Clinical trial NCT03478787
Conditions: Psoriasis
Keywords: Plaque Psoriasis
Sponsor: AbbVie
Start date: 2018-05-08; Completion date: 2020-07-08
Enrollment: 327 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this study is to evaluate the efficacy and safety of risankizumab compared with secukinumab for the treatment of adult subjects with moderate to severe plaque psoriasis who are candidates for systemic therapy.

Detailed description:

Arms: arm 1: Participants randomized to risankizumab receive 2 injections of active risankizumab (150 mg total dosage) subcutaneously (SC) at Weeks 0 and 4, and then every 12 weeks (q12w) thereafter until the last dose at Week 40 (Week 64 for participants in France). arm 2: Participants randomized to secukinumab receive 2 injections of active secukinumab (300 mg total dosage) SC at Weeks 0, 1, 2, 3, and 4, and then every 4 weeks (q4w) thereafter until the last dose at Week 48.
Interventions: intervention 1: risankizumab intervention 2: secukinumab
Intervention descriptions: intervention 1: Subcutaneous (SC) injection intervention 2: Subcutaneous (SC) injection

Protocol documents:
Prot_000.pdf: 
NCT03478787


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO PATIENTS
9
3
STUDY OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES
11
3.2
PRIMARY ENDPOINT
11
3.3
SECONDARY ENDPOINTS
11
3.4
SAFETY PARAMETERS
11
3.5
PHARMACOKINETIC ENDPOINTS
11
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
13
5
STUDY ACTIVITIES
15
5.1
ELIGIBILITY CRITERIA
15
5.2
CONTRACEPTION RECOMMENDATIONS
18
5.3
PROHIBITED MEDICATIONS AND THERAPY
19
5.4
PRIOR AND CONCOMITANT THERAPY
19
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
20
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
21
5.7
STUDY DRUG
21
5.8
RANDOMIZATION/DRUG ASSIGNMENT
22
5.9
PROTOCOL DEVIATIONS
22
6
SAFETY CONSIDERATIONS
23
6.1
COMPLAINTS AND ADVERSE EVENTS
23
6.2
CARDIOVASCULAR ADJUDICATION COMMITTEE
26
6.3
ANAPHYLAXIS ADJUDICATION COMMITTEE
27
6.4
PRODUCT COMPLAINT
27


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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
27
7.1
STATISTICAL AND ANALYTICAL PLANS
27
7.2
DEFINITION FOR ANALYSIS POPULATIONS
28
7.3
STATISTICAL ANALYSES FOR EFFICACY
28
7.4
ANALYSES OF PHARMACOKINETICS AND IMMUNOGENICITY
29
7.4
STATISTICAL ANALYSES FOR SAFETY
29
8
ETHICS
30
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
30
8.2
ETHICAL CONDUCT OF THE STUDY
30
8.3
SUBJECT CONFIDENTIALITY
30
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
30
10 DATA QUALITY ASSURANCE
30
11 COMPLETION OF THE STUDY
31
12 REFERENCES
31
LIST OF TABLES
TABLE 1.
TASKS OF THE EFFICACY ASSESSOR AND INVESTIGATOR
15
TABLE 2.
IDENTITY OF INVESTIGATIONAL PRODUCT
21
TABLE 3.
AREAS OF SAFETY INTEREST
25
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
13
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
33
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
35


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APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
36
APPENDIX D.
ACTIVITY SCHEDULE
37
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
42








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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
This study will provide essential data comparing risankizumab vs. secukinumab for the treatment of 
patients with moderate to severe plaque psoriasis who are candidates for systemic therapy.
Psoriasis is a chronic debilitating immune-mediated disease characterized by marked inflammation of 
the skin that results in thick, erythematous, scaly plaques involving the skin.  In most developed 
countries, prevalence is between 1.5 and 5%.1  Twenty-five percent of patients have moderate to severe 
disease with a considerable negative impact on psychosocial and economic status.2  It is increasingly 
recognized that psoriasis is more than a superficial disease, with 30% of patients having joint 
involvement and a high correlation between psoriasis and obesity, diabetes, depression, metabolic 
syndrome, and cardiovascular disease.3  While the majority of mild psoriasis patients are managed with 
topical therapies, those with moderate or severe and/or refractory disease usually require phototherapy 
and/or systemic therapy.
Oral systemic agents provide modest efficacy; therefore, patients are increasingly being treated with 
biologic agents such as tumor necrosis factor (TNF)-alpha inhibitors (etanercept and adalimumab), the 
interleukin (IL)-12/23 inhibitor (ustekinumab),4 and IL-17 receptor A (IL-17RA) inhibitors (secukinumab 
and ixekizumab).  Ustekinumab, a monoclonal antibody (mAb) targeting the common p40 subunit of 
IL-12 and IL-23, was approved for the treatment of psoriasis and psoriatic arthritis in 2009, and for 
Crohn's disease in 2016.  Secukinumab, an anti-IL-17A antibody was approved in the US for the 
treatment of psoriasis in 2015 and for the treatment of psoriatic arthritis and ankylosing spondylitis in 
2016.  In addition, other recently approved systemic agents for the treatment of psoriasis include an 
IL-17RA inhibitor (brodalumab) and an IL-23p19 inhibitor (guselkumab), which are also under 
investigation for psoriatic arthritis.  Another anti-IL-23p19 antibody, tildrakizumab, has been studied in 
Phase 3 psoriasis trials.
While the clinical efficacy of ustekinumab indicates a role for both IL-12 and IL-23 in the pathogenesis of 
psoriasis,5more recent data suggest that IL-23 is disproportionately involved in the maintenance of 
chronic psoriasis.5  IL-23 is thought to be involved in the pathophysiology of psoriasis via induction and 
maintenance of Th17 type cells, and other IL-23 responsive cells.  This is supported by recent clinical 
data indicating that monoclonal antibodies (mAb) that block IL-17A (the cytokine produced by Th17 
cells), IL-17RA, and direct blockade of IL-23 with IL-23p19 inhibitors, have high efficacy in psoriasis.6-9
There is still clinical need for increased efficacy as the most effective anti-TNF and anti-IL-12/23 agents 
provide approximately 75% improvement in psoriasis in about 50 to 80% of patients and these 
responses can be lost over time.  While the anti-IL-17A, -IL-17RA, and -IL-23p19 agents 
(i.e., secukinumab, ixekizumab, brodalumab and guselkumab) may provide better efficacy than anti-TNF 
therapies and ustekinumab, they require monthly or every other month injections.6,9
Risankizumab is currently being developed for the treatment of psoriasis (Phase 3 studies concluded) 
and Crohn's disease (currently in Phase 3 studies) and the treatment of ulcerative colitis, psoriatic 
arthritis, and asthma (in Phase 2 studies).  Risankizumab is a humanized mAb of the immunoglobin 


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(Ig)G1 subclass directed towards the p19 subunit of IL-23.  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.
The current study compares the safety and efficacy of risankizumab vs. secukinumab in subjects with 
moderate to severe plaque psoriasis.  For a more detailed description of the risankizumab drug profile, 
refer to the latest version of the investigator's brochure (IB).10  For a more detailed description of the 
secukinumab drug profile, refer to the latest version of the approved labeling information in your 
country.
Clinical Hypothesis
Risankizumab will be superior to secukinumab in subjects with moderate to severe plaque psoriasis in 
the achievement of ≥ 90% reduction from baseline Psoriasis Area Severity Index (PASI 90) at Week 52 
and will be non-inferior to secukinumab in the achievement of PASI 90 at week 16 with non-inferiority 
margin of 12%.
2.2 Benefits and Risks to Patients
Despite the availability of various psoriasis therapies, many subjects still do not respond adequately to 
these treatments, or gradually lose response over time.  Risankizumab is an antagonist specific for IL-23, 
which has been implicated in the pathophysiology of immune-mediated inflammatory diseases.  Non-
clinical studies have shown that risankizumab has minimal inhibitory effects on IL-12, the inhibition of 
which has been associated with increased risk of serious infections.11,12  Selective IL-23 inhibition may 
not increase risk of serious infection, including mycobacterial infections.13
In Phase 1 and Phase 2 studies of risankizumab in patients with psoriasis, the majority of subjects 
receiving risankizumab achieved 90% improvement of their disease and risankizumab was well 
tolerated.  Recently, positive top-line results were observed from 3 pivotal Phase 3 clinical trials 
evaluating risankizumab compared to ustekinumab, placebo, or adalimumab, for the treatment of 
patients with moderate to severe plaque psoriasis.14-16  After 16 weeks of treatment, all 3 studies met 
their co-primary endpoints of at least a 90% improvement in the Psoriasis Area and Severity Index 
(PASI 90) and a static physician global assessment (sPGA) score of clear or almost clear (sPGA 0 or 1) for 
risankizumab (150 mg) treatment vs. ustekinumab, placebo and adalimumab.14-16  The safety profile was 
consistent with that observed in Phase 2 clinical trials, with no important identified risks for 
risankizumab.  As with many immune modulating agents, risankizumab may impair immune function 
resulting in a risk of infection.  This will be monitored by collection of all AEs during the treatment and 
observation periods.  In addition, subjects with active infection will not be included in the study.
IL-23 inhibition is not known to increase the risk of tuberculosis (TB) infection or impair the response to 
TB infection in animal models.  No cases of active TB were reported across all risankizumab studies.  
Across all Phase 3 psoriasis studies, of the 71 subjects with latent tuberculosis (TB) who were 
concurrently treated with risankizumab and appropriate TB prophylaxis treatment, none developed 
active TB during the mean follow-up of 67.9 weeks.  In 2 Phase 3 psoriasis studies (Studies M15-992 and 
M15-997), of 31 subjects with latent TB at screening who did not receive prophylaxis during the study, 
none developed active TB over a mean follow-up of 58.5 weeks.  Thus, low risk subjects with positive 
QuantiFERON®-TB Gold testing do not need to be treated with antituberculosis therapy prior to 


