Clinical trial NCT04713592
Conditions: Psoriasis
Keywords: Psoriasis Plaque Psoriasis Moderate to Severe Plaque Psoriasis Plaque Psoriasis with Palmoplantar (Non-Pustular) Involvement (PPPsO) Risankizumab SKYRIZI ABBV-066
Sponsor: AbbVie
Start date: 2021-02-26; Completion date: 2023-04-20
Enrollment: 174 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Plaque Psoriasis is a chronic inflammatory disease in which skin cells build up and develop scaly red and white patches on the skin. It is caused by an overactive immune system where the body attacks healthy tissue by mistake. Palmoplantar (non-pustular) plaque psoriasis (PPPsO) represents a localized form of psoriasis in palms and soles. This study will evaluate how safe risankizumab is for the treatment of plaque psoriasis with palmoplantar involvement and to assess change in disease symptoms.

Risankizumab is an approved drug for the treatment of psoriasis. Study doctors put the participants in 1 of 2 groups, called treatment arms. Each group receives a different treatment. There is a 1 in 2 chance that participants will be assigned to placebo in Period A. In Period B, all the participants will receive risankizumab. Around 168 adult participants with a moderate to severe plaque psoriasis will be enrolled in approximately 55 sites across the world.

Participants will receive single subcutaneous (administered under the skin) risankizumab or placebo in period A (16 weeks). In period B (36 weeks), all participants will receive subcutaneous risankizumab once every 12 weeks.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Detailed description:

Arms: arm 1: Participants received subcutaneous placebo injections during the 16-week Double-blind Period at Baseline (Day 1) and Week 4. Starting at Week 16, all participants received open-label risankizumab 150 mg subcutaneous injections once every 12 weeks (q12w) at Weeks 16, 28, and 40. arm 2: Participants received risankizumab 150 mg subcutaneous injections during the 16-week Double-blind Period at Baseline (Day 1) and Week 4. Starting at Week 16, all participants received open-label risankizumab 150 mg subcutaneous injections once every 12 weeks (q12w) at Weeks 16, 28, and 40.
Interventions: intervention 1: Placebo for Risankizumab intervention 2: Risankizumab
Intervention descriptions: intervention 1: Subcutaneous (SC) Injection intervention 2: Subcutaneous (SC) Injection

Protocol documents:
Prot_000.pdf: 


  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
9
3
OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
10
3.2
PRIMARY ENDPOINT
12
3.3
SECONDARY ENDPOINTS
12
3.4
ADDITIONAL EFFICACY ENDPOINTS
13
3.5
SAFETY ENDPOINTS
13
3.6
PHARMACOKINETIC EVALUATION
14
3.7
BIOMARKER RESEARCH
14
4
INVESTIGATIONAL PLAN
14
4.1
OVERALL STUDY DESIGN AND PLAN
14
4.2
DISCUSSION OF STUDY DESIGN
15
5
STUDY ACTIVITIES
16
5.1
ELIGIBILITY CRITERIA
16
5.2
CONTRACEPTION RECOMMENDATIONS
20
5.3
PROHIBITED MEDICATIONS AND THERAPY
21
5.4
PRIOR AND CONCOMITANT THERAPY
22
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
23
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
24
5.7
STUDY DRUG
25
5.8
RANDOMIZATION/DRUG ASSIGNMENT
26
5.9
PROTOCOL DEVIATIONS
27
6
SAFETY CONSIDERATIONS
27
6.1
COMPLAINTS AND ADVERSE EVENTS
27
6.2
CARDIOVASCULAR ADJUDICATION COMMITTEE
31
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6.3
ANAPHYLAXIS ADJUDICATION COMMITTEE
31
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
32
7.1
STATISTICAL AND ANALYTICAL PLANS
32
7.2
DEFINITION FOR ANALYSIS POPULATIONS
32
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
32
7.4
STATISTICAL ANALYSES FOR EFFICACY
33
7.5
STATISTICAL ANALYSES FOR SAFETY
34
7.6
INTERIM ANALYSIS
35
7.7
OVERALL TYPE I ERROR CONTROL
35
7.8
SAMPLE SIZE DETERMINATION
35
7.9
STATISTICAL ANALYSIS OF OPTIONAL BIOMARKER DATA
35
8
ETHICS
35
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
35
8.2
ETHICAL CONDUCT OF THE STUDY
36
8.3
SUBJECT CONFIDENTIALITY
36
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
36
10 DATA QUALITY ASSURANCE
37
11 COMPLETION OF THE STUDY
37
12 REFERENCES
37
LIST OF TABLES
TABLE 1.
HYPOTHESES AND ESTIMANDS CORRESPONDING TO THE RANKED SECONDARY ENDPOINTS
12
TABLE 2.
DESCRIPTION OF STUDY DRUG AND PLACEBO
25
TABLE 3.
SUPPLEMENTAL ADVERSE EVENTS ECRFS
30
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
15
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
40
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
44
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
45
APPENDIX D.
ACTIVITY SCHEDULE
46
APPENDIX E.
SUMMARY OF CHANGES
50
APPENDIX F.
OPERATIONS MANUAL
52
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
This study will provide essential data for risankizumab in the treatment of adult patients with moderate 
to severe plaque psoriasis (PsO) with palmoplantar (non-pustular) involvement.
Psoriasis is a chronic debilitating immunologic disease characterized by marked inflammation and 
thickening of the epidermis that result in thick, scaly skin plaques.  In most developed countries, the 
prevalence in adults is between approximately 1.5 and 5%.1  About 20% of patients have moderate to 
severe disease with a considerable negative impact on psychosocial and economic status.2,3  It is 
increasingly recognized that PsO is more than a superficial disease, with 30% of patients having joint 
involvement and a high correlation between PsO and obesity, diabetes, depression, metabolic 
syndrome, and cardiovascular risk exits.4,5
Palmoplantar (non-pustular) plaque psoriasis (PPPsO) represents a localized form of PsO.  Approximately 
3 to 17% of all patients with PsO have palmoplantar involvement,6-8 presenting with well-defined 
erythematous, hyperkeratotic desquamative plaques (often with fissures) located on the palms and 
soles that can occur in isolation or in combination with generalized PsO.9  Palmoplantar (non-pustular) 
plaque psoriasis is considered by healthcare professionals as a difficult-to-treat disease manifestation of 
PsO.9  The thicker stratum corneum of the palms and soles represents a barrier to topical treatment 
agents.  Systemic treatments, such as methotrexate, cyclosporine, and some biologics, have shown 
limited efficacy in dedicated studies, compared with the results seen in patients who have PsO without 
palmoplantar involvement, indicating a medical need for increased treatment efficacy in the 
palmoplantar patient population.9-11
Typically, less than 5% of the body surface area (BSA) is affected by PsO in patients with palmoplantar 
involvement, precluding these patients from entering clinical research studies with biologics, which 
usually require a BSA involvement of ≥ 10%.11  This creates challenges in understanding if results of PsO 
clinical trials are applicable to patients with palmoplantar disease.  Assessing treatment options to 
address the unmet needs of patients with PPPsO is important, since palmoplantar involvement has a 
significantly greater impact on patients' quality of life compared to that of patients who have moderate 
to severe PsO without palmoplantar involvement.12  One reason for this is because PsO lesions of the 
dominant hand and/or feet impair patients' ability to work or perform daily activities.6,13  Therefore, in 
addition to the BSA involved, other factors such as location of the lesions and impact of PsO on patients'
quality of life, have been proposed to more accurately assess PsO severity in PPPsO patients.14
Positive results in PsO patients treated with risankizumab were reported in 4 pivotal Phase 3 clinical 
trials that evaluated risankizumab compared with ustekinumab, placebo, and adalimumab for the 
treatment of adult patients with moderate to severe PsO.  Results from these pivotal studies 
demonstrated that risankizumab is highly effective for the treatment of PsO, meeting co-primary 
endpoints of achieving PASI 90 (defined as at least a 90% improvement from Baseline in the Psoriasis 
Area and Severity Index [PASI]) and static Physician's Global Assessment (sPGA) score of "clear" or 
"almost clear" (0 or 1) versus comparator or placebo at Week 16 across all 4 studies.15-17  These Phase 3 
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PsO studies (M15-995 [Study 1311.28]; M16-008 [Study 1311.3]; and M15-992 [Study 1311.4]) enrolled 
moderate to severe psoriatic subjects with an affected BSA ≥10%, an sPGA of "moderate" or "severe"
(≥3).  A subset of subjects in these trials had documented palmoplantar involvement of their PsO, 
defined as a Palmoplantar Psoriasis Area and Severity Index (PPASI) > 0.  Efficacy data from this subject
subgroup showed significant improvement from Baseline PPASI in the risankizumab treatment group 
compared to subjects who received placebo (P < 0.01 in all 3 trials) at Week 16.  The response was 
sustained in the risankizumab-treated subjects until Week 52.18
Risankizumab (Skyrizi™) has been approved for the treatment of moderate to severe PsO and is 
currently being developed for Crohn's disease, ulcerative colitis, psoriatic arthritis (Phase 3 studies), and 
the treatment of atopic dermatitis and hidradentitis suppurativa (in Phase 2 studies).  Risankizumab is a 
humanized monoclonal antibody (mAb) of the immunoglobin (Ig)G1 subclass directed towards the p19 
subunit of interleukin-23 (IL-23).  The antibody (Ab) has been engineered to reduce Fcγ receptor and 
complement binding and potential charge heterogeneity.  Risankizumab binds with high affinity to 
human IL-23.
The current study compares the safety and efficacy of risankizumab versus placebo in adult subjects 
with moderate to severe PPPsO.  For a more detailed description of the risankizumab drug profile, refer 
to the latest version of the Investigator's Brochure (IB).17
Clinical Hypothesis
Risankizumab will provide superior efficacy compared to placebo with respect to Palmoplantar 
Investigator's Global Assessment (ppIGA) of "clear" or "almost clear" (0 or 1) with at least a 2-point
reduction from Baseline at Week 16, and will be well tolerated in adult subjects with PPPsO.
2.2 Benefits and Risks to Subjects
In Phase 1, Phase 2, and Phase 3 studies of risankizumab in patients with PsO, 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 systemic infection or clinically 
important infection will not be included in the study.
Subjects with a positive QuantiFERON®-TB (or interferon gamma release assay [IGRA] 
equivalent)/tuberculosis (TB) skin test result for 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.19,20  Subjects with positive QuantiFERON-TB testing (or IGRA 
equivalent)/TB skin test who have latent TB (defined by local guidelines) are not required to be treated 
(unless recommended by local guidelines or by investigator judgement) with TB prophylaxis prior to 
receiving risankizumab, but should be carefully monitored for any sign of TB reactivation.
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.21-23  Moreover, preclinical data have demonstrated a 
beneficial effect of IL-23 p19 inhibition in animal models, both for pre-existing and tumor-induction 
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models.24  While there is not enough clinical information at this time to rule out a risk of cancer with 
risankizumab, this risk is considered small.
Although rare, a potential for hepatic AEs 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 events (MACE), 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 with risankizumab.  While the likelihood of 
increased MACE is small, all suspected cardiovascular or cerebrovascular events (serious or nonserious) 
observed in this study will be adjudicated by an independent Cardiovascular Adjudication Committee 
(CAC).  The committee will remain blinded to treatment allocation (Section 6.2).
Local reactions to subcutaneously (SC) administered biologic therapies are usually limited to redness, 
swelling, or induration at the injection site.  Manifestations of systemic hypersensitivity reactions include 
anaphylaxis, pruritus, hypotension, and respiratory distress.  Both local and systemic hypersensitivity 
reactions are readily detectable, transient in nature, and manageable with standard medical treatment.  
Subjects will be closely monitored during study drug administration while at the site and be given 
instructions regarding management of signs and symptoms of anaphylaxis to be followed during home 
dosing visits.  An independent Anaphylaxis Adjudication Committee (AAC) will adjudicate observed 
systemic hypersensitivity and anaphylactic events.  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.25  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 current 
risankizumab Investigator Brochure.17
In view of the coronavirus disease of 2019 (COVID-19) pandemic, the benefit-risk profile of various 
immunomodulatory therapies on COVID-19 is being evaluated based on real world data and clinical trial 
data.  At this time, the effects of risankizumab on the course of COVID-19 are not well defined.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary
The primary objective of this study is to assess the safety and efficacy of risankizumab (150 mg) versus 
placebo for the treatment of signs and symptoms of moderate to severe plaque PsO in patients with 
palmoplantar (non-pustular) involvement.
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The primary efficacy objective is to demonstrate a higher rate of ppIGA of "clear" or "almost clear" (0 or 
1) with at least a 2-point reduction from Baseline at Week 16 with risankizumab treatment compared to 
placebo in the Intent-to-Treat (ITT) Population, which consists of all randomized subjects (Section 7.2).
The hypothesis corresponding to the primary endpoint (Section 3.2) is:

The proportion of subjects achieving ppIGA of 0 or 1 with at least a 2-point reduction from 
Baseline with risankizumab is greater than that with placebo at Week 16.
The estimand corresponding to the primary endpoint is defined using composite variable strategy:

Difference in the proportion of subjects achieving ppIGA of 0 or 1 with at least a 2-point 
reduction from Baseline at Week 16 without premature discontinuation of study drug due to
lack of efficacy prior to Week 16, in the risankizumab group in comparison with the placebo 
group in the ITT population.
Secondary
The secondary efficacy objectives are based on the ranked secondary endpoints as defined in 
Section 3.3.  The hypotheses and estimands corresponding to these ranked secondary endpoints are 
summarized in Table 1.
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Table 1.
Hypotheses and Estimands Corresponding to the Ranked Secondary Endpoints
Hypothesis
Estimand
1.
The proportion of subjects achieving PPASI 75 
with risankizumab is greater than that with 
placebo at Week 16.
Difference in the proportion of subjects achieving
PPASI 75 at Week 16 without premature 
discontinuation of study drug due to lack of efficacy 
prior to Week 16 in the risankizumab group in 
comparison with the placebo group in the ITT 
population.
2.
The proportion of subjects achieving PPASI 90 
with risankizumab is greater than that with 
placebo at Week 16.
Difference in the proportion of subjects achieving
PPASI 90 at Week 16 without premature 
discontinuation of study drug due to lack of efficacy 
prior to Week 16 in the risankizumab group in 
comparison with the placebo group in the ITT 
population.
3.
The proportion of subjects achieving sPGA of 
0 or 1 with at least a 2-point reduction from 
Baseline with risankizumab is greater than that 
with placebo at Week 16.
Difference in proportion of subjects achieving sPGA of 
0 or 1 with at least a 2-point reduction from Baseline 
at Week 16 without premature discontinuation of 
study drug due to lack of efficacy prior to Week 16 in 
the risankizumab group in comparison with the 
placebo group in the ITT population.
4.
The proportion of subjects achieving PPASI 100 
with risankizumab is greater than that with 
placebo at Week 16.
Difference in the proportion of subjects achieving
PPASI 100 at Week 16 without premature 
discontinuation of study drug due to lack of efficacy 
prior to Week 16 in the risankizumab group in 
comparison with the placebo group in the ITT 
population.
ITT = intent-to-treat; PPASI = Palmoplantar Psoriasis Area and Severity Index; sPGA = static Physician's Global Assessment
3.2 Primary Endpoint
The primary endpoint is the achievement of ppIGA of "clear" or "almost clear" (0 or 1) with at least a 
2-point reduction from Baseline at Week 16.
3.3 Secondary Endpoints
Secondary Endpoints (Ranked)
The following ranked secondary endpoints will be tested in a hierarchical order, only if the null 
hypothesis for the primary endpoint has been rejected:
1.
Achievement of ≥75% improvement from Baseline in Palmoplantar Psoriasis Area and Severity 
Index (PPASI 75) response at Week 16
2.
Achievement of ≥90% improvement from Baseline in Palmoplantar Psoriasis Area and Severity 
Index (PPASI 90) response at Week 16
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3.
Achievement of sPGA of "clear" or "almost clear" (0 or 1) with at least a 2-point reduction from 
Baseline at Week 16
4.
Achievement of 100% improvement from Baseline in Palmoplantar Psoriasis Area and Severity 
Index (PPASI 100) response at Week 16
3.4 Additional Efficacy Endpoints
All primary and ranked secondary endpoints will be analyzed at all other visits collected.  In addition, the 
following endpoints will be analyzed at all visits collected:

