Conditions: Psoriasis
Keywords: Psoriasis Risankizumab Plaque Psoriasis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 108
Healthy volunteers: no

Brief summary:
The objectives of this study were to evaluate the usability of the combination product of risankizumab in an autoinjector (AI), as well as to evaluate the efficacy, safety, and tolerability of risankizumab administered by AI for the treatment of adult participants with moderate to severe plaque psoriasis.

Detailed description:
This was a Phase 3 multicenter, single-arm, open-label study that evaluated usability and efficacy of the risankizumab-AI combination product. The study included a 30-day screening period with study visits at Weeks 0, 4, 16, 28, and 40 with a subsequent follow-up telephone call at approximately 20 weeks after the last dose of study drug (Week 48). Study drug dosing consisted of 4 self-administered doses given subcutaneously on Weeks 0, 4, 16, and 28. Dosing on Weeks 4 and 16 was self-administered at home.

Arms:
arm 1: Risankizumab solution (150 mg/mL) for injection; self-administered subcutaneously via a pre-filled autoinjector at Weeks 0, 4, 16, and 28

Interventions: intervention 1: Risankizumab intervention 2: Autoinjector
Intervention descriptions: intervention 1: Risankizumab to be injected subcutaneously (SC) intervention 2: Single dose pre-filled autoinjector containing risankizumab for SC injection

Protocol document:
Prot_000.pdf: 
NCT03875508


  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
STUDY OBJECTIVES AND ENDPOINTS
9
3.1
OBJECTIVES
9
3.2
KEY STUDY ENDPOINTS
9
3.3
ADDITIONAL ENDPOINTS
9
3.4
SAFETY ENDPOINTS
9
4
INVESTIGATIONAL PLAN
10
4.1
OVERALL STUDY DESIGN AND PLAN
10
4.2
DISCUSSION OF STUDY DESIGN
12
5
STUDY ACTIVITIES
13
5.1
ELIGIBILITY CRITERIA
13
5.2
CONTRACEPTION RECOMMENDATIONS
16
5.3
PROHIBITED MEDICATIONS AND THERAPY
17
5.4
PRIOR AND CONCOMITANT THERAPY
18
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
18
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
19
5.7
STUDY DRUG
19
5.8
RANDOMIZATION/DRUG ASSIGNMENT
20
5.9
PROTOCOL DEVIATIONS
20
6
SAFETY CONSIDERATIONS
21
6.1
COMPLAINTS AND ADVERSE EVENTS
21
6.2
CARDIOVASCULAR ADJUDICATION COMMITTEE
25
6.3
ANAPHYLAXIS ADJUDICATION COMMITTEE (AAC)
25
6.4
PRODUCT COMPLAINT
26


  
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
26
7.1
STATISTICAL AND ANALYTICAL PLANS
26
7.2
DEFINITION FOR ANALYSIS POPULATIONS
26
7.3
STATISTICAL ANALYSES FOR EFFICACY
26
7.4
STATISTICAL ANALYSES FOR SAFETY
27
7.5
STUDY INTERIM ANALYSIS
27
8
ETHICS
27
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
27
8.2
ETHICAL CONDUCT OF THE STUDY
27
8.3
SUBJECT CONFIDENTIALITY
28
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
28
10 DATA QUALITY ASSURANCE
28
11 COMPLETION OF THE STUDY
28
12 REFERENCES
28
LIST OF TABLES
TABLE 1.
TASKS OF THE EFFICACY ASSESSOR AND INVESTIGATOR.................................................................13
TABLE 2.
DESCRIPTION OF STUDY DRUG........................................................................................................20
TABLE 3.
ADVERSE EVENTS THAT REQUIRE SUPPLEMENTAL REPORTS ..........................................................24
TABLE 4.
STUDY ACTIVITY SCHEDULE.............................................................................................................35
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC..........................................................................................................................10
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
30


  
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APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
32
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
33
APPENDIX D.
ACTIVITY SCHEDULE
34
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
38
APPENDIX F.
OPERATIONS MANUAL
39






  
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Risankizumab is a fully humanized monoclonal antibody (mAb) of the immunoglobin G1 subclass 
directed towards interleukin (IL)-23p19.  The antibody has been engineered to reduce Fcγ receptor and 
complement binding and potential charge heterogeneity.  Risankizumab binds with high affinity to 
human IL-23.
Positive results were observed from 4 pivotal Phase 3 clinical trials that evaluated risankizumab 
compared with ustekinumab, placebo, and adalimumab for the treatment of patients with moderate to 
severe plaque psoriasis.  Results from these pivotal studies demonstrated that risankizumab is highly 
effective for the treatment of psoriasis, meeting co-primary endpoints of achieving at least a 90% 
improvement in the Psoriasis Area and Severity Index (PASI 90) and static physician global assessment 
(sPGA) score of clear or almost clear (0 or 1) versus comparator or placebo at Week 16 across all 
4 studies.1
In the pivotal Phase 3 clinical trials, the risankizumab 150-mg dose was administered with a 90-mg/mL 
formulation via 2 subcutaneous (SC) 75-mg injections.  To deliver a more patient-friendly experience, a 
new formulation was developed at 150 mg/mL that will enable delivery of the 150 mg dose with one SC 
injection.  This study will evaluate the risankizumab 150-mg/mL formulation self-administered by AI 
using the same dosing regimen of risankizumab (150 mg dose at Week 0, Week 4, and every 12 weeks 
thereafter) as used in the Phase 3 pivotal trials for psoriasis.
Clinical Hypothesis
No formal hypothesis test will be performed.  Summary data will be used to evaluate usability.
2.2 Benefits and Risks to Subjects
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.  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 adverse events (AEs) during the 
treatment and observation periods.  In addition, subjects with active infection will not be included in the
study.
Subjects with a positive QuantiFERON®-test or a positive purified protein derivative (PPD) skin test for 
tuberculosis (TB) must fulfill entry criteria as specified in Section 5.1 of this protocol.  Interleukin-23 
inhibition is not known to increase the risk of TB infection or impair the response to TB infection in 
animal models.2,3  There have been no cases of active TB, including no reactivation of TB in subjects 
diagnosed with latent TB, across the entire risankizumab development program.  Across the Phase 3 
psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with 
risankizumab and appropriate TB prophylaxis during the study, none developed active TB during a mean 


