Clinical trial NCT03105128
Conditions: Crohn's Disease
Keywords: Crohn's Disease (CD) Risankizumab ABBV-066 BI 655066
Sponsor: AbbVie
Start date: 2017-05-10; Completion date: 2021-04-14
Enrollment: 931 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of risankizumab versus placebo during induction therapy in participants with moderately to severely active Crohn's disease (CD).

Detailed description:

Arms: arm 1: Participants randomized to receive risankizumab dose 1 administered by intravenous (IV) infusion. arm 2: Participants randomized to receive risankizumab dose 2 administered by intravenous (IV) infusion. arm 3: Participants randomized to receive placebo for risankizumab administered by intravenous (IV) infusion. arm 4: Participants who received placebo in Period 1 and participants with inadequate response at Week 12 in Period 1 randomized to receive risankizumab dose 1 administered by intravenous (IV) infusion in Period 2. arm 5: Participants with inadequate response at Week 12 in Period 1 randomized to receive risankizumab dose 2 administered by subcutaneous (SC) injection in Period 2. arm 6: Participants with inadequate response at Week 12 in Period 1 randomized to receive risankizumab dose 3 administered by subcutaneous (SC) injection in Period 2.
Interventions: intervention 1: placebo for risankizumab intervention 2: risankizumab IV intervention 3: risankizumab SC
Intervention descriptions: intervention 1: Placebo for risankizumab administered by intravenous infusion intervention 2: Risankizumab administered by intravenous infusion intervention 3: Risankizumab administered by subcutaneous (SC) injection

Protocol documents:
Prot_000.pdf: 
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1.0
Title Page
Clinical Study Protocol M16-006
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Induction Study of the Efficacy 
and Safety of Risankizumab in Subjects with 
Moderately to Severely Active Crohn's Disease
Incorporating Administrative Change 1 and 
Amendments 1, 2, 3, 4, 5, 6, and 6.01 (United States 
Only)
AbbVie Investigational
  Product:
Risankizumab
Date:
01 September 2020
Development Phase:
3
Study Design:
Randomized, Double-Blind, Placebo-Controlled Parallel Group Design
EudraCT Number:
2016-003123-32
Investigators:
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
3-5-27, Mita,
Minato-ku
Tokyo 108-6302, 
Japan
Sponsor/Emergency 
  Contact:
Pharmaceutical 
Development
100 Research Drive, 
Suite 3009
Worchester, MA 01605
USA
Phone:
Mobile:
Fax:
Email:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT03105128


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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
17 February 2017
Amendment 1
05 July 2017
Amendment 2
29 September 2017
Amendment 3
09 July 2018
Amendment 4
22 February 2019
Amendment 5
19 December 2019
Amendment 6
28 July 2020
The purpose of this amendment is to:
●
Modification of language in Section 3.2 on the re-evaluation of the benefit and 
risk in light of the COVID-19 pandemic, to subjects participating in the study 
in Section 3.2
Rationale:  To clarify the effect of immunomodulatory therapies on the course 
of COVID-19 is currently unknown
●
Addition of Endpoint definitions in Section 5.3.3
Rationale: To include endpoints definitions for newly added secondary 
endpoints in Section 5.3.3.2 and Section 5.3.3.3
●
Revision of Co-Primary Endpoints in Section 5.3.3.1
Rationale:  Co-Primary endpoints were revised based on regulatory input
●
Section 5.3.3.2 updated to reflect new secondary endpoint ranking addition of 
new secondary endpoints, and update terms 
Rationale:  Reassessment based on evidence from the risankizumab CD 
Phase 2 study (Study M15-993), regulatory feedback, clinical relevance of 
endpoints to patients and physicians, alignment with study changes and 
updated terms
●
Revision to Determination of Sample Size in Section 8.2
Rationale:  To update power calculation for revised co-primary endpoint


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An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix K.


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-006
Name of Study Drug:  Risankizumab (ABBV-066)
Phase of Development:  3
Name of Active Ingredient:  Risankizumab
Date of Protocol Synopsis:  01 September 2020
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the 
Efficacy and Safety of Risankizumab in Subjects with Moderately to Severely Active Crohn's Disease
Objective:  The objective of Study M16-006 is to evaluate the efficacy and safety of risankizumab 
versus placebo during induction therapy in subjects with moderately to severely active Crohn's disease 
(CD).
Investigators:  Multicenter
Study Sites:  Approximately 400 sites
Study Population:  Males and females aged ≥ 18 to ≤ 80 years of age, or minimum age of adult consent 
according to local regulations at the Baseline visit, or aged 16 to < 18 years of age where locally 
permitted and who meet the definition of Tanner stage 5 development (refer to Appendix J) at the 
Baseline visit, with a diagnosis of moderately to severely active CD, defined as:
1.
average daily stool frequency (SF) ≥ 4 (when calculating SF, only the number of liquid or very soft 
stools should be recorded) and/or average daily abdominal pain (AP) score ≥ 2; plus
2.
endoscopic evidence of mucosal inflammation as measured by the Simple Endoscopic Score for CD 
(SES-CD). All eligible scores exclude the presence of narrowing component and are confirmed by 
a central reader.  Endoscopic activity is defined as a SES-CD of ≥ 3.  
The number of subjects enrolled with a SES-CD of ≥ 3 to < 6 for ileocolonic or colonic disease or 
SES-CD of 3 for isolated ileal disease will be no more than 85 subjects.  Once cap of no more than 
85 subjects is reached, enrollment criterion will be an eligibility SES-CD of ≥ 6 for ileocolonic or 
colonic disease, or eligibility SES-CD of ≥ 4 for isolated ileal disease.  
The study will enroll both subjects who have had an inadequate response (IR) to prior biologic therapy 
(bio-IR) and subjects who have not (non-bio-IR).  The bio-IR enrollment will be approximately 
540 subjects and the non-bio-IR enrollment will be approximately 315 subjects.
The bio-IR population is defined as subjects with documented intolerance or inadequate response to one 
or more of the approved anti-TNF or anti-integrin biologics for CD (infliximab, adalimumab, 
certolizumab, vedolizumab, ustekinumab and/or natalizumab). 
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 in the past but stopped therapy based on reasons other than 
inadequate response or intolerance (e.g., change in reimbursement coverage, well-controlled disease).
The percent of subjects with exposure, including intolerance or inadequate response, to ustekinumab will 
be no more than 20%.
Number of Subjects to be Enrolled:  Approximately 855 for the primary ITT population used for 
efficacy analysis; additionally, up to 85 subjects with lower SES-CD will be enrolled


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Methodology:  
Study M16-006 is a randomized, double blind, placebo-controlled 12-week induction study.
Subjects (n = 855) will be randomized 2:2:1 to 1200 mg risankizumab or 600 mg risankizumab or 
placebo intravenous (IV) given at Baseline, Weeks 4 and 8.  The randomization will be stratified by 
number of prior biologics failed (0, 1, > 1), Baseline steroid use (yes, no), and Baseline SES-CD 
(original, alternative), where the stratum of "original" includes the patients with baseline SES-CD of ≥ 6 
(or ≥ 4 for subjects with isolated ileal disease), and the stratum of "alternative" includes the patients with 
baseline SES-CD of ≥3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for isolated ileal 
disease.
Visits during the study will occur at Baseline and Weeks 4, 8, and 12/Premature Discontinuation (PD) to 
collect clinical and laboratory assessments of disease activity.  Subjects who do not achieve clinical 
response at Week 12 will be offered blinded risankizumab therapy in Induction Period 2 with evaluation 
for clinical response at Week 24.
All subjects will be provided with a subject diary where they will record CD related symptoms 
throughout the study.  Subjects will also be dispensed a patient information card at Screening.  
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.  All endoscopies will be evaluated using SES-CD and will be confirmed by a central 
reader.  Biopsy to confirm diagnosis (during Screening) or to rule out dysplasia/malignancy may be 
performed during the same time points as the endoscopy.  Optional exploratory research samples may be 
taken during the study.
At the Week 12/PD visit, all subjects will undergo an endoscopy for evaluation of mucosal 
inflammation.  It is expected that all subjects who remain in the study through at least Week 8 will have 
a Week 12/PD endoscopy.  All subjects achieving clinical response, defined as ≥ 30% decrease in 
average daily SF and/or ≥ 30% decrease in average daily AP score (both not worse than Baseline) at 
Week 12 may be eligible to enter Study M16-000.  Subjects are not eligible to enter Study M16-000 
until endoscopy has been completed (local reader results will be used for stratification for 
Study M16-000).
All subjects who do not achieve clinical response 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 Interactive Response 
Technologies (IRT) to Induction Period 2, a double-blind, double-dummy 12-week treatment period.
Subjects who received IV risankizumab induction treatment with inadequate clinical response at 
Week 12 will be randomized 1:1:1 to:
!
Group 1:  1200 mg IV risankizumab
!
Group 2:  360 mg SC risankizumab
!
Group 3:  180 mg SC risankizumab


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Methodology (Continued):
Subjects who received IV placebo induction treatment will receive:
!
Group 4:  1200 mg IV risankizumab
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 received treatment in Induction Period 2 will be reassessed and undergo a third endoscopy for 
evaluation of mucosal inflammation.  Subjects who achieve clinical response at Week 24 may be eligible 
to enter Study M16-000.  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 enter 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, immunomodulators (azathioprine [AZA], 6-mercaptopurine 
[6-MP], methotrexate [MTX]), and/or CD-related antibiotics.
Subjects taking aminosalicylates, immunomodulators, and/or CD-related antibiotics at Baseline must 
continue these treatments for the duration of the study.  Initiating and/or increasing doses of 
aminosalicylates, immunomodulators, and/or CD-related antibiotics during the study is prohibited.  
Decreasing doses of aminosalicylates, immunomodulators, and/or CD-related antibiotics is prohibited 
during the study, except in the event of moderate-to-severe treatment related toxicities and after 
discussion with the AbbVie Therapeutic Area Medical Director (TA MD).  CD-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
Subjects taking corticosteroids at Baseline must continue their concomitant treatment at the Baseline 
dose for the duration of the 12-week induction period.  Initiation and/or increasing doses of systemic 
and/or CD related corticosteroids during the entire study is prohibited.  Decreasing doses of 
corticosteroids is prohibited during the 12-week induction period, except in the event of moderate-to-
severe treatment related toxicities and after discussion with the AbbVie TA MD.
Subjects who receive Induction Period 2 treatment during Weeks 12 to 24 will be allowed to taper their 
corticosteroids at the discretion of the Investigator.  Increasing doses above the Baseline dose is 
prohibited.
Dose Selection
This study will evaluate two IV doses of risankizumab (600 mg and 1200 mg) during induction.  The 
selection of the doses in this study is 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 CD that explored 
200 mg and 600 mg doses.  The results from the Phase 2 study suggest a potential for increased benefit 
with 1200 mg administration. 


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Methodology (Continued):
Induction Period 2 will evaluate IV (1200 mg 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 (1200 mg IV at Weeks 12, 16, and 20) versus initiating maintenance 
dosing 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.  
The results from the Phase 2 study suggest a potential for increased benefit with 360 mg SC 
administration for maintenance regimen.
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.  At the timing of this amendment, the DMC has 
provided recommendation that the study may continue without modification and allowed enrollment to 
begin for 16 - 17 year-olds. 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.  
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:  
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.  Where locally permissible, subjects 16 to < 18 years of age who 
meet the definition of Tanner stage 5 for development (refer to Appendix J), at the Baseline Visit 
(sites will be notified when adolescents may enroll).
2.
Confirmed diagnosis of CD for at least 3 months prior to Baseline.  Appropriate documentation of 
biopsy results consistent with the diagnosis of CD, in the assessment of the Investigator, must be 
available.
3.
Crohn's disease activity index (CDAI) score 220 – 450 at Baseline.
4.
Endoscopic evidence of mucosal inflammation as documented by an SES-CD of ≥ 3. All eligible 
scores exclude the presence of narrowing component and are confirmed by a central reader. (Once 
cap of no more than 85 subjects is reached, enrollment criterion will be an SES-CD of ≥ 6 for 
ileocolonic or colonic disease or SES-CD of ≥ 4 for isolated ileal disease.)
5.
Average daily SF ≥ 4 and/or average daily AP score ≥ 2 at Baseline.
6.
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 (intolerance 
includes patients with a known TPMT genetic mutation or low activity).  
!
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, 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, Hong Kong, 
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, Hong Kong, 
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
Biologic Therapies for CD: 
!
Signs and symptoms of persistently (in the opinion of the Investigator) 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 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 certolizumab pegol (400 mg SC at 
Weeks 0, 2, and 4),
o
At least one 6-week induction regimen of vedolizumab (300 mg IV at 
Weeks 0, 2, and 6)
o
At least one 12-week induction regimen of natalizumab (300 mg IV every 
4 weeks)
o
At least one 8-week induction regimen of ustekinumab [260 mg (≤ 55 kg) or 
390 mg (> 55 to ≤ 85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at 
Week 8] (Once cap of no more than 20% ustekinumab exposed subjects is 
reached, subjects with prior ustekinumab exposure will not be allowed to 
enroll.)  


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Recurrence of symptoms during scheduled maintenance dosing following prior 
clinical benefit of the above biologics
!
Note:  Subjects who discontinued biologics 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
7.
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. 
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.
8.
Subjects must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.  In Japan, if the subject is < 20 years old, a subject's parent or 
legal guardian must be willing to give written informed consent.
Main Exclusion:  
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
Concomitant Medications and Treatments
2.
Subject on CD-related antibiotics who has not been on stable doses 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 current 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/intramuscular 
anti-infectives (non-CD-related) within 14 days prior to the Baseline visit.  This does not apply to 
TB prophylaxis.
7.
Subject who received exclusive enteral nutrition or any parenteral nutrition within 35 days prior to 
Baseline.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):
Medications and Treatments During the Screening Period (Continued)
8.
Subject who received any live bacterial or viral vaccination within 30 days (8 weeks for Japan) 
prior to Screening or during the Screening Period.
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 biologics: infliximab, adalimumab, certolizumab, vedolizumab, natalizumab) within 
8 weeks prior to Baseline, or ustekinumab within 12 weeks prior to Baseline  
Note:  If there is proper documentation of an undetectable drug level measured by a 
commercially available assay for any of the approved biologics above, there is no minimum 
washout prior to Baseline.
!
Any investigational biologic or other agent or procedure within 35 days or 5 half-lives prior to 
Baseline, whichever is longer.
12. Subject with prior exposure to p19 inhibitors (e.g., risankizumab).
13. Subject has been taking combination of two or more of the following:  oral budesonide, or 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, other than required for endoscopy, within 
14 days prior to endoscopy used for 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.
CD Related
18. Subject with currently known complications of CD such as:
!
abscess (abdominal or perianal),
!
symptomatic bowel strictures,
!
> 2 missing segments of the following 5 segments:  terminal ileum, right colon, transverse 
colon, sigmoid and left colon, and rectum
!
fulminant colitis,
!
toxic megacolon,
!
or any other manifestation that might require surgery while enrolled in the study.
19. Subject with ostomy or ileoanal pouch.
20. Subject diagnosed with short gut or short bowel syndrome.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
21. Subject with surgical bowel resection within the past 3 months prior to Baseline, or a history of 
≥3 bowel resections.
Safety
22. 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).
23. 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 or other intestinal pathogen during Screening,
!
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:
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 positive with anti-HCV 
antibody (HCV Ab)
24. 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.
25. 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.
26. Subject with current or previous 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.
27. Subject who has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, 
disorder or symptoms thereof.
28. 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.
29. 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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
Safety (Continued):
30. 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
!
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 after discussion and clearance 
with the TAMD. 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.
31. No known active COVID-19 infection.  Subject must not have signs/symptoms associated with 
COVID-19 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 viral clearance criteria: 
!
Symptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥24 hours 
apart after at least 10 days have passed since recovery, defined as resolution of fever without 
use of antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of breath)
!
Asymptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥ 24 hours 
apart after at least 10 days have passed since prior positive result (Note: subjects who develop 
symptoms will follow guidance above for symptomatic subjects)
Frequency or timing of COVID-19 testing and interval between testing for the above viral clearance 
criteria may be adjusted to account for epidemiological trends, updated information regarding 
infectivity and local/institutional guidelines.


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Investigational Product:
Risankizumab
Doses:
Risankizumab 1200 mg IV Q4W* 
Risankizumab 600 mg IV Q4W
Risankizumab 180 mg SC Q8W
Risankizumab 360 mg SC Q8W
*
If the 1200 mg dose is discontinued due to any reason, subjects will 
continue to enroll into the study and be randomized to either 
600 mg risankizumab or placebo at 2:1 ratio.  The randomization 
ratio and sample size may be further updated in an amendment to 
the protocol.  Subjects already randomized to treatment arms, 
including Induction Period 2, will receive blinded 600 mg 
risankizumab IV.
Mode of Administration:
Risankizumab solution for infusion (IV)
Risankizumab solution for injection (SC) 
Reference Therapy:
Placebo for risankizumab
Dose:
N/A
Mode of Administration:
Placebo solution for infusion (IV)
Placebo solution for injection (SC)
Duration of Treatment:  12 or 24 weeks 
The study will include a Screening period of up to 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 
treatment in Induction Period 2 with risankizumab 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 roll over into Study M16-000 or discontinue from the study 
prematurely.
Criteria for Evaluation:
Endpoint Definitions:
!
Clinical remission:  average daily SF ≤ 2.8 and not worse than Baseline AND average daily 
AP score ≤ 1 and not worse than Baseline
!
Enhanced clinical response:  ≥ 60% decrease in average daily SF and/or ≥ 35% decrease in 
average daily AP score and both not worse than Baseline, and/or clinical remission
!
Clinical response:  ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily 
AP score and both not worse than Baseline
!
Endoscopic response:  decrease in SES-CD > 50% from Baseline (or for subjects with isolated 
ileal disease and a Baseline SES-CD of 4, at least a 2 point reduction from Baseline), as scored 
by central reviewer
!
Ulcer-free endoscopy: SES-CD ulcerated surface subscore of 0 in subjects with SES-CD 
ulcerated surface subscore ≥ 1 at Baseline, as scored by a central reviewer
!
Endoscopic remission: SES-CD ≤ 4 and at least a 2 point reduction versus baseline and no 
subscore greater than 1 in any individual variable, as scored by a central reviewer


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Criteria for Evaluation (Continued):
Endpoint Definitions (Continued):
!
CDAI clinical response:  reduction of CDAI ≥100 points from baseline
!
CDAI clinical remission:  CDAI < 150
!
SF remission:  average daily SF ≤2.8 and not worse than baseline
!
AP remission:  average daily AP score ≤1 and not worse than baseline
Efficacy:
Co-Primary Endpoints:  
!
Proportion of subjects with CDAI clinical remission at Week 12 
!
Proportion of subjects with endoscopic response at Week 12
Ranked Secondary Endpoints:
1.
Proportion of subjects with clinical remission at Week 12
2.
Proportion of subjects with CDAI clinical response at Week 4
3.
Proportion of subjects with CDAI clinical response at Week 12
4.
Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) 
at Week 12
5.
Proportion of subjects with CDAI clinical remission at Week 4
6.
Proportion of subjects with CDAI clinical response and endoscopic response at Week 12 
7.
Proportion of subjects with SF remission at Week 12
8.
Proportion of subjects with AP remission at Week 12
9.
Proportion of subjects with endoscopic remission at Week 12
10. Proportion of subjects with enhanced clinical response at Week 4
11. Proportion of subjects with ulcer-free endoscopy at Week 12
12. Proportion of subjects with enhanced clinical response at Week 12
13. Proportion of subjects with resolution of extra-intestinal manifestations (EIMs) at Week 12, in 
subjects with any EIMs at Baseline 
14. Proportion of subjects with CD-related hospitalization through Week 12
15. Proportion of subjects without draining fistulas at Week 12 in subjects with draining fistulas at 
Baseline
For further information, including non-ranked endpoints, refer to protocol
Pharmacokinetics:
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 receive treatment in Induction Period 2.
Additionally, intensive pharmacokinetic assessment will be performed in 20 subjects after the 
3rd induction dose (Week 8 to 12).  For Subjects who consent to the intensive pharmacokinetic 
assessment, in addition to the time points above, blood samples will be 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.


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Criteria for Evaluation (Continued):
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 receive treatment in Induction Period 2.
Safety:
Safety analyses will be performed on safety set which includes all subjects who receive at least one dose 
of study drug.  Incidence of adverse events (AEs), changes in vital signs, physical examination results, 
and clinical laboratory data will be assessed throughout the study.
Exploratory Research Variables and Validation Studies (Optional):
Prognostic, surrogate, predictive and pharmacodynamics biomarkers signatures may be investigated.  
Samples for different applications, including but not limited to, pharmacogenetic, epigenetic, 
transcriptomic, proteomic, metabolomics, metagenomic and targeted investigations will be collected at 
various time points.  Assessments will include but may not be limited to nucleic acids, proteins, 
metabolites or lipids.
Statistical Methods:
Efficacy:
The co-primary endpoints are the proportion of subjects with CDAI clinical remission at Week 12 and 
proportion of subjects with endoscopic response at Week 12.  A total of approximately 855 subjects will 
be randomized into two risankizumab treatment groups and the placebo group in a 2:2:1 ratio 
(342 subjects for risankizumab 600 mg dose group, 342 subjects for risankizumab 1200 mg dose group, 
and 171 subjects for placebo group). When all patients complete their Week 12/PD visit, the database 
will be locked for the final analysis of 12-week induction period.  When all the patients who enter the 
induction Period 2 finish Week 24/PD visit, the database will be locked for the whole study and all the 
planned analysis for the induction Period 2 will be performed.
Assuming the Week 12 CDAI clinical remission rate will be 37% for one of the risankizumab dose 
groups and 17% for the placebo group, a sample size of 342 subjects for each of the risankizumab dose 
groups and 171 for the placebo group will have 99% power to detect the treatment difference between 
the risankizumab dose groups and placebo in CDAI clinical remission rates at Week 12 using Fisher's 
exact test at alpha of 0.025 (two-sided).
The bio-IR population is approximately 540 subjects.  The study will have 92% power to detect the 
treatment difference between one of the risankizumab dose groups and placebo in CDAI clinical 
remission at Week 12 using a Fisher's exact test a 0.025 significant level (two-sided) for the bio-IR 
population, assuming the Week 12 CDAI clinical remission rate will be 34% for the risankizumab dose 
groups and 15% for the placebo group for bio-IR subjects.  The non-bio-IR population is approximately
315 subjects.  The study will have 70% power to detect the treatment difference between one of the 
risankizumab dose groups and placebo in CDAI clinical remission, at Week 12 using a Fisher's exact test 
a 0.025 significant level (two-sided) for the non-bio-IR sub-population, assuming the Week 12 CDAI 
clinical remission rate will be 42% for the risankizumab dose groups and 21% for the placebo group for 
non-bio-IR subjects.


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Statistical Methods (Continued):
Efficacy (Continued):
The comparisons between each risankizumab dose versus placebo for the primary efficacy variable will 
be performed using the Cochran-Mantel-Haenszel (CMH) test adjusted by prior biologic use (0, 1, > 1) 
and Baseline steroid use (yes, no). Both of the co-primary efficacy endpoints will be tested at 
statistically significant of 0.025 for each of the risankizumab dose groups versus placebo to adjust for 
multiplicity.  A CMH based two-sided 95% confidence interval for the difference between treatment 
groups will be calculated.
The intent-to-treat (ITT) set includes all randomized subjects who have taken at least one dose of study 
drug.  The primary population for efficacy analysis are the subjects in the intent-to-treat analysis set who 
had baseline eligibility SES-CD of ≥ 6 (≥ 4 for isolated ileal disease).  Subjects who discontinue prior to 
Week 12 for any reason will be considered as "not-achieved" for CDAI clinical remission and 
endoscopic response endpoints.
In general, continuous secondary efficacy variables will be analyzed using a Mixed-Effect Model 
Repeated Measure (MMRM) model including factors for treatment group, visit, visit by treatment 
interaction, and stratification variables, for the longitudinal continuous endpoints.  The MMRM analysis 
is considered primary for inferential purposes.  
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 cohorts and study visits.  ADA titers will be tabulated for each 
subject at the respective study visits.  The effect of ADAs on risankizumab pharmacokinetics, efficacy 
and/or safety variable(s) and/or any additional analyses will be explored.
Safety:
Adverse events, laboratory data and vital signs are the primary safety parameters in this study.  All 
safety comparisons will be performed between treatment groups using the safety set.  Treatment 
emergent AEs are defined as events that begin or worsen either on or after the first dose of the study 
drug and within 140 days after the last dose of the study drug for subjects who do not participate in 
Study M16-000 or until first dose of study drug in Study M16-000 if the subject is enrolled in 
Study M16-000.  
An overview of treatment-emergent AEs, AEs leading to death and AEs leading to premature 
discontinuation (see details in the statistical analysis plan [SAP]), AEs by Medical Dictionary for Drug 
Regulatory Activities (MedDRA version) preferred term and system organ class, AEs by maximum 
relationship to study drug, and AEs by maximum severity will be summarized by number and 
percentage.  
Changes in laboratory data will be described using statistical characteristics and 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.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
6-MP
6-Mercaptopurine
AAC
Anaphylaxis adjudication committee
ADA
Anti-Drug Antibody
AE
Adverse event 
ALT
Alanine transaminase 
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AAC
Anaphylaxis adjudication committee
AP
Abdominal Pain
AST
Aspartate transaminase 
ATEMS
AbbVie Temperature Excursion Management System
AZA
Azathioprine
BCG
Bacillus Calmette-Guérin 
Bio-IR
Inadequate Response to biologic therapy
BUN
Blood urea nitrogen 
CAC
Cardiac Adjudication Committee
CD
Crohn's disease 
CDAI
Crohn's disease activity index
CHO
Chinese Hamster Ovary
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease - 2019
CRA
Clinical Research Associate
CSS
Crohn's Symptom Severity 
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest x-ray 
DILI
Drug-induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram 
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture


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EIM
Extra-Intestinal Manifestations
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
European Quality of Life 5 Dimensions
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FCP
Fecal Calprotectin
FDA
Food and Drug Administration 
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice 
HBV
Hepatitis B virus
HBc Ab
Hepatitis B core antibody
Hbs Ab
Hepatitis B surface antibody
Hbs Ag
Hepatitis B surface antigen 
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HCT
Hematocrit
HIV
Human immunodeficiency virus
hs-CRP
High-sensitivity C-Reactive Protein
IBDQ
Inflammatory Bowel Disease Questionnaire 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
IL
Interleukin 
IR
Inadequate response
IM
Intramuscular
INR
International Normalized Ratio
IRB
Institutional Review Board 
IRT
Interactive Response Technologies
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
MACE
Major Adverse Cardiovascular Events
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Drug Regulatory Activities


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MI
Multiple Imputation
MMR
Measles Mumps-Rubella
MMRM
Mixed-Effect Model Repeated Measure
MMRV
Measles Mumps-Rubella Varicella
MTX
Methotrexate 
nAb
Neutralizing antibodies
NRI
Non-responder imputation
N/A
Not Applicable
OC
Observed Case
OL
Open-Label
OPV
Oral Polio Vaccine
PCR
Polymerase Chain Reaction
PD
Premature Discontinuation
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity  
PK
Pharmacokinetics
PMM
Pattern Mixture Model
POR
Proof of Receipt 
PPD
Purified protein derivative 
QoL
Quality of Life
Q4w
Every 4 Weeks
Q8w
Every 8 Weeks 
RBC
Red blood cell 
RNA
Ribonucleic Acid
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SES-CD
Simple Endoscopic Score for Crohn's Disease
SF
Stool Frequency
SF-36 
36-Item Short Form Health Status Survey
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis 
TNF
Tumor Necrosis Factor 


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ULN
Upper Limit of Normal
WBC
White blood cell
WOCBP
Women of Childbearing Potential
WPAI-CD
Work Productivity and Impairment Questionnaire – Crohn's disease


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms........................................18
2.0
Table of Contents...................................................................22
3.0
Introduction ...........................................................................27
3.1
Differences Statement..............................................................................28
3.2
Benefits and Risks....................................................................................28
4.0
Study Objective......................................................................31
5.0
Investigational Plan...............................................................31
5.1
Overall Study Design and Plan:  Description ..........................................31
5.2
Selection of Study Population..................................................................39
5.2.1
Inclusion Criteria .....................................................................................40
5.2.2
Exclusion Criteria ....................................................................................43
5.2.3
Prior and Concomitant Therapy...............................................................49
5.2.3.1
Prior Therapy ...........................................................................................49
5.2.3.2
Concomitant Therapy...............................................................................50
5.2.3.3
Prohibited Therapy...................................................................................51
5.2.4
Contraception Recommendations ............................................................52
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Optional 
Exploratory Research/Validation Studies and Safety 
Assessments/Variables.............................................................................54
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................54
5.3.1.1
Study Procedures .....................................................................................54
5.3.1.2
Collection and Handling of Optional Exploratory 
Research/Validation Studies Samples......................................................72
5.3.2
Drug Concentration and Anti-Drug Antibody Measurements.................73
5.3.2.1
Collection of Samples for Analysis .........................................................73
5.3.2.2
Handling/Processing of Samples .............................................................73
5.3.2.3
Disposition of Samples ............................................................................74
5.3.2.4
Measurement Methods.............................................................................74


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5.3.3
Efficacy Variables....................................................................................74
5.3.3.1
Primary Variable......................................................................................75
5.3.3.2
Secondary Variables ................................................................................75
5.3.3.3
Other Endpoints .......................................................................................76
5.3.4
Safety Variables.......................................................................................77
5.3.5
Pharmacokinetic Variables ......................................................................78
5.3.6
Optional Exploratory Research/Validation Variables..............................78
5.4
Removal of Subjects from Therapy or Assessment.................................78
5.4.1
Discontinuation of Individual Subjects....................................................78
5.4.2
Discontinuation of Entire Study...............................................................80
5.5
Treatments................................................................................................81
5.5.1
Treatments Administered.........................................................................81
5.5.2
Identity of Investigational Product...........................................................81
5.5.2.1
Packaging and Labeling...........................................................................82
5.5.2.2
Storage and Disposition of Study Drug ...................................................82
5.5.2.3
Preparation/Reconstitution of Dosage Form............................................83
5.5.3
Method of Assigning Subjects to Treatment Groups...............................83
5.5.4
Selection and Timing of Dose for Each Subject......................................84
5.5.5
Blinding....................................................................................................84
5.5.5.1
Blinding of Investigational Product.........................................................84
5.5.5.2
Data Monitoring Committee....................................................................85
5.5.6
Treatment Compliance.............................................................................86
5.5.7
Drug Accountability.................................................................................86
5.6
Discussion and Justification of Study Design..........................................87
5.6.1
Discussion of Study Design and Choice of Control Groups....................87
5.6.2
Appropriateness of Measurements...........................................................88
5.6.3
Suitability of Subject Population .............................................................88
5.6.4
Selection of Doses in the Study ...............................................................88
6.0
Complaints .............................................................................90
6.1
Medical Complaints.................................................................................90
6.1.1
Definitions................................................................................................91
6.1.1.1
Adverse Event..........................................................................................91
6.1.1.2
Serious Adverse Events ...........................................................................92


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6.1.1.3
Areas of Safety Interest............................................................................93
6.1.2
Adverse Event Severity............................................................................95
6.1.3
Relationship to Study Drug......................................................................96
6.1.3.1
Lack of Efficacy or Worsening of Disease ..............................................97
6.1.4
Adverse Event Collection Period.............................................................97
6.1.5
Adverse Event Reporting.........................................................................97
6.1.5.1
Adverse Events Commonly Associated with CD in Study 
Population ................................................................................................99
6.1.6
Pregnancy...............................................................................................100
6.1.7
Cardiac Adjudication Committee ..........................................................100
6.1.8
Anaphylaxis Adjudication Committee...................................................101
6.2
Product Complaint .................................................................................101
6.2.1
Definition ...............................................................................................101
6.2.2
Reporting................................................................................................101
7.0
Protocol Deviations..............................................................102
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................103
8.1
Statistical and Analytical Plans..............................................................103
8.1.1
Datasets for Analysis .............................................................................103
8.1.1.1
Intent-to-Treat Analysis Set...................................................................103
8.1.1.2
Safety Analysis Set ................................................................................104
8.1.2
Definition of Missing Data Imputation..................................................104
8.1.3
Subject Disposition ................................................................................104
8.1.4
Demographics and Baseline Characteristics..........................................104
8.1.5
Prior and Concomitant Medications ......................................................105
8.1.6
Efficacy Analysis ...................................................................................105
8.1.6.1
Primary Efficacy Variables....................................................................105
8.1.6.2
Secondary Efficacy Variables................................................................106
8.1.7
Safety Analysis ......................................................................................107
8.1.8
Analysis of Optional Exploratory Variables..........................................107
8.1.9
Analysis of Pharmacokinetic and Pharmacodynamic Variables............108
8.2
Determination of Sample Size ...............................................................109
8.3
Randomization Methods ........................................................................110


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9.0
Ethics.....................................................................................111
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................111
9.2
Ethical Conduct of the Study.................................................................112
9.3
Subject Information and Consent...........................................................112
9.3.1
Informed Consent Form and Explanatory Material ...............................114
9.3.2
Revision of the Consent Form and Explanatory Material .....................115
10.0
Source Documents and Case Report Form 
Completion ...........................................................................115
10.1
Source Documents .................................................................................115
10.2
Case Report Forms.................................................................................116
10.3
Electronic Patient Reported Outcomes (ePRO).....................................117
11.0
Data Quality Assurance ......................................................118
12.0
Use of Information...............................................................119
13.0
Completion of the Study .....................................................120
14.0
Investigator's Agreement....................................................122
15.0
Reference List ......................................................................123
List of Tables
Table 1.
Clinical Laboratory Tests.........................................................................61
Table 2.
Identity of Investigational Product...........................................................82
Table 3.
Common Events Associated with CD....................................................100
List of Figures
Figure 1.
Study M16-006 Study Schematic ............................................................34
Figure 2.
Adverse Event Collection ........................................................................97
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................126
Appendix B.
List of Protocol Signatories....................................................................128


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Appendix C.
Study Activities for Efficacy, Safety, and PK/PD .................................129
Appendix D.
Study Activities – Optional Exploratory Research Samples .................134
Appendix E.
Sample SES-CD Scoring .......................................................................135
Appendix F.
Crohn's Disease Activity Index (CDAI) ................................................136
Appendix G.
Standard Weights...................................................................................137
Appendix H.
Optional Intensive PK Subjects .............................................................140
Appendix I.
Clinical Criteria for Diagnosing Anaphylaxis .......................................141
Appendix J.
Tanner Stage 5 for Development ...........................................................143
Appendix K.
Protocol Amendment:  List of Changes.................................................146


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3.0
Introduction
Crohn's disease (CD) encompasses a spectrum of clinical and pathological processes 
manifested by focal asymmetric, transmural, and occasionally granulomatous 
inflammation that can affect any segment of the gastrointestinal tract and presents with 
symptoms of fatigue, prolonged diarrhea with or without gross bleeding, abdominal pain, 
weight loss, and fever.1  The disease can affect persons of any age, and its onset is most 
common in the second and third decades.  Females are affected slightly more than males, 
and the risk for disease is higher in some ethnic groups.2,3  The incidence of CD has 
steadily increased in developed countries over the past 3 decades4 with recent estimates 
varying from 12.7 and 20.2 cases/100,000, and a prevalence of 319 and 
322 cases/100,000 in North America and Europe, respectively.5  In Asia, the incidence of 
CD is estimated to be 0.5 to 1.0 cases per 100,000 persons, with a prevalence rate ranging 
from 3.6 to 7.7.6,7
The exact cause of CD is still unknown, but is hypothesized to be the result of a 
dysregulated immune system in the context of a genetically susceptible individual.  It is 
thought that a combination of a patient's genetics, microbiome, immune response, and the 
environment result in an excessive and abnormal immune response in the gut that results 
in pathology seen in CD.2
The aim of medical treatment in CD has been focused on controlling inflammation and 
reducing symptoms.8  In addition to improving symptoms, an emerging goal of therapy is 
to heal the gut mucosa.  Resolution of intestinal ulcers, also known as mucosal healing 
has been associated with positive clinical benefits, including higher rates of clinical 
remission, fewer hospitalizations, and fewer abdominal surgeries.9,10  However, 
improvement of the appearance of the intestinal mucosa may be more difficult to achieve 
than symptomatic improvement alone.
Conventional pharmaceutical therapies (e.g., corticosteroids, aminosalicylates, 
thiopurines, methotrexate) are limited, do not always completely abate the inflammatory 
process, and have significant adverse effects.1,11  The advent of anti-TNFα agents 


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(e.g., adalimumab) and integrin inhibitors (e.g., vedolizumab) have been shown to achieve 
clinical remission in patients refractory to conventional therapies.9-13
Despite the benefits of available biologic therapies, many patients do not respond to initial 
treatment (primary loss of response) or lose treatment over time (secondary loss of 
response).  Regarding anti-TNF agents, approximately 40% of patients will experience 
primary non-response and secondary non-response occurs in 38% of patients at 6 months 
and 50% of patients at 1 year.12,14-17  Additionally, some patients are not candidates for 
available biologic therapies.  Therefore new therapeutic options are required in order to 
continue to improve the outcome of patients with CD.
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
This study is designed to evaluate the efficacy and safety of two risankizumab induction 
doses versus placebo in subjects with moderately to severely active CD.  The primary 
differences between Study M16-006 and the prior Phase 2 study of risankizumab in CD is 
that this study will test a higher dosing of 1200 mg.  Additionally, the endpoints in this 
study are different to reflect the changing regulatory requirements for pivotal 
registrational studies for new agents for the treatment of CD. 
3.2
Benefits and Risks
Data suggest that altered immune regulation at the epithelial barrier leads to an 
overproduction of inflammatory cytokines, tissue destruction, and aberrant tissue repair in 
CD.  Among the cytokines implicated in CD pathogenesis, data at the genetic, human 


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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 CD.  The data observed in the Phase 2 study, suggest that risankizumab 
will alleviate signs and symptoms of active CD and reduce mucosal inflammation.  
Participation in this study may help to generate future benefit for subjects with CD.
Though there are no serious adverse drug reactions known to be associated with 
risankizumab therapy, risks of participating in this study include risk of infection and risks 
related to the study specific procedures of blood sampling, infusion and injection of study 
drug, and colonoscopy with biopsy.
Blood sampling, intravenous (IV) infusions and subcutaneous (SC) injections can cause 
local bruising, inflammation, and pain.  Colonoscopy and biopsy, although generally well 
tolerated, can be associated with diarrhea, abdominal pain, and in more severe cases, 
perforation, bleeding, effects from anaesthetic 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.
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 
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 


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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.  At the timing of this amendment, the DMC has provided recommendation that 
the study may continue without modification and allowed enrollment to begin for 16 -
17 year-olds. 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-
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.


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The benefit-risk profile is considered appropriate for an experimental therapy at this stage 
of clinical development.
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
The objective of Study M16-006 is to evaluate the efficacy and safety of risankizumab 
versus placebo during induction therapy in subjects with moderately to severely active 
CD.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
The study was designed to enroll approximately 855 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.  In addition to the 
855 subjects, up to 85 subjects with a lower SES-CD, defined as an eligibility SES-CD of 
≥ 3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for isolated ileal disease will 
be enrolled in order to inform treatment effect in this patient population, but these subjects 
will not be included in the primary ITT population for efficacy analysis.
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy and safety of risankizumab as an induction therapy in 
subjects with moderately to severely active CD, defined as:
1.
average daily stool frequency (SF) ≥ 4 (when calculating SF, only the number of 
liquid or very soft stools should be recorded) and/or average daily abdominal pain 
(AP) score ≥ 2; plus 


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2.
endoscopic evidence of mucosal inflammation as measured by the Simple 
Endoscopic Score for CD (SES CD). All eligible scores exclude the presence of 
narrowing component and are confirmed by a central reader. Endoscopic activity 
is defined as SES-CD of ≥ 3.  
The number of subjects enrolled with a SES-CD of ≥ 3 to < 6 for ileocolonic or colonic 
disease or SES-CD of 3 for isolated ileal disease will be no more than 85 subjects.  
Once cap of no more than 85 subjects is reached, enrollment criterion will be an eligibility 
SES-CD of ≥ 6 for ileocolonic or colonic disease, or eligibility SES-CD of ≥ 4 for isolated 
ileal disease.
All endoscopies will be centrally read to document eligibility and for assessment at the 
time points indicated in Appendix C.  
The study will enroll both subjects who have had an inadequate response (IR) to prior 
biologic therapy (bio-IR) and subjects who have not (non-bio-IR).  
The bio-IR population is defined as subjects with documented intolerance or inadequate 
response to one or more of the approved anti-TNF or anti-integrin biologics for CD 
(infliximab, adalimumab, certolizumab, vedolizumab, ustekinumab and/or natalizumab).  
The bio-IR population will be approximately 540 subjects.  
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 in the past but stopped therapy based on reasons other than inadequate 
response or intolerance (e.g., change in reimbursement coverage, well-controlled disease).  
The non-bio IR population will be approximately 315 subjects.


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The percent of subjects with exposure, including intolerance or inadequate response, to 
ustekinumab will be no more than 20%.
The study duration may be up to 49 weeks, including a Screening period of up to 35 days, 
a 12-week induction period, 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 12, 16 and 20 and 
evaluation for clinical response at Week 24.
At the study visit indicated in Appendix C, all subjects will be provided with a subject 
diary where they will record CD related symptoms throughout the study.  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.  All endoscopies will be 
evaluated using SES-CD and will be confirmed by a central reader.  Biopsy to confirm 
diagnosis (during Screening) or to rule out dysplasia/malignancy may be performed 
during the same time points as the endoscopy.  Optional exploratory research samples 
may be taken during the study.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the study and randomized in a 2:2:1 ratio as shown in Figure 1.  At the 
timing of this amendment, the DMC has provided recommendation that the study may 
continue without modification and allowed enrollment to begin for 16 - 17 year-olds.   


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Figure 1.
Study M16-006 Study Schematic
a.
12-Week Induction Period
b. Induction Period 2
DC = discontinued; IR = subjects with inadequate clinical response to induction; IV = intravenous; R = subjects with 
clinical response; RR = re-randomize


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Screening Period
Within 35 days prior to the Baseline visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and 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.  The Screening period (35 days ± 7 days is 
granted around all study visits) may be extended as necessary after consultation with the 
AbbVie Therapeutic Area Medical Director (TA MD) for subjects who require initiation 
of prophylactic anti-TB therapy, or in case of external circumstances (e.g., due to the 
delay of availability of screening test results).
Laboratory values that are exclusionary can be re-tested once during the screening period 
upon discussion and clearance with TA MD. 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 SF, average daily AP, and CDAI calculated 
and meeting eligibility criteria before randomization at Baseline.
12-Week Induction Period
At the Baseline visit, subjects who meet all the inclusion criteria and none of the 
exclusion criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the 
study and randomized to the double-blind induction period where they will receive either 
risankizumab 1200 mg IV, risankizumab 600 mg IV, or placebo, given at Baseline and 


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Weeks 4 and 8.  The randomization at Baseline will be stratified by number of prior 
biologics failed (0, 1, > 1), steroid use at Baseline (yes, no), and Baseline SES-CD 
(original, alternative).
During this period of the study, subjects will visit the study site at Weeks 4, 8 and 12/PD.  
Subjects who do not achieve clinical response at Week 12 and choose to continue in the 
study will have additional visits at Weeks 16, 20 and 24 for blinded Induction Period 2 
with risankizumab.  A ± 7-day window is permitted around scheduled study visits.  An 
effort will be made to bring subjects back to their original scheduled visit (calculated from 
Baseline) if they are out of the visit window.
At the Week 12/PD visit, all subjects will undergo an endoscopy for evaluation of 
mucosal inflammation.  It is expected that all subjects who remain in the study through at 
least Week 8 will have a Week 12/PD endoscopy.  All subjects achieving clinical 
response, defined as ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in 
average daily AP score (both not worse than Baseline) at Week 12 may be eligible to 
enter Study M16-000.  Subjects are not eligible to enter Study M16-000 until endoscopy 
has been completed (local reader results will be used for stratification for 
Study M16-000).  
All subjects who do not achieve clinical response at Week 12 will be able to receive 
blinded risankizumab in Induction Period 2, as specified below.  Subjects are not eligible 
to receive blinded Induction Period 2 therapy until endoscopy has been completed.  
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.
Subjects who received risankizumab induction treatment will be randomized 1:1:1 to:
●
Group 1:  1200 mg IV risankizumab


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●
Group 2:  360 mg SC risankizumab
●
Group 3:  180 mg SC risankizumab
Subjects who received placebo induction treatment will receive:
●
Group 4:  1200 mg IV risankizumab
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 participated in the blinded Induction Period 2 will be 
reassessed and undergo a third endoscopy for evaluation of mucosal inflammation.  
Subjects who achieve clinical response at Week 24 may be eligible to enter 
Study M16-000.  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 
participate in the blinded 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 and/or 
ongoing AEs.
Concomitant aminosalicylates, corticosteroids, immunomodulators (azathioprine 
[AZA], 6-mercaptopurine [6-MP], methotrexate [MTX]), and/or CD-related 
antibiotics
Subjects taking aminosalicylates, immunomodulators, and/or CD-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 
CD-related antibiotics during the study is prohibited.  Decreasing doses of 
aminosalicylates, immunomodulators, and/or CD-related antibiotics is prohibited during 
the study, except in the event of moderate-to-severe treatment related toxicities and after 
discussion with the AbbVie Therapeutic Area Medical Director (TA MD).  CD-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.


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Concomitant Corticosteroids
Subjects taking corticosteroids at Baseline must continue their concomitant treatment at 
the Baseline dose for the duration of the 12-week induction period.  Initiation and/or 
increasing doses of systemic and/or CD related corticosteroids during the entire study is 
prohibited.  Decreasing doses of corticosteroids is prohibited during the 12-week 
induction period, except in the event of moderate-to-severe treatment related toxicities 
and after discussion with the AbbVie Therapeutic Area Medical Director (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.
Follow-Up Period/Premature Discontinuation (PD)
Subjects 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 M16-000 will have a follow-up call 140 days from the last 
dose of study drug to obtain information on any new or ongoing AEs.
Re-Screen
Subjects 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.  
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 


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re-screening provided the conditions noted in Section 5.3.1.1 are met and no more than 
90 days have passed since the collection date of the testing.  
If a subject is being rescreened within 14 days (≤ 14 days have passed) from the collection 
date of the previous screening testing, it is not required to repeat Screening testing for 
chemistry/hematology, urinalysis, serum pregnancy, and C. difficile provided that the 
subject's health status has not changed to warrant a repeat test.  In this case, all Baseline 
testing should be performed at the Baseline visit. 
If rescreening occurs more than 14 days (> 14 days have passed) from the collection date 
of the previous screening testing then new samples (chemistry/hematology, urinalysis, 
serum pregnancy, and C. difficile) should be collected during Rescreening.  In this case, 
chemistry/hematology, urinalysis do not need to be repeated at the Baseline visit if 
Baseline occurs within 14 days (≤ 14 days) from the date of rescreening testing provided 
that the subject's health status has not changed to warrant a repeat test.  
All subjects need to have their average daily SF, average daily AP, and CDAI calculated 
in order to verify eligibility criteria before randomization at Baseline.
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.  Sites may contact the AbbVie TA MD if there are questions on if subjects 
should or should not be re-screened.
5.2
Selection of Study Population
It is anticipated that approximately 855 subjects with active moderate to severe CD will 
be enrolled at approximately 400 sites worldwide.  Both non-bio-IR and bio-IR subjects 
will be included.  The bio-IR population will be a minimum of approximately 
540 subjects and the non-bio-IR population will be a minimum of approximately 
315 subjects.