Achievement of ppIGA of "clear" (0)

Achievement of sPGA of "clear" (0)

Change from Baseline in PPASI

Percent change from Baseline in PPASI

Change from Baseline in PASI

Percent change from Baseline in PASI among subjects with Baseline PASI ≥12

Change from Baseline in Patient Global Assessment of Skin Pain (PGA-SP), among subjects with 
Baseline Numerical Rating Scale (NRS) ≥4

Percentage change from Baseline in PGA-SP, among subjects with Baseline NRS ≥4

Change from Baseline in Psoriasis Symptom Scale (PSS)

Achievement of PSS 0 or 1

Change from Baseline in Dermatology Life Quality Index (DLQI)

Achievement of DLQI 0 or 1

Achievement of DLQI improvement (reduction) of ≥ 4 points, among subjects with Baseline 
DLQI ≥4
In addition, the achievement of ppIGA of "clear" (0), ppIGA of "clear" or "almost clear" (0 or 1) with at 
least a 2-point reduction from Baseline, and PPASI 75/90/100 response will also be summarized at later 
visits in Period B, among subjects who are randomized to risankizumab in Period A and have achieved 
the corresponding response status at the entry of Period B.
3.5 Safety Endpoints
The following safety evaluations will be performed throughout the study as measures of safety and 
tolerability:

Adverse event (AE) monitoring

Vital sign measurements
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
Physical examinations

Clinical laboratory testing
3.6 Pharmacokinetic Evaluation
The pharmacokinetics (PK) and immunogenicity of risankizumab have been well characterized in 
subjects with plaque PsO.  No samples will be collected for the purpose of PK and immunogenicity in this 
study, except in cases of hypersensitivity reactions.
3.7 Biomarker Research
For subjects who consent, optional blood samples (whole blood, serum, and plasma) will be collected as 
described in the Activity Schedule (Appendix D) to evaluate known and/or novel disease-related or 
drug-related biomarkers.  Types of biomarkers may include nucleic acids, proteins, lipids, and/or 
metabolites.  The objective of this research is to analyze samples for biomarkers that will help to 
understand PsO, related conditions, or response to treatment with risankizumab or similar compounds.  
Research may also include changes in epigenetics, gene expression, and proteomics that may associate 
with PsO, related conditions, or the subject's response to treatment.  This research is exploratory in 
nature and the results may not be included with the clinical study report.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3b multicenter, randomized, double-blind, parallel-group, placebo-controlled study to 
evaluate the safety and efficacy of risankizumab (150 mg) compared to placebo in adult subjects with 
moderate to severe plaque PsO with palmoplantar involvement.
The study is designed to enroll 168 subjects.  See Section 5 for information regarding eligibility criteria.
The study duration will be up to approximately 65 weeks.  The study is comprised of a Screening period 
of up to 35 days, a 52-week treatment period, and a follow-up phone call for safety.
The 52-week treatment duration includes Period A and Period B.

Period A, Double-Blind Period (Baseline [Day 1] to Week 16):  Eligible subjects will be centrally 
randomized at the Baseline visit in a 1:1 ratio to receive either risankizumab 150 mg as a single 
SC injection, or matching placebo.  Study drug administration will occur at Baseline and Week 4.  
Randomization will be stratified by Baseline ppIGA ("moderate" [3] versus "severe" [4]) and 
Baseline BSA (< 10% versus ≥10%).  The final efficacy evaluation of Period A will be at Week 16.

Period B, Open-label Period (Week 16 to Week 52):  Starting at Week 16, all subjects will receive 
open-label risankizumab 150 mg once every 12 weeks (q12w) at Weeks 16, 28, and 40.  The final 
efficacy evaluation will take place at Week 52.
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A follow-up phone call for safety will be conducted approximately 20 weeks after administration of the 
last dose of risankizumab.
A subgroup of approximately 15 subjects at prospectively selected sites will be asked to have skin 
photographs taken of their palms and soles to document disease response during the study.  Subjects 
who consent will have photographs taken at Baseline and Weeks 4, 16, 28, 40, and 52.  No efficacy 
analysis will be made from the obtained material.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual (Appendix F).
Figure 1.
Study Schematic
N = number of subjects; Wk = week
Solid arrows indicate administration of study drug at study visits.
4.2 Discussion of Study Design
Choice of Control Group
Placebo control will be used in this study to address potential confounding factors, such as placebo 
effect, potential investigator bias in safety and efficacy assessment, or regression to the mean in 
endpoint scoring.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study for assessing disease activity in adult subjects with moderate to severe 
PPPsO have been used in other studies assessing this subset of patients.11,15,16,26,27  All clinical and 
laboratory procedures in this study are standard and generally accepted.  Patient-reported outcome 
(PRO) measures in this study were included to assess patient symptoms and quality of life.
Suitability of Subject Population
Female or male adults with chronic PPPsO with or without psoriatic arthritis for at least 6 months prior 
to Baseline and a ppIGA of "moderate" or "severe" (≥3, at Screening and Baseline) and who are 
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candidates for systemic therapy are eligible for this study.  Eligible subjects must also have ≥1% BSA PsO
involvement, sPGA score of "moderate" or "severe" (≥ 3), PPASI ≥ 8 (moderate or severe disease),28 and 
at least 1 additional PsO plaque outside of the palms and soles at Screening and the Baseline visit.  At 
least 50% of the overall study population will be comprised of subjects with Baseline BSA ≥10%.  The 
selection criteria relating to safety ensure that enrolled subjects can safely be treated with risankizumab 
based on the current knowledge of this drug.
Selection of Doses in the Study
The risankizumab dosing regimen selected for the current study (i.e., 150 mg SC at Weeks 0, 4, and 
q12w thereafter up to Week 40) is the same as used in the risankizumab pivotal Phase 3 studies in 
subjects with moderate to severe chronic plaque PsO.  The risankizumab 150 mg SC dose has been 
shown to be efficacious with an acceptable safety profile and is considered appropriate for the 
treatment of subjects with plaque PsO.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects 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.
2. Employees of the Sponsor and/or study sites and their family members may not be enrolled in 
this study.
3. Subjects must be willing and able to comply with procedures required in this protocol.
Demographic and Laboratory Assessments
4. Adult male or female, at least 18 years old (subjects must also meet the legal age of majority 
per local law).
5. Laboratory values meeting the following criteria within the Screening period prior to the 
first dose of study drug:  

Serum aspartate aminotransaminase (AST) ≤2 × upper limit of normal (ULN);

Serum alanine aminotransaminase (ALT) ≤2 × ULN;

Serum total bilirubin ≤ 2.0 mg/dL; except for subjects with isolated elevation of indirect 
bilirubin relating to Gilbert syndrome;

Total white blood cell (WBC) count ≥3,000/µL;

Absolute neutrophil count (ANC) ≥1,500/µL;
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
Platelet count ≥100,000/µL;

Hemoglobin ≥10 g/dL (100 g/L).
Disease Activity
6. Female or male adults with chronic PPPsO (with or without psoriatic arthritis) for at least 
6 months prior to Baseline and a ppIGA of "moderate" or "severe" (≥3), at Screening and 
Baseline.
7. Subjects must have at Screening and Baseline:

Plaque PsO BSA involvement of ≥1%,

sPGA score of "moderate" or "severe" (≥ 3),

PPASI ≥ 8 (moderate or severe disease), and

At least 1 additional PsO plaque outside of the palms and soles.
At least 50% of the overall study population will be comprised of subjects with Baseline BSA 
≥10%.
8. Previously inadequately controlled disease by topicals, phototherapy, and/or systemic 
treatments.
9. Subject must be a candidate for systemic therapy as assessed by the investigator.
Subject History
10. Subject is judged to be in good general health, as determined by the investigator based upon 
the results of a medical history, physical examination, laboratory profile, and a 12-lead 
electrocardiogram (ECG) performed during the Screening period.
11. No forms of PsO other than chronic plaque-type PsO (e.g., pustular PsO, palmoplantar 
pustulosis, acrodermatitis of Hallopeau, erythrodermic, or guttate PsO).
12. No current drug-induced PsO or a drug-induced exacerbation of pre-existing psoriasis.
13. No active ongoing inflammatory skin diseases other than PsO and psoriatic arthritis that 
could interfere with the assessment of PsO (e.g., hyperkeratotic eczema).
14. Subjects must not have a history of clinically significant (per investigator's judgment) drug or 
alcohol abuse within the last 6 months.
15. Subjects must not have a 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.
16. Subjects must not have had major surgery performed within 12 weeks prior to 
randomization or planned during the conduct of the study (e.g., hip replacement, aneurysm 
removal, stomach ligation).
17. Subjects must not have evidence of:

Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, defined as:
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
HBV:  Hepatitis B surface antigen (HBs Ag) positive (+) test or detected sensitivity on the 
HBV DNA polymerase chain reaction (PCR) qualitative test for subjects who are hepatitis 
B core antibody (HBc Ab) positive (+) (and for hepatitis B surface antibody [HBs Ab] 
positive [+] subjects where mandated by local requirements).

HCV:  HCV RNA detectable in any subject with anti-HCV antibody (HCV Ab).

Human immunodeficiency virus (HIV), defined as confirmed positive anti-HIV Ab test.  Note:
In case a screened subject has a confirmed positive HIV Ab test, Eligibility Criterion 10 
(Subject is judged to be in good general health criteria…) should be selected in electronic 
case report form (eCRF) for documentation of screening failure.

Active TB.  For subjects with latent TB, please see Section 3.16 of the Operations Manual.

Active systemic infection/Clinically important infection during the last 2 weeks prior to 
Baseline visit as assessed by the investigator.
18. Subject must not have any of the following medical diseases or disorders: 

Recent (within past 6 months) cerebrovascular accident or myocardial infarction; 

History of an organ transplant which requires continued immunosuppression; 

Active or suspected malignancy or history of any malignancy within the last 5 years except 
for successfully treated non-melanoma skin cancer (NMSC) or localized carcinoma in-situ of 
the cervix.
19. Subject must not have concurrent clinically significant medical conditions other than the 
indication being studied or any other reason that the investigator determines would interfere 
with the subject's participation in this study, would make the subject an unsuitable candidate 
to receive study drug, or would put the subject at risk by participating in the study.
20. No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.  If 
a subject has signs/symptoms suggestive of SARS-CoV-2 infection, they should undergo 
molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection.  In addition, if based on the 
answers to the SARS-CoV-2 Infection Risk Assessment Tool the site considers the subject 
currently at risk for developing SARS-CoV-2 infection, then the subject should either be tested or 
advised to come back for study screening after 14 days.
Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may 
only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:

At least 14 days since first PCR test result have passed in asymptomatic patients or 14 days 
since recovery, defined as resolution of fever without use of antipyretics and improvement 
in symptoms.
Contraception
21. For all females of child-bearing potential; a negative serum pregnancy test at the Screening 
visit and a negative urine pregnancy test at Baseline prior to the first dose of study drug is 
required.
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22. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control, that is effective from Study Day 1 through at least 140 days (20 weeks or as 
guided by the local risankizumab label [if approved], whichever is longer) after the last dose of 
study drug (local practices may require 2 methods of birth control).  Female subjects of 
non-childbearing potential do not need to use birth control.
23. Female subjects may not be pregnant, breastfeeding, or considering becoming pregnant
during the study or for approximately 140 days (20 weeks or as guided by the local risankizumab 
label [if approved], whichever is longer) after the last dose of study drug.
Concomitant Medications (Prior Medication Restrictions)
24. No prior exposure to risankizumab.
25. Subject must not have received any live viral or bacterial vaccine within 4 weeks prior to the 
first dose of study drug, or expected need of live vaccination during study participation including 
at least 140 days (20 weeks or as guided by the local risankizumab label [if approved], whichever 
is longer) after the last dose of study drug.
26. 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 or was previously enrolled in this study.
27. Subject did not receive any systemic biologics to treat PsO for the following timeframes prior 
to the Baseline visit: 

Etanercept (Enbrel®) and biosimilar versions within 3 weeks;

Certolizumab (Cimzia®), adalimumab (Humira®), ixekizumab (Taltz®), brodalumab 
(Siliq®/Kyntheum®), infliximab (Remicade®), and biosimilar versions within 10 weeks;

Ustekinumab (Stelara®) and guselkumab (Tremfya®) within 15 weeks;

Tildrakizumab (Ilumya™) and secukinumab (Cosentyx®) within 20 weeks.
28. Subject did not receive for at least 30 days prior to randomization any: 

Other systemic immunomodulating treatments (including, but not limited to:  e.g., 
methotrexate, cyclosporine A, corticosteroids, cyclophosphamide, tofacitinib [Xeljanz®], 
apremilast [Otezla®]);

Other systemic PsO treatments (e.g., retinoids, fumarates, any other drug known to possibly 
benefit PsO);

Photochemotherapy (e.g., psoralen and ultraviolet A radiation [PUVA]), phototherapy (e.g., 
ultraviolet B rays [UVB]).
29. Subject did not receive for at least 14 days prior to randomization any topical treatment for 
PsO or any other skin condition (including, but not limited to: e.g., corticosteroids, vitamin D 
analogues, vitamin A analogues, pimecrolimus, retinoids, salicyl vaseline, salicylic acid, lactic 
acid, tacrolimus, tar, urea, or anthralin).
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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:

Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:

Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy.

Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals.

Postmenopausal, female:

Age > 55 years with no menses for 12 or more months without an alternative medical 
cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical 
cause AND a follicle-stimulation hormone (FSH) level > 30 IU/L.