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receiving risankizumab, but should be carefully monitored for any sign of TB reactivation.  However, to 
address the label of secukinumab, subjects with latent TB may only be randomized to this trial if 
sufficient treatment has been initiated according to local routine clinical practice (please refer to the TB 
Screen section of the Operations Manual for further guidance).
There is not enough information at this time to rule out a risk of cancer with risankizumab, but this risk 
is considered small with this type of compound as experience with the anti-IL-12/23 mAb ustekinumab 
has not suggested significant risk for cancer or serious infection.
Although rare, a potential for hepatic adverse events is under constant surveillance by sponsors and 
regulators.  Therefore, this study requires timely detection, evaluation, and follow-up of laboratory 
alterations in selected liver laboratory parameters to ensure subject safety.
Increases in major adverse cardiovascular (MACE) events, including myocardial infarction, 
cerebrovascular accident, and cardiovascular death, were initially reported with anti-IL-12/23 agents, 
such as ustekinumab, although an increased incidence of MACE events was not observed in longer term 
studies.  While the likelihood of increased MACE is small, all suspected cardiovascular events (serious or 
non-serious) observed in this study will be adjudicated.  An independent Cardiovascular Adjudication 
Committee (CAC) will be adjudicating all observed cardio- and cerebro-vascular events and will remain 
blinded to treatment allocation (Section 6.2).  Although Study M16-766 is an open-label study, 
information for adjudication purposes will be provided to the CAC in a blinded manner to ensure 
unbiased assessment.
Local reactions to subcutaneously (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 usually readily detectable, transient in nature, and 
manageable with standard medical treatment.  Subjects will be closely monitored during study drug 
administration.  An independent Anaphylaxis Adjudication Committee (AAC) will be adjudicating 
observed systemic hypersensitivity and anaphylactic events.  The AAC will remain blinded to treatment 
allocation (Section 6.3).
There are no important identified risks for risankizumab.10
In conclusion, the benefit-risk profile of risankizumab is considered appropriate for this stage of clinical 
development.
For further details, please see findings from completed studies, including safety data in the risankizumab 
Investigator Brochure.10
Secukinumab (Cosentyx®) has been approved as a safe and efficacious product for the treatment of 
plaque psoriasis in a number of countries for at least 3 years.  Please refer to the local label available to 
you for information regarding the efficacy and safety of this product.


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3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
The main objective of this study is to evaluate the efficacy and safety of risankizumab compared with 
secukinumab for the treatment of adult subjects with moderate to severe plaque psoriasis who are 
candidates for systemic therapy.
3.2 Primary Endpoint
The 2 primary endpoints are:
!
Proportion of subjects achieving a PASI 90 response at Week 52; superiority of risankizumab vs. 
secukinumab.
!
Proportion of subjects achieving a PASI 90 response at Week 16; non-inferiority of risankizumab 
vs. secukinumab with non-inferiority margin of 12%.
3.3 Secondary Endpoints
The multiplicity-controlled key secondary endpoints are:
!
Proportion of subjects achieving a PASI 100 response at Week 52; superiority of risankizumab vs. 
secukinumab;
!
Proportion of subjects achieving an sPGA 0 or 1 at Week 52; superiority of risankizumab vs. 
secukinumab;
!
Proportion of subjects achieving a PASI 75 response at Week 52; superiority of risankizumab vs. 
secukinumab.
Other efficacy endpoints include change and percent change from baseline in PASI and body surface 
area (BSA) as well as multiple levels of PASI and sPGA responses at all visits.
3.4 Safety Parameters
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiograms (ECG), and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.
3.5 Pharmacokinetic Endpoints
Serum risankizumab concentrations, anti-drug antibodies (ADA), and neutralizing antibodies (NAb) will 
be determined at the visits indicated in the Activity Schedule (Appendix D).  Serum risankizumab 
concentrations will be summarized at each sampling time point using descriptive statistics.  Anti-drug 


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antibody titers will be tabulated for each subject at the respective study visits.  The number and 
percentage of subjects with ADA and NAb will be calculated.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3, global, multicenter, randomized, open-label, efficacy assessor-blinded, active 
comparator study examining the effect of 150 mg risankizumab every 12 weeks vs. 300 mg secukinumab 
every 4 weeks in patients with moderate to severe plaque psoriasis.
Eligible subjects will be randomized to receive risankizumab or secukinumab in a 1:1 ratio.  The study is 
designed to randomize approximately 310 subjects (155 subjects/arm).  Participants randomized to 
receive secukinumab will receive 2 injections of active secukinumab (300 mg total dosage) 
subcutaneously at Weeks 0, 1, 2, 3, and 4, and then every 4 weeks (q4w) thereafter until the last dose at 
Week 48.  Participants randomized to receive risankizumab will receive 2 injections of active 
risankizumab (150 mg total dosage) subcutaneously at Weeks 0 and 4, and then every 12 weeks (q12w) 
thereafter until the last dose at Week 40.  Subjects in France who were randomized to risankizumab will 
have two additional dosing visits at Week 52 and Week 64 and a follow-up phone call 20 weeks after the 
last study drug dose.
The study duration will be up to 88 weeks.  The study comprises a 30-day Screening Period, a 52-week 
open-label study period and a 16-week follow-up period.  The follow-up period consists of a follow-up 
phone call 20 weeks after the last dose of study drug.  Subjects in France who were randomized to 
risankizumab will have two additional dosing visits at Week 52 and Week 64 and a follow-up phone call 
20 weeks after the last study drug dose.
The study schematic is shown in Figure 1.  Further details regarding study procedures are located in the 
Operations Manual.
See Section 5 for information regarding eligibility criteria.
The first primary analysis will be performed when the last subject completes the Week 16 visit.  There 
will not be a modification to trial conduct based on the results of the analysis.  Efficacy accessors will 
remain blinded for the duration of the study.


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Figure 1.
Study Schematic
4.2 Discussion of Study Design
Choice of Control Group
An active comparator group randomized to receive secukinumab will be used in this study to examine 
the effect of 150 mg risankizumab every 12 weeks vs. 300 mg secukinumab every 4 weeks in patients 
with moderate to severe plaque psoriasis.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with moderate to 
severe plaque psoriasis.  All clinical and laboratory procedures in this study are standard and generally 
accepted.
Suitability of Subject Population
Subjects who have stable moderate to severe chronic plaque psoriasis with or without psoriatic arthritis 
(definition includes ≥ 10% BSA psoriasis involvement, sPGA score of ≥ 3, and PASI ≥ 12 at Screening and 


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Baseline Visit) and who are candidates for systemic therapy are eligible for this study.  The selection 
criteria relating to safety guarantee that subjects enrolled can safely be treated with risankizumab based 
on the current knowledge of this drug.
Selection of Doses in the Study
The selected dose for risankizumab is aligned with the dose tested in Phase 3 global studies in subjects 
with moderate to severe plaque psoriasis.  The dose selected for evaluation is expected to be efficacious 
with an acceptable safety profile and considered appropriate for the treatment of patients with plaque 
psoriasis.  For secukinumab, the selected dose is as recommended in the approved product labeling for 
the treatment of plaque psoriasis.
Blinded Efficacy Assessor
A qualified physician (may be a non-dermatologist) or designee (may be a non-physician) from the site 
will be responsible for performing the efficacy assessments, including PASI, BSA, and sPGA at all
appropriate study visits (Table 1).  The site will make every attempt to have the same qualified physician 
or designee perform these assessments throughout the study for each subject.  The efficacy assessor 
must remain blinded to patient's treatment, clinical laboratory results, and all subject safety data during 
the course of the study.  The efficacy assessor will not view or discuss any subject specific safety data 
with the investigators or any other site personnel, with the exception of the dermatologic safety findings 
requiring urgent medical attention.  The efficacy assessor therefore cannot be the Principal Investigator.  
The efficacy assessor will not access patient's electronic case report form (eCRF) and will document the 
dermatologic assessments and potential dermatologic safety findings on paper worksheets that will be 
filed as source in the patient's record.  It is recommended that each study site has a designated back-up 
for the efficacy assessor.