  
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follow-up of 61 weeks on risankizumab.  Of the 33 subjects in Study M15-992 with a positive test for 
latent TB and who did not receive prophylaxis during the study, none developed active TB during the 
mean follow-up of 77 weeks on risankizumab.
Thus, low risk subjects with positive QuantiFERON testing do not need to be treated with anti-TB 
therapy prior to receiving risankizumab, but should be carefully monitored for any sign of TB 
reactivation.  Absence of TB reactivation, despite not receiving anti-TB prophylaxis, will provide 
important information in humans as to whether TB testing is required prior to treatment with 
risankizumab.4
Published literature indicates that inhibition of IL-23 is unlikely to increase the risk for cancer.  
Expression of IL-23 is increased in human tumors.  Preclinical data have moreover demonstrated 
beneficial effect of IL-23 p19 inhibition in animal models, both for pre-existing and tumor-induction 
models.  However, there is not enough clinical information at this time to rule out a risk of cancer with 
risankizumab, but this risk is considered small.
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 subjects' safety.
Increases in major adverse cardiovascular (MACE) events including myocardial infarction, 
cerebrovascular accident, and cardiovascular death, reported initially with anti-IL-12/23 agents, such as 
ustekinumab, have not been observed in longer term studies.  While the likelihood of increased MACE is 
small, all suspected cardiovascular events (serious or nonserious) observed in this study will be 
adjudicated by an independent adjudication committee.  An independent Cardiovascular Adjudication 
Committee (CAC) will adjudicate all observed cardio- and cerebro-vascular events and will remain 
blinded to treatment allocation (Section 6.2).
Injection-site reactions to biologic therapies may be characterized by redness, swelling, or induration at 
the injection site.  Manifestations of anaphylaxis may include pruritus, hypotension, swollen lips and 
tongue, abdominal pain, and respiratory distress.  Both local and systemic hypersensitivity reactions and 
anaphylaxis are readily detectable, transient in nature, and manageable with standard medical 
treatment.  Subjects will be closely monitored on site during study drug administration at Weeks 0 and 
28.  The duration of the post-drug-administration safety surveillance is 2 hours post-first dose and 
1 hour postdose at Week 28.  Subjects will be given instructions regarding management of signs and 
symptoms of anaphylaxis to be followed during home dosing at Weeks 4 and 16.  An independent 
Anaphylaxis Adjudication Committee (AAC) will adjudicate suspected anaphylactic reactions.  The AAC 
will remain blinded to treatment allocation (Section 6.3).
In conclusion, the benefit-risk profile of risankizumab is considered appropriate for this stage of clinical 
development.  Based on data from the integrated safety analyses, risankizumab is safe and well 
tolerated and demonstrates a favorable benefit-risk profile.  For further details, please see findings from 
completed studies, including safety data in the risankizumab Investigator Brochure.1


  
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3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
The objectives of this study are to evaluate the usability of the combination product of risankizumab in 
an AI, as well as to evaluate the efficacy, safety, and tolerability of risankizumab administered by AI for 
the treatment of adult patients with moderate to severe plaque psoriasis.
3.2 Key Study Endpoints
The following key endpoints will be evaluated:
•
Proportion of subjects with an Observer rating of successful subject self-administration, defined 
as any subjects who successfully completed the sequence of 4 critical steps in the Instructions 
for Use (IFU) without errors to administer study drug via the AI at Week 0 and 28
•
Proportion of subjects achieving at least 90% improvement from baseline in PASI (PASI 90) at 
Week 16
•
Proportion of subjects achieving sPGA clear or almost clear at Week 16
•
Proportion of subjects achieving 100% improvement from baseline in PASI (PASI 100) at 
Week 16
•
Proportion of subjects achieving at least 75% improvement from baseline in PASI (PASI 75) at 
Week 16
•
Proportion of subjects who had no potential hazards as measured by an Observer on the 
possible use-related hazards checklist for self-administration with AI at Week 0 and Week 28
•
Subject rating of acceptability by the Self-Injection Assessment Questionnaire (SIAQ; Operations 
Manual Appendix B) at each visit collected.
3.3 Additional Endpoints
•
Proportion of subjects achieving PASI 50/75/90/100, sPGA of clear, and sPGA of clear or almost 
clear, as well as change and percent change from baseline in PASI, at each visit collected.
3.4 Safety Endpoints
Safety evaluations include AE monitoring, physical examinations, vital sign measurements, and clinical 
laboratory testing (hematology and chemistry) as measures of safety and tolerability.


  
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3 multicenter, single-arm, open-label study that will evaluate usability of the 
risankizumab-AI combination product.  In addition, efficacy will be evaluated by a study treatment 
assessor.  The study includes a 30-day screening period with study visits at Week 0, 4, 16, 28, and 40 
with a subsequent follow-up telephone call at approximately 20 weeks after the last dose of study drug 
(Week 48).  Study drug dosing will consist of four self-administered doses given subcutaneously on 
Weeks 0, 4, 16, and 28.  Dosing on Week 4 and Week 16 will be self-administered at home.
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
AI = autoinjector
If an exclusionary laboratory result is obtained at the initial Screening Visit, one re-test of that particular 
test is allowed without repeating all other laboratory tests within the 30 day screening window.
Subjects who initially do not meet all eligibility criteria for the study may be permitted to repeat the 
Screening Visit one time following re-consent.  The subject must meet all eligibility criteria on the repeat 
Screening Visit in order to qualify for the study.  The repeat screening procedure is:


  
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•
A repeat of all screening procedures is needed at this repeat Screening Visit with these 
exceptions:
•
If the subject had a complete initial screening evaluation, including the assessment of an 
Interferon-Gamma Release Assay (IGRA; QuantiFERON Tuberculosis [TB] Gold In Tube test) 
or a PPD test (or equivalent), and electrocardiogram (ECG), these tests will not be required 
to be repeated at the repeat Screening Visit.
•
There is no minimum period of time a subject must wait prior to the repeat Screening Visit.
Subjects will be instructed at Week 0 (pre-injection) by the site staff on how to self-inject via the AI.  
Self-injections will be administered into one of the following body regions, changing the injection site if 
possible at each time point:  right thigh, left thigh, right abdominal area, left abdominal area.
At Week 0 (after training) and Week 28, subjects will be instructed by site staff to refer to the IFU (refer 
to Appendix E of the Operations Manual) and proceed with self-injection.  At the Week 4 and Week 16 
Visits, subjects will be sent home with one AI to be self-administered within 24 hours of the Week 4 and 
Week 16 Visit respectively, with instructions from the site staff to use the IFU.  The Week 0 and Week 28 
usability assessments will take place in the context of an observed assessment under the supervision of 
one site staff member.  Each assessment is to be conducted on a 1:1 basis.  The observer (site staff 
member) will measure and evaluate the subject's usability of the AI using the self-injection assessment
checklist as they observe the injections at Week 0 and Week 28.
Site staff will assess potential use-related hazards with a predefined possible hazards checklist (refer to 
Appendix G of the Operations Manual) for self-injections at Week 0 and Week 28.  During the self-
injection, if a subject is not acting in a safe or reasonable manner the observing site staff member is 
required to intervene.  Use errors, which could pose a risk to the health or well-being of a subject, 
require the observing staff member to ask the subject to pause, to point out the use error, and to decide 
whether to terminate the self-injection.  If the observing site staff member's judgment the self-injection 
can continue, they should correct the subject's usage of the product and notify the subject to 
recommence at the same point.  These errors will be documented from the list of potential use-related 
hazards.  Any risk of a health and safety incident could result in termination of the self-injection at the 
discretion of the observing site staff member.
Subject-derived usability assessment measures acceptability of the AI using the SIAQ.  Subjects will fill 
out the SIAQ PRE module (refer to Appendix B of the Operations Manual) immediately before the first 
self-injection at Week 0 and the POST module 20 to 40 minutes following self-injections at Week 0, 
Week 4, Week 16, and Week 28.  These modules are to be completed by subjects while alone in a quiet 
environment.  The subject's self-rated assessment of each item of the SIAQ, will be transformed during 
analysis to scores ranging from 0 (worst experience) to 10 (best experience) as described in Appendix B 
of the Operations Manual.
At Week 0, after the subject self-injects, the site will collect the used AI and examine them for technical 
performance.  The site will document the result in the appropriate eCRF.
See Section 5 for information regarding eligibility criteria.