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 140 days (20 weeks or as guided by the local risankizumab label [if approved], 
whichever is longer) 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 30 days prior to study Baseline.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence, defined as:  Refraining from heterosexual intercourse when 
this is in line with the preferred and usual lifestyle of the subject (periodic abstinence 
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[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable).
If required per local practices, 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 should be based on 
the local label.
5.3 Prohibited Medications and Therapy
1.
During the study, no biologic treatment is allowed.  Exception:  Treatment with commercially 
available risankizumab after the Week 52/Premature Discontinuation (PD) assessments if this 
has been determined as an appropriate subsequent treatment by the investigator in discussion 
with the subject.
2.
Systemic (including oral or injectable administrations) non-biologic therapy that can be used to 
treat PsO, including but not limited to cyclosporine, corticosteroids, methotrexate, retinoids, 
apremilast, and fumaric acid derivatives.
3.
Phototherapy treatment (UVB or ultraviolet A [UVA] phototherapy, including PUVA), laser 
therapy, tanning booth, or extended sun exposure that could affect disease severity or interfere 
with disease assessments.
4.
Topical PsO treatments, including but not limited to corticosteroids, anthralin, calcipotriene, 
topical vitamin D derivatives, retinoids, urea, α- or β-hydroxyl acids, and medicated shampoos 
(for example those that contain corticosteroids, coal tar, or vitamin D3 analogues).
5.
All other investigational drugs and enrollment in another clinical study are prohibited.
6.
Live attenuated vaccines are not permitted during study participation and including up to 
140 days (20 weeks or as guided by the local risankizumab label [if approved], whichever is 
longer) after the last dose of study drug.  Examples of live attenuated vaccines include, but are 
not limited to, the following:

Bacille Calmette-Guérin (BCG)

Zoster vaccine live (Zostavax®)

Measles mumps rubella or measles mumps rubella varicella

Monovalent live attenuated influenza A (intranasal)

Oral polio vaccine

Rotavirus

Seasonal trivalent live attenuated influenza (intranasal)

Smallpox

Oral typhoid vaccine
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
Varicella (chicken pox)

Yellow fever

Dengue (Dengvaxia®)
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.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject has received from 4 weeks prior to Screening or receives during 
the study must be recorded along with the reason for use; date(s) of administration, including start and 
end dates; and dosage information including dose, route, and frequency on the appropriate eCRF.
A detailed history of all prior biologic use will be obtained in the electronic data capture (EDC).
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with risankizumab can be located in the 
risankizumab Investigator's Brochure.17
Subjects must be able to safely discontinue any prohibited medications (including biologics) 5 half-lives 
or 4 weeks, whichever is longer, prior to initial study drug administration.  Subjects must be consented 
for the study prior to discontinuing any prohibited medications for the purpose of meeting study 
eligibility.
Non-live vaccines may be administered during screening or treatment period, if not contraindicated or 
medically inappropriate.
When possible, first dose of study drug should be given at least ± 7 days from non-live SARS-CoV-2 
vaccine administration. The potential impact of risankizumab on SARS-CoV-2 vaccination is unknown.  
The decision to receive a locally available non-live vaccine should be based on local guidance and an 
individual discussion between the treating physician and the subject and/or guardian.
Allowed Concomitant Medications/Therapy
Allowed concomitant medications and therapies include the following:

Moisturizers:  Provided that moisturizers (without active ingredients) have been used for at least 
2 weeks prior to Baseline and are anticipated to be continuously used at least until the Week 16 
visit.  Subjects should not apply emollients within 8 hours prior to study assessments.

Only inhaled, topical ophthalmic, or intranasal corticosteroids are permitted during the study.
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COVID-19 Pandemic-Related Vaccination Guidance
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
Operations Manual (Appendix F)for instructions on reporting any AEs associated with the COVID-19 
vaccine.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw from the study drug and/or study at any time.  Subjects must be 
withdrawn from the study drug and/or study for reasons including, but not limited to, the following:

The subject requests withdrawal from the study.

The investigator believes it is in the best interest of the subject.

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie Therapeutic Area (TA) Medical Director 
(MD).

Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.

Malignancy, except for localized NMSC or carcinoma in-situ of the cervix where discontinuation 
is at the discretion of the investigator.

The subject becomes pregnant while on study drug.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.

Post-Baseline occurrence of one or more of the following hepatic test abnormalities (confirmed 
on a second separate sample at least 48 hours apart):

ALT or AST > 8 × ULN;

ALT or AST > 5 × ULN for more than 2 weeks;

ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or international normalized ratio 
(INR) > 1.5;

ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%).

Subjects who meet any of the above criteria should be evaluated for an alternative etiology 
of the ALT or AST elevation and managed as medically appropriate.  If applicable, the 
alternative etiology should be documented (in the eCRF if reported as an AE).  If ALT or AST 
values return to the normal reference range or its Baseline value, study drug may be 
restarted.  If restarting study drug, documentation should include reason that rechallenge is 
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expected to be safe.  If after clinically appropriate evaluation, no alternative etiology for ALT 
or AST elevation is found or the ALT or AST elevation has not resolved or is not trending 
down toward normal, the subject should be discontinued from study drug.
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.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it may be necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than described in protocol to ensure all acceptable mitigation steps have been 
explored.
Refer to the Operations Manual in Appendix F for details on how to handle study activities/procedures.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
For subjects with documented COVID-19, the timing of next administration of study drug or possibility of 
premature discontinuation from study drug should be discussed with the AbbVie Medical Contact.  
Follow subsequent protocol Section 5.6 for subjects who discontinued study drug.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for safety and efficacy 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, the procedures outlined for the PD visit should 
be completed as soon as possible, preferably within 2 weeks.  In addition, if subject is willing, a 
follow-up phone call 140 days after the last dose of study drug may be completed to ensure all 
treatment-emergent AEs/serious adverse events (SAEs) have been resolved.  The 140-day follow-up 
phone call following the last dose administration of risankizumab study drug during the trial will not be 
required for any subject who initiates commercially available risankizumab after completion of the 
Week 52 visit or premature discontinuation visit.
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If a subject withdraws from study follow-up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed the subject has 
withdrawn and no longer wishes biomarker sample research to continue, samples will not be analyzed, 
and no new biomarker analysis data will be collected for the withdrawn subject or added to the existing 
data or database(s).  A subject may withdraw consent for optional biomarker research at any time and 
remain in the clinical study.  Data generated from clinical study and/or optional biomarker research, 
before subject withdrawal of consent, will remain part of the study results.
5.7 Study Drug
AbbVie will provide study drug for risankizumab or matching placebo.  AbbVie-provided study drug 
should not be substituted or alternately sourced unless otherwise directed by AbbVie.  Information 
about the study drug and placebo used in this study is presented in Table 2.
During Period A (Double-Blind Period), study site staff will administer study drug subcutaneously 
(risankizumab 150 mg or matching placebo in a pre-filled syringe [PFS]) at Baseline and Week 4 visits.  
Subjects will be trained by site staff on self-injection at the Baseline visit to proactively be prepared for 
at-home dosing by the subject or caregiver at Weeks 4, 28, and 40, should the need for a virtual visit 
arise due to COVID-19-related restrictions. Subjects may be retrained on self-injection at the Week 16 
visit.
During Period B (Open-Label Period), study site staff will administer risankizumab as a 150 mg SC dose 
(1 × 150 mg PFS) at Week 16, Week 28, and Week 40 visits.
Only subjects who self-administer study drug at home due to COVID-related visit modifications (e.g., 
virtual visit) will record the self-administered dosing in a subject dosing diary.
Table 2.
Description of Study Drug and Placebo
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Risankizumab (ABBV-066) 
Solution for 
injection in PFS
150 mg Active, 
150 mg/mL
SC injection
AbbVie Biotechnology 
Ltd., Barceloneta, 
Puerto Rico
Placebo for Risankizumab 
(ABBV-066) 
Solution for 
injection in PFS
Not applicable
SC injection
AbbVie Deutschland 
GmbH & Co. KG, 
Ludwigshafen, Germany
PFS = pre-filled syringe; SC = subcutaneous
Blinded risankizumab or placebo and 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.  Upon receipt, study drug must be kept protected from light in the original packaging, 
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in a refrigerator between 2°C to 8°C (36°F to 46°F).  A temperature log must be maintained for
documentation.  Study drug must be kept in a secure location and must not be frozen at any time.  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.  Upon receipt of the study drugs, the site will acknowledge receipt within the IRT system.  All 
blank spaces on the label will be completed by the site staff prior to dispensing to subjects.
AbbVie will not supply drug other than risankizumab and matching placebo, 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.  If a subject is unable to come to the study site to pick up 
their study drug due to COVID-19, a direct-to-patient (DTP) study drug shipment can be made from the 
study site to the subject if allowed by local regulations.  AbbVie will submit any required notifications to 
the regulatory authority as applicable.  Refer to the Operations Manual in Appendix F for details on DTP 
shipment of study drug.
5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the Screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial Screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule generated by Data and Statistical Sciences (DSS) at 
AbbVie.
Eligible subjects will be centrally randomized in a 1:1 ratio to risankizumab 150 mg or placebo groups 
during Treatment Period A. The randomization will be stratified by Baseline ppIGA ("moderate" [3]
versus "severe" [4]) and Baseline BSA (< 10% versus ≥10%).  All subjects will receive risankizumab 
150 mg during Treatment Period B.
All AbbVie personnel with direct oversight of the conduct and management of the study (with the 
exception of AbbVie Drug Supply Management Team) will remain blinded until the Primary Analysis at 
Week 16 is available.  The investigator, study site personnel, and the subject will remain blinded to each 
subject's treatment throughout the study.  To maintain the blind, the risankizumab PFS and placebo PFS 
provided for the study will be identical in appearance.  The IRT will provide access to unblinded subject 
treatment information in the case of a medical emergency.
In the event of a medical emergency in which the investigator believes that knowledge of study drug 
treatment is required, reasonable efforts must be made to contact the AbbVie emergency contact prior 
to breaking the blind, as long as it does not compromise subject safety.  However, if an urgent 
therapeutic intervention is necessary which warrants breaking the blind prior to contacting the AbbVie 
emergency contact, the investigator can directly access the IRT system to break the blind without 
AbbVie agreement.  The date and reason that the blind was broken must be recorded in the source 
documentation and eCRF, as applicable.
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5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
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.  Product complaints occurring during the 
study will be followed-up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE 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 AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, and/or if the investigator considers them 
to be AEs.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and/or the surgery/procedure has 
been pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If an AE, 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 an SAE within 24 hours of the site being made aware of the serious SAE (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, along with any suspected transmission of an 
infectious agent via a medicinal product if no other serious criterion 
is applicable.  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 AEs reported from the time of study drug administration until 140 days (20 weeks) after 
discontinuation of study drug administration will be collected, whether solicited or spontaneously 
reported by the subject.  In addition, study procedure-related serious and nonserious AEs will be 
collected from the time the subject signs the study-specific informed consent.
The following definitions will be used for Serious Adverse Reaction (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an Investigational Medicinal 
Product (IMP) related to any dose administered that result in an SAE as defined 
above.
SUSAR
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the sponsor 
or the investigator, is not listed in the applicable Reference Safety Information
(RSI), and meets one of the above serious criteria.  All individually reported SARs 
are considered suspected.
AbbVie will be responsible for SUSAR reporting for the 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.
Areas of Safety Interest/Safety Topics of Interest
Infections, especially opportunistic infections, are a potential risk with immunomodulators.  Subjects will 
be screened and monitored throughout the study for Areas of Safety Interest (ASI)/Safety Topics of 
Interest.  Screening procedures are outlined in the Activity Schedule (Appendix D).  In consideration of 
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
Grade 4 (Severe); Life-threatening consequences; urgent intervention indicated.

Grade 5 (Severe); Death related to AE.
If no specific criteria per CTCAE Version 5 guidelines are available for the reported event, the event 
should be graded per the investigator's judgment according to the definitions outlined above.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours 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 an 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 adjudicate 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 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
While no concerns with anaphylaxis/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 prespecified definitions.  This independent external AAC will adjudicate 
suspected anaphylactic reactions and will remain blinded to each subject's initial treatment allocation.  
The event terms to be adjudicated and the adjudication process are detailed in the AAC Charter.  A 
supplemental Hypersensitivity Reactions Signs and Symptoms eCRF will be used to collect information 
pertinent to the events.  In addition, the site may be contacted for additional source documentation.
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If a suspected systemic hypersensitivity reaction occurs at the investigative site, in addition to testing 
tryptase and histamine levels, drug (serum risankizumab concentration) and antidrug antibody 
(ADA)/neutralizing antibody (Nab) samples should also be collected.  If a systemic hypersensitivity 
reaction such as anaphylaxis is 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.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and ranked secondary 
analyses.  Complete and specific details of the statistical analysis will be described in the Statistical 
Analysis Plan (SAP).
The Primary Analysis will be conducted after all continuing subjects complete Week 16 and all data 
pertaining to Period A are cleaned.  This will be the only and final analysis for efficacy in Period A.  Study 
sites and subjects will remain blinded to their initial treatment assignment for the duration of the entire 
study.
7.2 Definition for Analysis Populations
The Intent-to-Treat (ITT) Population includes all randomized subjects. The ITT Population will be used 
for all efficacy analyses.  Subjects who are randomized to placebo in Period A and do not continue into 
Period B will not be included in the analysis in Period B.
The following populations will be used for the safety analysis:

The Safety Population in Period A (Safety_A) is defined as all subjects who are randomized and 
received at least 1 dose of study drug in Period A.

The Safety Population in Period B (Safety_B) is defined as all subjects who received at least 
1 dose of study drug in Period B.

The All Risankizumab Treated (ALL_RZB) Population is defined as subjects who received at least 
1 dose of risankizumab as the study drug.  This population will be used to provide a 
comprehensive summary of safety.
7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints
The primary endpoint (Section 3.2) and the ranked secondary endpoints (Section 3.3) will be analyzed in 
the ITT Population and the following method will be used to address potential intercurrent events:
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
Subjects discontinuing study drug due to lack of efficacy before Week 16 are considered as not 
achieving the response.
7.4 Statistical Analyses for Efficacy
Analysis of all efficacy endpoints will be conducted on the ITT Population based on treatment as 
randomized.
All statistical tests will be performed at a 2-sided alpha level of 0.05 in Period A. The 95% confidence 
interval (CI) of the treatment effect will be provided.

For categorical variables, comparison will be made between risankizumab and placebo using the 
Cochran-Mantel-Haenszel (CMH) test, adjusting for the actual values of stratification factors 
(Baseline ppIGA and Baseline BSA).  Non-Responder Imputation incorporating multiple 
imputation to handle missing data due to COVID-19 (NRI-C) will be the primary approach to 
handle missing values.

