graphical multiple testing procedure will be used to test the 
primary and secondary endpoints in the order as specified in Section 5.3.3.  The primary 
endpoint will be tested at the pre-specified significant alpha level of 0.05 (2-sided).  The 
secondary efficacy endpoints are divided into two groups.  The first group includes the 
first ten secondary endpoints. The second group includes all the remaining secondary 
endpoints which will be tested using the Holm procedure. If the primary endpoint 
achieves statistical significance, continued testing will follow a pre-specified weight of α 
allocation.
The details of the testing procedure will be specified and documented in SAP. 
The separate efficacy analysis for subjects who were randomized and received at least 
one dose of risankizumab during the Induction Period 2 in both Sub-Study 1 and 
Sub-Study 2 will be performed for exploratory purpose. 
8.1.6.1
Primary Efficacy Variables
The primary endpoint for both Phase 2b induction (Sub-Study 1) and Phase 3 induction 
(Sub-Study 2) is the achievement of clinical remission per Adapted Mayo score (defined 
as stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 
0, and endoscopic subscore ≤ 1 without the evidence of friability) at Week 12.
8.1.6.1.1
Analysis of Primary Endpoint
For Sub-Study 1 – Induction Period 1
The dose-response relationship among the risankizumab dose groups and the placebo 
group was characterized for the primary endpoint of clinical remission at Week 12 using 


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the Multiple Comparison Procedure and dose response Modeling (MCP-Mod)21,22 method 
based on the ITT1A Population.  Subjects with missing primary endpoint data at Week 12 
was classified as "not achieved" (non-responder imputation [NRI] method) for the 
primary endpoint.  Details were specified in the SAP. 
The pairwise comparison between each risankizumab treatment group and placebo was 
also performed using the Cochran-Mantel-Haenszel (CMH) test stratified by baseline 
corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7) with one-sided alpha 
level of 0.05.  A two-sided 90% confidence interval for the difference between treatment 
groups was constructed.  There was no multiplicity adjustment for the pairwise 
comparison.  The goal of the CMH test was to provide an estimation of the effect size for 
each dose to inform the dose selection for Phase 3, not for statistical inference purposes. 
The above analyses for Induction Period 1 in Sub-Study 1 were performed based on 
ITT1A as primary analysis.  Additional analysis based on ITT1 with additional subjects 
enrolled into risankizumab 1800 mg IV treatment group will be conducted separately as 
exploratory. 
For Sub-Study 2 – Induction Period 1
The primary analysis will compare the subjects in risankizumab 1200 mg IV group and 
placebo group based on the ITT2.  The difference between the treatment groups in the 
primary efficacy endpoint will be assessed using Cochran-Mantel-Haenszel (CMH) test 
stratified by Advanced Therapy-IR status (yes vs no), baseline steroid use (yes vs no), and 
baseline Adapted Mayo score (≤ 7 vs > 7) with two-sided alpha of 0.05.  A two-sided 
95% confidence interval for the difference between treatment groups will be constructed.
The Advanced Therapy-IR is defined as documented intolerance or inadequate response 
to advanced therapy including one or more of the approved biologics for UC (infliximab, 
adalimumab, golimumab, ustekinumab, and/or vedolizumab), approved JAK inhibitors for 
UC (tofacitinib, filgotinib, upadacitinib), and/or ozanimod. 


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NRI-MI, as defined in Section 8.1.2, will be used for missing data handling in primary 
analysis.
Sensitivity and subgroup analysis for the primary efficacy endpoint will be specified in 
SAP.
8.1.6.2
Secondary Efficacy Variables
Sub-Study 1 – Induction Period 1:
For Induction Period 1 in Sub-Study 1, the secondary efficacy variables listed in 
Section 5.3.3.2 were analyzed by treatment group for ITT1A as the primary analysis at the 
nominal α level of 0.05 (one-sided). 
Categorical secondary efficacy endpoints were analyzed using CMH controlling for 
stratification variables. NRI imputation were used for primary inference purpose except 
for occurrence of hospitalization and UC-related surgeries of which as observed data were 
used.  Continuous secondary efficacy endpoints were analyzed using a Mixed-Effect 
Model Repeated Measures (MMRM) method as the primary analysis.
Additional analysis based on ITT1 with additional subjects enrolled into risankizumab 
1800 mg IV will be conducted separately as exploratory purpose. 
No multiplicity adjustment will be performed.
Sub-Study 2 – Induction Period 1:
The secondary efficacy endpoints will be compared between the subjects in risankizumab 
dose group and placebo group based on ITT2. 
Categorical secondary efficacy endpoints will be analyzed using the same CMH test as 
that for primary endpoint as specified in Section 8.1.6.1.1.  NRI-MI, as defined in 
Section 8.1.2, will be the primary approach for missing data handling in the analyses of 


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categorical secondary efficacy endpoints except for UC-related hospitalization, of which 
AO data will be used.
Continuous secondary efficacy endpoints will be analyzed using RTB-MI as defined in 
Section 8.1.2 with MMRM (for endpoints with more than one post-baseline visits) or with 
ANCOVA (for endpoints with one post-baseline visit) models.
For all endpoints specified in Section 5.3.3.2, descriptive summary will be provided for 
ITT1_P2 and ITT2_P2 for exploratory purposes. 
8.1.7
Safety Analysis
Safety analysis in each sub-study will be carried out using the corresponding safety 
population as defined in Section 8.1.1.2.  The separate safety analysis for SAS1_P2 and 
SAS2_P2 will be performed for exploratory purpose.  Adverse events (AEs), laboratory 
data and vital signs are the primary safety parameters and will be analyzed in each sub-
study. 
Sub-Study 1 and Sub-Study 2 – Induction Period 1:
Treatment emergent AEs (TEAEs) for Induction Period 1 in both Sub-Study 1 and 
Sub-Study 2 are defined as events that begin or worsen either on or after the first dose of 
the study drug in Induction Period 1 and within 140 days after the last dose administration 
of the study drug for subjects who do not participate in the maintenance Study M16-066 
or until first dose of study drug in the maintenance Study M16-066 if the subject is 
enrolled into or until first dose of study drug in Induction Period 2 if the subject is 
enrolled into Induction Period 2. 
Sub-Study 1 and Sub-Study 2 – Induction Period 2:
TEAEs for Induction Period 2 in both Sub-Study 1 and Sub-Study 2 are defined as events 
that begin or worsen either on or after the first dose of the study drug in Induction 
Period 2 and within 140 days after the last dose administration of the study drug for 


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subjects who do not participate in the maintenance Study M16-066 or until first dose of 
study drug in the maintenance Study M16-066 if the subject is enrolled. 
An overview of TEAEs, including AEs of special interest such as serious infection, 
malignancies, major adverse cardiovascular events, systemic hypersensitivity 
reactions/infusion reactions, TEAEs leading to death and TEAEs leading to premature 
discontinuation, TEAEs by Medical Dictionary for Drug Regulatory Activities (MedDRA 
version 18.1 or later) preferred term and system organ class, TEAEs by maximum 
relationship to study drug, and TEAEs by maximum severity will be summarized by 
number and percentage.  Treatment group differences in the overall incidence of TEAEs 
will be assessed with Fisher's exact test for each preferred term.
Changes from Baseline in continuous laboratory and vital sign parameters will be 
summarized by treatment group for corresponding safety population in each sub-study.  
Treatment group differences in changes from Baseline between risankizumab and the 
placebo group may be analyzed using a one-way Analysis of Variance (ANOVA).  Vital 
signs and laboratory data will be summarized by descriptive statistics 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. 
Missing safety data will not be imputed.  More detailed safety analysis for Induction 
Period 1 and Induction Period 2 will be specified in SAP. 
8.1.8
Analysis of Optional Exploratory Variables
For exploratory biomarkers that are measured, including but not limited to 
pharmacogenetic, epigenetic, transcriptomic, proteomic, and metabolomic biomarkers, the 
association of biomarkers to the efficacy and safety endpoints may be explored for each 
biomarker one at a time, and also for combinations of biomarkers via some multivariate 
predictive modeling algorithms.  Optimal multivariate combinations of biomarkers that 
associate with efficacy endpoints, subject response/non-response (with respect to 
appropriate clinical endpoints), and also with safety endpoints may be explored via a 


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variety of statistical predictive modeling algorithms.  Cut-points for individual biomarkers 
and optimal combinations of biomarkers that differentiate the subject response with 
respect to efficacy/safety endpoints may be explored using the in-house developed 
subgroup identification algorithms:  Sequential BATTing, PRIM, AIM BATTing, and 
AIM Rule.  The significance of these multivariate combinations of biomarkers may be 
assessed via at least 20 iterations of 5-fold cross-validation.23,24
8.1.9
Analysis of Pharmacokinetic and Pharmacodynamic 
Variables
Serum risankizumab concentrations will be summarized at each time point for each 
dosing regimen using descriptive statistics.  ADA incidence will be summarized by cohort 
and study visits.  ADA titers will be tabulated for each subject at the respective study 
visits.  Data from this study may be combined with data from other studies for the 
population pharmacokinetic and exposure-response analyses and may not be part of the 
clinical study report.  Population pharmacokinetic and exposure-response analyses of only 
data from this study may not be conducted.  The following general methodology will be 
used for the population pharmacokinetic analysis Population pharmacokinetic analyses of 
risankizumab will be performed using the actual sampling time relative to dosing.  
Pharmacokinetic models will be build using a nonlinear mixed-effects modeling approach 
with NONMEM software (Version 7, or a higher version).  The structure of the starting 
pharmacokinetic model will be based on the pharmacokinetic analysis data from previous 
studies.  Systemic clearance and volume of distribution of risankizumab will be the 
pharmacokinetic parameters of major interest in the NONMEM analyses.  If necessary, 
other parameters, including the parameters describing absorption characteristics, may be 
estimated 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).


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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 fit, standard errors of model parameters and change in 
inter-subject and intra-subject error.
Once an appropriate base pharmacokinetic 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 NONMEM.  The 
relationship between these conditional estimates CL or V values with only potentially 
physiologically relevant or clinically meaningful covariates (such as ADA classification, 
subject age, sex, body weight, concomitant medications, possibly baseline inflammatory 
and disease markers) may be explored using stepwise forward selection method, or 
another suitable regression/smoothing method at a significance level of 0.01.  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 < 0.001 
corresponding to a decrease in objective function > 10.83 for one degree of freedom) of 
each covariate in the full model.
Linear or non-linear relationships of primary pharmacokinetic parameters with various 
covariates may also be explored.  Relationships between exposure and clinical 
observations (primary or secondary efficacy or safety variables of interest) may be 
explored.  Additional analyses will be performed if useful and appropriate. 
8.2
Determination of Sample Size
Sub-Study 1 (Phase 2b): 
For Sub-Study 1 (Phase 2b portion of the study), approximately 240 subjects in the Bio-
IR population were equally randomized using a 1:1:1:1 ratio to three risankizumab 
treatment groups (600 mg, 1200 mg and 1800 mg IV Q4W) and the placebo group.  The 
sample size for this study is based on the expected proportion of subjects who achieve 


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clinical remission per Adapted Mayo Score at Week 12.  Assuming clinical remission rate 
of 7% in the placebo arm and maximum of 25% in at least one of the risankizumab 
treatment groups at Week 12, a sample size of 60 subjects per treatment group is 
sufficient to test for the presence of a dose response signal, to select the best dose 
response model for the observed data out of a pre-specified set of candidate models, and 
to estimate target doses of interest (e.g., MED) via modeling using MCP-Mod (Multiple 
comparison procedure and modeling) approach.  This approach provides an average 
power of approximately 87% to detect a dose effect at 5% level of significance 
(one-sided) with the log linear, Emax, exponential, logistic and sigEmax models pre-
specified as likely candidates to characterize the dose response for risankizumab for the 
primary endpoint of clinical remission at Week 12 per Adapted Mayo Score. 
240 subjects were enrolled into Study M16-067 Sub-Study 1 for dose selection analysis.  
The additional subjects that enrolled during the dose selection analysis period were not 
part of the dose selection analysis, but will be evaluated separately as exploratory in the 
final CSR.
Study M16-067 Sub-Study 2 (Phase 3) 
For Sub-Study 2, approximately 966 subjects will be randomized to the risankizumab 
1200 mg IV dose or placebo in a randomization ratio of 2:1.  The sample size for this 
study is based on the expected proportion of subjects who achieve clinical remission per 
Adapted Mayo Score at Week 12.  The sample size has been re-assessed after analyzing 
combined PK, safety and efficacy results from Sub-Study 1.  It is determined to provide 
adequate power for the primary endpoint and selected ranked secondary endpoints and 
adequate responders to meet the sample size requirement for Study M16-066.  Assuming 
clinical remission rate of 6% in the placebo arm and 16% of the risankizumab treatment 
arm at Week 12, a sample size of 644:322 subjects in risankizumab 1200 mg IV dose and 
placebo group will provide at least 90% power to detect the 10% treatment difference in 
clinical remission rate between the risankizumab dose and placebo using two-sided 
Miettinen and Nurminen test at a 0.05 significant level.  The assumed remission rates 
were based on Sub-Study 1 for bio-IR population and on ustekinumab data for 


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Non-Bio-IR population.  The same sample size will also provide at least 90% power for 
ranked secondary endpoints, clinical remission per full mayo score at Week 12, 
endoscopic response at Week 12, endoscopic remission at Week 12, clinical response per 
adapted mayo score at Week 12 and clinical response per partial adapted mayo score at 
Week 4.
8.3
Randomization Methods
A total of approximately 1206 subjects (240 subjects in Sub-Study 1 and 966 subjects in 
Sub-Study 2) will be randomized into the study. 
240 subjects in Sub-Study 1 were randomized into three risankizumab dose groups and 
the placebo group in a 1:1:1:1 ratio (60 subjects for risankizumab 600 mg, 1200 mg and 
1800 mg dose group and placebo group respectively), stratified by Baseline corticosteroid 
use (yes vs. no) and Baseline Adapted Mayo score (≤ 7 vs. > 7).  During the dose analysis 
period, additional subjects will be enrolled to the risankizumab1800 mg IV Q4W dose 
group on an open-label basis.
At Week 12, subjects who received IV risankizumab induction and did not achieve 
clinical response were randomized 1:1:1 to Induction Period 2 (risankizumab 1800 mg IV, 
risankizumab 360 mg SC, and risankizumab 180 mg SC), stratified by baseline steroid use 
(yes vs no) and baseline Adapted Mayo score (≤ 7 vs > 7).
Approximately 966 subjects in Sub-Study 2 will be randomized into risankizumab 
1200 mg dose group and the placebo group in a 2:1 ratio (644 subjects for risankizumab 
1200 mg dose group, 322 subjects for placebo group) stratified by number of prior failed 
biologics (0, 1 vs > 1), baseline corticosteroid use (yes vs. no), and baseline Adapted 
Mayo score (≤ 7 vs. > 7).
At Week 12, subjects who received IV risankizumab induction and did not achieve 
clinical response were randomized 1:1:1 to Induction Period 2 (risankizumab 1200 mg IV, 
risankizumab 360 mg SC, and risankizumab 180 mg SC), stratified by number of prior 


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failed biologics (0, 1 vs > 1), baseline steroid use (yes vs no) and baseline Adapted Mayo 
score (≤ 7 vs > 7).
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 and approval by 
Regulatory Authority (ies), if required by local regulations prior to implementation of any 
changes made to the study design.  The investigator will be required to submit, maintain 
and archive study essential documents according to ICH GCP. 
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie. 
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 


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study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A. 
In the event of a state of emergency due to the COVID-19 pandemic or geo-political 
conflict in Ukraine and surrounding impacted regions leading to difficulties in performing 
protocol-specified procedures, AbbVie will engage with study site personnel in efforts to 
ensure the safety of subjects, maintain protocol compliance, and minimize risks to the 
integrity of the study while trying to best manage subject continuity of care.  This may 
include alternative methods for assessments (e.g., phone contacts or virtual site visits), 
alternative locations for data collection (e.g., use of a local lab instead of a central lab).  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
For adult subjects the investigator or his/her representative will explain the nature of the 
study to the subject, and answer all questions regarding this study.  Prior to any study-
related screening procedures being performed on the subject, the informed consent 
statement will be reviewed and signed and dated by the subject, the person who 
administered the informed consent, and any other signatories according to local 
requirements.  A copy of the informed consent form will be given to the subject and the 
original will be placed in the subject's medical record.  An entry must also be made in the 
subject's dated source documents to confirm that informed consent was obtained prior to 
any study-related procedures and that the subject received a signed copy.
It is possible that additional protocol modifications not outlined in this protocol may 
become necessary due to the geo-political conflict in Ukraine and surrounding impacted 
regions.  If this situation arises, in addition to the study informed consent, additional 
temporary verbal consent may be obtained prior to these adaptations or substantial 
changes in study conduct in accordance with local regulations.  An appropriately signed 


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and dated informed consent form should be obtained from the subject afterwards, as soon 
as possible. 
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form. 
Samples for exploratory research will only be collected after the subject has voluntarily 
signed and dated the separate written consent, approved by an IRB/IEC, after the nature of 
the testing has been explained and the subject has had an opportunity to ask questions.  If 
the subject does not consent to provide the optional samples, it will not impact the 
subject's participation in the study. 
For adolescent subjects, the investigator or his/her representative will explain the nature of 
the study and optional exploratory research samples to the subject and the subject's 
parent/legal guardian, and answer all questions regarding this study.  Adolescent subjects 
will be included in all discussions in order to obtain verbal or written assent.  Prior to any 
study-related screening procedures being performed on the subject, the informed consent 
statement will be reviewed and signed and dated by the subject's parent/legal guardian, the 
person who administered the informed consent, and any other signatories according to 
local requirements.  Additionally, in keeping with each institution's IRB/IEC 
requirements, an informed assent form may also be obtained by each subject prior to any 
study-related procedures being performed.  If a subject becomes of legal age during the 
course of the study, that subject will need to be re-consented.  A copy of the informed 
consent form and the assent form will be given to the subject and the subject's parent/legal 
guardian and the original will be placed in the subject's medical record.  An entry must 
also be made in the subject's dated source documents to confirm that informed consent 
was obtained prior to any study-related procedures and that the subject received a signed 
copy. 
Optional exploratory research samples from adolescent subjects will only be collected if 
the subject's parent/legal guardian has voluntarily signed and dated a separate written 


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informed consent, approved by an IRB/IEC, after the nature of the testing has been 
explained and the subject and subject's parent/legal guardian has had an opportunity to ask 
questions.  The separate informed consent must be signed before the optional samples are 
collected.  If the subject's parent/legal guardian does not consent to provide optional 
samples, 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(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents. 
During the COVID-19 pandemic or geo-political conflict in Ukraine and surrounding 
impacted regions, remote monitoring of data may be employed if allowed by the local 
regulatory authority, IRB/IEC, and the study site. 
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie. 
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 


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be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation. 
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media. 
10.3
Electronic Patient Reported Outcomes (ePRO)
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an ePRO system called Trialmax, provided by 
the technology vendor Signant 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, Signant Health, while the 
user acceptance testing of the study specific PRO design will be conducted and 
maintained at AbbVie.


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The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source, and maintained and 
managed by CRF Health. 
Internet access to the ePRO data will be provided by Signant 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 printouts from that media. 
The ePRO data will be collected by the following methods: 
Diary Based 
The ePRO data (stool information, bowel urgency, abdominal pain, nocturnal bowel 
movement, tenesmus, interrupted sleep due to UC symptoms, and general well-being, use 
of anti-diarrheals and endoscopy prep) will be collected electronically via a handheld 
device into which the patient 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 Signant 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.  Site staff are responsible for regularly checking that each subject is entering data 
consistently and accurately in the ePRO device via the password protected website.  If 
inconsistencies are noted the site staff are responsible for promptly contacting the subject 
to re-educate the subject on how to correctly complete the questionnaires at the required 
timepoints.


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Tablet Based
The ePRO data (IBDQ, SF-36, PGIS, PGIC, FACIT-F, WPAI-UC, EQ-5D-5L and UC-
SQ) will be collected electronically via a Tablet device into which the patient will directly 
enter the required pieces of information.  The electronic device will be programmed to 
allow data entry for only the visits specified in the protocol Appendix C and will not 
allow for patients to complete more than one of the same assessments at any one visit.  All 
data entered on the device will be immediately stored to the device itself and 
(manually/automatically) uploaded to a central server administrated by Signant 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. 
Investigator will enter the Physician Global Assessment (PGA) in the Trialmax system in 
every study visit. 
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF. 
12.0
Use of Information
All information concerning risankizumab and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information. 
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
risankizumab.  This information may be disclosed as deemed necessary by AbbVie to 
other clinical Investigators, other pharmaceutical companies, to the Food and Drug 
Administration (FDA) and to other governmental agencies.  To allow for the use of the 


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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. 
If this protocol or the information gained from the conduct of this study will be made 
public (disclosed/published), AbbVie will determine the information that is not yet in the 
public domain and if the disclosure of such information may undermine AbbVie's 
interests, will remain confidential at the time of disclosure/publication.
The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (by name and subject number).  This list will be maintained at the 
site 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 
data will be published or presented only in a way that does not identify any individual 
subject.
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 


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


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for risankizumab. 
2.
I have read this protocol and agree that the study is ethical. 
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines. 
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding. 
Protocol Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Induction Study to Evaluate the Efficacy and Safety of 
Risankizumab in Subjects with Moderately to Severely Active 
Ulcerative Colitis
Protocol Date:
16 December 2022 
Signature of Principal Investigator 
Date
Name of Principal Investigator (printed or typed) 


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15.0
Reference List
1.
Hanauer SB.  Update on the etiology, pathogenesis and diagnosis of ulcerative 
colitis.  Nat Clin Pract Gastroenterol Hepatol.  2004;1(1):26-31. 
2.
Molodecky NA, Soon IS, Rabi DM, et al.  Increasing incidence and prevalence of 
the inflammatory bowel diseases with time, based on systematic review.  
Gastroenterology.  2012;142(1):46-54.e42; quiz e30. 
3.
Sandler RS, Everhart JE, Donowitz M, et al.  The burden of selected digestive 
diseases in the United States.  Gastroenterology.  2002;122(5):1500-11. 
4.
Dignass A, Eliakim R, Magro F, et al.  Second European evidence-based consensus 
on the diagnosis and management of ulcerative colitis part 1:  definitions and 
diagnosis.  J Crohn's Colitis.  2012;6(10):965-90. 
5.
Rutter M, Saunders B, Wilkinson K, et al.  Severity of inflammation is a risk factor 
for colorectal neoplasia in ulcerative colitis.  Gastroenterology.  
2004;126(2):451-9. 
6.
Truelove SC, Witts LJ.  Cortisone and corticotrophin in ulcerative colitis.  Br Med 
J.  1959;1(5119):387-94. 
7.
Third European evidence-based consensus on diagnosis and management of 
ulcerative colitis.  Part 2:  current management.  Available from:  
https://doi.org/10.1093/ecco-jcc/jjx009. 
8.
Chaparro M, Ordás I, Cabré E, et al.  Safety of thiopurine therapy in inflammatory 
bowel disease:  long-term follow-up study of 3931 patients.  Inflamm Bowel Dis.  
2013;19(7):1404-10. 
9.
Kornbluth A, Sachar DB; Practice Parameters Committee of the American College 
of Gastroenterology.  Ulcerative colitis practice guidelines in adults:  American 
College of Gastroenterology, Practice Parameters Committee.  Am J Gastroenterol.  
2010;105(3):501-23; quiz 524. 


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10.
Beaugerie L, Brousse N, Bouvier AM, et al.  Lymphoproliferative disorders in 
patients receiving thiopurines for inflammatory bowel disease:  a prospective 
observational cohort study.  Lancet.  2009;374(9701):1617-25. 
11.
Aratari A, Papi C, Clemente V, et al.  Colectomy rate in acute severe ulcerative 
colitis in the infliximab era.  Dig Liver Dis.  2008;40(10):821-6. 
12.
Turner D, Walsh CM, Steinhart AH, et al.  Response to corticosteroids in severe 
ulcerative colitis:  a systematic review of the literature and a meta-regression.  Clin 
Gastroenterol Hepatol.  2007;5(1):103-10. 
13.
Sandborn WJ.  State-of-the-art:  immunosuppression and biologic therapy.  Dig 
Dis.  2010;28(3):536-42. 
14.
Rutgeerts P, Sandborn W, Feagan B, et al.  Infliximab for induction and 
maintenance therapy for ulcerative colitis.  N Engl J Med.  2005;353(23):2462-76. 
15.
Sandborn WJ, van Assche G, Reinisch W, et al.  Adalimumab induces and 
maintains clinical remission in patients with moderate-to-severe ulcerative colitis.  
Gastroenterology.  2012;142(2):257-65. 
16.
Feagan B, Greenberg G, Wild G, et al.  Treatment of ulcerative colitis with a 
humanized antibody to the alpha4beta7 integrin.  N Engl J Med.  
2005;352(24):2499-507. 
17.
Sandborn W, Feagan B, Marano C, et al.  Subcutaneous golimumab induces 
clinical response and remission in patients with moderate-to-severe ulcerative 
colitis.  Gastroenterology.  2014;146(1):85-95; quiz e14-5. 
18.
Siakavellas SI, Bamias G.  Role of the IL-23/IL-17 axis in Crohn's disease.  Discov 
Med.  2012;14(77):253-62. 
19.
Boyapati R, Satsangi J, Ho GT.  Pathogenesis of Crohn's disease.  F1000Prime 
Rep.  2015;7:44. 
20.
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE).  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_4
0. 


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21.
Pinheiro J, Bornkamp B, Bretz F.  Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures.  J Biopharm Stat.  
2006;16(5):639-56. 
22.
Bretz F, Pinheiro JC, Branson M.  Combining multiple comparisons and modeling 
techniques in dose-response studies.  Biometrics.  2005;61(3):738-48. 
23.
McKeegan E, Ansell P, Davis G, et al.  Plasma biomarker signature associated with 
improved survival in advanced non-small cell lung cancer patients on linifanib.  
Lung Cancer.  2015;90(2):296-301. 
24.
Chen G, Zhong H, Belousov A, et al.  A PRIM approach to predictive-signature 
development for patient stratification.  Stat Med.  2015;34(2):317-42 
25.
Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis.  N Engl J Med.  
1987;317(26):1625-9. 
26.
Lewis JD, Chuai S, Nessel L, et al.  Use of the noninvasive components of the 
Mayo Score to assess clinical response in ulcerative colitis.  Inflamm Bowel Dis.  
2008;14(12):1660-6. 
27.
Sampson HA, Muñoz-Furlong A, Campbell RL, et al.  Second symposium on the 
definition and management of anaphylaxis:  summary report--Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium.  J Allergy Clin Immunol.  2006;117(2):391-7. 
28.
Marshall WA, Tanner JM.  Variations in pattern of pubertal changes in girls.  Arch 
Dis Child.  1969;44(235):291-303. 
29.
Marshall WA, Tanner JM.  Variations in the pattern of pubertal changes in boys.  
Arch Dis Child.  1970;45(239):13-23. 


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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
Global Development Lead
Clinical Development, Immunology
Medical Director
Clinical Development, Immunology
Director
Statistics
Director Pharmacokinetics
Clinical Pharmacology and Pharmacometrics
Senior Scientist
Bioanalysis
Study Project Manager II
Clinical Operations


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Appendix C.
Study Activities Sub-Study 1 and Sub-Study 2
Screening Period 
(35 Days)a
Induction Period 1
Induction Period 2
Unschb
140-Day 
Follow-Upc
Activity 
Screening
Baseline
Week 4
Week 8
Week 12/PDw
Week 16
Week 20
Week 24
Informed consent
X 
Inclusion/Exclusion
X 
Xd
Medical/Surgery History
X 
Xd
Previous and Concomitant 
Medication
X 
Xd
X 
X 
X 
X 
X 
X 
X 
Physical Exame/Vital Signsf
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessmentg
SAEs only
X 
X 
X 
X 
X 
X 
X 
X 
X 
TB Screeningh
Xy
ECGi
Xy
Hepatitis B, Hepatitis C Screeningj
and HIV Testk
Xy
Xl
Xl
C. difficile toxin
Xx
Urinalysism,p
Xx
Xn
X 
X 
Pregnancy Testo,p
Xx
Xn
X 
X 
X 
X 
X 
X 
Chemistry and Hematologyp
Xx
Xn
X 
X 
X 
X 
X 
X 
COVID-19 Assessment
Xaa
hs-CRPp
X 
X 
X 
X 
X 
Serum Risankizumabq  
X 
X 
X 
X 
X 


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Screening Period 
(35 Days)a
Induction Period 1
Induction Period 2
Unschb
140-Day 
Follow-Upc
Activity 
Screening
Baseline
Week 4
Week 8
Week 12/PDw
Week 16
Week 20
Week 24
Serum Anti-Drug Antibody (ADA)q
and Neutralizing Anti-Drug 
Antibodies (nAb)q
X 
X 
X 
X 
X 
X 
Fecal calprotectin (FCP)r,p
X 
X 
X 
X 
Partial Adapted Mayobb
X 
X 
X 
X 
X 
Adapted Mayo/Full Mayos
X 
X 
X 
Endoscopys
X 
X 
X 
PGAz
X 
X 
X 
X 
X 
X 
X 
Intestinal Biopsiest
X 
X 
X 
Dispense Subject Diaryu
X 
Subject Diary Review
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Questionnaire:
UC-SQ
X 
X 
X 
X 
X 
X 
X 
X 
Subject Questionnaire:
PGIC
PGIS
X (PGIS 
Only)
X 
X 
X 
X 
X 
X 
X 
Subject Questionnaires:
  EQ-5D-5L
  FACIT-F 
  IBDQ 
  SF-36  
  WPAI-UC
X 
X 
X 
Study Drug Administrationv
X 
X 
X 
Xv
X 
X 


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a.
The Screening period is approximately 35 days.  It should be a minimum of 3 days for SFS and RBS calculation.  The Baseline Adapted Mayo score will be calculated using 
the data collected during the Screening period.  Baseline visit date will serve as the reference for all subsequent visits.  A ± 7 day window is permitted around all 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 a visit for 
evaluation and assessment.
c.
Subjects will be contacted 140 days following last dose of study drug for an assessment of any new or ongoing AEs, except subjects who roll-over into Study M16-066 after 
the end of study participation.
d.
Update inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information to assure subject eligibility.
e.
Physical examinations are full physical examinations at Screening and Week 12 and Week 24 if the subject receives blinded treatment during Induction Period 2.  Physical 
examinations at all other visits (including unscheduled visits) are symptom based.
f. 
Blood pressure, pulse rate, temperature, respiratory rate and weight should be performed before blood draws are performed.  
g.
Collection of SAEs begins the day the subject signs the informed consent.
h.
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).  PPD skin 
test is to be read 48 to 72 hours after placement.  In case of positive PPD/positive or repeat indeterminate IGRA testing, subjects may participate in the study if further work 
up (according to local practice/guidelines) is negative for active TB.
Subjects with a negative QuantiFERON-TB Gold (and/or PPD) test at Screening of the preceding Study M16-067 will be tested annually for TB by either the QuantiFERON-
TB Gold Test (or equivalent) or a TB Skin Test Purified Protein Derivative (PPD).  If PPD and/or the QuantiFERON-TB Gold test (or Interferon gamma release assay 
[IGRA] equivalent) is positive, or if there is a repeat indeterminate (note:  the first indeterminate results must be repeated) QuantiFERON-TB Gold test (or IGRA equivalent) 
upon retesting, patients may continue their participation in the study if further work up (according to local practice/guidelines) establishes conclusively that the patient has no 
evidence of active tuberculosis.
i.
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.  Subjects can 
have a repeat ECG at any time during the study as warranted based on the opinion of the Investigator. 
j.
Subjects will be tested for the presence of the HBV and HCV at Screening.  A positive result for the hepatitis B surface antigen (HBs Ag) or hepatitis C (HCV RNA 
detectable in any subject with anti-HCV Ab) will be exclusionary.  For subjects who are negative for HBs Ag but are positive for core antibodies (HBc Ab), HBV DNA PCR 
will be performed and any result that meets or exceeds detection sensitivity will be exclusionary.
k.
HIV testing will be performed at the central laboratory, which will report the results directly to the sites.  AbbVie will not receive results from the testing.
l.
Japan and China only:  for subjects with HBs Ab (+) and/or HBc Ab (+) at Screening, the HBV-DNA PCR test should be performed again at Week 12 and Week 24.  
Retesting at Week 12 and Week 24 is not necessary for subjects that have a history of HBV vaccine and are HBs Ab (+).
m.
Dipstick urinalysis will be completed by the sites at required visits.  A microscopic analysis will be performed by the central laboratory, in the event the dipstick results show 
leukocytes, nitrite, protein, ketones or blood greater than negative or glucose greater than normal.


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n.
Lab assessments will only need to be repeated at Baseline if the time between Screening and Baseline is greater than 14 days, or if the subject's health status has changed to 
warrant a repeat test.
o.
Serum pregnancy test will be performed on all WOCBP at Screening.  Urine pregnancy test will be performed locally as indicated in the table for all WOCBP.  The urine 
pregnancy test must be negative to receive study drug.  If any urine pregnancy test is positive, a serum pregnancy test will be performed by the central laboratory.  FSH will 
be performed in all female subjects < 55 years old with no menses for 12 months.
p.
Urinalysis, chemistry and hematology, hs-CRP, and FCP may be collected at other scheduled and unscheduled visits than indicated in the table if they are warranted by the 
Investigator.
q.
Serum risankizumab concentrations and ADA will be determined from samples collected just prior to dosing at every visit.  The date and time of sample collection will be 
captured on the lab requisition form.
r. 
Stool sample will be collected at each time point indicated in the table.  For the visit when endoscopy will be conducted, stool sample should be collected prior to bowel prep 
and should be returned to the site per the timelines specified in the lab manual.  If a sample cannot be obtained during the site visit, the site will give instructions and a stool 
sample supply kit.
s.
A full colonoscopy will be performed at Screening unless the subject underwent a full colonoscopy within 12 months prior to Screening.  There must be appropriate 
documentation available to confirm the diagnosis, extent of disease, and to exclude dysplasia and colon cancer.  If this is available, the screening endoscopy may be either a 
full colonoscopy or a flexible sigmoidoscopy.  All other endoscopies may be flexible sigmoidoscopies or colonoscopies at the discretion of the investigator.  Endoscopy 
at/during the screening period or within 45 days of the Baseline visit will be used to calculate the Mayo endoscopy subscore at Baseline.  Endoscopic evaluations using Mayo 
endoscopic subscore confirmed by central review will be done at Screening.  Endoscopies completed at Week 12 (or Week 24, for subjects who received blinded treatment 
during Induction Period 2), will use the local reader results for stratification for Study M16-066 and to evaluate clinical response for enrollment in Study M16-066.
t.
Biopsy for histologic assessment by central review will be conducted at each visit with endoscopy.  Biopsies may be done when performing the endoscopy to confirm UC 
diagnosis (if appropriate documentation for confirmation of the diagnosis does not exist), and/or to rule out dysplasia and colon cancer at the Investigator's discretion.  These 
samples will be processed and assessed locally.  Histology report should be available in the subject's source records.  
u.
Subjects should also be dispensed the patient information card.
v.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed.  Completion of PROs are permitted during 
administration of study drug.  Study drug will only be administered at Week 12 for subjects who receive blinded treatment during Induction Period 2.  Subjects will also be 
dispensed a patient information card.  In the event of a suspected systemic post-dose hypersensitivity reaction, serum risankizumab, ADA, and nAb should be collected once 
within 24 hours of the reaction.  In addition, tryptase sample should be obtained between 15 minutes to 3 hours of symptom onset, and no later than 6 hours, and another 
sample is requested a minimum of 2 weeks after the recorded event or at the next study visit.  Also, plasma histamine sample should be obtained within 5 to 15 minutes of the 
onset of symptoms and no later than 1 hour Histamine and tryptase samples are not applicable for China.
w.
PD refers to any premature discontinuation visit, occurred before or after W12 visit.


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x. 
For Rescreening, if a subject is being rescreened within 14 days (≤ 14 days have passed)from the collection date of the previous screening laboratory testing, repeat laboratory 
testing for chemistry/hematology, urinalysis, serum pregnancy, and C. difficile are not required unless, in the opinion of the Investigator, the subject's health status has 
changed.
y.
For Rescreening, if the subject had a complete initial screening evaluation including the TB test, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency 
virus (HIV), and electrocardiogram (ECG), these tests will not be required to be repeated for re-screening provided the conditions noted in Section XX are met and no more 
than 90 days have passed since the collection date of the testing.
z.
Physician Global Assessment (PGA) will be entered by the investigator in the Trialmax system and in the medical notes at all study visits.
aa.
Assessment for signs/symptoms of COVID-19 infection.  If the investigator suspects the possibility of COVID-19 based on the signs, symptoms and medical complaint (chief 
complaint, history of exposure, etc.), local laboratory testing must be completed to confirm negative for infection.
bb. If the event endoscopy cannot be performed at Week 12 or 24 due to COVID-19 pandemic restrictions or geo-political conflict in Ukraine and surrounding impacted regions, 
clinical response will be calculated using the Partial Adapted Mayo score. 


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Appendix D.
Study Activities 
Optional Exploratory Research Samples (Sub-Study 1) 
Screening Period (35 Days)
Induction Period 1
Induction Period 2
Samples Collecteda
Screening
Baseline
Week 4
Week 12/PDe
Week 24
Pharmacogeneticb
X 
Epigenetic
X 
X 
X 
X 
Transcriptomicb
X 
X 
X 
X 
Proteomic and targeted protein investigations (plasma)b
X 
X 
X 
X 
Proteomic and targeted protein investigations (serum)b
X 
X 
X 
X 
PBMC (US sites only)c
X 
X 
Stoolb
X 
X 
X 
Intestinal biopsies (RNA)b,d
X 
X 
X 
a.
Collections to be performed only if subject provides separate written consent to collect the exploratory research samples; if the separate consent is not signed, no samples can 
be collected.
b.
Based on the value of different technologies, samples may also be used to assess other biomarker signatures, including but not limited to metabolomics, lipidomics, 
proteomics, microbiome analysis and other approaches.
c.
Collected at US sites only.
d.
Biopsy may be done when performing the endoscopy. 
e. 
PD refers to any premature discontinuation visit, occurred before or after W12 visit.