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A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria and none of the exclusion criteria specified in this protocol.
5.2.1
Inclusion Criteria
1.
Male or female aged ≥ 18 to ≤ 80 years, or minimum age of adult consent 
according to local regulations, at the Baseline Visit.  Where locally permissible,
subjects 16 to < 18 years of age who meet the definition of Tanner stage 5 for 
development (refer to Appendix J) at the Baseline Visit (sites will be notified when 
adolescents may enroll).
2.
Confirmed diagnosis of CD for at least 3 months prior to Baseline.  Appropriate 
documentation of biopsy results consistent with the diagnosis of CD, in the 
assessment of the Investigator, must be available.
3.
Crohn's disease activity index (CDAI) score 220 – 450 at Baseline.
4.
Endoscopic evidence of mucosal inflammation as documented by the SES-CD of 
≥3. All eligible scores exclude the presence of narrowing component and are 
confirmed by a central reader. (Once cap of no more than 85 subjects is reached, 
enrollment criterion will be an SES-CD of ≥ 6 for ileocolonic or colonic disease or 
SES-CD of ≥ 4 for isolated ileal disease.)
5.
Average daily SF ≥ 4 and/or average daily AP score ≥ 2 at Baseline. 
6.
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 
(intolerance includes patients with a known TPMT genetic mutation or low 
activity).
●
Inadequate response is defined as outlined below:
○
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, 
balsalazide):


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●
Signs and symptoms of persistently active disease, in the opinion of the 
Investigator, during a current or prior course of at least 4 weeks of 
treatment with 2.4 g/day mesalamine, 4 g/day sulfasalazine, 1 g/day 
olsalazine, or 6.75 g/day balsalazide, 
○
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, 
Hong Kong, 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, 
Hong Kong, 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
○
Biologic therapies for CD: 
●
Signs and symptoms of persistently (in the opinion of the Investigator) 
active disease despite a history of one or more of the following:
○
At least one 6-week induction regimen of infliximab (≥ 5 mg/kg 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 certolizumab pegol 
(400 mg SC at Weeks 0, 2, and 4),
○
At least one 6-week induction regimen of vedolizumab (300 mg IV 
at Weeks 0, 2, and 6), 
○
At least one 12-week induction regimen of natalizumab (300 mg IV 
every 4 weeks)
○
At least one 8-week induction regimen of ustekinumab [260 mg 
(≤55 kg) or 390 mg (> 55 to ≤ 85 kg) or 520 mg (> 85 kg) IV, 
followed by 90 mg SC at Week 8] (Once cap of no more than 20% 
ustekinumab exposed subjects is reached, subjects with prior 
ustekinumab exposure will not be allowed to enroll.)  
●
Recurrence of symptoms during scheduled maintenance dosing 
following prior clinical benefit of the above biologics
●
Note:  Subjects who discontinued biologics 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
7.
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.
8.
Subject must be able and willing to give written informed consent and to comply 
with the requirements of this study protocol.  In Japan, if the subject is < 20 years 
old, a subject's parent or legal guardian must be willing to give written informed 
consent.
Rationale for Inclusion Criteria
1 – 6
To select the adequate subject population with a disease status 
representative of the target population for evaluation
7
The impact of risankizumab on pregnancy and reproduction is unknown 
8
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
Concomitant Medications and Treatments
2.
Subject on CD-related antibiotics who has not been on stable doses 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


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●
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 current 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/intramuscular anti-infectives (non-CD-related) within 14 days prior to the 
Baseline visit.  This does not apply to TB prophylaxis.
7.
Subject who received exclusive enteral nutrition or any parenteral nutrition within 
35 days prior to Baseline.
8.
Subject who received any live bacterial or viral vaccination within 30 days 
(8 weeks for Japan) prior to Screening or during the Screening Period.
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:  infliximab, adalimumab, certolizumab, vedolizumab, 
natalizumab within 8 weeks prior to Baseline or ustekinumab within 12 weeks 
prior to Baseline, or 
Note:  If there is proper documentation of an undetectable drug level measured 
by a commercially available assay for any of the approved biologics above, 
there is no minimum washout prior to Baseline.
●
any investigational biologic or other agent or procedure within 35 days or 
5 half-lives prior to Baseline, whichever is longer.


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12.
Subject with prior exposure to p19 inhibitors (e.g., risankizumab)
13.
Subject has been taking combination of two or more of the following:  oral 
budesonide, or 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, other than required for 
endoscopy, within 14 days prior to endoscopy used for 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 of Baseline or any history of clinically significant drug, or 
alcohol abuse in the last 12 months.
CD Related
18.
Subject with currently known complications of CD such as:
●
abscess (abdominal or perianal),
●
symptomatic bowel strictures,
●
> 2 missing segments of the following 5 segments:  terminal ileum, right 
colon, transverse colon, sigmoid and left colon, and rectum
●
fulminant colitis,
●
toxic megacolon,
●
or any other manifestation that might require surgery while enrolled in the 
study.
19.
Subject with ostomy or ileoanal pouch.
20.
Subject diagnosed with short gut or short bowel syndrome.


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21.
Subject with surgical bowel resection within the past 3 months prior to Baseline, or 
a history of ≥ 3 bowel resections.
Safety
22.
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).
23.
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 or other intestinal pathogen during Screening, 
●
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 Bacillus 
Calmette-Guérin (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;
○
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with 
positive anti-HCV antibody (HCV Ab)


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24.
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.
25.
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.
26.
Subject with current or previous 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.
27.
Subject who has severe, progressive, or uncontrolled renal, hepatic, hematological, 
endocrine, disorder or symptoms thereof.
28.
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.
29.
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.
30.
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


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●
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 after 
discussion and clearance with the TA MD. 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
31.
No known active COVID-19 infection. Subject must not have signs/symptoms 
associated with COVID-19 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 viral clearance criteria:
●
Symptomatic subjects: At least 2 negative viral tests in a row completed 
locally, ≥ 24 hours apart after at least 10 days have passed since recovery, 
defined as resolution of fever without use of antipyretics and improvement in 
respiratory symptoms (e.g., cough, shortness of breath)
●
Asymptomatic subjects: At least 2 negative viral tests in a row completed 
locally, ≥ 24 hours apart after at least 10 days have passed since prior positive 
result (Note: subjects who develop symptoms will follow guidance above for 
symptomatic subjects)
Frequency or timing of COVID-19 testing and interval between testing for the 
above viral clearance criteria may be adjusted to account for epidemiological 
trends, updated information regarding infectivity and local/institutional guidelines.
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


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18 – 21
To avoid complications of CD that may compromise the evaluations of 
efficacy and safety
22 – 31
To ensure the safety of the subject and or others
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 continues 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. 
CD specific medications (including but not limited to corticosteroids, aminosalicylates, 
immunomodulators [AZA, 6-MP, or MTX], and CD-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 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).


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5.2.3.2
Concomitant Therapy
Subjects taking aminosalicylates, immunomodulators, and/or CD-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 CD-
related antibiotics during the study is prohibited.  Decreasing doses aminosalicylates, 
immunomodulators, and/or CD-related antibiotics is prohibited during the study, except in 
the event of moderate-to-severe treatment related toxicities and after discussion with the 
AbbVie TA MD.  CD-related antibiotics may be discontinued in the blinded Induction 
Period 2 at the discretion of the Investigator.
Note:  the duration of the study includes the Induction Period 2.
Concomitant Corticosteroids
Subjects taking corticosteroids at Baseline must continue their concomitant treatment at 
the Baseline dose for the duration of the 12-week induction period.  Initiation and/or 
increasing doses of systemic and/or CD related corticosteroids during the entire study is 
prohibited.  Decreasing doses of corticosteroids is prohibited during the 12-week 
induction period, 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.
Setons are authorized as concomitant therapy in subjects with perianal fistulas and should 
be documented in the eCRF under concomitant medications.
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, the AbbVie TA MD 
should be contacted regarding possible permitted pre-medication with diphenhydramine 
hydrochloride and acetaminophen (or equivalents).  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®)
○
Vedolizumab (Entyvio®);


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●
Investigational agents (e.g., tofacitinib, 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
●
Cyclosporine, tacrolimus, or mycophenolate mofetil.
●
Concomitant cannabis use either recreational or for medical reasons.
●
Rectal therapy with any therapeutic enemas or suppositories, with the 
exception of those required for endoscopy, is prohibited during the study.
●
Apheresis (e.g., Adacolumn apheresis).
●
Exclusive enteral nutrition or any parenteral nutrition.
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding prohibited therapy.
5.2.4
Contraception Recommendations 
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.


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●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an Follicle-Stimulating Hormone (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, prior to 
Baseline 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, (must start at least 1 month prior to study.
○
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, (must start at least 1 month prior to 
study).
○
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).
○
Vasectomized sexual partner(s) (the vasectomized partner should have 
received medical assessment of the surgical success and is the sole sexual 
partner of 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/Validation Studies 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/validation studies (discussed in 
Section 5.3.1.2 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.  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/validation 
studies.  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, 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 CD-onset date, history of CD 
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 biologic, corticosteroid, immunomodulators (i.e., AZA, 6-MP, 
MTX), CD-related antibiotics, aminosalicylate or any other physician prescribed therapy 
for CD 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 active TB (during 
Screening) or 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.


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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.  Physical 
examinations at all other visits (including unscheduled visits) are symptom based and 
should include the assessment of EIMs as part of calculating the Crohn's disease activity 
index (CDAI).  The number of cutaneous fistulas should be recorded, including the 
number of fistulas draining upon gentle compression.  Fistulas will be classified as 
abdominal or perianal/anal.  Physical exam abnormalities noted by the Investigator at 
Baseline (including fistulas and fissures) will be recorded in the subject's medical history.  
Abnormalities noted after the Baseline visit will be evaluated and documented by the 
Investigator as to whether they are AEs.
Additionally, physical examination findings that are related to or part of each subject's 
medical history will be captured on the appropriate medical history eCRFs.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate, respiratory rate, and body temperature will be obtained at each visit.  Blood pressure, 
pulse rate, and respiratory rate should be measured before blood draws are performed.
Height will be measured at the Screening visit only (with shoes off) for subjects 
≥18 years of age.  Height will be re-measured at Week 12 and Week 24 (if applicable) for 
subjects < 18 years of age at Baseline.  Body weight will be measured at all scheduled 
visits, as specified in Appendix C.  All measurements will be recorded in metric units 
where applicable.


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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.  
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 Mycobacteria 
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.  IGRA 
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.  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 
active TB is diagnosed, the subject may not enroll in the study.  If presence of latent 
tuberculosis is established, then tuberculosis prophylaxis should be initiated and 
maintained according to local country guidelines.  It is also necessary to report the latent 
TB or positive TB testing in the source documents and eCRFs.


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●
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 
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."  
●
If PPD and/or the QuantiFERON®-TB Gold test (or IGRA equivalent) is 
positive, or if there is a repeat indeterminate QuantiFERON®-TB Gold test (or 
IGRA equivalent) upon retesting, subjects may continue in the study if further 
work up (according to local practice/guidelines) establishes conclusively that 
the subject has no evidence of active tuberculosis.  
●
If presence of latent tuberculosis is established, TB prophylaxis/treatment 
should be initiated and maintained according to local country guidelines. 
●
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, 


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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.
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 (CDAI, IBDQ, etc.) are obtained and before study drug administration 
during a visit.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  All abnormal laboratory tests that are considered clinically significant by 
the Investigator will be followed to a satisfactory resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing and shipping of these samples.
For serum chemistry tests and some exploratory biomarker 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.


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If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  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
Coagulation:
INRc
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)d
HBs Ag
HBs Ab
HBc Ab
HBV DNA PCR reflex only
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
Histaminee
Biomarkers:
High-Sensitivity C-Reactive Protein 
(hs-CRP)
Optional Biomarkers:
Stool Samples:
Blood, tissue and stool will be collected 
for optional exploratory 
research/validation studiesa
C. difficile toxin
Fecal calprotectin (FCP)
PK/Immunogenicity:
Serum risankizumabe
Serum anti-drug antibodies 
(ADA)e
Serum neutralizing antibodies 
(nAb)e
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 show 
leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.
c.
INR test only drawn if ALT or AST > 3 × ULN (upper limit of normal) and Total Bilirubin ≤ 2 × ULN (Refer to 
Section 5.4.1, for additional information).
d.
Only done at screening and calculated by the central laboratory.
e.
To be done with the occurrence of a suspected anaphylactic reaction (an additional sample of tryptase to be 
collected if possible at least 2 weeks post-reaction or at the next study visit); for ADA these samples are collected 
in addition to those specified in Appendix C.


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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 only:  for subjects with HBs Ab (+) and/or HBc Ab (+) at Screening, the HBV-
DNA PCR test should be performed as outlined in Appendix C.  In cases where the 
recurrence of HBV-DNA is observed, the subject should be discontinued from the study 
drug.  Retesting according to Appendix C is not necessary with subjects who have a 
history of HBV vaccine and are HBs Ab (+).
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 a 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 


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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, 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.
●
Plasma histamine: optimally, within 5 to 15 minutes of the onset of 
symptoms, and no later than 1 hour.
Stool Samples Collected:
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.  All stool samples should be collected before any bowel preparation for 
endoscopy is started and returned to the site per the instructions provided outside of this 
protocol.


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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.
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:


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●
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, 
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.  


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Blood draws should be performed, as much as possible, after all efficacy assessments, 
questionnaires (CDAI, IBDQ, etc.), and vital sign determinations are obtained and before 
study drug administration during a visit.  In order to maintain the study blind, local 
laboratory testing for hs-CRP for routine subject monitoring should not be performed.
Crohn's Disease Activity Index (CDAI) 
Average daily SF, average daily AP score, and well-being will be calculated from the 
subject diary.  During screening subjects will be instructed on how to calculate the 
number of very soft and liquid stools, including a visual depiction.  Physical exam and 
appropriate laboratory values will be calculated at all study visits beginning at Baseline.  
The Screening period will be a minimum of 7 days to calculate the Baseline scores.
The CDAI scores must be calculated using a central laboratory hematocrit (Hct) value 
from the same visit for all visits, except Baseline, where the most recent Screening Hct 
value will be used.  The final CDAI for all other visits will be calculated once the 
hematocrit value is received from the central lab.  If the Hct is missing due to technical 
issues (e.g., lost sample, clotted sample, etc.), the Hct value from the preceding visit may 
be used.
Instructions to calculate CDAI
●
To answer questions one (1) through three (3), entries from the 7 days prior 
to the visit should be used as recorded by the subject from the diary.
●
Diary entries should not be included in the 7 days evaluated prior to the visit 
if:  (1) the day the subject received medication for bowel preparation prior to 
endoscopy, (2) the day the subject underwent an endoscopy, and (3) 2 days 
following the endoscopy.  Diary entries, up to 14 days prior to the visit, will be 
used accordingly in order to provide the most recent data for 7 days prior to the 
respective study visit.  The 7 days do not need to be consecutive.
●
In question four (4), for the section regarding presence of anal fistulas and 
other fistulas, all fistulas detectable on physical examination (draining and 


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non-draining) should be captured on the CDAI and calculated into the CDAI 
score.
●
And the evaluation for fever should include all the days that are taken into 
account for the calculation of the CDAI.
●
When completing question five (5) ("Taking
Lomotil/Imodium/Loperamide/opiates for diarrhea, 0 = no, 1 = yes") on the 
CDAI, "no" should be answered if a subject is taking an opiate(s) solely for 
pain.  The use of these medications takes into account only the day of the 
scheduled visit and is only assessing their use as anti-diarrheals.
●
For question seven (7), hematocrit results from central laboratory will be used 
for the CDAI calculation.  If the hematocrit value contains more than 
one decimal point, the rounding will be allowed to the tenths decimal (e.g., Hct 
value 33.44 will be captured as 33.4, Hct value of 33.45 will be captured as 
33.5).  The Hct values either prior to completing the calculation or at the 
subtotal box 7 of the CDAI should not be rounded to a whole number.
●
For question eight (8), the height obtained at Screening should be used when 
selecting the standard weight in Appendix G, and this standard weight should 
be used for calculating every CDAI throughout subject participation in the 
study.
●
Standard height is calculated by using the height obtained at Screening 
(without shoes) adding one inch or 2.5 cm.  For subjects < 18 years of age at 
Baseline, height will be re-measured at Week 12 and Week 24 (if applicable) 
and standard height should be recalculated.
●
If the body weight obtained at the time of assessment is not captured in 
kilograms (kg), then when converting into kg, rounding should occur using the 
second digit after the decimal (also known as the hundredth place) where if the 
number is 0 – 4, then keep the first digit after the decimal (also known as the 
tenth place) unchanged.  If the second digit after the decimal is 5 – 9, then 
round up the first digit after the decimal (e.g., 90.246 would be captured as 
90.2 and 97.687 would be captured as 97.7).
●
The subtotal of box 8 should not be rounded to a whole number.
The calculation of the CDAI score is in Appendix F.


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Endoscopy
An endoscopy will be performed on the following visits:
●
During Screening*
●
Week 12/PD
●
Week 24 
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 Weeks 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:
1.
Biopsy confirmation of the diagnosis is available according to section "Biopsy 
During Endoscopy" below, as applicable.
2.
The endoscopy took place within 45 days prior to Baseline visit.
3.
The endoscopy was recorded in a video format as the endoscopic eligibility will be 
determined by the central reviewers.  
All ileocolonoscopies will be performed and recorded at the site in a video format.  Sites 
should also perform the SES-CD assessment and record the findings on the SES-CD score 
sheet (Appendix E) and in the appropriate eCRF.  
All endoscopies will be reviewed by a central reviewer who is blinded.  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 for stratification for Study M16-000.


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There will be a window of ± 7 days to conduct the ileocolonoscopy.  This window may be 
extended as necessary after consultation with the AbbVie TA MD in case of external 
circumstances.
The endoscopies performed at the time points described above will be used to provide the 
endoscopy subscores to calculate the SES-CD.  All attempts should be made by the 
endoscopist to explore all segments of the colon and terminal ileum, including intubation 
of the terminal ileum, at every endoscopy visit.  The endoscopy subscores by segment will 
be noted in the subject's source documents and in the database but the central reviewer's 
endoscopy subscore will be used for the efficacy analyses.
Biopsy During Endoscopy
Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the 
assessment of the Investigator, must be available in order to confirm the subject's 
eligibility for the study.  If this documentation is not available a diagnostic biopsy from 
the most affected 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.  
If any biopsy sample(s) are obtained, it should also be recorded on the video.  
Any biopsy sample(s) will be collected from the respective bowel segment during the 
withdrawal of the endoscope and after sufficient recording for the central reader to 
calculate the SES-CD.
The signed pathology report will be monitored by the responsible 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.


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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 M16-000.  Subjects should also be dispensed the patient 
information card at Screening.
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.
●
Inflammatory Bowel Disease Questionnaire (IBDQ) 
●
Work Productivity and Impairment Questionnaire – CD (WPAI-CD) 
●
Crohn's Symptom Severity (CSS) 
●
Patient Global Impression of Change (PGIC)
●
Patient Global Impression of Severity (PGIS)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
European Quality of Life 5 Dimensions (EQ-5D-5L)
●
36-Item Short Form Health Survey (SF-36)


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Due to the COVID-19 pandemic and any local restrictions, 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.  Also, the initial 20 subjects enrolled 
between the Phase 3 induction trials will be monitored on site for 2 hours after completion 
of each infusion.  Subjects should be observed after study drug administration until judged 
clinically stable by the study personnel.  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.
Study drug kits are assigned by the IRT following the subjects randomized treatment 
schedule.  (Refer to Section 5.5 for additional information).
During the Study Drug Dosing Period, a subject with confirmed (viral test positive) or 
suspected COVID-19 infection can only be dosed with study drug if the following 
COVID-19 viral clearance criteria are met: 
●
Symptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours apart 
after at least 10 days have passed since recovery, defined as resolution of fever 
without use of antipyretics and improvement in respiratory symptoms (e.g., 
cough, shortness of breath)
●
Asymptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours 
apart after at least 10 days have passed since prior positive result (note: 


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subjects who develop symptoms will follow guidance above for symptomatic 
subjects)
5.3.1.2
Collection and Handling of Optional Exploratory 
Research/Validation Studies Samples
Subjects will have the option to provide samples for exploratory research and validation 
studies.  Subjects may still participate in the study even if they decide not to participate in 
the optional exploratory research/validation.  The procedures for obtaining and 
documenting informed consent are discussed in Section 9.3.
Exploratory research can help to improve our understanding of how individuals respond 
to drugs and our ability to predict which patients would benefit from receiving specific 
therapies.  In addition, exploratory research may help to improve our understanding of 
how to diagnose and assess/monitor CD by assessing associations between disease 
characteristics, outcomes data and biomarkers of interests. 
Validation studies, including those related to the development of potential in vitro 
diagnostic tests, may be carried out retrospectively in order to assess associations between 
events of interest (i.e., efficacy and/or safety events) and candidate biomarkers.
AbbVie (or people or companies working with AbbVie) will store the biomarker 
exploratory research/validation studies samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
risankizumab (or drugs of this class) or this disease and related conditions continues, but 
for no longer than 20 years after study completion.
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.  The 
following samples will be collected according to Appendix D from each subject who 
consents to provide samples for exploratory research/validation studies:


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●
DNA samples for pharmacogenetic or epigenetic analyses
●
RNA samples for transcriptomic and/or epigenetic analyses
●
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 analyses.
Samples will be shipped to AbbVie or a designated laboratory for DNA/RNA extraction, 
if applicable, and/or analyses or long-term storage.  Instructions for the preparation and 
shipment of the samples will be provided in the laboratory manual.
5.3.2
Drug Concentration and Anti-Drug Antibody 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 appropriate eCRF.
For approximately 20 subjects who consent to participate in the Optional Intensive PK 
sampling, refer to Appendix H.  
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.


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5.3.2.3
Disposition of Samples
Frozen samples will be packed in dry ice (pellet form) sufficient to last 3 days during 
transport.  Samples will be shipped pursuant to 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. 
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
Endpoint definitions:
●
Clinical remission:  average daily SF ≤ 2.8 and not worse than Baseline AND 
average daily AP score ≤ 1 and not worse than Baseline
●
Enhanced clinical response:  ≥ 60% decrease in average daily SF and/or 
≥35% decrease in average daily AP score and both not worse than Baseline, 
and/or clinical remission
●
Clinical response:  ≥ 30% decrease in average daily SF and/or ≥ 30% 
decrease in average daily AP score and both not worse than Baseline
●
Endoscopic response:  decrease in SES-CD > 50% from Baseline (or for 
subjects with isolated ileal disease and a Baseline SES-CD of 4, at least a 
2 point reduction from Baseline), as scored by central reviewer


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●
Ulcer-free endoscopy:  SES-CD ulcerated surface subscore of 0 in subjects 
with SES-CD ulcerated surface subscore ≥ 1 at Baseline, as scored by a central 
reviewer
●
Endoscopic remission:  SES-CD ≤ 4 and at least a 2 point reduction versus 
baseline and no subscore greater than 1 in any individual variable, as scored by 
a central reviewer
●
CDAI clinical response:  reduction of CDAI ≥ 100 points from baseline
●
CDAI clinical remission:  CDAI < 150
●
SF remission:  average daily SF ≤ 2.8 and not worse than baseline
●
AP remission:  average daily AP score ≤ 1 and not worse than baseline
5.3.3.1
Primary Variable
Co-Primary Endpoints:  
●
Proportion of subjects with CDAI clinical remission at Week 12  
●
Proportion of subjects with endoscopic response at Week 12
5.3.3.2
Secondary Variables
Ranked Secondary Endpoints:
1.
Proportion of subjects with clinical remission at Week 12
2.
Proportion of subjects with CDAI clinical response at Week 4
3.
Proportion of subjects with CDAI clinical response at Week 12
4.
Change from baseline of Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT fatigue) at Week 12
5.
Proportion of subjects with CDAI clinical remission at Week 4
6.
Proportion of subjects with CDAI clinical response and endoscopic response at 
Week 12


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7.
Proportion of subjects with SF remission at Week 12
8.
Proportion of subjects with AP remission at Week 12
9.
Proportion of subjects with endoscopic remission at Week 12
10.
Proportion of subjects with enhanced clinical response at Week 4
11.
Proportion of subjects with ulcer-free endoscopy at Week 12
12.
Proportion of subjects with enhanced clinical response at Week 12
13.
Proportion of subjects with resolution of extra-intestinal manifestations (EIMs) at 
Week 12, in subjects with any EIMs at Baseline
14.
Proportion of subjects with CD-related hospitalization through Week 12
15.
Proportion of subjects without draining fistulas at Week 12 in subjects with 
draining fistulas at Baseline
5.3.3.3
Other Endpoints
Non-Ranked endpoints are:
●
Change from Baseline in IBDQ over time
●
Change from Baseline in individual IBDQ domain scores (bowel, emotional, 
social, systemic) over time
●
Proportion of subjects with IBDQ remission (IBDQ > 170 points) over time 
●
Proportion of subjects with IBDQ response (increase in IBDQ > 16 points 
from Baseline) over time 
●
Change from Baseline in WPAI-CD over time
●
Change from Baseline in EQ-5D-5L over time
●
Change from Baseline in FACIT-Fatigue total score and individual item score 
over time
●
Change from Baseline in Short Form-36 overtime
●
Change from Baseline in FCP over time


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●
Change from Baseline in hs-CRP over time
●
Change from Baseline in average daily AP score over time
●
Change from Baseline in average daily SF over time
●
Proportion of subjects with clinical remission over time
●
Proportion of subjects with enhanced clinical response over time
●
Proportion of subjects with clinical response over time
●
Change from Baseline in SES-CD at Week 12
●
Proportion of subjects with a SES-CD ulcerated surface subscore ≤ 1 in each 
segment at Week 12 in subjects with a SES-CD ulcerated surface subscore ≥ 2 
at Baseline
●
Change from baseline in PGIS over time 
●
PGIC over time
●
Proportion of subjects with endoscopic remission over time
●
Proportion of subjects with endoscopic response over time
●
Proportion of subjects with CD-related surgeries through Week 12
●
Proportion of subjects with any reduction in SES-CD at Week 12
●
Proportion of subjects with CDAI clinical remission over time
●
Proportion of subjects with CDAI clinical response over time
●
Change from Baseline in CDAI over time
●
Change from Baseline in CSS over time
Of note, over time will be measured at each study visit as specified in the study 
activity table
5.3.4
Safety Variables
Safety analyses will be performed on safety set which includes all subjects who receive at 
least one dose of study drug.  Incidence of AEs, changes in vital signs, physical 
examination results, and clinical laboratory data will be assessed throughout the study. 


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5.3.5
Pharmacokinetic Variables
Serum risankizumab concentrations will be determined during the treatment period and at 
the follow-up visit as outlined in Appendix C.  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.
5.3.6
Optional Exploratory Research/Validation 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 
biomarker signatures.  These assessments may be explored in the context of CD 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.  In addition, samples from this study may be banked for future 
use.  Samples may then be used to validate putative biomarker signatures obtained from a 
prospective study, leading to the development of diagnostic tests.  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 AE, safety concerns or failure to 
comply with the protocol.
Subjects will be withdrawn from the study immediately if any one of the following 
occurs:


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●
Clinically significant abnormal laboratory result(s) or AEs, which rule out 
continuation of the study drug, as determined by the Investigator in 
consultation with the AbbVie TA MD.
●
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 in the best interest of the subject not to enter 
Induction Period 2.
●
Subjects who experience a severe systemic hypersensitivity infusion/injection 
reaction or anaphylaxis
●
The subject requests withdrawal from the study.
●
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 TA MD.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie TA 
MD.
●
The subject becomes pregnant while on study drug.
●
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 study, as determined by the 
Investigator, in consultation with the AbbVie TA MD.
●
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%)


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If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the PD 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 
drug 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 M16-000.
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.
For subjects who 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. 
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
Each dose of blinded study drug (1200 mg risankizumab, 600 mg risankizumab, or 
placebo) will be administered intravenously to the subject during 12-Week Induction 
Period.
Each dose of blinded study drug (1200 mg risankizumab, 360 mg risankizumab, or 
180 mg risankizumab) will be administered intravenously or subcutaneously in Induction 
Period 2.
If the 1200 mg dose is discontinued due to any reason, subjects will continue to enroll into 
the study and be randomized to either 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.
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, the AbbVie TA MD 
should be contacted regarding possible permitted pre-medication with diphenhydramine 
hydrochloride and acetaminophen (or equivalents).  Individual dosage, timing, and route 
of administration would be determined by the Investigator.  Any pre-medications 
administered must be recorded on the appropriate eCRF.
Subjects who do not achieve clinical response at Week 12 will be eligible for Induction 
Period 2 with blinded risankizumab.  Blinded risankizumab will be administered either 
intravenously at Weeks 12, 16, and 20 or subcutaneously at Weeks 12 and 20.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 2.


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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)
N/A
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)
N/A
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
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.  
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 the 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 


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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 any 
temperature excursion must be reported to the Sponsor immediately.  Sites are responsible 
to report 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
All subjects will be assigned a unique identification number by the IRT at the Screening 
visit and will keep the same unique subject identification number throughout the study.  
Subjects who meet the inclusion and none of the exclusion criteria defined in 
Section 5.2.1 and Section 5.2.2 will be centrally randomized in a 2:2:1 ratio to one of the 
three treatment groups at Baseline during the 12-Week Induction Period of the study.  The 
randomization will be stratified by number of prior biologics failed (0, 1, > 1), Baseline 
steroid use (yes, no), and Baseline SES-CD (original, alternative).  The IRT will assign a 
randomization number that will encode the subject's treatment group assignment 
according to the randomization schedule generated by the Statistics Department at 
AbbVie.
IRT will provide the appropriate medication kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Section 5.5.  
Returned study drug should not be re-dispensed to any subject.


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At Week 12, subjects who do not achieve clinical response 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. 
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 and unblinded 
CRA/monitor (as applicable)), as well as the Investigator, the 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.  


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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.
5.5.5.2
Data Monitoring Committee 
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 prepared outside of the protocol and approved by AbbVie 
and the DMC members before a subject is initiated 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 timing of this amendment, the DMC has provided recommendation that the study 
may continue without modification and allowed enrollment to begin for 16 - 17 year-olds.  
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.  
The DMC will review safety data at a minimum of 6-month intervals throughout the 
course of the study.  The DMC will determine if more frequent DMC meetings are 
required based on review of the accumulating safety data.  In addition, ad-hoc DMC 
meetings will be scheduled in the event of any significant safety concerns.  Based on these 
reviews, the DMC will make recommendations, as appropriate, regarding the conduct and 
management of the study.


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The CAC and AAC adjudicate 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.
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 (blinded or unblinded as applicable) will verify that study 
drug supplies are received intact, at the appropriate temperature, and in the correct 
amounts from the depot.  This will be accomplished by documenting the condition of the 
shipment, verifying the kit numbers in the package against the Proof of Receipt (POR) or 
similar document included with each drug shipment, and documenting this verification by 
signing and dating the POR or similar document and via direct reporting in IRT.  The 
original POR note or similar document 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 
date received, the lot number, kit number(s), date and number of vials and syringes 
dispensed and subject number.  For this study, unless otherwise prohibited locally, these 
records will be maintained electronically as part of the IRT system.
An overall accountability of the study drug will be performed by the site and 
reconciliation will be performed by the CRA/monitor (blinded or unblinded according to 
the monitoring plan) throughout the study and at the site close-out visit.  After verification 


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of drug accountability, used study drug must be destroyed at the site according to local 
regulations governing biohazardous waste.  Destruction of used study supplies must be 
completed and documented in such a way that blinding is maintained for all blinded study 
personnel.  All unused supplies must be inventoried, accounted for and destroyed on site 
according to local procedures or regulation or returned to a destruction facility.  A copy of 
the, Return Consignment Form from IRT, in accordance with instructions provided by the 
monitor/CRA (blinded or unblinded according to the monitoring plan), will be included in 
the return shipments.
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.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Risankizumab is a selective IL-23 inhibitor that may provide improved clinical benefit to 
risk profile in CD patients.  The proposed study is a Phase 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 CD, who have had inadequate 
response or intolerance to aminosalicylates, oral locally acting corticosteroids, oral and/or 
IV systemic corticosteroids, immunomodulators, and/or biologic therapies.
The study consists of a 12 week induction period to evaluate the efficacy and safety of 
two different IV risankizumab doses (IV, 600 mg or 1200 mg, Q4w) versus placebo.  For 
subjects not in clinical response at Week 12, an optional blinded Induction Period 2 (IV, 
1200 mg, 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 or Induction Period 2 can 
enter Study M16-000 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 12-week placebo controlled study is necessary for registrational purposes.  
A comparative study utilizing placebo provides an unbiased assessment of the efficacy 
and safety profile of risankizumab.  To ensure all subjects are given the opportunity to 
receive potentially efficacious therapy, all subjects not responding after 12 weeks can 
participate in the blinded Induction Period 2 with risankizumab.
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 CD.  All clinical and laboratory procedures in this study are 
standard and generally accepted.  Central reading of endoscopy will increase study rigor 
and ensure enrollment of subjects with moderately to severely active CD.
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 CD who meet all of the inclusion criteria and none of the 
exclusion criteria are eligible for enrollment in this study.  The specific population chosen 
was based on the unmet medical need of those subjects with a history of inadequate 
response or intolerance to immunomodulators (AZA, 6-MP, or MTX), corticosteroids, 
and/or biologic therapies. 
5.6.4
Selection of Doses in the Study
AbbVie plans to evaluate two doses of risankizumab (600 mg and 1200 mg) via IV 
administration every 4 weeks (Q4w; Weeks 0, 4, 8) through induction (12-Week 
Induction Period) and an additional three doses of 1200 mg of risankizumab via IV 
administration (Q4w; Weeks 12, 16, 20) or two doses of 180 or 360 mg SC (Q8w, 
Weeks 12 and 20; Induction Period 2) for subjects who do not achieve clinical response at 
Week 12.  The selection of the doses in this study is informed by the analysis of the safety 
and efficacy data, as well as the exposure-response relationship of efficacy, of a Phase 2 


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study in subjects with CD (Study 1311.6) and the pharmacokinetic data from the 
completed studies in subjects with psoriasis (Studies 1311.1 and 1311.2).
Results from the placebo controlled Study 1311.6 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 with evaluation of 
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.  The evaluation of higher dose data (1200 mg IV Q4w) will facilitate a more robust 
characterization of the dose-response and exposure-response relationship for these 
efficacy endpoints.  Inclusion of 1200 mg IV dose 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 CD.  Furthermore, the 
projected steady state exposures for the 1200 mg IV risankizumab Q4w regimen in 
subjects with CD are covered by safety margins of ~1.6 and ~3.6 for Cmax and AUC0-28 days
respectively (relative to NOAEL identified in the 26 week GLP toxicology study).
Induction Period 2 will evaluate IV (1200 mg Q4w) or SC (180 mg or 360 mg Q8w) 
risankizumab.  The purpose of Induction Period 2 is to evaluate the efficacy and safety of 
re-induction of risankizumab versus starting maintenance dosing on clinical response.  
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.  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.  The results 
from the Phase 2 study suggest a potential for increased benefit with 360 mg SC 
administration for maintenance regimen.


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6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
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 an "Other" 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 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 eCRF.
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 any hepatic related AE 
●
Any 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 I 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 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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6.1.3.1
Lack of Efficacy or Worsening of Disease 
Events that are clearly consistent with progression of the underlying disease (CD) are 
considered an expected outcome for this study and will not be subject to expedited 
reporting. 
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 140 days 
from the last dose of study drug have elapsed will be collected, whether solicited or 
spontaneously reported by the subject.  In addition, serious adverse events and protocol-
related nonserious adverse events will be collected from the time the subject signed the 
study-specific informed consent.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 


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having access to the RAVE® system, or if RAVE® is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660
For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
Dept. R48S, Bldg. AP31-2
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:
100 Research Drive, Suite 3009
Worcester, MA 01605
Telephone Contact Information:
Office:
Mobile:
Email:
In emergency situations involving study subjects when the primary AbbVie 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 CD in Study 
Population
Certain events are anticipated to occur in the study population as known consequences of 
CD (e.g., as symptoms or due to disease progression) independent of drug exposure.  
These events are listed in Table 3.  These AEs, which should be captured on the 
appropriate eCRF, 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 CD population hence considered expected for 
reporting.


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Table 3.
Common Events Associated with CD
Fistulae
Abscesses
Stenoses/Obstruction
!
Anal fistula
!
Colovaginal fistula
!
Colovesical fistula
!
Enterocolonic fistula
!
Enterocutaneous fistula
!
Enterovaginal fistula
!
Female genital-digestive tract 
fistula
!
Ileal fistula
!
Ileorectal fistula
!
Ileovaginal fistula
!
Perineal fistula
!
Rectal fistula
!
Rectovaginal fistula
!
Anal abscess
!
Anorectal abscess
!
Rectal abscess
1.
Anal stenosis
2.
Ileal stenosis 
3.
Intestinal obstruction
4.
Small intestine obstruction
Others
!
Anal fissure
!
Worsening of Crohn's 
disease
!
Intestinal perforation
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.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
6.1.7
Cardiac Adjudication Committee
The independent external CAC will be adjudicating observed cardio- and cerebro-vascular 
events and will remain blinded to treatment allocation.  The events that are adjudicated 


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and the adjudication process will be detailed in the Cardiac Adjudication Committee 
Charter.  Dedicated eCRFs will be used for events of myocardial infarction-unstable 
angina, stroke-transient ischemic attack, and death.  In addition, the site may be contacted 
for additional source documentation for relevant events.
6.1.8
Anaphylaxis Adjudication Committee
The independent external AAC will be adjudicating observed potential anaphylactic 
events and will remain blinded to treatment allocation.  The events that are adjudicated 
and the adjudication process will be detailed in the Anaphylaxis 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 


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satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with AEs will be reported in the study summary.  All other 
complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
Investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal Investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified, 
including those that may be due to the COVID-19 pandemic) after a subject has been 
enrolled, the principal Investigator is responsible for notifying IEC/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.


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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objective of the statistical analyses is to evaluate the efficacy and safety of 
risankizumab versus placebo in subjects with moderately to severely active CD who had 
baseline eligibility SES-CD of ≥ 6 (≥ 4 for isolated ileal disease).
When all patients complete their Week 12/PD visit, the database will be locked and un-
blinded for the 12-week induction period.  The planned analysis for the 12-week induction 
period will be performed.  This is the only and final analysis for co-primary endpoints of 
the 12-week induction period.  When all the patients who enter the induction Period 2 
finish Week 24/PD visit, the database will be locked for the whole study and all the 
planned analyses for the induction Period 2 will be performed.
Complete, specific details of the statistical analyses will be described and fully 
documented in the study Statistical Analysis Plan (SAP).  The SAP will be finalized prior 
to the study database lock.
The impact of missing data due to COVID-19 will be monitored and appropriate
modifications to the analysis of primary and key secondary endpoints for handling such 
missing data will be reflected and incorporated in the final SAP.
8.1.1
Datasets for Analysis 
8.1.1.1
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set includes all randomized subjects who received at 
least one dose of study drug.  The primary population for efficacy analysis are the subjects 
in the intent-to-treat set who had baseline eligibility SES-CD of ≥ 6 (≥ 4 for isolated ileal 
disease).  The ITT subjects will be analyzed as randomized.


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8.1.1.2
Safety Analysis Set
The safety analysis set consists of all subjects who received at least one dose of the study 
drug.  The safety set will be analyzed as treated, according to treatment the subject 
actually received.  The safety set will be used for safety analysis.
8.1.2
Definition of Missing Data Imputation 
Missing data will be imputed using one or more of the following methods:
Non-Responder Imputation (NRI):  In NRI analyses, subjects who prematurely 
discontinue the study prior to efficacy assessment at Week 12 will be considered 
non-responders with respect to the efficacy endpoint. 
Observed Cases (OC):  The OC analysis will not impute values for missing evaluations, 
and thus a subject who does not have an evaluation on a scheduled visit will be excluded 
from the OC analysis for that visit.
8.1.3
Subject Disposition 
The number and percentage of subjects who are enrolled, randomized and received at 
least one dose of study drug, and the number of subjects who prematurely discontinued 
and the reason for premature discontinuation will be summarized by treatment group.  
Premature discontinuation of study drug will be summarized for each treatment group, as 
well as for all subjects combined, with frequencies and percentages overall and by reason 
for discontinuation for all randomized subjects who received at least one dose of study 
drug.  Subjects may have multiple reasons for prematurely discontinuing study drug, but 
will be counted no more than once for the total ("Any Reason").
8.1.4
Demographics and Baseline Characteristics
Demographics (where collection is allowed) and Baseline characteristics of the study 
subjects will be summarized using descriptive statistics.  Summary statistics for 
continuous variables will include the number of observations, mean, standard deviation, 


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median, and range for each treatment group.  For other categorical or discrete variables, 
frequencies and percentages will be computed in each category for each treatment group, 
as well as for all subjects combined.
8.1.5
Prior and Concomitant Medications
Prior therapy and medications will include all therapies and medications administered 
prior to the date of the first dose of study drug.  Prior therapy and medication will be 
summarized for all randomized subjects.  No statistical test will be performed.
Concomitant medications will be summarized for all randomized subjects.  Concomitant 
medications will be summarized using the World Health Organization Drug Dictionary 
with frequencies and percentages for each treatment group.  No statistical test will be 
performed. 
8.1.6
Efficacy Analysis
8.1.6.1
Primary Efficacy Variables
The co-primary endpoints are the proportion of subjects who achieve CDAI clinical 
remission at Week 12 and proportion of subjects with endoscopic response at Week 12.
The comparisons between each risankizumab dose versus placebo for the primary efficacy 
variable will be performed using the Cochran-Mantel-Haenszel (CMH) test adjusted by 
number of prior biologics failed (0, 1, > 1) and steroid use at Baseline (yes, no). A 
multiple testing procedure will be used to provide strong control of the type 1 error rate at 
alpha = 0.05 (2-sided) across analyses comparing each risankizumab dose level to placebo 
with respect to the co-primary endpoints, and ranked secondary endpoints. Specifically, 
testing will utilize a sequence of hypothesis testing for the co-primary endpoints followed 
by the ranked secondary endpoints, and will begin with testing each of the co-primary 
endpoints using α of 0.025 (2-sided) for each dose compared to placebo.  If both co-
primary endpoints achieve statistical significance within a dose level, continued testing 
will follow a pre-specified weight of α allocation between the single hypothesis within the 
family, as well as between the families of hypotheses across the doses. Details will be 


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provided in the Statistical Analysis Plan. A CMH based two-sided 95% confidence 
interval for the difference between treatment groups will be calculated. Subjects who 
discontinue prior to Week 12 for any reason will be considered as "not-achieved" for 
CDAI clinical remission and endoscopic response endpoints.
The analysis of co-primary efficacy endpoints will be performed in bio-IR and non-bio-IR 
population. Additional subgroup analyses will be outlined in the SAP.  Sensitivity 
analyses for missing data handling using MI, PMM and OC will be performed for co-
primary endpoints and details will be outlined in the SAP.
8.1.6.2
Secondary Efficacy Variables 
The secondary efficacy variables are divided into two groups.  The first group includes 
ranked secondary endpoints, which are ranked by clinical importance.  Statistical 
significance is assessed at the pre-specified alpha level (two-sided) in ranked endpoint 
order until the significant level exceeds the pre-specified alpha level.  No additional 
statistically significant treatment differences could be declared if the preceding ranked 
endpoint fails to achieve the pre-specified alpha level.  The second group includes all 
other additional secondary variables.  All analyses of secondary endpoints will be 
performed using the ITT analysis set. 
In general, continuous secondary efficacy variables will be analyzed using a Mixed-Effect 
Model Repeated Measure (MMRM) model including factors for treatment group, visit, 
visit by treatment interaction, and stratification variables, for the longitudinal continuous 
endpoints.  The MMRM analysis is considered primary for inferential purposes.  
Categorical secondary efficacy variables will be analyzed using the CMH test controlling 
for stratification variables.  Non-responder imputation for missing data will be used for 
categorical secondary endpoints. 
Analysis of Pattern Mixture Model (PMM) will be performed as sensitivity analyses for 
ranked secondary endpoints.


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8.1.7
Safety Analysis 
Safety analyses will be carried out using the safety analysis sets, which includes all 
subjects who receive at least one dose of study drug.  Incidence of AEs, including those 
related to study drug, changes in vital signs, physical examination results, and clinical 
laboratory values will be analyzed.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary.  Treatment-emergent AEs are defined as AEs that began or 
worsened in severity after initiation of study drug and within 140 days after the last dose 
of the study drug.  An overview of treatment-emergent AEs, including AEs leading to 
death and AEs leading to premature discontinuation (see details in the SAP), AEs by 
MedDRA preferred term and system organ class, AEs by maximum relationship to study 
drug, and AEs by maximum severity will be summarized by number and percentage.  
Continuous laboratory and vital sign parameters will be summarized for each treatment 
group by visit.  Treatment group differences between each of the risankizumab dosing 
groups and the placebo group for changes from Baseline may be analyzed using a one-
way Analysis of Variance (ANOVA).  Vital signs and laboratory data will be described by 
statistical characteristics and frequency of abnormal values.  In addition, shift tables and 
listings will be provided for abnormal values, whereby the normal range of the analyzing 
laboratory will be used.  Analysis details will be specified in the SAP.
8.1.8
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 
variety of statistical predictive modeling algorithms.  Cut-points for individual biomarkers 


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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.21,22
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.  In addition, ADA incidence will be 
summarized by cohorts 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 non-
linear 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/F or Vss/F 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
The co-primary endpoints are the proportion of subjects with CDAI clinical remission at 
Week 12 and proportion of subjects with endoscopic response at Week 12.  