For continuous variables, comparison will be made between risankizumab and placebo based on 
the fixed term of treatment from a Mixed-effect Model Repeat Measurement (MMRM), 
adjusting for treatment, actual values of stratification factors (Baseline ppIGA and Baseline BSA), 
and baseline value if applicable (if not duplicating the stratification factors).  The MMRM will be 
the primary approach to handle missing values.
Summary statistics will be provided in Period B by treatment groups.  Categorical endpoints will be 
summarized by the number and proportion of subjects who achieved the endpoint, as well as the 95% 
confidence interval of that proportion.  Continuous endpoints will be summarized by descriptive 
statistics including the mean, standard error, and the 95% confidence interval of the mean.
Analysis of the Primary Endpoints
Analysis of the primary endpoint, as described in Section 3.2, will be conducted on the ITT population 
based on treatment as randomized.
Comparison of the primary endpoint will be made between risankizumab and placebo using the CMH 
test adjusting for the actual values of stratification factors (Baseline ppIGA and Baseline BSA) with a 
2-sided significance level of 0.05.
NRI-C will be the primary approach to handle missing values.  A sensitivity analysis will also be 
performed for the primary efficacy endpoint, using multiple imputation (MI) to handle missing values.  
Analysis details for NRI-C, MI, and other sensitivity analyses (if applicable) will be provided in the SAP.
Analysis of the Secondary Endpoints
Analysis of all ranked secondary efficacy endpoints will be conducted on the ITT population based on 
treatment as randomized.
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To control the overall type I error rate, the null hypotheses for all ranked secondary endpoints will be 
tested in a hierarchical order as described in Section 3.3, with a 2-sided significance level of 0.05, only if 
the null hypothesis for the primary endpoint has been rejected.
Analysis of Additional Efficacy Endpoints
Additional endpoints, as described in Section 3.4, will also be analyzed.  Analysis details about additional 
efficacy endpoints will be provided in the SAP.
Subgroup Analysis for Efficacy
To evaluate the consistency of the efficacy across demographic and other baseline characteristics, 
summaries and analyses will be performed for selected subgroups for the primary efficacy endpoint.
Subgroup analysis will be performed on the primary endpoint using the following subgroups:

Age group (< 40 years, ≥40);

Sex (male, female);

Race (white, non-white);

Smoking (current, ex-, or never);

Body mass index (BMI) (normal:  < 25, overweight:  ≥25 to < 30, obese:  ≥30);

Baseline ppIGA ("moderate" [3], "severe" [4]);

Baseline BSA (< 10% versus ≥10%);

Psoriatic arthritis (yes, no); and

Body weight (≤100 kg, > 100 kg).
7.5 Statistical Analyses for Safety
All safety analyses will be performed on the Safety Population in each period.  Subjects will be analyzed 
based on the actual treatment received, defined as the first dose of treatment received after 
randomization. Treatment-emergent adverse events (TEAEs), laboratory assessments, and vital signs 
will be summarized.  Key safety variables will also be summarized on the ALL_RZB Population.  Details 
will be described in the SAP.
A TEAE for the Safety Population is defined as an AE newly occurred or worsened 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 patient years [PY]) of SAEs, deaths, and AEs leading to discontinuation will be provided as well.  Pre-
treatment AEs will be summarized separately.
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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.Interim Analysis
No interim analysis is planned for this study.
7.7 Overall Type I Error Control
Overall type I error rate will be controlled at a 2-sided significance level of 0.05 by testing the primary 
endpoint, followed by the ranked secondary endpoints, in a hierarchical order as described in 
Section 3.2 and Section 3.3.
7.8 Sample Size Determination
The ppIGA is an endpoint that has been used in another clinical trial in the palmoplantar psoriasis 
population and which is based on the modified Investigator's Global Assessment version of 2011.11,30  
Given the lack of historical ppIGA data from risankizumab trials, the assumption of response rates in the 
current study are based on the relevant endpoints of PPASI 75 and PPASI 90 from risankizumab PsO
Studies M15-992 (NCT02672852, Study 1311.4), M15-995 (NCT02684357, Study 1311.28), and M16-008 
(NCT02684370, Study 1311.3), among subjects who had Baseline PPASI of at least 8.  Among these 
subjects, approximately 80% and 75% of subjects from the risankizumab (RZB) group achieved PPASI 75 
and PPASI 90, respectively; compared to 50% and 40% in the placebo (PBO) group.
Assuming that 75% of subjects from the RZB group and 45% of subjects from the PBO group would
achieve the primary endpoint of ppIGA of "clear" or "almost clear" (0 or 1) with at least a 2-point
reduction from Baseline at Week 16, the sample size of 168 subjects (84 subjects per group) will provide
more than 90% power to detect the treatment difference between RZB and PBO, under a 2-sided 
significance level of 0.05.
7.9 Statistical Analysis of Optional Biomarker Data
Analysis may be conducted on optional biomarker data for the purpose of identification of prognostic, 
predictive, surrogate, and pharmacodynamic biomarkers associated with safety or efficacy.  The 
association of biomarkers to the efficacy or safety endpoints may be explored for each biomarker one at 
a time, and also for combinations of biomarkers via some multivariate predictive modeling approaches.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
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 
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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 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties in performing 
protocol-specified procedures, AbbVie will engage with study site personnel in efforts to ensure the 
safety of subjects, maintain protocol compliance, and minimize risks to the integrity of the study while 
trying to best manage subject continuity of care.  This may include alternative methods for assessments 
(e.g., phone contacts or virtual site visits), alternative locations for data collection (e.g., use of a local lab 
instead of a central lab), and shipping investigational product and/or supplies direct to subjects to 
ensure continuity of treatment where allowed.  Refer to the Operations Manual in Appendix F for 
additional details.  In all cases, these alternative measures must be allowed by local regulations and 
permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures are taken to 
protect the subjects against any immediate hazard.
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).  During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
Supplemental study case report forms should be completed in the event of COVID-19 related 
missed/virtual visits, study drug interruptions or discontinuations, or AEs (including capture of specific 
signs/symptoms of infection and testing results).
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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 investigator will conduct the study in compliance with the protocol and complete the study within 
the timeframe specified in the contract between the investigator and AbbVie.  Continuation of this study 
beyond this date must be mutually agreed upon in writing by both the investigator and AbbVie.  The 
investigator will provide a final report to the IEC/IRB following conclusion of the study and will forward a 
copy of this report to AbbVie or their representative.
The investigator must submit, maintain, and archive any records related to the study according to ICH 
GCP and all other applicable regulatory requirements.  If the investigator is not able to retain the 
records, he/she must notify AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the study.  
Selection criteria for this investigator will include level of participation as well as significant knowledge 
of the clinical research, investigational drug, and study protocol.  The signatory investigator for the study 
will review and sign the final study report in accordance with the European Agency for the Evaluation of 
Medicinal Products Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last contact, which will be a follow-up phone 
call for safety approximately 20 weeks after administration of the last dose of study drug (risankizumab).
12
REFERENCES
1.
World Health Organization. Global report on psoriasis. 2016. Available from: 
http://apps.who.int/iris/handle/10665/204417. Accessed on: 30 October 2017.
2.
Menter A, Griffiths CE. Current and future management of psoriasis. Lancet. 2007;370(9583):272-84.
3.
Helmick CG, Lee-Han H, Hirsch SC, et al. Prevalence of psoriasis among adults in the U.S.: 2003-2006 
and 2009-2010 National Health and Nutrition Examination Surveys. Am J Prev Med. 2014;47(1):37-
45.
4.
Mease PJ, Gladman DD, Papp KA, et al. Prevalence of rheumatologist-diagnosed psoriatic arthritis in 
patients with psoriasis in European/North American dermatology clinics. J Am Acad Dermatol. 
2013;69(5):729-35.
5.
Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential 
mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 
2010;130(7):1785-96.
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6.
Engin B, Askin O, Tuzun Y. Palmoplantar psoriasis. Clin Dermatol. 2017;35(1):19-27.
7.
Kumar B, Saraswat A, Kaur I. Palmoplantar lesions in psoriasis: a study of 3065 patients. Acta Derm 
Venereol. 2002;82(3):192-5.
8.
Yan D, Afifi L, Jeon C, et al. A cross-sectional study of the distribution of psoriasis subtypes in 
different ethno-racial groups. Dermatol Online J. 2018;24(7).
9.
Raposo I, Torres T. Palmoplantar psoriasis and palmoplantar pustulosis: current treatment and 
future prospects. Am J Clin Dermatol. 2016;17(4):349-58.
10. Janagond AB, Kanwar AJ, Handa S. Efficacy and safety of systemic methotrexate vs. acitretin in 
psoriasis patients with significant palmoplantar involvement: a prospective, randomized study. J Eur 
Acad Dermatol Venereol. 2013;27(3):e384-9.
11. Gottlieb A, Sullivan J, van Doorn M, et al. Secukinumab shows significant efficacy in palmoplantar 
psoriasis: Results from GESTURE, a randomized controlled trial. J Am Acad Dermatol. 2017;76(1):70-
80.
12. Chung J, Callis Duffin K, Takeshita J, et al. Palmoplantar psoriasis is associated with greater 
impairment of health-related quality of life compared with moderate to severe plaque psoriasis. J 
Am Acad Dermatol. 2014;71(4):623-32.
13. Farley E, Masrour S, McKey J, et al. Palmoplantar psoriasis: a phenotypical and clinical review with 
introduction of a new quality-of-life assessment tool. J Am Acad Dermatol. 2009;60(6):1024-31.
14. Strober B, Ryan C, van de Kerkhof P, et al. Recategorization of psoriasis severity: Delphi consensus 
from the International Psoriasis Council. J Am Acad Dermatol. 2020;82(1):117-22.
15. Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe 
plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-
controlled and ustekinumab-controlled phase 3 trials. Lancet. 2018;392(10148):650-61.
16. Reich K, Gooderham M, Thaci D, et al. Risankizumab compared with adalimumab in patients with 
moderate-to-severe plaque psoriasis (IMMvent): a randomised, double-blind, active-comparator-
controlled phase 3 trial. Lancet. 2019;394(10198):576-86.
17. AbbVie. Risankizumab Investigator's Brochure Edition 5. 13 May 2019.
18. Agency EM. Skyrizi (risankizumab) [SmPC]. Ludwigshafen, Germany: AbbVie Deutschland GmbH & 
Co. KG.; 2019.
19. 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-gamma responses if IL-12p70 is available. J Immunol. 2005;175(2):788-95.
20. O'Garra A, Redford PS, McNab FW, et al. The immune response in tuberculosis. Annu Rev Immunol. 
2013;31:475-527.
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21. Qian X, Gu L, Ning H, et al. Increased Th17 cells in the tumor microenvironment is mediated by IL-23 
via tumor-secreted prostaglandin E2. J Immunol. 2013;190(11):5894-902.
22. Baird AM, Leonard J, Naicker KM, et al. IL-23 is pro-proliferative, epigenetically regulated and 
modulated by chemotherapy in non-small cell lung cancer. Lung Cancer. 2013;79(1):83-90.
23. Hu WH, Chen HH, Yen SL, et al. Increased expression of interleukin-23 associated with progression of 
colorectal cancer. J Surg Oncol. 2017;115(2):208-12.
24. Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 
2006;442(7101):461-5.
25. AbbVie. Data on File, RRT165055.
26. Armstrong AW, Vender R, Kircik L. Secukinumab in the Treatment of Palmoplantar, Nail, Scalp, and 
Pustular Psoriasis. J Clin Aesthet Dermatol. 2016;9(6 Suppl 1):S12-S6.
27. Gottlieb AB, Kubanov A, van Doorn M, et al. Sustained efficacy of secukinumab in patients with 
moderate-to-severe palmoplantar psoriasis: 2.5-year results from GESTURE, a randomized, double-
blind, placebo-controlled trial. Br J Dermatol. 2020;182(4):889-99.
28. Menter A, Warren RB, Langley RG, et al. Efficacy of ixekizumab compared to etanercept and placebo 
in patients with moderate-to-severe plaque psoriasis and non-pustular palmoplantar involvement: 
results from three phase 3 trials (UNCOVER-1, UNCOVER-2 and UNCOVER-3). J Eur Acad Dermatol 
Venereol. 2017;31(10):1686-92.
29. US Department 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_Refer
ence_8.5x11.pdf.
30. Langley RG, Feldman SR, Nyirady J, et al. The 5-point Investigator's Global Assessment (IGA) Scale: A 
modified tool for evaluating plaque psoriasis severity in clinical trials. J Dermatolog Treat. 
2015;26(1):23-31.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AAC
Anaphylaxis Adjudication Committee
Ab
Antibody
ADA
Antidrug antibody
AE
Adverse event
ALT
Alanine aminotransaminase/aminotransferase
ANC
Absolute neutrophil count
AP
Alkaline phosphatase
ASI
Areas of safety interest
AST
Aspartate aminotransaminase/aminotransferase
BCG
Bacille Calmette-Guérin
BMI
Body-mass index
BSA
Body surface area
BUN
Blood urea nitrogen
CAC
Cardiovascular Adjudication Committee
CBC
Complete blood count
CI
Confidence interval
CK
Creatine kinase
CKD-EPI
Creatinine with eGFR
CMH
Cochran-Mantel-Haenszel
CS
Clinically significant
COVID-19
Coronavirus disease of 2019
CRO
Contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
D
Desquamation
DFP
Direct-from-patient
DLQI
Dermatology Life Quality Index
DSS
Data and Statistical Sciences
DSUR
Development safety update report
DTP
Direct-to-patient
E
Erythema
ECG
Electrocardiogram
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good clinical practice
GGT/γ-GT
Gamma-glutamyl transferase
h
Head
HBc Ab
Hepatitis B core antibody
HBs Ab
Hepatitis B surface antibody
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B virus
HBV Ab
Hepatitis B virus antibody
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HDL-C
High-density lipoprotein cholesterol
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
hsCRP
High-sensitivity C-reactive protein
I
Induration
IB
Investigator's Brochure
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
Independent ethics committee
Ig
Immunoglobin
IGRA
interferon gamma release assay
IL
Interleukin
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
l
Lower extremities
LDL-C
Low-density lipoprotein cholesterol
mAb
Monoclonal antibody
MACE
Major adverse cardiovascular events
MCV
Mean corpuscular volume
MD
Medical Director
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed-effect Model Repeat Measurement
NAb
Neutralizing antibody
NCI
National Cancer Institute
NCS
Not clinically significant
NMSC
Non-melanoma skin cancer
NRI
Non-responder imputation
NRI-C
Non-Responder Imputation incorporating multiple imputation to handle missing data 
due to COVID-19
NRS
Numerical Rating Scale
PASI
Psoriasis Area and Severity Index
PASI 90
Achievement of ≥90% improvement from Baseline in Psoriasis Area and Severity Index
PBO
Placebo
PCR
Polymerase chain reaction
PD
Premature Discontinuation
PFS
Pre-filled syringe
PGA-SP
Patient Global Assessment of Skin Pain
PK
Pharmacokinetics
PPASI
Palmoplantar Psoriasis Area and Severity Index
PPASI 75
Achievement of ≥75% improvement from Baseline in Palmoplantar Psoriasis Area and 
Severity Index
PPASI 90
Achievement of ≥90% improvement from Baseline in Palmoplantar Psoriasis Area and 
Severity Index
PPASI 100
Achievement of ≥100% improvement from Baseline in Palmoplantar Psoriasis Area and 
Severity Index
PPD
Purified protein derivative
ppIGA
Palmoplantar Investigator's Global Assessment
PPPsO
Palmoplantar plaque psoriasis
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STUDY M15-994  |  Version 2.0  |  EudraCT 2020-000581-42
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
PRO
Patient-reported outcome
PSD
Psoriasis Symptom Diary
PSI
Psoriasis Symptom Inventory
PsO
Psoriasis
PSS
Psoriasis Symptom Scale
PT
Preferred term
PUVA
Psoralen and ultraviolet A radiation
PY
Patient years
q12w
Once every 12 weeks
QTcF
QT interval corrected for heart rate using Fridericia's formula
RBC
Red blood cell
RSI
Reference Safety Information
RZB
Risankizumab
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAR
Serious adverse reaction
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Subcutaneous
SOC
System organ class
sPGA
Static Physician's Global Assessment
SUSAR
Suspected unexpected serious adverse reactions
t
Trunk
TA
Therapeutic Area
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
u
Upper extremities
UACR
Urine albumin-to-creatinine ratio
ULN
Upper limit of normal
UVA
Ultraviolet A rays
UVB
Ultraviolet B rays
WBC
White blood cell
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STUDY M15-994  |  Version 2.0  |  EudraCT 2020-000581-42
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M15-994:  IMMprint:  A Phase 3b Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study Evaluating Safety and Efficacy of Risankizumab Compared to Placebo in Adult 
Subjects with Moderate to Severe Plaque Psoriasis with Palmoplantar (Non-Pustular) Involvement
(PPPsO)
Protocol Date: 10 June 2021
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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CONFIDENTIAL INFORMATION
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Medical Monitor/Medical Director
Medical Affairs, Immunology
Associate Director
Clinical Program Development
Associate Director, Statistics
Data and Statistical Sciences
Director, Statistics
Data and Statistical Sciences
Senior Director/Statistics Therapeutic Area Head
Data and Statistical Sciences
Associate Director
Medical Writing (Protocol Author)
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STUDY M15-994  |  Version 2.0  |  EudraCT 2020-000581-42
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across the subject encounters.  The individual activities 
and allowed modifications due to COVID-19 are described in detail in the Operations Manual
(Appendix F).
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CONFIDENTIAL INFORMATION
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APPENDIX E. SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
11 December 2020
Administrative Change 1
24 March 2021
The purpose of this version is to update the following sections and incorporate necessary protocol 
modifications due to the COVID-19 pandemic and changes due to new safety information available as 
follows:
Modifications to the Protocol and Operations Manual due to State-of-Emergency or Pandemic 
Situations

Vaccine language was updated.  A COVID-19 vaccine eCRF is being implemented in the study.

Sections affected include: Protocol Section 5.4, Operations Manual Section 4.3
Rationale:  To ensure subject safety during state-of-emergency or pandemic situations.

In Section 2.1 of the Operations Manual, the activities list was updated to indicate that Week 16 
labs may be processed at a local lab, if needed.
Rationale: Vendor kit shortages due to the COVID-19 pandemic may necessitate the use of local 
labs.

In Section 3.12 of the Operations Manual, language was provided regarding acceptable 
modifications to ECG collection.
Rationale: Due to protocol modifications in state of emergency or pandemic situations, 
acceptable alternatives may need to be employed.
Protocol

Text was updated throughout the Protocol to align with revisions in the protocol template and 
changes due to new safety information available.

Sections include:  Section 5.1, Section 5.2, Section 5.4, Section 5.5, Section 6.1 (Table 3), 
Appendix D (Activity Schedule)
Rationale: Updated language to provide align with new safety information available and 
provide additional clarity.

Throughout the Protocol, made typographical, stylistic, and administrative updates.
Rationale:  To correct known typographical, stylistic, and administrative inconsistencies.
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STUDY M15-994  |  Version 2.0  |  EudraCT 2020-000581-42
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Operations Manual

Text was updated throughout the Operations Manual to align with revisions in the Operations 
Manual template and changes due to new safety information available.

Sections include:  Section 3.12, Section 3.16, Section 4.1
Rationale:  Updated language to provide align with new safety information available and 
provide additional clarity.

Protocol Section 2.1 was updated to clarify that vital signs, height, weight, and PASI would not 
be collected at virtual visits, if utilized (Week 4, Week 28, Week 40, and Week 52).  Hematology 
and clinical chemistry labs at Week 16 were updated with a "+" to indicate that these labs could 
be performed locally, if needed.
Rationale:  To provide clarity and correct the discrepancy between the text and visit activities 
lists.  Vendor kit shortages may result in the need to use local laboratories.

Throughout the Operations manual, made typographical, stylistic, and administrative updates.
Rationale:  To correct known typographical, stylistic, and administrative inconsistencies.
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SAP_001.pdf: 
Risankizumab
M15-994 – Statistical Analysis Plan
Version 3.0 – 16 May 2023
1
Statistical Analysis Plan for Study M15-994
A Phase 3b Multicenter, Randomized, Double-Blind, 
Parallel-Group, Placebo-Controlled Study Evaluating 
Safety and Efficacy of Risankizumab Compared to 
Placebo in Adult Subjects with Moderate to Severe 
Plaque Psoriasis with Palmoplantar (Non-Pustular) 
Involvement (PPPsO)
Date:  16 May 2023
Version 3.0
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M15-994 – Statistical Analysis Plan
Version 3.0 – 16 May 2023
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Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives, Hypotheses and Estimands................................................... 5
2.2
Study Design Overview.......................................................................... 7
2.3
Treatment Assignment and Blinding....................................................... 9
2.4
Sample Size Determination .................................................................. 10
3.0
Endpoints.............................................................................10
3.1
Primary Endpoint ................................................................................. 10
3.2
Secondary Endpoint ............................................................................. 11
3.3
Additional Endpoints............................................................................ 11
3.4
Safety Endpoints .................................................................................. 12
3.5
Pharmacokinetic Endpoints .................................................................. 12
4.0
Analysis Populations ...........................................................12
5.0
Subject Disposition..............................................................13
6.0
Study Drug Duration and Compliance ..............................13
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................14
7.1
Demographics and Baseline Characteristics.......................................... 14
7.2
Medical History.................................................................................... 15
7.3
Prior and Concomitant Medications...................................................... 15
8.0
Handling of Potential Intercurrent Events for the 
Primary Endpoint and Key Secondary Endpoints............16
9.0
Efficacy Analyses.................................................................16
9.1
General Considerations......................................................................... 16
9.2
Handling of Missing Data..................................................................... 17
9.2.1
Categorical Endpoints .......................................................................... 18
9.2.2
Continuous Endpoints .......................................................................... 19
9.3
Primary Efficacy Endpoint and Analyses.............................................. 20
9.3.1
Primary Efficacy Endpoint ................................................................... 20
9.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 20
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9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint............................................................................................... 21
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 21
9.4.1
Key Secondary Efficacy Endpoints....................................................... 21
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints .......................... 22
9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints ............................................................................... 24
9.5
Additional Efficacy Analyses ............................................................... 24
9.6
Efficacy Subgroup Analyses................................................................. 24
10.0
Safety Analyses....................................................................25
10.1
General Considerations......................................................................... 25
10.2
Adverse Events..................................................................................... 25
10.2.1
Treatment-Emergent Adverse Events.................................................... 26
10.2.2
Adverse Event Overview...................................................................... 26
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 27
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 27
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 28
10.2.6
Area of Safety Interest.......................................................................... 29
10.3
Analysis of Laboratory Data................................................................. 29
10.4
Analysis of Vital Signs......................................................................... 31
10.5
Safety Subgroup Analyses.................................................................... 31
10.6
Other Safety Analyses .......................................................................... 31
11.0
Other Analyses ....................................................................31
12.0
Interim Analyses..................................................................32
12.1
Data Monitoring Committee................................................................. 32
13.0
Overall Type-I Error Control.............................................32
14.0
Version History ...................................................................32
15.0
References............................................................................32
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List of Tables
Table 1.
Hypotheses and Estimands Corresponding to the Ranked 
Secondary Endpoints.............................................................................. 7
Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint............................................................................................... 21
Table 3.
Summary of the Estimand Attributes of the Ranked Secondary 
Efficacy Endpoint................................................................................. 23
Table 4.
SAP Version History Summary ............................................................ 32
List of Figures
Figure 1.
Study Schematic..................................................................................... 8
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 34
Appendix B.
Safety Topics of Interest....................................................................... 35
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 36
Appendix D.
Criteria for Potentially Clinically Important Vital Sign Values ............. 38
Appendix E.
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic for 
Dichotomized Outcome Variables ........................................................ 39
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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for risankizumab 
Study M15-994, A Phase 3b Multicenter, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study Evaluating Safety and Efficacy of Risankizumab Compared to 
Placebo in Adult Subjects with Moderate to Severe Plaque Psoriasis with Palmoplantar 
(Non-Pustular) Involvement (PPPsO).
Study M15-994 assesses the safety and efficacy of risankizumab (150 mg) versus placebo 
for the treatment of signs and symptoms of moderate to severe plaque psoriasis in patients 
with (non-pustular) palmoplantar involvement.
This SAP provides summaries of the planned statistical analyses for safety and efficacy 
endpoints, and overall type-I error control strategies.
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.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The primary objective of this study is to assess the safety and efficacy of risankizumab 
(150 mg) versus placebo for the treatment of signs and symptoms of moderate to severe 
plaque psoriasis in patients with (non-pustular) palmoplantar involvement.
Primary Efficacy
The primary efficacy objective is to demonstrate a higher rate of Palmoplantar 
Investigator's Global Assessment (ppIGA) of "clear" or "almost clear" (0 or 1) with at 
least a 2-point reduction from Baseline at Week 16 of treatment with risankizumab 
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(150 mg) compared to placebo in the Intent-to-Treat (ITT) Population, which consists of 
all randomized subjects (Section 5.0).
The hypothesis corresponding to the primary endpoint is:
●
The proportion of subjects achieving ppIGA of 0 or 1 with at least a 2-point 
reduction from Baseline with risankizumab is greater than that with placebo at 
Week 16.
The estimand corresponding to the primary endpoint is defined using composite variable 
strategy:
●
Difference in the proportion of subjects achieving ppIGA of 0 or 1 with at least 
a 2-point reduction from Baseline at Week 16 without premature 
discontinuation of study drug due to lack of efficacy prior to Week 16, in the 
risankizumab group in comparison with the placebo group in the ITT 
population.
Secondary Efficacy
The secondary efficacy objectives are based on the ranked secondary endpoints as defined 
in Section 3.2.  The hypotheses and estimands corresponding to these ranked secondary 
endpoints are summarized in Table 1.
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Table 1.
Hypotheses and Estimands Corresponding to the Ranked 
Secondary Endpoints
Hypothesis
Estimand
1. The proportion of subjects achieving 
PPASI 75 with risankizumab is greater 
than that with placebo at Week 16.
Difference in the proportion of subjects achieving 
PPASI 75 at Week 16 without premature 
discontinuation of study drug due to lack of efficacy 
prior to Week 16 in the risankizumab group in 
comparison with the placebo group in the ITT 
population.
2. The proportion of subjects achieving 
PPASI 90 with risankizumab is greater 
than that with placebo at Week 16.
Difference in the proportion of subjects achieving 
PPASI 90 at Week 16 without premature 
discontinuation of study drug due to lack of efficacy 
prior to Week 16 in the risankizumab group in 
comparison with the placebo group in the ITT 
population.
3. The proportion of subjects achieving 
sPGA of 0 or 1 with at least a 2-point 
reduction from Baseline with 
risankizumab is greater than that with 
placebo at Week 16.
Difference in proportion of subjects achieving sPGA of 
0 or 1 with at least a 2-point reduction from Baseline at 
Week 16 without premature discontinuation of study 
drug due to lack of efficacy prior to Week 16 in the 
risankizumab group in comparison with the placebo 
group in the ITT population.
4. The proportion of subjects achieving 
PPASI 100 with risankizumab is greater 
than that with placebo at Week 16.
Difference in the proportion of subjects achieving 
PPASI 100 at Week 16 without premature 
discontinuation of study drug due to lack of efficacy 
prior to Week 16 in the risankizumab group in 
comparison with the placebo group in the ITT 
population.
ITT = intent-to-treat; PPASI = Palmoplantar Psoriasis Area and Severity Index; sPGA = static Physician's Global 
Assessment
2.2
Study Design Overview
This is a Phase 3b, multicenter, randomized, double-blind, parallel group, placebo-
controlled study to evaluate the safety and efficacy of risankizumab (150 mg) compared to 
placebo in adult subjects with moderate to severe plaque psoriasis with palmoplantar 
involvement.
The study is comprised of a Screening period of up to 35 days, a 52-week treatment 
period, and a follow up phone call for safety.
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The 52-week treatment period includes Period A and Period B.
●
Period A, Double-Blind Period (Baseline to Week 16):  Eligible subjects will 
be centrally randomized at the Baseline visit in a 1:1 ratio to receive either 
risankizumab 150 mg as a single subcutaneous (SC) injection, or matching 
placebo.  Study drug administration will occur at Baseline and Week 4.  The 
final efficacy evaluation of Period A will be at Week 16.
●
Period B, Open-Label Period (Week 16 to Week 52):  Starting at Week 16, all 
subjects will receive open label risankizumab 150 mg once every 12 weeks at 
Weeks 16, 28, and 40.  The final efficacy evaluation of Period B will take place 
at Week 52.
A follow-up phone call for safety will be conducted approximately 20 weeks after 
administration of the last dose of risankizumab (e.g., Week 60).
The schematic of the study is shown in Figure 1.
Figure 1.
Study Schematic
abbvie 
.-4 
Risankizumab 150 mg {Wk 0, 4, then every 12 weeks), N=84 
.:.i 
"Cl 00 
-~ E II 
.g z 
C 
"' 
0:: 
Placebo (Week 0 and 4) 
Risankizumab 150 mg (Week 16 and every 12 weeks thereafter) 
N=84 
1 
J,k 
16 
28 
<:-- Period A ----x==---------
Solid arrows indicate administration of study drug at study visits. 
Wk= week. 
Period B 
40 
Jk 
Safely Follow-up 
Call 20 Weeks After 
52 
the Len Dose of 
----------~
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The Primary Analysis will be performed after the last ongoing subject completing the 
Week 16 visit or permanently discontinuing the placebo-controlled period, and the data up 
to Week 16 cutoff date have been cleaned.  
2.3
Treatment Assignment and Blinding
All subjects will be assigned a unique identification number by the interactive response 
technology (IRT) system at the screening visit.  For subjects who rescreen, the screening 
number assigned by the IRT at the initial screening visit should be used.  The IRT will 
assign a randomization number that will encode the subject's treatment group assignment 
according to the randomization schedule generated by Data and Statistical Sciences (DSS) 
at AbbVie.
Subjects will be centrally randomized at the Baseline visit in a 1:1 ratio to receive either 
SC risankizumab 150 mg or matching placebo during Period A, and all subjects will 
receive open label risankizumab 150 mg once every 12 weeks during Period B. 
Randomization will be stratified by Baseline ppIGA ("moderate" [3] versus "severe" [4]) 
and Baseline body surface area (BSA) affected (< 10% versus ≥ 10%).
All AbbVie personnel with direct oversight of the conduct and management of the study 
(with the exception of AbbVie Drug Supply Management Team) will remain blinded until 
the Primary Analysis at Week 16 is available.  The investigator, study site personnel, and 
the subject will remain blinded to each subject's treatment throughout the study.  To 
maintain the blind, the risankizumab pre-filled syringe (PFS) and placebo PFS provided 
for the study will be identical in appearance.
In the event of a medical emergency in which the investigator believes that knowledge of 
study drug treatment is required, reasonable efforts must be made to contact the AbbVie 
emergency contact prior to breaking the blind, as long as it does not compromise subject 
safety.  However, if an urgent therapeutic intervention is necessary which warrants 
breaking the blind prior to contacting the AbbVie emergency contact, the investigator can 
directly access the IRT system to break the blind without AbbVie agreement.  The date 
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and reason that the blind was broken must be recorded in the source documentation and 
electronic case report form (eCRF), as applicable.
2.4
Sample Size Determination
The ppIGA is an endpoint that has been used in another clinical trial in the palmoplantar 
psoriasis population and which is based on the modified Investigator's Global Assessment 
version of 2011.1,2  Given the lack of historical ppIGA data from risankizumab trials, the 
assumption of response rates in the current study are based on the relevant endpoints of 
PPASI 75 and PPASI 90 from risankizumab PsO Studies M15-992, M15-995, and 
M16-008, among subjects who had Baseline PPASI of at least 8.  Among these subjects, 
approximately 80% and 75% of subjects from the risankizumab (RZB) group achieved 
PPASI 75 and PPASI 90, respectively; compared to 50% and 40% in the placebo (PBO) 
group.
Assuming that 75% of subjects from the RZB group and 45% of subjects from the PBO 
group would achieve the primary endpoint of ppIGA of 0 or 1 with at least a 2-point 
reduction from Baseline at Week 16, the sample size of 168 subjects (84 subjects per 
group) will provide more than 90% power to detect the treatment difference between RZB 
and PBO, under a 2-sided significance level of 0.05.
3.0
Endpoints
3.1
Primary Endpoint
The primary endpoint is the achievement of ppIGA of 0 or 1 with at least a 2-point 
reduction from Baseline at Week 16.
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3.2
Secondary Endpoint
The following ranked secondary endpoints will be tested in a hierarchical order, only if 
the null hypothesis for the primary endpoint has been rejected:
1.
Achievement of PPASI 75 response at Week 16
2.
Achievement of PPASI 90 response at Week 16
3.
Achievement of sPGA of 0 or 1 with at least a 2-point reduction from Baseline at 
Week 16
4.
Achievement of PPASI 100 response at Week 16
3.3
Additional Endpoints
All primary and ranked secondary endpoints will be analyzed at all other visits collected.  
In addition, the following endpoints will be analyzed at all visits collected:
●
Achievement of ppIGA of "clear" (0)
●
Achievement of sPGA of "clear" (0)
●
Change from Baseline in PPASI
●
Percent change from Baseline in PPASI
●
Change from Baseline in PASI
●
Percent change from Baseline in PASI among subjects with Baseline PASI 
≥12
●
Change and percentage change from Baseline in Patient Global Assessment of 
Skin Pain (PGA-SP), among subjects with Baseline PGA-SP NRS ≥ 4
●
Change from Baseline in Psoriasis Symptom Scale (PSS)
●
Achievement of PSS 0 or 1
●
Change from Baseline in Dermatology Life Quality Index (DLQI)
●
Achievement of DLQI 0 or 1
●
Achievement of DLQI improvement (reduction) of ≥ 4 points, among subjects 
with Baseline DLQI ≥ 4
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In addition, the achievement of ppIGA of "clear" (0), ppIGA of "clear" or "almost clear" 
(0 or 1) with at least a 2-point reduction from Baseline, and PPASI 75/90/100 response 
will also be summarized at later visits in Period B, among subjects who are randomized to 
risankizumab in Period A and have achieved the corresponding response status at the 
entry of Period B.
3.4
Safety Endpoints
The following safety evaluations will be performed throughout the study as measures of 
safety and tolerability:
●
Adverse event (AE) monitoring
●
Vital sign measurements
●
Physical examinations
●
Clinical laboratory testing
3.5
Pharmacokinetic Endpoints
No PK data will be collected for the purpose of PK analysis in present study.
4.0
Analysis Populations
The Intent-to-Treat (ITT) Population includes all randomized subjects.  The ITT 
Population will be used for all efficacy analyses.  Subjects who are randomized to placebo 
in Period A and do not continue into Period B will be excluded from the analysis in 
Period B.
The following populations will be used for the safety analysis:
●
The Safety Population in Period A (Safety_A) is defined as all subjects who are 
randomized and received at least 1 dose of study drug in Period A.
●
The Safety Population in Period B (Safety_B) is defined as all subjects who 
received at least 1 dose of study drug in Period B.
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●
The All Risankizumab Treated (ALL_RZB) Population is defined as subjects 
who received at least 1 study drug of risankizumab.  This population will be 
used to provide a comprehensive summary of key safety variables.
5.0
Subject Disposition
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized by treatment groups:
●
Subjects randomized in the study
●
Subjects who received at least one dose of study drug in each Study Period
●
Subjects who completed each Study Period
●
Subjects who discontinued study drug in each Study Period (all reasons and 
primary reason)
For end of study participation, the number and percentage of subjects who did not 
complete each Study Period with associated reasons will be summarized overall and by 
treatment group.
6.0
Study Drug Duration and Compliance
For the Safety Populations in Period A and in Period B, the duration of treatment will be 
summarized by treatment groups.  The duration of treatment for each period is defined as 
follows:
Period A: the minimum of (the last dose date in Period A + 84 days, the end of study date 
+ 1 day, and the first dose date in Period B if not missing [and cutoff date during the 
Primary Analysis + 1 day]) minus the first dose date in Period A.
Period B: the minimum of (the last dose date in Period B + 84 days, and the end of study 
date + 1 day [and cutoff date during the Primary Analysis + 1 day]) minus the first dose 
date in Period B.
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The duration of treatment will also be summarized among the ALL_RZB Population, 
which is defined as: the minimum of (the last dose date of risankizumab + 84 days, and 
the end of study date + 1 day [and cutoff date during the Primary Analysis + 1 day]) 
minus the first dose date of risankizumab.
Duration of treatment will be summarized by descriptive statistics of mean, standard 
deviation, median, minimum and maximum, among the number of subjects treated in each 
period.
Treatment compliance will be summarized by treatment groups among the Safety 
Populations in Period A and in Period B.  The compliance will be summarized by the 
percentage of planned injections which are administered at each study drug administration 
visit.  The cumulative summary of compliance in each period will also be provided.  
When computing the compliance at each study drug administration visit for each 
treatment group, the denominator will include all subjects in this treatment group who 
received at least one dose of study drug in the Study Period and have not prematurely 
discontinued the study drug prior to that scheduled visit.
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 or 
≥40 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).
Baseline disease characteristics include history of psoriatic arthritis (yes, no), Baseline 
ppIGA categories, Baseline sPGA categories, Baseline BSA categories (< 10%, ≥ 10%), 
Baseline PASI, Baseline PPASI, Baseline BSA, Baseline PSS, Baseline PGA-SP, and 
Baseline DLQI.
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Demographics and baseline disease characteristics will be summarized among the ITT 
Population, overall and by treatment groups.  Categorical variables will be summarized 
with the number and percentage of subjects; percentages will be calculated based on the 
number of non-missing observations.  Continuous variables will be summarized with 
descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum).
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment groups.  The system organ class (SOC) will be 
presented in the 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.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic names.  A prior 
medication is defined as any medication taken prior to the first dose date of study drug.  A 
concomitant medication is defined as any medication that is started prior to the first dose 
date of study drug and continued to be taken on or after the first dose date of study drug, 
or any medication that is started on or after the first dose date of study drug, but not after 
the last dose date of study drug plus 140 days.  The number and percentage of subjects 
taking medications will be summarized by generic drug names based on the World Health 
Organization (WHO) Drug Dictionary for both prior and concomitant medications.
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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
Handling of Potential Intercurrent Events for the 
Primary Endpoint and Key Secondary Endpoints
The primary efficacy endpoint (defined in Section 3.1) and four ranked secondary 
endpoints (defined in Section 3.2), will be analyzed in the ITT Population and the 
following method will be used to address the potential intercurrent event:
●
Subjects who discontinue study drug due to lack of efficacy prior to Week 16 
will be considered as non-responders at Week 16.
9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted among the ITT Population.  All statistical tests 
will be performed at a 2-sided alpha level of 0.05.
The Primary Analysis will be conducted after all continuing subjects complete Week 16 
and all data pertaining to Period A are cleaned.  This will be the only and final analysis for 
efficacy in Period A.  Study sites and subjects will remain blinded to their initial treatment 
assignment for the duration of the entire study.
For categorical endpoints, comparisons will be made between risankizumab and placebo 
using the Cochran-Mantel-Haenszel (CMH) test, adjusting for the actual values of 
stratification factors (Baseline ppIGA and Baseline BSA categories).  In case of any 
stratum with zero subject in either treatment group, no stratification factor will be 
controlled.  Non-responder imputation (NRI) incorporating multiple imputation (MI) to 
handle missing data due to COVID-19 (NRI-C) will be the primary approach to handle 
missing values.
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For continuous endpoints, comparisons will be made between risankizumab and placebo 
based on the fixed term of treatment from a Mixed-effect Model Repeat Measurement 
(MMRM) model including the Baseline value and observed measurements at all post-
baseline visits, adjusting for the fixed effects of treatment, actual values of stratification 
factors, visit and treatment-by-visit interaction as covariates.  The MMRM will be the 
primary approach to handle missing values.
"Baseline" refers to the last non-missing observation on or before the date of the 
first administration of study drug or the date of randomization if no study drug is 
administered.  For variables where the assessment time is collected on the ePRO device, 
the baseline measurement must be prior to the time of the first administration of study 
drug.
9.2
Handling of Missing Data
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the study, or missing due to COVID-19 infection or logistic 
restriction.
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis and the interpretation 
of clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 
recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate.  
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Sensitivity analyses will be performed to assess the impact of missing data and the 
robustness of the conclusion.
Handling of missing data for the efficacy analyses is described below.
9.2.1
Categorical Endpoints
Non-Responder Imputation incorporating multiple imputation to handle missing 
data due to COVID-19 (NRI-C) will be the primary approach for handling missing data 
in the analysis of categorical endpoints.  The NRI-C will categorize any subject who does 
not have an evaluation during a pre-specified visit window as a non-responder for the 
visit.  The only exceptions are:  1) when the subject is a responder both before and after 
the visit window in the particular Study Period, the subject will be categorized as a 
responder for the visit; 2) missing data due to COVID-19 infection or logistical restriction 
will be handled by MI.  Subjects who discontinue study drug due to lack of efficacy will 
be counted as non-responders at later visits.  Subjects whose change/percent change from 
Baseline cannot be calculated because of a missing Baseline will be considered as a non-
responder at all post-baseline visits, unless the post-baseline value is zero.  More details 
are provided in Appendix E.
Of note, during the Primary Analysis upon completion of Week 16, the NRI-C analysis 
will only be performed at all visits up to Week 16.
Multiple Imputation (MI) will be used as a sensitivity analysis for the primary endpoint 
at Week 16.  PROC MI with the Markov Chain Monte Carlo (MCMC) statement will be 
first applied to generate 30 augmented datasets with monotonic missing pattern.  The 
random seed for the MCMC will be the SAS numerical value of the first subject 
randomization date.  PROC MI will then be used to impute 30 complete datasets using the 
regression method.  The random seed for this imputation step will be the SAS numerical 
value of the last subject randomization date.  The variables to be included in the 
imputation model are: treatment group, Baseline BSA, Baseline ppIGA category, and 
ppIGA measurements at each visit up to the end of the double blind Period A.  The 
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imputed post-baseline measurements will be rounded to the same precision as the 
observed data to determine the responder status.  Using the Cochran-Mantel-Haenszel 
(CMH) model adjusted by actual stratification factors (Baseline BSA category and 
Baseline ppIGA category), the imputed endpoints will be analyzed using each of the 
30 datasets.  SAS PROC MIANALYZE will be used to generate the final inferences of 
the risk difference between risankizumab and placebo.  Note that measurements will be 
considered as missing after discontinue study drug due to lack of efficacy before MI.  
Regardless of MI imputed values, subjects with a missing ppIGA assessment after 
discontinuation from study due to lack of efficacy will be counted as non-responders for 
these visits.
9.2.2
Continuous Endpoints
Mixed-Effect Model Repeat Measurement (MMRM) will be the primary approach to 
handle missing data for continuous endpoints.  The MMRM will be conducted using 
mixed model including observed measurements at all visits, using all available data even 
if a subject has missing data at some post-baseline visits.  The mixed model includes the 
fixed effects of categorical variables of treatment, actual stratification factors (Baseline 
BSA category and Baseline ppIGA category), visit and treatment-by-visit interaction at all 
post-baseline visits in each Study Period, and the continuous variable of Baseline 
measurement as covariates.  Subjects' observations after discontinued study drug due to 
lack of efficacy will be excluded from the model.  An unstructured variance covariance 
matrix (UN) will be used.  If the model cannot converge, an appropriate covariance 
structure matrix (e.g., autoregressive (1) or compound symmetry) will be used.  The 
parameter estimations are based on the method of restrictive maximum likelihood 
(REML).  The fixed effects will be used to report model-based means at corresponding 
visits.
Of note, during the Primary Analysis upon completion of Week 16, the MMRM analysis 
will only be performed at all visits up to Week 16.
Long-term efficacy in the Period 2 will be summarized using the observed case approach.
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Observed Case (OC):  The OC analysis will be used for the summaries of long-term 
efficacy in Period 2, which will use observed data.
9.3
Primary Efficacy Endpoint and Analyses
9.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the achievement of ppIGA of 0 or 1 with at least a 
2-point reduction from Baseline at Week 16 as defined in Section 3.1.
9.3.2
Main Analysis of Primary Efficacy Endpoint
The following null hypothesis corresponding to the primary endpoint will be tested under 
a two-sided significance level of 0.05:
●
There is no difference between risankizumab and placebo, with respect to the 
proportion of subjects achieving ppIGA of 0 or 1 with at least a 2-point 
reduction from Baseline at Week 16.
The primary endpoint will be analyzed among the ITT Population, using the Cochran-
Mantel-Haenszel (CMH) test adjusting for the actual values of stratification factors.
The attributes of the estimand corresponding to the primary efficacy endpoint are 
summarized in Table 2.
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Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent 
Events
Statistical 
Summary
ppIGA 0 or 1 
at Week 16
Risankizumab 
150 mg / 
Placebo
Achievement of 
ppIGA 0 or 1 
with a least 2-
point reduction 
from Baseline at 
Week 16
ITT
Subjects who 
discontinued 
study drug due 
to lack of 
efficacy prior to 
Week 16 will 
be considered 
as non-
responders.
Difference in 
proportion of 
subjects 
achieving ppIGA 
0 or 1 with a least
2-point reduction 
from Baseline at 
Week 16 between 
risankizumab 
150 mg and 
placebo
Comparison will be made between risankizumab and placebo using the CMH test, 
adjusting for the actual values of stratification factors (Baseline ppIGA and Baseline BSA 
categories).  NRI-C will be the primary approach to handle missing data.
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint
A sensitivity analysis using MI to handle missing data will be performed on the primary 
endpoint, as defined in Section 9.2.1.  Treatment, Baseline BSA, and the observed ppIGA
assessments at all Baseline and post-baseline visits will be included in the imputation 
model.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Key Secondary Efficacy Endpoints
The ranked secondary endpoints are as defined in Section 3.2.
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9.4.2
Main Analyses of Key Secondary Efficacy Endpoints
The following null hypotheses pertaining to the ranked secondary efficacy endpoints will 
be tested between the risankizumab and placebo groups among the ITT Population in a 
hierarchical order, only if the null hypothesis for the primary endpoint has been rejected:
1.
There is no difference between risankizumab and placebo, with respect to the 
proportion of subjects achieving PPASI 75 at Week 16
2.
There is no difference between risankizumab and placebo, with respect to the 
proportion of subjects achieving PPASI 90 at Week 16
3.
There is no difference between risankizumab and placebo, with respect to the 
proportion of subjects achieving sPGA of "clear" or "almost clear" (0 or 1) with at 
least a 2-point reduction from Baseline at Week 16
4.
There is no difference between risankizumab and placebo, with respect to the 
proportion of subjects achieving PPASI 100 at Week 16
Ranked secondary endpoints will be analyzed, using the CMH test adjusting for the actual 
values of stratification factors.  NRI-C will be the primary approach to handle missing 
data.
The attributes of the estimands corresponding to the ranked secondary efficacy endpoints 
are summarized in Table 3.
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Table 3.
Summary of the Estimand Attributes of the Ranked Secondary 
Efficacy Endpoint
Estimand Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
PPASI 75 at 
Week 16
Risankizumab 
150 mg / 
Placebo
Achievement 
of PPASI 75 
at Week 16
ITT
Subjects who 
discontinued study 
drug due to lack of 
efficacy prior to 
Week 16 will be 
considered as 
non-responders.
Difference in 
proportion of 
subjects achieving 
PPASI 75 at 
Week 16 between 
risankizumab 
150 mg and 
placebo
PPASI 90 at 
Week 16
Risankizumab 
150 mg / 
Placebo
Achievement 
of PPASI 90 
at Week 16
ITT
Subjects who 
discontinued study 
drug due to lack of 
efficacy prior to 
Week 16 will be 
considered as 
non-responders.
Difference in 
proportion of 
subjects achieving 
PPASI 90 at 
Week 16 between 
risankizumab 
150 mg and 
placebo
sPGA 0 or 1 at 
Week 16
Risankizumab 
150 mg / 
Placebo
Achievement 
of sPGA 0 or 
1 with a least 
2-point 
reduction 
from 
Baseline at 
Week 16
ITT
Subjects who 
discontinued study 
drug due to lack of 
efficacy prior to 
Week 16 will be 
considered as 
non-responders.
Difference in 
proportion of 
subjects achieving 
sPGA 0 or 1 with a 
least 2-point 
reduction from 
Baseline at 
Week 16 between 
risankizumab 
150 mg and 
placebo 
PPASI 100 at 
Week 16
Risankizumab 
150 mg / 
Placebo
Achievement 
of PPASI 
100 at 
Week 16 
ITT
Subjects who 
discontinued study 
drug due to lack of 
efficacy prior to 
Week 16 will be 
considered as 
non-responders.
Difference in 
proportion of 
subjects achieving 
PPASI 100 at 
Week 16 between 
risankizumab 
150 mg and 
placebo
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9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints
Not applicable.
9.5
Additional Efficacy Analyses
Additional efficacy endpoints will be compared between the risankizumab and placebo 
treatment groups among the ITT Population at each visit in Period A.
Categorical endpoints will be analyzed, using the CMH test adjusting for the actual values 
of stratification factors.  NRI-C will be the primary approach to handle missing data.
Continuous endpoints will be analyzed based on the fixed term of treatment from an 
MMRM model including the Baseline value and observed measurements at all post-
baseline visits, adjusting for the fixed effects of treatment, actual values of stratification 
factors, visit and treatment-by-visit interaction as covariates.
Summary statistics will be provided for the additional efficacy endpoints at each visit in 
Period B by treatment groups.  Categorical endpoints will be summarized by the number 
and proportion of subjects who achieved the endpoint, as well as the 95% confidence 
interval of that proportion.  Missing data will be handled by NRI-C.  Continuous 
endpoints will be summarized based on OC by descriptive statistics including the mean, 
standard error, and the 95% confidence interval of the mean.
9.6
Efficacy Subgroup Analyses
To evaluate the consistency of the efficacy over demographic and other baseline disease 
characteristics, the primary efficacy endpoint will be analyzed in selected subgroups as 
follows:
●
Age group (< 40 years, ≥ 40)
●
Sex (male, female)
●
Race (white, non-white)
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●
Smoking (current, ex- or never)
●
Body mass index (BMI) (normal:  < 25, overweight:  ≥ 25 to < 30, obese:  
≥30)
●
Baseline ppIGA ("moderate" [3], "severe" [4])
●
Baseline BSA (< 10% versus ≥ 10%);
●
Psoriatic arthritis (yes, no)
●
Body weight (≤ 100 kg, > 100 kg)
Of note, if the BMI ≥ 30 subgroup have fewer than 10% of the total subjects, it will be 
combined with its adjacent subgroup.
10.0
Safety Analyses
10.1
General Considerations
Safety analyses will include adverse events, laboratory, and vital sign measurements.
Safety data will be summarized among the Safety_A and Safety_B populations by 
treatment groups.  For the safety analysis, subjects are analyzed based on the actual 
treatment group, determined by the first dose of study drug that the subject received.
The overview of TEAEs, areas of safety interest (ASIs), and potentially clinically 
important (PCI) findings in laboratory variables and vital sign variables will be 
summarized among the ALL_RZB Population.
Missing safety data will not be imputed.
10.2
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 
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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.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) for each safety period are defined as 
follows:
Period A:  A TEAE in Period A is defined as any event with an onset date on or after the 
first dose date of study drug in Period A and within 140 days after the last dose date of 
study drug in Period A, as long as it does not exceed the first dose date in Period B.
Period B:  A TEAE in Period B is defined as any event with an onset date on or after the 
first dose date of study drug in Period B and within the minimum of (140 days after the 
last dose date of study drug in Period B, and the end of study date).
The All-Risankizumab Treated Period:  A TEAE is defined as any event with an onset 
date on or after the first dose date of risankizumab and within the minimum of (140 days 
after the last dose date of risankizumab, and the end of study date).
10.2.2
Adverse Event Overview
An overview of TEAEs by treatment groups in each period will be presented consisting of 
the number and percentage of subjects experiencing at least one event for each of the 
following TEAE categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE under the Areas of Safety Interest, as defined in 
Appendix B
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●
Any treatment-emergent AE leading to death
●
Any COVID-19 related TEAEs
All deaths will also be summarized:
●
COVID-19 related deaths
●
Deaths occurring ≤ 140 days after last dose of study drug
●
Deaths occurring > 140 days after last dose of study drug.
10.2.3
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 for the active group.
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted TEAEs per 100 patient-years will be provided, where TEAEs per 
100 patient-years of exposure are defined as the number of TEAEs 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 TEAEs (i.e., a preferred term will not be counted twice on 
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the same day for the same subject).  The exposure-adjusted TEAE rate per 100 patient-
years is calculated as:
where total patient years in each period are defined below.
Total patient years in Period A:  Sum of study drug exposure in Period A, defined as the 
minimum of (the last dose date in Period A + 140 days, the end of study date + 1 day, and 
the first dose date in Period B if not missing [and the cutoff date during the Primary 
Analysis + 1 day]) minus the first dose date in Period A, normalized by 365.25 and 
rounded to one decimal place.
Total patient years in Period B:  Sum of study drug exposure in Period B, defined as the 
minimum of (the last dose date in Period B + 140 days, and the end of study date + 1 day 
[and the cutoff date during the Primary Analysis + 1 day]) minus the first dose date in 
Period B, normalized by 365.25 and rounded to one decimal place.
Total patient years in the All-Risankizumab Treated Period:  Sum of study drug of 
risankizumab exposure, defined as the minimum of (the last risankizumab dose date + 
140 days, and the end of study date + 1 day [and the cutoff date during the Primary 
Analysis + 1 day]) minus the first risankizumab dose date, normalized by 365.25 and 
rounded to one decimal place.
10.2.5
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.
A listing of pre-treatment SAEs with onset dates prior to the first dose of study drug will 
be provided.
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10.2.6
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.
Tabular listings of selected area of safety interest will be provided.
10.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline derivation where SAE-
triggered 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.  The following descriptive statistics will be presented by 
treatment groups: number of observations, Baseline mean, visit mean, mean change from 
Baseline and its standard error, and the 95% confidence interval of the mean change from 
Baseline.
In addition, laboratory parameters will be tabulated using shift tables from Baseline to 
minimum and maximum values in each period (Period A and Period B), categorized by 
the toxicity grade according to NCI CTCAE Version 4.033 of the laboratory used for each 
sample.  A similar shift table will also be provided to summarize shifts from Baseline to 
the final post-baseline value in each period.
Laboratory abnormalities meeting CTC criteria grade 3 and 4 at least once in each period 
will be summarized.
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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 at least once in 
each period will be summarized.  Listings will be provided to summarize subject-level 
laboratory data for subjects meeting PCI criteria.
In addition, the frequencies and percentages of subjects with post baseline liver specific 
function test values in ALT/SGPT, AST/SGOT, alkaline phosphatase, and total bilirubin 
that meet the following criteria will be summarized by treatment groups:
●
ALT > 3.0 × ULN
●
ALT > 5.0 × ULN
●
ALT > 10.0 × ULN
●
ALT > 20.0 × ULN
●
AST > 3.0 × ULN
●
AST > 5.0 × ULN
●
AST > 10.0 × ULN
●
AST > 20.0 × ULN
●
Alkaline phosphatase > 1.5 × ULN
●
Total bilirubin > 1.5 × ULN
●
Total bilirubin > 2.0 × ULN
●
ALT and/or AST > 3.0 × ULN and Total bilirubin > 1.5 × ULN
●
ALT and/or AST > 3.0 × ULN and Total bilirubin > 2.0 × ULN
●
ALT > 3 × ULN and Total bilirubin > 1.5 × ULN
●
ALT > 3 × ULN and Total bilirubin > 2.0 × ULN
A listing of potentially clinically important (PCI) liver function laboratory values will 
include all subjects who met any of the following four criteria:
●
ALT > 3.0 × ULN, or
●
AST > 3.0 × ULN, or
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●
ALP > 1.5 × ULN, or
●
Total bilirubin > 1.5 × ULN.
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions will be provided.
●
ALT of > 3.0 × ULN or AST of > 3.0 × ULN,
●
Total bilirubin ≥ 2.0 × ULN
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure will be summarized.
Change from baseline to each applicable post-baseline visit will be summarized for each 
vital sign variable.  The following descriptive statistics will be presented by treatment 
groups: number of observations, Baseline mean, visit mean, mean change from Baseline 
and its standard error, and the 95% confidence interval of the mean change from Baseline.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix D).  For each vital sign PCI criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria at least once in each period will 
be summarized.  Listings will be provided to summarize subject-level vital sign data for 
subjects meeting PCI criteria.
10.5
Safety Subgroup Analyses
No subgroup for safety analyses.
10.6
Other Safety Analyses
No other safety analyses.
11.0
Other Analyses
No other analyses.
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12.0
Interim Analyses
12.1
Data Monitoring Committee
There is no data monitoring committee (DMC) planned in this study.
13.0
Overall Type-I Error Control
The Primary Analysis will be the only and final analysis for the primary and all ranked 
secondary efficacy endpoints.
Overall type-I error will be controlled by testing the primary efficacy endpoint, followed 
by the ranked secondary efficacy endpoints, in a hierarchical order as described in 
Section 9.3 and Section 9.4.
14.0
Version History
Table 4.
SAP Version History Summary
Version
Date
Summary
1.0
07 April 2021
Original version
2.0
11 July 2022
Clarified the time point of conducting Primary Analysis in 
Section 2.2.
Clarified in Section 9.5 that categorical endpoints in Period B 
will be summarized by NRI-C, and continuous endpoints in 
Period B will be summarized by OC. 
Updated summary criteria in Section 10.3 based on PSSAP 5.0.
Corrected a format issue in Table C-2. 
3.0
16 May 2023
Due to MedDRA version update, CMQ codes in Appendix B. 
Safety Topics of Interest were updated accordingly.
15.0
References
1.
Gottlieb A, Sullivan J, van Doorn M, et al.  Secukinumab shows significant 
efficacy in palmoplantar psoriasis: Results from GESTURE, a randomized 
controlled trial.  J Am Acad Dermatol.  2017;76(1):70-80.
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2.
Langley RGB, Feldman SR, Nyirady J, et al.  The 5-point Investigator's Global 
Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis severity 
in clinical trials.  J Dermatolog Treat.  2015;26(1):23-31.
3.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (2010).  
Available from: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. 
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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.
Safety Topics of Interest
Area of safety interest (ASI) will be identified using the following search criteria:
Area of Safety Interest
Search Criteria
MACE
Adjudicated terms will be identified as described in PSSAP Table 4 using 
CECAT and CETERM from the CE SDTM dataset.
Extended MACE
Adjudicated terms will be identified as described in PSSAP Table 3 (for 
MACE +) using CECAT and CETERM from the CE SDTM dataset.
Serious Infections
Serious AEs in the Infections and Infestations SOC 
Active Tuberculosis
Active Tuberculosis CMQ (code 10000002)
Opportunistic Infections 
excluding tuberculosis and 
herpes zoster
Opportunistic infection excluding tuberculosis and herpes zoster CMQ 
(code 10000105)
Injection Site Reactions
Narrow
Injection site reaction CMQ 
(code 10000091)
Malignant Tumours
Narrow
Malignant tumours (SMQ 20000194)
Non-melanoma Skin 
Cancer (NMSC)
Broad
Skin malignant tumours (SMQ 20000204) 
excluding terms identified by the 
Melanoma CMQ (code 10000100)
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.
Hypersensitivity 
Narrow
Hypersensitivity (SMQ 20000214)
Serious hypersensitivity 
reactions
Narrow
Serious AEs in the Hypersensitivity 
(SMQ 20000214)
Adjudicated Anaphylactic 
Reaction*
Adjudicated terms will be identified using SDTM data (e.g., CE and PR 
domains).
Hepatic Events 
Broad
Hepatic failure, fibrosis and cirrhosis and 
other liver damage-related conditions 
(SMQ 20000013)
Broad
Hepatitis, non-infectious (SMQ 20000010)
Broad
Cholestasis and jaundice of hepatic origin 
(SMQ 20000009)
Broad
Liver related investigations, signs and 
symptoms (SMQ 20000008)
Narrow
Liver-related coagulation and bleeding 
disturbances (SMQ 20000015)
*
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.
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
Total Bilirubin
mcmol/L
> 3.0 × ULN
ALP
U/L
> 5.0 × ULN
SGOT/AST
U/L
> 5.0 × ULN
SGPT/ALT
U/L
> 5.0 × ULN
Albumin
g/L
< 20
Glucose
mmol/L
< 2.2
> 13.9
Triglycerides
mmol/L
> 5.7
Creatinine
mcmol/L
> 3.0 × ULN or > 3.0 × baseline
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.
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Appendix D.
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
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Appendix E.
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic for 
Dichotomized Outcome Variables
1.0
Overview
1.1
Background and Justification for Missing at Random (MAR) 
Assumption
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impacts on treatment duration and the collection, analysis and the interpretation 
of clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 
recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate.  
In some cases, sensitivity analyses may be performed to assess the impact of missing data 
and the robustness of the conclusion.
1.2
FDA Guidance
FDA provided two guidance documents1,2 in March 2020 and June 2020 on the efficacy 
collection and possible changes in the statistical analysis plan:
●
"With respect to efficacy assessments, FDA recommends consultation with the 
appropriate review division regarding protocol modifications for the collection 
of efficacy endpoints, such as use of virtual assessments, delays in assessments, 
and alternative collection of research-specific specimens, if feasible.  For 
individual instances where efficacy endpoints are not collected, the reasons for 
failing to obtain the efficacy assessment should be documented (e.g., 
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identifying the specific limitation imposed by COVID-19 leading to the 
inability to perform the protocol-specified assessment)."
●
"If changes in the protocol will lead to amending data management and/or 
statistical analysis plans, the sponsor should consider doing so in consultation 
with the applicable FDA review division.  Prior to locking the database, 
sponsors should address in the statistical analysis plan how protocol deviations 
related to COVID-19 will be handled for the prespecified analyses."
1.3
EMA Guidance
EMA provided guidance3 in March 2020:
●
"At this point in time it is not possible to give general applicable advice on how 
the different aspects related to the pandemic should be handled, as implications 
on clinical trials are expected to be manifold.  Impact on the data collection, 
analysis and interpretation of results for each trial will need a thorough case-by-
case assessment."
●
"As a general principle, there are strong scientific reasons to conduct trials as 
planned and implement changes only when there is a convincing scientific 
reason that it improves interpretability of results."
1.4
Missing Data Handling for Missing Due to COVID-19 for 
Dichotomized Variables
In this document, a missing data handling method is proposed to handle missing data due 
to COVID-19 infection or logistical restrictions related to the COVID-19 pandemic under 
the general MAR framework.  In particular, we explain using multiple imputation (MI) to 
handle missing data due to COVID-19 in dichotomized variables in conjunction with non-
responder imputation (NRI) for missing data due to other reasons.
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2.0
Non-responder Imputation Incorporating Multiple 
Imputation (NRI)
2.1
Overall Description of the Method
For a dichotomized outcome variable with missing data, the NRI will categorize any 
subject who does not have evaluation during a pre-specified visit window as a non-
responder for the visit, with two exceptions:
●
If the subject is a responder both before and after the pre-specified visit window 
in the particular Study Period, the subject will be categorized as a responder for 
the visit.
●
If the reason for missing (e.g., missed visits, incomplete visit, out-of-schedule 
visits, or discontinuations of study drug) is due to COVID-19, the information 
will be captured in the database and the subject's response status will be 
imputed using multiple imputation.
Subjects whose change/percent change from Baseline cannot be calculated because of a 
missing Baseline will be considered as a non-responder at all post-baseline visits, unless 
the post-baseline value is zero.
Non-responder imputation incorporating multiple imputation (NRI) for missing due to 
COVID-19 will be implemented as follows.
2.2
Multiple Imputation (MI) and MAR Assumption
When a dichotomized variable is derived from a continuous scale, for example, PPASI 75 
(at least a 75% reduction in PPASI relative to Baseline), the multiple imputation will be 
applied to the original scale, PPASI (ranges from 0 – 72) assuming multivariate normal 
distribution.  Then the dichotomized variable will be derived from the imputed value.
The MI procedure assumes that the data are missing at random (MAR).  That is, for an 
outcome variable Y, the probability that an observation is missing depends only on the 
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observed values of other variables, not on the unobserved values of the outcome variable 
Y.  Statistical inference from the MI procedure is valid under the MAR assumption.
2.3
Imputation Algorithm 
It is reasonable to assume the missing values of the longitudinal data for an outcome 
variable (e.g., PPASI, the original scale of PPASI 75, at each post-baseline visit) follows a 
monotone missing pattern.  In practice, the missing data of the outcome variable might 
have an arbitrary (non-monotone) missing data pattern.  An extra step may be added 
accordingly, to augment data into a monotone missing pattern.
For the outcome variable (e.g., PPASI at each visit), K 'complete' datasets can be 
generated in two steps: augmentation step and imputation step.  K, the number of 
repetitions, is determined below.
Augmentation Step
For datasets with non-monotone missing data pattern, the augmentation step will first 
impute enough values to augment the data into a monotonic missing pattern:
Markov Chain Monte Carlo (MCMC) will be applied to augment the data using PROC MI 
with the MCMC IMPUTE=monotone statement, assuming a multivariate normal 
distribution.  The augmented data will be used in the subsequent imputation step to 
generate 'complete' datasets.  Covariates included in the model are treatment group, 
Baseline BSA, Baseline ppIGA category, Baseline (if other than Baseline ppIGA), and all 
post-baseline visits of the outcome variable up to the end of the Study Period.  Of note, 
categorical variables are included using the form of dummy variables.
Repeat the imputation process K=30 times using the procedure described above to form 
K=30 monotone missing datasets, where K is determined as described in "Repetition of 
Imputations (K)."
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Imputation Step
For missing data with monotone missing patterns, the choice of multiple imputation using 
a parametric regression model that assumes multivariate normality is appropriate.
The imputation step is described below:
●
The imputation model for the missing data is a regression model, which 
controls for treatment group, Baseline BSA, Baseline ppIGA category, Baseline 
(if other than Baseline ppIGA), and all post-baseline visits of the outcome 
variable up to the end of the Study Period.  The covariates included in the 
model and the order of these variables are consistent with the augmentation 
step.
●
For each monotone missing dataset, using SAS PROC MI with MONOTONE 
REG model statement, the outcome variable at each post-baseline visit with 
missing values will be imputed sequentially with covariates constructed from 
their corresponding sets of preceding variables.
A 'complete' dataset with imputed values for the missing data is generated after the 
augmentation and imputation steps are completed.
Repetition of Imputations (K)
Repetition of imputations, K, must be determined in advance.  When estimating the 
overall variance of multiple imputation, the additional sampling variance is the between-
imputation variance divided by K.  This value represents the sampling error associated 
with the overall or average coefficient estimates.  It is used as a correction factor for using 
a specific number of imputations.  The more imputations (K) are conducted, the more 
precise the parameter estimates will be.  For example, with a 1% power falloff tolerance 
in multiple imputation, as compared to an infinite number of imputations, multiple 
imputation requires 20 repetitions of imputation for 30% missing information and 
40 repetitions for 50% missing information (Graham, Olchowski, and Gilreath 20074).  In 
the usual clinical settings expecting less than 30% missing information, K=30 repetitions 
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are deemed sufficient.  When missingness exceeds 30%, depending on the power falloff 
tolerance level, number of repetitions may need to be increased.  Recent research4
suggested that the number of repetitions (K) should be at least equal to the percentage of 
missing (White et al., 20116).
2.4
Derivation of Response Status and Non-Responder 
Imputation
For each 'complete' dataset, the imputed post-baseline values will be rounded to the same 
precision as the observed data.  Response status (e.g., PPASI 75 at each visit) will be 
determined accordingly.
The imputed response status for missing due to reasons other than COVID-19 will be 
overridden by non-responder imputation (Section 2.1) to ensure that multiple imputation 
is only applied to missing due to COVID-19:
●
Using NRI approach, all missing due to reasons other than COVID-19 will be 
categorized as non-responders.  In addition, subjects whose change/percent 
change from Baseline cannot be calculated because of a missing Baseline will 
be considered as a non-responder at all post-baseline visits, unless the post-
baseline value is zero.
●
The only exception is that a subject will be categorized as a responder for the 
visit if the subject is a responder both before and after an SAP-specified visit 
window in the particular Study Period.
2.5
Analysis
The statistical analysis will use the Cochran-Mantel-Haenszel (CMH) test adjusted by the 
actual stratification factors (Baseline BSA category and Baseline ppIGA category).
2.5.1
Analysis of Each Dataset
For each of the K 'complete' datasets, the CMH test will be used to estimate the treatment 
difference versus placebo and the corresponding standard error.
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2.5.2
Synthesis of Results for Statistical Inference
The results from the K 'complete' datasets will be synthesized using the SAS procedure 
PROC MIANALYZE, following Rubin's formula (Rubin, 19875), to derive the MI 
estimator of the treatment difference for the final inferences.
Rubin's formula
We fit the analysis model to the kth 'complete' dataset, denoting the estimate of the 
treatment difference q by θ ̃k from the kth 'complete' dataset, and denoting the 
corresponding estimate of the variance as Vk.
The MI estimator of q (point estimator obtained from PROC MIANALIZE), θ ̃MI, is the 
average of the K individual estimators:
The estimated variance of θ ̃MI, is a combination of the between- and within-imputation 
variability as follows:
Where 
is the within-imputation variability and
is the between-imputation variance. 
It has been shown5 that the statistic
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has an approximate tv distribution where v=(K-1)[(1+W/B)]^2.  Statistical inference, 
including hypothesis testing and confidence intervals for the treatment effect, will be 
based on this T-statistic.
3.0
Sample SAS Code
/**********************/
/*IMPUTATION ALGORITHM*/
/**********************/
/*NOTE: THIS APPROACH REQUIRES NO MISSING IN CATEGORICAL COVARIATES AND 
REQUIRES AT LEAST ONE OBSERVATION IN BASELIBE OR ONE OF THE POST-
BASELINE VISIT*/
/*PRE-AUGMENTATION – CREATE DUMMY FOR CATEGORICAL VARIABLES*/
/********************************************/
DATA PPASI_2; SET PPASI;
  /*THE MCMC STATMENT BELOW ASSUMES MULTI-VARIATE NORMAL*/
  IF TRT01PN=1 THEN TRT1=1; ELSE TRT1=0;
  /*BASELINE BSA and BASELINE PPIGA CATEGORY*/
  IF BSAGR1N = 1 THEN REG1 = 1 ;ELSE REG1 = 0;
  IF PPIGAGR1N = 1 THEN REG2 = 1 ;ELSE REG2 = 0;
RUN;
/*AUGMENTATION STEP -- TO HAVE 30 MONOTONE MISSING DATASETS*/
PROC MI DATA= PPASI_2 OUT= PPASI_MONO NIMPUTE=30 SEED= 21423 /*RANDOM 
SEED PRE-DEFINED*/
  ROUND=. . . 0.1 0.1 0.1 /*VALUE ROUND TO 1ST DECIMAL*/
  MIN=. . . 0 0 0
/*MINIMUM VALUE OF PPASI IS 0*/
  MAX=. . . 72 72 72   /*MAXIMUM VALUE OF PPASI IS 72*/
MCMC IMPUTE=MONOTONE ;
/*NOTE: CATEGORICAL VARIABLES SUCH AS TRT1 TRT2 ARE DUMMY, CREATED 
ABOVE*/
/*NOTE: ALL OTHER NON-DUMMIED COVARIATES MUST BE CONTINUOUS*/
/*SUPPOSE STRATAN (NUMERIC VARIABLE FOR STRATA) HAS ONLY 2 LEVELS, NO 
NEED TO CREATE DUMMY*/
VAR TRT1 BSABL REG2 BASE WK4 WK16;
/*CAUTION TO USE THE "BY" STATEMENT IN MCMC: */
/*MVN MODEL IS FITTED WITHIN EACH 'BY' GROUP, INSTEAD OF ACROSS ALL 
GROUPS*/
RUN;
/*IMPUTATION STEP – DETERMINE IMPUTATION DISTRIBUTION AND RANDOMLY 
IMPUTE MISSING VALUE TO GENERATE 'COMPLETE' DATASETS*/
/***************************************************/
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PROC MI DATA= PPASI_MONO OUT= PPASI_FULL NIMPUTE=1 SEED= 21931
/*RANDOM 
SEED PRE-DEFINED*/
  ROUND= =. . . 0.1 0.1 0.1 /*VALUE ROUND TO 1ST DECIMAL*/
  MIN=. . .  0 0 0
/*MINIMUM VALUE OF PPASI IS 0*/
  MAX=. . .  72 72 72 /*MAXIMUM VALUE OF PPASI IS 72*/
  MINMAXITER=1000;
  /*CLASS CATEGORICAL VARIABLES TRT1 AND REG2*/
  CLASS TRT1 REG2;
  VAR TRT1 BSABL REG2 BASE WK4 WK16;
  MONOTONE REG (WK4 WK16);  /* IMPUTED SEQUENTIALLY, FROM WK 4 TO 16, 
WITH COVARIATES CONSTRUCTED FROM THE CORRESPONDING PRECEDING VARIABLES*/
  BY _IMPUTATION_;                   /*FOR EACH OF THE 30 MONOTONE 
MISSING DATASETS, IMPUTE A 'COMPLETE' DATASET*/
RUN;
/*DETERMINE DICHOTOMOUS RESPONSE STATUS, PPASI 75 AT WEEK 16*/
DATA ALL; SET PPASI_FULL;
  IF 0<=WK16<=0.25*BASE THEN PPASI75_16=1;
    ELSE PPASI75_16=0;
RUN;
/***********************************************************************
*/
/*         DATA HANDLING STEPS TO MERGE COVID-19 STATUS OMITTED         
*/
/*            PLACE TO ADD DATA HANDLING AND MERGING STEPS              
*/
/***********************************************************************
*/
/*FOR MI, SKIP THE FOLLOWING CODE, PROCEED TO THE CODE AFTER ANALYSIS 
MODEL *//*OVERRIDE MISSING VALUES NOT DUE TO COVID-19 WITH TRADITIONAL 
NRI*/
DATA ALLF; SET ALL;
  /*COVID19_XX='Y' IF MISSING AT WEEK XX IS DUE TO COVID-19; IF NOT, 
OVERRIDE WITH TRADITIONAL NRI*/
  /*VARIABLE PPASI75NRI_XX: TRADITIONAL NRI DATA AT WEEK XX, WHICH 
COVERS THE SPECIAL HANDLING SUCH AS THE BEFORE-AND-AFTER EXCEPTION IN 
THE PARTICULAR STUDY PERIOD*/
  IF COVID19_16 NE 'Y' THEN PPASI75_16= PPASI75NRI_16;
RUN;
PROC SORT DATA=ALLF; BY _IMPUTATION_ SUBJID; RUN;
/****************/
/*ANALYSIS MODEL*/
/****************/
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/*KEY CODE: ANALYZING EACH 'COMPLETE' DATASET*/
/***********************************/
/*INDIVIDUAL-LEVEL DATA --> # OF RESPONDERS & # OF SUBJECTS, TO BE READ-
IN TO PROC STDRATE*/
PROC FREQ DATA=ALL;
  BY _IMPUTATION_;
  TABLES TRT01PN*STRATAN* PPASI75_16/LIST NOCUM NOPRINT OUT=COUNT_TABLE;
  /*WEEK 16 RESULTS AS AN EXAMPLE*/
RUN;
DATA COUNT_TABLE; SET COUNT_TABLE;
  DROP PERCENT;
RUN;
PROC TRANSPOSE DATA=COUNT_TABLE OUT=FREQ_TABLE PREFIX=RESP;
ID PPASI75_16;
BY _IMPUTATION_ TRT01PN STRATAN;
VAR COUNT;
RUN;  
DATA FREQ_TABLE1; SET FREQ_TABLE;
  CASE=RESP1;
  SIZE=SUM(RESP0, RESP1);
  KEEP _IMPUTATION_ TRT01PN STRATAN CASE SIZE;
RUN;
/*RE-ORDER TO SET 1 (PLACEBO) AS THE REFERENCE GROUP*/
DATA FREQ_TABLE2; SET FREQ_TABLE1;
  IF TRT01PN=2 THEN TRT01PN=0;
RUN;
/*CALCULATE THE COMMON RISK DIFF FOR EACH COMPLETE DATASET*/
PROC STDRATE DATA=FREQ_TABLE2
  METHOD=MH STAT=RISK EFFECT=DIFF;
  BY _IMPUTATION_;
  POPULATION GROUP=TRT01PN EVENT=CASE TOTAL=SIZE;
  STRATA STRATAN / ORDER=DATA STATS(CL=NONE) EFFECT;
  ODS OUTPUT EFFECT=EFFECT;
RUN;
/*COMBINING RESULTS USING PROC MIANALYZE*/
/****************************************/
PROC MIANALYZE DATA=EFFECT;
  ODS OUTPUT PARAMETERESTIMATES=RISK_DIFF_MH;  
  MODELEFFECTS RiskDiff;
  STDERR StdErr;
RUN;
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4.0
Reference
1.
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-
19 Pandemic - Guidance for Industry, Investigators, and Institutional Review 
Boards.  FDA.  2020.
2.
Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency - Guidance for Industry.  FDA.  2020.
3.
Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials.  EMA.  2020.
4.
Graham JW, Olchowski AE, Gilreath TD.  How many imputations are really 
needed?  Some practical clarifications of multiple imputation theory.  Prev Sci  
2007;8(3):206-13.
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