  
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Further details regarding study procedures are located in the Operations Manual.
An interim analysis will occur after all ongoing subjects complete the Week 28 Visit.  Efficacy assessors 
will remain blinded for the duration of the study.
4.2 Discussion of Study Design
Choice of Control Group
This is an open-label study.  There is no control group.
Appropriateness of Measurements
Standard statistical, efficacy, and safety 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.
The SIAQ evaluates patients' experiences with self-injection and enables assessment of their success in 
giving self-injections and the likelihood of them adhering to a self-injection regimen.5  It has been 
validated in patients with rheumatoid arthritis and measured in patients with psoriasis and psoriatic 
arthritis.6-8
Suitability of Subject Population
Subjects who have moderate to severe plaque psoriasis, defined as a PASI score ≥ 12, body surface area 
(BSA) involvement ≥ 10%, and sPGA ≥ 3 who are candidates for systemic therapy are eligible for this 
study.  Criteria such as laboratory values (minimums and maximums) and subject history (absence of 
chronic infections such as human immunodeficiency virus [HIV], hepatitis B or C [HBV, HCV]), and other 
exclusions are specified to ensure subject safety and to allow adequate evaluation of the study drug.  
The study population selected reflects a standard population for moderate to severe psoriasis trials with 
new treatment intervention.
Selection of Doses in the Study
The risankizumab dosing regimen selected for the current study is the same as used in the risankizumab 
pivotal Phase 3 studies in subjects with moderate to severe chronic plaque psoriasis.  Risankizumab has 
been found to be safe and well tolerated with no dose limiting safety findings following single- or 
multiple-dose administration at doses up to 
 mg SC or 1800 mg intravenously in Phase 1 to 3 clinical 
studies.1
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 


  
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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.
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 to be included in the study.  Anything other than a 
positive response to the questions below will result in exclusion from study participation.


  
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Consent
1. Subjects or their legally authorized representative 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:
•
Serum aspartate transaminase < 2 × upper limit of normal (ULN);
•
Serum alanine transaminase < 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 count > 3,000/μL;
•
Absolute neutrophil count > 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 including 
self-administration of study drug.
Disease Activity
5. Diagnosis of chronic plaque psoriasis for at least 6 months before the baseline visit.
6. Subject meets the following disease activity criteria:
•
Stable moderate to severe chronic plaque psoriasis, defined as ≥ 10% BSA psoriasis 
involvement, sPGA score of ≥ 3, and PASI ≥ 12 at Screening and baseline visit;
•
Candidate for systemic therapy as assessed by the investigator;
Subject History
7. 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 human immunodeficiency virus, viral hepatitis (hepatitis B, 
hepatitis C), and/ or active TB.  Subjects with a positive QuantiFERON®-TB /purified protein 


  
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derivative (tuberculin) 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 TB.  If presence of latent TB is established, subjects are not required to be treated 
with prophylactic anti-TB therapy prior to or during the study, if the subject is considered 
low risk for reactivation per investigator judgment.
•
Active systemic infection during the last 2 weeks prior to baseline visit (exception: common 
cold), as assessed by the investigator.
8. 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 or localized 
carcinoma in situ of the cervix.
9. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months.
10. 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 electrocardiogram), 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;
11. 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.
12. 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
13. For all females of child-bearing potential; a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at baseline and following visits (as outlined in the 
Study Activity Table of this protocol) prior to the first dose of study drug.
14. Female subjects 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
15. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study or for approximately 140 days (20 weeks) after the last dose of study drug.
16. Additional local requirements may apply.


  
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Concomitant Medications
17. No previous exposure to risankizumab.
18. 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.
19. 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 is currently 
enrolled in another clinical study.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:
•
Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
•
Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause
•
Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicule-stimulating hormone (FSH) level > 40 IU/L
•
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy)
•
Females who have not experienced menarche (at least one menstrual period)
•
Females, of Childbearing Potential
Females of childbearing potential must avoid pregnancy while taking study drug(s) and for at 
least 140 days after the last dose of study drug.
Females must commit to one of the following methods of birth control:
•
Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 1 month 
prior to study Baseline (Study Day 1)
•
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study Baseline (Study Day 1)
•
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure)
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS)


  
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•
Vasectomized sexual partner(s) (the vasectomized partner[s] has received medical 
assessment of the surgical success and is the sole sexual partner of the study subject).
•
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.
If required per local guidelines, male or female condom with or without spermicide OR cap, diaphragm 
or sponge with spermicide should be used in addition to one of the birth control methods listed above 
(excluding true abstinence).
Contraception recommendations related to use of concomitant therapies prescribed per standard of 
care should be based on the local label.
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 or biosimilar versions within 12 weeks;
•
Etanercept or biosimilar versions within 6 weeks;
•
Ixekizumab, brodalumab, secukinumab, or other IL-17 inhibitors within 16 weeks;
•
Ustekinumab, efalizumab, guselkumab, tildrakizumab, mirikizumab, or 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 (US Class 6 - 7) 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).


  
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7.
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.
Live or attenuated vaccines are NOT allowed during the study and for 140 days after the last dose of 
study drug.  Examples of such vaccines include but are not limited to the following:
•
Live attenuated influenza
•
Herpes zoster (i.e., Zostavax®)
•
Rotavirus
•
Varicella (chicken pox)
•
Measles-mumps-rubella (MMR) or measles mumps rubella varicella (MMRV)
•
Oral polio vaccine (OPV)
•
Smallpox
•
Yellow fever
•
Bacille Calmette-Guérin (BCG)
•
Oral typhoid
Vaccines that are inactivated, toxoid, or biosynthetic may be administered at any time without 
restrictions.  Examples of common vaccines that meet these criteria include but are not limited to:  
injectable influenza vaccine, pneumococcal, pertussis (Tdap), and Shingrix®.
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 AbbVie clinical monitor should be 
contacted when there are questions regarding concomitant medications.
Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 4 weeks 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 AE(s) that preclude continuation of the 
study medication, as determined by the Investigator and the Therapeutic Area Medical Director 
(TA MD) (as applicable).
•
The Investigator believes withdrawal from the study is in the best interest of the subject.


  
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•
The subject requests withdrawal from the study.
•
Eligibility 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 AbbVie TA MD, after 
consultation with the Investigator
•
Introduction of prohibited medications and continuation of the study drug would place the 
subject at risk as determined by the AbbVie TA MD
•
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 
(NMSC) or carcinoma in-situ of the cervix, where discontinuation is at the discretion of the 
Investigator.
•
Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
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, a follow-up phone call 20 weeks (140 days) after the 
last dose of study drug may be completed to ensure all treatment-emergent AEs/serious AEs (SAEs) have 
been resolved.
5.7 Study Drug
Information about the study drug used in this study is presented in Table 2.


  
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Table 2.
Description of Study Drug
Study Drug
Dosage Form
Strength
Route of 
Administration
Risankizumab (ABBV-066) 
Solution for injection in 
AI 
150 mg/1.0 mL 
(150 mg/mL)
SC injection
AI = auto-injector; SC = subcutaneous
Open-label risankizumab 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.  Risankizumab kits 
will be kept protected from light in their original packaging, in a refrigerator between 2°C to 8°C (36°F to 
46°F), and within a secure limited access storage area, and in accordance with the recommended 
storage conditions on the label.  Risankizumab must not be frozen at any time.  At the Week 4 and 
Week 16 visits, subjects will be provided with a cooler bag and ice pack to maintain adequate storage 
temperature of the study drug kit.  They will also be provided with a sharps containers to allow the 
subjects to safely transport the used AI back to the study site after self-administration of the dose at 
home.
Upon receipt, study drug should be stored as specified on the label 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.
AbbVie will not supply drug other than risankizumab, and study drug will only be used for the conduct of 
this study.  AbbVie provided study drug should not be substituted or alternately sourced unless 
otherwise directed by AbbVie.
5.8 Randomization/Drug Assignment
All subjects will receive open-label risankizumab; 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 


  
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identified), the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable), 
and 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.
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 24 hours of the study site's knowledge of the event via the Product Complaint form.  Product 
Complaints occurring during the study will be followed-up to a satisfactory conclusion.  All follow-up 
information is to be reported to AbbVie (or an authorized representative) and documented in source as 
required by AbbVie.  Product Complaints associated with adverse events will be reported in the study 
summary.  All other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint condition.  In 
instances where a return is requested, every effort should be made by the investigator to return the 
product within 30 days.  If returns cannot be accommodated within 30 days, the site will need to 
provide justification and an estimated date of return.
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 which does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not the event is considered causally related to the 
use of the product.
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.