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A total of approximately 855 subjects will be randomized into two risankizumab 
treatment groups and the placebo group in a 2:2:1 ratio (342 subjects for risankizumab 
600 mg dose group, 342 subjects for risankizumab 1200 mg dose group, and 171 subjects 
for placebo group).  Assuming the Week 12 CDAI clinical remission rate will be 37% for 
one of the risankizumab dose groups and 17% for the placebo group, a sample size of 342 
subjects for each of the risankizumab dose groups and 171 for the placebo group will have 
99% power to detect the treatment difference between the risankizumab dose groups and 
placebo in CDAI clinical remission rates at Week 12 using Fisher's exact test at alpha of 
0.025 (two-sided).  Assuming the Week 12 endoscopic response rate will be 25.5% for 
one of the risankizumab dose groups and 8% for the placebo group, this sample size will 
have 99% power to detect the treatment difference between the risankizumab dose groups 
and placebo in endoscopic response rates at Week 12 using a Fisher's exact test at alpha of 
0.025 (two-sided).
In addition, with sample size of approximately 540 bio-IR subjects, this study will have 
approximately 92% power for the bio-IR population to detect the treatment difference 
between one of the risankizumab dose groups and placebo in CDAI clinical remission 
rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) for the bio-IR 
population, assuming the Week 12 CDAI clinical remission rate will be 34% for the 
risankizumab dose groups and 15% for the placebo group.  Similarly, with sample size of 
approximately 315 non-bio-IR subjects, this study will have 70% power to detect the 
treatment difference between one of the risankizumab dose groups and placebo in CDAI 
clinical remission rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) 
for the non-bio-IR population, assuming the Week 12 CDAI clinical remission rate will be 
42% for the risankizumab dose groups and 21% for the placebo group for non-bio-IR 
subjects.
8.3
Randomization Methods
A total of approximately 855 subjects will be randomized into two risankizumab dose 
groups and the placebo group in a 2:2:1 ratio (342 subjects for risankizumab 600 mg dose 
group, 342 subjects for risankizumab 1200 mg dose group, and 171 subjects for placebo 


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group).  Randomization will be stratified by number of prior biologics failed (0, 1, > 1), 
the steroid use at Baseline (yes, no), and Baseline SES-CD (original, alternative), where 
the stratum of "original" includes the patients with baseline SES-CD of ≥ 6 (or ≥ 4 for 
subjects with isolated ileal disease), and the stratum of "alternative" includes the patients 
with baseline SES-CD of ≥3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for 
isolated ileal disease.  
Subjects with clinical non-response to risankizumab at Week 12 will be re-randomized in 
a 1:1:1 ratio to 1200 mg IV dose group, 360 mg SC dose group, or 180 mg SC dose 
group.  Subjects with clinical non-response to placebo at Week 12 will blindly receive 
1200 mg risankizumab IV dose. 
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.
Following local regulation, substantial amendments may also be reviewed and approved 
by the national competent authority.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP and all other applicable regulatory requirements.


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


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original will be placed in the subject's medical record.  An entry must also be made in the 
subject's dated source documents to confirm that informed consent was obtained prior to 
any study-related procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
The optional samples for intensive PK analyses will only be collected if the subject has 
voluntarily signed and dated the intensive PK section of the main ICF, approved by an 
IRB/IEC, after the nature of the testing has been explained and the subject has had an 
opportunity to ask questions.  
Samples for exploratory research/validation studies will only be collected if the subject 
has voluntarily signed and dated the separate written consent for exploratory 
research/validation studies, approved by an IRB/IEC, after the nature of the testing has 
been explained and the subject has had an opportunity to ask questions.  The separate 
written consent must be signed before the exploratory research/validation studies samples 
are collected and testing is performed.  If the subject does not consent to the exploratory 
research/validation studies, it will not impact the subject's participation in the study.
For adolescent subjects, the investigator or his/her representative will explain the nature of 
the study 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 


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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.
Genetic and non-genetic biomarker analysis will only be performed if the subject's 
parent/legal guardian has voluntarily signed and dated a separate genetic and non-genetic 
biomarker 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 genetic and non-genetic biomarker informed consent must 
be signed before the genetic and non-genetic biomarker testing is performed.  If the 
subject's parent/legal guardian does not consent to the genetic and non-genetic biomarker 
testing, 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.


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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.
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, ECGs, 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.  IRT may also be the source for drug accountability.  Data collected 
during this study must be recorded on the appropriate source documents.  The Investigator 
Awareness Date (SAE eCRF) may serve as the source for this data point.  This AE data 
point required for eCRF completion can be entered directly in the eCRF.
The Investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.


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10.2
Case Report Forms
Electronic case report forms (eCRF) 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 eCRF data for this study are 
being collected with an EDC system called Rave® provided by the technology vendor 
Medidata Solutions Incorporated, NY, USA.  The EDC system and the study-specific 
eCRFs will comply with Title 21 CFR Part 11.  The documentation related to the 
validation of the EDC system is available through the vendor, Medidata, while the 
validation of the study-specific eCRFs will be conducted by AbbVie and will be 
maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
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 study 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 


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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 CRF Health of Plymouth Meeting, PA, USA.  The ePRO system is 
in compliance with Title 21 CFR Part 11.  The documentation related to the system 
validation of the ePRO system is available through the vendor, CRF Health, while the 
user acceptance testing of the study specific PRO design will be conducted and 
maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source, and maintained and 
managed by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study to the site Investigator, 
as well as delegated personnel.  Such access will be removed from Investigator sites 
following the receipt of the study archive.  Data from the ePRO system will be archived 
on appropriate data media (CD-ROM, etc.) and provided to the Investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the Investigator to make 
paper print-outs from that media.
The ePRO data will be collected by the following methods:
Diary Based
The ePRO data (number of liquid or very soft stools, use of medications used for 
endoscopy preparation, abdominal pain, and general well-being) will be collected 
electronically via a handheld device into which the subject will record the required pieces 
of information on a daily basis.  The electronic device will be programmed to allow data 


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entry once per day.  All data entered on the device will be immediately stored to the 
device itself and manually/automatically uploaded to a central server administrated by 
CRF Health.  The investigational site staff will be able to access all uploaded subject 
entered data via a password protected website, up until the generation, receipt and 
confirmation of the study archive.
Tablet Based
The PROs listed below will be collected electronically via a Tablet device into which the 
subject will directly enter the required pieces of information while at the site.  The 
electronic device will be programmed to allow data entry for only the visits specified in 
the protocol and will not allow for subjects to complete more than one of the same 
assessment 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 CRF Health.  The investigational site staff will be able to access all uploaded subject 
entered data via a password protected website, up until the generation, receipt and 
confirmation of the study archive.
●
CSS
●
PGIC
●
PGIS
●
EQ-5D-5L
●
FACIT-F
●
IBDQ 
●
SF-36
●
WPAI-CD
11.0
Data Quality Assurance
To ensure data integrity and subject safety, a study monitor will, throughout the study, 
verify that all subjects signed agreement of informed consent prior to any study-specific 
procedures being conducted.  The study monitor will confirm that the Investigator is 


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conducting the study in compliance with the protocol, GCP and applicable regulations, 
and verify that the information reported in the eCRF is complete, accurate, and supported 
by information in source documents.
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
All information concerning 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 
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.


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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/validation studies that may be done using the samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management, hence, neither the Investigator, the subject, nor 
the subject's physician (if different from the Investigator) will be informed of individual 
subject results, should analyses be performed, nor will anyone not directly involved in this 
research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from exploratory research/validation 
studies from this study may be used in scientific publications or presented at medical 
conventions.  Exploratory research/validation studies data will be published or presented 
only in a way that does not identify any individual subject.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the Investigator (Director of the Site in Japan) 
and AbbVie.  The Investigator will provide a final report to the IEC/IRB following 
conclusion of the study, and will forward a copy of this report to AbbVie or their 
representative.
The Investigator (Director of the Site in Japan) must submit, maintain, and archive any 
records related to the study according to ICH GCP and all other applicable regulatory 
requirements.  If the Investigator (Director of the Site in Japan) is not able to retain the 
records, he/she must notify AbbVie to arrange alternative archiving options.


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AbbVie will select the signatory Investigator from the Investigators who participate in the 
study.  Selection criteria for this Investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products Guidance 
on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for 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 of the Efficacy and Safety of Risankizumab in 
Subjects with Moderately to Severely Active Crohn's Disease
Protocol Date:
01 September 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Hanauer SB, Sandborn W; Practice Parameters Committee of the American 
College of Gastroenterology.  Management of Crohn's disease in adults.  Am J 
Gastroenterol.  2001;96(3):635-43.
2.
Loftus EV Jr.  Clinical epidemiology of inflammatory bowel disease:  incidence, 
prevalence, and environmental influences.  Gastroenterology.  
2004;126(6):1504-17. 
3.
Probert CS, Jayanthi V, Rampton DS, et al.  Epidemiology of inflammatory bowel 
disease in different ethnic and religious groups:  limitations and aetiological clues.  
Int J Colorectal Dis.  1996;11(1):25-8. 
4.
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.
5.
Baumgart DC, Sandborn WJ.  Crohn's disease.  Lancet.  2012;380(9853):1590-605.
6.
Leong RW, Lau JY, Sung JJ.  The epidemiology and phenotype of Crohn's disease 
in the Chinese population.  Inflamm Bowel Dis.  2004;10(5):646-51.
7.
Lee YM, Fock K, See SJ, et al.  Racial differences in the prevalence of ulcerative 
colitis and Crohn's disease in Singapore.  J Gastroenterol Hepatol.  
2000;15(6):622-5.
8.
Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of 
American College of Gastroenterology.  Management of Crohn's disease in adults.  
Am J Gastroenterol.  2009;104(2):465-83.
9.
Froslie KF, Johnsen J, Moum BA, et al.  Mucosal healing in inflammatory bowel 
disease:  results from a Norwegian population-based cohort.  Gastroenterology.  
2007;133(2):412-22.
10.
Kakkar A, Wasan SK, Farraye FA.  Targeting mucosal healing in Crohn's disease.  
Gastroenterol Hepatol (NY).  2011;7(6):374-80.


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11.
Dignass A, Van Assche G, Lindsay JO, et al; European Crohn's and Colitis 
Organisation (ECCO).  The second European evidence-based consensus on the 
diagnosis and management of Crohn's disease:  current management. J Crohns 
Colitis.  2010;4(1):28-62.  Erratum in:  J Crohn's Colitis.  2010;4(3):353.
12.
Colombel JF, Sandborn WJ, Rutgeerts P, et al.  Adalimumab for maintenance of 
clinical response and remission in patients with Crohn's disease:  the CHARM trial.  
Gastroenterology.  2007;132(1):52-65.
13.
Sandborn WJ, Feagan BG, Rutgeerts P, et al.  Vedolizumab as induction and 
maintenance therapy for Crohn's disease.  N Engl J Med.  2013;369(8):711-21. 
14.
Targan SR, Hanauer SB, van Deventer SJ, et al.  A short-term study of chimeric 
monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease.  N 
Engl J Med.  1997;337(15):1029-35.
15.
Hanauer SB, Feagan BG, Lichtenstein GR, et al; ACCENT I Study Group.  
Maintenance infliximab for Crohn's disease:  the ACCENT I randomised trial.  
Lancet.  2002;359(9317):1541-9.
16.
Hanauer SB, Sandborn WJ, Rutgeerts P, et al.  Human anti-tumor necrosis factor 
monoclonal antibody (adalimumab) in Crohn's disease:  the CLASSIC-I trial.  
Gastroenterology.  2006; 130(2):323-33.
17.
Sandborn WJ, Feagan BG, Stoinov S, et al; RECISE 1 Study Investigators.  
Certolizumab pegol for the treatment of Crohn's disease.  N Engl J Med.  
2007;357(3):228-38.
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 
Rep2015, Apr 2;7:44.  doi:  10.12703/P7-44.  eCollection 2015.
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.
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.
22.
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.
23.
Daperno M, D'Haens G, Van Assche G, et al.  Development and validation of a 
new, simplified endoscopic activity score for Crohn's disease:  the SES-CD.  
Gastrointest Endosc.  2004;60(4):505-12.
24.
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.
25.
Marshall WA, Tanner JM.  Variations in pattern of pubertal changes in girls.  Arch 
Dis Child.  1969;44(235):291-303.
26.
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/competent authority 
reviewed and approved the initial clinical investigation and all amendments.


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


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


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Appendix C.
Study Activities for Efficacy, Safety, and PK/PD
Screening Period
(35 Days)a
12-Week Double-Blind Induction
Induction Period 2
Unschb
140-Day
Follow-Upc
Activity
Screening
Baseline
Week 4
Week 8
Week 12/PD
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
X
X
X
X
X
X
X
X
X
X
TB Screeningh
Xy
ECGi
Xy
Hepatitis B, Hepatitis C 
Screeningj, and HIV Testl
Xy
Xk
Xk
C. difficile toxin
Xx
Urinalysism,n
Xx
Xo
X
X
Pregnancy Testp
Xx
X
X
X
X
X
X
X
Chemistry and Hematologyn
Xx
Xo
X
X
X
X
X
X
Optional Blood Sample for 
Biologic Drug Level
X
COVID-19 Assessmentz
X
hs-CRPn
X
X
X
X
X
Serum Risankizumabq
X
X
X
X
X


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Screening Period
(35 Days)a
12-Week Double-Blind Induction
Induction Period 2
Unschb
140-Day
Follow-Upc
Activity
Screening
Baseline
Week 4
Week 8
Week 12/PD
Week 16
Week 20
Week 24
Serum Anti-Drug Antibody 
(ADA)q,w and Neutralizing 
Anti-Drug Antibodies (nAb)q
X
X
X
X
X
X
Fecal calprotectin (FCP)n, r
X
X
X
X
Crohn's Disease Activity Index 
(CDAI)
Xt
X
X
X
X
X
X
X
Endoscopy/SES-CDu
X
X
X
Intestinal Biopsiesv
X
X
X
Dispense Subject Diarys
X
Subject Diary Review
X
X
X
X
X
X
X
X
Subject Questionnaire:
CSS
X
X
X
X
X
X
X
X
Subject Questionnaire:
PGIC and PGIS
X (PGIS 
only)
X
X
X
X
X
X
X
Subject Questionnaires:
  EQ-5D-5L
  FACIT-F
  IBDQ
  SF-36  
  WPAI-CD
X
X
X
X
Study Drug Administrationw
X
X
X
Xw
X
X
a.
The Screening period should be a minimum of 4 days, preferably 7 days for CDAI calculation, (refer to Section 5.3.1.1).  The Baseline CDAI 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.


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c.
Subjects will be contacted 140 days following last dose of study drug for an assessment of any new or ongoing AEs, except those subjects who roll-over into Study M16-000 
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 treatment in Induction Period 2.  Physical examinations at 
all other visits (including unscheduled visits) are symptom based and should include the assessment of EIMs and a count of the number of cutaneous fistulas as part of 
calculating the CDAI. 
f.
Blood pressure, pulse rate, temperature, respiratory rate and weight should be performed before blood draws are performed.  Height will be measured at Screening only (with 
shoes off and then adding 1 inch or 2.5 cm) for subjects ≥ 18 years of age.  Height will be re-measured at Week 12 and Week 24 (if applicable) for subjects < 18 years of age 
at Baseline.
g.
Collection of SAEs and protocol-related nonserious AEs 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.
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.
For Japan 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 with subjects that have a history of HBV vaccine and are HBs Ab (+).
l.
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. 
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.
n.
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.
o.
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.


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p.
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.  
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 eCRF.  If the subject consented to the optional intensive PK sampling, refer to Appendix H.
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 instructions provided outside of this protocol.  If a sample cannot be obtained during the site visit, the site will give instructions and a 
stool sample supply kit.
s.
Subjects should also be dispensed the patient information card.
t.
Diary information collected during Screening will serve to calculate Baseline CDAI.  During screening, subjects will be instructed on how to calculate the number of very soft 
and liquid stools, including a visual depiction.  CDAI should be completed at the Baseline visit, just prior to randomization.  
u.
Endoscopy at/during the screening period or within 45 days of the Baseline visit will be used to calculate the SES-CD score at Baseline.  Endoscopic evaluations using SES 
CD confirmed by central reader will be done at Screening.  Endoscopies completed at Week 12 and Week 24, for those subjects who receive treatment in Induction Period 2, 
will use the local reader results for stratification for Study M16-000. 
v.
Biopsies may be done when performing the endoscopy to confirm CD 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.
w.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed, including endoscopy.  Completion of PROs are 
permitted during administration of study drug.  At Week 12, study drug will only be administered for subjects who are to receive treatment in 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.
x.
For Rescreening, if a subject is being rescreened within 14 days (≤ 14 days have passed) from the collection date of the previous screening testing, it is not required to repeat 
Screening testing for chemistry/hematology, urinalysis, serum pregnancy, and C. difficile provided that the subject's health status has not changed to warrant a repeat test.
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 5.3.1.1 are met and no 
more than 90 days have passed since the collection date of the testing.


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z.
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.


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Appendix D.
Study Activities – Optional Exploratory Research Samples
Screening Period (35 Days)
12-Week Double-Blind Induction
Samples Collecteda,b
Screening
Baseline
Week 12/PD
Pharmacogenetic
X
Transcriptomic and epigeneticc
X
X
Proteomic and targeted protein investigations (plasma)c
X
X
Proteomic and targeted protein investigations (serum)c
X
X
Stool
X
X
Intestinal biopsies (RNA)d
X
X
a.
Collections to be performed only if subject provides separate written consent to collect the exploratory research/validation studies 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.
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.
d.
Biopsy may be done when performing the endoscopy.  


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Appendix E.
Sample SES-CD Scoring
SES-CD Scoring23
Rectum
Sigmoid and 
Left Colon
Transverse 
Colon
Right 
Colon
Ileum
Total
Size of Ulcers 
Enter:
0 if none
1 if aphthous ulcers (Ø 0.1 to 0.5 cm)
2 if large ulcers (Ø 0.5 to 2 cm)
3 if very large ulcers (Ø > 2 cm)
Ulcerated Surface
Enter:
0 if none
1 if < 10%
2 if 10% – 30%
3 if > 30%
Affected Surface
Enter:
0 if unaffected segments
1 if < 50%
2 if 50% – 75%
3 if > 75%
Presence of Narrowing
Enter:
0 if none
1 if single, can be passed
2 if multiple, can be passed
3 if cannot be passed
TOTAL = 


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


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


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Standard Height
cm (Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women)
kg (Pounds)
158.8 (62.5)
62.1 (137.0)
57.4 (126.5)
160.0 (63.0)
62.6 (138.0)
58.0 (128.0)
161.3 (63.5)
63.0 (139.0)
58.7 (129.5)
162.6 (64.0)
63.5 (140.0)
59.4 (131.0)
163.8 (64.5)
64.1 (141.3)
60.1 (132.5)
165.1 (65.0)
64.6 (142.5)
60.8 (134.0)
166.4 (65.5)
65.2 (143.8)
61.4 (135.5)
167.6 (66.0)
65.8 (145.0)
62.1 (137.0)
168.9 (66.5)
66.4 (146.5)
62.8 (138.5)
170.2 (67.0)
67.1 (148.0)
63.5 (140.0)
171.5 (67.5)
67.8 (149.5)
64.2 (141.5)
172.7 (68.0)
68.5 (151.0)
64.9 (143.0)
174.0 (68.5)
69.2 (152.5)
65.5 (144.5)
175.3 (69.0)
69.8 (154.0)
66.2 (146.0)
176.5 (69.5)
70.5 (155.5)
66.9 (147.5)
177.8 (70.0)
71.2 (157.0)
67.6 (149.0)
179.1 (70.5)
71.9 (158.5)
68.3 (150.5)
180.3 (71.0)
72.6 (160.0)
68.9 (152.0)
181.6 (71.5)
73.4 (161.8)
69.6 (153.5)
182.9 (72.0)
74.1 (163.5)
70.3 (155.0)
184.2 (72.5)
75.0 (165.3)
71.2 (156.9
185.4 (73.0)
75.7 (167.0)
71.9 (158.5)
186.7 (73.5)
76.6 (169.0)
72.6 (160.2)
188.0 (74.0)
77.5 (171.0)
73.4 (161.8)
189.2 (74.5)
78.4 (172.8)
74.1 (163.4)
190.5 (75.0)
79.1 (174.5)
74.9 (165.1)
191.8 (75.5)
80.2 (176.8)
75.6 (166.8)
193.0 (76.0)
81.2 (179.0)
76.4 (168.4)
194.3 (76.5)
82.0 (180.8)
77.2 (170.1)
195.6 (77.0)
82.9 (182.9)
77.9 (171.8)
196.9 (77.5)
83.9 (185.0)
78.7 (173.5)


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Standard Height
cm (Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women)
kg (Pounds)
198.1 (78.0)
84.9 (187.2)
79.5 (175.2)
199.4 (78.5)
85.9 (189.4)
80.3 (177.0)
200.7 (79.0)
86.9 (191.6)
81.0 (178.7)
201.9 (79.5)
87.9 (193.9)
81.8 (180.5)
203.2 (80.0)
89.0 (196.2)
82.6 (182.2)
204.5 (80.5)
90.0 (198.6)
*Standard height is calculated 
using actual height obtained at 
screening (without shoes) plus 
one inch
205.7 (81.0)
91.1 (200.9)
*Indoor clothing weighing 
5 pounds for men and 3 pounds 
for women
207.0 (81.5)
92.2 (203.3)
*Centimeters × 0.3937 = inches
208.3 (82.0)
93.3 (205.8)
*Pounds × 0.4535 = kilograms


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Appendix H.
Optional Intensive PK Subjects
Samples for pharmacokinetics (PK) analysis will be collected in all subjects as described 
in Appendix C (Prior to dose at the specified weeks).  For the subjects who consent to the 
optional intensive PK sampling, in addition to the time points in Appendix C, blood 
samples 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.


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Appendix I.
Clinical Criteria for Diagnosing Anaphylaxis
Anaphylaxis24 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):
a) Infants and children:  low systolic BP (age specific) or greater than 30% 
decrease in systolic BP*


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b) Adults:  systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person's baseline.
PEF:  peak expiratory flow; BP:  blood pressure
*
low systolic BP for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + 
[2 × age]) from 1 to 10 years, and less than 90 mg Hg 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:  histamine and tryptase.  A blood sample 
for ADA assessment will also be collected along with 1 hour blood samples for above 
assessments.  Separate instructions for the collection, handling, storage and shipping of 
these labs will be provided outside of the study protocol.


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Appendix J.
Tanner Stage 5 for Development
Tanner Stage 5 for Development25,26
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


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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
●
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


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Appendix K.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M16-006
Name of Study Drug:  Risankizumab (ABBV-066)
Phase of Development:  3
Name of Active Ingredient:  Risankizumab
Date of Protocol Synopsis:  28 July 2020
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the 
Efficacy and Safety of Risankizumab in Subjects with Moderately to Severely Active Crohn's Disease
Objective:  The objective of Study M16-006 is to evaluate the efficacy and safety of risankizumab 
versus placebo during induction therapy in subjects with moderately to severely active Crohn's disease 
(CD).
Investigators:  Multicenter
Study Sites:  Approximately 400 sites


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Study Population:  Males and females aged ≥ 18 to ≤ 80 years of age, or minimum age of adult consent 
according to local regulations at the Baseline visit, or aged 16 to < 18 years of age where locally 
permitted and who meet the definition of Tanner stage 5 development (refer to Appendix J) at the 
Baseline visit, with a diagnosis of moderately to severely active CD, defined as:
1.
average daily stool frequency (SF) ≥ 4 (when calculating SF, only the number of liquid or very soft 
stools should be recorded) and/or average daily abdominal pain (AP) score ≥ 2; plus
2.
endoscopic evidence of mucosal inflammation as measured by the Simple Endoscopic Score for CD 
(SES-CD). All eligible scores exclude the presence of narrowing component and are confirmed by 
a central reader.  Endoscopic activity is defined as a SES-CD of ≥ 3.  
The number of subjects enrolled with a SES-CD of ≥ 3 to < 6 for ileocolonic or colonic disease or 
SES-CD of 3 for isolated ileal disease will be no more than 85 subjects.  Once cap of no more than 
85 subjects is reached, enrollment criterion will be an eligibility SES-CD of ≥ 6 for ileocolonic or 
colonic disease, or eligibility SES-CD of ≥ 4 for isolated ileal disease.  
The study will enroll both subjects who have had an inadequate response (IR) to prior biologic therapy 
(bio-IR) and subjects who have not (non-bio-IR).  The bio-IR enrollment will be approximately 
540 subjects and the non-bio-IR enrollment will be approximately 315 subjects.
The bio-IR population is defined as subjects with documented intolerance or inadequate response to one 
or more of the approved anti-TNF or anti-integrin biologics for CD (infliximab, adalimumab, 
certolizumab, vedolizumab, ustekinumab and/or natalizumab). 
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 in the past but stopped therapy based on reasons other than 
inadequate response or intolerance (e.g., change in reimbursement coverage, well-controlled disease).
The percent of subjects with exposure, including intolerance or inadequate response, to ustekinumab will 
be no more than 20%.
Number of Subjects to be Enrolled:  Approximately 855 for the primary ITT population used for 
efficacy analysis; additionally, up to 85 subjects with lower SES-CD will be enrolled


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Methodology:  
Study M16-006 is a randomized, double blind, placebo-controlled 12-week induction study.
Subjects (n = 855) will be randomized 2:2:1 to 1200 mg risankizumab or 600 mg risankizumab or 
placebo intravenous (IV) given at Baseline, Weeks 4 and 8.  The randomization will be stratified by 
number of prior biologics failed (0, 1, > 1), Baseline steroid use (yes, no), and Baseline SES-CD 
(original, alternative), where the stratum of "original" includes the patients with baseline SES-CD of ≥ 6 
(or ≥ 4 for subjects with isolated ileal disease), and the stratum of "alternative" includes the patients with 
baseline SES-CD of ≥3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for isolated ileal 
disease.
Visits during the study will occur at Baseline and Weeks 4, 8, and 12/Premature Discontinuation (PD) to 
collect clinical and laboratory assessments of disease activity.  Subjects who do not achieve clinical 
response at Week 12 will be offered blinded risankizumab therapy in Induction Period 2 with evaluation 
for clinical response at Week 24.
All subjects will be provided with a subject diary where they will record CD related symptoms 
throughout the study.  Subjects will also be dispensed a patient information card at Screening.  
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.  All endoscopies will be evaluated using SES-CD and will be confirmed by a central 
reader.  Biopsy to confirm diagnosis (during Screening) or to rule out dysplasia/malignancy may be 
performed during the same time points as the endoscopy.  Optional exploratory research samples may be 
taken during the study.
At the Week 12/PD visit, all subjects will undergo an endoscopy for evaluation of mucosal 
inflammation.  It is expected that all subjects who remain in the study through at least Week 8 will have 
a Week 12/PD endoscopy.  All subjects achieving clinical response, defined as ≥ 30% decrease in 
average daily SF and/or ≥ 30% decrease in average daily AP score (both not worse than Baseline) at 
Week 12 may be eligible to enter Study M16-000.  Subjects are not eligible to enter Study M16-000 
until endoscopy has been completed (local reader results will be used for stratification for 
Study M16-000).
All subjects who do not achieve clinical response 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 Interactive Response 
Technologies (IRT) to Induction Period 2, a double-blind, double-dummy 12-week treatment period.
Subjects who received IV risankizumab induction treatment with inadequate clinical response at 
Week 12 will be randomized 1:1:1 to:
!
Group 1:  1200 mg IV risankizumab
!
Group 2:  360 mg SC risankizumab
!
Group 3:  180 mg SC risankizumab


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Methodology (Continued):
Subjects who received IV placebo induction treatment will receive:
!
Group 4:  1200 mg IV risankizumab
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 received treatment in Induction Period 2 will be reassessed and undergo a third endoscopy for 
evaluation of mucosal inflammation.  Subjects who achieve clinical response at Week 24 may be eligible 
to enter Study M16-000.  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 enter 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, immunomodulators (azathioprine [AZA], 6-mercaptopurine 
[6-MP], methotrexate [MTX]), and/or CD-related antibiotics.
Subjects taking aminosalicylates, immunomodulators, and/or CD-related antibiotics at Baseline must 
continue these treatments for the duration of the study.  Initiating and/or increasing doses of 
aminosalicylates, immunomodulators, and/or CD-related antibiotics during the study is prohibited.  
Decreasing doses of aminosalicylates, immunomodulators, and/or CD-related antibiotics is prohibited 
during the study, except in the event of moderate-to-severe treatment related toxicities and after 
discussion with the AbbVie Therapeutic Area Medical Director (TA MD).  CD-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
Subjects taking corticosteroids at Baseline must continue their concomitant treatment at the Baseline 
dose for the duration of the 12-week induction period.  Initiation and/or increasing doses of systemic 
and/or CD related corticosteroids during the entire study is prohibited.  Decreasing doses of 
corticosteroids is prohibited during the 12-week induction period, except in the event of moderate-to-
severe treatment related toxicities and after discussion with the AbbVie TA MD.
Subjects who receive Induction Period 2 treatment during Weeks 12 to 24 will be allowed to taper their 
corticosteroids at the discretion of the Investigator.  Increasing doses above the Baseline dose is 
prohibited.
Dose Selection
This study will evaluate two IV doses of risankizumab (600 mg and 1200 mg) during induction.  The 
selection of the doses in this study is 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 CD that explored 
200 mg and 600 mg doses.  The results from the Phase 2 study suggest a potential for increased benefit 
with 1200 mg administration. 


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Methodology (Continued):
Induction Period 2 will evaluate IV (1200 mg 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 (1200 mg IV at Weeks 12, 16, and 20) versus initiating maintenance 
dosing 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.  
The results from the Phase 2 study suggest a potential for increased benefit with 360 mg SC 
administration for maintenance regimen.
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.  At the timing of this amendment, the DMC has 
provided recommendation that the study may continue without modification and allowed enrollment to 
begin for 16 - 17 year-olds. 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.  
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:  
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.  Where locally permissible, subjects 16 to < 18 years of age who 
meet the definition of Tanner stage 5 for development (refer to Appendix J), at the Baseline Visit 
(sites will be notified when adolescents may enroll).
2.
Confirmed diagnosis of CD for at least 3 months prior to Baseline.  Appropriate documentation of 
biopsy results consistent with the diagnosis of CD, in the assessment of the Investigator, must be 
available.
3.
Crohn's disease activity index (CDAI) score 220 – 450 at Baseline.
4.
Endoscopic evidence of mucosal inflammation as documented by an SES-CD of ≥ 3. All eligible 
scores exclude the presence of narrowing component and are confirmed by a central reader. (Once 
cap of no more than 85 subjects is reached, enrollment criterion will be an SES-CD of ≥ 6 for 
ileocolonic or colonic disease or SES-CD of ≥ 4 for isolated ileal disease.)
5.
Average daily SF ≥ 4 and/or average daily AP score ≥ 2 at Baseline.
6.
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 (intolerance 
includes patients with a known TPMT genetic mutation or low activity).  
!
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, 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, Hong Kong, 
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, Hong Kong, 
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
Biologic Therapies for CD: 
!
Signs and symptoms of persistently (in the opinion of the Investigator) 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 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 certolizumab pegol (400 mg SC at 
Weeks 0, 2, and 4),
o
At least one 6-week induction regimen of vedolizumab (300 mg IV at 
Weeks 0, 2, and 6)
o
At least one 12-week induction regimen of natalizumab (300 mg IV every 
4 weeks)
o
At least one 8-week induction regimen of ustekinumab [260 mg (≤ 55 kg) or 
390 mg (> 55 to ≤ 85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at 
Week 8] (Once cap of no more than 20% ustekinumab exposed subjects is 
reached, subjects with prior ustekinumab exposure will not be allowed to 
enroll.)  


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Recurrence of symptoms during scheduled maintenance dosing following prior 
clinical benefit of the above biologics
!
Note:  Subjects who discontinued biologics 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
7.
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. 
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.
8.
Subjects must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.  In Japan, if the subject is < 20 years old, a subject's parent or 
legal guardian must be willing to give written informed consent.
Main Exclusion:  
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
Concomitant Medications and Treatments
2.
Subject on CD-related antibiotics who has not been on stable doses 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 current 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/intramuscular 
anti-infectives (non-CD-related) within 14 days prior to the Baseline visit.  This does not apply to 
TB prophylaxis.
7.
Subject who received exclusive enteral nutrition or any parenteral nutrition within 35 days prior to 
Baseline.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):
Medications and Treatments During the Screening Period (Continued)
8.
Subject who received any live bacterial or viral vaccination within 30 days (8 weeks for Japan) 
prior to Screening or during the Screening Period.
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 biologics: infliximab, adalimumab, certolizumab, vedolizumab, natalizumab) within 
8 weeks prior to Baseline, or ustekinumab within 12 weeks prior to Baseline  
Note:  If there is proper documentation of an undetectable drug level measured by a 
commercially available assay for any of the approved biologics above, there is no minimum 
washout prior to Baseline.
!
Any investigational biologic or other agent or procedure within 35 days or 5 half-lives prior to 
Baseline, whichever is longer.
12. Subject with prior exposure to p19 inhibitors (e.g., risankizumab).
13. Subject has been taking combination of two or more of the following:  oral budesonide, or 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, other than required for endoscopy, within 
14 days prior to endoscopy used for 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.
CD Related
18. Subject with currently known complications of CD such as:
!
abscess (abdominal or perianal),
!
symptomatic bowel strictures,
!
> 2 missing segments of the following 5 segments:  terminal ileum, right colon, transverse 
colon, sigmoid and left colon, and rectum
!
fulminant colitis,
!
toxic megacolon,
!
or any other manifestation that might require surgery while enrolled in the study.
19. Subject with ostomy or ileoanal pouch.
20. Subject diagnosed with short gut or short bowel syndrome.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
21. Subject with surgical bowel resection within the past 3 months prior to Baseline, or a history of 
≥3 bowel resections.
Safety
22. 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).
23. 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 or other intestinal pathogen during Screening,
!
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:
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 positive with anti-HCV 
antibody (HCV Ab)
24. 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.
25. 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.
26. Subject with current or previous 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.
27. Subject who has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, 
disorder or symptoms thereof.
28. 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.
29. 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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
Safety (Continued):
30. 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
!
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 after discussion and clearance 
with the TAMD. 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.
31. No known active COVID-19 infection.  Subject must not have signs/symptoms associated with 
COVID-19 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 viral clearance criteria: 
!
Symptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥24 hours 
apart after at least 10 days have passed since recovery, defined as resolution of fever without 
use of antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of breath)
!
Asymptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥ 24 hours 
apart after at least 10 days have passed since prior positive result (Note: subjects who develop 
symptoms will follow guidance above for symptomatic subjects)
Frequency or timing of COVID-19 testing and interval between testing for the above viral clearance 
criteria may be adjusted to account for epidemiological trends, updated information regarding 
infectivity and local/institutional guidelines.


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Investigational Product:
Risankizumab
Doses:
Risankizumab 1200 mg IV Q4W* 
Risankizumab 600 mg IV Q4W
Risankizumab 180 mg SC Q8W
Risankizumab 360 mg SC Q8W
*
If the 1200 mg dose is discontinued due to any reason, subjects will 
continue to enroll into the study and be randomized to either 
600 mg risankizumab or placebo at 2:1 ratio.  The randomization 
ratio and sample size may be further updated in an amendment to 
the protocol.  Subjects already randomized to treatment arms, 
including Induction Period 2, will receive blinded 600 mg 
risankizumab IV.
Mode of Administration:
Risankizumab solution for infusion (IV)
Risankizumab solution for injection (SC) 
Reference Therapy:
Placebo for risankizumab
Dose:
N/A
Mode of Administration:
Placebo solution for infusion (IV)
Placebo solution for injection (SC)
Duration of Treatment:  12 or 24 weeks 
The study will include a Screening period of up to 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 
treatment in Induction Period 2 with risankizumab 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 roll over into Study M16-000 or discontinue from the study 
prematurely.
Criteria for Evaluation:
Endpoint Definitions:
!
Clinical remission:  average daily SF ≤ 2.8 and not worse than Baseline AND average daily 
AP score ≤ 1 and not worse than Baseline
!
Enhanced clinical response:  ≥ 60% decrease in average daily SF and/or ≥ 35% decrease in 
average daily AP score and both not worse than Baseline, and/or clinical remission
!
Clinical response:  ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily 
AP score and both not worse than Baseline
!
Endoscopic response:  decrease in SES-CD > 50% from Baseline (or for subjects with isolated 
ileal disease and a Baseline SES-CD of 4, at least a 2 point reduction from Baseline), as scored 
by central reviewer
!
Ulcer-free endoscopy: SES-CD ulcerated surface subscore of 0 in subjects with SES-CD 
ulcerated surface subscore ≥ 1 at Baseline, as scored by a central reviewer
!
Endoscopic remission: SES-CD ≤ 4 and at least a 2 point reduction versus baseline and no 
subscore greater than 1 in any individual variable, as scored by a central reviewer


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Criteria for Evaluation (Continued):
Endpoint Definitions (Continued):
!
CDAI clinical response:  reduction of CDAI ≥100 points from baseline
!
CDAI clinical remission:  CDAI < 150
Efficacy:
Co-Primary Endpoints:  
!
Proportion of subjects with clinical remission at Week 12 
!
Proportion of subjects with endoscopic response at Week 12
Ranked Secondary Endpoints:
1.
Proportion of subjects with CDAI clinical remission at Week 12
2.
Proportion of subjects with CDAI clinical response at Week 4
3.
Proportion of subjects with clinical remission at Week 4 
4.
Proportion of subjects with CDAI clinical response at Week 12 
5.
Mean change from baseline of induction in FACIT fatigue at Week 12 
6.
Mean change from baseline of induction in IBDQ total score at Week 12 
7.
Proportion of subjects with enhanced clinical response and endoscopic response at Week 12 
8.
Proportion of subjects with endoscopic remission at Week 12
9.
Proportion of subjects with enhanced clinical response at Week 4
10. Proportion of subjects with ulcer-free endoscopy at Week 12
11. Enhanced clinical response at Week 12
12. Proportion of subjects with resolution of extra-intestinal manifestations (EIMs) at Week 12, in 
subjects with any EIMs at Baseline 
13. Proportion of subjects with CD-related hospitalization through Week 12
14. Proportion of subjects without draining fistulas at Week 12 in subjects with draining fistulas at 
Baseline
For further information, including non-ranked endpoints, refer to protocol
Pharmacokinetics:
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 receive treatment in Induction Period 2.
Additionally, intensive pharmacokinetic assessment will be performed in 20 subjects after the 
3rd induction dose (Week 8 to 12).  For Subjects who consent to the intensive pharmacokinetic 
assessment, in addition to the time points above, blood samples will be 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.
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 receive treatment in Induction Period 2.


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Criteria for Evaluation (Continued):
Safety:
Safety analyses will be performed on safety set which includes all subjects who receive at least one dose 
of study drug.  Incidence of adverse events (AEs), changes in vital signs, physical examination results, 
and clinical laboratory data will be assessed throughout the study.
Exploratory Research Variables and Validation Studies (Optional):
Prognostic, surrogate, predictive and pharmacodynamics biomarkers signatures may be investigated.  
Samples for different applications, including but not limited to, pharmacogenetic, epigenetic, 
transcriptomic, proteomic, metabolomics, metagenomic and targeted investigations will be collected at 
various time points.  Assessments will include but may not be limited to nucleic acids, proteins, 
metabolites or lipids.
Statistical Methods:
Efficacy:
The co-primary endpoints are the proportion of subjects with clinical remission at Week 12 and 
proportion of subjects with endoscopic response at Week 12.  A total of approximately 855 subjects will 
be randomized into two risankizumab treatment groups and the placebo group in a 2:2:1 ratio 
(342 subjects for risankizumab 600 mg dose group, 342 subjects for risankizumab 1200 mg dose group, 
and 171 subjects for placebo group). When all patients complete their Week 12/PD visit, the database 
will be locked for the final analysis of 12-week induction period.  When all the patients who enter the 
induction Period 2 finish Week 24/PD visit, the database will be locked for the whole study and all the 
planned analysis for the induction Period 2 will be performed.
Sample size calculation is based on the larger sample size needed to detect treatment difference for each 
of the co-primary endpoints.  Since historical data show slightly lower event rate and similar treatment 
difference versus placebo for the endoscopic response rate than the clinical remission rate at Week 12, 
clinical remission rates at Week 12 are used for power calculation.  Assuming the Week 12 clinical 
remission rate will be 27.8% for one of the risankizumab dose groups and 12% for the placebo group, a 
sample size of 342 subjects for each of the risankizumab dose groups and 171 for the placebo group will 
have 97% power to detect the treatment difference between the risankizumab dose groups and placebo in 
clinical remission rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided).
The bio-IR population is approximately 540 subjects.  The study will have 80% power to detect the 
treatment difference between one of the risankizumab dose groups and placebo in clinical remission 
rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) for the bio-IR population, 
assuming the Week 12 clinical remission rate will be 24.2% for the risankizumab dose groups and 10% 
for the placebo group for bio-IR subjects.  The non-bio-IR population is approximately 315 subjects.  
The study will have 72% power to detect the treatment difference between one of the risankizumab dose 
groups and placebo in clinical remission rates, at Week 12 using Fisher's exact test at alpha of 0.025 
(two-sided) for the non-bio-IR sub-population, assuming the Week 12 clinical remission rate will be 
35% for the risankizumab dose groups and 15% for the placebo group for non-bio-IR subjects.
The comparisons between each risankizumab dose versus placebo for the primary efficacy variable will 
be performed using the Cochran-Mantel-Haenszel (CMH) test adjusted by prior biologic use (0, 1, > 1) 
and Baseline steroid use (yes, no). Both of the co-primary efficacy endpoints will be tested at 
statistically significant of 0.025 for each of the risankizumab dose groups versus placebo to adjust for 
multiplicity.  A CMH based two-sided 95% confidence interval for the difference between treatment 
groups will be calculated. 


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Statistical Methods (Continued):
Efficacy (Continued):
The intent-to-treat (ITT) set includes all randomized subjects who have taken at least one dose of study 
drug.  The primary population for efficacy analysis are the subjects in the intent-to-treat analysis set who 
had baseline eligibility SES-CD of ≥ 6 (≥ 4 for isolated ileal disease). If the average daily SF or average 
daily AP score data at Week 12 are missing, the non-responder imputation (NRI) approach will be 
applied.  Subjects who discontinue prior to Week 12 for any reason will be considered as "not-achieved"
for clinical remission and endoscopic response endpoints.
In general, continuous secondary efficacy variables will be analyzed using a Mixed-Effect Model 
Repeated Measure (MMRM) model including factors for treatment group, visit, visit by treatment 
interaction, and stratification variables, for the longitudinal continuous endpoints.  The MMRM analysis 
is considered primary for inferential purposes.  
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 cohorts and study visits.  ADA titers will be tabulated for each 
subject at the respective study visits.  The effect of ADAs on risankizumab pharmacokinetics, efficacy 
and/or safety variable(s) and/or any additional analyses will be explored.
Safety:
Adverse events, laboratory data and vital signs are the primary safety parameters in this study.  All 
safety comparisons will be performed between treatment groups using the safety set.  Treatment 
emergent AEs are defined as events that begin or worsen either on or after the first dose of the study 
drug and within 140 days after the last dose of the study drug for subjects who do not participate in 
Study M16-000 or until first dose of study drug in Study M16-000 if the subject is enrolled in 
Study M16-000.  
An overview of treatment-emergent AEs, AEs leading to death and AEs leading to premature 
discontinuation (see details in the statistical analysis plan [SAP]), AEs by Medical Dictionary for Drug 
Regulatory Activities (MedDRA version) preferred term and system organ class, AEs by maximum 
relationship to study drug, and AEs by maximum severity will be summarized by number and 
percentage.  
Changes in laboratory data will be described using statistical characteristics and 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.


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M16-006
Name of Study Drug:  Risankizumab (ABBV-066)
Phase of Development:  3
Name of Active Ingredient:  Risankizumab
Date of Protocol Synopsis:  01 September 2020
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the 
Efficacy and Safety of Risankizumab in Subjects with Moderately to Severely Active Crohn's Disease
Objective:  The objective of Study M16-006 is to evaluate the efficacy and safety of risankizumab 
versus placebo during induction therapy in subjects with moderately to severely active Crohn's disease 
(CD).
Investigators:  Multicenter
Study Sites:  Approximately 400 sites
Study Population:  Males and females aged ≥ 18 to ≤ 80 years of age, or minimum age of adult consent 
according to local regulations at the Baseline visit, or aged 16 to < 18 years of age where locally 
permitted and who meet the definition of Tanner stage 5 development (refer to Appendix J) at the 
Baseline visit, with a diagnosis of moderately to severely active CD, defined as:
1.
average daily stool frequency (SF) ≥ 4 (when calculating SF, only the number of liquid or very soft 
stools should be recorded) and/or average daily abdominal pain (AP) score ≥ 2; plus
2.
endoscopic evidence of mucosal inflammation as measured by the Simple Endoscopic Score for CD 
(SES-CD). All eligible scores exclude the presence of narrowing component and are confirmed by 
a central reader.  Endoscopic activity is defined as a SES-CD of ≥ 3.  
The number of subjects enrolled with a SES-CD of ≥ 3 to < 6 for ileocolonic or colonic disease or 
SES-CD of 3 for isolated ileal disease will be no more than 85 subjects.  Once cap of no more than 
85 subjects is reached, enrollment criterion will be an eligibility SES-CD of ≥ 6 for ileocolonic or 
colonic disease, or eligibility SES-CD of ≥ 4 for isolated ileal disease.  
The study will enroll both subjects who have had an inadequate response (IR) to prior biologic therapy 
(bio-IR) and subjects who have not (non-bio-IR).  The bio-IR enrollment will be approximately 
540 subjects and the non-bio-IR enrollment will be approximately 315 subjects.
The bio-IR population is defined as subjects with documented intolerance or inadequate response to one 
or more of the approved anti-TNF or anti-integrin biologics for CD (infliximab, adalimumab, 
certolizumab, vedolizumab, ustekinumab and/or natalizumab). 
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 in the past but stopped therapy based on reasons other than 
inadequate response or intolerance (e.g., change in reimbursement coverage, well-controlled disease).
The percent of subjects with exposure, including intolerance or inadequate response, to ustekinumab will 
be no more than 20%.
Number of Subjects to be Enrolled:  Approximately 855 for the primary ITT population used for 
efficacy analysis; additionally, up to 85 subjects with lower SES-CD will be enrolled


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Methodology:  
Study M16-006 is a randomized, double blind, placebo-controlled 12-week induction study.
Subjects (n = 855) will be randomized 2:2:1 to 1200 mg risankizumab or 600 mg risankizumab or 
placebo intravenous (IV) given at Baseline, Weeks 4 and 8.  The randomization will be stratified by 
number of prior biologics failed (0, 1, > 1), Baseline steroid use (yes, no), and Baseline SES-CD 
(original, alternative), where the stratum of "original" includes the patients with baseline SES-CD of ≥ 6 
(or ≥ 4 for subjects with isolated ileal disease), and the stratum of "alternative" includes the patients with 
baseline SES-CD of ≥3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for isolated ileal 
disease.
Visits during the study will occur at Baseline and Weeks 4, 8, and 12/Premature Discontinuation (PD) to 
collect clinical and laboratory assessments of disease activity.  Subjects who do not achieve clinical 
response at Week 12 will be offered blinded risankizumab therapy in Induction Period 2 with evaluation 
for clinical response at Week 24.
All subjects will be provided with a subject diary where they will record CD related symptoms 
throughout the study.  Subjects will also be dispensed a patient information card at Screening.  
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.  All endoscopies will be evaluated using SES-CD and will be confirmed by a central 
reader.  Biopsy to confirm diagnosis (during Screening) or to rule out dysplasia/malignancy may be 
performed during the same time points as the endoscopy.  Optional exploratory research samples may be 
taken during the study.
At the Week 12/PD visit, all subjects will undergo an endoscopy for evaluation of mucosal 
inflammation.  It is expected that all subjects who remain in the study through at least Week 8 will have 
a Week 12/PD endoscopy.  All subjects achieving clinical response, defined as ≥ 30% decrease in 
average daily SF and/or ≥ 30% decrease in average daily AP score (both not worse than Baseline) at 
Week 12 may be eligible to enter Study M16-000.  Subjects are not eligible to enter Study M16-000 
until endoscopy has been completed (local reader results will be used for stratification for 
Study M16-000).
All subjects who do not achieve clinical response 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 Interactive Response 
Technologies (IRT) to Induction Period 2, a double-blind, double-dummy 12-week treatment period.
Subjects who received IV risankizumab induction treatment with inadequate clinical response at 
Week 12 will be randomized 1:1:1 to:
!
Group 1:  1200 mg IV risankizumab
!
Group 2:  360 mg SC risankizumab
!
Group 3:  180 mg SC risankizumab


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Methodology (Continued):
Subjects who received IV placebo induction treatment will receive:
!
Group 4:  1200 mg IV risankizumab
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 received treatment in Induction Period 2 will be reassessed and undergo a third endoscopy for 
evaluation of mucosal inflammation.  Subjects who achieve clinical response at Week 24 may be eligible 
to enter Study M16-000.  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 enter 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, immunomodulators (azathioprine [AZA], 6-mercaptopurine 
[6-MP], methotrexate [MTX]), and/or CD-related antibiotics.
Subjects taking aminosalicylates, immunomodulators, and/or CD-related antibiotics at Baseline must 
continue these treatments for the duration of the study.  Initiating and/or increasing doses of 
aminosalicylates, immunomodulators, and/or CD-related antibiotics during the study is prohibited.  
Decreasing doses of aminosalicylates, immunomodulators, and/or CD-related antibiotics is prohibited 
during the study, except in the event of moderate-to-severe treatment related toxicities and after 
discussion with the AbbVie Therapeutic Area Medical Director (TA MD).  CD-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
Subjects taking corticosteroids at Baseline must continue their concomitant treatment at the Baseline 
dose for the duration of the 12-week induction period.  Initiation and/or increasing doses of systemic 
and/or CD related corticosteroids during the entire study is prohibited.  Decreasing doses of 
corticosteroids is prohibited during the 12-week induction period, except in the event of moderate-to-
severe treatment related toxicities and after discussion with the AbbVie TA MD.
Subjects who receive Induction Period 2 treatment during Weeks 12 to 24 will be allowed to taper their 
corticosteroids at the discretion of the Investigator.  Increasing doses above the Baseline dose is 
prohibited.
Dose Selection
This study will evaluate two IV doses of risankizumab (600 mg and 1200 mg) during induction.  The 
selection of the doses in this study is 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 CD that explored 
200 mg and 600 mg doses.  The results from the Phase 2 study suggest a potential for increased benefit 
with 1200 mg administration. 