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Table 1.
Tasks of the Efficacy Assessor and Investigator
Activities
Responsible Party
Assesses PASI, BSA, sPGA
Efficacy Assessora
Looks for any potential dermatologic safety finding
Efficacy Assessor
Documents the efficacy assessments and any potential 
safety findings on worksheets
Efficacy Assessor
Assesses safety
Investigator
Knows treatment allocation
Investigator
Reviews laboratory data
Investigator
Conduct the complete and any targeted physical 
examinationsb
Investigator
Completes the CRF
Investigator, unblinded study team
Documents findings in the e-CRF
Investigator, unblinded study team
Reports information about safety findingsc
Investigator
a.
The efficacy assessor is a physician or a designee that is blinded to all aspects of the study other than the efficacy 
assessments.
b.
The investigator will also look for potential dermatologic safety findings.
c.
If the efficacy assessor identifies a safety issue this will be transmitted to the investigator over the worksheet.  
Dermatologic safety findings requiring urgent medical attention will be the only safety issues that the efficacy assessor 
may discuss with the investigator.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening 
or study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old.
3. Laboratory values meeting the following criteria within the screening period prior to the 
first dose of study drug:


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!
Serum aspartate transaminase (AST) < 2 × ULN;
!
Serum alanine transaminase (ALT) < 2 × ULN;
!
Serum direct bilirubin ≤ 2.0 mg/dL; except for subjects with isolated elevation of indirect 
bilirubin relating to a confirmed diagnosis of Gilbert syndrome;
!
Total white blood cell (WBC) count > 3,000/μL;
!
Absolute neutrophil count (ANC) > 1,500/μL;
!
Platelet count > 100,000/μL;
!
Hemoglobin > 8 g/dL.
4. Are willing or able to comply with procedures required in this protocol.
Disease Activity
5. Diagnosis of chronic plaque psoriasis with or without psoriatic arthritis for at least 6 months 
before the Baseline Visit;
6. Subject has stable moderate to severe chronic plaque psoriasis with or without psoriatic 
arthritis
!
Subject has ≥ 10% BSA psoriasis involvement, sPGA score of ≥ 3, and PASI ≥ 12 at Screening 
and Baseline Visit;
7. Subject must be a candidate for systemic therapy as assessed by the investigator;
8. Subject must be an acceptable candidate to receive secukinumab according to the local label 
for this compound.
Subject History
9. No history of:
!
Erythrodermic psoriasis, generalized or localized pustular psoriasis, medication-induced or 
medication-exacerbated psoriasis, or new onset guttate psoriasis;
!
Active skin disease other than psoriasis that could interfere with the assessment of 
psoriasis;
!
Chronic infections including HIV, viral hepatitis (hepatitis B, hepatitis C), and/ or active 
tuberculosis.  Subjects with a positive QuantiFERON®-TB /PPD test result 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.  If presence of latent tuberculosis is 
established, then treatment must have been initiated and maintained according to local 
country guidelines.  The patient will not be eligible for randomization if latent tuberculosis is 
present and is untreated as per local guidelines.
Active systemic infection during the last 2 weeks prior to Baseline Visit (exception:  common 
cold) prior to Baseline Visit, as assessed by the investigator;


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10. No history of any documented active or suspected malignancy or history of any malignancy 
within the last 5 years except for successfully treated non-melanoma skin cancer (NMSC) or 
localized carcinoma in situ of the cervix;
11. No history of clinically significant (per Investigator's judgment) drug or alcohol abuse within 
the last 6 months.
12. No history of inflammatory bowel disease.
13. No history of underlying medical diseases or problems including but not limited to the 
following:
!
Subject has been a previous recipient of a solid organ transplant;
!
Evidence of a current or previous disease, medical condition (including chronic alcohol or 
drug abuse) other than psoriasis, surgical procedure (i.e., organ transplant), medical 
examination finding (including vital signs and ECG), or laboratory value at the screening visit 
outside the given range that, in the opinion of the investigator, is clinically significant and 
would make the study participant unreliable to adhere to the protocol or to complete the 
trial, compromise the safety of the patient, or compromise the quality of the data.
14. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class.
15. No major surgery performed within 12 weeks prior to randomization or planned to be 
performed during the conduct of the trial (e.g., hip replacement, aneurysm removal, stomach 
ligation) as assessed by the Investigator.
Contraception
16. Women of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and must have a negative urine pregnancy test at the Baseline Visit and following 
visits (as outlined in the Study Activity Table of this protocol) prior to study drug administration;
17. If female, subject must be postmenopausal OR permanently surgically sterile OR for a 
woman of child bearing potential be practicing at least one protocol-specified method of birth 
control (Section 5.2) that is effective from the Baseline Visit through at least 140 days (20 weeks) 
after the last dose of study drug;
18. Female subjects must not be pregnant, breastfeeding or considering becoming pregnant 
during the study and for approximately 140 days (20 weeks) after the last dose of the study 
drug;
19. Additional local requirements may apply.
Concomitant Medications
20. No previous exposure to risankizumab;
21. No previous exposure to secukinumab;
22. No use of any restricted medication as specified in the prohibited medications/therapy 
section or any drug considered likely to interfere with the safe conduct of the study.


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23. Subject must not have been treated with any investigational drug within 30 days or 5 half 
lives of the drug (whichever is longer) prior to the first dose of study drug or currently be 
enrolled in another clinical study.
5.2 Contraception Recommendations
If female, subject must be either postmenopausal or practicing a birth control method outlined below.
Postmenopausal is defined as:
!
Age > 55 years with no menses for 12 or more months without an alternative medical cause.
!
Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause 
AND an FSH level > 40 IU/L.
OR
!
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy).
Women of childbearing potential are defined as having experienced menarche and are:
!
Not postmenopausal (as defined above);
!
Not permanently sterilized (e.g., hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy).
Women of childbearing potential must practice at least 1 of the following methods of birth control 
through 20 weeks after the last study drug dose is given.
!
Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal) associated with inhibition of ovulation initiated at least 1 month prior to study 
Baseline Day 1.
!
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study Baseline Day 1.
!
Bilateral tubal occlusion/ligation.
!
Intrauterine device (IUD).
!
Intrauterine hormone-releasing system (IUS).
!
Vasectomized sexual partner(s) (provided the vasectomized partner has received medical 
assessment of the surgical success and is the sole sexual partner of the trial participant).
!
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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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.3 Prohibited Medications and Therapy
Prohibited medications and therapy are defined as using the following prohibited concomitant psoriasis 
treatments within the specified timeframe prior to Baseline Visit and throughout the study.
1.
Any systemic biologic to treat psoriasis:
!
Adalimumab, infliximab and biosimilar versions within 12 weeks;
!
Etanercept and biosimilar versions within 6 weeks;
!
Ixekizumab, brodalumab, and other IL-17 inhibitors within 16 weeks;
!
Ustekinumab, efalizumab, guselkumab, tildrakizumab, mirikizumab, and other IL-23 
inhibitors within 24 weeks.
2.
Systemic non-biologic therapy for psoriasis, including but not limited to cyclosporine, 
corticosteroids, methotrexate, oral retinoids, apremilast, and fumaric acid derivatives within 
4 weeks.
3.
Phototherapy treatment, laser therapy, tanning booth, or extended sun exposure that could 
affect disease severity or interfere with disease assessments within 4 weeks.
4.
Topical psoriasis treatments, including but not limited to corticosteroids, anthralin, 
calcipotriene, topical vitamin D derivatives, retinoids, urea, alpha- or beta-hydroxyl acids, and 
medicated shampoos (for example those that contain > 3% salicylic acid, corticosteroids, coal tar 
or vitamin D3 analogues) within 2 weeks.
!
Exception:  Subjects are allowed to use bland (containing no psoriasis treatment) emollients 
and shampoos and/or low potency topical corticosteroids on the palms, soles, face, 
inframammary area, and groin only.
5.
Treatment with an experimental non-biologic for psoriasis within 4 weeks or five half-lives of the 
drug (whichever is longer).
6.
Treatment with an experimental biologic for psoriasis within 12 weeks or five half-lives of the 
drug (whichever is longer).
Receipt of any live vaccine within 6 weeks or is expected to need live vaccination during study 
participation, including at least 20 weeks after the last dose of study drug.
5.4 Prior and Concomitant Therapy
Stable doses of concomitant therapies for chronic conditions, for which neither the condition nor the 
treatment are judged to exclude the patient from participation are permissible.  All concomitant 
medications should be carefully evaluated by the investigator, and the clinical monitor should be 
contacted when there are questions regarding concomitant medications.
Any medication or vaccine (including over the counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject has received from 4 weeks prior to screening or receives during 


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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
the study must be recorded along with the reason for use, date(s) of administration including start and 
end dates, and dosage information including dose, route, and frequency on the appropriate eCRF.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with risankizumab can be located in the 
Risankizumab Investigator's Brochure.
Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 4 weeks, 
whichever is longer, prior to initial study drug administration.  Subjects must be consented for the study 
prior to discontinuing any prohibited medications for the purpose of meeting study eligibility.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject will be discontinued from study drug if any of the following occurs:
!
Clinically significant abnormal laboratory result(s) or adverse event(s) that preclude continuation 
of the study medication, as determined by the Investigator and the Therapeutic Area Medical 
Director (TAMD) (as applicable).
!
The Investigator believes withdrawal from the study is in the best interest of the subject.
!
The subject requests withdrawal from the study.
!
Inclusion and/or exclusion criteria violation(s) are noted after the subject started study drug, if 
continuation of the study drug would place the subject at risk as determined by the TAMD, after 
consultation with the Investigator
!
Subjects need to initiate a prohibited medications and continuation of the study drug would 
place the subject at risk as determined by the AbbVie TAMD
!
Subject develops active TB at any time during the study.
!
Subject becomes pregnant while participating in the study.
!
Subject is diagnosed with a malignancy.  Exception:  localized non-melanoma skin cancer or 
carcinoma in-situ of the cervix, where discontinuation is at the discretion of the Investigator.
!
Subject is significantly non-compliant with study procedures.
!
Post baseline occurrence of any of the following laboratory tests:
!
ALT or AST > 8 × ULN;
!
ALT or AST > 5 × ULN for more than 2 weeks;
!
ALT or AST > 3 × ULN and Total Bilirubin > 2 × ULN or INR > 1.5;
!
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  At a minimum, 2 telephone calls must be made and 
1 certified letter must be sent and documented in the subject's source documentation.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The Investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the Investigator.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue the study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they discontinue 
treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit (PD visit) should be completed as soon as 
possible, preferably within 2 weeks.  In addition, if subject is willing, a 140-day follow-up phone call after 
the last dose of study drug will be completed to ensure all treatment-emergent AEs/serious AEs (SAEs) 
have been resolved.
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the Investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
Investigator's best clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.
5.7 Study Drug
Study site staff will administer study drug or comparator subcutaneously (risankizumab 150 mg 
[2 × 75 mg pre-filled syringe] or secukinumab 300 mg [2 × 150 mg pre-filled syringe]) (Table 2).
Table 2.
Identity of Investigational Product
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Risankizumab 
(ABBV-066)
Solution for 
injection in pre-
filled syringe
75 mg/0.83 mL
Subcutaneous 
injection
Boehringer 
Ingelheim
Secukinumab
Solution for 
injection in pre-
filled syringe
150 mg/mL
Subcutaneous 
injection
Novartis
AbbVie will not supply drug other than risankizumab and secukinumab.  Risankizumab and secukinumab
will be packaged in quantities sufficient to accommodate study design.  Each kit will be labeled per local 
requirements and this label must remain affixed to the kit.  Upon receipt, study drug should be stored as 


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
specified on the label in their original packaging and kept in a secure location.  A temperature log must 
be maintained for documentation.  Each kit will contain a unique kit number.  This kit number is 
assigned to a subject via interactive response technology (IRT) and encodes the appropriate study drug 
to be dispensed at the subject's corresponding study visit.  All blank spaces on the label will be 
completed by the site staff prior to dispensing to subjects.  Study drug will only be used for the conduct 
of this study.  Instructions for drug preparation will be provided by AbbVie.
5.8 Randomization/Drug Assignment
Each subject will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  Subjects may only be rescreened one time.  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.  Subjects will be randomized in a 1:1 ratio to one of 
two treatment groups:
!
Group 1:  Risankizumab 150 mg (N = 155)
!
Group 2:  Secukinumab 300 mg (N = 155)
The randomization will be stratified by weight (≤ 100 kg vs. > 100 kg) and prior systemic biologic for 
psoriasis.
This is an open-label study; however, the efficacy assessor will remain blinded to each subject's 
treatment, clinical laboratory results, and all subject safety data during the course of the study.
In the event of a medical emergency in which the Investigator believes that knowledge of study drug 
treatment is required for the efficacy assessor, reasonable efforts must be made to contact the AbbVie 
Emergency Contact.
The date and reason that the efficacy assessor's blind was broken must be recorded in the source 
documentation and eCRF, as applicable.
5.9 Protocol Deviations
The Investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the Investigator is responsible for notifying Independent Ethics Committee 
(IEC)/Independent Review Board (IRB), regulatory authorities (as applicable), and AbbVie.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
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.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Medical Complaints/Adverse Events and Serious Adverse Events
An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that 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.
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study.  All adverse events will be followed to a satisfactory conclusion.
If an adverse event meets any of the following criteria, it is to be reported to AbbVie or CRO (as 
appropriate) as a serious adverse event 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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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.
All adverse events reported from the time of study drug administration until 140 days or 5 half-lives 
(taking both risankizumab and secukinumab half-lives into consideration) after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, serious adverse events and protocol-related non-serious adverse events will be collected from 
the time the subject signs the study-specific informed consent.
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.
Areas of Safety Interest
Infections, especially opportunistic infections, are a theoretical risk with immunomodulators.  Subjects 
will be screened and monitored throughout the study for Areas of Safety Interest (ASI) (Table 3).  
Screening procedures are outlined in the Activity Schedule (Appendix D).
If any of the following serious adverse events (SAEs) are reported, then the following supplemental 
report must be completed.




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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
When criteria are available, events should be graded as described in the National Cancer Institute 
Common Terminology Criteria for Adverse Events.17  If no grading criteria are provided for the reported 
event, the event should be graded as mild, moderate, or severe per the Investigator's judgment.
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Moderate
Minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL).
Severe
Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.  
Life-threatening consequences; urgent intervention indicated.
Death related to AE.
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie within 
1 working day of the site becoming aware of the pregnancy.  Subjects who become pregnant during the 
study must be discontinued (Section 5.5).
Information regarding a pregnancy occurrence in a study subject and the outcome of the pregnancy will 
be collected.
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.
6.2 Cardiovascular Adjudication Committee
An independent adjudication committee will be adjudicating all observed cardio- and cerebro-vascular 
events and will remain blinded to treatment allocation.  The events that are adjudicated and the 
adjudication process will be detailed in the CAC Adjudication Committee Charter.  Dedicated eCRFs will 
be used for:
!
Myocardial Infarction or Unstable Angina Adverse Event;
!
Heart Failure Adverse Event;
!
Cerebral Vascular Accident and Transient Ischemic Attack Adverse Event;
!
Death;
!
Cardiovascular procedures.
In addition, the site may be contacted for additional source documentation for relevant events.


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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.3 Anaphylaxis Adjudication Committee
While no concerns with systemic hypersensitivity have been identified with the use of risankizumab, the 
sponsor has established an independent, blinded, expert committee to adjudicate events of anaphylaxis 
based on pre-specified definition.  This independent external AAC will be adjudicating observed 
suspected anaphylactic reactions and will remain blinded to treatment allocation.  The events that are 
adjudicated and the adjudication process will be detailed in the Anaphylaxis Adjudication Committee 
Charter.  A supplemental Hypersensitivity/Anaphylactic reactions 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.
In the event a serious systemic hypersensitivity reaction such as anaphylaxis occurs while the 
subject/patient is not on site, every effort should be made to obtain serum tryptase and histamine levels 
from the treating facility to help better understand and characterize the diagnosis.
6.4 Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The objectives of the statistical analyses are to evaluate the efficacy and safety of risankizumab versus 
secukinumab in patients with moderate to severe plaque psoriasis both short- and long-term.
For ease of description, Period A refers to Week 0 – 16, and Period B refers to the rest of the study.
The Primary Analysis for all efficacy endpoints pertaining to Period A will be conducted after all 
continuing subjects completed Week 16 and all data pertaining to Period A are cleaned and when a 
database lock will occur to enable the analysis.  This is the one and final efficacy analysis for Period A.  
The results will be included in an interim clinical study report (CSR) to support the efficacy and safety 
evaluation of the initial 16 weeks of treatment.


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The Primary Analysis for all efficacy endpoints in Period B will be conducted after all continuing subjects 
have completed Week 52 and all data pertaining to Week 52 are cleaned and when a database lock will 
occur to enable the analysis.
The efficacy assessors will remain blinded for the duration of the entire study.
The statistical analyses will be described and fully documented in the Statistical Analysis Plan (SAP).  The 
SAP will be finalized prior to the database lock for the Primary Analysis for Period A.  Complete and 
specific details of the statistical analyses will be described in the Statistical Analysis Plan Supplement 
(SAP-S), which will be finalized prior to database lock for the Primary Analysis for Period A as well.  The 
statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The Intent-to-Treat (ITT) Population will be used for the efficacy analyses.
The ITT Population is defined as all subjects who are randomized at Baseline.
The following populations will be used for safety analysis:
!
The Safety Population is defined as all subjects who are randomized at Baseline and received at 
least one dose of study drug.
!
The All Risankizumab Treated (All_RZB) Population is defined as subjects who receive at least 
one dose of risankizumab in the study.
In order to evaluate the impact of major protocol violations on the primary efficacy endpoint in 
Period A, additional sensitivity analyses will be performed on a Per-protocol Population, which excludes 
subjects with major protocol deviations that potentially affect the primary efficacy endpoints.  The 
criteria for exclusion of subjects from the Per-protocol Population will be fully defined in the 
classification plan and the exclusion of subjects from the Per-protocol Population for the analysis in 
Period A will be finalized before the database lock.  Additional sensitivity analysis for the primary 
endpoint in Period B may be performed if deemed necessary.
7.3 Statistical Analyses for Efficacy
Primary Analysis
The efficacy analysis will be conducted in the ITT Population, and Per-protocol Population for Period A, 
and for Period B if defined.  The ITT Population will be analyzed by treatment group as randomized.
Comparison of the primary endpoint will be made between risankizumab group and secukinumab group 
using the Cochran-Mantel-Haenszel test adjusting for the stratification factors.  For the primary analysis, 
Non-Responder Imputation (NRI) will be used.  The analysis will be repeated using last observation 
carried forward (LOCF) and Multiple Imputation (MI).


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
A graphic approach will be utilized for multiplicity control.  Details of multiplicity control and analyses 
methods are provided in the SAP.  Specifically, the initial alpha spending between the 
two primary endpoints will be 0.0375 for Period A, and 0.0125 for Period B.
Sample Size Estimation
The assumptions for the secukinumab Week 16 and Week 52 PASI 90 response rates of 69.7% and 
60.6%, respectively, are based on weighted average from secukinumab studies SCULPTURE, ERASURE, 
FIXTURE, JUNCTURE, and CLEAR.  The assumptions for the risankizumab Week 16 and Week 52 PASI 90 
response rates of 75.1% and 81.3%, respectively, are based on weighted average from UltiMMa-1 and 
UltiMMa-2 trials.
The non-inferiority margin was chosen based on the treatment effect of secukinumab versus placebo in 
PASI 90 response rate at Week 16.  A 12% non-inferiority margin preserves 80% of the treatment effect 
of secukinumab over placebo.
Approximately 310 subjects (155 subjects per treatment group) will provide more than 90% power to 
detect the difference of risankizumab and secukinumab at Week 52 using a two-sided alpha level of 
0.0125, and 90% power to determine the non-inferiority of risankizumab relative to secukinumab using 
a tolerance limit of 12% and a two-sided alpha level of 0.0375 at Week 16.
7.4
Analyses of Pharmacokinetics and Immunogenicity
Serum risankizumab concentrations will be summarized at each sampling time point using descriptive 
statistics.  For immunogenicity assessment, the number and percentage of subjects with ADA and NAb 
will be calculated.  In addition, ADA titers will be tabulated for each subject at the respective study visits.  
Additional analyses combining PK, ADA, and NAb data from this study and other studies may be 
conducted if appropriate.
7.4 Statistical Analyses for Safety
All safety analyses will be performed in the safety populations.
Pre-treatment AEs will be summarized separately.
All treatment-emergent adverse events (AEs), serious adverse events (SAEs), AEs leading to 
discontinuation, and Areas of Safety Interest (ASI) will be collected during the study.  A treatment-
emergent AE (TEAE) is defined as an event with onset or worsening after the first study dose of study 
drug and within 140 days after the last dose of injection for risankizumab or secukinumab 
administrations.  The number and percentages of subjects experiencing TEAE will be tabulated using the 
Medical Dictionary for Drug Regulatory Activities (MedDRA®) system organ class and preferred term.  
Summaries (including percentages and event per 100 patient-year) of SAEs, deaths, AEs leading to 
discontinuation, and Areas of Safety Interest will be provided as well.  For selected laboratory and vital 
signs parameters, mean change from baseline and percentage of subject with evaluations meeting pre-
defined criteria for Potentially Clinically Important values will be summarized.


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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any participant is enrolled.  Any amendment to the protocol 
will require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (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 Investigator are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted and data are generated, documented, and reported 
in compliance with the protocol, ICH GCP, and applicable regulatory requirements.


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11
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 and AbbVie.  Continuation of this study 
beyond this date must be mutually agreed upon in writing by both the investigator 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 must submit, maintain, and archive any records related to the study according to ICH 
GCP and all other applicable regulatory requirements.  If the investigator is not able to retain the 
records, he/she must notify AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the study.  
Selection criteria for this investigator will include level of participation as well as significant knowledge 
of the clinical research, investigational drug, and study protocol.  The signatory investigator for the study 
will review and sign the final study report in accordance with the European Agency for the Evaluation of 
Medicinal Products (EMEA) Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.
12
REFERENCES
1.
World Health Organization.  Global report on psoriasis.  2016.  Available from:  
http://apps.who.int/iris/handle/10665/204417.  Accessed on:  30 October 2017.
2.
Menter A, Griffiths CEM.  Psoriasis 2:  current and future management of psoriasis.  Lancet.  
2007;370:272-84.
3.
Davidovici BB, Sattar N, Joerg PC, et al; Psoriasis Education and Learning Syllabus (PEARLS).  
Psoriasis and systemic inflammatory diseases:  potential mechanistic links between skin disease 
and co-morbid conditions.  J Invest Dermatol.  2010;130(7):1785-96.
4.
Reich K, Puig L, Paul C; TRANSIT investigators.  One-year safety and efficacy of ustekinumab and 
results of dose adjustment after switching from inadequate methotrexate treatment:  the 
TRANSIT randomised trial in moderate-to-severe plaque psoriasis.  Br J Dermatol.  
2014;170(2):435-44.
5.
Smith RLI, Warren RB, Eyre S, et al.  Polymorphisms in the IL-12beta and IL-23R genes are 
associated with psoriasis of early onset in a UK cohort.  J Invest Dermatol.  2008;128(5):1325-7.
6.
Gordon KB, Blauvelt A, Papp KA, et al; UNCOVER-1 study group; UNCOVER-2 study group; 
UNCOVER-3 study group.  Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis.  
N Engl J Med.  2016;375(4):345-56.
7.
Lebwohl M, Strober B, Menter A, et al.  Phase 3 studies comparing brodalumab with 
ustekinumab in psoriasis.  N Engl J Med.  2015;373(14):1318-28.


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8.
Reich K, Armstrong AW, Foley P, et al.  Efficacy and safety of guselkumab, an anti-interleukin-23 
monoclonal antibody, compared with adalimumab for the treatment of patients with moderate 
to severe psoriasis with randomized withdrawal and retreatment:  results from the phase III, 
double-blind, placebo- and active comparator-controlled VOYAGE 2 trial.  J Am Acad Dermatol.  
2017;76(3):418-31.
9.
Blauvelt A, Papp KA, Griffiths CE, et al.  Efficacy and safety of guselkumab, an anti-interleukin-23 
monoclonal antibody, compared with adalimumab for the continuous treatment of patients 
with moderate to severe psoriasis:  results from the phase III, double-blinded, placebo- and 
active comparator-controlled VOYAGE 1 trial.  J Am Acad Dermatol.  2017;76(3):405-17.
10. AbbVie.  Risankizumab Investigator's Brochure Edition 2.  25 October 2017.
11. Filipe-Santos O, Bustamante J, Chapgier A, et al.  Inborn errors of IL-12/23 and IFN-γ-mediated 
immunity:  molecular, cellular, and clinical features.  Semin Immunol.  2006;18(6):347-61.
12. Meeran SM, Mantena S, Meleth S, et al.  Interleukin-12deficient mice are at greater risk of UV 
radiation-induced skin tumors and malignant transformation of papillomas to carcinomas.  Mol 
Cancer Ther.  2006;5(4):825-32.
13. Chackerian AA, Chen SJ, Brodie SJ, et al.  Neutralization or absence of the interleukin-23 
pathway does not compromise immunity to mycobacterial infection.  Infect Immun.  
2006;74(11):6092-9.
14. AbbVie.  Data on File, RRT165191.
15. AbbVie.  Data on File, RRT165192.
16. AbbVie.  Data on File, RRT165055.
17. US Dept. of Health and Human Services.  Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0.  28 May 2009.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40.  
Accessed on:  16 January 2018.