  
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An elective surgery/procedure scheduled to occur during a study will not be considered an adverse 
event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre planned prior to study entry.  However, if the pre-existing condition 
deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done will be considered 
an adverse event.
If an adverse event, whether associated with study drug or not, meets any of the following criteria, it is 
to be reported to AbbVie clinical pharmacovigilance or contract research organization (CRO) (as 
appropriate) as a serious adverse event within 24 hours of the site being made aware of the serious 
adverse event (refer to Section 4.3 of the Operations Manual for reporting details and contact 
information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This does 
not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a study subject.  Disability is 
not intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle).


  
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Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent Serious 
Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or stillbirth 
is considered an important medical event.  Examples of such 
events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
All adverse events reported from the time of study drug administration until 20 weeks (140 days) 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 nonserious 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 requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
If AEs in any of the following areas of safety interest (ASI) are reported during the study, then the 
corresponding supplemental report must be completed (Table 3).




  
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•
Grade 4 (Severe); Life-threatening consequences; urgent intervention indicated.  
•
Grade 5 (Severe); Death related to AE.
The investigator will use the following definitions to assess the relationship of the adverse event to the 
use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie within 1 working 
day after the site becomes aware of the pregnancy.  Subjects who become pregnant during the study 
must be discontinued (Section 5.5).  If a pregnancy occurs in a study subject, information regarding the 
pregnancy and the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes 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 as outlined in Table 3.
In addition, the site may be contacted for additional source documentation for relevant events.
6.3 Anaphylaxis Adjudication Committee (AAC)
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 definitions.  This independent external Anaphylaxis Adjudication Committee 
(AAC) will adjudicate suspected anaphylactic reactions and will remain blinded to treatment allocation.  
The event terms to be adjudicated and the adjudication process are detailed in the AAC Charter.  A 
supplemental Hypersensitivity Reactions eCRF will be used to collect information pertinent to the events 
(Table 3).  In addition, the site may be contacted for additional source documentation.
If a suspected systemic hypersensitivity reaction occurs at the investigative site, subjects should be 
tested for tryptase and histamine levels.  If a systemic hypersensitivity reaction such as anaphylaxis is 


  
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observed or reported while the subject is not at the investigative site, every effort should be made to 
obtain tryptase and histamine levels from the treating facility to help better 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 statistical analysis will be described and fully documented in the Statistical Analysis Plan (SAP).  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, which is defined as all subjects who have at least one dose of study 
drug in Study M16-005, will be used for the efficacy and usability analyses.  The Safety Population, which 
is defined as all subjects who received at least one dose of study drug in Study M16-005, will be used for 
all safety analyses.  In this study, the safety population is the same as the ITT population.
7.3 Statistical Analyses for Efficacy
All summary statistics for the efficacy analysis will be conducted in the ITT Population.  No statistical 
tests will be performed.
Non-Responder Imputation (NRI) will be used for categorical endpoints.  Mixed-effect Model Repeat 
Measurements (MMRM) will be used for continuous endpoints.
Details on the efficacy analyses are provided in the Statistical Analysis Plan (SAP).
Sample Size Estimation
This study is designed to enroll approximately 100 subjects who will self-administer the risankizumab-AI 
combination product at Weeks 0, 4, 16, and 28.


  
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Assuming the point estimate is 90% for the proportion of subjects with an observer rating of successful 
subject self-administration at Week 28, the current sample size of 100 subjects will provide a 
95% confidence interval of ± 5.9% around a point estimate.
In addition, assuming comparable response rates as the Phase 3 pivotal studies, with the current sample 
size of 100, the PASI 90 rate at Week 16 can be estimated with a 95% confidence interval of ± 8.6% 
when the point estimate is 74%; and the sPGA of clear or almost clear rate at Week 16 can be estimated 
with a 95% confidence interval of ± 7.0% when the point estimate is 85%.
7.4 Statistical Analyses for Safety
All safety analyses will be performed on the Safety Populations.  A treatment-emergent adverse event 
(TEAE) is defined as an event with onset or worsening after the first dose of study drug and within 
20 weeks (140 days) after the last dose of study drug.  The number and percentage of subjects 
experiencing TEAEs will be tabulated using the Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class (SOC) and preferred term (PT), by severity, and by relationship to the study drug as 
assessed by the investigator.  Summaries (including percentages and events per 100 PYs) of SAEs, 
deaths, and AEs leading to discontinuation will be provided as well.  Pre-treatment AEs will be 
summarized separately.  For selected laboratory parameters, a listing of all subjects with any laboratory 
value that is above Grade 3 of Common Toxicity Criteria will be provided.  Mean change in laboratory 
and vital signs variables will be summarized.  Additional details for the safety analysis are provided in the 
SAP.
7.5 Study Interim Analysis
An interim analysis will occur after all ongoing subjects complete the Week 28 Visit.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject 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 subject 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 


  
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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 with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the last subject's last visit.
12
REFERENCES
1.
AbbVie.  Risankizumab Investigator's Brochure Edition 3.  10 May 2018.
2.
Khader SA, Pearl JE, Sakamoto K, et al.  IL-23 compensates for the absence of IL 12p70 and is 
essential for the IL-17 response during tuberculosis but is dispensable for protection and 
antigen-specific IFN-y responses if IL-12p70 is available.  J Immunol.  2005;175(2):788-95.
3.
O'Garra A, Redford PS, McNab FW, et al.  The immune response in tuberculosis.  Annu Rev 
Immunol.  2013;31:475-527.
4.
Tsai TF, Blauvelt A, Gong Y, et al.  Secukinumab treatment shows no evidence for reactivation of 
previous or latent TB infection in subjects with psoriasis:  a pooled phase 3 safety analysis.  J Am 
Acad Dermatol.  2015;607.


  
STUDY M16-005  |  Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.
Keininger D, Coteur G.  Assessment of self-injection experience in patients with rheumatoid 
arthritis:  psychometric validation of the Self-Injection Assessment Questionnaire (SIAQ).  Health 
Qual Life Outcomes.  2011;9:2.  
6.
Blauvelt A, Prinz JC, Gottlieb AB, et al.  FEATURE Study Group.  Secukinumab administration by 
pre-filled syringe:  efficacy, safety and usability results from a randomized controlled trial in 
psoriasis (FEATURE).  Br J Dermatol.  2015;172(2):484-93.
7.
Nash P, Mease PJ, McInnes IB, et al.  FUTURE 3 study group.  Efficacy and safety of secukinumab 
administration by autoinjector in patients with psoriatic arthritis:  results from a randomized, 
placebo-controlled trial (FUTURE 3).  Arthritis Res Ther.  2018;20(1):47.
8.
Lacour J, Paul C, Jazayeri S, et al.  Secukinumab administration by autoinjector maintains 
reduction of plaque psoriasis severity over 52 weeks:  results of the randomized controlled 
JUNCTURE trial.  J Eur Acad Dermatol Venereol.  2017;31 (5):847-56.
9.
US Dept. of Health and Human Services.  Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0.  27 November 2017.  Available from: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R 
eference_8.5x11.pdf.