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Methodology (Continued):
Induction Period 2 will evaluate IV (1200 mg 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 (1200 mg IV at Weeks 12, 16, and 20) versus initiating maintenance 
dosing 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.  
The results from the Phase 2 study suggest a potential for increased benefit with 360 mg SC 
administration for maintenance regimen.
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.  At the timing of this amendment, the DMC has 
provided recommendation that the study may continue without modification and allowed enrollment to 
begin for 16 - 17 year-olds. 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.  
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:  
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.  Where locally permissible, subjects 16 to < 18 years of age who 
meet the definition of Tanner stage 5 for development (refer to Appendix J), at the Baseline Visit 
(sites will be notified when adolescents may enroll).
2.
Confirmed diagnosis of CD for at least 3 months prior to Baseline.  Appropriate documentation of 
biopsy results consistent with the diagnosis of CD, in the assessment of the Investigator, must be 
available.
3.
Crohn's disease activity index (CDAI) score 220 – 450 at Baseline.
4.
Endoscopic evidence of mucosal inflammation as documented by an SES-CD of ≥ 3. All eligible 
scores exclude the presence of narrowing component and are confirmed by a central reader. (Once 
cap of no more than 85 subjects is reached, enrollment criterion will be an SES-CD of ≥ 6 for 
ileocolonic or colonic disease or SES-CD of ≥ 4 for isolated ileal disease.)
5.
Average daily SF ≥ 4 and/or average daily AP score ≥ 2 at Baseline.
6.
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 (intolerance 
includes patients with a known TPMT genetic mutation or low activity).  
!
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, 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, Hong Kong, 
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, Hong Kong, 
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
Biologic Therapies for CD: 
!
Signs and symptoms of persistently (in the opinion of the Investigator) 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 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 certolizumab pegol (400 mg SC at 
Weeks 0, 2, and 4),
o
At least one 6-week induction regimen of vedolizumab (300 mg IV at 
Weeks 0, 2, and 6)
o
At least one 12-week induction regimen of natalizumab (300 mg IV every 
4 weeks)
o
At least one 8-week induction regimen of ustekinumab [260 mg (≤ 55 kg) or 
390 mg (> 55 to ≤ 85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at 
Week 8] (Once cap of no more than 20% ustekinumab exposed subjects is 
reached, subjects with prior ustekinumab exposure will not be allowed to 
enroll.)  


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Recurrence of symptoms during scheduled maintenance dosing following prior 
clinical benefit of the above biologics
!
Note:  Subjects who discontinued biologics 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
7.
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. 
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.
8.
Subjects must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.  In Japan, if the subject is < 20 years old, a subject's parent or 
legal guardian must be willing to give written informed consent.
Main Exclusion:  
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
Concomitant Medications and Treatments
2.
Subject on CD-related antibiotics who has not been on stable doses 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 current 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/intramuscular 
anti-infectives (non-CD-related) within 14 days prior to the Baseline visit.  This does not apply to 
TB prophylaxis.
7.
Subject who received exclusive enteral nutrition or any parenteral nutrition within 35 days prior to 
Baseline.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):
Medications and Treatments During the Screening Period (Continued)
8.
Subject who received any live bacterial or viral vaccination within 30 days (8 weeks for Japan) 
prior to Screening or during the Screening Period.
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 biologics: infliximab, adalimumab, certolizumab, vedolizumab, natalizumab) within 
8 weeks prior to Baseline, or ustekinumab within 12 weeks prior to Baseline  
Note:  If there is proper documentation of an undetectable drug level measured by a 
commercially available assay for any of the approved biologics above, there is no minimum 
washout prior to Baseline.
!
Any investigational biologic or other agent or procedure within 35 days or 5 half-lives prior to 
Baseline, whichever is longer.
12. Subject with prior exposure to p19 inhibitors (e.g., risankizumab).
13. Subject has been taking combination of two or more of the following:  oral budesonide, or 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, other than required for endoscopy, within 
14 days prior to endoscopy used for 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.
CD Related
18. Subject with currently known complications of CD such as:
!
abscess (abdominal or perianal),
!
symptomatic bowel strictures,
!
> 2 missing segments of the following 5 segments:  terminal ileum, right colon, transverse 
colon, sigmoid and left colon, and rectum
!
fulminant colitis,
!
toxic megacolon,
!
or any other manifestation that might require surgery while enrolled in the study.
19. Subject with ostomy or ileoanal pouch.
20. Subject diagnosed with short gut or short bowel syndrome.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
21. Subject with surgical bowel resection within the past 3 months prior to Baseline, or a history of 
≥3 bowel resections.
Safety
22. 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).
23. 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 or other intestinal pathogen during Screening,
!
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:
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 positive with anti-HCV 
antibody (HCV Ab)
24. 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.
25. 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.
26. Subject with current or previous 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.
27. Subject who has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, 
disorder or symptoms thereof.
28. 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.
29. 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.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
Safety (Continued):
30. 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
!
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 after discussion and clearance 
with the TAMD. 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.
31. No known active COVID-19 infection.  Subject must not have signs/symptoms associated with 
COVID-19 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 viral clearance criteria: 
!
Symptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥24 hours 
apart after at least 10 days have passed since recovery, defined as resolution of fever without 
use of antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of breath)
!
Asymptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥ 24 hours 
apart after at least 10 days have passed since prior positive result (Note: subjects who develop 
symptoms will follow guidance above for symptomatic subjects)
Frequency or timing of COVID-19 testing and interval between testing for the above viral clearance 
criteria may be adjusted to account for epidemiological trends, updated information regarding 
infectivity and local/institutional guidelines.


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Investigational Product:
Risankizumab
Doses:
Risankizumab 1200 mg IV Q4W* 
Risankizumab 600 mg IV Q4W
Risankizumab 180 mg SC Q8W
Risankizumab 360 mg SC Q8W
*
If the 1200 mg dose is discontinued due to any reason, subjects will 
continue to enroll into the study and be randomized to either 
600 mg risankizumab or placebo at 2:1 ratio.  The randomization 
ratio and sample size may be further updated in an amendment to 
the protocol.  Subjects already randomized to treatment arms, 
including Induction Period 2, will receive blinded 600 mg 
risankizumab IV.
Mode of Administration:
Risankizumab solution for infusion (IV)
Risankizumab solution for injection (SC) 
Reference Therapy:
Placebo for risankizumab
Dose:
N/A
Mode of Administration:
Placebo solution for infusion (IV)
Placebo solution for injection (SC)
Duration of Treatment:  12 or 24 weeks 
The study will include a Screening period of up to 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 
treatment in Induction Period 2 with risankizumab 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 roll over into Study M16-000 or discontinue from the study 
prematurely.
Criteria for Evaluation:
Endpoint Definitions:
!
Clinical remission:  average daily SF ≤ 2.8 and not worse than Baseline AND average daily 
AP score ≤ 1 and not worse than Baseline
!
Enhanced clinical response:  ≥ 60% decrease in average daily SF and/or ≥ 35% decrease in 
average daily AP score and both not worse than Baseline, and/or clinical remission
!
Clinical response:  ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily 
AP score and both not worse than Baseline
!
Endoscopic response:  decrease in SES-CD > 50% from Baseline (or for subjects with isolated 
ileal disease and a Baseline SES-CD of 4, at least a 2 point reduction from Baseline), as scored 
by central reviewer
!
Ulcer-free endoscopy: SES-CD ulcerated surface subscore of 0 in subjects with SES-CD 
ulcerated surface subscore ≥ 1 at Baseline, as scored by a central reviewer
!
Endoscopic remission: SES-CD ≤ 4 and at least a 2 point reduction versus baseline and no 
subscore greater than 1 in any individual variable, as scored by a central reviewer


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Criteria for Evaluation (Continued):
Endpoint Definitions (Continued):
!
CDAI clinical response:  reduction of CDAI ≥100 points from baseline
!
CDAI clinical remission:  CDAI < 150
!
SF remission:  average daily SF ≤2.8 and not worse than baseline
!
AP remission:  average daily AP score ≤1 and not worse than baseline
Efficacy:
Co-Primary Endpoints:  
!
Proportion of subjects with CDAI clinical remission at Week 12 
!
Proportion of subjects with endoscopic response at Week 12
Ranked Secondary Endpoints:
1.
Proportion of subjects with clinical remission at Week 12
2.
Proportion of subjects with CDAI clinical response at Week 4
3.
Proportion of subjects with CDAI clinical response at Week 12
4.
Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) 
at Week 12
5.
Proportion of subjects with CDAI clinical remission at Week 4
6.
Proportion of subjects with CDAI clinical response and endoscopic response at Week 12 
7.
Proportion of subjects with SF remission at Week 12
8.
Proportion of subjects with AP remission at Week 12
9.
Proportion of subjects with endoscopic remission at Week 12
10. Proportion of subjects with enhanced clinical response at Week 4
11. Proportion of subjects with ulcer-free endoscopy at Week 12
12. Proportion of subjects with enhanced clinical response at Week 12
13. Proportion of subjects with resolution of extra-intestinal manifestations (EIMs) at Week 12, in 
subjects with any EIMs at Baseline 
14. Proportion of subjects with CD-related hospitalization through Week 12
15. Proportion of subjects without draining fistulas at Week 12 in subjects with draining fistulas at 
Baseline
For further information, including non-ranked endpoints, refer to protocol
Pharmacokinetics:
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 receive treatment in Induction Period 2.
Additionally, intensive pharmacokinetic assessment will be performed in 20 subjects after the 
3rd induction dose (Week 8 to 12).  For Subjects who consent to the intensive pharmacokinetic 
assessment, in addition to the time points above, blood samples will be 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.


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Criteria for Evaluation (Continued):
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 receive treatment in Induction Period 2.
Safety:
Safety analyses will be performed on safety set which includes all subjects who receive at least one dose 
of study drug.  Incidence of adverse events (AEs), changes in vital signs, physical examination results, 
and clinical laboratory data will be assessed throughout the study.
Exploratory Research Variables and Validation Studies (Optional):
Prognostic, surrogate, predictive and pharmacodynamics biomarkers signatures may be investigated.  
Samples for different applications, including but not limited to, pharmacogenetic, epigenetic, 
transcriptomic, proteomic, metabolomics, metagenomic and targeted investigations will be collected at 
various time points.  Assessments will include but may not be limited to nucleic acids, proteins, 
metabolites or lipids.
Statistical Methods:
Efficacy:
The co-primary endpoints are the proportion of subjects with CDAI clinical remission at Week 12 and 
proportion of subjects with endoscopic response at Week 12.  A total of approximately 855 subjects will 
be randomized into two risankizumab treatment groups and the placebo group in a 2:2:1 ratio 
(342 subjects for risankizumab 600 mg dose group, 342 subjects for risankizumab 1200 mg dose group, 
and 171 subjects for placebo group). When all patients complete their Week 12/PD visit, the database 
will be locked for the final analysis of 12-week induction period.  When all the patients who enter the 
induction Period 2 finish Week 24/PD visit, the database will be locked for the whole study and all the 
planned analysis for the induction Period 2 will be performed.
Assuming the Week 12 CDAI clinical remission rate will be 37% for one of the risankizumab dose 
groups and 17% for the placebo group, a sample size of 342 subjects for each of the risankizumab dose 
groups and 171 for the placebo group will have 99% power to detect the treatment difference between 
the risankizumab dose groups and placebo in CDAI clinical remission rates at Week 12 using Fisher's 
exact test at alpha of 0.025 (two-sided).
The bio-IR population is approximately 540 subjects.  The study will have 92% power to detect the 
treatment difference between one of the risankizumab dose groups and placebo in CDAI clinical 
remission at Week 12 using a Fisher's exact test a 0.025 significant level (two-sided) for the bio-IR 
population, assuming the Week 12 CDAI clinical remission rate will be 34% for the risankizumab dose 
groups and 15% for the placebo group for bio-IR subjects.  The non-bio-IR population is approximately
315 subjects.  The study will have 70% power to detect the treatment difference between one of the 
risankizumab dose groups and placebo in CDAI clinical remission, at Week 12 using a Fisher's exact test 
a 0.025 significant level (two-sided) for the non-bio-IR sub-population, assuming the Week 12 CDAI 
clinical remission rate will be 42% for the risankizumab dose groups and 21% for the placebo group for 
non-bio-IR subjects.


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Statistical Methods (Continued):
Efficacy (Continued):
The comparisons between each risankizumab dose versus placebo for the primary efficacy variable will 
be performed using the Cochran-Mantel-Haenszel (CMH) test adjusted by prior biologic use (0, 1, > 1) 
and Baseline steroid use (yes, no). Both of the co-primary efficacy endpoints will be tested at 
statistically significant of 0.025 for each of the risankizumab dose groups versus placebo to adjust for 
multiplicity.  A CMH based two-sided 95% confidence interval for the difference between treatment 
groups will be calculated.
The intent-to-treat (ITT) set includes all randomized subjects who have taken at least one dose of study 
drug.  The primary population for efficacy analysis are the subjects in the intent-to-treat analysis set who 
had baseline eligibility SES-CD of ≥ 6 (≥ 4 for isolated ileal disease).  Subjects who discontinue prior to 
Week 12 for any reason will be considered as "not-achieved" for CDAI clinical remission and 
endoscopic response endpoints.
In general, continuous secondary efficacy variables will be analyzed using a Mixed-Effect Model 
Repeated Measure (MMRM) model including factors for treatment group, visit, visit by treatment 
interaction, and stratification variables, for the longitudinal continuous endpoints.  The MMRM analysis 
is considered primary for inferential purposes.  
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 cohorts and study visits.  ADA titers will be tabulated for each 
subject at the respective study visits.  The effect of ADAs on risankizumab pharmacokinetics, efficacy 
and/or safety variable(s) and/or any additional analyses will be explored.
Safety:
Adverse events, laboratory data and vital signs are the primary safety parameters in this study.  All 
safety comparisons will be performed between treatment groups using the safety set.  Treatment 
emergent AEs are defined as events that begin or worsen either on or after the first dose of the study 
drug and within 140 days after the last dose of the study drug for subjects who do not participate in 
Study M16-000 or until first dose of study drug in Study M16-000 if the subject is enrolled in 
Study M16-000.  
An overview of treatment-emergent AEs, AEs leading to death and AEs leading to premature 
discontinuation (see details in the statistical analysis plan [SAP]), AEs by Medical Dictionary for Drug 
Regulatory Activities (MedDRA version) preferred term and system organ class, AEs by maximum 
relationship to study drug, and AEs by maximum severity will be summarized by number and 
percentage.  
Changes in laboratory data will be described using statistical characteristics and 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.


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Section 3.2  Benefits and Risks
Last paragraph previously read:
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study have been re-evaluated.  Based on the limited information to 
date, no additional risk to study participants is anticipated with the use of risankizumab.
Has been changed to read:
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.
Section 5.2.2  Exclusion Criteria
Subsection Rationale for Exclusion Criteria
Previously read:
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 – 21
To avoid complications of CD that may compromise the evaluations of 
efficacy and safety
22 – 30
To ensure the safety of the subject and or others
Has been changed to read:
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


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18 – 21
To avoid complications of CD that may compromise the evaluations of 
efficacy and safety
22 – 31
To ensure the safety of the subject and or others
Section 5.3.3  Efficacy Variables
Add:  new ninth and tenth bullet
●
SF remission:  average daily SF ≤ 2.8 and not worse than baseline
●
AP remission:  average daily AP score ≤ 1 and not worse than baseline
Section 5.3.3.1  Primary Variable
First bullet previously read:
Proportion of subjects with clinical remission at Week 12
Has been changed to read:
Proportion of subjects with CDAI clinical remission at Week 12
Section 5.3.3.2  Secondary Variables
First bullet previously read:
Proportion of subjects with CDAI clinical remission at Week 12
Has been changed to read:
Proportion of subjects with clinical remission at Week 12
Section 5.3.3.2  Secondary Variable
Delete:  Item 3
Proportion of subjects with clinical remission at Week 4
Section 5.3.3.2  Secondary Variable
Item 5, 6, 7, 8, 9, 10, and 11 previously read:
5.
Mean change from baseline of induction in FACIT fatigue at Week 12 


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6.
Mean change from baseline of induction in IBDQ total score at Week 12 
7.
Proportion of subjects with enhanced clinical response and endoscopic response at 
Week 12 
8.
Proportion of subjects with endoscopic remission at Week 12
9.
Proportion of subjects with enhanced clinical response at Week 4
10. Proportion of subjects with ulcer-free endoscopy at Week 12
11. Enhanced clinical response at Week 12
Has been changed to read:
4.
Change from baseline of Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT fatigue) at Week 12
5.
Proportion of subjects with CDAI clinical remission at Week 4
6.
Proportion of subjects with CDAI clinical response and endoscopic response at 
Week 12
7.
Proportion of subjects with SF remission at Week 12
8.
Proportion of subjects with AP remission at Week 12
9.
Proportion of subjects with endoscopic remission at Week 12
10. Proportion of subjects with enhanced clinical response at Week 4
11. Proportion of subjects with ulcer-free endoscopy at Week 12
12. Proportion of subjects with enhanced clinical response at Week 12
Section 5.3.3.3  Other Endpoints
Delete:  third bullet
Change from Baseline individual IBDQ item under Bowel Symptom domain (for Q1, Q5, 
Q9, Q13, Q17, Q20, Q22, Q24, Q26, and Q29) over time


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Section 5.3.3.3  Other Endpoints
Eighth bullet previously read:
Change from Baseline in FACIT-Fatigue overtime
Has been changed to read:
Change from Baseline in FACIT-Fatigue total score and individual item score over time
Section 5.3.3.3  Other Endpoints
Last bullet
Add:  new last paragraph
Of note, over time will be measured at each study visit as specified in the study activity 
table
Section 8.1.6.1  Primary Efficacy Variables
First paragraph previously read:
The co-primary endpoints are the proportion of subjects who achieve clinical remission at 
Week 12 and proportion of subjects with endoscopic response at Week 12.
Has been changed to read:
The co-primary endpoints are the proportion of subjects who achieve CDAI clinical 
remission at Week 12 and proportion of subjects with endoscopic response at Week 12.
Section 8.1.6.1  Primary Efficacy Variables
Second paragraph, seventh and eighth sentence previously read:
If average daily SF or average daily AP score or endoscopic data at Week 12 are missing, 
the NRI approach will be applied.  Subjects who discontinue prior to Week 12 for any 
reason will be considered as "not-achieved" for clinical remission and endoscopic 
response endpoints.


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Has been changed to read:
Subjects who discontinue prior to Week 12 for any reason will be considered as "not-
achieved" for CDAI clinical remission and endoscopic response endpoints.
Section 8.2  Determination of Sample Size
First paragraph previously read:
The co-primary endpoints are the proportion of subjects with clinical remission at 
Week 12 and proportion of subjects with endoscopic response at Week 12.
Has been changed to read:
The co-primary endpoints are the proportion of subjects with CDAI clinical remission at 
Week 12 and proportion of subjects with endoscopic response at Week 12.
Section 8.2  Determination of Sample Size
Second paragraph
Delete:  first and second sentence
Sample size calculation is based on the larger sample size needed to detect treatment 
difference for each of the co-primary endpoints.  Since historical data show slightly lower 
event rate and similar treatment difference versus placebo for the endoscopic response 
rate than the clinical remission rate at Week 12, clinical remission rates at Week 12 are 
used for power calculation.
Section 8.2  Determination of Sample Size
Second paragraph, fourth sentence previously read:
Assuming the Week 12 clinical remission rate will be 27.8% for one of the risankizumab 
dose groups and 12% for the placebo group, a sample size of 342 subjects for each of the 
risankizumab dose groups and 171 for the placebo group will have 97% power to detect 
the treatment difference between the risankizumab dose groups and placebo in clinical 
remission rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided).


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Has been changed to read:
Assuming the Week 12 CDAI clinical remission rate will be 37% for one of the 
risankizumab dose groups and 17% for the placebo group, a sample size of 342 subjects 
for each of the risankizumab dose groups and 171 for the placebo group will have 99% 
power to detect the treatment difference between the risankizumab dose groups and 
placebo in CDAI clinical remission rates at Week 12 using Fisher's exact test at alpha of 
0.025 (two-sided).
Section 8.2  Determination of Sample Size
Last paragraph previously read:
In addition, with sample size of approximately 540 bio-IR subjects, this study will have 
approximately 80% power for the bio-IR population to detect the treatment difference 
between one of the risankizumab dose groups and placebo in clinical remission rates at 
Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) for the bio-IR population, 
assuming the Week 12 clinical remission rate will be 24.2% for the risankizumab dose 
groups and 10% for the placebo group.  Similarly, with sample size of approximately 
315 non-bio-IR subjects, this study will have 72% power to detect the treatment 
difference between one of the risankizumab dose groups and placebo in clinical remission 
rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) for the non-bio-IR 
population, assuming the Week 12 clinical remission rate will be 35% for the 
risankizumab dose groups and 15% for the placebo group for non-bio-IR subjects.
Has been changed to read:
In addition, with sample size of approximately 540 bio-IR subjects, this study will have 
approximately 92% power for the bio-IR population to detect the treatment difference 
between one of the risankizumab dose groups and placebo in CDAI clinical remission 
rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) for the bio-IR 
population, assuming the Week 12 CDAI clinical remission rate will be 34% for the 
risankizumab dose groups and 15% for the placebo group.  Similarly, with sample size of 
approximately 315 non-bio-IR subjects, this study will have 70% power to detect the 


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treatment difference between one of the risankizumab dose groups and placebo in CDAI 
clinical remission rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) 
for the non-bio-IR population, assuming the Week 12 CDAI clinical remission rate will be 
42% for the risankizumab dose groups and 21% for the placebo group for non-bio-IR 
subjects.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical Development, Immunology
Clinical Development, Immunology
Statistics
Statistics
Clinical Pharmacology and Pharmacometrics
Bioanalysis
Clinical Operations
Has been changed to read:
Name
Title
Functional Area
Clinical Development, Immunology
Clinical Development, Immunology
Statistics
Statistics
Clinical Pharmacology and Pharmacometrics
Bioanalysis
Clinical Operations


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1.0
Title Page
Clinical Study Protocol M16-006
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Induction Study of the Efficacy 
and Safety of Risankizumab in Subjects with 
Moderately to Severely Active Crohn's Disease
Incorporating Administrative Change 1 and 
Amendments 1, 2, 3, 4, 5, and 6
AbbVie Investigational
  Product:
Risankizumab
Date:
28 July 2020
Development Phase:
3
Study Design:
Randomized, Double-Blind, Placebo-Controlled Parallel Group Design
EudraCT Number:
2016-003123-32
Investigators:
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
3-5-27, Mita,
Minato-ku
Tokyo 108-6302, 
Japan
Sponsor/Emergency 
  Contact:
Pharmaceutical 
Development
100 Research Drive, 
Suite 3009
Worchester, MA 01605
USA
Phone:
Mobile:
Fax:
Email:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
17 February 2017
Amendment 1
05 July 2017
Amendment 2
29 September 2017
Amendment 3
09 July 2018
Amendment 4
22 February 2019
Amendment 5
19 December 2019
The purpose of this amendment is to:
●
Addition of language on the re-evaluation of the benefit and risk in light of the 
COVID-19 pandemic, to subjects participating in the study in Section 3.2
Rationale:  To clarify the updated benefit-risk balance to participating 
subjects
●
Addition of exclusion criteria language in Section 5.2.2
Rationale:  To exclude subjects with active COVID-19 infection from 
enrollment into study
●
Addition of study procedure language in Section 5.3.1.1, Section 9.2
Rationale:  To modify study visits/protocol-specified procedures impacted by 
changes in local regulations due to the COVID-19 pandemic, as necessary to 
ensure the safety of subjects, including visit frequency, alternative methods of 
assessments, locations for data collection permitted by IRB/IEC
●
Addition of protocol language regarding site responsibility in Section 5.5.2.2, 
Section 5.5.7
Rationale:  To align with study-related training materials and documented 
study processes regarding site responsibility for reporting temperature 
excursions and for drug accountability/destruction
●
Addition of adverse event language in Section 6.1.1.1


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Rationale:  To align with AbbVie approved COVID-19 infection adverse event 
data collection processes
●
Addition of protocol deviation language in Section 7.0
Rationale:  To clarify that deviations include deviations occurring due to 
COVID-19 
●
Addition of language to address missing data due to COVID-19 in the 
statistical analysis plan in Section 8.1
Rationale:  To clarify that modifications to the analysis for missing data due 
to COVID-19 infection will be incorporated into the statistical analysis plan
●
Addition of protocol modification language regarding data monitoring during 
COVID-19 in Section 10.1
Rationale:  To clarify that due to the COVID-19 infection, remote source data 
verification will be allowed if necessary and permitted by the local regulatory 
authority, IRB/IEC, and the study site
●
Clarification of HIV results language throughout protocol
Rationale:  To align with study-related training materials regarding the 
handling of subject HIV results during screening
●
Addition of event in Study Activities Table in Appendix C
Rationale:  The addition of COVID-19 testing during subject study screening 
period
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix K.


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-006
Name of Study Drug:  Risankizumab (ABBV-066)
Phase of Development:  3
Name of Active Ingredient:  Risankizumab
Date of Protocol Synopsis:  28 July 2020
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the 
Efficacy and Safety of Risankizumab in Subjects with Moderately to Severely Active Crohn's Disease
Objective:  The objective of Study M16-006 is to evaluate the efficacy and safety of risankizumab 
versus placebo during induction therapy in subjects with moderately to severely active Crohn's disease 
(CD).
Investigators:  Multicenter
Study Sites:  Approximately 400 sites
Study Population:  Males and females aged ≥ 18 to ≤ 80 years of age, or minimum age of adult consent 
according to local regulations at the Baseline visit, or aged 16 to < 18 years of age where locally 
permitted and who meet the definition of Tanner stage 5 development (refer to Appendix J) at the 
Baseline visit, with a diagnosis of moderately to severely active CD, defined as:
1.
average daily stool frequency (SF) ≥ 4 (when calculating SF, only the number of liquid or very soft 
stools should be recorded) and/or average daily abdominal pain (AP) score ≥ 2; plus
2.
endoscopic evidence of mucosal inflammation as measured by the Simple Endoscopic Score for CD 
(SES-CD). All eligible scores exclude the presence of narrowing component and are confirmed by 
a central reader.  Endoscopic activity is defined as a SES-CD of ≥ 3.  
The number of subjects enrolled with a SES-CD of ≥ 3 to < 6 for ileocolonic or colonic disease or 
SES-CD of 3 for isolated ileal disease will be no more than 85 subjects.  Once cap of no more than 
85 subjects is reached, enrollment criterion will be an eligibility SES-CD of ≥ 6 for ileocolonic or 
colonic disease, or eligibility SES-CD of ≥ 4 for isolated ileal disease.  
The study will enroll both subjects who have had an inadequate response (IR) to prior biologic therapy 
(bio-IR) and subjects who have not (non-bio-IR).  The bio-IR enrollment will be approximately 
540 subjects and the non-bio-IR enrollment will be approximately 315 subjects.
The bio-IR population is defined as subjects with documented intolerance or inadequate response to one 
or more of the approved anti-TNF or anti-integrin biologics for CD (infliximab, adalimumab, 
certolizumab, vedolizumab, ustekinumab and/or natalizumab). 
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 in the past but stopped therapy based on reasons other than 
inadequate response or intolerance (e.g., change in reimbursement coverage, well-controlled disease).
The percent of subjects with exposure, including intolerance or inadequate response, to ustekinumab will 
be no more than 20%.
Number of Subjects to be Enrolled:  Approximately 855 for the primary ITT population used for 
efficacy analysis; additionally, up to 85 subjects with lower SES-CD will be enrolled


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
5
Methodology:  
Study M16-006 is a randomized, double blind, placebo-controlled 12-week induction study.
Subjects (n = 855) will be randomized 2:2:1 to 1200 mg risankizumab or 600 mg risankizumab or 
placebo intravenous (IV) given at Baseline, Weeks 4 and 8.  The randomization will be stratified by 
number of prior biologics failed (0, 1, > 1), Baseline steroid use (yes, no), and Baseline SES-CD 
(original, alternative), where the stratum of "original" includes the patients with baseline SES-CD of ≥ 6 
(or ≥ 4 for subjects with isolated ileal disease), and the stratum of "alternative" includes the patients with 
baseline SES-CD of ≥3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for isolated ileal 
disease.
Visits during the study will occur at Baseline and Weeks 4, 8, and 12/Premature Discontinuation (PD) to 
collect clinical and laboratory assessments of disease activity.  Subjects who do not achieve clinical 
response at Week 12 will be offered blinded risankizumab therapy in Induction Period 2 with evaluation 
for clinical response at Week 24.
All subjects will be provided with a subject diary where they will record CD related symptoms 
throughout the study.  Subjects will also be dispensed a patient information card at Screening.  
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.  All endoscopies will be evaluated using SES-CD and will be confirmed by a central 
reader.  Biopsy to confirm diagnosis (during Screening) or to rule out dysplasia/malignancy may be 
performed during the same time points as the endoscopy.  Optional exploratory research samples may be 
taken during the study.
At the Week 12/PD visit, all subjects will undergo an endoscopy for evaluation of mucosal 
inflammation.  It is expected that all subjects who remain in the study through at least Week 8 will have 
a Week 12/PD endoscopy.  All subjects achieving clinical response, defined as ≥ 30% decrease in 
average daily SF and/or ≥ 30% decrease in average daily AP score (both not worse than Baseline) at 
Week 12 may be eligible to enter Study M16-000.  Subjects are not eligible to enter Study M16-000 
until endoscopy has been completed (local reader results will be used for stratification for 
Study M16-000).
All subjects who do not achieve clinical response 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 Interactive Response 
Technologies (IRT) to Induction Period 2, a double-blind, double-dummy 12-week treatment period.
Subjects who received IV risankizumab induction treatment with inadequate clinical response at 
Week 12 will be randomized 1:1:1 to:
!
Group 1:  1200 mg IV risankizumab
!
Group 2:  360 mg SC risankizumab
!
Group 3:  180 mg SC risankizumab


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
6
Methodology (Continued):
Subjects who received IV placebo induction treatment will receive:
!
Group 4:  1200 mg IV risankizumab
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 received treatment in Induction Period 2 will be reassessed and undergo a third endoscopy for 
evaluation of mucosal inflammation.  Subjects who achieve clinical response at Week 24 may be eligible 
to enter Study M16-000.  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 enter 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, immunomodulators (azathioprine [AZA], 6-mercaptopurine 
[6-MP], methotrexate [MTX]), and/or CD-related antibiotics.
Subjects taking aminosalicylates, immunomodulators, and/or CD-related antibiotics at Baseline must 
continue these treatments for the duration of the study.  Initiating and/or increasing doses of 
aminosalicylates, immunomodulators, and/or CD-related antibiotics during the study is prohibited.  
Decreasing doses of aminosalicylates, immunomodulators, and/or CD-related antibiotics is prohibited 
during the study, except in the event of moderate-to-severe treatment related toxicities and after 
discussion with the AbbVie Therapeutic Area Medical Director (TA MD).  CD-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
Subjects taking corticosteroids at Baseline must continue their concomitant treatment at the Baseline 
dose for the duration of the 12-week induction period.  Initiation and/or increasing doses of systemic 
and/or CD related corticosteroids during the entire study is prohibited.  Decreasing doses of 
corticosteroids is prohibited during the 12-week induction period, except in the event of moderate-to-
severe treatment related toxicities and after discussion with the AbbVie TA MD.
Subjects who receive Induction Period 2 treatment during Weeks 12 to 24 will be allowed to taper their 
corticosteroids at the discretion of the Investigator.  Increasing doses above the Baseline dose is 
prohibited.
Dose Selection
This study will evaluate two IV doses of risankizumab (600 mg and 1200 mg) during induction.  The 
selection of the doses in this study is 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 CD that explored 
200 mg and 600 mg doses.  The results from the Phase 2 study suggest a potential for increased benefit 
with 1200 mg administration. 


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
7
Methodology (Continued):
Induction Period 2 will evaluate IV (1200 mg 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 (1200 mg IV at Weeks 12, 16, and 20) versus initiating maintenance 
dosing 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.  
The results from the Phase 2 study suggest a potential for increased benefit with 360 mg SC 
administration for maintenance regimen.
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.  At the timing of this amendment, the DMC has 
provided recommendation that the study may continue without modification and allowed enrollment to 
begin for 16 - 17 year-olds. 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.  
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.


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
8
Diagnosis and Main Criteria for Inclusion/Exclusion:  
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.  Where locally permissible, subjects 16 to < 18 years of age who 
meet the definition of Tanner stage 5 for development (refer to Appendix J), at the Baseline Visit 
(sites will be notified when adolescents may enroll).
2.
Confirmed diagnosis of CD for at least 3 months prior to Baseline.  Appropriate documentation of 
biopsy results consistent with the diagnosis of CD, in the assessment of the Investigator, must be 
available.
3.
Crohn's disease activity index (CDAI) score 220 – 450 at Baseline.
4.
Endoscopic evidence of mucosal inflammation as documented by an SES-CD of ≥ 3. All eligible 
scores exclude the presence of narrowing component and are confirmed by a central reader. (Once 
cap of no more than 85 subjects is reached, enrollment criterion will be an SES-CD of ≥ 6 for 
ileocolonic or colonic disease or SES-CD of ≥ 4 for isolated ileal disease.)
5.
Average daily SF ≥ 4 and/or average daily AP score ≥ 2 at Baseline.
6.
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 (intolerance 
includes patients with a known TPMT genetic mutation or low activity).  
!
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, 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,


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
9
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, Hong Kong, 
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, Hong Kong, 
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
Biologic Therapies for CD: 
!
Signs and symptoms of persistently (in the opinion of the Investigator) 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 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 certolizumab pegol (400 mg SC at 
Weeks 0, 2, and 4),
o
At least one 6-week induction regimen of vedolizumab (300 mg IV at 
Weeks 0, 2, and 6)
o
At least one 12-week induction regimen of natalizumab (300 mg IV every 
4 weeks)
o
At least one 8-week induction regimen of ustekinumab [260 mg (≤ 55 kg) or 
390 mg (> 55 to ≤ 85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at 
Week 8] (Once cap of no more than 20% ustekinumab exposed subjects is 
reached, subjects with prior ustekinumab exposure will not be allowed to 
enroll.)  


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
10
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Recurrence of symptoms during scheduled maintenance dosing following prior 
clinical benefit of the above biologics
!
Note:  Subjects who discontinued biologics 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
7.
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. 
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.
8.
Subjects must be able and willing to give written informed consent and to comply with the 
requirements of this study protocol.  In Japan, if the subject is < 20 years old, a subject's parent or 
legal guardian must be willing to give written informed consent.
Main Exclusion:  
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
Concomitant Medications and Treatments
2.
Subject on CD-related antibiotics who has not been on stable doses 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 current 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/intramuscular 
anti-infectives (non-CD-related) within 14 days prior to the Baseline visit.  This does not apply to 
TB prophylaxis.
7.
Subject who received exclusive enteral nutrition or any parenteral nutrition within 35 days prior to 
Baseline.


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
11
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):
Medications and Treatments During the Screening Period (Continued)
8.
Subject who received any live bacterial or viral vaccination within 30 days (8 weeks for Japan) 
prior to Screening or during the Screening Period.
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 biologics: infliximab, adalimumab, certolizumab, vedolizumab, natalizumab) within 
8 weeks prior to Baseline, or ustekinumab within 12 weeks prior to Baseline  
Note:  If there is proper documentation of an undetectable drug level measured by a 
commercially available assay for any of the approved biologics above, there is no minimum 
washout prior to Baseline.
!
Any investigational biologic or other agent or procedure within 35 days or 5 half-lives prior to 
Baseline, whichever is longer.
12. Subject with prior exposure to p19 inhibitors (e.g., risankizumab).
13. Subject has been taking combination of two or more of the following:  oral budesonide, or 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, other than required for endoscopy, within 
14 days prior to endoscopy used for 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.
CD Related
18. Subject with currently known complications of CD such as:
!
abscess (abdominal or perianal),
!
symptomatic bowel strictures,
!
> 2 missing segments of the following 5 segments:  terminal ileum, right colon, transverse 
colon, sigmoid and left colon, and rectum
!
fulminant colitis,
!
toxic megacolon,
!
or any other manifestation that might require surgery while enrolled in the study.
19. Subject with ostomy or ileoanal pouch.
20. Subject diagnosed with short gut or short bowel syndrome.


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
12
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
21. Subject with surgical bowel resection within the past 3 months prior to Baseline, or a history of 
≥3 bowel resections.
Safety
22. 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).
23. 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 or other intestinal pathogen during Screening,
!
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:
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 positive with anti-HCV 
antibody (HCV Ab)
24. 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.
25. 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.
26. Subject with current or previous 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.
27. Subject who has severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, 
disorder or symptoms thereof.
28. 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.
29. 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.


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
13
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
Safety (Continued):
30. 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
!
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 after discussion and clearance 
with the TAMD. 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.
31. No known active COVID-19 infection.  Subject must not have signs/symptoms associated with 
COVID-19 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 viral clearance criteria: 
!
Symptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥24 hours 
apart after at least 10 days have passed since recovery, defined as resolution of fever without 
use of antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of breath)
!
Asymptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥ 24 hours 
apart after at least 10 days have passed since prior positive result (Note: subjects who develop 
symptoms will follow guidance above for symptomatic subjects)
Frequency or timing of COVID-19 testing and interval between testing for the above viral clearance 
criteria may be adjusted to account for epidemiological trends, updated information regarding 
infectivity and local/institutional guidelines.


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
14
Investigational Product:
Risankizumab
Doses:
Risankizumab 1200 mg IV Q4W* 
Risankizumab 600 mg IV Q4W
Risankizumab 180 mg SC Q8W
Risankizumab 360 mg SC Q8W
*
If the 1200 mg dose is discontinued due to any reason, subjects will 
continue to enroll into the study and be randomized to either 
600 mg risankizumab or placebo at 2:1 ratio.  The randomization 
ratio and sample size may be further updated in an amendment to 
the protocol.  Subjects already randomized to treatment arms, 
including Induction Period 2, will receive blinded 600 mg 
risankizumab IV.
Mode of Administration:
Risankizumab solution for infusion (IV)
Risankizumab solution for injection (SC) 
Reference Therapy:
Placebo for risankizumab
Dose:
N/A
Mode of Administration:
Placebo solution for infusion (IV)
Placebo solution for injection (SC)
Duration of Treatment:  12 or 24 weeks 
The study will include a Screening period of up to 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 
treatment in Induction Period 2 with risankizumab 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 roll over into Study M16-000 or discontinue from the study 
prematurely.
Criteria for Evaluation:
Endpoint Definitions:
!
Clinical remission:  average daily SF ≤ 2.8 and not worse than Baseline AND average daily 
AP score ≤ 1 and not worse than Baseline
!
Enhanced clinical response:  ≥ 60% decrease in average daily SF and/or ≥ 35% decrease in 
average daily AP score and both not worse than Baseline, and/or clinical remission
!
Clinical response:  ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily 
AP score and both not worse than Baseline
!
Endoscopic response:  decrease in SES-CD > 50% from Baseline (or for subjects with isolated 
ileal disease and a Baseline SES-CD of 4, at least a 2 point reduction from Baseline), as scored 
by central reviewer
!
Ulcer-free endoscopy:  SES-CD ulcerated surface subscore of 0 in subjects with SES-CD 
ulcerated surface subscore ≥ 1 at Baseline, as scored by a central reviewer
!
Endoscopic remission: SES-CD ≤ 4 and at least a 2 point reduction versus baseline and no 
subscore greater than 1 in any individual variable, as scored by a central reviewer


Risankizumab
M16-006 Protocol Amendment 6
EudraCT 2016-003123-32
15
Criteria for Evaluation (Continued):
Endpoint Definitions (Continued):
!
CDAI clinical response:  reduction of CDAI ≥100 points from baseline
!
CDAI clinical remission:  CDAI < 150
Efficacy:
Co-Primary Endpoints:  
!
Proportion of subjects with clinical remission at Week 12 
!
Proportion of subjects with endoscopic response at Week 12
Ranked Secondary Endpoints:
1.
Proportion of subjects with CDAI clinical remission at Week 12
2.
Proportion of subjects with CDAI clinical response at Week 4
3.
Proportion of subjects with clinical remission at Week 4 
4.
Proportion of subjects with CDAI clinical response at Week 12 
5.
Mean change from baseline of induction in FACIT fatigue at Week 12 
6.
Mean change from baseline of induction in IBDQ total score at Week 12 
7.
Proportion of subjects with enhanced clinical response and endoscopic response at Week 12 
8.
Proportion of subjects with endoscopic remission at Week 12
9.
Proportion of subjects with enhanced clinical response at Week 4
10. Proportion of subjects with ulcer-free endoscopy at Week 12
11. Enhanced clinical response at Week 12
12. Proportion of subjects with resolution of extra-intestinal manifestations (EIMs) at Week 12, in 
subjects with any EIMs at Baseline 
13. Proportion of subjects with CD-related hospitalization through Week 12
14. Proportion of subjects without draining fistulas at Week 12 in subjects with draining fistulas at 
Baseline
For further information, including non-ranked endpoints, refer to protocol
Pharmacokinetics:
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 receive treatment in Induction Period 2.
Additionally, intensive pharmacokinetic assessment will be performed in 20 subjects after the 
3rd induction dose (Week 8 to 12).  For Subjects who consent to the intensive pharmacokinetic 
assessment, in addition to the time points above, blood samples will be 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.
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 receive treatment in Induction Period 2.


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Criteria for Evaluation (Continued):
Safety:
Safety analyses will be performed on safety set which includes all subjects who receive at least one dose 
of study drug.  Incidence of adverse events (AEs), changes in vital signs, physical examination results, 
and clinical laboratory data will be assessed throughout the study.
Exploratory Research Variables and Validation Studies (Optional):
Prognostic, surrogate, predictive and pharmacodynamics biomarkers signatures may be investigated.  
Samples for different applications, including but not limited to, pharmacogenetic, epigenetic, 
transcriptomic, proteomic, metabolomics, metagenomic and targeted investigations will be collected at 
various time points.  Assessments will include but may not be limited to nucleic acids, proteins, 
metabolites or lipids.
Statistical Methods:
Efficacy:
The co-primary endpoints are the proportion of subjects with clinical remission at Week 12 and 
proportion of subjects with endoscopic response at Week 12.  A total of approximately 855 subjects will 
be randomized into two risankizumab treatment groups and the placebo group in a 2:2:1 ratio 
(342 subjects for risankizumab 600 mg dose group, 342 subjects for risankizumab 1200 mg dose group, 
and 171 subjects for placebo group). When all patients complete their Week 12/PD visit, the database 
will be locked for the final analysis of 12-week induction period.  When all the patients who enter the 
induction Period 2 finish Week 24/PD visit, the database will be locked for the whole study and all the 
planned analysis for the induction Period 2 will be performed.
Sample size calculation is based on the larger sample size needed to detect treatment difference for each 
of the co-primary endpoints.  Since historical data show slightly lower event rate and similar treatment 
difference versus placebo for the endoscopic response rate than the clinical remission rate at Week 12, 
clinical remission rates at Week 12 are used for power calculation.  Assuming the Week 12 clinical 
remission rate will be 27.8% for one of the risankizumab dose groups and 12% for the placebo group, a 
sample size of 342 subjects for each of the risankizumab dose groups and 171 for the placebo group will 
have 97% power to detect the treatment difference between the risankizumab dose groups and placebo in 
clinical remission rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided).
The bio-IR population is approximately 540 subjects.  The study will have 80% power to detect the 
treatment difference between one of the risankizumab dose groups and placebo in clinical remission 
rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) for the bio-IR population, 
assuming the Week 12 clinical remission rate will be 24.2% for the risankizumab dose groups and 10% 
for the placebo group for bio-IR subjects.  The non-bio-IR population is approximately 315 subjects.  
The study will have 72% power to detect the treatment difference between one of the risankizumab dose 
groups and placebo in clinical remission rates, at Week 12 using Fisher's exact test at alpha of 0.025 
(two-sided) for the non-bio-IR sub-population, assuming the Week 12 clinical remission rate will be 
35% for the risankizumab dose groups and 15% for the placebo group for non-bio-IR subjects.
The comparisons between each risankizumab dose versus placebo for the primary efficacy variable will 
be performed using the Cochran-Mantel-Haenszel (CMH) test adjusted by prior biologic use (0, 1, > 1) 
and Baseline steroid use (yes, no). Both of the co-primary efficacy endpoints will be tested at 
statistically significant of 0.025 for each of the risankizumab dose groups versus placebo to adjust for 
multiplicity.  A CMH based two-sided 95% confidence interval for the difference between treatment 
groups will be calculated. 