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Optional Exploratory Research Samples (Sub-Study 2) 
Screening Period (35 Days)a
Induction Period 1
Induction Period 2
Samples Collecteda
Screening
Baseline
Week 4
Week 
12/PDd
Week 24
Pharmacogeneticb
X 
Epigeneticb
X 
X 
X 
Transcriptomicb
X 
X 
X 
Proteomic and targeted protein investigations (plasma)b
X 
X 
X 
Intestinal biopsies (RNA)b,c
X 
X 
X 
a.
Collections to be performed only if subject provides separate written consent to collect the exploratory research samples; if the separate consent is not signed, no samples can 
be collected.
b.
Based on the value of different technologies, samples may also be used to assess other biomarker signatures, including but not limited to metabolomics, lipidomics, and other 
approaches.
c.
Biopsy may be done when performing the endoscopy. 
d.
PD refers to any premature discontinuation visit, occurred before or after W12 visit.


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Appendix E.
Script for Collection of Mayo Scores for Use in Study M16-067* 
●
3 different Mayo Scores are evaluated in this protocol: 
1.
Full Mayo Score 
2.
Adapted Mayo Score 
3.
Partial Adapted Mayo Score 
1.
The Full Mayo Score is a composite of the following subscores:  Stool Frequency 
subscore, Rectal Bleeding subscore, Endoscopy subscore, and Physician's Global 
Assessment subscore.
●
In the protocol Full Mayo Score is calculated at the visits specified in 
Appendix C to evaluate study endpoints as described in Section 5.3.3. 
2.
The adapted Mayo Score is a composite of the following subscores:  Stool 
Frequency subscore, Rectal Bleeding subscore and Endoscopy subscore 
In the protocol adapted Mayo Score is calculated:
●
To evaluate subject eligibility at screening as described in Section 5.2.1
●
To be used as stratification factor at baseline
●
To evaluate if subjects achieve clinical response at W12 and W24 as described 
in Section 5.1  
●
To evaluate study endpoints as described in Section 5.3.3 at the visits specified 
in Appendix C
3.
The Partial Adapted Mayo Score is a composite of the following subscores:  Stool 
Frequency subscore and Rectal Bleeding subscore. 
●
In the protocol Partial Adapted Mayo Score is calculated at the visits specified 
in Appendix C to evaluate study endpoints as described in Section 5.3.3
* 
Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-ASA therapy for mildly to moderately active ulcerative 
colitis.  N Engl J Med.  1987;317(26):1625-9.25
Lewis JD, Chuai S, Nessel L, et al.  Use of the noninvasive components of the Mayo Score to assess clinical 
response in ulcerative colitis.  Inflamm Bowel Dis.  2008;14(12):1660-6.26


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Subscores: 
Stool frequency Subscore* 
0 = Normal number of stools for this subject 
1 = 1 – 2 stools more than normal 
2 = 3 – 4 stools more than normal 
3 = 5 or more stools more than normal 
* 
Each patient serves as his or her own control to establish normal stool frequency and the degree of 
abnormal stool frequency.  
Rectal bleeding Subscore**
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passed 
** The daily bleeding score represents the most severe bleeding of the day.  
Endoscopy Subscore:  Findings of flexible sigmoidoscopy
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration)
Physician's Global Assessment Subscore*** 
0 = Normal (Subscores are 0) 
1 = Mild disease (Subscores are mostly 1's) 
2 = Moderate disease (Subscores are 1 to 2) 
3 = Severe disease (Subscores are 2 to 3) 
*** The physician's global assessment acknowledges the three other subscores, the subject's daily 
record of abdominal discomfort and functional assessment, and other observations such as physical 
findings, and the subject's performance status.  
Source:  Schroeder 1987.25
Stool Frequency Subscore
●
The stool frequency subscore is calculated by comparing the stool frequency to 
a reference number.  The reference number is the number of stools per day 
(24 hours) that is typical for the subject when having active UC but not 
experiencing a flare and needs to be designated once prior to enrollment.  The 
reference number should represent a full number of at least 1. 


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●
Subjects will record the daily number of stools throughout the trial.  Using 
these numbers, the Stool Frequency subscore will be assessed for each study 
day as follows:  
○
A number of bowel movements lower than or equal to the reference 
number of bowel movements should be scored as 0 = Normal. 
○
One or 2 bowel movements more than the reference number of bowel 
movements should be scored as 1. 
○
Three or 4 bowel movements more than the reference number of bowel 
movements should be scored as 2. 
○
Five or more bowel movements more than the reference number of bowel 
movements should be scored as 3. 
●
The Stool Frequency subscores based on 3 days prior to each study visit will 
be averaged and used for the Stool Frequency subscore for each study visit. 
●
The Stool Frequency subscore during days which the subject received 
anti-diarrheal medication will be scored as a 3.
●
Diary entries for stool frequency should not be included in the 3 days prior to 
the visit that are evaluated for the Stool Frequency subscore for the following 
days:  (1) the day the subject received medication for bowel preparation prior 
to endoscopy, (2) the day the subject underwent an endoscopy, and (3) 2 days 
following the endoscopy.  Earlier diary entries will be used accordingly in 
order to provide the most recent data for 3 days prior to the respective study 
visit.
Rectal Bleeding Subscore
●
Subjects will be assigned a daily rectal bleeding subscore value as follows: 
○
No visible blood with stool during the respective day should be scored as 
0. 
○
Visible blood with stool less than half the time during the respective day 
should be scored as 1. 
○
Visible blood with stool at least half the time during the respective day 
should be scored as 2. 


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○
A score of 3 for bleeding requires subjects to have at least 50% of bowel 
movements accompanied by visible blood and at least one bowel 
movement with blood alone. 
●
The score entries into subject's diary based on 3 days prior to each study visit 
will be averaged and used for the Rectal Bleeding subscore for each study 
visit.  
●
Diary entries for rectal bleeding should not be included in the 3 days prior to 
the visit that are evaluated for the Rectal Bleeding subscore for the following 
days:  (1) the day the subject received medication for bowel preparation prior 
to endoscopy, (2) the day the subject underwent an endoscopy, and (3) 2 days 
following the endoscopy.  Earlier diary entries will be used accordingly in 
order to provide the most recent data for 3 days prior to the respective study 
visit.
Physician's Global Assessment Subscore
●
The physician's global assessment acknowledges the 2 subject-reported 
subscores, the endoscopy subscore as applicable, the subject's daily record of 
abdominal discomfort and general well-being during based on the 3 days prior 
to the visit, and other observations such as physical findings, and the subject's 
performance status in order to assess disease activity as follows:
○
0 = Normal
○
1 = Mild disease
○
2 = Moderate disease
○
3 = Severe disease
Investigator will enter the PGA in the Trialmax study system and record it in the medical 
notes at each study visit. 


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Endoscopy Subscore
●
The endoscopist should evaluate each observed segment of the colon (rectum, 
sigmoid, descending colon, transverse colon, ascending colon/cecum) by using 
the classification as follows:
○
0 = Normal or inactive disease
○
1 = Mild disease (erythema, decreased vascular pattern)
○
2 = Moderate disease (marked erythema, absent vascular pattern, friability, 
erosions) 
○
3 = Severe disease (spontaneous bleeding, ulceration) 
●
The endoscopic subscore for the subject will be the worst score of the observed 
segments.
●
The local endoscopist should also separately assess presence or absence of 
friability (yes/no).
●
The endoscopy will be recorded (not a still image) and sent to a central review 
vendor for scoring as described in the central review charter. 
* 
Schroeder KW, Tremaine WJ, Ilstrup DM.  Coated oral 5-ASA therapy for mildly to moderately active ulcerative 
colitis.  N Engl J Med.  1987;317(26):1625-9.25
Lewis JD, Chuai S, Nessel L, et al.  Use of the noninvasive components of the Mayo Score to assess clinical 
response in ulcerative colitis.  Inflamm Bowel Dis.  2008;14(12):1660-6.26


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Appendix F.
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis27 is highly likely when any one of the following 3 criteria are fulfilled: 
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
b.
Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence) 
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours): 
a.
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips tongue-uvula) 
b.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
c.
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d.
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
e.
Infants and children:  low systolic BP (age specific) or greater than 30% 
decrease in systolic BP*
f.
Adults:  systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person's baseline 


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PEF:  peak expiratory flow; BP:  blood pressure
* 
low systolic BP for children is defined as less than 70 mmHg from 1 month to 1 year, less than (70 mmHg + 
[2 × age]) from 1 to 10 years, and less than 90 mgHg from 11 to 17 years. 
Serious Systemic Hypersensitivity Reaction:  A hypersensitivity reaction is a clinical 
sign or symptom, or constellation of signs or symptoms, caused by an inappropriate and 
excessive immunologic reaction to study drug administration.  A systemic 
hypersensitivity reaction is a hypersensitivity reaction that does not occur at the local site 
of study drug administration (e.g., not an injection site reaction).  A serious systemic 
hypersensitivity reaction is a systemic hypersensitivity reaction that fulfills criteria for a 
serious adverse event as specified in Section 6.1.1.2. 
In the event of an anaphylactic reaction, blood samples will be drawn per Appendix C
after the onset of the reaction.  This will include:  ADA, nAb, histamine and tryptase.  
Separate instructions for the collection, handling, storage and shipping of these labs will 
be provided outside of the study protocol.  Histamine and tryptase samples are not 
applicable for China.


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Appendix G.
Tanner Stage 5 for Development*
Puberty and the Tanner Stages – developed by Professor James M Tanner 
Introduction 
Adolescents experience several types of maturation, including cognitive (the development 
of formal operational thought), psychosocial (the stages of adolescence), and biologic.  
The complex series of biologic transitions are known as puberty, and these changes may 
impact psychosocial factors. 
The most visible changes during puberty are growth in stature and development of 
secondary sexual characteristics.
Equally profound are changes in body composition; the achievement of fertility; and 
changes in most body systems, such as the neuroendocrine axis, bone size, and 
mineralization; and the cardiovascular system.  As an example, normal cardiovascular 
changes, including greater aerobic power reserve, electrocardiographic changes, and 
blood pressure changes, occur during puberty. 
The normal sequence of pubertal events and perils of puberty are reviewed here.  This is 
within the normal ranges and does not take into account Precocious Puberty or Delayed 
Puberty. 
Tanner Stages
Conceptually, pubertal maturation can be described in terms of sequence, timing, and 
tempo (Puberty consists of a series of predictable events, and the sequence of changes in 
secondary sexual characteristics has been categorized by several groups.  The staging 
system utilized most frequently is that published by Marshall and Tanner and the 
sequence of changes, commonly referred to as "Tanner stages," is described below.


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Boys – development of external genitalia 
Stage 1:  Prepubertal
Stage 2:  Enlargement of scrotum and testes; scrotum skin reddens and changes in texture 
Stage 3:  Enlargement of penis (length at first); further growth of testes 
Stage 4:  Increased size of penis with growth in breadth and development of glans; testes 
and scrotum larger, scrotum skin darker 
Stage 5:  Adult genitalia
Girls – breast development 
Stage 1:  Prepubertal
Stage 2:  Breast bud stage with elevation of breast and papilla; enlargement of areola
Stage 3:  Further enlargement of breast and areola; no separation of their contour 
Stage 4:  Areola and papilla form a secondary mound above level of breast 
Stage 5:  Mature stage: projection of papilla only, related to recession of areola 
Boys and girls – pubic hair 
Stage 1:  Prepubertal (can see velus hair similar to abdominal wall)
Stage 2:  Sparse growth of long, slightly pigmented hair, straight or curled, at base of 
penis or along labia 
Stage 3:  Darker, coarser and more curled hair, spreading sparsely over junction of pubes 
Stage 4:  Hair adult in type, but covering smaller area than in adult; no spread to medial 
surface of thighs 
Stage 5:  Adult in type and quantity, with horizontal distribution ("feminine") 
Boys Growth 
●
Stage 1:  5 – 6 cm/year
●
Stage 2:  5 – 6 cm/year
●
Stage 3:  7 – 8 cm/year
●
Stage 4:  10 cm/year


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●
Stage 5:  No further height increase after 17 years 
Girls Growth
●
Stage 1:  5 – 6 cm/year
●
Stage 2:  7 – 8 cm/year
●
Stage 3:  8 cm/year
●
Stage 4:  7 cm/year
●
Stage 5:  No further height after 16 years 
* 
Marshall WA, Tanner JM.  Variations in pattern of pubertal changes in girls.  Arch Dis Child.  
1969;44(235):291-303.28
Marshall WA, Tanner JM.  Variations in the pattern of pubertal changes in boys.  Arch Dis Child.  
1970;45(239):13-23.29


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Appendix H.
Optional Intensive PK Subjects
At the time of this amendment, intense PK sub-study had been already completed during 
Sub-Study 1. 
Samples for pharmacokinetics (PK) analysis will be collected in all subjects as described 
in Appendix C (Prior to dose at Weeks 4, 8, 12/PD and 24).  For the subjects who consent 
to the optional intensive PK sampling, in addition to the time points above, blood for PK 
evaluation will be collected per the schedule shown below.  All other study procedures 
should be conducted as outlined in Section 5.0. 
●
Week 8:  immediately after completion of infusion and 2 hours post 
completion of infusion 
●
Weeks 9, 10, 11.  A visit window of ± 3 days would be applicable for these 
visits
PK samples should be processed according to the guidelines in Section 5.3.2.2 and 
Section 5.3.2.3.  Subjects will follow all other protocol-specified procedures (as outlined 
in Appendix C).
NOTE:  The date and time of site-administered dose and blood sample collection will be 
recorded to the nearest minute in the source documents and will be recorded to the nearest 
minute on the eCRF. 

SAP_001.pdf: 


















































































































































Document Approval
Study Report Appendix - m16067-sap-v2-substudy2 - 14-Feb-2023
Version: 1.0
Date: 14-Feb-2023
Company ID: 20230214-0900f9f6860359f7-1.0-en
Signed by:
Date:
Meaning of
Signature:
14-Feb-2023
21:00 UTC
Approver
13-Feb-2023
13:10 UTC
Approver
11-Feb-2023
22:23 UTC
Author
10-Feb-2023
22:25 UTC
Approver - Statistics
10-Feb-2023
22:22 UTC
Approver


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Statistical Analysis Plan Sub-Study 1 of Study 
M16-067
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Induction Study to Evaluate the 
Efficacy and Safety of Risankizumab in Subjects 
with Moderately to Severely Active Ulcerative 
Colitis Who Have Failed Prior Biologic Therapy
Date:  18 November 2020
Version 6.0
 


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypotheses ........................................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................8
2.4
Sample Size Determination......................................................................10
3.0
Endpoints................................................................................11
3.1
Primary Endpoint(s).................................................................................11
3.2
Secondary Endpoint(s).............................................................................11
3.3
Other Efficacy Endpoints.........................................................................13
3.4
Safety Endpoint(s) ...................................................................................14
4.0
Analysis Populations .............................................................14
5.0
Subject Disposition................................................................15
6.0
Study Drug Duration and Compliance................................16
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................18
7.1
Demographics and Baseline Characteristics............................................18
7.2
Medical History .......................................................................................21
7.3
Prior and Concomitant Medications ........................................................21
8.0
Efficacy Analyses...................................................................22
8.1
General Considerations............................................................................22
8.2
Handling of Missing Data........................................................................22
8.3
Primary Efficacy Endpoint(s) and Analyses............................................24
8.3.1
Primary Efficacy Endpoint(s) ..................................................................24
8.3.2
Handling of Missing Data for the Primary Efficacy Endpoint(s)............24
8.3.3
Primary Efficacy Analysis .......................................................................24
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s) ......................25
8.4
Secondary Efficacy Analyses...................................................................26
8.5
Additional Efficacy Analyses ..................................................................26
8.6
Efficacy Subgroup Analyses....................................................................27
9.0
Safety Analyses ......................................................................28
 


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9.1
General Considerations............................................................................28
9.2
Adverse Events ........................................................................................28
9.2.1
Treatment-Emergent Adverse Events ......................................................29
9.2.2
Adverse Event Overview .........................................................................30
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................30
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................31
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................31
9.2.6
Adverse Events of Safety Interest............................................................31
9.3
Analysis of Laboratory Data....................................................................31
9.4
Analysis of Vital Signs ............................................................................33
9.5
Safety Subgroup Analyses .......................................................................34
9.6
Other Safety Analyses..............................................................................34
10.0
Other Analyses.......................................................................34
11.0
Interim Analyses....................................................................34
11.1
Data Monitoring Committee....................................................................34
12.0
Overall Type-I Error Control ..............................................35
13.0
Version History......................................................................36
14.0
References...............................................................................36
List of Tables
Table 1.
SAP Version History Summary...............................................................36
List of Figures
Figure 1.
Induction Period 1 of Study M16-067 Sub-Study 1* (Phase 2b) ..............7
Figure 2.
Induction Period 2 of Study M16-067 (Sub-Study 1)................................8
List of Appendices
Appendix A.
Protocol Deviations..................................................................................38
 


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Appendix B.
Definition of Adverse Events of Safety Interest ......................................39
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints ...............42
Appendix D.
Common Toxicity Criteria (CTC) Grade for Laboratory Data................44
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Sub-study 1 of 
Study M16-067 only, A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Induction Study to Evaluate the Efficacy and Safety of Risankizumab in Subjects with 
Moderately to Severely Active Ulcerative Colitis Who Have Failed Prior Biologic 
Therapy.
M16-067 comprises 2 sub-studies: a Phase 2b dose-ranging induction sub-study (Sub-
study 1) and a Phase 3 induction sub-study (Sub-study 2).  Sub-study 1 (Phase 2b 
induction) is to characterize the efficacy, safety, and pharmacokinetics of risankizumab as 
induction treatment in subjects with moderately to severely active UC and to identify the 
appropriate induction dose of risankizumab for further evaluation in Sub-study 2 (Phase 3 
induction).  Sub-study 2 (Phase 3 induction) is to evaluate the efficacy and safety of 
risankizumab compared to placebo in inducing clinical remission in subjects with 
moderately to severely active UC.
The analyses of pharmacokinetic and biomarker analyses will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 or later 
(SAS Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol amendment 2 dated 
February 14, 2018.  Details are outlined in Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
●
The objectives of Sub-Study 1 (Phase 2b induction) are to characterize the 
efficacy, safety, and pharmacokinetics of risankizumab as induction treatment 
 


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in subjects with moderately to severely active Ulcerative Colitis (UC) and to 
identify the appropriate induction dose of risankizumab for further evaluation 
in Sub-Study 2 (Phase 3 induction)
2.2
Study Design Overview
Sub-study 1 is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled 
study.  The study will enroll patients who have had intolerance or inadequate response 
(IR) to prior biologic therapy (bio-IR).
In Induction Period 1, approximately 240 subjects will be randomized in a 1:1:1:1 ratio as 
shown in Figure 1. Once all 240 randomized subjects have completed the 12-week 
Induction Period 1, dose response and exposure response analysis for the key efficacy and 
safety variables will be performed.  During the analysis, Sub-Study 1 will continue to 
enroll additional subjects in the 1800 mg dosing group, on an open-label basis, to avoid 
interrupting the study activities during the analysis period and to generate a sufficient 
number of subjects with clinical response to be enrolled into the maintenance Study M16-
066.
At Week 12, subjects who do not achieve clinical response will be randomized by 
Interactive Response Technologies (IRT) to Induction Period 2 (see schematics in 
Figure 2), a double-blind, double-dummy 12-week treatment period to evaluate 
reinduction with risankizumab versus starting maintenance dosing on clinical response 
status. 
For details of the study design, visits and variables collected at each visits, refer to the 
protocol.
 


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Figure 1.
Induction Period 1 of Study M16-067 Sub-Study 1* (Phase 2b)
DC = discontinue; IR = subjects with inadequate clinical response; IV = intravenous; R = subjects with clinical 
response; SS-1 = Sub-Study 1
*
DBL for Study M16-067 Sub-Study 1 occurs after first randomized 240 subjects complete 12 weeks assessment.  
After 240 subjects have been enrolled and before the dose has been selected for Sub-Study 2, additional subjects 
will continue to be enrolled into Sub-Study 1, where they will be assigned to the risankizumab 1800 mg IV 
Wks 0, 4 and 8 dosing group.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2.
Induction Period 2 of Study M16-067 (Sub-Study 1)
DC = discontinue; RZB = risankizumab; IR = subjects with inadequate response; IV = intravenous; Plb = placebo; 
R = subjects with clinical response; RR = re-randomize; SC = subcutaneous; TBD = to be determined
*
Subjects who enter from Study M16-067 Sub-Study 1 will receive risankizumab 1800 mg IV.
2.3
Treatment Assignment and Blinding
Sub-Study 1 (Phase 2b Induction):
Induction Period 1:
Subjects (n = 240) who meet all of the inclusion criteria and none of the exclusion criteria 
will be randomized into the study in a 1:1:1:1 ratio to one of the following treatment 
groups:
●
Group 1:  Risankizumab 1800 mg IV Weeks 0, 4, 8 (n = 60)
●
Group 2:  Risankizumab 1200 mg IV Weeks 0, 4, 8 (n = 60)
●
Group 3:  Risankizumab 600 mg IV Weeks 0, 4, 8 (n = 60)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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●
Group 4:  Placebo IV Weeks 0, 4, 8 (n = 60)
The randomization at baseline will be stratified by baseline steroid use (yes vs no) and 
baseline Adapted Mayo score (≤ 7 vs > 7).  Endoscopy and evaluation of clinical response 
and remission will occur at Week 12.
Induction Period 2:
At Week 12, subjects who do not achieve clinical response will be randomized by 
Interactive Response Technologies (IRT) to Induction Period 2, a double-blind, double-
dummy 12-week treatment period to evaluate reinduction with risankizumab versus 
starting maintenance dosing on clinical response status.
Subjects who received IV risankizumab induction will be randomized 1:1:1 to:
●
Group 1:  1800 mg IV risankizumab Weeks 12, 16, 20
●
Group 2:  360 mg SC risankizumab Weeks 12, 20
●
Group 3:  180 mg SC risankizumab Weeks 12, 20
Subjects who received IV placebo induction treatment will receive:
●
Group 4:  1800 mg IV risankizumab Weeks 12, 16, 20
Subjects randomized in Groups 1 and 4 will receive placebo SC and subjects randomized 
in Groups 2 and 3 will received placebo IV, in order to keep the blind.  The IV 
risankizumab dose or matching IV placebo will be given at Weeks 12, 16, and 20.  The 
SC risankizumab dose or matching SC placebo will be given at Weeks 12, and 20.
Dose Selection Analysis:
During this analysis, Sub-Study 1 will continue to enroll additional subjects in the 
1800 mg dosing group, on an open-label basis, to avoid interrupting the study activities 
 


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during the analysis period and to generate a sufficient number of subjects with clinical 
response to be enrolled into the maintenance Study M16-066.
2.4
Sample Size Determination
Sub-Study 1 (Phase 2b):
For Sub-Study 1 (Phase 2b portion of the study), approximately 240 subjects in the 
Bio-IR population will be equally randomized using a 1:1:1:1 ratio to three risankizumab 
treatment groups (600 mg, 1200 mg and 1800 mg IV Q4W) and the placebo group.  The 
sample size for this study is based on the expected proportion of subjects who achieve 
clinical remission per Adapted Mayo Score at Week 12.  Assuming clinical remission rate 
of 7% in the placebo arm and maximum of 25% in at least one of the risankizumab 
treatment groups at Week 12, a sample size of 60 subjects per treatment group is 
sufficient to test for the presence of a dose response signal, to select the best dose 
response model for the observed data out of a pre-specified set of candidate models, and 
to estimate target doses of interest (e.g., MED) via modeling using MCP-Mod (Multiple 
comparison procedure and modeling) approach.1,2  The assumptions for the rates of 
clinical remission were estimated based on the meta-analysis of Phase 3 induction studies 
of the marketed drugs for patient population who have had intolerance or inadequate 
response to prior biologic therapy.  This approach provides an average power of 
approximately 87% to detect a dose effect at 5% level of significance (one-sided) with the 
linear, Emax (ED50 = 600 per dosing visit), exponential (δ = 600 per dosing visit), logistic 
(ED50 = 600 per dosing visit and δ = 160) and sigEmax (ED50 = 600 per dosing visit and 
h = 3) models pre-specified as likely candidates to characterize the dose response for 
risankizumab for the primary endpoint of clinical remission at Week 12 per Adapted 
Mayo Score.
A minimum of 240 subjects will be enrolled into Study M16-067 Sub-Study 1 for dose 
selection analysis.  The additional subjects enrolled during the dose selection analysis 
period will not be part of the dose selection analysis, but will be evaluated separately as 
exploratory in the final CSR.
 


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3.0
Endpoints
Endpoint definitions (Sub-Study 1):
●
Clinical Remission per Adapted Mayo:  stool frequency subscore (SFS) ≤ 1, 
and not greater than baseline, rectal bleeding subscore (RBS) = 0, and 
endoscopic subscore ≤ 1
●
Clinical Response per Adapted Mayo:  decrease from Baseline ≥ 2 points and 
≥ 30%, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1
●
Clinical Response per Partial Adapted Mayo (without endoscopy):  
decrease from Baseline ≥ 1 points and ≥ 30%, PLUS a decrease in RBS ≥ 1 or 
an absolute RBS ≤ 1
●
Clinical Remission per Full Mayo:  Full Mayo score ≤ 2 with no subscore > 1
●
Endoscopic Improvement:  endoscopy subscore of 0 or 1
●
Endoscopic Remission:  endoscopic subscore = 0
●
Histologic Remission:  Geboes score < 2.0
●
Mucosal Healing:  endoscopic and histologic remission
Note:  Evidence of friability during endoscopy in subjects with otherwise "mild" 
endoscopic activity will confer an endoscopic subscore of 2.
3.1
Primary Endpoint(s)
The primary endpoint for Phase 2b induction (Sub-Study 1) is the proportion of subjects 
who achieve clinical remission per Adapted Mayo score at Week 12.
3.2
Secondary Endpoint(s)
The secondary endpoints for Sub-Study 1 are:
Ranked Secondary Endpoints:
 


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1.
The achievement of endoscopic improvement at Week 12
2.
The achievement of clinical remission per Full Mayo score at Week 12 in subjects 
with a Full Mayo score of 6 to 12 at Baseline
3.
The achievement of clinical response per Adapted Mayo score at Week 12
4.
The achievement of clinical response per Partial Adapted Mayo score at Week 4
5.
The achievement of endoscopic remission at Week 12
6.
Occurrence of hospitalizations through Week 12
7.
The achievement of mucosal healing at Week 12
8.
Change from Baseline in UC-Symptom Questionnaire (UC-SQ) at Week 12
9.
Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) at 
Week 12
10.
Change from Baseline in Short Form-36 at Week 12
11.
Change from Baseline in Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-F) at Week 12
12.
UC-related surgeries through Week 12
Non-Ranked Secondary Efficacy Endpoints:
●
The achievement of SFS = 0, RBS = 0, and endoscopic subscore = 0 at Week 
12
●
The achievement of SFS ≤ 1 over time
●
The achievement of RBS = 0 over time
●
Change from Baseline in Partial Adapted Mayo score over time
●
Change from Baseline in Full Mayo score at Week 12
●
Change from Baseline in SFS over time
●
Change from Baseline in RBS over time
●
Change from Baseline in hs-CRP over time
 


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●
Change from Baseline in FCP over time
●
Change from Baseline in Ulcerative Colitis Endoscopic Index of Severity 
(UCEIS) at Week 12
●
The achievement of histologic remission at Week 12
●
Change from Baseline in European Quality of Life 5 Dimensions (EQ-5D-5L) 
over time
●
Change in Work Productivity and Impairment Questionnaire – UC (WPAI-UC) 
over time
●
Time to clinical response per partial adapted Mayo score
●
Change from baseline in Patient Global Impression of Severity (PGIS) over 
time
●
Patient Global Impression of Change (PGIC) over time
●
The achievement of clinical remission per Adapted Mayo over time
●
The achievement of endoscopic improvement over time
●
The achievement of endoscopic remission over time
●
The achievement of no bowel urgency at Week 12
●
The achievement of no abdominal pain at Week 12
●
Achieving response in IBDQ bowel symptom domain (increase of IBDQ bowel 
symptom domain score ≥ 6 from baseline) at Week 12
●
Change from Baseline in subject-reported stool frequency (absolute values)
●
Change from Baseline in percentage of colonic segments with an endoscopic 
subscore ≤ 1 (local read)
3.3
Other Efficacy Endpoints
The primary and/or secondary efficacy endpoints are listed in Section 3.1 and/or 
Section 3.2, respectively.  All the efficacy endpoints listed in Section 3.1 and Section 3.2
during Induction Period 2 are exploratory endpoints.
 


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3.4
Safety Endpoint(s)
Adverse events, vital signs, physical examination results, and clinical laboratory data will 
be assessed throughout the study.
4.0
Analysis Populations
The following population sets will be used for the analyses.
Intent-to-Treat Analysis Set
Sub-Study 1 – Induction Period 1:
The Intent-to-Treat (ITT) Analysis Set for Induction Period 1 in Sub-Study 1 includes all 
randomized subjects who received at least one dose of study drug during Sub-Study 1 
(denoted as ITT1A) at the time of dose-selection analysis.  The set of all the additional 
subjects who received at least one dose of risankizumab 1800 mg IV treatment group after 
240 subjects were randomized during the dose-selection period is denoted as ITT1B.  The 
ITT for Induction Period 1 in Sub-Study 1 will be denoted ITT1 and will be the 
combination of ITT1A and ITT1B.
Sub-Study 1 Induction Period 2:
Subjects who received at least one dose of risankizumab during Induction Period 2 in  
Sub-Study 1 (denoted as ITT1_P2)  will be analyzed separately for exploratory purposes.
Safety Analysis Set
For the safety analysis set in each sub-study, subjects will be analyzed in a treatment 
group based on the treatment actually received, not randomized.  The safety analysis in 
each sub-study will be based on the corresponding safety analysis set.
 


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Sub-Study 1 – Induction Period 1
The Safety Analysis Set for Induction Period 1 in Sub-Study 1 includes all subjects who 
received at least one dose of study drug during Induction Period 1 in Sub-Study 1 
(denoted as SAS1A) at the time of dose-selection analysis.  The set of all the additional 
subjects who received at least one dose of risankizumab 1800 mg IV treatment group after 
240 subjects were randomized during the dose-selection period is denoted as SAS1B.  The 
Safety Analysis Set for Induction Period 1 in Sub-Study 1 in Period 1 will be denoted 
SAS1 and will be the combination of SAS1A and SAS1B.
Sub-Study 1 Induction Period 2:
Subjects who received at least one dose of risankizumab during the Induction Period 2
after Week 12 in Sub-Study 1 (denoted as SAS1_P2) will be analyzed separately for 
exploratory purposes.
5.0
Subject Disposition
The number of subjects will be tabulated by country, investigator site and overall for the 
following sets:  Induction Period 1 ITT1A, ITT1B and Induction Period 2 ITT1_P2 
populations, Safety populations, subjects who completed study by period, and subjects 
who prematurely discontinued for study drug or study by period, for each treatment group 
and overall, as appropriate.
In addition, the number and percentage of subjects who discontinued study drug or study 
will be summarized by reason for each treatment group and overall.  All reasons and 
primary reasons for discontinuation of study drug will be summarized as recorded on the 
eCRF by the following categories:
●
Adverse event (AE)
●
Lost to follow-up
●
Withdraw consent
●
Lack of efficacy
 


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●
COVID-19 infection
●
COVID-19 logistical restrictions
●
Other
Subjects may have more than one reason for discontinuing study drug, but they will be 
counted once for the total number of discontinuations.  Subjects have only one primary 
reason for discontinuing study drug or discontinuing from the study.
6.0
Study Drug Duration and Compliance
Induction Period:
For the safety populations SAS1A and SAS1B, the duration of exposure to study drug 
will be summarized for each treatment group in the induction Period 1.
●
Duration of exposure in the induction Period 1:
○
If the subjects went to Study M16-066 after the induction Period 1:
●
Duration of exposure = min (the first study drug dose date in 
Study M16-066 – the first study drug dose date in induction Period 1, 
the last study drug dose date in the induction period – the first study 
drug dose date in the induction period + 28 days),
○
If the subject went to the induction Period 2 after induction Period 1:
●
Duration of exposure = min (the first study drug dose date in the 
induction Period 2 – the first study drug dose date in induction 
Period 1, the last study drug dose date in induction Period 1 – the 
first study drug dose date in induction Period 1 + 28 days),
○
Otherwise:
●
Duration of exposure = the last study drug dose date in induction 
Period 1 – the first study drug dose date in induction Period 1 
+ 28 days,
Where study drug dose date refers to recorded dates of injections of study drug.
 


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For each treatment group and total in the induction period, the duration of exposure will 
be summarized by the number of subjects treated, as well as the mean, standard deviation, 
median, minimum and maximum values.  In addition, the number and percentage of 
subjects exposed to study drug will be summarized for the following exclusive duration 
intervals:
●
1 – 28 days
●
29 – 56 days
●
57 – 84 days
●
85 – 112 days
●
> 112 days
Induction Period 2:
For the safety population SAS1_P2, the duration of exposure to study drug will be 
summarized for each treatment group in induction Period 2.
●
Duration of exposure in induction Period 2:
○
If the subjects went to Study M16-066 after induction Period 2:
●
Duration of exposure = min (the first study drug dose date in 
Study M16-066 – the first study drug dose date in induction Period 2, 
the last study drug dose date in induction Period 2 – the first study drug 
dose date in induction Period 2 + 28 days),
○
Otherwise:
●
Duration of exposure = the last study drug dose date in induction 
Period 2 – the first study drug dose date in induction Period 2 
+ 28 days,
Where study drug dose date refers to recorded dates of injections of study drug.
For each treatment group and total in induction Period 2, the duration of exposure will be 
summarized by the number of subjects treated, as well as the mean, standard deviation, 
 


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median, minimum and maximum values.  In addition, the number and percentage of 
subjects exposed to study drug will be summarized for the following exclusive duration 
intervals:
●
1 – 28 days
●
29 – 56 days
●
57 – 84 days 
●
85 – 112 days
●
> 112 days
Treatment compliance is calculated as follows:
 = 	
    	/  
	
    	/  
	 × 100%
Number of subjects receiving study drug and dose will be summarized for both periods in 
Sub-Study 1 and 2 based on safety analysis set using descriptive statistics. Subjects with 
missing data for the number of injections returned will be excluded from the summary.
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 ITT1A and ITT1B populations 
overall and by treatment group.  Categorical variables will be summarized with the 
number and percentage of subjects; percentages will be calculated based on the number of 
non-missing observations.  Continuous variables will be summarized with descriptive 
statistics (number of non-missing observations, mean and standard deviation, median, 
minimum and maximum).
7.1
Demographics and Baseline Characteristics
The following demographic, as measured at baseline of the study, will be summarized.
 


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Continuous variables:
●
Age (years)
●
Body weight (kg)
●
Body weight – Female (kg)
●
Body weight – Male (kg)
●
Height (cm)
●
Height – Female (cm)
●
Height – Male (cm)
●
Body Mass Index (kg/m2)
Categorical variables:
●
Sex (male, female)
●
Age (< 18, 18 - < 40, 40 - < 65, ≥ 65)
●
Race (American Indian/Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Multiple)
●
Race (White, Non-White)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Tobacco use (Never, current, former, unknown)
●
Alcohol use (Never, current, former, unknown)
●
Body Mass Index (kg/m2):
o
Underweight [< 18.5 kg/m2]
o
Normal [≥ 18.5 and < 25 kg/m2]
o
Overweight [≥ 25 and < 30 kg/m2]
o
Obese [≥ 30 kg/m2]
The following baseline characteristics, as measured at baseline of the study, will be 
summarized.
 


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Continuous variables:
●
Blood Pressure (systolic/diastolic) (mmHg)
●
Pulse (bpm)
●
Respiratory Rate (RPM)
●
Temperature (°C)
●
IBDQ total score and its components
●
Full Mayo score and its components (stool frequency, rectal bleeding, PGA, 
and endoscopy subscores)
●
Partial Mayo score
●
Adapted Mayo score
●
hs-CRP (mg/L)
●
Fecal Calprotectin (mg/kg)
●
Albumin (g/L)
●
Short Form 36 Health Survey (SF-36) and its components
●
European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
WPAI and its components
●
Ulcerative Colitis Symptoms Questionnaire (UC-SQ)
●
Disease duration
Categorical variables:
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Baseline aminosalicylates use (yes, no)
●
Baseline anti TNF use (yes, no)
●
Baseline biologics use (yes, no)
●
Baseline hs-CRP (≤ 5 mg/L, > 5 mg/L)
●
Disease duration (≤ 3 years, > 3 years)
 


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Disease extent (left-sided, extensive/pancolitis, limited to rectum)
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Region (US, ex-US)
In addition, clinical tests including TB test and electrocardiogram assessment at screening 
will be summarized.
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group for the Induction Period 1 ITT1A, ITT1B and 
the Induction Period 2 ITT1_P2 Populations.  The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC.  Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications including UC specific medications (corticosteroids, 
aminosalicylates, immunosuppressant agents, and UC-related antibiotics) that the subject 
has received within 90 days of baseline will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug.  This includes medications with a start date before the first study drug 
administration date, regardless of the end date of these medications.  Medications taken on 
the day of the first dose of study drug are not counted as prior medications.
A concomitant medication is defined as any medication that started prior to the date of the 
first dose of study drug and continued to be taken after the first dose of study drug or any 
medication that started on or after the date of the first dose of study drug, but not after the 
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taking medications will be summarized by generic drug name based on the World Health 
Organization (WHO) Drug Dictionary for both prior and concomitant medications.
8.0
Efficacy Analyses
8.1
General Considerations
The primary and secondary efficacy endpoints will be analyzed based on ITT1A in 
Induction Period 1 of Sub-Study 1 as the primary analysis.
The primary and ranked secondary efficacy endpoints will be analyzed based on ITT1B in 
Induction Period 1 of Sub-study 1 as the exploratory analysis.
All analyses for the efficacy endpoints in Induction Period 2 will also be performed based 
on ITT1_P2 for Sub-Study 1 for exploratory purpose.
For all efficacy endpoints, the descriptive statistics will be provided by treatment group 
for each induction period in each sub-study.  The statistics include number of 
observations, mean, standard deviation, minimum, median, and maximum for continuous 
variables; and number and percentage of subjects for categorical variables.
8.2
Handling of Missing Data
UC-related corticosteroids Censoring
For both Periods 1 and 2, the following subjects will be censored for efficacy assessments 
from that point through the end of the study.
●
subjects not on UC-related corticosteroids (systemic or locally acting 
corticosteroids for UC) at Baseline who then initiated during the study or
●
subjects on UC-related corticosteroids who have dosages increased to greater 
than the dose taken at Baseline.
I.e., these subjects will be considered as 'Not Achieved' for binary endpoints (Y/N) and 
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For composite endpoint, censoring will be applied on each component before calculating 
the composite endpoint.  If any component is censored, the composite endpoint will be 
considered as censored.  These subjects will continue to be evaluated in the safety 
population.  In addition, hospitalizations and UC-related surgeries will not be censored.
Handling of Missing Data
Missing data will be imputed using the following methods for the efficacy analyses.
●
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.  All the other 
imputations will be performed after OC.
●
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. According to the NRI approach, all missing values will 
be considered as 'Not Achieved.'
●
Last Observation Carried Forward (LOCF): The LOCF analyses will use the 
completed evaluation from the previous visit for efficacy measures assessed to 
impute missing data at later visits. Baseline and Pre-Baseline value will not be 
used for the imputation.  If there are no non-missing values after the Baseline, 
then the LOCF value also will be missing.
●
Mixed-Effect Model Repeat Measurement (MMRM):  The repeated measures 
analysis will be conducted using a mixed model including OC at all visits.  The 
mixed model includes the categorical fixed effects of treatment, visit and 
treatment-by-visit interaction, main stratification factors at randomization, and 
the continuous fixed covariates of baseline measurement.  An unstructured 
variance covariance matrix will be used.  Parameter estimation is based on the 
assumption of data being missing at random and using the method of restrictive 
maximum likelihood (REML).
●
Hybrid Multiple Imputation Method. Primary endpoint of clinical remission 
will be analyzed using hybrid multiple imputation (MI) method.  Subjects who 
discontinue study prior to Week 12 due to lack of efficacy or AEs will be 
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for other reasons will be categorized according to multiple imputations.  MI 
approach will be used as a sensitivity analysis for the primary endpoint.  For the 
primary endpoint, 20 'complete' datasets will be generated using SAS PROC 
MI.  The seed will be 12345.  The imputed post-baseline measurements will be 
rounded to the same precision as the observed data before the determination of 
responder status.  Using the Cochran-Mantel-Haenszel (CMH) model adjusted 
by main stratification factors, the imputed endpoints will be analyzed using 
each of the 20 datasets.  SAS PROC MIANALYZE will be used to generate the 
final inferences of the risk difference between treatment groups.
8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Endpoint(s)
The primary endpoint of this study is the proportion of subjects who achieve clinical 
remission per Adapted Mayo score (defined as stool frequency subscore ≤ 1 and not 
greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1) at 
Week 12.
8.3.2
Handling of Missing Data for the Primary Efficacy 
Endpoint(s)
Subjects with missing primary endpoint data at Week 12 will be classified as "not 
achieved" (non-responder imputation [NRI] method) for the primary analysis.
8.3.3
Primary Efficacy Analysis
For Sub-Study 1 – Induction Period 1:
The dose-response relationships among the three risankizumab dose groups (600 mg, 
1200 mg and 1800 mg) and placebo group will be characterized for the primary endpoint 
at Week 12 using Multiple Comparison Procedure - Modeling (MCP-Mod)1,2 approach 
based on ITT1A population.  The response based on the primary analysis approach NRI 
will be used, and ADDPLAN DF software will be used to perform the MCP-Mod 
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A set of 5 pre-specified standardized candidate dose-response models (including log-
linear, Emax, exponential, logistic and sigEmax) will be utilized to examine the dose-
response relationship.  A statistically significant dose response relationship will be 
declared if at least one model is identified by the MCP-Mod method to be statistically 
significant at α = 0.05 (one-sided).  The fitted dose response curves will be presented 
graphically for all statistically significant models along with confidence bands.  The 
minimum effective dose (MED) will be identified for each statistically significant model 
based on the pre-specified clinical meaningful target.  The weighted MED across all 
significant models will be calculated, with weight being inverse of model AIC.
The pairwise comparison between the treatment groups will also be performed using the 
Cochran-Mantel-Haenszel (CMH) test stratified by baseline corticosteroid use and 
baseline Adapted Mayo score (≤ 7 and > 7) with one-sided alpha level of 0.05.  A 
two-sided 90% confidence interval for the difference between treatment groups and 
placebo will be constructed.  There will be no multiplicity adjustment for the pairwise 
comparison.  The goal of the CMH test is to provide an estimation of the effect size for 
each dose to inform the dose selection for Phase 3, not for statistical inference purposes.
Descriptive statistics based on ITT1B will be provided as an exploratory analysis.  NRI 
will be used as imputation method.
8.3.4
Additional Analyses of the Primary Efficacy Endpoint(s)
The following sensitivity analyses for the primary endpoint of clinical remission will be 
conducted:
●
The primary analysis will be repeated using a hybrid multiple imputation 
method.  Subjects who discontinue study drug prior to Week 12 due to lack of 
efficacy or adverse events will be considered as "not achieved" for the clinical 
remission.  Subjects who discontinue for other reasons will be categorized
according to multiple imputations.
●
An analysis of observed cases, which excludes those subjects with missing data 
at scheduled assessment visits.
 


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8.4
Secondary Efficacy Analyses
Sub-Study 1 – Induction Period 1:
For Induction Period 1 in Sub-Study 1, the ranked secondary and non-ranked secondary 
efficacy variables listed in Section 3.2 will be analyzed by treatment group for ITT1A as 
the primary analysis at the nominal α level of 0.05 (one-sided). 
Continuous secondary efficacy variables will be analyzed using a Mixed-Effect Model 
Repeated Measures (MMRM) method.  It will be used for primary inference purpose.  
Analysis of Covariance (ANCOVA) model using LOCF imputation method will be 
applied as sensitivity analysis.
Categorical secondary efficacy variables will be analyzed using the CMH test controlling 
for stratification variables.  NRI imputation will be used for primary inference purpose 
and observed case analyses will be used for sensitivity analysis.
Additional exploratory analysis based on ITT1B will be provided for all ranked secondary 
efficacy variables: continuous secondary efficacy variables will be analyzed using 
MMRM method and descriptive statistics will be provided for categorical secondary 
efficacy variables with NRI imputation method.
8.5
Additional Efficacy Analyses
The efficacy analysis for subjects who were randomized and received at least one dose of 
risankizumab during the Induction Period 1 in Sub-study 1 (both ITT1A and ITT1B 
populations) and the Induction Period 2 in Sub-Study 1 (ITT1_P2 population)  will be 
performed for exploratory purpose at the nominal α level of 0.05 (two-sided).  
Definition of Time to Event (Clinical Response Per Partial Adapted Mayo Score)
Time to event is defined as number of days from the date of the first dosing to the date of 
the first occurrence of an event.  It is calculated as (date of first occurrence of Event – date 
of the first dosing + 1).  Subjects who discontinue from study prior to experiencing the 
 


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event are censored at the time of discontinuation.  Subjects who are not experiencing the 
event are censored at the date of last non-missing measurement of partial adapted Mayo 
score.  Pairwise comparison between each treatment group and placebo will be performed 
by log-rank test and Cox proportional hazards regression analysis including treatment and 
baseline stratification factors as covariates.
Time to event analysis will be based on OC data.
8.6
Efficacy Subgroup Analyses
Subgroup analysis for the primary endpoint, clinical remission per Adapted Mayo Score at 
Week 12, will be conducted by the subgroups specified listed below for 
ITT1A population.  The difference in the primary efficacy endpoint between the treatment 
groups in each subgroup will be assessed using a Chi-squared test or Fisher's exact test if 
≥ 20% of the cells have expected cell count < 5.  Non-responder imputation (NRI) 
method, where subjects with missing data at scheduled assessment visits will be 
considered as "not achieved" for the clinical remission, will be used for primary analysis.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Baseline Adapted Mayo Score (≤ 7, > 7)
●
Baseline Partial Adapted Mayo Score (≤ 4, > 4)
●
Prior exposure to biologic therapy (1, > 1)
●
Baseline weight (≤ median, > median)
●
Presence of pancolitis at Baseline (yes, no)
●
Disease duration at Baseline (≤ median, > median)
●
Baseline hs-CRP (≤ 3 mg/L, > 3 mg/L)
●
Baseline Albumin (≤ median, > median)
 


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●
Baseline Calprotectin (≤ median, > median)
●
Region (US, ex-US)
9.0
Safety Analyses
9.1
General Considerations
Safety analysis in each sub-study will be carried out using the corresponding safety 
analysis set as defined in Section 4.0.  Safety analyses performed on the SAS1A for 
Sub-Study 1 are considered as primary safety analysis in Sub-study 1.  The separate safety 
analysis for SAS1B, SAS1_P2 will be performed for exploratory purpose.  Adverse 
events (AEs), laboratory data and vital signs are the primary safety parameters and will be 
analyzed in each sub study.
The following summary statistics will be presented for subjects who have both baseline 
and post-baseline values for laboratory parameters and vital signs:  the mean value at 
Baseline and at each respective protocol specified visit, and the mean, standard deviation 
and median for changes from Baseline.  Categorical data will be summarized using 
frequencies and percentages.  The number of non-missing values will be given.  Missing 
safety data will not be imputed.
A subject's actual treatment will be determined by the most frequent dose regimen 
received.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
 


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multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
Sub-Study 1 – Induction Period 1:
Treatment emergent AEs (TEAEs) for Induction Period 1 in Sub-Study 1 are defined as 
events that begin or worsen either on or after the first dose of the study drug in Induction 
Period 1 and within 140 days after the last dose administration of the study drug for 
subjects who do not participate in the maintenance Study M16-066, or until the first dose 
of study drug in the maintenance Study M16-066 if the subject is enrolled into Study 
M16-066, or until the first dose of study drug in Induction Period 2 if the subject is 
enrolled into Induction Period 2.
Sub-Study 1 – Induction Period 2:
TEAEs for Induction Period 2 in Sub-Study 1 are defined as events that begin or worsen 
either on or after the first dose of the study drug in Induction Period 2 and within 140 days 
after the last dose administration of the study drug for subjects who do not participate in 
the maintenance Study M16-066 or until first dose of study drug in the maintenance Study 
M16-066 if the subject is enrolled into Study M16-066.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent, unless the study drug start time and the adverse event start time are 
collected and the adverse event start time is prior to the study drug start time.  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).
All analyses of AEs will be based on the number of patients with AEs (not the number of 
AEs).  Treatment group differences in the overall incidence of TEAEs will be assessed 
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Treatment labels for the safety analyses in Sub-Study 1 will be assigned accounting for 
the two induction periods:
a.
Induction Period 1 will consist of four treatment labels:  Placebo, 
Risankizumab 1800 mg IV, Risankizumab 1200 mg IV, and Risankizumab 600 
mg IV.
b. Induction Period 2 will consist of three treatment labels:  Risankizumab 1800 
mg IV, Risankizumab 360 mg SC, Risankizumab 180 mg SC.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent adverse event of safety interest.
●
Any COVID-19 related TEAE
●
All deaths
●
Any COVID-19 related deaths
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events, including COVID-19 related TEAE, 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 
 


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adverse events will be counted once for each subject for calculating percentages, unless 
stated otherwise.  In addition, if the same adverse event occurs multiple times within a 
subject, the highest severity and level of relationship to investigational product will be 
reported.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency for the total active group.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
exposure in 100 patient-years.
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
9.2.6
Adverse Events of Safety Interest
Adverse events of safety interest will be summarized by SOC and PT and will be based on 
standardized or company MedDRA queries (SMQs or CMQs), or based on adjudication 
results.  Adverse events of special interest and detailed information about the search 
criteria are provided in Appendix B.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol (e.g., hematology and clinical chemistry) 
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Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between treatment groups (each active vs. 
placebo).
Changes in laboratory parameters will be tabulated using shift tables either by NCI CTC 
criteria or categorized as low, normal, or high based on the normal ranges of the 
laboratory used for each sample.  A shift table from baseline either to the worse value 
(based on NCI CTC criteria) during treatment or 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.
Laboratory abnormalities meeting CTC criteria Grade 3 and 4 will be summarized.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (Appendix C).  For each laboratory PCI criterion, the number and 
percentage of subjects who have a laboratory value meeting the criteria will be 
summarized.  Listings will be provided to summarize subject-level laboratory data for
subjects meeting PCI criteria.
In addition, ALT/SGPT, AST/SGOT, alkaline phosphatase, and total bilirubin will be 
categorized as follows:
●
< 1.5 × ULN
●
≥ 1.5 × ULN – < 3.0 × ULN
●
≥ 3.0 × ULN – < 5.0 × ULN
●
≥ 5.0 × ULN – < 10.0 × ULN
●
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●
≥ 20.0 × ULN
A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
●
ALT ≥ 3 × ULN, or
●
AST ≥ 3 × ULN, or
●
Alkaline phosphatase ≥ 1.5 × ULN, or
●
Total bilirubin ≥ 2 × ULN.
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions will be provided.
●
ALT of > 3 × ULN or AST of > 3 × ULN,
●
associated with an increase in bilirubin ≥ 2 × ULN,
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, and body 
temperature will be summarized.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
baseline mean, and visit mean.  The change from baseline mean, standard error, and 
95% confidence interval will be presented for the mean change from baseline within each 
treatment group and difference between treatment groups (active vs. placebo).
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 
 


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will be provided to summarize subject-level vital sign data for subjects meeting PCI 
criteria.
9.5
Safety Subgroup Analyses
Not applicable.
9.6
Other Safety Analyses
Not applicable.
10.0
Other Analyses
Not applicable.
11.0
Interim Analyses
The first interim lock will take place when approximately 240 subjects in Sub-Study 1 
have completed the Week 12 visit (including those who discontinue prior to the 
Week 12 visit).
The second interim lock will take place when all the subjects in Sub-Study 1 have 
completed the Week 24 visit (including those who discontinue prior to the Week 12 visit).
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.
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12.0
Overall Type-I Error Control
Sub-Study 1 (Phase 2b) – Induction Period 1:
Sub-Study 1 is the Phase 2b randomized, placebo-controlled dose ranging study.  The 
primary, the ranked secondary and non-ranked secondary efficacy variables will be 
analyzed by treatment group for the Intent-to-Treat (ITT) analysis set for Sub-Study 1, 
defined in Section 4.0, at the nominal α level of 0.05 (one-sided).  No multiplicity 
adjustment will be performed for the Phase 2b dose ranging study.
No multiplicity adjustment will be applied to non-ranked secondary efficacy endpoints 
listed in Section 3.2.  The analysis for non-ranked secondary efficacy endpoints will be 
performed at the nominal α level of 0.05 (two-sided).
Sub-Study 1– Induction Period 2:
For Induction Period 2, no multiplicity adjustment will be performed for all efficacy 
endpoints listed in Section 3.3.  The analysis for all efficacy endpoints will be performed 
at the nominal α level of 0.05 (two-sided) for exploratory purpose.
 


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13.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
10 May 2017
Original version
2.0
13 Nov 2017
The definition of clinical remission per adapted mayo score has expanded to 
include 'stool frequency subscore (SFS) ≤ 1 and not greater than baseline.'
Efficacy endpoints have been updated to reflect changes in the protocol.
CTCAE is now used for assessing AE severity.
3.0
19 Feb 2018
MCP-Mod section updated to address regulatory feedback.  The 105-day 
follow up period has been updated to 140-day follow up period to reflect 
changes in protocol.  Analysis methods for secondary continuous efficacy 
endpoints have been updated in Section 6.3.  The placebo clinical remission 
rate was update from 10% to 7% to reflect the results of a more recent meta-
analysis.  For continuous secondary efficacy endpoints, MMRM method will 
be used for primary inference purpose and ANCOVA model using LOCF 
imputation method will be applied as sensitivity analysis.  The Hochberg 
procedure for multiplicity adjustment has been changed to Holm procedure.  
The search criteria for Serious Infections in the Summary of Adverse Events 
of Safety Interest table has been updated to reflect a change in convention.
4.0
05 Mar 2019
Figure 4 in Section 4.6 was updated to reflect that the final group of 
endpoints will utilize the Holm procedure.  Section 7.3 was updated per 
changes to the PSSAP.
5.0
25 Nov 2019
Section of subject disposition is added.  Section of study drug duration and 
compliance is added.  Section of demographics, baseline characteristics is 
added.  More details on subgroups are provided in section of efficacy 
subgroup analyses.  AESI and PCS criteria updated per PSSAP.
6.0
16 Nov 2020
Added Covid-19 related safety summary.  Added BMI categorical summary.  
Updated Hy’s Lawu, AESI and PCS criteria per PSSAP.  Updated UC-
related corticosteroids Censoring per immunology convention.  Removing 
analyses on Sub-study 2 from this SAP since it will be described in a 
standalone SAP.
14.0
References
1.
Pinheiro J, Bornkamp B, Bretz F.  Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures.  J Biopharm Stat.  
2006;16(5):639-56.
 


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2.
Bretz F, Pinheiro JC, Branson M.  Combining multiple comparisons and modeling 
techniques in dose-response studies.  Biometrics.  2005;61(3):738-48.
3.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
4.
Holm S.  A simple sequentially rejective multiple test procedure.  Scand J Stat.  
1979:65-70.
 


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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 Safety Interest
Adverse Events of Safety Interest (AESI) will be identified using the following search 
criteria:
ASI Grouping
Categories 
(ASI)
Search Criteria
Terms to Display
Include 
in AE 
Overview 
(Y/N)
Adjudicated CV 
Events
MACE
Adjudicated terms will be 
identified using CECAT and 
CETERM from the CE 
SDTM dataset.
Display underlined 
terms defined by the 
following adjudicated 
terms:

CV Death which 
includes 
adjudicated results 
of:  Sudden 
Cardiac death, 
Death due to 
Acute MI, Death 
due to Heart 
Failure, Death due 
to CV Procedures, 
Death due to CV 
Hemorrhage, 
Death due to Other 
CV Causes 
(specify), Death 
due to stroke

Non-fatal 
Myocardial 
infarction

Non-fatal Stroke
Y
Extended 
MACE
Adjudicated terms will be 
identified (for MACE +) 
using CECAT and 
CETERM from the CE 
SDTM dataset.
Display underlined 
terms from MACE 
and underlined terms 
below:

Hospitalization for 
Unstable Angina

Coronary 
Revascularization 
Procedures
N
 


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ASI Grouping
Categories 
(ASI)
Search Criteria
Terms to Display
Include 
in AE 
Overview 
(Y/N)
Serious 
Infections, TB, 
and 
Opportunistic 
Infections 
(including 
Herpes Zoster)
Serious 
Infections
Serious PTs of the SOC 
Infections and Infestations 
PTs
Y
Active TB
Active Tuberculosis CMQ 
(code 80000188)
PTs
Y
Opportunistic 
Infections 
Excluding 
Tuberculosis 
and Herpes 
Zoster
Opportunistic infections 
CMQ excluding 
Tuberculosis and Herpes 
Zoster (code 800000189)
PTs
Y
Herpes Zoster
Herpes zoster CMQ (code 
80000175)
PTs
N
Malignancies
Malignant 
Tumours
Narrow Malignant tumours 
(SMQ 20000194)
Malignant Tumours
Y
Non-Melanoma 
Skin Cancer 
(NMSC)
Broad Skin malignant 
tumours (SMQ 20000204) 
excluding terms identified 
by the Melanoma CMQ 
(code 80000119)
PTs
N
Malignancies 
excluding 
NMSC
'Malignancies excluding 
NMSC' is identified by the 
'Malignant Tumours' search 
excluding terms identified 
by the 'Non-melanoma skin 
cancer' (NMSC) search.
PTs
Y
 


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ASI Grouping
Categories 
(ASI)
Search Criteria
Terms to Display
Include 
in AE 
Overview 
(Y/N)
Hypersensitivity 
Reaction 
Hypersensitivity
Narrow Hypersensitivity 
(SMQ 20000214)
PTs
Y –
serious 
events 
only
Anaphylactic 
Reaction
Serious 
Anaphylactic 
Reactions
Narrow Serious AEs in the 
Anaphylactic Reaction SMQ 
(SMQ 20000021)
PTs
Y
Adjudicated 
Anaphylactic 
Reaction
Adjudicated terms will be 
identified using SDTM data 
(e.g., CE and PR domains).
PTs
Y
Hepatic Events
Hepatic Events
Broad
Hepatic failure, fibrosis and 
cirrhosis and other liver 
damage-related conditions 
(SMQ 20000013) Broad 
Hepatitis, non-infectious 
(SMQ 20000010) Broad 
Cholestasis and jaundice of 
hepatic origin 
(SMQ 20000009) Broad
Liver related investigations, 
signs and symptoms 
(SMQ 20000008) Narrow 
Liver-related coagulation 
and bleeding disturbances 
(SMQ 20000015)
PTs
N
Injection site 
reactions
Injection site reaction CMQ
(code 80000019)
PTs
N
 


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCI) laboratory findings are described in 
Table C-1 and Table C-2, and the PCI criteria for vital sign findings are described in 
Table C-3.
Table C-1.
Criteria for Potentially Clinically Important Hematology Values
Hematology Variables
Units
Definition of Potentially Clinically Significant Current 
(Version 4.03) CTCAE Grade 3 or Greater
Very Low
Hemoglobin
g/L
< 80.0
Platelets count
109/L
< 50.0
WBC count
109/L
< 2.0
Neutrophils
109/L
< 1.0
Lymphocytes
109/L
< 0.5
Note:
A post-baseline value must be more extreme than the baseline value (higher CTC grade than baseline) to be 
considered a potentially clinically important finding.
 


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Table C-2.
Criteria for Potentially Clinically Important Chemistry Values
Chemistry Variables
Units
Definition of Potentially Clinically Significant 
Current (Version 4.03) NCI CTCAE Grade 3 or 
Greater
Very Low
Very High
TBL
mcmol/L
> 3.0 × ULN
ALP
U/L
> 5.0 × ULN
SGOT/AST
U/L
> 5.0 × ULN
SGPT/ALT
U/L
> 5.0 × ULN
Albumin
g/L
< 20
Glucose
mmol/L
< 2.2
> 13.9
Triglycerides
mmol/L
> 5.7
Creatinine
mcmol/L
> 3.0 × ULN(> 3.0 × BL)
Sodium
mmol/L
< 130
> 155
Potassium
mmol/L
< 3.0
> 6.0
Calcium
mmol/L
< 1.75
> 3.1
Total Cholesterol
mmol/L
> 10.34
GGT
> 5.0 × ULN
Note:
A post-baseline value must be more extreme than the baseline value (higher CTC grade than baseline) to be 
considered a potentially clinically important finding.
Table C-3.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure 
(mmHg)
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood 
pressure (mmHg)
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
 


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Appendix D.
Common Toxicity Criteria (CTC) Grade for Laboratory Data
Test
Grade 1
Grade 2
Grade 3
Grade 4
Chemistry Variables
SGPT/ALT 
increased
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
SGOT/AST 
increased
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
GGT increased
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
ALP increased
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
TBL increased
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 10.0 × ULN
> 10.0 × ULN
Creatinine*
increased
> 1 – 1.5 × baseline 
(BL); > ULN – 1.5 × 
ULN
> 1.5 – 3.0 × BL;
> 1.5 – 3.0 × ULN
> 3.0 × BL;
> 3.0 – 6.0 × ULN
> 6.0 × ULN
CPK increased
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 10.0 × ULN
> 10.0 × ULN
Total Cholesterol 
increased
> ULN - 7.75
> 7.75 - 10.34
> 10.34 - 12.92
> 12.92
Albumin decreased
< LLN - 30
< 30 - 20
< 20
N/A
Triglycerides 
increased
1.71 - 3.42
> 3.42 - 5.7
> 5.7 - 11.4
> 11.4
Glucose
< LLN - 3.0 or
> ULN - 8.9
< 3.0 - 2.2 or
> 8.9 - 13.9
< 2.2 - 1.7 or
> 13.9 - 27.8
< 1.7 or > 27.8
Sodium 
< LLN – 130 or
> ULN - 150
> 150 – 155
< 130 – 120 or
> 155 - 160
< 120 or > 160
Potassium
< LLN - 3.0 or
> ULN - 5.5
< LLN - 3.0 or
> 5.5 - 6.0
< 3.0 - 2.5 or
> 6.0 - 7.0
< 2.5 or > 7.0
Calcium
< LLN - 2.0 or
> ULN - 2.9
< 2.0 - 1.75 or
> 2.9 - 3.1
< 1.75 - 1.5 or
> 3.1 - 3.4
< 1.5 or > 3.4
Hematology Variables
Hemoglobin 
decreased
< LLN – 100.0 g/L
< 100.0 – 80.0 g/L
< 80.0 – 65.0 g/L
< 65.0 g/L
Neutrophil count 
decreased
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
WBC decreased
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Lymphocyte count 
decreased
< LLN – 0.8 × 109/L
< 0.8 – 0.5 × 109/L
< 0.5 – 0.2 × 109/L
< 0.2 × 109/L
Platelets count 
decreased
< LLN - 75.0 × 109/L
< 75.0 - 50.0 × 109/L
< 50.0 - 25.0 × 109/L
< 25.0 × 109/L
*
If the calculation based on BL results in a different grade than the calculation based on ULN, use the higher grade.