  
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
AAC
Anaphylaxis Adjudication Committee
AE
Adverse event
AI
autoinjector
ASI
areas of special interest
BCG
Bacille Calmette-Guérin
BSA
body surface area
CAC
Cardiovascular Adjudication Committee
Cardiac
Cardiovascular
CRO
contract research organization
ECG
Electrocardiogram
eCRF
electronic case report form
FSH
follicle-stimulating hormone
GCP
Good clinical practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IFU
Instructions for Use
IL
interleukin
IMP
Investigational Medicinal Product
IRB
Institutional review board
IRT
interactive response technology
ITT
intent-to-treat
IU
International Unit
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
mAb
monoclonal antibody
MACE
major adverse cardiac event
MedDRA
Medical Dictionary for Regulatory Activities
MMR
measles-mumps-rubella


  
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MMRM
Model Repeat Measurements
MMRV
measles mumps rubella varicella
NMSC
non-melanoma skin cancer
NRI
non-responder imputation
OPV
Oral polio vaccine
PASI
Psoriasis Area Severity Index
PD visit
Premature Discontinuation visit
PPD
purified protein derivative (tuberculin)
PT
preferred term
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
subcutaneous
SIAQ
Self-injection Assessment Questionnaire
SOC
system organ class
sPGA
static Physician Global Assessment
SUSAR
Suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States


  
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-005:  Usability of the Risankizumab Autoinjector Combination Product in Adults with 
Moderate to Severe Plaque Psoriasis 
Protocol Date:  20 March 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)


  
STUDY M16-005  |  Version 3.0
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Immunology Development
Immunology Development
Clinical Program Development
Data and Statistical Sciences 
Medical Writing (Protocol Author) 


  
STUDY M16-005  |  Version 3.0
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across the subject encounters.  The individual activities 
are described in detail in the Operations Manual.








  
STUDY M16-005  |  Version 3.0
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol 
Date
Version 2.0
21 January 2019
Version 1.0
27 November 2018
The purpose of this version is to:
•
Clarify required laboratory tests in Appendix D of the protocol
•
Add collection of AI from subjects at Week 28 in Appendix D of the protocol
•
Clarify study procedures in Sections 4.1, 5.4, and 5.6 of the protocol
•
Incorporate AE severity details in Section 6.1 of the protocol
•
Update contact information in the Operations Manual
•
Clarify study drug administration and follow up-call procedures in Section 2.1 of the Operations 
Manual
•
Clarify clinical laboratory information in Section 3.13 of the Operations Manual
•
Clarify drug accountability requirements in Section 5.5 of the Operations Manual
•
Correct PASI criteria cut-off percentages in Appendix C of the Operations Manual


  
STUDY M16-005  |  Version 3.0
CONFIDENTIAL INFORMATION
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APPENDIX F. OPERATIONS MANUAL

SAP_001.pdf: 
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Statistical Analysis Plan for Study M16-005
A Multicenter, Single-Arm, Open-Label Study to 
Assess the Usability of the Risankizumab 
Autoinjector Combination Product in Adult Patients 
with Moderate to Severe Plaque Psoriasis
Date:  22 April 2020
Version 5.0
NCT03875508


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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypotheses ........................................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................7
3.0
Endpoints..................................................................................8
3.1
Key Efficacy and Usability Endpoints.......................................................8
3.2
Additional Efficacy Endpoints...................................................................9
3.3
Safety Endpoints ........................................................................................9
3.4
Additional Endpoints .................................................................................9
4.0
Analysis Populations ...............................................................9
5.0
Subject Disposition................................................................10
6.0
Study Drug Duration and Compliance................................10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................11
7.1
Demographics and Baseline Characteristics............................................11
7.2
Medical History .......................................................................................11
7.3
Prior and Concomitant Medications ........................................................12
8.0
Efficacy Analyses...................................................................12
8.1
General Considerations............................................................................12
8.2
Handling of Missing Data........................................................................12
8.3
Efficacy and Usability Analysis...............................................................14
8.3.1
Key Usability Analysis ............................................................................14
8.3.2
Handling of Missing Data for the Key Usability Analysis ......................14
8.4
Key Efficacy Analysis .............................................................................14
8.4.1
Supportive Secondary Efficacy Analyses ................................................15
8.5
Additional Efficacy Analyses ..................................................................15
8.6
Efficacy Subgroup Analyses....................................................................15
9.0
Safety Analyses ......................................................................15
9.1
General Considerations............................................................................15


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9.2
Adverse Events ........................................................................................15
9.2.1
Treatment-Emergent Adverse Events ......................................................16
9.2.2
Adverse Event Overview .........................................................................16
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................17
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................17
9.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................18
9.2.6
Area of Safety Interest .............................................................................18
9.3
Analysis of Laboratory Data....................................................................18
9.4
Analysis of Vital Signs ............................................................................20
9.5
Safety Subgroup Analyses .......................................................................20
9.6
Other Safety Analyses..............................................................................20
10.0
Other Analyses.......................................................................20
11.0
Interim Analyses....................................................................21
11.1
Data Monitoring Committee....................................................................21
11.2
Interim Analysis.......................................................................................21
12.0
Overall Type-I Error Control ..............................................21
13.0
Version History......................................................................22
14.0
References...............................................................................22
List of Tables
Table 1.
SAP Version History Summary...............................................................22
List of Figures
Figure 1.
Study Schematic.........................................................................................7
List of Appendices
Appendix A.
Protocol Deviations..................................................................................23
Appendix B.
Definition of Area of Safety Interest........................................................24


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints ...............26


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for risankizumab 
Study M16-005 A Multicenter, Single-Arm, Open-Label Study to Assess the Usability of 
the Risankizumab Autoinjector Combination Product in Adult Patients with Moderate to 
Severe Plaque Psoriasis.  Study M16-005 evaluates the usability of the combination 
product of risankizumab in an AI and to evaluate the efficacy, safety, and tolerability of 
risankizumab 150 mg/mL administered by AI for the treatment of adult patients with 
moderate to severe plaque psoriasis.
This SAP provides summaries of the planned statistical analyses for efficacy and safety 
endpoints, interim analysis, and overall type-I error control strategies.
There will be no analyses of pharmacokinetic endpoints in this study.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 13.0.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
The objectives of this study are to evaluate the usability of the combination product of 
risankizumab in an AI and to evaluate the efficacy, safety, and tolerability of 
risankizumab 150 mg/mL administered by AI for the treatment of adult patients with 
moderate to severe plaque psoriasis.
The following key endpoints will be evaluated:


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●
Proportion of subjects with an Observer rating of successful subject self-
administration, defined as any subjects who successfully completed the 
sequence of 4 critical steps in the Instructions for Use (IFU) without errors to 
administer study drug via the AI at Week 0 and Week 28
●
Proportion of subjects achieving at least 90% improvement from baseline in 
the Psoriasis Area and Severity Index (PASI) (PASI 90) at Week 16
●
Proportion of subjects achieving sPGA clear or almost clear at Week 16
●
Proportion of subjects achieving 100% improvement from baseline in PASI 
(PASI 100) at Week 16
●
Proportion of subjects achieving at least 75% improvement from baseline in 
PASI (PASI 75) at Week 16
●
Proportion of subjects achieving sPGA of clear at Week 16.
●
Proportion of subjects who had no potential hazards as measured by an 
Observer on the possible use-related hazards checklist for self-administration 
with AI at Week 0 and Week 28
●
Subject rating of acceptability by the Self-Injection Assessment Questionnaire 
(SIAQ; Operations Manual Appendix B) at each visit collected.
2.2
Study Design Overview
This is a Phase 3 multicenter, single-arm, open-label study that will evaluate usability of 
the risankizumab-AI combination product.  In addition, efficacy will be evaluated by an 
efficacy assessor.  The study includes a 30-day screening period with study visits at 
Week 0, 4, 16, 28, and 40 with a subsequent follow-up telephone call at approximately 
20 weeks after the last dose of study drug (Week 48).  Study drug dosing will consist of 
four self-administered doses given subcutaneously on Weeks 0, 4, 16, and 28.  Dosing on 
Week 4 and Week 16 will be self-administered at home.  Efficacy assessments will be 
performed at each study visit (Weeks 0, 4, 16, 28, and 40).
The schematic of the study is shown in Figure 1.


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Figure 1.
Study Schematic
2.3
Treatment Assignment and Blinding
All subjects will receive open-label risankizumab. 
2.4
Sample Size Determination
This study is designed to enroll approximately 100 subjects who will self-administer the 
risankizumab-AI combination product at Weeks 0, 4, 16, and 28.
Assuming the point estimate is 90% for the proportion of subjects with an observer rating 
of successful subject self-administration at Week 28, the current sample size of 
100 subjects will provide a 95% confidence interval of ± 5.9% around a point estimate.


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In addition, assuming comparable response rates as the Phase 3 pivotal studies, with the 
current sample size of 100, the PASI 90 rate at Week 16 can be estimated with a 95% 
confidence interval of ± 8.6% when the point estimate is 74%; and the sPGA of clear or 
almost clear rate at Week 16 can be estimated with a 95% confidence interval of ± 7.0%
when the point estimate is 85%.
3.0
Endpoints
3.1
Key Efficacy and Usability Endpoints
The following key endpoints will be evaluated:
●
Proportion of subjects with an Observer rating of successful subject self-
administration, defined as any subjects who successfully completed the 
sequence of 4 critical steps in the IFU without errors to administer study drug 
via the AI at Week 0 and 28
●
Proportion of subjects achieving at least 90% improvement from baseline in 
PASI (PASI 90) at Week 16
●
Proportion of subjects achieving sPGA clear or almost clear at Week 16
●
Proportion of subjects achieving 100% improvement from baseline in PASI 
(PASI 100) at Week 16
●
Proportion of subjects achieving at least 75% improvement from baseline in 
PASI (PASI 75) at Week 16
●
Proportion of subjects achieving sPGA of clear at Week 16.
●
Proportion of subjects who had no potential hazards as measured by an 
observer on the possible use-related hazards checklist for self-administration 
with AI at Week 0 and Week 28
●
Subject rating of acceptability by the Self-Injection Assessment Questionnaire 
(SIAQ) at each visit collected.


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3.2
Additional Efficacy Endpoints
All key efficacy endpoints will be analyzed at all other visits collected. Additional 
variables to be provided will include the proportion of subjects achieving PASI 50, as 
well as change and percent change from baseline in PASI, at each visit collected.
3.3
Safety Endpoints
The following endpoints will be included in the safety analyses:
●
Treatment emergent adverse events (TEAEs);
●
Serious adverse events (SAEs);
●
Areas of safety interest (ASI);
●
Adverse events (AEs) leading to discontinuation;
●
Vital signs and laboratory tests.
3.4
Additional Endpoints
There are no additional endpoints planned other than those described above.
4.0
Analysis Populations
The following population sets will be used for the analyses.
The intent-to-treat (ITT) Population, which is defined as all subjects who have at least 
1 dose of study drug in Study M16-005, will be used for the efficacy and usability 
analyses.
The Safety Analysis Population, which is defined as all subjects who received at least 
1 dose of study drug in Study M16-005, will be used for all safety analyses.  In this study, 
the safety population is the same as the ITT population.


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5.0
Subject Disposition
The total number of subjects who were treated, completed, and discontinued will be 
summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized:
●
Subjects who received at least one study drug;
●
Subjects who completed study;
●
Subjects who discontinued study drug (all reasons and primary reason);
●
Subjects who discontinued study (all reasons and primary reason)
For end of study participation, the number and percentage of subjects who completed this 
study (or did not with associated reasons) will be summarized overall.
6.0
Study Drug Duration and Compliance
Duration of treatment is defined for each subject as last dose date minus first dose date + 
84 days.  Duration of treatment will be summarized using the number of subjects treated, 
mean, standard deviation, median, minimum and maximum.
Treatment compliance will be summarized for the entire treatment period and each study 
drug administration visit for the ITT population.
There will be a summary of the number of subjects receiving study drug and dose at each 
study drug administration visit.  This will be repeated on the cumulative number of doses.
When computing compliance at each study drug administration visit, the denominator will 
include all subjects in each analysis population who have not prematurely discontinued 
the study drug prior to the scheduled study drug injection.


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7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI).  Categorical demographic variables include sex, ethnicity, race, age (< 40, 40 – 65, 
≥ 65 years), weight (≤ 100 or > 100 kg), BMI (< 25, ≥ 25 – < 30, ≥ 30 kg/m2), tobacco 
user (current, former, never, unknown), and alcohol user (current, former, never, 
unknown).
Disease characteristics include prior systemic biologic for psoriasis (0 vs. ≥ 1), PASI 
(Psoriasis Area and Severity Index), BSA (Body Surface Area), sPGA categories, history 
of psoriatic arthritis (yes, no), duration of plaque psoriasis (in years).
Demographics and baseline characteristics will be summarized for the ITT Population.  
Categorical variables will be summarized with the number and percentage of subjects 
based on the number of non-missing observations.  Continuous variables will be 
summarized with descriptive statistics (number of non-missing observations, mean and 
standard deviation, median, minimum and maximum).
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall.  The system organ class (SOC) will be presented in alphabetical 
order, and the preferred terms will be presented in alphabetical order within each SOC.  
Subjects reporting more than one condition/diagnosis will be counted only once in each 
corresponding category (SOC or preferred term).
Medical history will be summarized among the ITT Population.