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Statistical Methods (Continued):
Efficacy (Continued):
The intent-to-treat (ITT) set includes all randomized subjects who have taken at least one dose of study 
drug.  The primary population for efficacy analysis are the subjects in the intent-to-treat analysis set who 
had baseline eligibility SES-CD of ≥ 6 (≥ 4 for isolated ileal disease). If the average daily SF or average 
daily AP score data at Week 12 are missing, the non-responder imputation (NRI) approach will be 
applied.  Subjects who discontinue prior to Week 12 for any reason will be considered as "not-achieved"
for clinical remission and endoscopic response endpoints.
In general, continuous secondary efficacy variables will be analyzed using a Mixed-Effect Model 
Repeated Measure (MMRM) model including factors for treatment group, visit, visit by treatment 
interaction, and stratification variables, for the longitudinal continuous endpoints.  The MMRM analysis 
is considered primary for inferential purposes.  
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 cohorts and study visits.  ADA titers will be tabulated for each 
subject at the respective study visits.  The effect of ADAs on risankizumab pharmacokinetics, efficacy 
and/or safety variable(s) and/or any additional analyses will be explored.
Safety:
Adverse events, laboratory data and vital signs are the primary safety parameters in this study.  All 
safety comparisons will be performed between treatment groups using the safety set.  Treatment 
emergent AEs are defined as events that begin or worsen either on or after the first dose of the study 
drug and within 140 days after the last dose of the study drug for subjects who do not participate in 
Study M16-000 or until first dose of study drug in Study M16-000 if the subject is enrolled in 
Study M16-000.  
An overview of treatment-emergent AEs, AEs leading to death and AEs leading to premature 
discontinuation (see details in the statistical analysis plan [SAP]), AEs by Medical Dictionary for Drug 
Regulatory Activities (MedDRA version) preferred term and system organ class, AEs by maximum 
relationship to study drug, and AEs by maximum severity will be summarized by number and 
percentage.  
Changes in laboratory data will be described using statistical characteristics and 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.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
6-MP
6-Mercaptopurine
AAC
Anaphylaxis adjudication committee
ADA
Anti-Drug Antibody
AE
Adverse event 
ALT
Alanine transaminase 
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AAC
Anaphylaxis adjudication committee
AP
Abdominal Pain
AST
Aspartate transaminase 
ATEMS
AbbVie Temperature Excursion Management System
AZA
Azathioprine
BCG
Bacillus Calmette-Guérin 
Bio-IR
Inadequate Response to biologic therapy
BUN
Blood urea nitrogen 
CAC
Cardiac Adjudication Committee
CD
Crohn's disease 
CDAI
Crohn's disease activity index
CHO
Chinese Hamster Ovary
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease - 2019
CRA
Clinical Research Associate
CSS
Crohn's Symptom Severity 
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest x-ray 
DILI
Drug-induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram 
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture


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EIM
Extra-Intestinal Manifestations
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
European Quality of Life 5 Dimensions
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FCP
Fecal Calprotectin
FDA
Food and Drug Administration 
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice 
HBV
Hepatitis B virus
HBc Ab
Hepatitis B core antibody
Hbs Ab
Hepatitis B surface antibody
Hbs Ag
Hepatitis B surface antigen 
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HCT
Hematocrit
HIV
Human immunodeficiency virus
hs-CRP
High-sensitivity C-Reactive Protein
IBDQ
Inflammatory Bowel Disease Questionnaire 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
IL
Interleukin 
IR
Inadequate response
IM
Intramuscular
INR
International Normalized Ratio
IRB
Institutional Review Board 
IRT
Interactive Response Technologies
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
MACE
Major Adverse Cardiovascular Events
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Drug Regulatory Activities


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MI
Multiple Imputation
MMR
Measles Mumps-Rubella
MMRM
Mixed-Effect Model Repeated Measure
MMRV
Measles Mumps-Rubella Varicella
MTX
Methotrexate 
nAb
Neutralizing antibodies
NRI
Non-responder imputation
N/A
Not Applicable
OC
Observed Case
OL
Open-Label
OPV
Oral Polio Vaccine
PCR
Polymerase Chain Reaction
PD
Premature Discontinuation
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity  
PK
Pharmacokinetics
PMM
Pattern Mixture Model
POR
Proof of Receipt 
PPD
Purified protein derivative 
QoL
Quality of Life
Q4w
Every 4 Weeks
Q8w
Every 8 Weeks 
RBC
Red blood cell 
RNA
Ribonucleic Acid
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SES-CD
Simple Endoscopic Score for Crohn's Disease
SF
Stool Frequency
SF-36 
36-Item Short Form Health Status Survey
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis 
TNF
Tumor Necrosis Factor 


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ULN
Upper Limit of Normal
WBC
White blood cell
WOCBP
Women of Childbearing Potential
WPAI-CD
Work Productivity and Impairment Questionnaire – Crohn's disease


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms........................................18
2.0
Table of Contents...................................................................22
3.0
Introduction ...........................................................................27
3.1
Differences Statement..............................................................................28
3.2
Benefits and Risks....................................................................................28
4.0
Study Objective......................................................................31
5.0
Investigational Plan...............................................................31
5.1
Overall Study Design and Plan:  Description ..........................................31
5.2
Selection of Study Population..................................................................39
5.2.1
Inclusion Criteria .....................................................................................40
5.2.2
Exclusion Criteria ....................................................................................43
5.2.3
Prior and Concomitant Therapy...............................................................49
5.2.3.1
Prior Therapy ...........................................................................................49
5.2.3.2
Concomitant Therapy...............................................................................50
5.2.3.3
Prohibited Therapy...................................................................................51
5.2.4
Contraception Recommendations ............................................................52
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Optional 
Exploratory Research/Validation Studies and Safety 
Assessments/Variables.............................................................................54
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................54
5.3.1.1
Study Procedures .....................................................................................54
5.3.1.2
Collection and Handling of Optional Exploratory 
Research/Validation Studies Samples......................................................72
5.3.2
Drug Concentration and Anti-Drug Antibody Measurements.................73
5.3.2.1
Collection of Samples for Analysis .........................................................73
5.3.2.2
Handling/Processing of Samples .............................................................73
5.3.2.3
Disposition of Samples ............................................................................74
5.3.2.4
Measurement Methods.............................................................................74


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5.3.3
Efficacy Variables....................................................................................74
5.3.3.1
Primary Variable......................................................................................75
5.3.3.2
Secondary Variables ................................................................................75
5.3.3.3
Other Endpoints .......................................................................................76
5.3.4
Safety Variables.......................................................................................77
5.3.5
Pharmacokinetic Variables ......................................................................77
5.3.6
Optional Exploratory Research/Validation Variables..............................78
5.4
Removal of Subjects from Therapy or Assessment.................................78
5.4.1
Discontinuation of Individual Subjects....................................................78
5.4.2
Discontinuation of Entire Study...............................................................80
5.5
Treatments................................................................................................81
5.5.1
Treatments Administered.........................................................................81
5.5.2
Identity of Investigational Product...........................................................81
5.5.2.1
Packaging and Labeling...........................................................................82
5.5.2.2
Storage and Disposition of Study Drug ...................................................82
5.5.2.3
Preparation/Reconstitution of Dosage Form............................................83
5.5.3
Method of Assigning Subjects to Treatment Groups...............................83
5.5.4
Selection and Timing of Dose for Each Subject......................................84
5.5.5
Blinding....................................................................................................84
5.5.5.1
Blinding of Investigational Product.........................................................84
5.5.5.2
Data Monitoring Committee....................................................................85
5.5.6
Treatment Compliance.............................................................................86
5.5.7
Drug Accountability.................................................................................86
5.6
Discussion and Justification of Study Design..........................................87
5.6.1
Discussion of Study Design and Choice of Control Groups....................87
5.6.2
Appropriateness of Measurements...........................................................88
5.6.3
Suitability of Subject Population .............................................................88
5.6.4
Selection of Doses in the Study ...............................................................88
6.0
Complaints .............................................................................90
6.1
Medical Complaints.................................................................................90
6.1.1
Definitions................................................................................................91
6.1.1.1
Adverse Event..........................................................................................91
6.1.1.2
Serious Adverse Events ...........................................................................92


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6.1.1.3
Areas of Safety Interest............................................................................93
6.1.2
Adverse Event Severity............................................................................95
6.1.3
Relationship to Study Drug......................................................................96
6.1.3.1
Lack of Efficacy or Worsening of Disease ..............................................97
6.1.4
Adverse Event Collection Period.............................................................97
6.1.5
Adverse Event Reporting.........................................................................97
6.1.5.1
Adverse Events Commonly Associated with CD in Study 
Population ................................................................................................99
6.1.6
Pregnancy...............................................................................................100
6.1.7
Cardiac Adjudication Committee ..........................................................100
6.1.8
Anaphylaxis Adjudication Committee...................................................101
6.2
Product Complaint .................................................................................101
6.2.1
Definition ...............................................................................................101
6.2.2
Reporting................................................................................................101
7.0
Protocol Deviations..............................................................102
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................103
8.1
Statistical and Analytical Plans..............................................................103
8.1.1
Datasets for Analysis .............................................................................103
8.1.1.1
Intent-to-Treat Analysis Set...................................................................103
8.1.1.2
Safety Analysis Set ................................................................................104
8.1.2
Definition of Missing Data Imputation..................................................104
8.1.3
Subject Disposition ................................................................................104
8.1.4
Demographics and Baseline Characteristics..........................................104
8.1.5
Prior and Concomitant Medications ......................................................105
8.1.6
Efficacy Analysis ...................................................................................105
8.1.6.1
Primary Efficacy Variables....................................................................105
8.1.6.2
Secondary Efficacy Variables................................................................106
8.1.7
Safety Analysis ......................................................................................107
8.1.8
Analysis of Optional Exploratory Variables..........................................107
8.1.9
Analysis of Pharmacokinetic and Pharmacodynamic Variables............108
8.2
Determination of Sample Size ...............................................................109
8.3
Randomization Methods ........................................................................111


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9.0
Ethics.....................................................................................111
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................111
9.2
Ethical Conduct of the Study.................................................................112
9.3
Subject Information and Consent...........................................................113
9.3.1
Informed Consent Form and Explanatory Material ...............................115
9.3.2
Revision of the Consent Form and Explanatory Material .....................115
10.0
Source Documents and Case Report Form 
Completion ...........................................................................115
10.1
Source Documents .................................................................................115
10.2
Case Report Forms.................................................................................116
10.3
Electronic Patient Reported Outcomes (ePRO).....................................117
11.0
Data Quality Assurance ......................................................119
12.0
Use of Information...............................................................119
13.0
Completion of the Study .....................................................120
14.0
Investigator's Agreement....................................................122
15.0
Reference List ......................................................................123
List of Tables
Table 1.
Clinical Laboratory Tests.........................................................................61
Table 2.
Identity of Investigational Product...........................................................82
Table 3.
Common Events Associated with CD....................................................100
List of Figures
Figure 1.
Study M16-006 Study Schematic ............................................................34
Figure 2.
Adverse Event Collection ........................................................................97
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................126
Appendix B.
List of Protocol Signatories....................................................................128


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Appendix C.
Study Activities for Efficacy, Safety, and PK/PD .................................129
Appendix D.
Study Activities – Optional Exploratory Research Samples .................134
Appendix E.
Sample SES-CD Scoring .......................................................................135
Appendix F.
Crohn's Disease Activity Index (CDAI) ................................................136
Appendix G.
Standard Weights...................................................................................137
Appendix H.
Optional Intensive PK Subjects .............................................................140
Appendix I.
Clinical Criteria for Diagnosing Anaphylaxis .......................................141
Appendix J.
Tanner Stage 5 for Development ...........................................................143
Appendix K.
Protocol Amendment:  List of Changes.................................................146


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3.0
Introduction
Crohn's disease (CD) encompasses a spectrum of clinical and pathological processes 
manifested by focal asymmetric, transmural, and occasionally granulomatous 
inflammation that can affect any segment of the gastrointestinal tract and presents with 
symptoms of fatigue, prolonged diarrhea with or without gross bleeding, abdominal pain, 
weight loss, and fever.1  The disease can affect persons of any age, and its onset is most 
common in the second and third decades.  Females are affected slightly more than males, 
and the risk for disease is higher in some ethnic groups.2,3  The incidence of CD has 
steadily increased in developed countries over the past 3 decades4 with recent estimates 
varying from 12.7 and 20.2 cases/100,000, and a prevalence of 319 and 
322 cases/100,000 in North America and Europe, respectively.5  In Asia, the incidence of 
CD is estimated to be 0.5 to 1.0 cases per 100,000 persons, with a prevalence rate ranging 
from 3.6 to 7.7.6,7
The exact cause of CD is still unknown, but is hypothesized to be the result of a 
dysregulated immune system in the context of a genetically susceptible individual.  It is 
thought that a combination of a patient's genetics, microbiome, immune response, and the 
environment result in an excessive and abnormal immune response in the gut that results 
in pathology seen in CD.2
The aim of medical treatment in CD has been focused on controlling inflammation and 
reducing symptoms.8  In addition to improving symptoms, an emerging goal of therapy is 
to heal the gut mucosa.  Resolution of intestinal ulcers, also known as mucosal healing 
has been associated with positive clinical benefits, including higher rates of clinical 
remission, fewer hospitalizations, and fewer abdominal surgeries.9,10  However, 
improvement of the appearance of the intestinal mucosa may be more difficult to achieve 
than symptomatic improvement alone.
Conventional pharmaceutical therapies (e.g., corticosteroids, aminosalicylates, 
thiopurines, methotrexate) are limited, do not always completely abate the inflammatory 
process, and have significant adverse effects.1,11  The advent of anti-TNFα agents 


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(e.g., adalimumab) and integrin inhibitors (e.g., vedolizumab) have been shown to achieve 
clinical remission in patients refractory to conventional therapies.9-13
Despite the benefits of available biologic therapies, many patients do not respond to initial 
treatment (primary loss of response) or lose treatment over time (secondary loss of 
response).  Regarding anti-TNF agents, approximately 40% of patients will experience 
primary non-response and secondary non-response occurs in 38% of patients at 6 months 
and 50% of patients at 1 year.12,14-17  Additionally, some patients are not candidates for 
available biologic therapies.  Therefore new therapeutic options are required in order to 
continue to improve the outcome of patients with CD.
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
This study is designed to evaluate the efficacy and safety of two risankizumab induction 
doses versus placebo in subjects with moderately to severely active CD.  The primary 
differences between Study M16-006 and the prior Phase 2 study of risankizumab in CD is 
that this study will test a higher dosing of 1200 mg.  Additionally, the endpoints in this 
study are different to reflect the changing regulatory requirements for pivotal 
registrational studies for new agents for the treatment of CD. 
3.2
Benefits and Risks
Data suggest that altered immune regulation at the epithelial barrier leads to an 
overproduction of inflammatory cytokines, tissue destruction, and aberrant tissue repair in 
CD.  Among the cytokines implicated in CD pathogenesis, data at the genetic, human 


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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 CD.  The data observed in the Phase 2 study, suggest that risankizumab 
will alleviate signs and symptoms of active CD and reduce mucosal inflammation.  
Participation in this study may help to generate future benefit for subjects with CD.
Though there are no serious adverse drug reactions known to be associated with 
risankizumab therapy, risks of participating in this study include risk of infection and risks 
related to the study specific procedures of blood sampling, infusion and injection of study 
drug, and colonoscopy with biopsy.
Blood sampling, intravenous (IV) infusions and subcutaneous (SC) injections can cause 
local bruising, inflammation, and pain.  Colonoscopy and biopsy, although generally well 
tolerated, can be associated with diarrhea, abdominal pain, and in more severe cases, 
perforation, bleeding, effects from anaesthetic 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.
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 
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 


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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.  At the timing of this amendment, the DMC has provided recommendation that 
the study may continue without modification and allowed enrollment to begin for 16 -
17 year-olds. 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-
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.


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The benefit-risk profile is considered appropriate for an experimental therapy at this stage 
of clinical development.
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study have been re-evaluated.  Based on the limited information to 
date, no additional risk to study participants is anticipated with the use of risankizumab.
4.0
Study Objective
The objective of Study M16-006 is to evaluate the efficacy and safety of risankizumab 
versus placebo during induction therapy in subjects with moderately to severely active 
CD.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
The study was designed to enroll approximately 855 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.  In addition to the 
855 subjects, up to 85 subjects with a lower SES-CD, defined as an eligibility SES-CD of 
≥ 3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for isolated ileal disease will 
be enrolled in order to inform treatment effect in this patient population, but these subjects 
will not be included in the primary ITT population for efficacy analysis.
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy and safety of risankizumab as an induction therapy in 
subjects with moderately to severely active CD, defined as:
1.
average daily stool frequency (SF) ≥ 4 (when calculating SF, only the number of 
liquid or very soft stools should be recorded) and/or average daily abdominal pain 
(AP) score ≥ 2; plus 


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2.
endoscopic evidence of mucosal inflammation as measured by the Simple 
Endoscopic Score for CD (SES CD). All eligible scores exclude the presence of 
narrowing component and are confirmed by a central reader. Endoscopic activity 
is defined as SES-CD of ≥ 3.  
The number of subjects enrolled with a SES-CD of ≥ 3 to < 6 for ileocolonic or colonic 
disease or SES-CD of 3 for isolated ileal disease will be no more than 85 subjects.  
Once cap of no more than 85 subjects is reached, enrollment criterion will be an eligibility 
SES-CD of ≥ 6 for ileocolonic or colonic disease, or eligibility SES-CD of ≥ 4 for isolated 
ileal disease.
All endoscopies will be centrally read to document eligibility and for assessment at the 
time points indicated in Appendix C.  
The study will enroll both subjects who have had an inadequate response (IR) to prior 
biologic therapy (bio-IR) and subjects who have not (non-bio-IR).  
The bio-IR population is defined as subjects with documented intolerance or inadequate 
response to one or more of the approved anti-TNF or anti-integrin biologics for CD 
(infliximab, adalimumab, certolizumab, vedolizumab, ustekinumab and/or natalizumab).  
The bio-IR population will be approximately 540 subjects.  
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 in the past but stopped therapy based on reasons other than inadequate 
response or intolerance (e.g., change in reimbursement coverage, well-controlled disease).  
The non-bio IR population will be approximately 315 subjects.


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The percent of subjects with exposure, including intolerance or inadequate response, to 
ustekinumab will be no more than 20%.
The study duration may be up to 49 weeks, including a Screening period of up to 35 days, 
a 12-week induction period, 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 12, 16 and 20 and 
evaluation for clinical response at Week 24.
At the study visit indicated in Appendix C, all subjects will be provided with a subject 
diary where they will record CD related symptoms throughout the study.  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.  All endoscopies will be 
evaluated using SES-CD and will be confirmed by a central reader.  Biopsy to confirm 
diagnosis (during Screening) or to rule out dysplasia/malignancy may be performed 
during the same time points as the endoscopy.  Optional exploratory research samples 
may be taken during the study.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled into the study and randomized in a 2:2:1 ratio as shown in Figure 1.  At the 
timing of this amendment, the DMC has provided recommendation that the study may 
continue without modification and allowed enrollment to begin for 16 - 17 year-olds.   


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Figure 1.
Study M16-006 Study Schematic
a.
12-Week Induction Period
b. Induction Period 2
DC = discontinued; IR = subjects with inadequate clinical response to induction; IV = intravenous; R = subjects with 
clinical response; RR = re-randomize


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Screening Period
Within 35 days prior to the Baseline visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and 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.  The Screening period (35 days ± 7 days is 
granted around all study visits) may be extended as necessary after consultation with the 
AbbVie Therapeutic Area Medical Director (TA MD) for subjects who require initiation 
of prophylactic anti-TB therapy, or in case of external circumstances (e.g., due to the 
delay of availability of screening test results).
Laboratory values that are exclusionary can be re-tested once during the screening period 
upon discussion and clearance with TA MD. 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 SF, average daily AP, and CDAI calculated 
and meeting eligibility criteria before randomization at Baseline.
12-Week Induction Period
At the Baseline visit, subjects who meet all the inclusion criteria and none of the 
exclusion criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the 
study and randomized to the double-blind induction period where they will receive either 
risankizumab 1200 mg IV, risankizumab 600 mg IV, or placebo, given at Baseline and 


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Weeks 4 and 8.  The randomization at Baseline will be stratified by number of prior 
biologics failed (0, 1, > 1), steroid use at Baseline (yes, no), and Baseline SES-CD 
(original, alternative).
During this period of the study, subjects will visit the study site at Weeks 4, 8 and 12/PD.  
Subjects who do not achieve clinical response at Week 12 and choose to continue in the 
study will have additional visits at Weeks 16, 20 and 24 for blinded Induction Period 2 
with risankizumab.  A ± 7-day window is permitted around scheduled study visits.  An 
effort will be made to bring subjects back to their original scheduled visit (calculated from 
Baseline) if they are out of the visit window.
At the Week 12/PD visit, all subjects will undergo an endoscopy for evaluation of 
mucosal inflammation.  It is expected that all subjects who remain in the study through at 
least Week 8 will have a Week 12/PD endoscopy.  All subjects achieving clinical 
response, defined as ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in 
average daily AP score (both not worse than Baseline) at Week 12 may be eligible to 
enter Study M16-000.  Subjects are not eligible to enter Study M16-000 until endoscopy 
has been completed (local reader results will be used for stratification for 
Study M16-000).  
All subjects who do not achieve clinical response at Week 12 will be able to receive 
blinded risankizumab in Induction Period 2, as specified below.  Subjects are not eligible 
to receive blinded Induction Period 2 therapy until endoscopy has been completed.  
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.
Subjects who received risankizumab induction treatment will be randomized 1:1:1 to:
●
Group 1:  1200 mg IV risankizumab


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●
Group 2:  360 mg SC risankizumab
●
Group 3:  180 mg SC risankizumab
Subjects who received placebo induction treatment will receive:
●
Group 4:  1200 mg IV risankizumab
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 participated in the blinded Induction Period 2 will be 
reassessed and undergo a third endoscopy for evaluation of mucosal inflammation.  
Subjects who achieve clinical response at Week 24 may be eligible to enter 
Study M16-000.  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 
participate in the blinded 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 and/or 
ongoing AEs.
Concomitant aminosalicylates, corticosteroids, immunomodulators (azathioprine 
[AZA], 6-mercaptopurine [6-MP], methotrexate [MTX]), and/or CD-related 
antibiotics
Subjects taking aminosalicylates, immunomodulators, and/or CD-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 
CD-related antibiotics during the study is prohibited.  Decreasing doses of 
aminosalicylates, immunomodulators, and/or CD-related antibiotics is prohibited during 
the study, except in the event of moderate-to-severe treatment related toxicities and after 
discussion with the AbbVie Therapeutic Area Medical Director (TA MD).  CD-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.


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Concomitant Corticosteroids
Subjects taking corticosteroids at Baseline must continue their concomitant treatment at 
the Baseline dose for the duration of the 12-week induction period.  Initiation and/or 
increasing doses of systemic and/or CD related corticosteroids during the entire study is 
prohibited.  Decreasing doses of corticosteroids is prohibited during the 12-week 
induction period, except in the event of moderate-to-severe treatment related toxicities 
and after discussion with the AbbVie Therapeutic Area Medical Director (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.
Follow-Up Period/Premature Discontinuation (PD)
Subjects 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 M16-000 will have a follow-up call 140 days from the last 
dose of study drug to obtain information on any new or ongoing AEs.
Re-Screen
Subjects 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.  
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 


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re-screening provided the conditions noted in Section 5.3.1.1 are met and no more than 
90 days have passed since the collection date of the testing.  
If a subject is being rescreened within 14 days (≤ 14 days have passed) from the collection 
date of the previous screening testing, it is not required to repeat Screening testing for 
chemistry/hematology, urinalysis, serum pregnancy, and C. difficile provided that the
subject's health status has not changed to warrant a repeat test.  In this case, all Baseline 
testing should be performed at the Baseline visit. 
If rescreening occurs more than 14 days (> 14 days have passed) from the collection date 
of the previous screening testing then new samples (chemistry/hematology, urinalysis, 
serum pregnancy, and C. difficile) should be collected during Rescreening.  In this case, 
chemistry/hematology, urinalysis do not need to be repeated at the Baseline visit if 
Baseline occurs within 14 days (≤ 14 days) from the date of rescreening testing provided 
that the subject's health status has not changed to warrant a repeat test.  
All subjects need to have their average daily SF, average daily AP, and CDAI calculated 
in order to verify eligibility criteria before randomization at Baseline.
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.  Sites may contact the AbbVie TA MD if there are questions on if subjects 
should or should not be re-screened.
5.2
Selection of Study Population
It is anticipated that approximately 855 subjects with active moderate to severe CD will 
be enrolled at approximately 400 sites worldwide.  Both non-bio-IR and bio-IR subjects 
will be included.  The bio-IR population will be a minimum of approximately 
540 subjects and the non-bio-IR population will be a minimum of approximately 
315 subjects.


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A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria and none of the exclusion criteria specified in this protocol.
5.2.1
Inclusion Criteria
1.
Male or female aged ≥ 18 to ≤ 80 years, or minimum age of adult consent 
according to local regulations, at the Baseline Visit.  Where locally permissible, 
subjects 16 to < 18 years of age who meet the definition of Tanner stage 5 for 
development (refer to Appendix J) at the Baseline Visit (sites will be notified when 
adolescents may enroll).
2.
Confirmed diagnosis of CD for at least 3 months prior to Baseline.  Appropriate 
documentation of biopsy results consistent with the diagnosis of CD, in the 
assessment of the Investigator, must be available.
3.
Crohn's disease activity index (CDAI) score 220 – 450 at Baseline.
4.
Endoscopic evidence of mucosal inflammation as documented by the SES-CD of 
≥3. All eligible scores exclude the presence of narrowing component and are 
confirmed by a central reader. (Once cap of no more than 85 subjects is reached, 
enrollment criterion will be an SES-CD of ≥ 6 for ileocolonic or colonic disease or 
SES-CD of ≥ 4 for isolated ileal disease.)
5.
Average daily SF ≥ 4 and/or average daily AP score ≥ 2 at Baseline. 
6.
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 
(intolerance includes patients with a known TPMT genetic mutation or low 
activity).
●
Inadequate response is defined as outlined below:
○
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, 
balsalazide):


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●
Signs and symptoms of persistently active disease, in the opinion of the 
Investigator, during a current or prior course of at least 4 weeks of 
treatment with 2.4 g/day mesalamine, 4 g/day sulfasalazine, 1 g/day 
olsalazine, or 6.75 g/day balsalazide, 
○
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, 
Hong Kong, 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, 
Hong Kong, 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
○
Biologic therapies for CD: 
●
Signs and symptoms of persistently (in the opinion of the Investigator) 
active disease despite a history of one or more of the following:
○
At least one 6-week induction regimen of infliximab (≥ 5 mg/kg 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 certolizumab pegol 
(400 mg SC at Weeks 0, 2, and 4),
○
At least one 6-week induction regimen of vedolizumab (300 mg IV 
at Weeks 0, 2, and 6), 
○
At least one 12-week induction regimen of natalizumab (300 mg IV 
every 4 weeks)
○
At least one 8-week induction regimen of ustekinumab [260 mg 
(≤55 kg) or 390 mg (> 55 to ≤ 85 kg) or 520 mg (> 85 kg) IV, 
followed by 90 mg SC at Week 8] (Once cap of no more than 20% 
ustekinumab exposed subjects is reached, subjects with prior 
ustekinumab exposure will not be allowed to enroll.)  
●
Recurrence of symptoms during scheduled maintenance dosing 
following prior clinical benefit of the above biologics
●
Note:  Subjects who discontinued biologics 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
7.
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.
8.
Subject must be able and willing to give written informed consent and to comply 
with the requirements of this study protocol.  In Japan, if the subject is < 20 years 
old, a subject's parent or legal guardian must be willing to give written informed 
consent.
Rationale for Inclusion Criteria
1 – 6
To select the adequate subject population with a disease status 
representative of the target population for evaluation
7
The impact of risankizumab on pregnancy and reproduction is unknown 
8
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
Concomitant Medications and Treatments
2.
Subject on CD-related antibiotics who has not been on stable doses 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


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●
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 current 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/intramuscular anti-infectives (non-CD-related) within 14 days prior to the 
Baseline visit.  This does not apply to TB prophylaxis.
7.
Subject who received exclusive enteral nutrition or any parenteral nutrition within 
35 days prior to Baseline.
8.
Subject who received any live bacterial or viral vaccination within 30 days 
(8 weeks for Japan) prior to Screening or during the Screening Period.
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:  infliximab, adalimumab, certolizumab, vedolizumab, 
natalizumab within 8 weeks prior to Baseline or ustekinumab within 12 weeks 
prior to Baseline, or 
Note:  If there is proper documentation of an undetectable drug level measured 
by a commercially available assay for any of the approved biologics above, 
there is no minimum washout prior to Baseline.
●
any investigational biologic or other agent or procedure within 35 days or 
5 half-lives prior to Baseline, whichever is longer.


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12.
Subject with prior exposure to p19 inhibitors (e.g., risankizumab)
13.
Subject has been taking combination of two or more of the following:  oral 
budesonide, or 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, other than required for 
endoscopy, within 14 days prior to endoscopy used for 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 of Baseline or any history of clinically significant drug, or 
alcohol abuse in the last 12 months.
CD Related
18.
Subject with currently known complications of CD such as:
●
abscess (abdominal or perianal),
●
symptomatic bowel strictures,
●
> 2 missing segments of the following 5 segments:  terminal ileum, right 
colon, transverse colon, sigmoid and left colon, and rectum
●
fulminant colitis,
●
toxic megacolon,
●
or any other manifestation that might require surgery while enrolled in the 
study.
19.
Subject with ostomy or ileoanal pouch.
20.
Subject diagnosed with short gut or short bowel syndrome.


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21.
Subject with surgical bowel resection within the past 3 months prior to Baseline, or 
a history of ≥ 3 bowel resections.
Safety
22.
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).
23.
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 or other intestinal pathogen during Screening, 
●
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 Bacillus 
Calmette-Guérin (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;
○
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with 
positive anti-HCV antibody (HCV Ab)


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24.
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.
25.
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.
26.
Subject with current or previous 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.
27.
Subject who has severe, progressive, or uncontrolled renal, hepatic, hematological, 
endocrine, disorder or symptoms thereof.
28.
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.
29.
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.
30.
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


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●
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 after 
discussion and clearance with the TA MD. 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
31.
No known active COVID-19 infection. Subject must not have signs/symptoms 
associated with COVID-19 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 viral clearance criteria:
●
Symptomatic subjects: At least 2 negative viral tests in a row completed 
locally, ≥ 24 hours apart after at least 10 days have passed since recovery, 
defined as resolution of fever without use of antipyretics and improvement in 
respiratory symptoms (e.g., cough, shortness of breath)
●
Asymptomatic subjects: At least 2 negative viral tests in a row completed 
locally, ≥ 24 hours apart after at least 10 days have passed since prior positive 
result (Note: subjects who develop symptoms will follow guidance above for 
symptomatic subjects)
Frequency or timing of COVID-19 testing and interval between testing for the 
above viral clearance criteria may be adjusted to account for epidemiological 
trends, updated information regarding infectivity and local/institutional guidelines.
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


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18 – 21
To avoid complications of CD that may compromise the evaluations of 
efficacy and safety
22 – 30
To ensure the safety of the subject and or others
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 continues 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. 
CD specific medications (including but not limited to corticosteroids, aminosalicylates, 
immunomodulators [AZA, 6-MP, or MTX], and CD-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 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).


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5.2.3.2
Concomitant Therapy
Subjects taking aminosalicylates, immunomodulators, and/or CD-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 CD-
related antibiotics during the study is prohibited.  Decreasing doses aminosalicylates, 
immunomodulators, and/or CD-related antibiotics is prohibited during the study, except in 
the event of moderate-to-severe treatment related toxicities and after discussion with the 
AbbVie TA MD.  CD-related antibiotics may be discontinued in the blinded Induction 
Period 2 at the discretion of the Investigator.
Note:  the duration of the study includes the Induction Period 2.
Concomitant Corticosteroids
Subjects taking corticosteroids at Baseline must continue their concomitant treatment at 
the Baseline dose for the duration of the 12-week induction period.  Initiation and/or 
increasing doses of systemic and/or CD related corticosteroids during the entire study is 
prohibited.  Decreasing doses of corticosteroids is prohibited during the 12-week 
induction period, 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.
Setons are authorized as concomitant therapy in subjects with perianal fistulas and should 
be documented in the eCRF under concomitant medications.
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, the AbbVie TA MD 
should be contacted regarding possible permitted pre-medication with diphenhydramine 
hydrochloride and acetaminophen (or equivalents).  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®)
○
Vedolizumab (Entyvio®);


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●
Investigational agents (e.g., tofacitinib, 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
●
Cyclosporine, tacrolimus, or mycophenolate mofetil.
●
Concomitant cannabis use either recreational or for medical reasons.
●
Rectal therapy with any therapeutic enemas or suppositories, with the 
exception of those required for endoscopy, is prohibited during the study.
●
Apheresis (e.g., Adacolumn apheresis).
●
Exclusive enteral nutrition or any parenteral nutrition.
The AbbVie TA MD identified in Section 6.1.5 should be contacted if there are any 
questions regarding prohibited therapy.
5.2.4
Contraception Recommendations 
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.


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●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an Follicle-Stimulating Hormone (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, prior to 
Baseline 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, (must start at least 1 month prior to study.
○
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, (must start at least 1 month prior to 
study).
○
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).
○
Vasectomized sexual partner(s) (the vasectomized partner should have 
received medical assessment of the surgical success and is the sole sexual 
partner of 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/Validation Studies 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/validation studies (discussed in 
Section 5.3.1.2 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.  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/validation 
studies.  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, 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 CD-onset date, history of CD 
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 biologic, corticosteroid, immunomodulators (i.e., AZA, 6-MP, 
MTX), CD-related antibiotics, aminosalicylate or any other physician prescribed therapy 
for CD 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 active TB (during 
Screening) or 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.


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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.  Physical 
examinations at all other visits (including unscheduled visits) are symptom based and 
should include the assessment of EIMs as part of calculating the Crohn's disease activity 
index (CDAI).  The number of cutaneous fistulas should be recorded, including the 
number of fistulas draining upon gentle compression.  Fistulas will be classified as 
abdominal or perianal/anal.  Physical exam abnormalities noted by the Investigator at 
Baseline (including fistulas and fissures) will be recorded in the subject's medical history.  
Abnormalities noted after the Baseline visit will be evaluated and documented by the 
Investigator as to whether they are AEs.
Additionally, physical examination findings that are related to or part of each subject's 
medical history will be captured on the appropriate medical history eCRFs.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate, respiratory rate, and body temperature will be obtained at each visit.  Blood pressure, 
pulse rate, and respiratory rate should be measured before blood draws are performed.
Height will be measured at the Screening visit only (with shoes off) for subjects 
≥18 years of age.  Height will be re-measured at Week 12 and Week 24 (if applicable) for 
subjects < 18 years of age at Baseline.  Body weight will be measured at all scheduled 
visits, as specified in Appendix C.  All measurements will be recorded in metric units 
where applicable.


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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.  
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 Mycobacteria 
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.  IGRA 
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.  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 
active TB is diagnosed, the subject may not enroll in the study.  If presence of latent 
tuberculosis is established, then tuberculosis prophylaxis should be initiated and 
maintained according to local country guidelines.  It is also necessary to report the latent 
TB or positive TB testing in the source documents and eCRFs.


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●
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 
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."  
●
If PPD and/or the QuantiFERON®-TB Gold test (or IGRA equivalent) is 
positive, or if there is a repeat indeterminate QuantiFERON®-TB Gold test (or 
IGRA equivalent) upon retesting, subjects may continue in the study if further 
work up (according to local practice/guidelines) establishes conclusively that 
the subject has no evidence of active tuberculosis.  
●
If presence of latent tuberculosis is established, TB prophylaxis/treatment 
should be initiated and maintained according to local country guidelines. 
●
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, 


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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.
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 (CDAI, IBDQ, etc.) are obtained and before study drug administration 
during a visit.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  All abnormal laboratory tests that are considered clinically significant by 
the Investigator will be followed to a satisfactory resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing and shipping of these samples.
For serum chemistry tests and some exploratory biomarker 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.


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If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  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
Coagulation:
INRc
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)d
HBs Ag
HBs Ab
HBc Ab
HBV DNA PCR reflex only
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
Histaminee
Biomarkers:
High-Sensitivity C-Reactive Protein 
(hs-CRP)
Optional Biomarkers:
Stool Samples:
Blood, tissue and stool will be collected 
for optional exploratory 
research/validation studiesa
C. difficile toxin
Fecal calprotectin (FCP)
PK/Immunogenicity:
Serum risankizumabe
Serum anti-drug antibodies 
(ADA)e
Serum neutralizing antibodies 
(nAb)e
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 show 
leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.
c.
INR test only drawn if ALT or AST > 3 × ULN (upper limit of normal) and Total Bilirubin ≤ 2 × ULN (Refer to 
Section 5.4.1, for additional information).
d.
Only done at screening and calculated by the central laboratory.
e.
To be done with the occurrence of a suspected anaphylactic reaction (an additional sample of tryptase to be 
collected if possible at least 2 weeks post-reaction or at the next study visit); for ADA these samples are collected 
in addition to those specified in Appendix C.


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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 only:  for subjects with HBs Ab (+) and/or HBc Ab (+) at Screening, the HBV-
DNA PCR test should be performed as outlined in Appendix C.  In cases where the 
recurrence of HBV-DNA is observed, the subject should be discontinued from the study 
drug.  Retesting according to Appendix C is not necessary with subjects who have a 
history of HBV vaccine and are HBs Ab (+).
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 a 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 


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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, 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.
●
Plasma histamine: optimally, within 5 to 15 minutes of the onset of 
symptoms, and no later than 1 hour.
Stool Samples Collected:
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.  All stool samples should be collected before any bowel preparation for 
endoscopy is started and returned to the site per the instructions provided outside of this 
protocol.


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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.
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:


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●
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, 
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.  


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Blood draws should be performed, as much as possible, after all efficacy assessments, 
questionnaires (CDAI, IBDQ, etc.), and vital sign determinations are obtained and before 
study drug administration during a visit.  In order to maintain the study blind, local 
laboratory testing for hs-CRP for routine subject monitoring should not be performed.
Crohn's Disease Activity Index (CDAI) 
Average daily SF, average daily AP score, and well-being will be calculated from the 
subject diary.  During screening subjects will be instructed on how to calculate the 
number of very soft and liquid stools, including a visual depiction.  Physical exam and 
appropriate laboratory values will be calculated at all study visits beginning at Baseline.  
The Screening period will be a minimum of 7 days to calculate the Baseline scores.
The CDAI scores must be calculated using a central laboratory hematocrit (Hct) value 
from the same visit for all visits, except Baseline, where the most recent Screening Hct 
value will be used.  The final CDAI for all other visits will be calculated once the 
hematocrit value is received from the central lab.  If the Hct is missing due to technical 
issues (e.g., lost sample, clotted sample, etc.), the Hct value from the preceding visit may 
be used.
Instructions to calculate CDAI
●
To answer questions one (1) through three (3), entries from the 7 days prior 
to the visit should be used as recorded by the subject from the diary.
●
Diary entries should not be included in the 7 days evaluated prior to the visit 
if:  (1) the day the subject received medication for bowel preparation prior to 
endoscopy, (2) the day the subject underwent an endoscopy, and (3) 2 days 
following the endoscopy.  Diary entries, up to 14 days prior to the visit, will be 
used accordingly in order to provide the most recent data for 7 days prior to the 
respective study visit.  The 7 days do not need to be consecutive.
●
In question four (4), for the section regarding presence of anal fistulas and 
other fistulas, all fistulas detectable on physical examination (draining and 


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non-draining) should be captured on the CDAI and calculated into the CDAI 
score.
●
And the evaluation for fever should include all the days that are taken into 
account for the calculation of the CDAI.
●
When completing question five (5) ("Taking
Lomotil/Imodium/Loperamide/opiates for diarrhea, 0 = no, 1 = yes") on the 
CDAI, "no" should be answered if a subject is taking an opiate(s) solely for 
pain.  The use of these medications takes into account only the day of the 
scheduled visit and is only assessing their use as anti-diarrheals.
●
For question seven (7), hematocrit results from central laboratory will be used 
for the CDAI calculation.  If the hematocrit value contains more than 
one decimal point, the rounding will be allowed to the tenths decimal (e.g., Hct 
value 33.44 will be captured as 33.4, Hct value of 33.45 will be captured as 
33.5).  The Hct values either prior to completing the calculation or at the 
subtotal box 7 of the CDAI should not be rounded to a whole number.
●
For question eight (8), the height obtained at Screening should be used when 
selecting the standard weight in Appendix G, and this standard weight should 
be used for calculating every CDAI throughout subject participation in the 
study.
●
Standard height is calculated by using the height obtained at Screening 
(without shoes) adding one inch or 2.5 cm.  For subjects < 18 years of age at 
Baseline, height will be re-measured at Week 12 and Week 24 (if applicable) 
and standard height should be recalculated.
●
If the body weight obtained at the time of assessment is not captured in 
kilograms (kg), then when converting into kg, rounding should occur using the 
second digit after the decimal (also known as the hundredth place) where if the 
number is 0 – 4, then keep the first digit after the decimal (also known as the 
tenth place) unchanged.  If the second digit after the decimal is 5 – 9, then 
round up the first digit after the decimal (e.g., 90.246 would be captured as 
90.2 and 97.687 would be captured as 97.7).
●
The subtotal of box 8 should not be rounded to a whole number.
The calculation of the CDAI score is in Appendix F.


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Endoscopy
An endoscopy will be performed on the following visits:
●
During Screening*
●
Week 12/PD
●
Week 24 
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 Weeks 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:
1.
Biopsy confirmation of the diagnosis is available according to section "Biopsy 
During Endoscopy" below, as applicable.
2.
The endoscopy took place within 45 days prior to Baseline visit.
3.
The endoscopy was recorded in a video format as the endoscopic eligibility will be 
determined by the central reviewers.  
All ileocolonoscopies will be performed and recorded at the site in a video format.  Sites 
should also perform the SES-CD assessment and record the findings on the SES-CD score 
sheet (Appendix E) and in the appropriate eCRF.  
All endoscopies will be reviewed by a central reviewer who is blinded.  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 for stratification for Study M16-000.


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There will be a window of ± 7 days to conduct the ileocolonoscopy.  This window may be 
extended as necessary after consultation with the AbbVie TA MD in case of external 
circumstances.
The endoscopies performed at the time points described above will be used to provide the 
endoscopy subscores to calculate the SES-CD.  All attempts should be made by the 
endoscopist to explore all segments of the colon and terminal ileum, including intubation 
of the terminal ileum, at every endoscopy visit.  The endoscopy subscores by segment will 
be noted in the subject's source documents and in the database but the central reviewer's 
endoscopy subscore will be used for the efficacy analyses.
Biopsy During Endoscopy
Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the 
assessment of the Investigator, must be available in order to confirm the subject's 
eligibility for the study.  If this documentation is not available a diagnostic biopsy from 
the most affected 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.  
If any biopsy sample(s) are obtained, it should also be recorded on the video.  
Any biopsy sample(s) will be collected from the respective bowel segment during the 
withdrawal of the endoscope and after sufficient recording for the central reader to 
calculate the SES-CD.
The signed pathology report will be monitored by the responsible 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.


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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 M16-000.  Subjects should also be dispensed the patient 
information card at Screening.
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.
●
Inflammatory Bowel Disease Questionnaire (IBDQ) 
●
Work Productivity and Impairment Questionnaire – CD (WPAI-CD) 
●
Crohn's Symptom Severity (CSS) 
●
Patient Global Impression of Change (PGIC)
●
Patient Global Impression of Severity (PGIS)
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
●
European Quality of Life 5 Dimensions (EQ-5D-5L)
●
36-Item Short Form Health Survey (SF-36)


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Due to the COVID-19 pandemic and any local restrictions, 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.  Also, the initial 20 subjects enrolled 
between the Phase 3 induction trials will be monitored on site for 2 hours after completion 
of each infusion.  Subjects should be observed after study drug administration until judged 
clinically stable by the study personnel.  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.
Study drug kits are assigned by the IRT following the subjects randomized treatment 
schedule.  (Refer to Section 5.5 for additional information).
During the Study Drug Dosing Period, a subject with confirmed (viral test positive) or 
suspected COVID-19 infection can only be dosed with study drug if the following 
COVID-19 viral clearance criteria are met: 
●
Symptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours apart 
after at least 10 days have passed since recovery, defined as resolution of fever 
without use of antipyretics and improvement in respiratory symptoms (e.g., 
cough, shortness of breath)
●
Asymptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours 
apart after at least 10 days have passed since prior positive result (note: 


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subjects who develop symptoms will follow guidance above for symptomatic 
subjects)
5.3.1.2
Collection and Handling of Optional Exploratory 
Research/Validation Studies Samples
Subjects will have the option to provide samples for exploratory research and validation 
studies.  Subjects may still participate in the study even if they decide not to participate in 
the optional exploratory research/validation.  The procedures for obtaining and 
documenting informed consent are discussed in Section 9.3.
Exploratory research can help to improve our understanding of how individuals respond 
to drugs and our ability to predict which patients would benefit from receiving specific 
therapies.  In addition, exploratory research may help to improve our understanding of 
how to diagnose and assess/monitor CD by assessing associations between disease 
characteristics, outcomes data and biomarkers of interests. 
Validation studies, including those related to the development of potential in vitro 
diagnostic tests, may be carried out retrospectively in order to assess associations between 
events of interest (i.e., efficacy and/or safety events) and candidate biomarkers.
AbbVie (or people or companies working with AbbVie) will store the biomarker 
exploratory research/validation studies samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
risankizumab (or drugs of this class) or this disease and related conditions continues, but 
for no longer than 20 years after study completion.
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.  The 
following samples will be collected according to Appendix D from each subject who 
consents to provide samples for exploratory research/validation studies:


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●
DNA samples for pharmacogenetic or epigenetic analyses
●
RNA samples for transcriptomic and/or epigenetic analyses
●
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 analyses.
Samples will be shipped to AbbVie or a designated laboratory for DNA/RNA extraction, 
if applicable, and/or analyses or long-term storage.  Instructions for the preparation and 
shipment of the samples will be provided in the laboratory manual.
5.3.2
Drug Concentration and Anti-Drug Antibody 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 appropriate eCRF.
For approximately 20 subjects who consent to participate in the Optional Intensive PK 
sampling, refer to Appendix H.  
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.