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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
ADA
anti-drug antibody
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASI
areas of safety interest
AST
aspartate aminotransferase
BCG
Bacille Calmette-Guérin
BSA
body surface area
CAC
Cardiovascular Adjudication Committee
CV
cardiovascular
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
IB
Investigator's brochure
ICH
International Council for Harmonisation
IEC
independent ethics committee
Ig
immunoglobin
IL
interleukin
IRB
Institutional Review Board
IRT
interactive response technology
ITT
Intent-to-treat
mAb
monoclonal antibody
MACE
major adverse cardiovascular events
NAb
neutralizing antibody
PASI
Psoriasis Area Severity Index
PD
Premature discontinuation
PFS
Pre-filled syringe


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PK
pharmacokinetic
PsO
psoriasis
SAE
serious adverse event
SAP
statistical analysis plan
SC
Subcutaneous
sPGA
static Physician Global Assessment
SUSAR
suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TEAE
Treatment-emergent adverse event
TNF
tumor necrosis factor
ULN
upper limit of normal
WBC
white blood cell


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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-766:  Risankizumab versus Secukinumab for Subjects with Moderate to Severe Plaque 
Psoriasis
Protocol Date:  16 August 2019
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
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., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
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. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
International Development
Clinical Program Development
Clinical Program Development
Pharmacokinetics
Data and Statistical Sciences
Medical Writing


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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across the eight Period 1 subject encounters.  The individual 
activities are described in detail in the Operations Manual.








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g.
If appropriate, a targeted physical exam should be performed at any other visit (e.g., to evaluate a reported adverse event).
h.
The ECG should be performed prior to blood collection.  For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required; 
provided all protocol-required documentation is available, and nothing has changed in the subject's health status since the time of the test that warrants a repeat test.
i.
At Screening visit until prior to the first dose of study drug, serious AEs and protocol-related non-serious AEs that occur after a subject signs the informed consent have to be 
collected.  From the time of first study drug administration until 20 weeks (140 days) following discontinuation of study treatment has elapsed, all AEs and SAEs will be 
collected, whether solicited or spontaneously reported by the subject.  If appropriate, a targeted physical exam should be performed.
j.
Should be tested at Screening if the female subject is < 55 years of age AND has had no menses for ≥ 12 months AND has no history of permanent surgical sterilization.
k.
For all women of childbearing potential, collect serum for pregnancy test at Screening.  If the serum pregnancy test is positive the subject is considered a screen failure.  If 
serum pregnancy test comes back borderline, a repeat test is necessary (pregnancy is an exclusion criterion).  If still borderline ≥ 3 days later, this will be considered 
documentation of continued lack of a positive result and the subject can be enrolled into the study.
l.
For all female subjects of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits when the female subjects will receive study drug.  More 
frequent pregnancy tests will be performed throughout the study if required per local/country requirements.  If urine pregnancy test (which is performed at the site) is 
negative, begin or continue dosing.  If urine pregnancy test is positive, withhold dosing and perform a serum pregnancy test.  Pregnant subjects must discontinue from study 
drug treatment.  Refer to Section 6.1 Complaints and Adverse Events for additional details.
m.
Lipid testing required at BL and Week 52.  A minimum 8-hour fast is requested.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-fasting 
status will be recorded in study source documentation and lab requisition.
n.
TB testing will be performed at Screening Visit and at Week 64 visit.  Refer to TB Screen section of the operations manual for further information.
o.
HIV testing will be performed at Screening Visit.  The Investigator must discuss any local reporting requirements to local health agencies with the subject.  The site will report 
confirmed positive results to their health agency per local regulations, if necessary.  If a subject has a confirmed positive result, the Investigator must discuss with the subject 
the potential implications to the subject's health and subject should receive or be referred for clinical care promptly.  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 and will not be made aware of any positive result.
p.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory.  A microscopic analysis will be performed in the event the dipstick results show leukocytes, 
nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.
q.
PK and ADA samples should be collected prior to the dose at dosing visits.  For subjects who prematurely discontinue from study drug treatment prior to Week 52, PK and ADA 
samples will be collected at any time during the PD visit.
r.
Study drug will be administered at the study site by authorized site personnel (e.g., study nurse) after all study procedures have been completed.
s.
Only applies to subjects in France who were randomized to risankizumab.
Note:
Visit window is ± 3 days.  Any of the procedures may be performed at an unscheduled visit at the discretion of the Investigator.


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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
15 February 2018
The purpose of this version is to:
!
Extend the study to provide two additional dosing visits at Week 52 and Week 64 for active 
subjects on risankizumab in France only (Section 1, Synopsis; Section 4.1, Overall Study Design 
and Plan and Figure 1, Appendix D, Activity Schedule).
Rationale: Provide continued risankizumab therapy to subjects who were randomized to 
risankizumab and successfully completed the study until risankizumab is available in France.  
Data from the IMMhance study (Study M15-992) showed that patients receiving continuous 
risankizumab treatment had significantly longer median time to relapse compared with those 
who withdrew risankizumab (and received placebo).
!
Revise wording on timing of the primary analysis for all efficacy endpoints in Period B 
(Section 7.1, Statistical and Analytical Plans).
Rationale: To clarify that the timing of the planned primary analysis of all efficacy endpoints in 
Period B has not changed.
!
Add Week 64 measurements for prior/concomitant therapy, vital signs, adverse event 
assessment, local urine pregnancy test, central laboratory tests (clinical chemistry, hematology), 
and central lab – TB screening (Appendix D, Activity Schedule).
Rationale:  To continue to monitor routine safety parameters.  
!
Add that no dose of risankizumab will be administered at the PD visit (Appendix D, Activity 
Schedule Footnote a).
!
Rationale:  To clarify that additional dosing of risankizumab has been added to Week 52/PD 
visit; however this should only apply to the Week 52 and not the PD visit.
In addition to these modifications, this amendment contains the following minor change:
!
Update contact information for emergency medical contact and updated list of protocol 
signatories (Appendix C, List of Protocol Signatories).
!
Correct minor clerical errors for consistency throughout the protocol.

SAP_001.pdf: 
Risankizumab
M16-766 – Statistical Analysis Plan
Version 4.0 – 22 Oct 2019
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1.0
Title Page
Statistical Analysis Plan
Study M16-766
A Multicenter, Randomized, Open Label, Efficacy 
Assessor-Blinded Study of Risankizumab Compared 
to Secukinumab for the Treatment of Adult Subjects 
with Moderate to Severe Plaque-type Psoriasis who 
are Candidates for Systemic Therapy
Date:  22 Oct 2019
Version 4.0
NCT03478787


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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................4
4.0
Study Background...................................................................4
4.1
Objective....................................................................................................4
4.2
Study Design..............................................................................................4
4.2.1
Study Design and Design Diagram............................................................4
4.2.2
Variables Used for Stratification at Randomization ..................................6
4.3
Endpoint.....................................................................................................7
4.3.1
Primary Efficacy Endpoint ........................................................................7
4.3.2
Secondary Efficacy Endpoint ....................................................................7
4.3.3
Exploratory Efficacy Endpoint ..................................................................7
4.3.4
Safety Endpoint..........................................................................................8
4.3.5
Pharmacokinetic Endpoint.........................................................................8
4.4
Sample Size Justification ...........................................................................8
4.5
Interim Analysis.........................................................................................9
4.6
Multiplicity Testing Procedures for Type-I Error Control ........................9
4.7
Missing Data Imputation..........................................................................11
5.0
Analysis Populations and Important Subgroups ...............12
5.1
Analysis Population .................................................................................12
5.2
Subgroup..................................................................................................13
6.0
Efficacy Analysis....................................................................13
6.1
General Considerations............................................................................13
6.2
Primary Efficacy Analysis .......................................................................14
6.3
Secondary Efficacy Analysis ...................................................................14
6.4
Other Efficacy Analysis...........................................................................14
6.5
Efficacy Subgroup Analysis ....................................................................15
7.0
Safety Analysis.......................................................................15
7.1
General Consideration .............................................................................15
7.2
Analysis of Adverse Events.....................................................................16
7.3
Analysis of Laboratory Data....................................................................16


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7.4
Analysis for Vital Signs and ECG Parameters ........................................17
8.0
Summary of Changes ............................................................17
9.0
References...............................................................................18
List of Figures
Figure 1.
Study Schematic.........................................................................................6
Figure 2.
Graphical Approach for Type-I Error Control.........................................11


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3.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analysis for risankizumab 
study Protocol M16-766.  Further details and analysis conventions to guide the statistical 
programming work will be in a supplement document.
Analyses will be performed using SAS® version 9.4 (SAS. Institute, Inc., Cary, NC 
27513) or higher using the UNIX operating system.
SAP will not be updated in case of future administrative or minor amendments to the 
protocol unless the changes have an impact on the analysis of the study data.
4.0
Study Background
4.1
Objective
The objective of this study is to evaluate the efficacy and safety of risankizumab 
compared with secukinumab for the treatment of adult subjects with moderate to severe 
plaque-type psoriasis who are candidates for systemic therapy.  
4.2
Study Design
4.2.1
Study Design and Design Diagram
This is a Phase 3, global, multicenter, randomized, open-label, efficacy assessor-blinded, 
active comparator study examining the effect of 150 mg risankizumab versus 300 mg 
secukinumab in patients with moderate to severe plaque psoriasis who are candidates for 
systemic therapy.  The study is designed to randomize approximately 310 subjects 
(155 subjects/arm).  
The study duration will be up to 88 weeks. The study comprises a 30-day Screening 
Period, a 52-week open-label study period and a 16-week follow-up period. The follow-
up period consists of a follow-up phone call 20 weeks after the last dose of study drug. 
Subjects in France who were randomized to risankizumab will have two additional dosing 


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visits at Week 52 and Week 64 and a follow-up phone call 20 weeks after the last study 
drug dose.
For ease of description, Period A refers to Week 0 – 16, and Period B refers to the rest of 
the study.
Eligible subjects will be randomized to receive risankizumab or secukinumab in a 
1:1 ratio as shown below in Figure 1:
●
Treatment A (risankizumab SC injection):  2 injections of risankizumab 
75 mg (150 mg total dosage) received subcutaneously at Weeks 0, 4, and every 
12 weeks (q12w) thereafter until at Week 40. Subjects in France who were 
randomized to risankizumab will have two additional dosing visits at Week 52 
and Week 64.
●
Treatment B (secukinumab SC injection):  2 injections of secukinumab 
150 mg (300 mg total dosage) received subcutaneously at Weeks 0, 1, 2, 3, 4, 
and every 4 weeks (q4w) thereafter until the last dose at Week 48. 


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Figure 1.
Study Schematic
The primary analysis for Period A will be performed when the last subject completes the 
Week 16 visit.  There will not be a modification to trial conduct based on the results of the 
analysis.  Efficacy accessors will remain blinded for the duration of the study.
The Primary Analysis for all efficacy endpoints in Period B will be conducted after all 
continuing subjects have completed Week 52 and all data pertaining to Week 52 are 
cleaned and when a database lock will occur to enable the analysis.
4.2.2
Variables Used for Stratification at Randomization 
The randomization will be stratified by weight (≤ 100 kg vs. > 100 kg) and prior systemic 
biologic for psoriasis (0 vs. ≥ 1).


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4.3
Endpoint
4.3.1
Primary Efficacy Endpoint
The two primary endpoints are:
●
Proportion of subjects achieving a Psoriasis Area Severity Index (PASI) 90 
response at Week 52; superiority of risankizumab vs secukinumab.
●
Proportion of subjects achieving a PASI 90 response at Week 16; non-
inferiority of risankizumab vs. secukinumab with a non-inferiority margin of 
12%.
4.3.2
Secondary Efficacy Endpoint
The multiplicity-controlled, ranked key secondary endpoints are:
●
Proportion of subjects achieving a PASI 100 response at Week 52; superiority 
of risankizumab vs. secukinumab;
●
Proportion of subjects achieving a static physician global assessment (sPGA) 0 
or 1 at Week 52; superiority of risankizumab vs. secukinumab;
●
Proportion of subjects achieving a PASI 75 response at Week 52; superiority 
of risankizumab vs. secukinumab.
4.3.3
Exploratory Efficacy Endpoint
The exploratory endpoints listed below will be analyzed for all visits in which the 
assessments are performed (other than those already included as primary or secondary 
endpoints):
●
Proportion of subjects achieving ≥ 75%/90%/100% reduction from baseline in 
PASI score (PASI 75/90/100); 
●
Proportion of subjects achieving sPGA score of clear (0) or almost clear (0 or 
1); 


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●
Change and percent change from baseline in PASI and body surface area 
(BSA). 
4.3.4
Safety Endpoint
Safety evaluations as a measure of safety and tolerability for the entire study duration 
include:
●
Treatment emergent adverse events (TEAEs)
●
Serious adverse events (SAEs) 
●
Areas of safety interest
●
Adverse event (AE) leading to discontinuation
●
Vital signs, laboratory tests, physical examination and electrocardiogram 
(ECG) findings
4.3.5
Pharmacokinetic Endpoint
The pharmacokinetic endpoints will be analyzed separately.
4.4
Sample Size Justification
There are two primary null hypotheses:
●
Risankizumab is not different from secukinumab in achieving a PASI 90 
response at Week 52. 
●
Risankizumab is inferior to secukinumab by 12% in achieving a PASI 90 
response at Week 16.
The two null hypotheses will be tested in graphical procedures as illustrated in Section 4.6
with initial two-sided type I error 0.0125 and 0.0375, respectively. 
The assumptions for the secukinumab Week 16 and Week 52 PASI 90 response rates of 
69.7% and 60.6%, respectively, are based on weighted average from secukinumab studies 
SCULPTURE, ERASURE, FIXTURE, JUNCTURE, and CLEAR.  The assumptions for 


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the risankizumab Week 16 and Week 52 PASI 90 response rates of 75.1% and 81.3%, 
respectively, are based on weighted average from UltiMMa-1 and UltiMMa-2 trials.
The calculation of sample size is based on ADDPLAN software using superiority test and 
non-inferiority test.  The details of the formula can be found in:  Wassmer, G (2003)1 and 
Farrington, CP and Manning, G (1990).2
The non-inferiority margin was chosen based on the treatment effect of secukinumab 
versus placebo in PASI 90 response rate at Week 16.  A 12% non-inferiority margin 
preserves 80% of the treatment effect of secukinumab over placebo.
Approximately 310 subjects (155 subjects per treatment group) will provide more than 
90% power to detect the difference of risankizumab and secukinumab at Week 52 using a 
two-sided alpha level of 0.0125, and 90% power to determine the non-inferiority of 
risankizumab relative to secukinumab using a tolerance limit of 12% and a two-sided 
alpha level of 0.0375 at Week 16.
4.5
Interim Analysis
The primary analysis for Period A (Week 0 – 16) will be performed when the last subject 
completes the Week 16 visit.  There will not be a modification to trial conduct based on 
the results of the analysis.  Efficacy accessors will remain blinded for the duration of the 
study.
4.6
Multiplicity Testing Procedures for Type-I Error Control
The statistical comparisons for the two primary efficacy variables and the three ranked 
secondary variables will be carried out using graphical procedures as shown in Figure 2. 
The 2 primary hypotheses are:
●
H1:  Risankizumab is not different from secukinumab in achieving a PASI 90 
response at Week 52. 


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●
H2:  Risankizumab is inferior to secukinumab by 12% in achieving a PASI 90 
response at Week 16.
The second null hypothesis (H2) will be tested with a two-sided type I error 0.0375.  If the 
result is significant (p-value < 0.0375), then the 0.0375 will be passed to the first null 
hypothesis (H1), which will be tested with a two-sided type I error 0.05.  On the other 
hand, if the result of H2 is not significant (p-value ≥ 0.0375), then H1 will be tested with a 
two-sided type I error 0.0125.
The multiplicity-controlled, ranked key secondary hypotheses are: 
●
H3:  Risankizumab is not different from secukinumab in achieving a PASI 100 
response at Week 52.
●
H4:  Risankizumab is not different from secukinumab in achieving an sPGA 0 
or 1 at Week 52.
●
H5:  Risankizumab is not different from secukinumab in achieving a PASI 75 
response at Week 52.
The three null hypotheses of secondary endpoints (H3, H4, and H5) will be tested in a 
sequential order with initial two-sided type I error of H3 same as that in H1, only when 
H1 is significant at its two-sided alpha level.  The statistically significant results for the 
comparison in the higher rank of secondary endpoints are necessary to initiate the testing 
of the next comparison in the lower rank.  
The details of using graphical procedures to control family wise type-I error could be 
found in Bretz, F, Maurer, W, Brannath, W, & Posch, M (2009).3


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Figure 2.
Graphical Approach for Type-I Error Control
4.7
Missing Data Imputation
Missing data will be imputed using the following methods for the efficacy analyses:
●
Non-Responder Imputation (NRI):  The NRI analysis will categorize any 
subject who has missing value at a specific visit as non-responder for that visit.  
The only exception is when if the subject is a responder both before and after a 
specific visit window, then the subject will be categorized as a responder for 
the visit.  The NRI will be the primary approach in the analysis of categorical 
variables. 
●
Last Observation Carried Forward (LOCF):  The LOCF analyses will use the 
completed evaluation from the previous visit within the particular period for 
efficacy measures assessed to impute missing data at later visits in the same 
period.  LOCF will be the primary approach in the analysis of continuous 
variables, and a secondary approach for categorical variables.


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●
As-observed:  The as-observed analysis will not impute values for missing 
evaluations.  As-observed analysis will be the secondary approach in the 
analysis of continuous variables.
●
Multiple Imputation (MI):  The MI will be used as a sensitivity approach to 
impute missing data in primary endpoints.
5.0
Analysis Populations and Important Subgroups
5.1
Analysis Population
The Intent-to-Treat (ITT) Population will be used for the efficacy analyses.  The ITT 
Population is defined as all subjects who are randomized at Baseline. 
The following populations will be used for safety analysis:
●
The Safety Population is defined as all subjects who are randomized at 
Baseline (ITT population) and received at least one dose of study drug.  The 
Safety Population will be used to perform the 52-week head-to-head safety 
analysis between the two treatment groups.
●
The All Risankizumab Treated (All_RZB) Population is defined as subjects 
who receive at least one dose of risankizumab in the study. The All_RZB 
Population will be used to perform a comprehensive safety summary for 
risankizumab.
In order to evaluate the impact of major protocol violations on the primary efficacy 
endpoints, additional sensitivity analyses will be performed on a Per-protocol Population, 
which excludes subjects with major protocol deviations that potentially affect the primary 
efficacy endpoints.  The criteria for exclusion of subjects from the Per-protocol 
Population will be fully defined in the classification plan and the exclusion of subjects 
from the Per-protocol Population for the analysis will be finalized before the database 
lock.  


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5.2
Subgroup
Subgroup analyses will be performed for the primary endpoints by demographics and 
baseline characteristics as described in detail below (Section 6.5).
6.0
Efficacy Analysis
6.1
General Considerations
The Primary Analysis for all efficacy endpoints pertaining to Period A will be conducted 
after all continuing subjects have completed Week 16 and all data pertaining to Period A 
are cleaned and a database lock will occur to enable the analysis.  This is the one and final 
efficacy analysis for Period A.  The results will be included in an interim clinical study 
report (CSR) to support the efficacy and safety evaluation in the initial 16 weeks of 
treatment. 
The Primary Analysis for all efficacy endpoints in Period B will be conducted after all 
continuing subjects have completed Week 52 and all data pertaining to Week 52 are 
cleaned and when a database lock will occur to enable the analysis.
The efficacy assessors will remain blinded for the duration of the entire study.
The efficacy analysis will be conducted in the ITT Population and Per-protocol 
Population.  The ITT Population will be analyzed by treatment group as randomized.  For 
the Per-protocol Population, subjects will be analyzed as randomized.
Comparison of the primary endpoints will be made between risankizumab group and 
secukinumab group using the Cochran-Mantel-Haenszel test adjusting for stratification by 
weight (≤ 100 kg vs. > 100 kg) and prior systemic biologic use for psoriasis.  For the 
primary analysis, Non-Responder Imputation (NRI) will be used.  The analysis will be 
repeated using last observation carried forward (LOCF) and Multiple Imputation (MI). 
Categorical variables will be analyzed using Cochran-Mantel-Haenszel (CMH) test, 
stratified by weight (≤ 100 kg vs. > 100 kg) and prior systemic biologic use for psoriasis. 


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Continuous variables will be analyzed using ANCOVA method, with treatment, pooled 
center, and Baseline values in the model.
6.2
Primary Efficacy Analysis
The two primary endpoints are:
●
Proportion of subjects achieving a PASI 90 response at Week 52; superiority 
of risankizumab vs secukinumab.
●
Proportion of subjects achieving a PASI 90 response at Week 16; non-
inferiority of risankizumab vs. secukinumab with non-inferiority margin of 
12%.
6.3
Secondary Efficacy Analysis
The multiplicity-controlled, ranked key secondary endpoints are:
●
Proportion of subjects achieving a PASI 100 response at Week 52; superiority 
of risankizumab vs. secukinumab;
●
Proportion of subjects achieving an sPGA 0 or 1 at Week 52; superiority of 
risankizumab vs. secukinumab;
●
Proportion of subjects achieving a PASI 75 response at Week 52; superiority 
of risankizumab vs. secukinumab.
6.4
Other Efficacy Analysis
Other efficacy endpoints include PASI 75/90/100, sPGA of clear or almost clear (0 or 1), 
change and percent change from baseline in PASI 75/90/100 and body surface area 
(BSA), except the ones that already included in the primary and secondary endpoints at all 
visits.


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6.5
Efficacy Subgroup Analysis
To evaluate the consistency of the efficacy across demographic and other baseline 
characteristics, summaries and analyses will be performed for selected subgroups for the 
primary efficacy variables.
Subgroup analyses will be performed on the primary endpoints using the following 
subgroups:
●
Age group (< 40 years, ≥ 40);
●
Sex (male, female);
●
Race (white, non-white);
●
Smoking (current, ex or never)
●
BMI (normal:  < 25, over weight:  ≥ 25 – < 30, obese:  ≥ 30);
●
Baseline PASI score (by median);
●
Baseline sPGA (3, 4)
●
Psoriatic arthritis (yes, no)
●
Prior biologic treatment (0, ≥1)
7.0
Safety Analysis
7.1
General Consideration
Safety analyses will include adverse events, laboratory, vital sign measurements and ECG 
parameter.  Safety summaries will be provided using the safety populations.  
The Safety Population will be analyzed as treated, based on the actual treatment received 
at the randomization visit.
Safety analysis in the All_RZB Population will be performed upon study completion.


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7.2
Analysis of Adverse Events
A treatment-emergent AE (TEAE) among the Safety Population is defined as an event 
with onset or worsening on or after the first dose of study drug until the minimal of 
(i) 140 days following the last pre-Week 52 dose of risankizumab or secukinumab and 
(ii) the additional dose on or after Week 52.
A TEAE among the All_RZB Population is defined as an event with onset or worsening 
on or after the first dose of risankizumab until 140 days following the last dose of 
risankizumab throughout the study.
All safety analyses will be performed in the safety populations.  Pre-treatment AEs will be 
summarized separately.
Safety summaries will also be provided among the All_RZB Population upon study 
completion.
All treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs 
leading to discontinuation, and Areas of Safety Interest (ASI) will be analyzed during the 
study.  The number and percentages of subjects experiencing TEAE will be tabulated 
using the Medical Dictionary for Drug Regulatory Activities (MedDRA®) system organ 
class and preferred term.  Summaries (including percentages and event per 
100 patient-years) of SAEs, deaths, AEs leading to discontinuation, and Areas of Safety 
Interest will be provided as well. 
7.3
Analysis of Laboratory Data
Mean change in laboratory and vital signs variables will be summarized among the Safety 
Population.  For selected lab parameters, summaries of subjects with clinically significant 
laboratory abnormalities will be provided among the Safety Population and the All_RZB 
Population.


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7.4
Analysis for Vital Signs and ECG Parameters
Mean change from baseline will be summarized among the Safety Population. 
Summaries of subjects with clinically significant vital sign determinations or ECG values 
will be provided among the Safety Population and the All_RZB Population.
8.0
Summary of Changes
Section 6.1.  Corrected 'For the Per-protocol Population, subjects will be analyzed as 
treated' to 'For the Per-protocol Population, subjects will be analyzed as randomized' to be 
consistent with the protocol.
Section 7.1.  Clarified 'The Safety Population will be analyzed as treated, based on the 
actual treatment received at the randomization visit.  Safety analysis in the All_RZB 
Population will only be needed if at least one secukinumab subject (as treated) received 
risankizumab later in the study.'
Section 6.5.  Corrected the subgroup of 'Psoriatic arthritis (yes [diagnosed or suspected], 
no)' to 'Psoriatic arthritis (yes, no).'
Section 6.5.  Corrected the subgroup of 'Psoriasis Therapy History (Phototherapy or 
Photochemotherapy, TNF Antagonist, Other biologics, Non-biologic systemic therapy, 
All biologics, Naïve to all' with 'Prior biologic treatment (0, ≥ 1)).'
The following changes are made to align with the protocol amendment Version 1.1 in 
France:
●
Section 4.2.1.  Updated the study design.
●
Section 5.1.  Updated the definitions for the Safety Population and the 
All_RZB Population.
●
Section 6.1.  Updated the timing for the Primary Analysis for all efficacy 
endpoints in Period B
●
Section 7.  Updated the timing for safety summaries among the All_RZB 
Population.  Clarified the TEAE definition among the All_RZB Population.  


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And clarified the safety summaries to be performed among the All_RZB 
Population.
9.0
References
1.
Wassmer G.  Data-driven analysis strategies for proportion studies in adaptive 
group sequential test designs.  J Biopharm Stat.  2003;13(4):585-603.
2.
Farrington CP, Manning G.  Test statistics and sample size formulae for 
comparative binomial trials with null hypothesis of non-zero risk difference or non-
unity relative risk.  Stat Med.  1990;9(12):1447-54.
3.
Bretz F, Maurer W, Brannath W.  A graphical approach to sequentially rejective 
multiple test procedures.  Stat Med.  2009;28(4):586-604.