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7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug.  A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken on or after the first dose of study 
drug or any medication that newly started on or after the date of the first dose of study 
drug, but not after the date of the last dose of study drug plus 28 days.  The number and 
percentage of subjects taking medications will be summarized by generic drug name 
based on the World Health Organization (WHO) Drug Dictionary for both prior and 
concomitant medications.
In addition, subjects' prior biologic therapy for psoriasis will also be summarized by the 
reason for discontinuation.
Prior and concomitant medications will be summarized among the ITT Population.
8.0
Efficacy Analyses
8.1
General Considerations
All summary statistics for the efficacy and usability analysis will be conducted in the ITT 
Population.  No statistical tests will be performed.
All efficacy endpoints will be summarized up to Week 28 during this analysis.
Categorical variables will be summarized by frequencies, percentages, and the 95% 
confidence intervals (CIs).  Continuous variables will be summarized by least square 
mean, standard error, and the 95% CIs.
8.2
Handling of Missing Data
Missing data will be imputed using the following methods for the efficacy analyses:


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●
Non-Responder Imputation (NRI):  The NRI analysis will categorize any 
subject who does not have evaluation during a specific visit window as a non-
responder for that visit.  The exceptions are: (1) if the subject is a responder 
both before and after a specific visit window in the particular period, then the 
subject will be categorized as a responder for the visit; (2) when the subject 
missed a visit due to COVID-19 pandemic, the missing assessment from that 
visit will be imputed using Multiple Imputation (MI) to determine the 
corresponding response status.  In present study, only Week 28 or later visits 
may be affected by the COVID-19 pandemic.  The NRI will be the primary 
missing data imputation approach in the analyses of categorical variables.
●
Modified-NRI:  Patients who discontinue study drug due to lack of efficacy or 
due to AE of worsening of psoriasis and do not have Week 16 measurements 
will be counted as non-responders.  Other patients will be summarized using 
as-observed data.  The modified-NRI analysis will be the sensitivity approach 
to handle missing data in the analysis of key efficacy endpoints specified in 
Section 3.1.
●
As-observed:  The as-observed analysis will include all available assessments 
on a scheduled visit. No missing assessments will be imputed. The as-
observed analysis will be the sensitivity approach to handle missing data in the 
analysis of the key efficacy endpoints specified in Section 3.1.
●
Mixed-effect Model Repeat Measurement (MMRM):  The repeated measures 
analysis will be conducted using a mixed model including baseline value and 
observed measurements at all post-baseline visits, using all available data even 
if a subject has missing data at some post-baseline visits.  The mixed model 
includes visit as the covariate.  An unstructured variance covariance matrix 
will be used.  Parameter estimation is based on the assumption of data being 
missing at random and using the method of restrictive maximum likelihood 
(REML).  MMRM will be the primary approach in the analysis of continuous 
variables.
The key usability endpoints will be summarized by as-observed cases.


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8.3
Efficacy and Usability Analysis
8.3.1
Key Usability Analysis
The following key usability endpoints will be evaluated:
●
Proportion of subjects with an Observer rating of successful subject self-
administration, defined as any subjects who successfully completed the 
sequence of 4 critical steps in the Instructions for Use (IFU) without errors to 
administer study drug via the AI at Week 0 and Week 28
●
Proportion of subjects who had no potential hazards as measured by an 
Observer on the possible use-related hazards checklist for self-administration 
with AI at Week 0 and Week 28
●
Subject rating of acceptability by the Self-Injection Assessment Questionnaire 
(SIAQ) at each visit collected.
8.3.2
Handling of Missing Data for the Key Usability Analysis
The key usability endpoints will be summarized by as-observed cases.
8.4
Key Efficacy Analysis
The following key efficacy endpoints will be evaluated:
●
Proportion of subjects achieving PASI 90 at Week 16
●
Proportion of subjects achieving sPGA clear or almost clear at Week 16
●
Proportion of subjects achieving PASI 100 at Week 16
●
Proportion of subjects achieving PASI 75 at Week 16
●
Proportion of subjects achieving sPGA of clear at Week 16.
Key efficacy endpoints at Week 16 will be analyzed using NRI method to handle missing 
data.  Modified-NRI analysis and as-observed analysis will also be performed to handle 
missing data as sensitivity analyses.


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8.4.1
Supportive Secondary Efficacy Analyses
There are no additional supportive secondary efficacy analyses planned other than those 
described above.
8.5
Additional Efficacy Analyses
All key efficacy endpoints will be analyzed at all other visits collected. Additional 
variables to be provided will include the proportion of subjects achieving PASI 50, as 
well as change and percent change from baseline in PASI, at each visit collected.
Non-Responder Imputation (NRI) will be used for categorical endpoints to handle missing 
data.  Mixed-effect Model Repeat Measurements (MMRM) will be used for continuous 
endpoints.
8.6
Efficacy Subgroup Analyses
No efficacy subgroup analyses are planned.
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Analysis Population.  Safety analyses will 
include adverse events, laboratory, and vital sign measurements.
Missing safety data will not be imputed.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  When summarizing the number and percentages of subjects, subjects with 
multiple occurrences of the same adverse event will be counted once, and only the 


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maximum severity level will be presented in the severity summaries, and the 
worst/highest relationship level in the relationship summaries. 
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any event newly developed 
on or after the first dosing of study drug to 20 weeks (140) days after the last dose of 
study drug.
9.2.2
Adverse Event Overview
An overview of TEAEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any adjudicated MACE
●
Any infection
●
Any serious infection
●
Any tuberculosis
●
Any malignant tumor
●
Any malignant tumor excluding NMSC
●
Any serious hypersensitivity 
●
Any treatment-emergent AE leading to death
All deaths will also be summarized: 
●
Deaths occurring ≤ 140 days after last dose of study drug
●
Deaths occurring > 140 days after last dose of study drug.


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9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and by SOC and PT; by maximum severity and by SOC and PT; 
and by SOC and PT listing associated subject number.  When summarizing the number 
and percentages of subjects, subjects with multiple occurrences of the same adverse event 
will be counted once, and only the maximum severity level will be presented in the 
severity summaries, and the worst/highest relationship level in the relationship
summaries. 
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency.
9.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
exposure in 100 patient-years.
Note that one event per preferred term per day per subject will be counted in the 
calculation of the number of AEs (i.e., a preferred term will not be counted twice on the 
same day for the same subject).  See the calculation method below.
,
where total patient years is defined as the sum of the study drug exposure (defined as date 
of last dose – date of first dose + 140 days (5 half-lives)) of all subjects normalized by 
365.25, and rounded to one decimal place.
Years
Patient 
Total
TEAEs
of
Number 
100!


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9.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
Treatment-emergent SAEs (including deaths) and AEs leading to study drug 
discontinuation will be summarized by SOC and PT and in listing format.
Pre-treatment SAEs with onset dates prior to the first dose of study drug will be 
summarized separately.
9.2.6
Area of Safety Interest
Detailed information about the search criteria for areas of safety interest (ASIs) are 
provided in Appendix B.
The final list will be based on the most updated final version of risankizumab Product 
Safety Statistical Analysis Plan, which is consistent to the most updated risankizumab 
Risk Management Plan.
In addition, any injection site reactions by CMQ (code 80000019) will also be 
summarized by preferred terms in this study.
Tabular listings of selected area of safety interest will be provided.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  The 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.
Mean change from baseline to each applicable post-baseline visit will be summarized for 
selected laboratory variables, with the number of observations, baseline mean, and visit 
mean.  The change from baseline mean, standard error, and 95% confidence interval will 
be presented for the mean change from baseline.


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Changes in laboratory parameters will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample.  A 
shift table from baseline to minimum and maximum value (based on normal range), will 
be created.  A similar shift table will be provided to summarize shifts from baseline to the 
final post-baseline value.
Laboratory abnormalities meeting CTC criteria grade 3 and 4 will be summarized.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (Appendix C).  For each laboratory PCI criterion, the number and 
percentage of subjects who have a laboratory value meeting the criteria will be 
summarized.  Listings will be provided to summarize subject-level laboratory data for 
subjects meeting PCI criteria.
In addition, ALT/SGPT, AST/SGOT, alkaline phosphatase, and total bilirubin will be 
categorized as follows:
●
< 1.5 × ULN
●
≥ 1.5 × ULN – < 3.0 × ULN
●
≥ 3.0 × ULN – < 5.0 × ULN
●
≥ 5.0 × ULN – < 10.0 × ULN
●
≥ 10.0 × ULN – < 20.0 × ULN
●
≥ 20.0 × ULN
A listing of potentially clinically important liver function laboratory values will include 
all subjects who met any of the following four criteria:
●
ALT ≥ 3 × ULN, or
●
AST ≥ 3 × ULN, or
●
Alkaline Phosphatase ≥ 1.5 × ULN, or 
●
Total bilirubin ≥ 2 × ULN.