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5.3.2.3
Disposition of Samples
Frozen samples will be packed in dry ice (pellet form) sufficient to last 3 days during 
transport.  Samples will be shipped pursuant to 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. 
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
Endpoint definitions:
●
Clinical remission:  average daily SF ≤ 2.8 and not worse than Baseline AND 
average daily AP score ≤ 1 and not worse than Baseline
●
Enhanced clinical response:  ≥ 60% decrease in average daily SF and/or 
≥35% decrease in average daily AP score and both not worse than Baseline, 
and/or clinical remission
●
Clinical response:  ≥ 30% decrease in average daily SF and/or ≥ 30% 
decrease in average daily AP score and both not worse than Baseline
●
Endoscopic response:  decrease in SES-CD > 50% from Baseline (or for 
subjects with isolated ileal disease and a Baseline SES-CD of 4, at least a 
2 point reduction from Baseline), as scored by central reviewer


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●
Ulcer-free endoscopy:  SES-CD ulcerated surface subscore of 0 in subjects 
with SES-CD ulcerated surface subscore ≥ 1 at Baseline, as scored by a central 
reviewer
●
Endoscopic remission:  SES-CD ≤ 4 and at least a 2 point reduction versus 
baseline and no subscore greater than 1 in any individual variable, as scored by 
a central reviewer
●
CDAI clinical response:  reduction of CDAI ≥ 100 points from baseline
●
CDAI clinical remission:  CDAI < 150
5.3.3.1
Primary Variable
Co-Primary Endpoints:  
●
Proportion of subjects with clinical remission at Week 12  
●
Proportion of subjects with endoscopic response at Week 12
5.3.3.2
Secondary Variables
Ranked Secondary Endpoints:
1.
Proportion of subjects with CDAI clinical remission at Week 12
2.
Proportion of subjects with CDAI clinical response at Week 4 
3.
Proportion of subjects with clinical remission at Week 4 
4.
Proportion of subjects with CDAI clinical response at Week 12 
5.
Mean change from baseline of induction in FACIT fatigue at Week 12 
6.
Mean change from baseline of induction in IBDQ total score at Week 12 
7.
Proportion of subjects with enhanced clinical response and endoscopic response at 
Week 12 
8.
Proportion of subjects with endoscopic remission at Week 12
9.
Proportion of subjects with enhanced clinical response at Week 4


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10.
Proportion of subjects with ulcer-free endoscopy at Week 12
11.
Enhanced clinical response at Week 12
12.
Proportion of subjects with resolution of extra-intestinal manifestations (EIMs) at 
Week 12, in subjects with any EIMs at Baseline
13.
Proportion of subjects with CD-related hospitalization through Week 12
14.
Proportion of subjects without draining fistulas at Week 12 in subjects with 
draining fistulas at Baseline
5.3.3.3
Other Endpoints
Non-Ranked endpoints are:
●
Change from Baseline in IBDQ over time
●
Change from Baseline in individual IBDQ domain scores (bowel, emotional, 
social, systemic) over time
●
Change from Baseline individual IBDQ item under Bowel Symptom domain 
(for Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, and Q29) over time
●
Proportion of subjects with IBDQ remission (IBDQ > 170 points) over time 
●
Proportion of subjects with IBDQ response (increase in IBDQ > 16 points 
from Baseline) over time 
●
Change from Baseline in WPAI-CD over time
●
Change from Baseline in EQ-5D-5L over time
●
Change from Baseline in FACIT-Fatigue overtime 
●
Change from Baseline in Short Form-36 overtime
●
Change from Baseline in FCP over time
●
Change from Baseline in hs-CRP over time
●
Change from Baseline in average daily AP score over time
●
Change from Baseline in average daily SF over time
●
Proportion of subjects with clinical remission over time


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●
Proportion of subjects with enhanced clinical response over time
●
Proportion of subjects with clinical response over time
●
Change from Baseline in SES-CD at Week 12
●
Proportion of subjects with a SES-CD ulcerated surface subscore ≤ 1 in each 
segment at Week 12 in subjects with a SES-CD ulcerated surface subscore ≥ 2 
at Baseline
●
Change from baseline in PGIS over time 
●
PGIC over time
●
Proportion of subjects with endoscopic remission over time
●
Proportion of subjects with endoscopic response over time
●
Proportion of subjects with CD-related surgeries through Week 12
●
Proportion of subjects with any reduction in SES-CD at Week 12
●
Proportion of subjects with CDAI clinical remission over time
●
Proportion of subjects with CDAI clinical response over time
●
Change from Baseline in CDAI over time
●
Change from Baseline in CSS over time
5.3.4
Safety Variables
Safety analyses will be performed on safety set which includes all subjects who receive at 
least one dose of study drug.  Incidence of AEs, changes in vital signs, physical 
examination results, and clinical laboratory data will be assessed throughout the study. 
5.3.5
Pharmacokinetic Variables
Serum risankizumab concentrations will be determined during the treatment period and at 
the follow-up visit as outlined in Appendix C.  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.


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5.3.6
Optional Exploratory Research/Validation 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 
biomarker signatures.  These assessments may be explored in the context of CD 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.  In addition, samples from this study may be banked for future 
use.  Samples may then be used to validate putative biomarker signatures obtained from a 
prospective study, leading to the development of diagnostic tests.  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 AE, 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 AEs, which rule out 
continuation of the study drug, as determined by the Investigator in 
consultation with the AbbVie TA MD.
●
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 in the best interest of the subject not to enter 
Induction Period 2.


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●
Subjects who experience a severe systemic hypersensitivity infusion/injection 
reaction or anaphylaxis
●
The subject requests withdrawal from the study.
●
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 TA MD.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie TA 
MD.
●
The subject becomes pregnant while on study drug.
●
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 study, as determined by the 
Investigator, in consultation with the AbbVie TA MD.
●
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 PD 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 


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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 
drug 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 M16-000.
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.
For subjects who 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. 
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
Each dose of blinded study drug (1200 mg risankizumab, 600 mg risankizumab, or 
placebo) will be administered intravenously to the subject during 12-Week Induction 
Period.
Each dose of blinded study drug (1200 mg risankizumab, 360 mg risankizumab, or 
180 mg risankizumab) will be administered intravenously or subcutaneously in Induction 
Period 2.
If the 1200 mg dose is discontinued due to any reason, subjects will continue to enroll into 
the study and be randomized to either 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.
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, the AbbVie TA MD 
should be contacted regarding possible permitted pre-medication with diphenhydramine 
hydrochloride and acetaminophen (or equivalents).  Individual dosage, timing, and route 
of administration would be determined by the Investigator.  Any pre-medications 
administered must be recorded on the appropriate eCRF.
Subjects who do not achieve clinical response at Week 12 will be eligible for Induction 
Period 2 with blinded risankizumab.  Blinded risankizumab will be administered either 
intravenously at Weeks 12, 16, and 20 or subcutaneously at Weeks 12 and 20.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 2.


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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)
N/A
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)
N/A
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
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.  
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 the 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 


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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 any 
temperature excursion must be reported to the Sponsor immediately.  Sites are responsible 
to report 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
All subjects will be assigned a unique identification number by the IRT at the Screening 
visit and will keep the same unique subject identification number throughout the study.  
Subjects who meet the inclusion and none of the exclusion criteria defined in 
Section 5.2.1 and Section 5.2.2 will be centrally randomized in a 2:2:1 ratio to one of the 
three treatment groups at Baseline during the 12-Week Induction Period of the study.  The 
randomization will be stratified by number of prior biologics failed (0, 1, > 1), Baseline 
steroid use (yes, no), and Baseline SES-CD (original, alternative).  The IRT will assign a 
randomization number that will encode the subject's treatment group assignment 
according to the randomization schedule generated by the Statistics Department at 
AbbVie.
IRT will provide the appropriate medication kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Section 5.5.  
Returned study drug should not be re-dispensed to any subject.


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At Week 12, subjects who do not achieve clinical response 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. 
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 and unblinded 
CRA/monitor (as applicable)), as well as the Investigator, the 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.  


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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.
5.5.5.2
Data Monitoring Committee 
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 prepared outside of the protocol and approved by AbbVie 
and the DMC members before a subject is initiated 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 timing of this amendment, the DMC has provided recommendation that the study 
may continue without modification and allowed enrollment to begin for 16 - 17 year-olds.  
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.  
The DMC will review safety data at a minimum of 6-month intervals throughout the 
course of the study.  The DMC will determine if more frequent DMC meetings are 
required based on review of the accumulating safety data.  In addition, ad-hoc DMC 
meetings will be scheduled in the event of any significant safety concerns.  Based on these 
reviews, the DMC will make recommendations, as appropriate, regarding the conduct and 
management of the study.


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The CAC and AAC adjudicate 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.
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 (blinded or unblinded as applicable) will verify that study 
drug supplies are received intact, at the appropriate temperature, and in the correct 
amounts from the depot.  This will be accomplished by documenting the condition of the 
shipment, verifying the kit numbers in the package against the Proof of Receipt (POR) or 
similar document included with each drug shipment, and documenting this verification by 
signing and dating the POR or similar document and via direct reporting in IRT.  The 
original POR note or similar document 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 
date received, the lot number, kit number(s), date and number of vials and syringes 
dispensed and subject number.  For this study, unless otherwise prohibited locally, these 
records will be maintained electronically as part of the IRT system.
An overall accountability of the study drug will be performed by the site and 
reconciliation will be performed by the CRA/monitor (blinded or unblinded according to 
the monitoring plan) throughout the study and at the site close-out visit. After verification 


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of drug accountability, used study drug must be destroyed at the site according to local 
regulations governing biohazardous waste.  Destruction of used study supplies must be 
completed and documented in such a way that blinding is maintained for all blinded study 
personnel.  All unused supplies must be inventoried, accounted for and destroyed on site 
according to local procedures or regulation or returned to a destruction facility.  A copy of 
the, Return Consignment Form from IRT, in accordance with instructions provided by the 
monitor/CRA (blinded or unblinded according to the monitoring plan), will be included in 
the return shipments.
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.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Risankizumab is a selective IL-23 inhibitor that may provide improved clinical benefit to 
risk profile in CD patients.  The proposed study is a Phase 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 CD, who have had inadequate 
response or intolerance to aminosalicylates, oral locally acting corticosteroids, oral and/or 
IV systemic corticosteroids, immunomodulators, and/or biologic therapies.
The study consists of a 12 week induction period to evaluate the efficacy and safety of 
two different IV risankizumab doses (IV, 600 mg or 1200 mg, Q4w) versus placebo.  For 
subjects not in clinical response at Week 12, an optional blinded Induction Period 2 (IV, 
1200 mg, 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 or Induction Period 2 can 
enter Study M16-000 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 12-week placebo controlled study is necessary for registrational purposes.  
A comparative study utilizing placebo provides an unbiased assessment of the efficacy 
and safety profile of risankizumab.  To ensure all subjects are given the opportunity to 
receive potentially efficacious therapy, all subjects not responding after 12 weeks can 
participate in the blinded Induction Period 2 with risankizumab.
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 CD.  All clinical and laboratory procedures in this study are 
standard and generally accepted.  Central reading of endoscopy will increase study rigor 
and ensure enrollment of subjects with moderately to severely active CD.
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 CD who meet all of the inclusion criteria and none of the 
exclusion criteria are eligible for enrollment in this study.  The specific population chosen 
was based on the unmet medical need of those subjects with a history of inadequate 
response or intolerance to immunomodulators (AZA, 6-MP, or MTX), corticosteroids, 
and/or biologic therapies. 
5.6.4
Selection of Doses in the Study
AbbVie plans to evaluate two doses of risankizumab (600 mg and 1200 mg) via IV 
administration every 4 weeks (Q4w; Weeks 0, 4, 8) through induction (12-Week 
Induction Period) and an additional three doses of 1200 mg of risankizumab via IV 
administration (Q4w; Weeks 12, 16, 20) or two doses of 180 or 360 mg SC (Q8w, 
Weeks 12 and 20; Induction Period 2) for subjects who do not achieve clinical response at 
Week 12.  The selection of the doses in this study is informed by the analysis of the safety 
and efficacy data, as well as the exposure-response relationship of efficacy, of a Phase 2 


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study in subjects with CD (Study 1311.6) and the pharmacokinetic data from the 
completed studies in subjects with psoriasis (Studies 1311.1 and 1311.2).
Results from the placebo controlled Study 1311.6 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 with evaluation of 
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.  The evaluation of higher dose data (1200 mg IV Q4w) will facilitate a more robust 
characterization of the dose-response and exposure-response relationship for these 
efficacy endpoints.  Inclusion of 1200 mg IV dose 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 CD.  Furthermore, the 
projected steady state exposures for the 1200 mg IV risankizumab Q4w regimen in 
subjects with CD are covered by safety margins of ~1.6 and ~3.6 for Cmax and AUC0-28 days
respectively (relative to NOAEL identified in the 26 week GLP toxicology study).
Induction Period 2 will evaluate IV (1200 mg Q4w) or SC (180 mg or 360 mg Q8w) 
risankizumab.  The purpose of Induction Period 2 is to evaluate the efficacy and safety of 
re-induction of risankizumab versus starting maintenance dosing on clinical response.  
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.  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.  The results 
from the Phase 2 study suggest a potential for increased benefit with 360 mg SC 
administration for maintenance regimen.


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6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
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 an "Other" 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 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 eCRF.
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 any hepatic related AE 
●
Any 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 I 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 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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6.1.3.1
Lack of Efficacy or Worsening of Disease 
Events that are clearly consistent with progression of the underlying disease (CD) are 
considered an expected outcome for this study and will not be subject to expedited 
reporting. 
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 140 days 
from the last dose of study drug have elapsed will be collected, whether solicited or 
spontaneously reported by the subject.  In addition, serious adverse events and protocol-
related nonserious adverse events will be collected from the time the subject signed the 
study-specific informed consent.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 


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having access to the RAVE® system, or if RAVE® is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660
For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
Dept. R48S, Bldg. AP31-2
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:
100 Research Drive, Suite 3009
Worcester, MA 01605
Telephone Contact Information:
Office:
Mobile:
Email:
In emergency situations involving study subjects when the primary AbbVie 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 CD in Study 
Population
Certain events are anticipated to occur in the study population as known consequences of 
CD (e.g., as symptoms or due to disease progression) independent of drug exposure.  
These events are listed in Table 3.  These AEs, which should be captured on the 
appropriate eCRF, 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 CD population hence considered expected for 
reporting.


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Table 3.
Common Events Associated with CD
Fistulae
Abscesses
Stenoses/Obstruction
!
Anal fistula
!
Colovaginal fistula
!
Colovesical fistula
!
Enterocolonic fistula
!
Enterocutaneous fistula
!
Enterovaginal fistula
!
Female genital-digestive tract 
fistula
!
Ileal fistula
!
Ileorectal fistula
!
Ileovaginal fistula
!
Perineal fistula
!
Rectal fistula
!
Rectovaginal fistula
!
Anal abscess
!
Anorectal abscess
!
Rectal abscess
1.
Anal stenosis
2.
Ileal stenosis 
3.
Intestinal obstruction
4.
Small intestine obstruction
Others
!
Anal fissure
!
Worsening of Crohn's 
disease
!
Intestinal perforation
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.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
6.1.7
Cardiac Adjudication Committee
The independent external CAC will be adjudicating observed cardio- and cerebro-vascular 
events and will remain blinded to treatment allocation.  The events that are adjudicated 


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and the adjudication process will be detailed in the Cardiac Adjudication Committee 
Charter.  Dedicated eCRFs will be used for events of myocardial infarction-unstable 
angina, stroke-transient ischemic attack, and death.  In addition, the site may be contacted 
for additional source documentation for relevant events.
6.1.8
Anaphylaxis Adjudication Committee
The independent external AAC will be adjudicating observed potential anaphylactic 
events and will remain blinded to treatment allocation.  The events that are adjudicated 
and the adjudication process will be detailed in the Anaphylaxis 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 


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satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with AEs will be reported in the study summary.  All other 
complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
Investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal Investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified, 
including those that may be due to the COVID-19 pandemic) after a subject has been 
enrolled, the principal Investigator is responsible for notifying IEC/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.


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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objective of the statistical analyses is to evaluate the efficacy and safety of 
risankizumab versus placebo in subjects with moderately to severely active CD who had 
baseline eligibility SES-CD of ≥ 6 (≥ 4 for isolated ileal disease).
When all patients complete their Week 12/PD visit, the database will be locked and un-
blinded for the 12-week induction period.  The planned analysis for the 12-week induction 
period will be performed.  This is the only and final analysis for co-primary endpoints of 
the 12-week induction period.  When all the patients who enter the induction Period 2 
finish Week 24/PD visit, the database will be locked for the whole study and all the 
planned analyses for the induction Period 2 will be performed.
Complete, specific details of the statistical analyses will be described and fully 
documented in the study Statistical Analysis Plan (SAP).  The SAP will be finalized prior 
to the study database lock.
The impact of missing data due to COVID-19 will be monitored and appropriate
modifications to the analysis of primary and key secondary endpoints for handling such 
missing data will be reflected and incorporated in the final SAP.
8.1.1
Datasets for Analysis 
8.1.1.1
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set includes all randomized subjects who received at 
least one dose of study drug.  The primary population for efficacy analysis are the subjects 
in the intent-to-treat set who had baseline eligibility SES-CD of ≥ 6 (≥ 4 for isolated ileal 
disease).  The ITT subjects will be analyzed as randomized.


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8.1.1.2
Safety Analysis Set
The safety analysis set consists of all subjects who received at least one dose of the study 
drug.  The safety set will be analyzed as treated, according to treatment the subject 
actually received.  The safety set will be used for safety analysis.
8.1.2
Definition of Missing Data Imputation 
Missing data will be imputed using one or more of the following methods:
Non-Responder Imputation (NRI):  In NRI analyses, subjects who prematurely 
discontinue the study prior to efficacy assessment at Week 12 will be considered 
non-responders with respect to the efficacy endpoint. 
Observed Cases (OC):  The OC analysis will not impute values for missing evaluations, 
and thus a subject who does not have an evaluation on a scheduled visit will be excluded 
from the OC analysis for that visit.
8.1.3
Subject Disposition 
The number and percentage of subjects who are enrolled, randomized and received at 
least one dose of study drug, and the number of subjects who prematurely discontinued 
and the reason for premature discontinuation will be summarized by treatment group.  
Premature discontinuation of study drug will be summarized for each treatment group, as 
well as for all subjects combined, with frequencies and percentages overall and by reason 
for discontinuation for all randomized subjects who received at least one dose of study 
drug.  Subjects may have multiple reasons for prematurely discontinuing study drug, but 
will be counted no more than once for the total ("Any Reason").
8.1.4
Demographics and Baseline Characteristics
Demographics (where collection is allowed) and Baseline characteristics of the study 
subjects will be summarized using descriptive statistics.  Summary statistics for 
continuous variables will include the number of observations, mean, standard deviation, 


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median, and range for each treatment group.  For other categorical or discrete variables, 
frequencies and percentages will be computed in each category for each treatment group, 
as well as for all subjects combined.
8.1.5
Prior and Concomitant Medications
Prior therapy and medications will include all therapies and medications administered 
prior to the date of the first dose of study drug.  Prior therapy and medication will be 
summarized for all randomized subjects.  No statistical test will be performed.
Concomitant medications will be summarized for all randomized subjects.  Concomitant 
medications will be summarized using the World Health Organization Drug Dictionary 
with frequencies and percentages for each treatment group.  No statistical test will be 
performed. 
8.1.6
Efficacy Analysis
8.1.6.1
Primary Efficacy Variables
The co-primary endpoints are the proportion of subjects who achieve clinical remission at 
Week 12 and proportion of subjects with endoscopic response at Week 12.
The comparisons between each risankizumab dose versus placebo for the primary efficacy 
variable will be performed using the Cochran-Mantel-Haenszel (CMH) test adjusted by 
number of prior biologics failed (0, 1, > 1) and steroid use at Baseline (yes, no). A 
multiple testing procedure will be used to provide strong control of the type 1 error rate at 
alpha = 0.05 (2-sided) across analyses comparing each risankizumab dose level to placebo 
with respect to the co-primary endpoints, and ranked secondary endpoints. Specifically, 
testing will utilize a sequence of hypothesis testing for the co-primary endpoints followed 
by the ranked secondary endpoints, and will begin with testing each of the co-primary 
endpoints using α of 0.025 (2-sided) for each dose compared to placebo.  If both co-
primary endpoints achieve statistical significance within a dose level, continued testing 
will follow a pre-specified weight of α allocation between the single hypothesis within the 
family, as well as between the families of hypotheses across the doses. Details will be 


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provided in the Statistical Analysis Plan. A CMH based two-sided 95% confidence 
interval for the difference between treatment groups will be calculated. If average daily 
SF or average daily AP score or endoscopic data at Week 12 are missing, the NRI 
approach will be applied.  Subjects who discontinue prior to Week 12 for any reason will 
be considered as "not-achieved" for clinical remission and endoscopic response endpoints.
The analysis of co-primary efficacy endpoints will be performed in bio-IR and non-bio-IR 
population. Additional subgroup analyses will be outlined in the SAP.  Sensitivity 
analyses for missing data handling using MI, PMM and OC will be performed for co-
primary endpoints and details will be outlined in the SAP.
8.1.6.2
Secondary Efficacy Variables 
The secondary efficacy variables are divided into two groups.  The first group includes 
ranked secondary endpoints, which are ranked by clinical importance.  Statistical 
significance is assessed at the pre-specified alpha level (two-sided) in ranked endpoint 
order until the significant level exceeds the pre-specified alpha level.  No additional 
statistically significant treatment differences could be declared if the preceding ranked 
endpoint fails to achieve the pre-specified alpha level.  The second group includes all 
other additional secondary variables.  All analyses of secondary endpoints will be 
performed using the ITT analysis set. 
In general, continuous secondary efficacy variables will be analyzed using a Mixed-Effect 
Model Repeated Measure (MMRM) model including factors for treatment group, visit, 
visit by treatment interaction, and stratification variables, for the longitudinal continuous 
endpoints.  The MMRM analysis is considered primary for inferential purposes.  
Categorical secondary efficacy variables will be analyzed using the CMH test controlling 
for stratification variables.  Non-responder imputation for missing data will be used for 
categorical secondary endpoints. 
Analysis of Pattern Mixture Model (PMM) will be performed as sensitivity analyses for 
ranked secondary endpoints.


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8.1.7
Safety Analysis 
Safety analyses will be carried out using the safety analysis sets, which includes all 
subjects who receive at least one dose of study drug.  Incidence of AEs, including those 
related to study drug, changes in vital signs, physical examination results, and clinical 
laboratory values will be analyzed.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary.  Treatment-emergent AEs are defined as AEs that began or 
worsened in severity after initiation of study drug and within 140 days after the last dose 
of the study drug.  An overview of treatment-emergent AEs, including AEs leading to 
death and AEs leading to premature discontinuation (see details in the SAP), AEs by 
MedDRA preferred term and system organ class, AEs by maximum relationship to study 
drug, and AEs by maximum severity will be summarized by number and percentage.  
Continuous laboratory and vital sign parameters will be summarized for each treatment 
group by visit.  Treatment group differences between each of the risankizumab dosing 
groups and the placebo group for changes from Baseline may be analyzed using a one-
way Analysis of Variance (ANOVA).  Vital signs and laboratory data will be described by 
statistical characteristics and frequency of abnormal values.  In addition, shift tables and 
listings will be provided for abnormal values, whereby the normal range of the analyzing 
laboratory will be used. Analysis details will be specified in the SAP.
8.1.8
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 
variety of statistical predictive modeling algorithms.  Cut-points for individual biomarkers 


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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.21,22
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.  In addition, ADA incidence will be 
summarized by cohorts 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 non-
linear 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/F or Vss/F 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
The co-primary endpoints are the proportion of subjects with clinical remission at 
Week 12 and proportion of subjects with endoscopic response at Week 12.  


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Sample size calculation is based on the larger sample size needed to detect treatment 
difference for each of the co-primary endpoints.  Since historical data show slightly lower 
event rate and similar treatment difference versus placebo for the endoscopic response 
rate than the clinical remission rate at Week 12, clinical remission rates at Week 12 are 
used for power calculation.  A total of approximately 855 subjects will be randomized into 
two risankizumab treatment groups and the placebo group in a 2:2:1 ratio (342 subjects 
for risankizumab 600 mg dose group, 342 subjects for risankizumab 1200 mg dose group, 
and 171 subjects for placebo group).  Assuming the Week 12 clinical remission rate will 
be 27.8% for one of the risankizumab dose groups and 12% for the placebo group, a 
sample size of 342 subjects for each of the risankizumab dose groups and 171 for the 
placebo group will have 97% power to detect the treatment difference between the 
risankizumab dose groups and placebo in clinical remission rates at Week 12 using 
Fisher's exact test at alpha of 0.025 (two-sided).  Assuming the Week 12 endoscopic 
response rate will be 25.5% for one of the risankizumab dose groups and 8% for the 
placebo group, this sample size will have 99% power to detect the treatment difference 
between the risankizumab dose groups and placebo in endoscopic response rates at 
Week 12 using a Fisher's exact test at alpha of 0.025 (two-sided).
In addition, with sample size of approximately 540 bio-IR subjects, this study will have 
approximately 80% power for the bio-IR population to detect the treatment difference 
between one of the risankizumab dose groups and placebo in clinical remission rates at 
Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) for the bio-IR population, 
assuming the Week 12 clinical remission rate will be 24.2% for the risankizumab dose 
groups and 10% for the placebo group.  Similarly, with sample size of approximately 
315 non-bio-IR subjects, this study will have 72% power to detect the treatment 
difference between one of the risankizumab dose groups and placebo in clinical remission 
rates at Week 12 using Fisher's exact test at alpha of 0.025 (two-sided) for the non-bio-IR 
population, assuming the Week 12 clinical remission rate will be 35% for the 
risankizumab dose groups and 15% for the placebo group for non-bio-IR subjects.


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8.3
Randomization Methods
A total of approximately 855 subjects will be randomized into two risankizumab dose 
groups and the placebo group in a 2:2:1 ratio (342 subjects for risankizumab 600 mg dose 
group, 342 subjects for risankizumab 1200 mg dose group, and 171 subjects for placebo 
group).  Randomization will be stratified by number of prior biologics failed (0, 1, > 1), 
the steroid use at Baseline (yes, no), and Baseline SES-CD (original, alternative), where 
the stratum of "original" includes the patients with baseline SES-CD of ≥ 6 (or ≥ 4 for 
subjects with isolated ileal disease), and the stratum of "alternative" includes the patients 
with baseline SES-CD of ≥3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for 
isolated ileal disease.  
Subjects with clinical non-response to risankizumab at Week 12 will be re-randomized in 
a 1:1:1 ratio to 1200 mg IV dose group, 360 mg SC dose group, or 180 mg SC dose 
group.  Subjects with clinical non-response to placebo at Week 12 will blindly receive 
1200 mg risankizumab IV dose. 
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.
Following local regulation, substantial amendments may also be reviewed and approved 
by the national competent authority.


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Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP and all other applicable regulatory requirements.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies, as required by 
local regulations.  During the conduct of the study, the Investigator should promptly 
provide written reports (e.g., ICH Expedited Reports, and any additional reports required 
by local regulations) to the IEC/IRB of any changes that affect the conduct of the study 
and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
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 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.


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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.
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.
The optional samples for intensive PK analyses will only be collected if the subject has 
voluntarily signed and dated the intensive PK section of the main ICF, approved by an 
IRB/IEC, after the nature of the testing has been explained and the subject has had an 
opportunity to ask questions.  
Samples for exploratory research/validation studies will only be collected if the subject 
has voluntarily signed and dated the separate written consent for exploratory 
research/validation studies, approved by an IRB/IEC, after the nature of the testing has 
been explained and the subject has had an opportunity to ask questions.  The separate 
written consent must be signed before the exploratory research/validation studies samples 
are collected and testing is performed.  If the subject does not consent to the exploratory 
research/validation studies, it will not impact the subject's participation in the study.
For adolescent subjects, the investigator or his/her representative will explain the nature of 
the study 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 


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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.
Genetic and non-genetic biomarker analysis will only be performed if the subject's 
parent/legal guardian has voluntarily signed and dated a separate genetic and non-genetic 
biomarker 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 genetic and non-genetic biomarker informed consent must 
be signed before the genetic and non-genetic biomarker testing is performed.  If the 
subject's parent/legal guardian does not consent to the genetic and non-genetic biomarker 
testing, 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.


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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.
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, ECGs, 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.  IRT may also be the source for drug accountability.  Data collected 
during this study must be recorded on the appropriate source documents.  The Investigator 
Awareness Date (SAE eCRF) may serve as the source for this data point.  This AE data 
point required for eCRF completion can be entered directly in the eCRF.


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The Investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
10.2
Case Report Forms
Electronic case report forms (eCRF) 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 eCRF data for this study are 
being collected with an EDC system called Rave® provided by the technology vendor 
Medidata Solutions Incorporated, NY, USA.  The EDC system and the study-specific 
eCRFs will comply with Title 21 CFR Part 11.  The documentation related to the 
validation of the EDC system is available through the vendor, Medidata, while the 
validation of the study-specific eCRFs will be conducted by AbbVie and will be 
maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
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.


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Medidata will provide access to the EDC system for the duration of the study 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 CRF Health of Plymouth Meeting, PA, USA.  The ePRO system is 
in compliance with Title 21 CFR Part 11.  The documentation related to the system 
validation of the ePRO system is available through the vendor, CRF Health, while the 
user acceptance testing of the study specific PRO design will be conducted and 
maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source, and maintained and 
managed by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study to the site Investigator, 
as well as delegated personnel.  Such access will be removed from Investigator sites 
following the receipt of the study archive.  Data from the ePRO system will be archived 
on appropriate data media (CD-ROM, etc.) and provided to the Investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the Investigator to make 
paper print-outs from that media.
The ePRO data will be collected by the following methods:


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Diary Based
The ePRO data (number of liquid or very soft stools, use of medications used for 
endoscopy preparation, abdominal pain, and general well-being) will be collected 
electronically via a handheld device into which the subject will record the required pieces 
of information on a daily basis.  The electronic device will be programmed to allow data 
entry once per day.  All data entered on the device will be immediately stored to the 
device itself and manually/automatically uploaded to a central server administrated by 
CRF Health.  The investigational site staff will be able to access all uploaded subject 
entered data via a password protected website, up until the generation, receipt and 
confirmation of the study archive.
Tablet Based
The PROs listed below will be collected electronically via a Tablet device into which the 
subject will directly enter the required pieces of information while at the site.  The 
electronic device will be programmed to allow data entry for only the visits specified in 
the protocol and will not allow for subjects to complete more than one of the same 
assessment 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 CRF Health.  The investigational site staff will be able to access all uploaded subject 
entered data via a password protected website, up until the generation, receipt and 
confirmation of the study archive.
●
CSS
●
PGIC
●
PGIS
●
EQ-5D-5L
●
FACIT-F
●
IBDQ 
●
SF-36
●
WPAI-CD


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11.0
Data Quality Assurance
To ensure data integrity and subject safety, a study monitor will, throughout the study, 
verify that all subjects signed agreement of informed consent prior to any study-specific 
procedures being conducted.  The study monitor will confirm that the Investigator is 
conducting the study in compliance with the protocol, GCP and applicable regulations, 
and verify that the information reported in the eCRF is complete, accurate, and supported 
by information in source documents.
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
All information concerning 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 
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.


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


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


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for 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 of the Efficacy and Safety of Risankizumab in 
Subjects with Moderately to Severely Active Crohn's Disease
Protocol Date:
28 July 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Hanauer SB, Sandborn W; Practice Parameters Committee of the American 
College of Gastroenterology.  Management of Crohn's disease in adults.  Am J 
Gastroenterol.  2001;96(3):635-43.
2.
Loftus EV Jr.  Clinical epidemiology of inflammatory bowel disease:  incidence, 
prevalence, and environmental influences.  Gastroenterology.  
2004;126(6):1504-17. 
3.
Probert CS, Jayanthi V, Rampton DS, et al.  Epidemiology of inflammatory bowel 
disease in different ethnic and religious groups:  limitations and aetiological clues.  
Int J Colorectal Dis.  1996;11(1):25-8. 
4.
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.
5.
Baumgart DC, Sandborn WJ.  Crohn's disease.  Lancet.  2012;380(9853):1590-605.
6.
Leong RW, Lau JY, Sung JJ.  The epidemiology and phenotype of Crohn's disease 
in the Chinese population.  Inflamm Bowel Dis.  2004;10(5):646-51.
7.
Lee YM, Fock K, See SJ, et al.  Racial differences in the prevalence of ulcerative 
colitis and Crohn's disease in Singapore.  J Gastroenterol Hepatol.  
2000;15(6):622-5.
8.
Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of 
American College of Gastroenterology.  Management of Crohn's disease in adults.  
Am J Gastroenterol.  2009;104(2):465-83.
9.
Froslie KF, Johnsen J, Moum BA, et al.  Mucosal healing in inflammatory bowel 
disease:  results from a Norwegian population-based cohort.  Gastroenterology.  
2007;133(2):412-22.
10.
Kakkar A, Wasan SK, Farraye FA.  Targeting mucosal healing in Crohn's disease.  
Gastroenterol Hepatol (NY).  2011;7(6):374-80.


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11.
Dignass A, Van Assche G, Lindsay JO, et al; European Crohn's and Colitis 
Organisation (ECCO).  The second European evidence-based consensus on the 
diagnosis and management of Crohn's disease:  current management.  J Crohns 
Colitis.  2010;4(1):28-62.  Erratum in:  J Crohn's Colitis.  2010;4(3):353.
12.
Colombel JF, Sandborn WJ, Rutgeerts P, et al.  Adalimumab for maintenance of 
clinical response and remission in patients with Crohn's disease:  the CHARM trial.  
Gastroenterology.  2007;132(1):52-65.
13.
Sandborn WJ, Feagan BG, Rutgeerts P, et al.  Vedolizumab as induction and 
maintenance therapy for Crohn's disease.  N Engl J Med.  2013;369(8):711-21. 
14.
Targan SR, Hanauer SB, van Deventer SJ, et al.  A short-term study of chimeric 
monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease.  N 
Engl J Med.  1997;337(15):1029-35.
15.
Hanauer SB, Feagan BG, Lichtenstein GR, et al; ACCENT I Study Group.  
Maintenance infliximab for Crohn's disease:  the ACCENT I randomised trial.  
Lancet.  2002;359(9317):1541-9.
16.
Hanauer SB, Sandborn WJ, Rutgeerts P, et al.  Human anti-tumor necrosis factor 
monoclonal antibody (adalimumab) in Crohn's disease:  the CLASSIC-I trial.  
Gastroenterology.  2006; 130(2):323-33.
17.
Sandborn WJ, Feagan BG, Stoinov S, et al; RECISE 1 Study Investigators.  
Certolizumab pegol for the treatment of Crohn's disease.  N Engl J Med.  
2007;357(3):228-38.
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 
Rep2015, Apr 2;7:44.  doi:  10.12703/P7-44.  eCollection 2015.
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.
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.
22.
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.
23.
Daperno M, D'Haens G, Van Assche G, et al.  Development and validation of a 
new, simplified endoscopic activity score for Crohn's disease:  the SES-CD.  
Gastrointest Endosc.  2004;60(4):505-12.
24.
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.
25.
Marshall WA, Tanner JM.  Variations in pattern of pubertal changes in girls.  Arch 
Dis Child.  1969;44(235):291-303.
26.
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/competent authority 
reviewed and approved the initial clinical investigation and all amendments.


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


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


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Appendix C.
Study Activities for Efficacy, Safety, and PK/PD
Screening Period
(35 Days)a
12-Week Double-Blind Induction
Induction Period 2
Unschb
140-Day
Follow-Upc
Activity
Screening
Baseline
Week 4
Week 8
Week 12/PD
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
X
X
X
X
X
X
X
X
X
X
TB Screeningh
Xy
ECGi
Xy
Hepatitis B, Hepatitis C 
Screeningj, and HIV Testl
Xy
Xk
Xk
C. difficile toxin
Xx
Urinalysism,n
Xx
Xo
X
X
Pregnancy Testp
Xx
X
X
X
X
X
X
X
Chemistry and Hematologyn
Xx
Xo
X
X
X
X
X
X
Optional Blood Sample for 
Biologic Drug Level
X
COVID-19 Assessmentz
X
hs-CRPn
X
X
X
X
X
Serum Risankizumabq
X
X
X
X
X


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Screening Period
(35 Days)a
12-Week Double-Blind Induction
Induction Period 2
Unschb
140-Day
Follow-Upc
Activity
Screening
Baseline
Week 4
Week 8
Week 12/PD
Week 16
Week 20
Week 24
Serum Anti-Drug Antibody 
(ADA)q,w and Neutralizing 
Anti-Drug Antibodies (nAb)q
X
X
X
X
X
X
Fecal calprotectin (FCP)n, r
X
X
X
X
Crohn's Disease Activity Index 
(CDAI)
Xt
X
X
X
X
X
X
X
Endoscopy/SES-CDu
X
X
X
Intestinal Biopsiesv
X
X
X
Dispense Subject Diarys
X
Subject Diary Review
X
X
X
X
X
X
X
X
Subject Questionnaire:
CSS
X
X
X
X
X
X
X
X
Subject Questionnaire:
PGIC and PGIS
X (PGIS 
only)
X
X
X
X
X
X
X
Subject Questionnaires:
  EQ-5D-5L
  FACIT-F
  IBDQ
  SF-36  
  WPAI-CD
X
X
X
X
Study Drug Administrationw
X
X
X
Xw
X
X
a.
The Screening period should be a minimum of 4 days, preferably 7 days for CDAI calculation, (refer to Section 5.3.1.1).  The Baseline CDAI 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.


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c.
Subjects will be contacted 140 days following last dose of study drug for an assessment of any new or ongoing AEs, except those subjects who roll-over into Study M16-000 
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 treatment in Induction Period 2.  Physical examinations at 
all other visits (including unscheduled visits) are symptom based and should include the assessment of EIMs and a count of the number of cutaneous fistulas as part of 
calculating the CDAI. 
f.
Blood pressure, pulse rate, temperature, respiratory rate and weight should be performed before blood draws are performed.  Height will be measured at Screening only (with 
shoes off and then adding 1 inch or 2.5 cm) for subjects ≥ 18 years of age.  Height will be re-measured at Week 12 and Week 24 (if applicable) for subjects < 18 years of age 
at Baseline.
g.
Collection of SAEs and protocol-related nonserious AEs 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.
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.
For Japan 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 with subjects that have a history of HBV vaccine and are HBs Ab (+).
l.
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. 
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.
n.
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.
o.
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.


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p.
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.  
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 eCRF.  If the subject consented to the optional intensive PK sampling, refer to Appendix H.
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 instructions provided outside of this protocol.  If a sample cannot be obtained during the site visit, the site will give instructions and a 
stool sample supply kit.
s.
Subjects should also be dispensed the patient information card.
t.
Diary information collected during Screening will serve to calculate Baseline CDAI.  During screening, subjects will be instructed on how to calculate the number of very soft 
and liquid stools, including a visual depiction.  CDAI should be completed at the Baseline visit, just prior to randomization.  
u.
Endoscopy at/during the screening period or within 45 days of the Baseline visit will be used to calculate the SES-CD score at Baseline.  Endoscopic evaluations using SES 
CD confirmed by central reader will be done at Screening.  Endoscopies completed at Week 12 and Week 24, for those subjects who receive treatment in Induction Period 2, 
will use the local reader results for stratification for Study M16-000. 
v.
Biopsies may be done when performing the endoscopy to confirm CD 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.
w.
Administration of drug will be performed after all assessments and examinations scheduled for that day have been completed, including endoscopy.  Completion of PROs are 
permitted during administration of study drug.  At Week 12, study drug will only be administered for subjects who are to receive treatment in 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.
x.
For Rescreening, if a subject is being rescreened within 14 days (≤ 14 days have passed) from the collection date of the previous screening testing, it is not required to repeat 
Screening testing for chemistry/hematology, urinalysis, serum pregnancy, and C. difficile provided that the subject's health status has not changed to warrant a repeat test.
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 5.3.1.1 are met and no 
more than 90 days have passed since the collection date of the testing.


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z.
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.


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Appendix D.
Study Activities – Optional Exploratory Research Samples
Screening Period (35 Days)
12-Week Double-Blind Induction
Samples Collecteda,b
Screening
Baseline
Week 12/PD
Pharmacogenetic
X
Transcriptomic and epigeneticc
X
X
Proteomic and targeted protein investigations (plasma)c
X
X
Proteomic and targeted protein investigations (serum)c
X
X
Stool
X
X
Intestinal biopsies (RNA)d
X
X
a.
Collections to be performed only if subject provides separate written consent to collect the exploratory research/validation studies 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.
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.
d.
Biopsy may be done when performing the endoscopy.  


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Appendix E.
Sample SES-CD Scoring
SES-CD Scoring23
Rectum
Sigmoid and 
Left Colon
Transverse 
Colon
Right 
Colon
Ileum
Total
Size of Ulcers 
Enter:
0 if none
1 if aphthous ulcers (Ø 0.1 to 0.5 cm)
2 if large ulcers (Ø 0.5 to 2 cm)
3 if very large ulcers (Ø > 2 cm)
Ulcerated Surface
Enter:
0 if none
1 if < 10%
2 if 10% – 30%
3 if > 30%
Affected Surface
Enter:
0 if unaffected segments
1 if < 50%
2 if 50% – 75%
3 if > 75%
Presence of Narrowing
Enter:
0 if none
1 if single, can be passed
2 if multiple, can be passed
3 if cannot be passed
TOTAL = 


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


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


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Standard Height
cm (Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women)
kg (Pounds)
158.8 (62.5)
62.1 (137.0)
57.4 (126.5)
160.0 (63.0)
62.6 (138.0)
58.0 (128.0)
161.3 (63.5)
63.0 (139.0)
58.7 (129.5)
162.6 (64.0)
63.5 (140.0)
59.4 (131.0)
163.8 (64.5)
64.1 (141.3)
60.1 (132.5)
165.1 (65.0)
64.6 (142.5)
60.8 (134.0)
166.4 (65.5)
65.2 (143.8)
61.4 (135.5)
167.6 (66.0)
65.8 (145.0)
62.1 (137.0)
168.9 (66.5)
66.4 (146.5)
62.8 (138.5)
170.2 (67.0)
67.1 (148.0)
63.5 (140.0)
171.5 (67.5)
67.8 (149.5)
64.2 (141.5)
172.7 (68.0)
68.5 (151.0)
64.9 (143.0)
174.0 (68.5)
69.2 (152.5)
65.5 (144.5)
175.3 (69.0)
69.8 (154.0)
66.2 (146.0)
176.5 (69.5)
70.5 (155.5)
66.9 (147.5)
177.8 (70.0)
71.2 (157.0)
67.6 (149.0)
179.1 (70.5)
71.9 (158.5)
68.3 (150.5)
180.3 (71.0)
72.6 (160.0)
68.9 (152.0)
181.6 (71.5)
73.4 (161.8)
69.6 (153.5)
182.9 (72.0)
74.1 (163.5)
70.3 (155.0)
184.2 (72.5)
75.0 (165.3)
71.2 (156.9
185.4 (73.0)
75.7 (167.0)
71.9 (158.5)
186.7 (73.5)
76.6 (169.0)
72.6 (160.2)
188.0 (74.0)
77.5 (171.0)
73.4 (161.8)
189.2 (74.5)
78.4 (172.8)
74.1 (163.4)
190.5 (75.0)
79.1 (174.5)
74.9 (165.1)
191.8 (75.5)
80.2 (176.8)
75.6 (166.8)
193.0 (76.0)
81.2 (179.0)
76.4 (168.4)
194.3 (76.5)
82.0 (180.8)
77.2 (170.1)
195.6 (77.0)
82.9 (182.9)
77.9 (171.8)
196.9 (77.5)
83.9 (185.0)
78.7 (173.5)


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Standard Height
cm (Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women)
kg (Pounds)
198.1 (78.0)
84.9 (187.2)
79.5 (175.2)
199.4 (78.5)
85.9 (189.4)
80.3 (177.0)
200.7 (79.0)
86.9 (191.6)
81.0 (178.7)
201.9 (79.5)
87.9 (193.9)
81.8 (180.5)
203.2 (80.0)
89.0 (196.2)
82.6 (182.2)
204.5 (80.5)
90.0 (198.6)
*Standard height is calculated 
using actual height obtained at 
screening (without shoes) plus 
one inch
205.7 (81.0)
91.1 (200.9)
*Indoor clothing weighing 
5 pounds for men and 3 pounds 
for women
207.0 (81.5)
92.2 (203.3)
*Centimeters × 0.3937 = inches
208.3 (82.0)
93.3 (205.8)
*Pounds × 0.4535 = kilograms


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Appendix H.
Optional Intensive PK Subjects
Samples for pharmacokinetics (PK) analysis will be collected in all subjects as described 
in Appendix C (Prior to dose at the specified weeks).  For the subjects who consent to the 
optional intensive PK sampling, in addition to the time points in Appendix C, blood 
samples 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.


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Appendix I.
Clinical Criteria for Diagnosing Anaphylaxis
Anaphylaxis24 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):
a) Infants and children:  low systolic BP (age specific) or greater than 30% 
decrease in systolic BP*


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b) Adults:  systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person's baseline.
PEF:  peak expiratory flow; BP:  blood pressure
*
low systolic BP for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + 
[2 × age]) from 1 to 10 years, and less than 90 mg Hg 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:  histamine and tryptase.  A blood sample 
for ADA assessment will also be collected along with 1 hour blood samples for above 
assessments.  Separate instructions for the collection, handling, storage and shipping of 
these labs will be provided outside of the study protocol.


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Appendix J.
Tanner Stage 5 for Development
Tanner Stage 5 for Development25,26
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


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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
●
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


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Appendix K.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.2  Synopsis
Subsection Diagnosis and Main Criteria for Inclusion/Exclusion:
Heading "Main Exclusion:"
Subheading "Safety"
Add:  new Criterion 31
31. No known active COVID-19 infection.  Subject must not have signs/symptoms associated with 
COVID-19 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 viral clearance criteria: 
!
Symptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥ 24 hours apart 
after at least 10 days have passed since recovery, defined as resolution of fever without use of 
antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of breath)
!
Asymptomatic subjects: At least 2 negative viral tests in a row completed locally, ≥ 24 hours apart 
after at least 10 days have passed since prior positive result (Note: subjects who develop 
symptoms will follow guidance above for symptomatic subjects)
Frequency or timing of COVID-19 testing and interval between testing for the above viral clearance 
criteria may be adjusted to account for epidemiological trends, updated information regarding 
infectivity and local/institutional guidelines.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
COVID-19
Coronavirus Disease - 2019
Section 3.2  Benefits and Risks
Add:  new last paragraph
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study have been re-evaluated.  Based on the limited information to 
date, no additional risk to study participants is anticipated with the use of risankizumab.


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Section 5.2.2  Exclusion Criteria
Subsection Safety
Add:  new Criterion 31
31.
No known active COVID-19 infection. Subject must not have signs/symptoms 
associated with COVID-19 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 viral clearance 
criteria:
●
Symptomatic subjects: At least 2 negative viral tests in a row completed 
locally, ≥ 24 hours apart after at least 10 days have passed since recovery, 
defined as resolution of fever without use of antipyretics and improvement in 
respiratory symptoms (e.g., cough, shortness of breath)
●
Asymptomatic subjects: At least 2 negative viral tests in a row completed 
locally, ≥ 24 hours apart after at least 10 days have passed since prior positive 
result (Note: subjects who develop symptoms will follow guidance above for 
symptomatic subjects)
Frequency or timing of COVID-19 testing and interval between testing for the 
above viral clearance criteria may be adjusted to account for epidemiological 
trends, updated information regarding infectivity and local/institutional guidelines.
Section 5.3.1.1  Study Procedures
Add:  new last paragraph
Study visits may be impacted by changes in local regulations due to the COVID-19 
pandemic.  This may include changes such as phone or virtual visits, visits at alternative 
locations, or changes in the visit frequency and timing of study procedures, among others.  
Every effort should be made to ensure the safety of subjects and site staff, while 
maintaining the integrity of the study.


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Section 5.3.1.1  Study Procedures
Subsection Informed Consent
Add:  new last paragraph
Due to the COVID-19 pandemic, 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.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Add:  new fifth and sixth paragraph
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  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.
Section 5.3.1.1  Study Procedures
Subsection HIV
Seventh sentence previously read:
AbbVie will not receive results from the testing and will not be made aware of any 
positive result.  


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Has been changed to read:
AbbVie will not receive results from the testing.
Section 5.3.1.1  Study Procedures
Subsection Outcomes and Questionnaires
Add:  new last paragraph
Due to the COVID-19 pandemic and any local restrictions, 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.
Section 5.3.1.1  Study Procedures
Subsection Study Drug Dispensing/Administration
Add:  new last paragraph and bullet list
During the Study Drug Dosing Period, a subject with confirmed (viral test positive) or 
suspected COVID-19 infection can only be dosed with study drug if the following 
COVID-19 viral clearance criteria are met: 
●
Symptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours apart 
after at least 10 days have passed since recovery, defined as resolution of fever 
without use of antipyretics and improvement in respiratory symptoms (e.g., 
cough, shortness of breath)
●
Asymptomatic subjects: At least 2 negative viral tests in a row, ≥ 24 hours 
apart after at least 10 days have passed since prior positive result (note: 
subjects who develop symptoms will follow guidance above for symptomatic 
subjects)


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Section 5.5.2.2  Storage and Disposition of Study Drug
Third paragraph, last sentence previously read:
Study drug should be quarantined and not dispensed until AbbVie or AbbVie 
Temperature Excursion Management System (ATEMS) deems the drug as acceptable.
Has been changed to read:
Sites are responsible to report 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.
Section 5.5.7  Drug Accountability
Second paragraph, first sentence previously read:
In addition, an accurate running inventory of study drug will be kept by the site (blinded 
or unblinded staff, as applicable) on a Site Drug Accountability log including date 
received, the lot number, kit number(s), date and number of vials and syringes dispensed 
and subject number.  
Has been changed to read:
In addition, IRT will be used to document investigational product accountability including 
date received, the lot number, kit number(s), date and number of vials and syringes 
dispensed and subject number.  
Section 5.5.7  Drug Accountability
Third paragraph, first sentence previously read:
An overall accountability of the study drug will be performed and verified by the 
CRA/monitor (blinded or unblinded according to the monitoring plan) throughout the 
study and at the site close-out visit.  


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Has been changed to read:
An overall accountability of the study drug will be performed by the site and 
reconciliation will be performed by the CRA/monitor (blinded or unblinded according to 
the monitoring plan) throughout the study and at the site close-out visit.  
Section 5.5.7  Drug Accountability
Third paragraph, fourth and fifth sentence previously read:
All unused supplies must be inventoried, accounted for and destroyed on site according to 
local procedures or regulation or returned to a destruction facility by the monitor/CRA 
(blinded or unblinded according to the monitoring plan).  A copy of the Drug 
Accountability Form, in accordance with instructions provided by the monitor/CRA 
(blinded or unblinded according to the monitoring plan), will be included in the return 
shipments.  
Has been changed to read:
All unused supplies must be inventoried, accounted for and destroyed on site according to 
local procedures or regulation or returned to a destruction facility.  A copy of the, Return 
Consignment Form from IRT, in accordance with instructions provided by the 
monitor/CRA (blinded or unblinded according to the monitoring plan), will be included in 
the return shipments.  
Section 6.1.1.1  Adverse Event
Add:  new fourth, fifth, and sixth paragraph
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
events (including capture of specific signs/symptoms of infection and testing results).
COVID-19 infections should be captured as adverse events. If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above.  The following COVID-19 related supplemental eCRFs should be 
completed:


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●
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.
Section 7.0  Protocol Deviations
First paragraph, last sentence previously read:
If a protocol deviation occurs (or is identified) after a subject has been enrolled, the 
principal Investigator is responsible for notifying IEC/IRB regulatory authorities (as 
applicable), and AbbVie.
Has been changed to read:
If a protocol deviation occurs (or is identified, including those that may be due to the 
COVID-19 pandemic) after a subject has been enrolled, the principal Investigator is 
responsible for notifying IEC/IRB regulatory authorities (as applicable), and AbbVie.
Section 8.1  Statistical and Analytical Plans
Add:  new last paragraph
The impact of missing data due to COVID-19 will be monitored and appropriate
modifications to the analysis of primary and key secondary endpoints for handling such 
missing data will be reflected and incorporated in the final SAP.
Section 9.2  Ethical Conduct of the Study
Add:  new last paragraph
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will engage with study site 
personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., phone contacts or 


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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.
Section 10.1  Source Documents
Add:  new last paragraph
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical Development, Immunology
Clinical Development, Immunology
Statistics
Statistics
Clinical Pharmacology and Pharmacometrics
Bioanalysis
Clinical Operations
Has been changed to read:
Name
Title
Functional Area
Clinical Development, Immunology
Clinical Development, Immunology
Statistics
Statistics
Clinical Pharmacology and Pharmacometrics
Bioanalysis
Clinical Operations


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Appendix C.  Study Activities for Efficacy, Safety, and PK/PD
Add:  new Activity "COVID-19 Assessmentz"
Screening Period
(35 Days)a
12-Week Double-Blind Induction
Induction Period 2
Unschb
140-Day
Follow-Upc
Activity
Screening
Baseline
Week 4
Week 8
Week 12/PD
Week 16
Week 20
Week 24
COVID-19 Assessmentz
X


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Appendix C.  Study Activities for Efficacy, Safety, and PK/PD
Table note "l.," last sentence previously read:
AbbVie will not receive results from the testing and not be made aware of any positive 
result.
Has been changed to read:
AbbVie will not receive results from the testing. 
Appendix C.  Study Activities for Efficacy, Safety, and PK/PD
Add:  new table note "z."
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.

SAP_001.pdf: 
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Statistical Analysis Plan for Study M16-006
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Induction Study of the Efficacy 
and Safety of Risankizumab in Subjects with 
Moderately to Severely Active Crohn's Disease
Date:  23 November 2020
Version 5.0
NCT03105128


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives, Hypotheses and Estimands .....................................................5
2.2
Study Design Overview .............................................................................9
2.3
Treatment Assignment and Blinding .......................................................12
2.4
Sample Size Determination......................................................................12
3.0
Endpoints................................................................................14
3.1
Primary Endpoint(s).................................................................................15
3.2
Secondary Endpoint(s).............................................................................15
3.3
Other Efficacy Endpoint(s)......................................................................17
3.4
Safety Endpoint(s) ...................................................................................21
3.5
Additional Endpoint(s).............................................................................21
4.0
Analysis Populations .............................................................21
5.0
Subject Disposition................................................................23
6.0
Study Drug Duration and Compliance................................24
6.1
Study Drug Duration................................................................................24
6.2
Study Drug Compliance...........................................................................27
6.2.1
Intravenous Therapy ................................................................................27
6.2.2
Subcutaneous Therapy.............................................................................28
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................28
7.1
Demographics and Baseline Characteristics............................................28
7.2
Medical History .......................................................................................30
7.3
Prior and Concomitant Medications ........................................................31
8.0
Efficacy Analyses...................................................................31
8.1
General Considerations............................................................................31
8.2
Handling of Potential Intercurrent Events ...............................................33
8.2.1
Premature Discontinuation of Study Drug...............................................33
8.2.2
CD-Related Corticosteroid Therapy ........................................................34
8.3
Handling of Missing Data........................................................................34
8.3.1
Categorical Endpoints..............................................................................35


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8.3.2
Continuous Endpoints..............................................................................36
8.4
Primary Efficacy Endpoint(s) and Analyses............................................38
8.4.1
Primary Efficacy Endpoint(s) ..................................................................38
8.4.2
Handling of Missing Data for the Primary Efficacy Endpoint(s)............39
8.4.3
Primary Efficacy Analysis .......................................................................39
8.4.4
Additional Analyses of the Primary Efficacy Endpoint(s) ......................40
8.5
Secondary Efficacy Analyses...................................................................40
8.5.1
Key Secondary Efficacy Analyses...........................................................40
8.5.2
Supportive Secondary Efficacy Analyses ................................................41
8.6
Additional Efficacy Analyses ..................................................................41
8.7
Efficacy Subgroup Analyses....................................................................43
9.0
Safety Analyses ......................................................................44
9.1
General Considerations............................................................................44
9.2
Adverse Events ........................................................................................45
9.2.1
Treatment-Emergent Adverse Events ......................................................46
9.2.2
Adverse Event Overview .........................................................................47
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................48
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................48
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................49
9.2.6
Areas of Safety Interest............................................................................49
9.3
Analysis of Laboratory Data....................................................................49
9.4
Analysis of Vital Signs ............................................................................51
10.0
Interim Analyses....................................................................52
10.1
Data Monitoring Committee....................................................................52
11.0
Overall Type-I Error Control ..............................................52
12.0
Version History......................................................................56
13.0
References...............................................................................57
List of Tables
Table 1.
Subgroups for Efficacy Analysis .............................................................44


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Table 2.
SAP Version History Summary...............................................................56
List of Figures
Figure 1.
Study Schematic.........................................................................................9
Figure 2.
Graphical Multiple Testing Procedure for US Specific Protocol ............54
Figure 3.
Graphical Multiple Testing Procedure for Global Protocol Outside 
US ............................................................................................................55
List of Appendices
Appendix A.
Protocol Deviations..................................................................................59
Appendix B.
Areas of Safety Interest (ASI)..................................................................60
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............64
Appendix D.
Crohn's Disease Activity Index (CDAI) ..................................................66
Appendix E.
Simple Endoscopic Score – CD (SES-CD)..............................................68
Appendix F.
Inflammatory Bowel Disease Questionnaire (IBDQ)..............................70
Appendix G.
FACIT-Fatigue.........................................................................................72
Appendix H.
Random Seeds..........................................................................................74
Appendix I.
Geographic Region ..................................................................................75
Appendix J.
Definition of Estimand for Primary and Ranked Secondary 
Endpoints .................................................................................................76


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for risankizumab 
Study M16-006 "A Multicenter, Randomized, Double-Blind, Placebo Controlled 
Induction Study of the Efficacy and Safety of Risankizumab in Subjects with Moderately 
to Severely Active Crohn's Disease."
Pharmacokinetics/pharmacodynamics, pharmacogenetics, and selected biomarkers will be 
analyzed separately and are not included in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 12.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The objective of this study is to evaluate the efficacy and safety of risankizumab versus 
placebo during induction therapy in subjects with moderately to severely active Crohn's 
Disease (CD).
Primary Efficacy Objective
●
For US-specific protocol:
The primary efficacy objective of the study for US-specific protocol is to demonstrate a 
higher rate of a) CDAI clinical remission (defined as Crohn's disease activity index
[CDAI] < 150), and b) endoscopic response (defined as decreasing in Simple Endoscopic 


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Score – CD [SES-CD] > 50% from baseline [or for subjects with isolated ileal disease and 
a baseline SES-CD of 4, at least a 2 point reduction from baseline], as scored by central 
reviewer) after 12 weeks of treatment with risankizumab when compared to placebo based 
on Intent-to-Treat (ITT) population ITT1A (see Section 4.0).
Hypotheses corresponding to the primary efficacy objective and endpoints for US-
specific protocol are:
●
The proportion of subjects achieving CDAI clinical remission treated with 
risakizumab is greater than that treated with placebo at Week 12
●
The proportion of subjects achieving endoscopic response treated with 
risakizumab is greater than that treated with placebo at Week 12
The estimands corresponding to the primary efficacy objective for US-specific protocol
are defined as follows:
●
Difference in the percentage of subjects achieving CDAI clinical remission at 
Week 12 regardless of premature discontinuation of study drug and without 
initiation or dose escalation of CD-related corticosteroids (See Section 8.2.2) in 
each of the risankizumab 1200 mg intravenous (IV) and risankizumab 600 mg 
IV groups in comparison with the placebo group in the ITT1A population
●
Difference in the percentage of subjects achieving endoscopic response at 
Week 12 regardless of premature discontinuation of study drug and without 
initiation or dose escalation of CD-related corticosteroids (See Section 8.2.2) in 
each of the risankizumab 1200 mg IV and risankizumab 600 mg IV groups in 
comparison with the placebo group in the ITT1A population. 
●
For global protocol outside US:
The primary efficacy objective of the study for global protocol outside US is to 
demonstrate a higher rate of a) clinical remission (defined as average daily stool 
frequency [SF] ≤ 2.8 and not worse than baseline AND average daily abdominal pain 
[AP] score ≤ 1 and not worse than baseline), and b) endoscopic response after 12 weeks of 


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treatment with risankizumab when compared to placebo based on Intent-to-Treat (ITT) 
population ITT1A.
Hypotheses corresponding to the primary efficacy objective and endpoints for global 
protocol outside US is:
●
The proportion of subjects achieving clinical remission treated with 
risakizumab is greater than that treated with placebo at Week 12
●
The proportion of subjects achieving endoscopic response treated with 
risakizumab is greater than that treated with placebo at Week 12
The estimands corresponding to the primary efficacy objective for global protocol outside 
US are defined as follows:
●
Difference in the percentage of subjects achieving clinical remission at Week 
12 regardless of premature discontinuation of study drug and without initiation 
or dose escalation of CD-related corticosteroids (See Section 8.2.2) in each of 
the risankizumab 1200 mg IV and risankizumab 600 mg IV groups in 
comparison with the placebo group in the ITT1A population
●
Difference in the percentage of subjects achieving endoscopic response at 
Week 12 regardless of premature discontinuation of study drug and without 
initiation or dose escalation of CD-related corticosteroids (See Section 8.2.2) in 
each of the risankizumab 1200 mg IV and risankizumab 600 mg IV groups in 
comparison with the placebo group in the ITT1A population. 
Secondary Efficacy Objectives
For both US-specific protocol and global protocol outside US:
The secondary efficacy objectives of this study are to demonstrate higher efficacy of 
treatment with risankizumab when compared to placebo with respect to the ranked
secondary endpoints specified in Section 3.2 under each protocol. The ranked secondary 
efficacy objectives will be assessed based on ITT1A population.


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Hypotheses corresponding to the secondary efficacy objectives and endpoints are: 
1.
For each of the ranked binary secondary endpoints (Section 3.2), greater proportion 
of subjects with improvement for the endpoint is achieved with risankizumab
when compared to that of placebo; 
2.
For each of the ranked continuous endpoints (Section 3.2), greater mean change 
from baseline for the endpoint is achieved with risankizumab when compared to 
that of placebo.
For each of the binary ranked secondary endpoints except for CD-related hospitalization 
endpoint, the estimands corresponding to the secondary efficacy objectives are defined as 
follows: Difference in the percentage of subjects achieving the endpoint regardless of 
premature discontinuation of study drug and without initiation or dose escalation of CD-
related corticosteroids (See Section 8.2.2) in each of the risankizumab 1200 mg IV and 
risankizumab 600 mg IV groups in comparison with the placebo group in the ITT1A
population.
For the secondary endpoint of "Occurrence of CD-related hospitalization through Week 
12," the estimand is defined as follows: Difference in the percentage of subjects having 
CD-related hospitalization through Week 12 regardless of premature discontinuation of 
study drug and regardless of initiation or dose escalation of CD-related corticosteroids
(See Section 8.2.2) in each of the risankizumab 1200 mg IV and risankizumab 600 mg IV 
groups in comparison with the placebo group in the ITT1A population.
For each of the continuous ranked secondary endpoints, the estimands corresponding to 
the secondary efficacy objectives are defined as follows: Difference in the mean change 
from baseline for the endpoint regardless of premature discontinuation of study drug and 
if subjects would not initiate or escalate dose of CD-related corticosteroids (See Section 
8.2.2) in each of the risankizumab 1200 mg IV and risankizumab 600 mg IV groups in 
comparison with the placebo groups in the ITT1A population.


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2.2
Study Design Overview
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy and safety of risankizumab as an induction therapy in 
subjects with moderately to severely active CD.
The study consists of the following periods:
1.
Screening period of up to a maximum of 35 days
2.
12-week randomized, double-blinded IV therapy induction period (12-Week 
Induction Period) 
3.
12-week randomized, double-blinded, double-dummy Induction Period 2 
(Induction Period 2) for subjects who do not achieve clinical response at Week 12  
4.
20-week follow up period from the last dose of study drug.
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
a.
12-Week Induction Period


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Figure 1.
Study Schematic (Continued)
b. Induction Period 2
DC = discontinued; IR = subjects with inadequate clinical response to induction; IV = intravenous; R = subjects with 
clinical response; RR = re-randomize 
Approximately 855 patients with moderate to severe CD who had baseline eligible SES-
CD (eligible SES-CD is defined as total SES-CD score excluding presence of narrowing 
subscore) of ≥ 6 (≥ 4 for isolated ileal disease) are to be randomized in a ratio of 2:2:1 to 
one of the three following treatment groups in the 12-Week Induction Period. 
●
Placebo IV (n = 342)
●
Risankizumab 600 mg IV (n = 342)
●
Risankizumab 1200 mg IV (n = 171)
In addition to the 855 subjects, up to 85 subjects with a lower SES-CD, defined as an 
eligible SES-CD of ≥ 3 to < 6 for ileocolonic or colonic disease or SES-CD of 3 for 
isolated ileal disease will be enrolled in order to inform treatment effect in this patient 
population, but these subjects will not be included in the primary ITT population for 
efficacy analysis.


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Each treatment group receives the corresponding dose of risankizumab or placebo IV 
infusion at Week 0, Week 4, and Week 8.  At Week 12, patients are evaluated for clinical 
response, defined as ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in 
average daily AP score and both not worse than baseline.  
Visits for clinical evaluation will occur at baseline/Week 0, Weeks 4, 8, and 12 or 
Premature Discontinuation (PD).  
Subjects, who do not achieve clinical response at Week 12 will be randomized by 
Interactive Response Technologies (IRT) to the Induction Period 2, a double-blind, double 
dummy 12-week treatment period. Subjects who received risankizumab induction 
treatment during the 12-Week Induction Period will be randomized 1:1:1 to:
●
Risankizumab 1200 mg IV 
●
Risankizumab 360 mg subcutaneous (SC) 
●
Risankizumab 180 mg subcutaneous (SC) 
Subjects who received placebo induction treatment during the 12-Week Induction Period 
will receive:
●
Risankizumab 1200 mg IV
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 participated in the blinded Induction Period 2 will be 
reassessed and undergo a third endoscopy for evaluation of mucosal inflammation.  
Subjects who achieve clinical response at Week 24 may be eligible to enter the Study 
M16-000.  Subjects without clinical response at Week 24, as well as all subjects who are 
terminated the study early (including subjects who are eligible for but do not participate in 
the blinded Induction Period 2), will be discontinued and have a follow-up call 140 days 


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from the last dose of study drug to obtain information on any new and/or ongoing adverse 
events (AEs).
2.3
Treatment Assignment and Blinding
At baseline, eligible patients will be randomized to three parallel groups with 1200 mg IV 
and 600 mg IV dose of risankizumab treatments or placebo in a 2:2:1 ratio.  The 12-Week 
Induction Period randomization will be stratified by number of prior biologics failed (0, 1, 
> 1), baseline steroid use (Yes, No), and baseline eligible SES-CD (original, alternative), 
where the stratum of "original" includes the patients with baseline eligible SES-CD of ≥ 6 
(or ≥ 4 for subjects with isolated ileal disease), and the stratum of "alternative" includes 
the patients with baseline eligible SES-CD of ≥ 3 to < 6 for ileocolonic or colonic disease 
or SES-CD of 3 for isolated ileal disease.
Subjects with clinical non-response to risankizumab at Week 12 will be re-randomized in 
a 1:1:1 ratio to risankizumab 1200 mg IV dose group, risankizumab 360 mg SC dose 
group, or risankizumab 180 mg SC dose group in the Induction Period 2.  Subjects with 
clinical non-response to placebo at Week 12 will blindly receive risankizumab 1200 mg 
IV dose.  No stratification will be made for the Induction Period 2 randomization.
2.4
Sample Size Determination
For US-specific protocol, the co-primary endpoints are the achievement of CDAI clinical 
remission at Week 12 and the achievement of endoscopic response at Week 12.  For 
global protocol outside US, the co-primary endpoints are the achievement of clinical 
remission at Week 12 and the achievement of endoscopic response at Week 12.
Sample size calculation is based on the larger sample size needed to detect treatment 
difference between the risankizumab treatment group and the placebo group for each of 
the co-primary endpoints.  Since historical data show slightly lower event rate and similar 
treatment difference for the endoscopic response rate compared to the clinical remission 
rate at Week 12, as well as the larger treatment difference for the CDAI clinical remission 
rate compared to the clinical remission rate at Week 12, clinical remission rates at Week 


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12 are used for power calculation.  A total of 855 subjects will be randomized into the two 
risankizumab treatment groups and the placebo group in a 2:2:1 ratio (342 subjects for the 
risankizumab 600 mg dose group, 342 subjects for the risankizumab 1200 mg dose group, 
and 171 subjects for the placebo group).  Assuming the clinical remission rate at Week 12 
will be 27.8% for one of the risankizumab treatment groups and 12% for the placebo 
group, a sample size of 342 subjects for the risankizumab group and 171 for the placebo 
group will have 97% power to detect the treatment difference between risankizumab and 
placebo using a Fisher's exact test at a 0.025 significant level (two-sided).  Assuming the 
Week 12 CDAI clinical remission rate will be 37% for one of the risankizumab treatment 
groups and 17% for the placebo group, this sample size will have 99% power to detect the 
treatment difference between risankizumab and placebo using a Fisher's exact test at a 
0.025 significant level (two-sided).  Assuming the Week 12 endoscopic response rate will 
be 25.5% for one of the risankizumab treatment groups and 8% for the placebo group, this 
sample size will have 99% power to detect the treatment difference between risankizumab 
and placebo using a Fisher's exact test at a 0.025 significant level (two-sided).
In addition, with sample size of approximately 540 bio-IR subjects, the study will have 
approximately 76% power to detect the treatment difference between one of the 
risankizumab treatment groups and the placebo group in clinical remission rates at Week 
12 using a Fisher's exact test at a 0.025 significant level (two-sided) for the bio-IR 
population, assuming the Week 12 clinical remission rate will be 23.5% for one of the 
risankizumab treatment groups and 10% for the placebo group for bio-IR subjects.  The
study will have approximately 92% power for the bio-IR population to detect the 
treatment difference between one of the risankizumab dose groups and placebo in CDAI 
clinical remission rates at Week 12 using Fisher's exact test at a 0.025 significant level 
(two-sided) for the bio-IR population, assuming the Week 12 CDAI clinical remission rate 
will be 34% for one of the risankizumab treatment groups and 15% for the placebo group.  
The rates are based on the results from the Phase 2 Study 1311.6, where the study 
population comprised approximately 95% bio-IR subjects, and account for lower rates 
adjustment for ustekinumab failure patients.  


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Similarly, with sample size of approximately 315 non-bio-IR subjects, the study will have 
72% power to detect the treatment difference between one of the risankizumab treatment 
groups and placebo in clinical remission rates at Week 12 using a Fisher's exact test at a 
0.025 significant level (two-sided) for the non-bio-IR population, assuming the Week 12 
clinical remission rate will be 35% for one of the risankizumab treatment groups and 15% 
for the placebo group for non-bio-IR subjects.  The study will have 70% power to detect 
the treatment difference between one of the risankizumab treatment groups and the 
placebo group in CDAI clinical remission rates at Week 12 using Fisher's exact test at a 
0.025 significant level (two-sided) for the non-bio-IR population, assuming the Week 12 
CDAI clinical remission rate will be 42% for one of the risankizumab treatment groups 
and 21% for the placebo group for non-bio-IR subjects.  The non-bio-IR population is 
expected to have higher remission rates and a wider treatment difference than the bio-IR 
population.  Similar trends for greater remission rates and treatment differences by prior 
biologic use were observed in prior pivotal studies with ustekinumab, vedolizumab and 
adalimumab.
3.0
Endpoints
Below are the definitions of the endpoints used in the efficacy analysis:
●
Clinical remission:  average daily SF ≤ 2.8 and not worse than baseline AND 
average daily AP score ≤ 1 and not worse than baseline
●
Enhanced clinical response:  ≥ 60% decrease in average daily SF and/or 
≥35% decrease in average daily AP score and both not worse than baseline, 
and/or clinical remission
●
Clinical response:  ≥ 30% decrease in average daily SF and/or ≥ 30% decrease 
in average daily AP score and both not worse than baseline
●
Endoscopic response:  decrease in SES-CD > 50% from baseline (or for 
subjects with isolated ileal disease and a baseline SES-CD of 4, at least a 
2 point reduction from baseline), as scored by central reviewer


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●
Ulcer-free endoscopy:  SES-CD ulcerated surface subscore of 0 in subjects 
with SES-CD ulcerated surface subscore ≥ 1 at baseline, as scored by a central 
reviewer
●
Endoscopic remission:  SES-CD ≤ 4 and at least a 2 point reduction versus 
baseline and no subscore greater than 1 in any individual variable, as scored by 
a central reviewer
●
CDAI clinical response:  reduction of CDAI ≥ 100 points from baseline
●
CDAI clinical remission:  CDAI < 150
●
SF remission: average daily SF ≤ 2.8 and not worse than baseline
●
AP remission: average daily AP score ≤ 1 and not worse than baseline
3.1
Primary Endpoint(s)
For US-specific protocol, the co-primary efficacy endpoints are
●
The achievement of CDAI clinical remission at Week 12 
●
The achievement of endoscopic response at Week 12
For global protocol outside US, the co-primary efficacy endpoints are
●
The achievement of clinical remission at Week 12 
●
The achievement of endoscopic response at Week 12
3.2
Secondary Endpoint(s)
For US-specific protocol, the secondary endpoints under overall type I error control 
are: 
1.
The achievement of clinical remission at Week 12
2.
The achievement of CDAI clinical response at Week 4 
3.
The achievement of CDAI clinical response at Week 12 


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4.
Change from baseline in Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-Fatigue) at Week 12 
5.
The achievement of CDAI clinical remission at Week 4 
6.
The achievement of CDAI clinical response and endoscopic response at Week 12 
7.
The achievement of SF remission at Week 12 
8.
The achievement of AP remission at Week 12
9.
The achievement of endoscopic remission at Week 12
10.
The achievement of enhanced clinical response at Week 4
11.
The achievement of ulcer-free endoscopy at Week 12
12.
The achievement of enhanced clinical response at Week 12
13.
The achievement of resolution of extra-intestinal manifestations (EIMs) at Week 
12, in subjects with any EIMs at baseline
14.
Occurrence of CD-related hospitalization through Week 12
15.
The achievement of no draining fistulas at Week 12 in subjects with draining 
fistulas at baseline
For global protocol outside US, the secondary endpoints under overall type I error 
control are:
1.
The achievement of CDAI clinical remission at Week 12
2.
The achievement of CDAI clinical response at Week 4 
3.
The achievement of clinical remission at Week 4 
4.
The achievement of CDAI clinical response at Week 12 
5.
Change from baseline in FACIT-Fatigue at Week 12 


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6.
Change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) total 
score at Week 12 
7.
The achievement of enhanced clinical response and endoscopic response at Week 
12 
8.
The achievement of endoscopic remission at Week 12
9.
The achievement of enhanced clinical response at Week 4
10.
The achievement of ulcer-free endoscopy at Week 12
11.
The achievement of enhanced clinical response at Week 12
12.
The achievement of resolution of EIMs at Week 12, in subjects with any EIMs at 
baseline
13.
Occurrence of CD-related hospitalization through Week 12
14.
The achievement of no draining fistulas at Week 12 in subjects with draining 
fistulas at baseline
15.
Change from baseline in Work Productivity and Impairment Questionnaire –
Crohn's disease (WPAI-CD) Overall Work Impairment at Week 12
16.
Change from baseline in Short Form-36 (SF-36) Physical Component Summary 
(PCS) score at Week 12
3.3
Other Efficacy Endpoint(s)
The primary and secondary efficacy endpoints are listed in Section 3.1 and Section 3.2, 
respectively.  The additional efficacy endpoints for each induction period are:  
12-Week Induction Period:
●
Change from baseline in IBDQ at Week 4, Week 12 respectively
●
Change from baseline in individual IBDQ domain scores (bowel, emotional, 
social, systemic) at Week 4, Week 12 respectively


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●
The achievement of IBDQ remission (IBDQ > 170 points) at Week 4, Week 12 
respectively
●
The achievement of IBDQ response (increase in IBDQ > 16 points from 
baseline) at Week 4, Week 12 respectively
●
Change from baseline in WPAI-CD at Week 4, Week 12 respectively
●
Change from baseline in European Quality of Life 5 Dimensions (EQ-5D-5L)
at Week 4, Week 12 respectively
●
Change from baseline in FACIT-Fatigue total score and individual items at 
Week 4, Week 12 respectively
●
The achievement of increase in FACIT-Fatigue total score from baseline ≥7 at 
Week 12
●
The achievement of increase in FACIT-Fatigue total score from baseline ≥9 at 
Week 12
●
The achievement of increase in FACIT-Fatigue total score from baseline ≥11 at 
Week 12
●
Change from baseline in Short Form-36 (PCS and Mental Component 
Summary score [MCS] and all 8 domain scores) at Week 4, Week 12 
respectively
●
Change from baseline in Fecal calprotectin (FCP) at Week 4, Week 12 
respectively
●
Change from baseline in high-sensitivity C-reactive protein (hs-CRP) at Week 
4, Week 8, Week 12 respectively
●
Change from baseline in average daily AP score at Week 4, Week 8, Week 12 
respectively
●
Change from baseline in average daily SF at Week 4, Week 8, Week 12 
respectively
●
The achievement of clinical remission at Week 4, Week 8, Week 12 
respectively
●
The achievement of enhanced clinical response at Week 4, Week 8, Week 12 
respectively
●
The achievement of clinical response at Week 4, Week 8, Week 12 respectively


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●
Change from baseline in SES-CD at Week 12
●
The achievement of a SES-CD ulcerated surface subscore ≤ 1 at Week 12 in 
subjects with a SES-CD ulcerated surface subscore ≥ 2 at baseline
●
Patient Global Impression of Severity (PGIS) response at Week 4, Week 8, 
Week 12 respectively
●
The achievement of subjects who report symptoms to be "Minimal" or 
"Absent" on the PGIS at Week 4, Week 8, Week 12 respectively, for subjects 
who did not report symptoms to be "Minimal" or "Absent" at baseline
●
Patient Global Impression of Change (PGIC) response at Week 4, Week 8, 
Week 12 respectively
●
The achievement of subjects who are "Very much improved" or "Much 
improved" on the Patient Global Impression of Change (PGIC) at Week 4, 
Week 8, Week 12 respectively
●
Change from baseline in PGIS at Week 4, Week 8, Week 12 respectively
●
Occurrence of CD-related surgeries through Week 12
●
The achievement of any reduction in SES-CD at Week 12
●
The achievement of CDAI clinical remission at Week 4, Week 8, Week 12 
respectively
●
The achievement of CDAI clinical response at Week 4, Week 8, Week 12 
respectively
●
The achievement of SF remission at Week 4, Week 8, Week 12 respectively
●
The achievement of AP remission at Week 4, Week 8, Week 12 respectively
●
Change from baseline in CDAI at Week 4, Week 8, Week 12 respectively
●
Change from baseline in Crohn's Symptom Severity (CSS) at Week 4, Week 8, 
Week 12 respectively
●
The achievement of resolution of extra-intestinal manifestations (EIMs) at 
Week 4, Week 8, Week 12 respectively, in subjects with any EIMs at baseline
●
The achievement of no draining fistulas at Week 4, Week 8, Week 12 
respectively, in subjects with draining fistulas at baseline
●
The achievement of no non-draining fistulas at Week 4, Week 8, Week 12 
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●
The achievement of no anal fissure at Week 4, Week 8, Week 12 respectively, 
in subjects with anal fissure at baseline
Induction Period 2:
●
The achievement of clinical remission at Week 16, 20, 24 respectively
●
The achievement of endoscopic response at Week 24
●
The achievement of CDAI clinical remission at Week 16, 20, 24 respectively
●
The achievement of CDAI clinical response at Week 16, 20, 24 respectively
●
The achievement of SF remission at Week 16, 20, 24 respectively
●
The achievement of AP remission at Week 16, 20, 24 respectively
●
Change from baseline in FACIT-Fatigue at Week 24
●
Change from baseline in IBDQ total score at Week 24
●
The achievement of enhanced clinical response and endoscopic response at 
Week 24 
●
The achievement of CDAI clinical response and endoscopic response at Week 
24 
●
The achievement of endoscopic remission at Week 24
●
The achievement of enhanced clinical response at Week 16, 20, 24 respectively
●
The achievement of ulcer-free endoscopy at Week 24
●
The achievement of resolution of extra-intestinal manifestations (EIMs) at 
Week 16, 20, 24 respectively, in subjects with any EIMs at baseline
●
Occurrence of CD-related hospitalization from Week 12 through Week 24
●
The achievement of no draining fistulas at Week 16, 20, 24 respectively, in 
subjects with draining fistulas at baseline
●
Change from baseline in WPAI-CD at Week 24
●
Change from baseline in SF-36 (PCS, MCS and all 8 domain scores) at Week 
24


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3.4
Safety Endpoint(s)
●
Treatment-emergent adverse event
●
Laboratory data
●
Vital signs
3.5
Additional Endpoint(s)
Pharmacokinetics/pharmacodynamics, pharmacogenetics, and selected biomarkers will be 
analyzed separately and are not included in this SAP.
4.0
Analysis Populations
The following population sets are defined and will be used for the statistical analyses.
Significant non-compliance was identified at an investigational site (Investigator ID 
). As a result of this finding, efficacy data for the subjects enrolled at this
investigational site will be excluded from the statistical analyses. Safety data for those 
subjects will be included in the statistical analyses. There were 5 subjects enrolled at the 
site with Investigator ID
in this study.
Intent-to-Treat Population
The Intent-to-Treat (ITT) population includes subjects who received at least one dose of 
study drug.
12-Week Induction Period:
The Intent-to-Treat population for the 12-Week Induction Period (denoted as ITT1) 
includes randomized subjects who received at least one dose of study drug during the 12-
Week Induction Period.
●
ITT1A: This Intent-to-Treat population for the 12-Week Induction Period 
includes the subjects in ITT1 who had baseline eligible SES-CD of ≥ 6 (≥ 4 for 


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isolated ileal disease).  This population will be the primary population for 
efficacy analysis of the 12-Week Induction Period. 
●
ITT1B: This Intent-to-Treat population for the 12-Week Induction Period 
includes the subjects who are in ITT1 set but did not have baseline eligible
SES-CD of ≥ 6 (≥ 4 for isolated ileal disease).  This population will be used for 
exploratory efficacy analysis purpose.
Induction Period 2:
The Intent-to-Treat population for the Induction Period 2 (denoted as ITT2) includes 
subjects who are randomized and received at least one dose of risankizumab during the 
Induction Period 2, and the subjects who received placebo induction treatment during 
12-Week Induction Period and entered the Induction Period 2 (denoted as 
placebo/risankizumab).  The placebo/risankizumab subjects will be analyzed as a separate 
treatment group in the Induction Period 2.
●
ITT2A: This Intent-to-Treat population for Induction Period 2 includes 
subjects in ITT2 who had baseline eligible SES-CD of ≥ 6 (≥ 4 for isolated ileal 
disease).  This population will be used for exploratory efficacy analysis 
purpose.
●
ITT2B: This Intent-to-Treat population for Induction Period 2 includes the 
subjects who are in ITT2 set but did not have baseline eligible SES-CD of ≥ 6 
(≥ 4 for isolated ileal disease).  This population will be used for exploratory 
efficacy analysis purpose.
For the corresponding ITT populations, subjects were assigned to a treatment group based 
on the randomization or re-randomization schedule, regardless of the treatment actually 
received.  The demographics/baseline and efficacy analysis will be based on the
corresponding ITT population. 


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Safety Population
For the safety populations, subjects were assigned to a treatment group based on the 
treatment actually received.  The safety population (SA) consists of all subjects who 
received at least one dose of study medication.  The safety analysis in each induction 
period will be based on the following safety population. 
12-Week Induction Period:
●
SA1: This safety population for the 12-Week Induction Period consists of all 
subjects who received at least one dose of study medication from the 12-Week 
Induction Period.  
●
SA1A: This safety population for the 12-Week Induction Period includes the 
subjects in SA1 set who had baseline eligible SES-CD of ≥6 (≥4 for isolated 
ileal disease).
Induction Period 2:
●
SA2: This safety population for the Induction Period 2 consists of subjects who 
received at least one dose of risankizumab during the Induction Period 2. 
●
SA2A: This safety population for the Induction Period 2 includes the subjects 
in SA2 set who had baseline eligible SES-CD of ≥6 (≥4 for isolated ileal 
disease).
All Risankizumab:
●
SA-ALL: This safety population includes all subjects who received at least one 
dose of risankizumab any time during the study.
5.0
Subject Disposition
The total number of subjects who were enrolled, randomized and treated will be 
summarized.  


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A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects enrolled/randomized in the study 
●
Subjects who took at least one dose of study drug (ITT1A for the 12-Week 
Induction Period, ITT2 for the Induction Period 2 and ITT1 for the entire study)
●
Subjects who completed study drug (SA1A for the 12-Week Induction Period, 
SA2 for the Induction Period 2 and SA1 for the entire study)
●
Subjects who prematurely discontinued study drug (SA1A for the 12-Week 
Induction Period, SA2 for the Induction Period 2 and SA1 for the entire study)
●
Subjects who prematurely discontinued from study (ITT1A for the 12-Week 
Induction Period, ITT2 for the Induction Period 2 and ITT1 for the entire study)
●
Subjects who completed study (ITT1A for the 12-Week Induction Period, ITT2 
for the Induction Period 2 and ITT1 for the entire study)
For end of study participation, the number and percentage of subjects who completed the 
protocol defined follow-up period (or did not with associated reasons) will be summarized 
overall and by treatment group.
6.0
Study Drug Duration and Compliance
6.1
Study Drug Duration
12-Week Induction Period:
For the safety population SA1A, the duration of exposure to study drug will be 
summarized for each treatment group in the 12-Week Induction Period.  The study drug 
dose date refers to recorded dates of infusion/injections of study drug.
●
Duration of exposure in the 12-Week Induction Period:
○
If the subject enrolled into M16-000 after the 12-Week Induction Period: 
●
Duration of exposure = min(the first study drug dose date in 
M16-000 – the first study drug dose date in the 12-Week Induction 
Period, the last study drug dose date in the 12-Week Induction Period –


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the first study drug dose date in the 12-Week Induction Period +28 
days),
○
If the subject enrolled into the Induction Period 2 after the 12-Week 
Induction Period:
●
Duration of exposure = min(the first study drug dose date in the 
Induction Period 2 – the first study drug dose date in the 12-Week 
Induction Period, the last study drug dose date in the 12-Week 
Induction Period – the first study drug dose date in the 12-Week 
Induction Period +28 days),
○
Otherwise:
●
Duration of exposure = the last study drug dose date in the 12-Week 
Induction Period – the first study drug dose date in the 12-Week 
Induction Period +28 days.
For each treatment group and total in this 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 SA2A, the duration of exposure to study drug will be 
summarized for each treatment group in the Induction Period 2.  The study drug dose date 
refers to recorded dates of infusion/injections of study drug.


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●
Duration of exposure in the Induction Period 2:
○
If the subject enrolled into M16-000 after the Induction Period 2: 
●
Duration of exposure = min(the first study drug dose date in M16-000 
– the first study drug dose date in the Induction Period 2, the last study 
drug dose date in the Induction Period 2 – the first study drug dose date 
in the Induction Period 2 +28 days [for IV dose] or 56 days [for SC 
dose]),
○
Otherwise:
●
Duration of exposure = the last study drug dose date in the Induction 
Period 2 – the first study drug dose date in the Induction Period 2 +28
days (for IV dose) or 56 days (for SC dose).
For each treatment group and total in the Induction Period 2, 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
ALL Risankizumab: 
For all risankizumab population SA-ALL, the duration of exposure to study drug will be 
summarized for all risankizumab treatment group over the whole course of the study.  The 
study drug dose date refers to recorded dates of infusion/injections of study drug.
●
Duration of exposure for all risankizumab:
○
If the subject enrolled into M16-000: 


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●
Duration of exposure = min(the first study drug dose date in 
M16-000 – the first risankizumab dose date in M16-006, the last 
risankizumab dose date in M16-006 – the first risankizumab dose date 
in M16-006 +28 days [if the last dose is IV dose] or 56 days [if the last 
dose is SC dose]),
○
Otherwise:
●
Duration of exposure = the last risankizumab dose date in M16-006 
– the first risankizumab dose date in M16-006 +28 days [if the last 
dose is IV dose] or 56 days [if the last dose is SC dose].
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 risankizumab will be summarized for the 
following exclusive duration intervals:
●
1 – 28 days
●
29 – 56 days
●
57 – 84 days 
●
85 – 112 days
●
113 – 140 days
●
141 – 196 days
●
>196 days
6.2
Study Drug Compliance
The treatment compliance (%) of study drug information will be summarized for safety 
populations SA1 and SA2:
6.2.1
Intravenous Therapy
●
Percent of subjects who received full volume
●
Average infusion duration (hours)
●
Treatment compliance (%)


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6.2.2
Subcutaneous Therapy
●
Total number of injections received
●
Treatment compliance (%)
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics and baseline or disease characteristics will be summarized for the ITT1A, 
ITT1B, ITT2A, ITT2B, SA1A population overall and by treatment group. Medical 
history and prior medications will be summarized for the ITT1A population overall and 
by treatment group. Concomitant medications will be summarized for the ITT1A and 
ITT2 population overall and by treatment group. Categorical variables will be 
summarized with the number and percentage of subjects; percentages will be calculated 
based on the number of non-missing observations. Continuous variables will be 
summarized with descriptive statistics (number of non-missing observations, mean and 
standard deviation, median, minimum and maximum).
7.1
Demographics and Baseline Characteristics
The following demographic and baseline or disease characteristics will be summarized at 
the baseline of the study, where the baseline refers to the last non-missing observation 
before the first administration of any study drug.
Demographics
●
Age (years)
●
Age category [< 18, [18, 40), [40, 65), ≥ 65] 
●
Sex [male/female]
●
Race [American Indian/Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Multiple]
●
Ethnicity [Hispanic/Latino, Non-Hispanic/Latino]
●
Geographic region (as defined in Appendix I)


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Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [currently smokes, ex-smoker, never smoked, unknown]
●
Alcohol Use [current drinker, former drinker, non-drinker, unknown]
Vital Signs
●
Systolic and diastolic blood pressure (mmHg)
●
Pulse (bpm)
●
Body temperature (°C)
●
Body weight (kg) – overall and by sex
●
Body weight category (< 60 kg, ≥ 60 kg)
●
Height (cm)
●
Body Mass Index (kg/m2)
●
BMI Category 
○
Underweight [< 18.5 kg/m2]
○
Normal [≥ 18.5 and < 25 kg/m2]
○
Overweight [≥ 25 and < 30 kg/m2]
○
Obese [≥ 30 kg/m2]
Patient Reported Outcomes at Baseline
●
IBDQ – total score and domain scores
●
WPAI-CD – 4 sub-scores
●
CSS – total score
●
FACIT-Fatigue – total score and 13 item scores 
●
EQ-5D-5L – Index score and Vas Pain
●
SF-36 – 8 domain scores, PCS and MCS
●
Average Daily Stool Frequency
●
Average Daily Abdominal Pain


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Other Assessments at Baseline
●
CDAI 
●
SES-CD 
●
Crohn's Disease Duration (years)
●
Fecal calprotectin
●
Baseline corticosteroid use (yes, no) 
●
Baseline immunomodulator use (yes, no)
●
Biologics failure history (0, 1, >1)
●
TNF failure history (0, 1, >1) within bio-IR population
●
Vedolizumab failure history (yes, no) within bio-IR population
●
Ustekinumab failure history (yes, no) within bio-IR population
●
hs-CRP
●
Draining fistulas (yes, no) 
●
Non-draining fistulas (yes, no)
●
Anal fissures (yes, no)
●
Crohn's Disease Location Per SES-CD (colonic only, ileal only, ileal-colonic)
●
Extra Intestinal Manifestation (yes, no)
In addition, some clinical tests at baseline such as TB test, pregnancy test and 
electrocardiogram assessment will be summarized. Crohn's Disease history (Montreal 
classification) and Crohn's Disease surgical history will be summarized separately as well.
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report. The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group. The system organ class (SOC) will be 
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order within each SOC. Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of any 
study drug.  A concomitant medication for 12-Week Induction Period is defined as any 
medication other than study drug that (1) was started prior to the first dose of study drug 
and continued to be taken after the first dose of study drug in the 12-Week Induction 
Period or (2) was started after the first dose of study drug during the 12-Week Induction 
Period, but prior to the first dose of Induction Period 2 if the subject enters Induction 
Period 2 or prior to the first dose of M16-000 if the subject enters M16-000, or prior to the 
last dose + 140 days if the subject does not enter Induction Period 2 nor M16-000.
A concomitant medication for Induction Period 2 is defined as any medication other than 
study drug that (1) was started prior to the first dose of study drug in Induction Period 2 
and continued to be taken after the first dose of study drug in Induction Period 2 or (2) 
was started after the first dose of study drug in Induction Period 2, but prior to first dose 
of M16-000 if the subject enters M16-000, or last dose + 140 days if the subject does not 
enter M16-000.  Information about concomitant medications can be collected up to 
140 days after last dose, as per protocol.
The number and percentage of subjects taking medications will be summarized by generic 
drug name based on the World Health Organization (WHO) Drug Dictionary for both 
prior and concomitant medications.
8.0
Efficacy Analyses
8.1
General Considerations
The primary and secondary efficacy endpoints as specified in Section 3.1 and Section 3.2
will be analyzed based on ITT1A for 12-Week Induction Period.  The difference between 


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treatment groups for the primary and ranked secondary efficacy endpoints will be tested 
with graphical multiplicity adjustment1 to ensure a strong control of family-wise type I 
error rate at significance level α = 0.05 (two-sided) (see Section 11.0).  Analyses of other 
efficacy endpoints for 12-Week Induction Period as specified in Section 3.3 will be 
performed using ITT1A at the nominal significance level α = 0.05 (two-sided) without 
multiplicity adjustment. 
Analyses for other efficacy endpoints as specified in Section 3.3 for Induction Period 2 
will be performed using ITT2A.  Since the Induction Period 2 is for exploratory purpose, 
no multiplicity adjustment will be performed.
For all efficacy endpoints, the descriptive statistics will be provided by period and by 
treatment group in which the subjects were randomized to at the beginning of each period.  
The statistics include number of observations, mean, standard deviation, minimum, 
median, and maximum for continuous variables, and number and percent for discrete 
variables. 
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the actual stratum the subject belongs to.
When all subjects complete their Week 12/PD visit, the database will be locked and un-
blinded for the 12-Week Induction Period.  The planned analysis for the 12-Week 
Induction Period will be performed.  This is the only and final efficacy analysis for the 12-
Week Induction Period.  When all the subjects who enter the Induction Period 2 finish 
Week 24/PD visit, the database will be locked for the whole study and all the planned 
analysis for the Induction Period 2 will be performed.
Analysis of Binary Variables:
For binary variables, frequencies and percentages will be reported for each treatment 
group.  Pairwise comparison of each risankizumab group and placebo will be performed 
using the Cochran Mantel-Haenszel (CMH) test adjusting for stratification factors.  If 
there is a stratum for a treatment group that has no subject in it, a value of 0.1 will be 


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added to all cells in the corresponding table in order to prevent dividing by 0, as suggested 
in Greenland and Robins (1985)3.  Point estimates and 95% confidence interval (CI)s for 
the difference in proportions between each of risankizumab treatment groups and placebo 
will be provided.  Construction of CI for the common risk difference will be based on the 
Mantel-Haenszel estimate adjusting for stratification factors.  For binary endpoints with 
small number of sample size (such as achievement of no draining fistulas at Week 12 in 
subjects with draining fistulas at baseline), or small number of responders (such as 
occurrence of CD-related hospitalization through Week 12), Chi-square test (or Fisher's 
exact test if ≥ 20% of the cells have expected cell count < 5) will be performed.
Analysis of Continuous Variables:
For continuous variables, the model based mean and standard error will be provided.  The 
baseline and visit means will also be presented for each treatment group.  Continuous
variables collected longitudinally will be using a Mixed-Effect Model Repeated 
Measurement (MMRM) model.  Continuous efficacy variables which are collected at only 
one post-baseline visit (such as SES-CD) will be analyzed using an Analysis of 
Covariance (ANCOVA) model.  Point estimates and 95% CIs of mean change from 
baseline within treatment groups, and between each risankizumab treatment group and 
placebo will be provided.  The baseline refers to the last non-missing observation before 
the first administration of any study drug or randomization if no study drug is given.
8.2
Handling of Potential Intercurrent Events
Potential intercurrent events considered in this study include 1) premature discontinuation 
of study drug and 2) initiation or dose escalation of CD-related corticosteroids defined in 
Section 8.2.2. Intercurrent events will be handled using the following methods for the 
efficacy analysis:
8.2.1
Premature Discontinuation of Study Drug
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8.2.2
CD-Related Corticosteroid Therapy
The CD-related corticosteroids intercurrent event is defined as follows.
●
Subjects not on CD-related corticosteroids (systemic or locally acting 
corticosteroids for CD) at baseline who initiated CD-related corticosteroids 
during the study;
●
Subjects on CD-related systemic corticosteroids at baseline who have dosages 
increased to greater than the prednisone equivalent dose of corticosteroid taken 
at baseline, or initiation of any rectal corticosteroids during the study regardless 
of rectal corticosteroid dose;
●
Subjects on CD-related rectal corticosteroids at baseline who have dosages 
increased to greater than the dose taken at baseline, or initiation of any new 
type of rectal or any systemic corticosteroids during the study.
The time point of the CD-related corticosteroids intercurrent event is defined as the earlier 
date when one or more of the scenarios above occurs for a subject.  As such, all 
measurements at or after the occurrence of the CD-related corticosteroids intercurrent 
event through the end of the study will not be used in the analysis and will be handled as 
specified in Appendix J. 
8.3
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the clinical trials, or missing due to Coronavirus disease 2019
(COVID-19) infection or logistic restriction.
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis, and the interpretation 
of clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 


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recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate.  
The intent is to provide reliable estimates of the treatment effects under the scenario 
without the impact of COVID-19 pandemic.
Missing data for the efficacy analyses will be handled using the methods described below.
Handling of missing data in IBDQ and FACIT-Fatigue is shown in Appendix F and 
Appendix G. 
8.3.1
Categorical Endpoints
For binary efficacy endpoints, missing data will be handled using the following 
approaches:
●
The primary approach for handling missing data in the analysis of binary
endpoints will use Non-Responder Imputation (NRI) while incorporating 
Multiple Imputation (MI) to handle missing data due to COVID-19 (NRI-C).
○
The NRI-C will categorize any subject who does not have an evaluation 
during a pre-specified visit window (either due to missing assessment or 
due to early withdrawal from the study) as a non-responder for the visit. 
The only exception is that missing data due to COVID-19 infection or 
logistical restriction will be handled by MI.  At each visit, subjects will be 
characterized as responders or non-responders based on MI imputed values 
if missing due to Covid-19, otherwise subjects will be considered as non-
responder for missing due to other reasons in the NRI-C approach. Of 
note, subjects will be counted as non-responders thereafter and will not be 
imputed by MI after the CD-related corticosteroids censoring time point as 
specified in Section 8.2.2 and Appendix J.
●
A sensitivity analysis for binary endpoints will use NRI with No special data 
handling for missing due to COVID-19 (NRI-NC).


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○
NRI-NC will be performed in the same way as NRI-C without the 
exception above.  Missing due to COVID-19 infection or logistical 
restriction will also be counted as non-responders. This is the same 
method as "NRI" as defined in the protocol.
●
Details on MI method are described below:  
○
Markov Chain Monte Carlo (MCMC) will be first applied to augment data 
into monotonic missing pattern, where applicable, and PROC MI will be 
used to generate 30 datasets using the regression method.  If the binary 
endpoints are derived from the continuous variables, PROC MI will be 
applied to the continuous variables.  The variables to be included in the 
imputation model are: treatment group, randomization stratification factors 
(Number of prior biologics failed (0, 1, > 1), baseline steroid use (Yes, 
No)), age, gender, weight and if applicable, baseline measurement and 
post-baseline measurements at each visit up to the end of the analysis 
period.  The random seed for MCMC and the random seed for PROC MI 
are specified in Appendix H.  The imputed post-baseline measurements 
will be rounded to the same precision as the observed data before the 
determination of responder status.  Prior to applying CMH model, subjects 
will be characterized as responders or non-responders based on MI 
imputed values if missing due to Covid-19, otherwise subjects will be 
considered as non-responder for missing due to other reasons in the NRI-C 
approach.  Using the CMH model adjusted by randomization stratification 
factors, the endpoints will be analyzed using each of the 30 imputed 
datasets.  SAS PROC MIANALYZE will be used to generate the final 
inferences of the risk difference between the risankizumab treatment group 
and placebo group, using Rubin's rule.  The CD-related corticosteroid 
censoring rule, as specified in Section 8.2.2 and Appendix J, will be 
applied before and after applying MI for efficacy assessments.
8.3.2
Continuous Endpoints
For continuous efficacy endpoints where Mixed-Effect Model Repeat Measurement 
(MMRM) analysis or Analysis of Covariance (ANCOVA) is performed, missing data will 
be handled using the following approaches.


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●
Mixed-Effect Model Repeat Measurement (MMRM):  The repeat measurement 
analysis will be conducted using a mixed model including observed 
measurements at all post-baseline visits, after the CD-related corticosteroids 
censoring rule is applied (see Section 8.2.2 and Appendix J).  The mixed model 
includes the categorical fixed effects of treatment, visit and treatment-by-visit 
interaction, stratification factors at randomization, and the continuous fixed 
covariates of baseline measurement.  An unstructured variance covariance 
matrix will be used.  Parameter estimation is based on the method of restrictive 
maximum likelihood (REML).  MMRM will be the primary approach in the 
analysis of continuous variables. 
●
ANCOVA-C: For continuous efficacy variables that are collected at only one 
post-baseline visit (such as SES-CD), the missing data due to COVID-19 will 
be imputed using MI first before applying the ANCOVA model.
In addition, As Observed (AO) and Pattern Mixture Model (PMM) will be performed as 
sensitivity analysis, if appropriate, for categorical or continuous endpoints.
●
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 censoring for steroids or not.
●
Pattern Mixture Model (PMM): Subjects will be classified into pre-specified 
missing data patterns and the pattern variables will be defined based on these 
patterns.  The random effect PMM5 approach will be performed, which 
includes the pattern variables in the model to examine the effect of missing-
data patterns on the outcomes of interest.  PROC GLIMMIX will be used in 
PMM approach for handling categorical endpoints, and PROC MIXED will be 
used for handling continuous endpoints.  The model includes categorical effects 
of treatment, visit, treatment-by-visit interaction, missing-data pattern and 
treatment-by-pattern interaction, and the main stratification factors at 
randomization, and the continuous fixed covariates of baseline measurement, if 
applicable.  The overall treatment effect can be estimated by averaging over the 
estimates from the different missing-data patterns.


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8.4
Primary Efficacy Endpoint(s) and Analyses
8.4.1
Primary Efficacy Endpoint(s)
The co-primary endpoints for the primary analysis of efficacy are:
●
For US specific protocol:
○
The achievement of CDAI clinical remission at Week 12 
○
The achievement of endoscopic response at Week 12
●
For global protocol outside US:
○
The achievement of clinical remission at Week 12 
○
The achievement of endoscopic response at Week 12
The primary estimand for US specific protocol is the following:
●
Difference in the percentage of subjects achieving CDAI clinical remission at 
Week 12 regardless of premature discontinuation of study drug and without 
initiation or dose escalation of CD-related corticosteroids (See Section 8.2.2) in 
each of the risankizumab 1200mg IV and risankizumab 600mg IV groups in 
comparison with the placebo group in the ITT1A population
●
Difference in the percentage of subjects achieving endoscopic response at 
Week 12 regardless of premature discontinuation of study drug and without 
initiation or dose escalation of CD-related corticosteroids (See Section 8.2.2) in 
each of the risankizumab 1200mg IV and risankizumab 600mg IV groups in 
comparison with the placebo group in the ITT1A population.
The primary estimand for global protocol outside US is the following:
●
Difference in the percentage of subjects achieving clinical remission at Week 
12 regardless of premature discontinuation of study drug and without initiation 
or dose escalation of CD-related corticosteroids (See Section 8.2.2) in each of 
the risankizumab 1200mg IV and risankizumab 600mg IV groups in 
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●
Difference in the percentage of subjects achieving endoscopic response at 
Week 12 regardless of premature discontinuation of study drug and without 
initiation or dose escalation of CD-related corticosteroids (See Section 8.2.2) in 
each of the risankizumab 1200mg IV and risankizumab 600mg IV groups in 
comparison with the placebo group in the ITT1A population.
Details in estimand definition are outlined in Appendix J.
8.4.2
Handling of Missing Data for the Primary Efficacy 
Endpoint(s)
The NRI-C approach for handling missing data will be used for primary analysis for the 
co-primary endpoints for the 12-Week Induction Period.
The NRI-NC and PMM approaches for handling missing data will be conducted as 
sensitivity analyses for the co-primary endpoints for the 12-Week Induction Period if 
applicable.  For PMM approach, the pre-specified missing-data patterns are given as 
below.  Other missing data patterns could be explored if deemed necessary.
Missing-data Patterns
Non-completers (missing at Week 4 or at Week 8 or at Week 12)
Completers
8.4.3
Primary Efficacy Analysis
The co-primary endpoints will be analyzed between placebo and each of risankizumab 
600 mg IV and 1200 mg IV groups using the CMH test, stratified by the randomization 
factors of number of prior biologics failed (0, 1, > 1) and baseline steroid use (Yes, No) 
based on ITT1A.  A CMH based two-sided 95% CI for the difference between treatment 
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8.4.4
Additional Analyses of the Primary Efficacy Endpoint(s)
For the co-primary efficacy endpoints, an additional analysis using the same CMH test
will be performed using As Observed (AO) data handling without any imputation. The 
analysis will be conducted using the ITT1A population.
8.5
Secondary Efficacy Analyses
8.5.1
Key Secondary Efficacy Analyses
The estimands corresponding to the secondary efficacy endpoints are defined in Section 
2.1.  Details in estimand definition for the key secondary endpoints are outlined in 
Appendix J.
In general, continuous secondary efficacy endpoints with repeat measurements will be 
analyzed using a MMRM model including factors for treatment group, visit, visit by 
treatment interaction, stratification variables and the continuous fixed covariates of 
baseline measurement.  The MMRM analysis is considered primary for inferential 
purposes.  Continuous secondary efficacy variables which are collected at only one post-
baseline visit (such as SES-CD) will be analyzed using ANCOVA-C approach. 
Categorical secondary efficacy variables will be analyzed using the CMH test controlling 
for stratification variables (prior biologics failed [0, 1, > 1] and baseline steroid use [Yes, 
No]), except for the endpoints related to draining fistulas and CD-related hospitalization.  
A CMH based two-sided 95% CI for the difference between each risankizumab treatment 
group and placebo group will be constructed.  The endpoints of "The achievement of no 
draining fistulas at Week 12 in subjects with draining fistulas at baseline" and 
"Occurrence of CD-related hospitalization through Week 12" will be analyzed using Chi-
square test (or Fisher's exact test if ≥ 20% of the cells have expected cell count < 5). 
The NRI-C method will be the primary approach for missing data handling for categorical 
secondary endpoints except for CD-related hospitalization and draining fistulas.  The 
endpoint of "The achievement of no draining fistulas at Week 12 in subjects with draining 
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small sample size.  The endpoint of "Occurrence of CD-related hospitalization through 
Week 12" will be analyzed based on the observed data using AO approach only. 
In addition, NRI-NC for missing data handling will be applied as sensitivity analyses for 
the binary secondary endpoints except for CD-related hospitalization and draining fistulas
endpoints. 
Analysis of PMM will also be performed as sensitivity analyses for ranked secondary 
endpoints as appropriate.  Analysis of PMM will not be performed for the endpoint of 
"The achievement of no draining fistulas at Week 12 in subjects with draining fistulas at 
baseline" due to the small sample size.
8.5.2
Supportive Secondary Efficacy Analyses
For the categorical secondary efficacy endpoints, the same CMH analysis will be repeated 
using As Observed (AO) data handling without any imputation as an additional analysis.
The analysis will be conducted using the ITT1A population.
8.6
Additional Efficacy Analyses
Other continuous and categorical efficacy endpoints for the 12-Week Induction Period 
will be analyzed using ITT1A similarly as the secondary efficacy endpoints as described 
in Section 8.5.  No multiplicity adjustment will be performed.  The chi-square test (or 
Fisher's exact test if ≥ 20% of the cells have expected cell count < 5 for analyses of binary 
outcomes) will be used for the following endpoints:
●
Patient Global Impression of Severity (PGIS) response at Week 4, Week 8, 
Week 12 respectively
●
Patient Global Impression of Change (PGIC) response at Week 4, Week 8, 
Week 12 respectively
●
The achievement of no draining fistulas at Week 4, Week 8, Week 12 
respectively, in subjects with draining fistulas at baseline
●
The achievement of no non-draining fistulas at Week 4, Week 8, Week 12 
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●
The achievement of no anal fissure at Week 4, Week 8, Week 12 respectively, 
in subjects with anal fissure at baseline
PGIC response and PGIS response endpoints will be analyzed based on the observed data 
using AO approach.  The draining fistulas endpoint, non-draining fistulas endpoint and 
anal fissure endpoint will be analyzed using NRI-NC approach due to the small sample 
size.
Analyses for other efficacy endpoints as specified in Section 3.3 for Induction Period 2 
will be performed using ITT2A for exploratory purpose.  Point estimate and 95% CI for 
each treatment group as well as point estimate and 95% CI for pairwise treatment 
differences (i.e., risankizumab 1200mg IV – risankizumab 360mg SC, risankizumab 
1200mg IV – risankizumab 180mg SC, risankizumab 360mg SC - risankizumab 180mg 
SC) will be presented based on the observed data for randomized subjects using AO 
approach.  The subjects in the non-randomized risankizumab 1200mg IV group, who took 
the placebo in the 12-Week Induction Period, will be displayed separately using 
descriptive statistics.  No p-value will be provided.
In addition, the following selected endpoints will be analyzed using ITT1B for 
exploratory purpose.  Point estimate and 95% CI for each treatment group as well as point 
estimate and 95% CI for treatment differences between each risankizumab group and the 
placebo group will be presented based on the observed data using AO approach.  No p-
value will be provided.  
●
The achievement of CDAI clinical remission at Week 12 
●
The achievement of clinical remission at Week 12 
●
The achievement of endoscopic response at Week 12
●
The achievement of SES-CD ≤ 2 or 2 points reduction from the baseline at 
Week 12 among the subjects with baseline eligible SES-CD of >=3 to 6 for 
ileocolonic or colonic disease or 3 for isolated ileal disease
●
The achievement of any reduction in SES-CD at Week 12


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Similarly, the following selected endpoints will be analyzed using ITT2B for exploratory 
purpose.  Point estimate and 95% CI for each treatment group as well as point estimate 
and 95% CI for pairwise treatment differences will be presented based on the observed 
data for randomized subjects using AO approach.  The subjects in the non-randomized 
risankizumab 1200mg IV group, who took the placebo in the 12-Week Induction Period, 
will be displayed separately using descriptive statistics.  No p-value will be provided.  
●
The achievement of CDAI clinical remission at Week 24 
●
The achievement of clinical remission at Week 24 
●
The achievement of endoscopic response at Week 24
●
The achievement of SES-CD ≤ 2 or 2 points reduction from the baseline at 
Week 24 among the subjects with baseline eligible SES-CD of >=3 to <6 for 
ileocolonic or colonic disease or 3 for isolated ileal disease
●
The achievement of any reduction in SES-CD at Week 24
8.7
Efficacy Subgroup Analyses
To evaluate the consistency of the efficacy over demographic and other baseline 
characteristics, subgroup analysis will be performed for the co-primary endpoints for the 
subgroups listed in Table 1 below using ITT1A. 
For efficacy subgroup analysis, point estimate and 95% CI for each treatment group as 
well as point estimate and 95% CI for treatment differences between each risankizumab 
group and the placebo group will be presented.  No p-value will be provided.  If any of the 
resulting subgroups except for age, sex and race has fewer than 10% of the planned study 
size, the subgroup analyses for that category will not be presented.


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Table 1.
Subgroups for Efficacy Analysis
Subgroup Factor
Categories
Age
< 18, [18, 40), [40, 65), ≥ 65
Sex
Male or Female
Weight
< 60 kg or ≥ 60 kg
Race
White or non-White
Geographic Region
North America, South/Central America, 
Western Europe, Eastern Europe, Asia, 
Other
Prior Biologics Failed
Yes or No, if Yes, please analyze (1, > 1)  
Prior Ustekinumab Failure (within bio-IR population)
Prior TNF Failure (within subjects with Prior TNF Failure)
Prior Vedolizumab Failure (within bio-IR population)
Baseline Steroids Use 
Yes or No
1, >1
Yes or No
Yes or No
Baseline Immunodulator Use
Yes or No
Baseline CDAI
≤ median or > median
Baseline CDAI
≤ 300 or > 300
Baseline SF
≤ median or > median
Baseline AP Score
≤ median or > median
Baseline SES-CD
≤ median or > median
Baseline SES-CD
≤ 15 or > 15
Disease Duration at Baseline
≤ median or > median
Disease Duration at Baseline
≤ 5 years or > 5 years
Baseline hs-CRP 
≤ median or > median
Baseline hs-CRP 
≤ 5 mg/L or > 5 mg/L
Baseline Calprotectin
≤ median or > median
Baseline Calprotectin
≤ 250 mg/kg or > 250 mg/kg 
Crohn's Disease Location at Baseline
Colonic only, Ileal only, Ileal-colonic
9.0
Safety Analyses
9.1
General Considerations
Safety analyses will include reporting of adverse events, laboratory, and vital signs 
measurements by treatment group, including a total group for all subjects on 


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risankizumab.  All safety analyses will be performed for the 12-Week Induction Period at 
the time of database lock.  The separate safety analysis for subjects who received at least 
one dose of risankizumab during the Induction Period 2 will be performed.
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 risk difference and 95% CI between each risankizumab 
group and placebo group will be presented for safety analysis.
For the safety analysis, subjects are assigned to a treatment group based on the treatment 
actually received, regardless of the treatment randomized.
For the 12-Week Induction Period analysis, the baseline for safety analysis is defined as 
the last available measurement before study drug administration for all subjects.  For the 
Induction Period 2 analysis, the baseline for safety analysis will be the last available 
measurement before the first dose of risankizumab administration in Induction Period 2.
Missing safety data will not be imputed.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock. The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.


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9.2.1
Treatment-Emergent Adverse Events
12-Week Induction Period:  Treatment emergent AEs (TEAEs) for the 12-Week 
Induction Period are defined as events that begin either on or after the first dose of the 
study drug in the 12-Week Induction Period and until the first dose of study drug in the 
Study M16-000 if the subject is enrolled into the Study M16-000 or until first dose of 
study drug in Induction Period 2 if the subject is enrolled into Induction Period 2, or 
within 140 days after the last dose administration of the study drug in 12-Week Induction 
Period if the subject does not participate in the Study M16-000 or the Induction Period 2.
Induction Period 2:  Treatment-emergent AEs (TEAEs) for the Induction Period 2 are 
defined as events that begin either on or after the first dose of the study medication in the 
Induction Period 2 and until first dose of study drug in the Study M16-000 if the subject is 
enrolled into the Study M16-000 or within 140 days after the last dose of the study drug in 
the Induction Period 2 if the subject does not participate in the Study M16-000.  
All Risankizumab:  Treatment-emergent AEs (TEAEs) for "All Risankizumab" are 
defined as events that begin either on or after the first dose of risankizumab and until first 
dose of study drug in the Study M16-000 if the subject is enrolled into the Study M16-000 
or within 140 days after the last dose of risankizumab in the study if the subject does not 
participate in the Study M16-000.
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 treatment-emergent AEs will be summarized overall, as well as by primary MedDRA 
SOC and Preferred Term. The SOCs will be presented in alphabetical order, and the PTs 
will be presented in alphabetical order within each SOC.


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The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.  The risk difference and 95% CI between each risankizumab group and 
placebo group will be presented.
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 COVID-19
●
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
●
Treatment-emergent AEs of Safety Interest including
○
Adjudicated MACE events
○
Serious infections
○
Active Tuberculosis
○
Opportunistic infections excluding tuberculosis and herpes zoster
○
Malignant tumors
○
Malignancies excluding NMSC
○
Hypersensitivity – serious events only
○
Adjudicated anaphylactic reaction
○
Serious anaphylactic reaction
●
All deaths
○
Deaths occurring ≤ 140 days after last dose of study drug
○
Deaths occurring > 140 days after last dose of study drug
○
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The exposure adjusted rate for AE overview will be presented as well. 
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT; and by 
subject number and SOC and PT. Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise. In addition, if the same 
adverse event occurs multiple times within a subject, the highest severity and level of 
relationship to investigational product will be reported.
In addition, treatment-emergent adverse events and SAEs will be summarized by PT and 
sorted by decreasing frequency for the total risankizumab group. 
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided for all TEAEs, where AEs 
per 100 patient-years of exposure are defined as the number of AEs divided by the total
exposure in 100 patient-years, where the total exposure is calculated as the time from the 
first study drug dose date in the relevant period/study to the last study drug dose date 
+140 days in the relevant period/study or the first dose date of the next period/study, 
whichever occurs earlier.
The exposure adjusted incidence rate (censored at the time of first event) may be 
conducted for deaths and selected Areas of Safety Interest categories including 
adjudicated cardiovascular events, malignant tumors, non-melanoma skin cancer 
(NMSC), and malignant tumors excluding NMSC, as appropriate. 


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9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.  Exposure-adjusted SAEs per 100 
patient-years by SOC and PT will be provided as well.
9.2.6
Areas of Safety Interest
The Areas of Safety Interest (ASI) categories are listed in Appendix B, which include 
serious infections, tuberculosis, opportunistic infections, herpes zoster, malignancies, 
hypersensitivity reaction, anaphylactic reactions, hepatic events, injection site reactions, 
adjudicated cardiovascular events.  These will be summarized by PT and will be based on 
standardized or company MedDRA queries (SMQs or CMQs), or based on adjudication 
results.  The risk difference and 95% CI between each risankizumab group and placebo 
group will be presented.  Exposure-adjusted ASI per 100 patient-years by PT or 
adjudication terms will be provided as well.
Additional ASI may be considered for tabulation/summary based on recommendations 
from Clinical and Safety teams, as deemed appropriate.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded. The 
clinical laboratory tests defined in the protocol (e.g., hematology and clinical chemistry) 
will be summarized.
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 
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observations, baseline mean, and visit mean. The change from baseline mean, standard 
error, and 95% CI will be presented for the mean change from baseline within each 
treatment group and difference between each risankizumab group and placebo group.
Changes in laboratory parameters will be tabulated using shift tables either based on 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 will be evaluated based on Potentially Clinically Significant
(PCS) criteria (Appendix C). For each laboratory PCS criterion, the number and 
percentage of subjects who have a laboratory value meeting the criteria will be 
summarized by treatment group. Listings will be provided to summarize subject-level 
laboratory data for subjects meeting PCS criteria.
The liver-specific laboratory tests include the serum glutamic pyruvic transaminase 
(SGPT/ALT), serum glutamic-oxaloacetic transaminase (SGOT/AST), alkaline 
phosphatase (ALP), and total bilirubin (TBL).  The frequencies and percentages of 
subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN


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●
Alkaline phosphatase ≥ 1.5 × ULN
●
(ALT and/or AST ≥ 3 × ULN) and (TBL ≥ 1.5 × ULN)
●
(ALT and/or AST ≥ 3 × ULN) and (TBL ≥ 2 × ULN)
where ULN is the upper limit of normal.
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 at 
any post-baseline visit:
●
ALT ≥ 3 × ULN, or
●
AST ≥ 3 × ULN, or
●
Alkaline phosphatase ≥ 1.5 × ULN, or
●
Total bilirubin ≥ 1.5 × ULN.
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions at any post-baseline visit will be provided:
●
ALT of > 3 × ULN or AST of > 3 × ULN, 
●
Total bilirubin ≥ 2 × ULN.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate and body 
weight 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% 


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CI will be presented for the mean change from baseline within each treatment group and 
difference between each risankizumab group and placebo group.
Key vital sign variables will be evaluated based on potentially clinically significant (PCS) 
criteria (Appendix C). For each vital sign PCS criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized. Listings 
will be provided to summarize subject-level vital sign data for subjects meeting PCS
criteria.
10.0
Interim Analyses
There will be no efficacy interim analysis planned for this study.
10.1
Data Monitoring Committee
An external independent data monitoring committee (DMC) composed of persons 
independent of AbbVie and with relevant expertise in their field will review unblinded 
safety data from the ongoing study.  The primary responsibility of the DMC will be to 
protect the safety of the subjects participating in this study.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no alpha adjustment is needed.
11.0
Overall Type-I Error Control
Both of the co-primary efficacy endpoints will be tested at two-sided significance level of 
0.025 to control the overall type I error rate at alpha = 0.05 (2-sided) for the multiple 
comparisons between each risankizumab dose versus placebo using a multiple testing 
procedure.1  In addition, the overall type I error rate of efficacy evaluation based on the 
co-primary and ranked secondary endpoints for the two doses will be strongly controlled 
at 0.05 (2-sided) level.  Specifically, the testing will utilize the sequence of hypothesis 
testing for the co-primary endpoints followed by the ranked secondary endpoints in the


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order as specified in Section 3.2, and will begin with testing each of the co-primary 
endpoints using α of 0.025 (2-sided) for each dose compared to placebo.  If both co-
primary endpoints achieve statistical significance within a dose level, continued testing 
will follow a pre-specified weight of α allocation between the single hypothesis within the 
family, as well as between the families of hypotheses across the doses (denoted as node).  
The iterative graphical testing procedures are provided in Figure 1 for US specific 
protocol and Figure 2 for global protocol outside US.
In the graphs, the arrows specify the weight of α allocation between nodes.  Once a 
hypothesis is rejected (i.e., deemed the endpoint is significant) at its assigned significance 
level, its significance level will be allocated to the subsequent node.  If more than 
one arrow originates from a node, the significance level will be split between multiple 
subsequent nodes following the pre-specified weight.  The numbers on the arrows denote 
the weights.  For example, the weight 1 denotes 100% transfer of significance level to the 
next node, and the weight 1/2 denotes 50% and 50% splitting of significance level 
between the 2 nodes connected to it.
The two co-primary endpoints will be tested at the same α level in order to allocate the 
significance level to the next sequence of ranked secondary endpoints in the graph.  The 
last group of ranked secondary endpoints in the graph will be tested using the Holm 
procedure.2


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Figure 2.
Graphical Multiple Testing Procedure for US Specific Protocol


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Figure 3.
Graphical Multiple Testing Procedure for Global Protocol Outside 
US


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12.0
Version History
Table 2.
SAP Version History Summary
SAP Version
Date
1.0
06 OCT 2017
2.0
13 NOV 2018
3.0
25 FEB 2019
4.0
07 FEB 2020
Summary of Changes Between the Previous Version and the Current Version
1.
This version of SAP (Version 5) incorporated estimand language according to the 
guidance provided in ICH E9 R1 Addendum.
2.
The co-primary endpoints and ranked secondary endpoints have been updated for 
US/FDA regulatory purpose in Section 3.0 based on FDA's comments.
3.
Two endpoints (WPAI-CD and SF-36) have been moved from exploratory 
endpoints to ranked secondary endpoints for outside US/FDA regulatory purpose in 
Section 3.0 based on EMA's comments.
4.
The endpoints related to non-draining fistula and anal fissure, and the endpoints 
related to FACIT-Fatigue have been added as other efficacy endpoints in Section 
3.0 for clinical importance.
5.
The sample size justification has been updated in Section 2.4 to clarify the sample 
size calculation for different regulatory purpose. 
6.
The exclusion of the data from non-compliance sites has been added in Section 4.0.
7.
The graphic multiple testing procedures have been updated in Section 11.0 for 
US/FDA regulatory purpose and outside US/FDA regulatory purpose respectively. 
8.
Missing imputation methods have been updated in Section 8.3 to include more 
details for multiple imputation method, as well as introducing NRI-C method for 
handling missing data due to Covid-19 pandemic.


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9.
CD-related corticosteroid therapy censoring convention has been added in Section 
8.2.2 to clarify the rules for efficacy censoring.
10.
The primary, secondary and other efficacy analyses have been updated in Section 
8.0 to use NRI-C method as the primary approach for handling missing data.
11.
The language of "The risk difference and 95% CI between risankizumab group and 
placebo group will be presented for safety analysis" has been added in Section 9.0
based on agency's feedback.
12.
The language of "The exposure adjusted incidence rate (censored at the time of first 
event) may be conducted for selected ASI categories as appropriate."  has been 
added in Section 9.2.4 based on agency's feedback.
13.
Details about FACIT-Fatigue has been added in Appendix G.
14.
Areas of Safety Interest (ASI) have been updated in Appendix B to revise the ASI 
categories following new standard.
15.
Random seeds have been added in Appendix H.
Summary of Changes Between the Current Version of SAP and Protocol
1. Missing imputation methods have been updated to include more details for multiple 
imputation method, as well as introducing NRI-C method for handling missing data 
due to Covid-19 pandemic.
2. Two endpoints (WPAI-CD and SF-36) have been moved from exploratory endpoints 
to ranked secondary endpoints for outside US/FDA regulatory purpose based on 
EMA's comments.
13.0
References
1.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.


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2.
Holm S.  A simple sequentially rejective multiple test procedure.  Scand J Stat.  
1979;6:65-70.
3.
Greenland S, Robins JM.  Estimation of a common effect parameter from sparse 
follow-up data.  Biometrics.  1985;41(1):55-68.
4.
Berglund PA.  An introduction to multiple imputation of complex sample data 
using SAS® v9.2.  2010.  Report No:  21-2010.
5.
Hedeker D, Gibbons RD.  Application of random-effects pattern-mixture models 
for missing data in longitudinal studies. Psychological methods.  1997;2(1):64-78.


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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.
Areas of Safety Interest (ASI)
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 
all CETERM values with 
CEDECOD = 
"Cardiovascular death" or 
CETERM="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, 
Tuberculosis, 
opportunistic infections 
and herpes zoster
Serious 
infections
Serious AEs 
within the 
Infections and 
Infestations SOC
PTs
Y
Active 
Tuberculosis
Active 
Tuberculosis  
CMQ (code 
80000188)
PTs
Y
Opportunistic 
infections 
excluding 
tuberculosis and 
herpes zoster
Opportunistic 
infections 
excluding 
tuberculosis and 
herpes zoster
CMQ 
(code 80000189)
PTs
Y
Herpes Zoster
Herpes zoster 
CMQ (code 
80000175)
PTs
N
Malignancies
Malignant 
Tumours
Narrow
Malignant 
tumours 
(SMQ 20000194)
PTs
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
N
Serious 
hypersensitivity
Serious AE 
within narrow
Hypersensitivity 
(SMQ 20000214)
PTs
Y
Anaphylactic Reaction
Adjudicated 
Anaphylactic 
Reaction
Adjudicated terms 
will be identified 
using SDTM data 
(e.g., CE and PR 
domains).
Adjudicated term defined in the 
charter
Y
Serious 
anaphylactic 
reactions
Serious AE 
within narrow
Anaphylactic 
reaction 
(SMQ 20000021); 
PTs
Y


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ASI Grouping
Categories 
(ASI)
Search Criteria
Terms to Display
Include 
in AE 
Overview 
(Y/N)
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
Injection site 
reaction 
assessment and 
infusion site 
reaction 
assessment CRFs
Terms on the CRF


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Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints
The criteria for Potentially Clinically Significant (PCS) laboratory findings are described 
in Table C-1 and Table C-2, and the PCS criteria for vital sign findings are described in 
Table C-3.
Table C-1.
Criteria for Potentially Clinically Significant Hematology Values
Hematology Variables
Units
Definition of Grade 3 or Greater
Very Low
Hemoglobin
g/dL
< 8.0
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 a higher grade than the baseline CTC grade to be considered a potentially 
clinically significant finding.
Table C-2.
Criteria for Potentially Clinically Significant Chemistry Values
Chemistry Variables
Units
Definition of Grade 3 or Greater
Very Low
Very High
TBL
mcmol/L
> 3.0 × 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 (corrected for 
albumin)
mmol/L
< 1.75
> 3.1
Total Cholesterol
mmol/L
> 10.34
GGT
> 5.0 × ULN
ALP
> 5.0 × ULN


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Table C-2.
Criteria for Potentially Clinically Significant Chemistry Values
(Continued)
Note:
A post-baseline value must be a higher grade than the baseline CTC grade to be considered a potentially 
clinically significant finding.
Table C-3.
Criteria for Potentially Clinically Significant 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.
Crohn's Disease Activity Index (CDAI)
The Crohn's Disease Activity Index (CDAI) is a composite instrument that includes 
patient symptoms evaluated over 7 days (abdominal pain, stool frequency and general 
well-being), as well as physical and laboratory findings.  These items are scored 
individually, weighted, and do not contribute equally to the overall score.  The CDAI is 
derived from summing up the weighted individual scores of eight items as outlined below: 
Factor
Subtotal
1.
Number of liquid or very soft stools 
(Record the frequency per day)
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
2
2.
Abdominal pain rating:
0 = none, 1 = mild, 2 = moderate,
3 = severe
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
5
3.
General well-being:
0 = generally well, 1 = slightly 
underpar, 2 = poor, 3 = very poor, 
4 = terrible
__+___+___+___+___+___+___=___
Days:  1    2    3    4    5    6    7    Sum
×
7
4.
Number of 6 listed categories the 
subject now has
Check all items that apply:
☐
Arthritis/arthralgia
☐
Iritis/uveitis
☐
Erythema nodosum/pyoderma 
gangrenosum/aphthous 
stomatitis
☐
Fissure, abscess and/or anal 
fistula (draining/non-draining)
☐
Other cutaneous fistula 
(draining/non-draining) Fistula
☐
Fever over 100°F (37.8°C) 
during past week
_________________________________ 
_________________________________
Record "0" if no categories checked
×
20
5.
Taking Lomotil/Imodium/
Loperamide/opiates for diarrhea
0 = no, 1 = yes
________
×
30
6.
Abdominal mass
0 = none, 2 = questionable,
5 = defined
________
×
10
7.
Hematocrit:  ___.__
Male:  (47 – hematocrit) =
Female:  (42 – hematocrit) =
Subtotal
If hematocrit > normal, enter "0"
×
6


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Factor
Subtotal
8.
Body weight:  ___.__(kg)
Standard weight:  ___.__(kg)
100 × [1 – (Body wt/Standard wt)] =
Percent below standard weight:  ______
If body wt > std. wt, enter "0"
×
1
Total
CDAI with higher score indicates more severe disease.  For the calculation of CDAI and 
components at each visit, the following rules will be applied:
●
The 7 most recent useable days out of the 14 days preceding the visit will be 
used.
●
If 7 useable days are not available, an average will be calculated based on the 
number of days with available data as follows:
○
Data for days with missing diary entries will be imputed using the average 
of the non-missing days, in order to calculate a CDAI and components 
based on 7 days.
○
An average for the most recent 6 days will be calculated if data for only 
6 days are available
○
An average for the most recent 5 days will be calculated if data for only 
5 days are available
○
An average for the most recent 4 days will be calculated if data for only 
4 days are available
●
If the minimum number of days of diary data (i.e., 4 days for CDAI and 
components) are not available, then the subject's score for that visit will be 
considered missing.
The CDAI score is set to missing under the following conditions:
1.
If there are less than 4 days of any diary data.
2.
If any component other than the diary data is missing.


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Appendix E.
Simple Endoscopic Score – CD (SES-CD)
SES-CD is calculated based the sum of individual segment values for four endoscopic 
variables (presence and size of ulcers, ulcerated surface, affected surface and presence of 
narrowing).  Each variable in each segment be scored 0 to 3 resulting in SES-CD values 
ranging from 0 to 56 with higher scores indicating more severe disease.
SES-CD Scoring:
Rectum
Sigmoid and 
Left Colon
Transverse 
Colon
Right 
Colon
Ileum
Total
Size of Ulcers 
Enter:
0 if none
1 if aphthous ulcers (Ø 0.1 to 0.5 cm)
2 if large ulcers (Ø 0.5 to 2 cm)
3 if very large ulcers (Ø > 2 cm)
Ulcerated Surface
Enter:
0 if none
1 if < 10%
2 if 10% – 30%
3 if > 30%
Affected Surface
Enter:
0 if unaffected segments
1 if < 50%
2 if 50% – 75%
3 if > 75%


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Rectum
Sigmoid and 
Left Colon
Transverse 
Colon
Right 
Colon
Ileum
Total
Presence of Narrowing
Enter:
0 if none
1 if single, can be passed
2 if multiple, can be passed
3 if cannot be passed
TOTAL = 


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Appendix F.
Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ is a 32-item (ranges 1 – 7) self-report questionnaire for patients with IBD to 
evaluate the patient reported outcomes across 4 dimensions:  bowel symptoms (loose 
stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social 
function (work attendance, need to cancel social events), and emotional function (anger, 
depression, irritability).  The IBDQ total Score ranges from 32 to 224 with a higher score 
indicating better outcome.  
The derivation of the IBDQ total score and the four IBDQ domain scores are as follows:
Domain Scores:
●
S1. BOWEL SYMPTOM:           Q1 + Q5 + Q9 + Q13 + Q17 + Q20 + Q22 + 
Q24 + Q26 + Q29
[score ranges from 10 - 70],
●
S2. SOCIAL FUNCTION:          Q4 + Q8 + Q12 + Q16 + Q28
[score ranges from 5 - 35],
●
S3. SYSTEMIC SYMPTOM:     Q2 + Q6 + Q10 + Q14 + Q18
[score ranges from 5 - 35],


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●
S4. EMOTIONAL FUNCTION: Q3 + Q7 + Q11 + Q15 + Q19 + Q21 + Q23 + 
Q25 + Q27 + Q30 + Q31 + Q32
[score ranges from 12 - 84].
Total Score:
IBDQ Total Score = SUM of (bowel symptom domain score, social function domain 
score, systemic symptom domain score, emotional function domain score).
The following convention applies to Inflammatory Bowel Disease Questionnaire 
(IBDQ):
When not more than 20% of items in a domain of IBDQ were missing, it was substituted 
with the mean values from the items completed in the particular domain; otherwise, they 
were treated as missing.  The 20% threshold in each domain is:  bowel symptom domain:  
2 items, systemic symptom domain:  1 item, social function domain:  1 item, emotional 
function domain:  2 items.  If any of the 4 domain scores is missing, the total IBDQ score 
will be set to missing.


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Appendix G.
FACIT-Fatigue
The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system is a 
comprehensive compilation of questions that measure health related quality of life in 
patients with cancer and other chronic diseases (www.facit.org).  The FACIT-Fatigue 
scale is a symptom-specific subscale of FACIT and is composed of 13 fatigue-related 
questions as follows.  The response to each question is as follows: 0=Not at all, 1=A little 
bit, 2=Somewhat, 3=Quite a bit, 4=Very much.
1.
I feel fatigued
2.
I feel weak all over
3.
I feel listless ("washed out")
4.
I feel tired
5.
I have trouble starting things because I am tired
6.
I have trouble finishing things because I am tired
7.
I have energy
8.
I am able to do my usual activities
9.
I need to sleep during the day
10.
I am too tired to eat
11.
I need help doing my usual activities
12.
I am frustrated by being too tired to do the things I want to do
13.
I have to limit my social activity because I am tired
In order to have higher values representing lower level of fatigue, all of the items, except 
for item 7 "I have energy" and item 8 "I am able to do my usual activities," are assigned 
reversed scores: reversed score = 4 – raw score.  The total FACIT-Fatigue score will then 
be calculated as follows:


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●
FACIT-Fatigue score = 13∀[Sum of answered-item scores / Number of items 
answered]
The score ranges from 0 to 52, 52 being the lowest level of fatigue. 
When there are missing data, provided that more than 50% of the items (i.e., at least 7 of 
13 items) were answered in FACIT-Fatigue questionnaire, the total score will not be 
deemed as missing but be calculated as the mean response for all the non-missing-value
items.  If less than 50% of the items were answered, the total score will have a missing 
value.


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Appendix H.
Random Seeds
In case of non-convergence, the random seed will be updated by adding 100000 at each 
attempt until convergence of model happens.
Table H-1.  Random Seeds for NRI-C
Variables
Random Seed
MCMC Procedure
PROC MI
CDAI
50001
60001
SES-CD (for 20 individual variables)
50002
60002
SF score
50003
60003
AP score
50004
60004
EIM
50005
60005
FACIT-Fatigue
50006
60006
IBDQ total score
50009
60009
PGIS
50010
60010
PGIC
50011
60011


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


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Appendix J.
Definition of Estimand for Primary and Ranked Secondary 
Endpoints
Estimand
Attributes of the Estimand
Population
Endpoint(s)
Treatment
Intercurrent Events
Statistical 
Summary
Primary
ITT1A
population 
For US 
specific 
protocol:
Achievement 
of CDAI 
clinical 
remission at 
Week 12.
Achievement 
of endoscopic 
response at 
Week 12.
For global 
protocol 
outside US:
Achievement 
of clinical 
remission at 
Week 12.
Achievement 
of endoscopic 
response at 
Week 12.
Risankizumab 
1200 mg IV 
vs. placebo
Risankizumab 
600 mg IV vs. 
placebo
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of CD-
related corticosteroids
All data after IE1 will 
be used.
All subjects will be 
considered as non-
responders at or after 
IE2
Proportion of 
subjects 
achieving 
CDAI 
clinical 
remission.
Proportion of 
subjects 
achieving 
clinical 
remission.
Proportion of 
subjects 
achieving 
endoscopic 
response.
Binary Key 
Secondary
ITT1A
population
Binary 
secondary 
endpoints as 
defined in 
Section 3.2
except for 
CD-related 
hospitalizatio
n endpoint
Risankizumab
1200 mg IV 
vs. placebo
Risankizumab
600 mg IV vs. 
placebo
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of CD-
related corticosteroids
All data after IE1 will 
be used.
All subjects will be 
considered as non-
responders at or after 
IE2
Proportion of 
subjects 
achieving 
each binary 
secondary 
endpoint


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Estimand
Attributes of the Estimand
Population
Endpoint(s)
Treatment
Intercurrent Events
Statistical 
Summary
Continuous 
Key 
Secondary
ITT1A
population 
Change from 
Baseline in 
IBDQ total 
score/FACIT-
F score at 
Week 12
Risankizumab
1200 mg IV 
vs. placebo
Risankizumab
600 mg IV vs. 
placebo
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of CD-
related corticosteroids
All data after IE1 will 
be used.
All data after IE2 will 
not be used.  MMRM 
will be the primary 
approach for the 
analysis. 
Mean change 
from 
Baseline in 
IBDQ total 
score and 
FACIT-F 
score
CD-related 
hospitalizati
on
ITT1A
population
Occurrence of 
CD-related 
hospitalizatio
n through 
Week 12
Risankizumab
1200 mg IV 
vs. placebo
Risankizumab
600 mg IV vs. 
placebo
IE1: premature 
discontinuation of 
study drug
IE2: Initiation or dose 
escalation of CD-
related corticosteroids
All data after IE1 will 
be used.
All data after IE2 will 
be used
Proportion of 
subjects 
having at 
least one
CD-related 
hospitalizati
on through 
Week 12
In addition, a supplementary analysis corresponding to the AO analysis specified in 
Section 8.3.2 will be conducted for the primary and key binary secondary endpoints in 
which all data after IE1 and IE2 will be included in the analysis.