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A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions will be provided.  
●
ALT of > 3 × ULN or AST of > 3 × ULN, 
●
Associated with an increase in total bilirubin ≥ 2 × ULN,
●
Alkaline Phosphatase < 2 × ULN
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure will be summarized.
Mean change from baseline to each applicable post-baseline visit will be summarized for 
each vital sign variable, with the number of observations, baseline mean, and visit mean.  
The change from baseline mean, standard error, and 95% confidence interval will be 
presented for the mean change from baseline.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C).  For each vital sign PCI criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized.  Listings 
will be provided to summarize subject-level vital sign data for subjects meeting PCI 
criteria.
9.5
Safety Subgroup Analyses
No safety subgroup analyses are planned.
9.6
Other Safety Analyses
No other safety analyses are planned.
10.0
Other Analyses
No other analyses are planned.


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11.0
Interim Analyses
11.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review safety data from the ongoing 
study.  The primary responsibility of the DMC will be to protect the safety of the subjects 
participating in this study.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no alpha adjustment is needed.
11.2
Interim Analysis
An interim analysis will occur after all ongoing subjects complete the Week 28 Visit.  All 
efficacy variables up to Week 28, as well as all observed safety and usability variables, 
will be summarized during this analysis.
12.0
Overall Type-I Error Control
No statistical tests will be performed in this single-arm, open-label study.
Since there are no efficacy analyses for early stopping planned for the DMC review, no 
alpha spending is needed due to the DMC review.


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13.0
Version History
Table 1.
SAP Version History Summary
Version
Date
Summary
1.0
28 Nov 2018
Original version
2.0
02 Jan 2019
Added more statistical analysis details to the document.
Deleted the wording of "blinded efficacy assessor" to be consistent 
with the protocol admin change 1. 
3.0
19 Jul 2019
Added more statistical analysis details to the document.
4.0
17 Apr 2020
Clarified weight and BMI categories in demographics.
Clarified items to be summarized for disposition to align with the 
new standard table. 
Removed baseline BSA from MMRM model in efficacy analysis, 
as most BSA information is covered by the corresponding 
components in baseline PASI.
Updated the definition of concomitant medication to align with the 
most updated risankizumab PSSAP.
Clarified shift tables, PCI, and ASI definitions for safety analysis, 
to align with the most updated risankizumab PSSAP.
Corrected the dates in version history.
Added the AE summary of any injection site reactions, according 
to FDA suggestion.
Added details about how to handle missing data due to COVID-19 
in the NRI analysis.
Added modified-NRI and as-observed sensitivity analyses for the 
key efficacy endpoints. 
Added sPGA clear at Week 16 to key efficacy endpoints. 
5.0
22 Apr 2020
Corrected a typo at Section 8.3.1 that there are 4 critical steps in 
the Instructions for Use (IFU) of achieving an observer rating of 
successful subject self-administration. 
14.0
References


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


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Appendix B.
Definition of Area of Safety Interest
Area of safety interest (ASI) will be identified using the following search criteria:
Area of Safety 
Interest
Search Criteria
Include in AE 
Overview (Y/N)
MACE
Adjudicated terms will be identified as described in PSSAP 
Table 3 using CECAT and CETERM from the CE SDTM 
dataset.
Y
Extended MACE
Adjudicated terms will be identified as described in PSSAP 
Table 3 (for MACE +) using CECAT and CETERM from the 
CE SDTM dataset.
N
Serious Infections
Serious AEs in the Infections and Infestations SOC 
Y
Tuberculosis
Active Tuberculosis CMQ (code 80000188)
Y
Opportunistic 
Infections
Opportunistic infection excluding tuberculosis and herpes 
zoster CMQ (code 80000189)
N
Fungal Infections
Fungal infections CMQ (code 80000063)
N
Malignant 
Tumours
Narrow
Malignant tumours (SMQ 20000194)
Y
Non-melanoma 
Skin Cancer 
(NMSC)
Broad
Skin malignant tumours (SMQ 20000204) 
excluding terms identified by the Melanoma 
CMQ (code 80000119)
N
Malignant 
Tumours
excluding NMSC
'Malignant Tumours excluding NMSC' is identified by the 
'Malignant Tumours' search excluding terms identified by the 
'Non-melanoma skin cancer (NMSC)' search.
Y
Hypersensitivity 
Narrow
Hypersensitivity (SMQ 20000214)
Y – serious 
events only
Adjudicated 
Anaphylactic 
Reaction*
Adjudicated terms will be identified using SDTM data 
(e.g., CE and PR domains).
N
Hepatic Events 
Broad
Hepatic failure, fibrosis and cirrhosis and other 
liver damage-related conditions 
(SMQ 20000013)
N
Broad
Hepatitis, non-infectious (SMQ 20000010)
N
Broad
Cholestasis and jaundice of hepatic origin 
(SMQ 20000009)
N
Broad
Liver related investigations, signs and 
symptoms (SMQ 20000008)
N


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Area of Safety 
Interest
Search Criteria
Include in AE 
Overview (Y/N)
Narrow
Liver-related coagulation and bleeding 
disturbances (SMQ 20000015)
N
*
Events will be identified for adjudication by Anaphylactic Reaction SMQ Broad search as specified in the RISA 
AAC Charter.


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCI) laboratory findings are described in 
Table C-1 and Table C-2, and the PCI criteria for vital sign findings are described in 
Table C-3.
Table C-1.
Criteria for Potentially Clinically Important Hematology Values
Hematology Variables
Units
Definition of Potentially Clinically Important:
NCI CTCAE (Version 4) Grade 3 or Greater
Very Low
Hemoglobin
g/dL
< 8.0
Platelets count
109/L
< 50.0
WBC count
109/L
< 2.0
Neutrophils
109/L
< 1.0
Lymphocytes
109/L
< 0.5
Note:
A post-baseline grade must be more extreme than the baseline grade to be considered a potentially clinically 
important finding.


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Table C-2.
Criteria for Potentially Clinically Important Chemistry Values
Chemistry Variables
Units
Definition of Potentially Clinically Important NCI 
CTCAE (Version 4) Grade 3 or Greater
Very Low
Very High
TBL
mcmol/L
> 3.0 × ULN
Alkaline Phosphatase
U/L
> 5.0 × ULN
SGOT/AST
U/L
> 5.0 × ULN
SGPT/ALT
U/L
> 5.0 × ULN
Albumin
g/L
< 20
Glucose
mmol/L
< 2.2
> 13.9
Triglycerides
mmol/L
> 5.7
Creatinine
mcmol/L
> 3.0 × ULN
Sodium
mmol/L
< 130
> 155
Potassium
mmol/L
< 3.0
> 6.0
Calcium
mmol/L
< 1.75
> 3.1
CPK
U/L
> 5.0 × ULN
Total Cholesterol
mmol/L
> 10.34
GGT
> 5.0 × ULN
Note:
A post-baseline grade must be more extreme than the baseline grade to be considered a potentially clinically 
important finding.
Table C-3.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Signs Variables
Criterion
Definition of Potentially Clinically Important
Systolic Blood Pressure 
(mmHg)
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic Blood Pressure 
(mmHg)
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline