Clinical trial NCT04908475
Conditions: Psoriasis
Keywords: Psoriasis Plaque Psoriasis Risankizumab ABBV-066 Skyrizi Apremilast
Sponsor: AbbVie
Start date: 2021-06-09; Completion date: 2023-04-20
Enrollment: 352 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Psoriasis (PsO) is a chronic disease characterized by marked inflammation of the skin that results in thick, red, scaly plaques. This study will assess how safe and effective risankizumab is compared to apremilast in adult participants with moderate plaque psoriasis. Adverse events and change in disease symptoms will be monitored.

Risankizumab (Skyrizi) and apremilast are approved drugs for the treatment of moderate to severe PsO. Approximately 330 participants with moderate plaque psoriasis (PsO) will be enrolled across approximately 55 sites globally.

The study has 2 periods : Period A from Baseline to Week 16, and Period B, from Week 16 to Week 52. In Period A, participants will be randomly placed into 2 groups to receive either subcutaneous risankizumab or oral apremilast for 16 weeks. In Period B, participants who received apremilast in Period A will again be randomly assigned to 1 of the 2 groups to receive either risankizumab or apremilast for 36 weeks. At weeks 28 and 40, participants considered non-responders to apremilast based on their psoriasis score will be offered to receive risankizumab.

There may be a higher burden for participants in this study compared to usual standard of care. Participants will attend regular visits per routine clinical practice. The effect of the treatment will be checked by medical assessments, checking for side effects, and questionnaires.

Detailed description:

Arms: arm 1: Risankizumab 150 mg as a single subcutaneous (SC) injection at at Baseline (Day 1) and Week 4 (Period A) and at Weeks 16, 28, and 40 (Period B). arm 2: Participants receive apremilast 30 mg orally twice daily (BID) in Period A and re-randomized to receive either risankizumab 150 mg as a single SC injection at Weeks 16, 20, 32 in Period B or apremilast 30 mg orally BID from Week 16 up to Week 52 in Period B. For those taking apremilast in Period B, non-responders at Week 28 and Week 40 will be offered to receive risankizumab as rescue medication.
Interventions: intervention 1: Risankizumab intervention 2: Apremilast
Intervention descriptions: intervention 1: Subcutaneous injection intervention 2: Oral Tablets

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
8
3
OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
10
3.2
PRIMARY ENDPOINTS
11
3.3
SECONDARY ENDPOINTS
12
3.4
ADDITIONAL EFFICACY ENDPOINTS
12
3.5
SAFETY ENDPOINTS
13
3.6
PHARMACOKINETIC EVALUATION
13
4
INVESTIGATIONAL PLAN
13
4.1
OVERALL STUDY DESIGN AND PLAN
13
4.2
DISCUSSION OF STUDY DESIGN
15
5
STUDY ACTIVITIES
17
5.1
ELIGIBILITY CRITERIA
17
5.2
CONTRACEPTION RECOMMENDATIONS
21
5.3
PROHIBITED MEDICATIONS AND THERAPY
23
5.4
PRIOR AND CONCOMITANT THERAPY
24
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
24
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
26
5.7
STUDY DRUG
27
5.8
RANDOMIZATION/DRUG ASSIGNMENT
27
5.9
PROTOCOL DEVIATIONS
28
6
SAFETY CONSIDERATIONS
28
6.1
COMPLAINTS AND ADVERSE EVENTS
28
6.2
CARDIOVASCULAR ADJUDICATION COMMITTEE
34
6.3
ANAPHYLAXIS ADJUDICATION COMMITTEE
34
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
34
7.1
STATISTICAL AND ANALYTICAL PLANS
34
7.2
DEFINITION FOR ANALYSIS POPULATIONS
35
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
36
7.4
STATISTICAL ANALYSES FOR EFFICACY
36
7.5
STATISTICAL ANALYSES FOR SAFETY
38
7.6
INTERIM ANALYSIS
39
7.7
OVERALL TYPE I ERROR CONTROL
39
7.8
SAMPLE SIZE DETERMINATION
39
8
ETHICS
40
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
40
8.2
ETHICAL CONDUCT OF THE STUDY
40
8.3
SUBJECT CONFIDENTIALITY
40
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
40
10 DATA QUALITY ASSURANCE
41
11 START AND COMPLETION OF THE STUDY
41
12 REFERENCES
41
LIST OF TABLES
TABLE 1.
TASKS OF THE EFFICACY ASSESSOR AND INVESTIGATORS
17
TABLE 2.
IDENTITY OF INVESTIGATIONAL PRODUCT
27
TABLE 3.
SUPPLEMENTAL ADVERSE EVENTS ECRFS
32
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
15
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
43
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
46
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
47
APPENDIX D.
ACTIVITY SCHEDULE
48
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
53
APPENDIX F.
OPERATIONS MANUAL
54
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
Psoriasis (PsO) 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 exists.4,5
This study seeks to demonstrate that a significantly higher proportion of patients with moderate PsO 
treated with risankizumab can achieve a high level of skin clearance (≥Psoriasis Area and Severity Index 
[PASI] 90) compared to patients treated with apremilast providing a significant improvement in patient 
outcomes.
Evidence generated to date has demonstrated the benefits of risankizumab compared to other 
advanced therapies for PsO, such as adalimumab, ustekinumab, and secukinumab in moderate to severe 
PsO.6-9  However, no head-to-head data currently exist between risankizumab and apremilast.
Risankizumab (Skyrizi™) has been approved for the treatment of moderate to severe PsO and is 
currently being developed for Crohn's disease, ulcerative colitis, and psoriatic arthritis (PsA) (Phase 3 
studies).  Risankizumab is a humanized monoclonal antibody 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.
This study is designed to evaluate the efficacy and safety of risankizumab versus apremilast for the 
treatment of adult subjects with moderate plaque PsO who are candidates for systemic therapy.  In 
addition, the study aims to evaluate the efficacy and safety of switching to risankizumab versus 
continuing on apremilast for subjects with moderate plaque PsO who do not achieve ≥75% reduction 
from Baseline in Psoriasis Area Severity Index (PASI 75) after 16 weeks of treatment with apremilast.
For a more detailed description of the risankizumab drug profile, refer to the latest version of the 
Investigator's Brochure (IB).8
2.2 Benefits and Risks to Subjects
In risankizumab studies 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 
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periods.  In addition, subjects with active systemic infection or clinically important infection will not be 
included in the study.
This study is designed to learn more about the treatment effect of risankizumab compared with 
apremilast in adult subjects with moderate plaque PsO who are candidates for systemic therapy as well 
as to learn more about the potential treatment effect of switching to risankizumab in a subset of 
apremilast-treated subjects considered as non-responders after 16 weeks of treatment as compared 
with continuing with apremilast.
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.  IL-23 inhibition is not known to increase the risk of TB infection or impair the response to 
TB infection in animal models.10,11  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.12-14  Moreover, preclinical data have demonstrated a 
beneficial effect of IL-23 p19 inhibition in animal models, both for pre-existing and tumor-induction 
models.15  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 (MACE) events, including myocardial infarction, cerebrovascular 
accident, and cardiovascular death, reported initially with anti-IL-12/23 agents, such as ustekinumab, have 
not been observed in longer term studies 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 administered biologic therapies are usually limited to redness, swelling, 
or induration at the injection site.  Manifestations of systemic hypersensitivity reactions may include 
anaphylaxis, generalized urticaria, 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.  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.16  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 IB.8
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Apremilast (Otezla®) was first approved as a safe and efficacious product for the treatment of plaque 
PsO by the United States Food and Drug Administration in 2014 and by the European Medicines Agency 
in 2015; since then, it has been approved in a number of additional countries.  Please refer to the local 
label available to you for information regarding the efficacy and safety of this product.17,18
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 and clinical trial data.  
At this time, the effects of risankizumab or apremilast on the course of COVID-19 are not well defined.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
The objective of the study is to evaluate the efficacy and safety of risankizumab versus apremilast for 
the treatment of adult subjects with moderate plaque PsO who are candidates for systemic therapy.
In addition, the study aims to evaluate the efficacy and safety of switching to risankizumab versus 
continuing on apremilast for subjects with moderate plaque PsO who do not achieve PASI 75 after 
16 weeks of treatment with apremilast.
Primary Efficacy Objective
The primary efficacy objective in Period A is to demonstrate a higher rate of a) PASI 90 (defined as ≥90% 
reduction from Baseline in PASI) and b) sPGA 0 or 1 with at least 2-grade improvement from Baseline 
after 16 weeks of treatment with risankizumab when compared to apremilast based on Intent to Treat 
(ITT) Population in Period A (ITT_A), which consists of all randomized subjects.
The hypotheses corresponding to the co-primary endpoints in Period A are:

The proportion of subjects achieving PASI 90 in the risankizumab (RZB) group is greater than 
that in the APR group at Week 16, among the ITT_A Population.

The proportion of subjects achieving sPGA 0 or 1 with at least 2-grade improvement from 
Baseline in the RZB group is greater than that in the apremilast (APR) group at Week 16, among 
the ITT_A Population.
The primary efficacy objective in Period B is to demonstrate a higher rate of PASI 90 after switching the 
treatment at Week 16 from APR to RZB for 36 weeks (APR/RZB) when compared to continuing with APR 
(APR/APR) based on the Intent to Treat Population in Period B for Week 16 APR-PASI75NRs (ITT_B_NR), 
which consists of subjects who are randomized to APR at Baseline, fail to achieve PASI 75 at Week 16, 
and are re-randomized.
The hypothesis corresponding to the primary endpoint in Period B is:

The proportion of APR-PASI75NR subjects achieving PASI 90 in the APR/RZB group is greater 
than that in the APR/APR group at Week 52, among the ITT_B_NR Population.
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Key Secondary Efficacy Objectives
The key secondary efficacy objective in Period A is to demonstrate higher efficacy of treatment with RZB 
when compared to APR with respect to the ranked and only secondary endpoint in Period A, as specified 
in Section 3.3 below.
The hypothesis corresponding to the ranked and only secondary endpoint in Period A is:

The proportion of subjects achieving PASI 75 in the RZB group is greater than that in the APR 
group at Week 16, among the ITT_A Population.
The key secondary efficacy objectives in Period B are to demonstrate higher efficacy of treatment with 
APR/RZB when compared to APR/APR among APR-PASI75NRs, with respect to the key secondary 
endpoints in a ranked order in Period B, as specified in Section 3.3 below.
The hypotheses corresponding to the ranked secondary endpoints in Period B are:

The proportion of APR-PASI75NR subjects achieving PASI 75 in the APR/RZB group is greater 
than that in the APR/APR group at Week 52, among the ITT_B_NR Population.

The proportion of APR-PASI75NR subjects achieving sPGA 0 or 1 with at least 2-grade 
improvement from Baseline in the APR/RZB group is greater than that in the APR/APR group at 
Week 52, among the ITT_B_NR Population.
Estimands Corresponding to the Primary and Ranked Secondary Endpoints
The estimand corresponding to each of the primary and ranked secondary endpoints in Period A is 
defined using composite variable strategy as follows:

Difference in the proportion of subjects achieving the corresponding endpoint at Week 16, 
without receiving alternative PsO treatment, regardless of premature discontinuation of study 
drug, in the RZB group in comparison with the APR group among the ITT_A population.
The estimand corresponding to each of the primary and ranked secondary endpoints in Period B is 
defined using composite variable strategy:

Difference in the proportion of subjects achieving the corresponding endpoint at Week 52 
without satisfying the rescue criteria or receiving the rescue medication, and without receiving 
alternative PsO treatment, regardless of premature discontinuation of study drug in the 
APR/RZB group in comparison with the APR/APR group among the ITT_B_NR population.
3.2 Primary Endpoints
Co-Primary Endpoints in Period A:

Achievement of PASI 90 at Week 16, among subjects in the ITT_A Population.
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
Achievement of sPGA 0 or 1 with at least 2-grade improvement from Baseline at Week 16, 
among subjects in the ITT_A Population.
Primary Endpoint in Period B:

Achievement of PASI 90 at Week 52, among subjects in the ITT_B_NR Population.
3.3 Secondary Endpoints
Ranked Secondary Endpoint in Period A:

Achievement of PASI 75 at Week 16, among subjects in the ITT_A Population.
Ranked Secondary Endpoints in Period B:

Achievement of PASI 75 at Week 52, among subjects in the ITT_B_NR Population.

Achievement of sPGA 0 or 1 with at least 2-grade improvement from Baseline at Week 52, 
among subjects in the ITT_B_NR Population.
3.4 Additional Efficacy Endpoints
All variables listed above as primary or ranked secondary endpoints will also be analyzed at all other 
visits collected.  Additionally, the following endpoints will be evaluated at all visits collected:

Achievement of 100% reduction from Baseline in PASI (PASI 100)

Achievement of sPGA 0

Change from Baseline in PASI

Percent change from Baseline in PASI

Change from Baseline in body surface area (BSA)

Achievement of Palmoplantar Investigator's Global Assessment (ppIGA) 0 or 1, among subjects 
with Baseline ppIGA of at least 3

Change from Baseline in Psoriasis Scalp Severity Index (PSSI), among subjects with Baseline 
scores > 0

Change from Baseline in Nail Psoriasis Severity Index (NAPSI), among subjects with Baseline 
scores > 0

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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
Change from Baseline in Work Productivity and Activity Impairment (WPAI) scores

Treatment Satisfaction Questionnaire for Medication version 9 (TSQM-9) scores (at each 
post-Baseline visit in Period A)

Change from Entry of Period B in TSQM-9 scores, among subjects who are re-randomized at 
Week 16

Change from Baseline in Psoriasis Symptoms Scale (PSS) scores

Percentage change from Baseline in PSS, among subjects with Baseline scores > 0

Achievement of PSS 0

Achievement of PSS 0 or 1
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

Physical examinations

Clinical laboratory testing (hematology and chemistry)
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.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 4, global, multicenter, randomized, open-label, efficacy assessor-blinded, active 
comparator study examining the effect of risankizumab compared to apremilast in adult subjects with 
moderate plaque PsO who are candidates for systemic therapy.
The study is designed to enroll 330 subjects.  See Section 5.1 for information regarding enrollment 
criteria.
The study duration for subjects administered risankizumab or provided apremilast will be up to 
approximately 69 weeks or 61 weeks, respectively.  The study is comprised of a Screening period of up 
to 35 days, a 52week treatment period, and a follow-up phone call for safety.  Depending on the 
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treatment at the end of the study, the follow-up phone call for safety will be conducted approximately 
20 weeks (140 days) after administration of the last dose of risankizumab (i.e., Week 40 for subjects 
originally randomized to risankizumab and Week 44 for subjects switched from apremilast to 
risankizumab) or approximately 4 weeks (28 days) after the last dose of apremilast (for subjects who 
remain on the APR arm after re-randomization).
The 52-week treatment duration includes Period A and Period B:

Period A (Baseline to Week 16):  Eligible subjects will be centrally randomized at the Baseline 
(Day 1) visit in a 1:2 ratio to receive either risankizumab 150 mg as a single subcutaneous (SC) 
injection (Arm 1) or apremilast 30 mg orally twice daily (BID) (Arm 2).  The randomization will be 
stratified by Baseline body weight (≤100 kg, > 100 kg) and prior exposure to any systemic 
and/or biologic treatment for PsO (0, ≥1).  Study drug administration for apremilast will occur 
beginning at Baseline (Day 1) based on the dose titration schedule from Day 1 to Day 5 and will 
continue with 30 mg BID until the day prior to the Week 16 visit where re-randomization will 
occur.  Study drug administration for risankizumab will occur at Baseline (Day 1) and Week 4.  
The final efficacy evaluation for Period A will take place at Week 16.

Period B (Week 16 to Week 52):  Subjects initially randomized to risankizumab (Arm 1) will 
continue to receive risankizumab 150 mg as a single SC injection at Weeks 16, 28, and 40.  
Subjects initially randomized to apremilast (Arm 2) will be re-randomized at the Week 16 visit in 
a 1:1 ratio to receive either risankizumab 150 mg as a single SC injection at Weeks 16, 20, 32, 
and 44 (Arm 2a) or apremilast 30 mg orally BID up to Week 52 (Arm 2b).  Rerandomization will 
be stratified by PASI 75 response (responder, non-responder) at Week 16.  Rescue risankizumab 
will be offered to subjects who are re-randomized to apremilast (Arm 2b) and are PASI 50 non-
responders at Week 28 (Arm 3a; rescue risankizumab will be administered at Weeks 28, 32, and 
44) or Week 40 (Arm 3b; rescue risankizumab will be administered at Weeks 40 and 44).  The 
final efficacy evaluation will take place at Week 52.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual (Appendix F).
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Figure 1.
Study Schematic
BID = twice daily; PASI = Psoriasis Area Severity Index; SC = subcutaneous
4.2 Discussion of Study Design
Choice of Control Group
An active comparator group randomized to receive apremilast will be used in this study to examine the 
effect of 150 mg risankizumab every 12 weeks versus 30 mg apremilast BID in subjects with moderate 
plaque PsO who are candidates for systemic therapy.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy and 
safety-related measurements in this study are standard for assessing disease activity in subjects with 
moderate plaque PsO.  All clinical and laboratory procedures in this study are standard and generally 
accepted.  All patient-reported outcomes (PRO) measures in this study were adequately developed and 
validated to measure specific concepts of interest relevant to this study.
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Suitability of Subject Population
Male or female subjects with a diagnosis of moderate chronic plaque PsO (with or without PsA) for at 
least 6 months prior to Baseline and who are candidates for systemic therapy are eligible for this study.  
Eligible subjects must also have moderate chronic plaque PsO as defined by BSA ≥ 10% and ≤ 15%, PASI 
≥12, and sPGA = 3 (moderate) based on a 5-point scale (0 to 4) at Screening and the Baseline Visit.  The 
selection criteria relating to safety guarantee that subjects enrolled can safely be treated with 
risankizumab or apremilast based on the current knowledge of these drugs.
Selection of Doses in the Study
The selected dose of 150 mg SC for risankizumab is the same as the approved labeled dose in the 
treatment of moderate to severe plaque PsO tested in Phase 3 global studies in subjects with moderate 
to severe plaque PsO.  The risankizumab 150 mg SC dose has been shown to be efficacious with an 
acceptable safety profile and considered appropriate for the treatment of patients with moderate 
plaque PsO.  For apremilast, the selected dose is as recommended in the approved product labeling for 
the treatment of plaque PsO.
Blinded Efficacy Assessor
A qualified physician (may be a non-dermatologist) or designee (may be a non-physician) from the site 
will be responsible for performing the efficacy assessments, including PASI, BSA, and sPGA at all 
appropriate study visits (Table 1).  The site will make every attempt to have the same qualified physician 
or designee perform these assessments throughout the study for each subject.  The efficacy assessor 
must remain blinded to patient's treatment, clinical laboratory results, and all subject safety data during 
the course of the study.  The efficacy assessor will not view or discuss any subject specific safety data 
with the investigators or any other site personnel, with the exception of the dermatologic safety findings 
requiring urgent medical attention.  The efficacy assessor therefore cannot be the Principal Investigator.  
The efficacy assessor will not access patient's electronic case report form (eCRF) and will document the 
dermatologic assessments and potential dermatologic safety findings on paper worksheets that will be 
filed as source in the patient's record.  It is recommended that each study site has a designated back-up 
for the efficacy assessor.
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Table 1.
Tasks of the Efficacy Assessor and Investigators
Activities
Responsible Party
Assesses PASI, sPGA, BSA, ppIGA, NAPSI, and PSSI
Efficacy Assessora
Looks for any potential dermatologic safety finding
Efficacy Assessor
Documents the efficacy assessments and any potential 
dermatologic safety findings on worksheets
Efficacy Assessor
Assesses safety
Investigator
Knows treatment allocation
Investigator
Reviews laboratory data
Investigator
Conduct the complete and any targeted physical 
examinationsb
Investigator
Completes the CRF
Investigator, unblinded study team
Documents findings in the eCRF
Investigator, unblinded study team
Reports information about safety findingsc
Investigator
BSA = body surface area; CRF = case report form; eCRF = electronic case report form; NAPSI = Nail Psoriasis Severity Index; 
PASI = Psoriasis Area and Severity Index; ppIGA = Palmoplantar Investigator's Global Assessment; PSSI = Psoriasis Scalp Severity 
Index; sPGA = Static Physician Global Assessment
a.
The efficacy assessor is a physician or a designee that is blinded to all aspects of the study other than the efficacy 
assessments.
b.
The investigator will also look for potential dermatologic safety findings.
c.
If the efficacy assessor identifies a safety issue this will be transmitted to the investigator over the worksheet via paper 
collection.  Dermatologic safety findings requiring urgent medical attention will be the only safety issues that the efficacy 
assessor may discuss with the investigator.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects 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.
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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 transaminase (AST) ≤ 2 × upper limit of normal (ULN);

Serum alanine transaminase (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 ≥ 1,500/µL;

Platelet count ≥ 100,000/µL;

Hemoglobin ≥ 10 g/dL (100 g/L);

Estimated glomerular filtration rate by the Chronic Kidney Disease Epidemiology 
Collaboration equation (eGFR [CKD-EPI]) ≥30 mL/min/1.73 m2.
Disease/Condition Activity
6. Male or female subject with a diagnosis of chronic plaque PsO with or without PsA, for at 
least 6 months prior to Baseline.
7. Stable moderate chronic plaque PsO at both Screening and Baseline as defined as:

BSA ≥10% and ≤ 15%,

PASI ≥12, and

sPGA = 3 (moderate) based on a 5-point scale (0 to 4).
8. PsO 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. Subject must not have any form of PsO other than chronic plaque PsO (e.g., pustular PsO, 
palmoplantar pustulosis, acrodermatitis of Hallopeau, erythrodermic, or guttate PsO).
12. Subject must not have a history of current drug-induced PsO or a drug-induced exacerbation 
of pre-existing PsO.
13. Subject must not have a history of active ongoing inflammatory skin diseases other than PsO 
and PsA that could interfere with the assessment of PsO (e.g., hyperkeratotic eczema).
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14. Subject must not have a history of severe renal insufficiency defined as creatinine clearance
< 30 mL/min and/or requiring hemodialysis or peritoneal dialysis.
15. Subject must not have a history of clinically significant (per investigator's judgment) drug or 
alcohol abuse within the last 6 months.
16. Subject must not have a history of an allergic reaction or significant sensitivity to 
constituents of the study drugs (and its excipients) and/or other products in the same class.
17. Subject 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).
18. 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., polymerase chain reaction [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.
19. Subjects must not have evidence of:
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, defined as:

HBV:  Hepatitis B surface antigen (HBs Ag) positive (+) test or detected sensitivity on the 
HBV DNA 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 3.13 of the Operations Manual.
Active systemic infection/Clinically important infection during the last 2 weeks prior to 
Baseline visit as assessed by the investigator.
20. Subjects 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;
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
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.

Prior history of suicide attempt at any time in the subject's lifetime prior to signing the 
informed consent and randomization, or major depression or suicidal ideation or attempt 
requiring hospitalization within the last 3 years prior to signing the informed consent.

Hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose 
malabsorption.
21. 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.
Contraception
22. 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.
23. Risankizumab:

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.

Female subjects may not be pregnant, breastfeeding, or considering becoming pregnant or 
donating eggs 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.
Apremilast:

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 28 days (or as guided by 
the local apremilast label, 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.

Female subjects may not be pregnant, breastfeeding, or considering becoming pregnant or 
donating eggs during the study or for approximately 28 days (or as guided by the local 
apremilast label, whichever is longer) after the last dose of study drug.
Concomitant Medications (Prior Medication Restrictions)
24. Subject must not have had any prior exposure to risankizumab or apremilast.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
25. Subject must not have received any live viral or bacterial vaccine within 4 weeks prior to the 
first dose of study drug, or expect the need for 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 risankizumab or at least 28 days after the last dose of 
apremilast.
26. 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.
27. Subject did not receive for at least 30 days prior to Baseline any: 

Other systemic immunomodulating treatments (including, but not limited to:  e.g., 
methotrexate, cyclosporine A, corticosteroids, cyclophosphamide, tofacitinib [Xeljanz®]);

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]) or prolonged exposure or use of tanning booths or ultraviolet light 
sources.
28. 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 be currently 
enrolled in another interventional clinical study.
29. Subject did not receive for at least 14 days prior to Baseline 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).
30. Subject must not be treated with any strong cytochrome P450 enzyme inducers (e.g., 
rifampin, phenobarbital, carbamazepine, phenytoin, St. John's Wort) within 30 days or 5 half-
lives of start of treatment with apremilast.
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:
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1.
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.
2.
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-stimulating hormone (FSH) level > 30 IU/L.

Females, of Childbearing Potential
Females of childbearing potential must avoid pregnancy while taking study drug 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 risankizumab or 28 days (or as guided by the local 
apremilast label, whichever is longer) after the last dose of apremilast.  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 Day 1.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device.

Intrauterine hormone-releasing system.

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 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable).
For those subjects who are re-randomized to risankizumab or are rescued with risankizumab, 
contraception guidelines for risankizumab apply.
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).
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 (including any biosimilar thereof) to treat moderate 
plaque PsO 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, 
and fumaric acid derivatives.  Exception:  Treatment with commercially available apremilast 
after the Week 52/PD assessments if this has been determined as an appropriate subsequent 
treatment by the investigator in discussion with the subject.
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.
For subjects on apremilast:  strong cytochrome P450 enzyme inducers (e.g., rifampin, 
phenobarbital, carbamazepine, phenytoin, and St. John's Wort).
7.
Live attenuated vaccines (except non-replicating live vaccines, e.g., JYNNEOS monkeypox 
vaccine) 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 risankizumab or up to 28 days after the last dose of apremilast.
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

Varicella (chicken pox)
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
Yellow fever

Dengue (Dengvaxia®)
5.4 Prior and Concomitant Therapy
Stable doses of other concomitant therapies for chronic conditions, for which neither the condition nor 
the treatment are judged to exclude the subject 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 electronic 
case report form (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 and/or apremilast can be 
located in the risankizumab Investigator's Brochure8 or apremilast label.17,18
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.
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 (Day 1) 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, ophthalmic, otic, or intranasal corticosteroids are permitted during the study.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time 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 Sponsor.
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
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 when continuation of the study drug would 
place the subject at risk.

The investigator determines the subject is significantly noncompliant with study procedures.

Post-Baseline occurrence of new or worsening psychiatric symptoms, including suicidal ideation 
or a suicidal attempt.

Post-Baseline occurrence of one or more of the following hepatic abnormalities (confirmed on a 
second separate sample as 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 source documents. 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 their site if they have 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 has been 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.
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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than described in the protocol, to ensure all acceptable mitigation steps have 
been explored.
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
During the study drug dosing period, a subject with confirmed (viral test positive) or suspected COVID-
19 infection can only be dosed with study drug if the following COVID-19 viral clearance criteria are met:

At least 14 days since first positive test result have passed in asymptomatic patients or at least 
14 days since recovery, defined as resolution of fever without use of antipyretics and 
improvement in symptoms.
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects must be discussed 
with the AbbVie medical contact, along with the possibility of premature discontinuation from the study 
drug dosing period.  Follow subsequent protocol Section 5.6 for subjects who discontinued study drug.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue the study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they discontinue 
treatment with study drug early.
If, during the course of study drug administration, the subject prematurely discontinues study drug use, 
the subject has the option to continue in the study and complete the remaining visits as scheduled.  If 
remaining visits will be completed, a PD visit is not required.  If the subject does not continue in the 
study, the procedures outlined for the PD visit must be completed, ideally within 2 weeks of the decision 
and preferably prior to the initiation of another therapy.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the Investigator feels 
are necessary to treat the subject's condition.
Following discontinuation of the study drug, the subject will be treated in accordance with the 
Investigator's best clinical judgment.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit (PD visit) should be completed as soon as 
possible, preferably within 2 weeks.  In addition, if subject is willing, a follow-up phone call 
approximately 140 days (20 weeks) after the last dose of risankizumab or approximately 28 days after 
the last dose of apremilast may be completed to ensure all treatment-emergent AEs/serious adverse 
events (SAEs) have been resolved.  The 140-day (20-week) or 28-day follow-up phone calls following the 
last dose of risankizumab or apremilast, respectively, during the trial will not be required for any subject 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
who initiates commercially available risankizumab or apremilast upon or after the study Completion 
Visit (i.e., Week 52 or during the follow-up period) or PD visit.
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.
5.7 Study Drug
Study site staff will administer risankizumab (150 mg [1 × 1 mL 150 mg/mL pre-filled syringe]) 
subcutaneously or study staff will provide apremilast (30 mg [10 mg, 20 mg, 30 mg, film-coated tablets]) 
beginning at Baseline (Day 1) (Table 2).
Apremilast subject dosing (orally) will be recorded on a subject dosing diary.  The subject will be 
instructed to return all apremilast packaging (even if empty) to the study site personnel at each study 
visit.  The study site personnel will document compliance.
Table 2.
Identity of Investigational Product
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Risankizumab 
(ABBV-066)
Solution for 
injection in pre-
filled syringe (PFS)
150 mg (1x 1 mL 
150 mg/mL PFS)
Subcutaneous 
injection
AbbVie
Apremilast
Tablets
10 mg, 20 mg, 30 mg 
film-coated tablets
Oral
Amgen
AbbVie will not supply drug other than risankizumab and apremilast.  AbbVie provided study drugs 
should not be substituted or alternately sourced unless otherwise directed by AbbVie.
Open-label risankizumab and apremilast will be packaged in quantities sufficient to accommodate study 
design.  Each risankizumab kit or apremilast package will be labeled per local requirements and this label 
must remain affixed to the respective packaging.  Upon receipt, study drug should be stored as specified 
on the label in their original packaging and kept in a secure location.  A temperature log must be 
maintained for documentation.  Each kit or package will contain a unique kit or package number.  This 
number is assigned to a subject via interactive response technology (IRT) and encodes the appropriate 
study drug to be dispensed at the subject's corresponding study visit.  All blank spaces on the label will 
be completed by the site staff prior to dispensing to subjects.  Study drugs will only be used for the 
conduct of this study.
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.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Study treatment duration includes Period A and Period B:

Period A (Baseline to Week 16):  Eligible subjects will be centrally randomized at the Baseline 
(Day 1) visit in a 1:2 ratio to receive either risankizumab 150 mg as a single SC injection (Arm 1) 
or apremilast orally with a dose titration from Day 1 to Day 5 and continuing with 30 mg BID 
until the day prior to Week 16 (Arm 2).  The randomization will be stratified by Baseline body 
weight (≤100 kg, > 100 kg) and prior exposure to any systemic and/or biologic treatment for 
PsO (0, ≥ 1).

Period B (Week 16 to Week 52):  Subjects initially randomized to apremilast (Arm 2) will be 
rerandomized at the Week 16 visit in a 1:1 ratio to receive either risankizumab 150 mg as a 
single SC injection (Arm 2a) or apremilast 30 mg orally BID (Arm 2b).  Rerandomization will be 
stratified by PASI 75 response (responder, non-responder) at Week 16.  Rescue risankizumab 
will be offered for subjects who are re-randomized to the apremilast arm and are PASI 50 non-
responders at Week 28 (Arm 3a) or Week 40 (Arm 3b).
This is an open-label study; however, the efficacy assessor will remain blinded to each subject's 
treatment, clinical laboratory results, and all subject safety data during the course of the study.
In the event of a medical emergency in which the Investigator believes that knowledge of study drug 
treatment is required for the efficacy assessor, reasonable efforts must be made to contact the AbbVie 
Emergency Contact.
The date and reason that the efficacy assessor's blind was broken must be recorded in the source 
documentation and eCRF, as applicable.
5.9 Protocol Deviations
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 the investigational 
products must be reported to AbbVie.
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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 damage or not 
working properly, or packaging issues.
Product complaints concerning the investigational products and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.
Reporting will be done via electronic data capture (EDC).  The date the product complaint details are 
entered into EDC and the form is saved represents the date reported to AbbVie.  A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue.  If a back-up paper form is used, the date the form is emailed to RD_PQC_QA@abbvie.com 
represents the date reported to AbbVie.
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor.  Product complaints associated with adverse events 
will be reported in the study summary. Product complaints occurring during the study will be followed 
up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events:  Study Drug
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 
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 
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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 as an SAE within 24 hours of the site being made aware of 
the 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).
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 risankizumab or apremilast administration until 140 days (20 weeks) 
after discontinuation of risankizumab administration or 28 days after discontinuation of apremilast 
administration will be collected, whether solicited or spontaneously reported by the subject.  After 
140 days (20 weeks) following the last dose of study drug or completion of study treatment only 
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spontaneously reported SAEs will be collected (nonserious AEs will not be collected.)  In addition, study 
procedure-related serious and nonserious AEs will be collected from the time the subject signs the 
study-specific informed consent.  If a subject prematurely discontinues study participation and begins 
commercially available risankizumab (Skyrizi) or apremilast (Otezla) all adverse events reported by 
healthcare professionals or the patient, will be captured as postmarketing reports.  The follow-up phone
call following the last dose of risankizumab during the study will not occur for subjects who begin 
commercially available risankizumab or apremilast.
The following definitions will be used for Serious Adverse Reactions (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 unexpected (not listed in the applicable Reference Safety 
Information [RSI]), and meets one of the above serious criteria.
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 
the ASI, the following supplemental eCRF(s) must be completed if AEs in any of the following areas are 
reported during the study (Table 3).
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Additionally, apremilast administration should be evaluated at any time during the study in the following 
circumstances:

Psychiatric disorders:  If subjects suffered from new or worsening psychiatric symptoms, or 
suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment 
with apremilast.

Diarrhea, nausea, and vomiting: If patients develop severe diarrhea, nausea, or vomiting, 
discontinuation of treatment with apremilast may be considered.

Weight decrease: If unexplained or clinically significant weight loss occurs, evaluate weight loss 
and according to outcomes of the assessment, consider discontinuation of apremilast.
Adverse Event Severity and Relationship to Study Drug
Adverse events must be graded to the 5 criteria described in the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.19
Grades:  Grade refers to the severity of the AE.  The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this guideline:

Grade 1 (Mild); asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.

Grade 2 (Moderate); minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.

Grade 3 (Severe); medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.

Grade 4 (Severe); Life-threatening consequences; urgent intervention indicated.

Grade 5 (Severe); Death related to AE
The investigator will use the following definitions to assess the relationship of the 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 
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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 pre-specified definitions.  This independent external Anaphylaxis 
Adjudication Committee (AAC) will adjudicate suspected anaphylactic reactions and will remain blinded 
to treatment allocation.  The event terms to be adjudicated and the adjudication process are detailed in 
the AAC Charter.  A supplemental Hypersensitivity Reactions 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.
If a suspected systemic hypersensitivity reaction occurs at the investigative site, in addition to testing 
tryptase and histamine levels, PK, 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 for Period A will be conducted after all continuing subjects have completed 
Week 16 visit and the database is locked.  This will be the only and final analysis for the primary and 
secondary efficacy endpoints for Period A.
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The Primary Analysis for Period B will be conducted after all continuing subjects have completed 
Week 52 visit and the database is locked.  This will be the only and final analysis for the primary and 
secondary efficacy endpoints for Period B.
The final analysis will be conducted upon study completion.  The statistical analysis will be described and 
fully documented in the SAP.  All statistical tests will be performed at a two-sided alpha level of 0.05.  
The statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The Intent to Treat Population in Period A (ITT_A) includes all randomized subjects.  The ITT_A 
Population will be used for all efficacy analyses in Period A.
The Intent to Treat Population for APRPASI75NRs in Period B (ITT_B_NR) includes subjects who are 
randomized at Baseline (Day 1), fail to achieve PASI 75 at Week 16, and are re-randomized.  The 
ITT_B_NR Population will be used for the analysis comparing switch-to-RZB (APR/RZB) versus continue-
with-APR (APR/APR) among APR-PASINRs in Period B.
The Intent to Treat Population for APR-PASI75 responders in Period B (ITT_B_R) includes subjects who 
are randomized to APR at Baseline, achieve PASI 75 at Week 16, and are re-randomized (APR-PASI75Rs).  
The ITT_B_R Population will be used for the summary of efficacy for APR/RZB and APR/APR among 
APR-PASI75Rs in Period B.
The Intent to Treat Population for Period B combined Population (ITT_B_Combined) includes subjects 
who are randomized to APR at Baseline and are re-randomized at Week 16.  The ITT_B_Combined 
Population will be used for combined analysis (APR-PASI75NRs and APR-PASI75Rs) between subjects 
re-randomized to APR/RZB and APR/APR in Period B.
The Intent to Treat Population for Long Term Efficacy (ITT_LT) includes subjects who are randomized to 
receive continuous RZB (i.e., all subjects randomized to RZB at Baseline) and subjects who are 
randomized and re-randomized to receive continuous APR, including half of the subjects randomized to 
APR at Baseline and prematurely discontinued from study before entering Period B.  The ITT_LT 
Population will be used for the analysis comparing long term efficacy between continuous treatment of 
RZB/RZB and APR/APR in Period B.
The Intent to Treat Population for Rescued Population (ITT_Res) includes subjects who are 
re-randomized to APR at Week 16, fail to achieve PASI 50 at Week 28 and Week 40, and receive RZB as 
the rescue medication.  The ITT_Res Population will be used for the summary of efficacy after being 
rescued with RZB.
Each ITT Population will have a corresponding Safety Population.  In addition, an all risankizumab 
treated (ALL_RZB) Population will be utilized for a comprehensive safety summary of RZB.  The ALL_RZB 
Population is defined as all subjects who receive at least one dose of RZB as the study drug.
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7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints
The co-primary endpoints (Section 3.2) and the ranked secondary endpoint (Section 3.3) in Period A will 
be analyzed in the ITT_A Population and subjects with the following intercurrent event will be 
considered as non-responders:

Subjects who receive alternative PsO treatment regardless of premature discontinuation of 
study drug before Week 16.
The primary endpoints (Section 3.2) and the ranked secondary endpoints (Section 3.3) in Period B will be 
analyzed in the ITT_B_NR Population and subjects with the following intercurrent event will be 
considered as non-responders:

Subjects who receive alternative PsO treatment regardless of premature discontinuation of 
study drug before Week 52.

Subjects who satisfy rescue criteria or receive the rescue medication at Week 28 or Week 40.
7.4 Statistical Analyses for Efficacy
Summary and Analysis of the Primary Endpoints
All statistical tests will be performed at a 2-sided alpha level of 0.05.
Analysis of the co-primary endpoints in Period A will be conducted among the ITT_A Population based 
on treatment as randomized.  The number and proportion (n, %) of subjects achieving the endpoints will 
be summarized within each treatment group.  Comparison of the proportion of responders for each 
co-primary endpoint will be made between the RZB and APR groups (i.e., adjusted difference, 95% CI, 
p-value) using the Cochran-Mantel-Haenszel (CMH) test adjusting for the actual values of stratification 
factors in the initial randomization at Baseline.
Analysis of the primary endpoint in Period B will be conducted among the ITT_B_NR Population based 
on treatment as re-randomized.  The number and proportion (n, %) of subjects achieving the endpoint 
will be summarized within each treatment group.  Comparison of the proportion of responders will be 
made between the APR/RZB and APR/APR groups (i.e., difference, 95% CI, p-value) using the Chi-square 
test.  Subjects who satisfy the rescue criteria at Week 28 or Week 40 or receive rescue medication in 
Period B will be counted as non-responders for the primary endpoint in Period B.
Non-Responder Imputation incorporating multiple imputation to handle missing data due to COVID-19 
(NRI-MI) will be used to handle missing data.
Summary and Analysis of Ranked Secondary Endpoints
Analysis of the ranked secondary endpoint in Period A will be conducted among the ITT_A Population 
based on treatment as randomized.  The number and proportion (n, %) of subjects achieving the 
endpoint will be summarized within each treatment group.  Comparison of the proportion of responders 
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will be made between RZB and APR groups (i.e., adjusted difference, 95% CI, p-value) using the CMH test 
adjusting for the actual values of stratification factors in the initial randomization at Baseline.
Analysis of the ranked secondary endpoints in Period B will be conducted among the ITT_B_NR 
Population based on treatment as rerandomized.  The number and proportion (n, %) of subjects 
achieving the endpoint will be summarized within each treatment group.  Comparison of the proportion 
of responders will be made between APR/RZB and APR/APR groups (i.e., difference, 95% CI, p-value) 
using the Chi-square test.  Subjects who satisfy the rescue criteria at Week 28 or Week 40 or receive 
rescue medication will be counted as non-responders for the ranked secondary endpoints in Period B.
NRI-MI will be used to handle missing data.
Summary and Analysis of Additional Efficacy Endpoints
Additional binary endpoints will be analyzed among each Population as follows:

Comparison of additional endpoints among the ITT_A and ITT_LT Populations will be made using 
CMH test adjusting for the actual values of stratification factors in the initial randomization at 
Baseline.  NRI-MI will be used to handle missing data.

Comparison of additional endpoints among the ITT_B_NR Population will be made using 
Chi-square test.  NRI-MI will be used to handle missing data.

Comparison of additional endpoints among the ITT_B_Combined Population will be made using 
CMH test adjusting for the actual value of the stratification factor in the re-randomization at 
Week 16.  NRI-MI will be used to handle missing data.

Summary statistics will be provided for additional endpoints among the ITT_B_R Population.  
NRI-MI will be used to handle missing data.

Summary statistics will be provided for additional endpoints among the ITT_Res Population, 
based on Observed Cases (OC).
Additional continuous endpoints will be analyzed among each Population as follows:

Comparison of additional endpoints on ITT_A and ITT_LT Population will be made based on the 
fixed term of treatment from a Mixed-effect Model Repeat Measurement (MMRM), adjusting 
for treatment, actual values of stratification factors and Baseline value if applicable (if not 
duplicating the stratification factors).

Comparison of additional endpoints on ITT_B_NR Population will be made based on the fixed 
term of treatment from a MMRM, adjusting for treatment and Baseline value.

Comparison of additional endpoints among the ITT_B_Combined Population will be made based 
on the fixed term of treatment from a MMRM, adjusting for treatment, actual values of 
stratification factors in the re-randomization at Week 16 and Baseline value.

Summary statistics will be provided for additional endpoints among the ITT_B_R Population, 
based on the fixed term of treatment from a MMRM, adjusting for treatment and Baseline 
value.
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
Summary statistics will be provided for additional endpoints among the ITT_Res Population, 
based on OCs.
Subgroup Analysis for Efficacy
Subgroup analysis will be performed on co-primary endpoints in Period A using the following subgroups:

Age group:  < 40, ≥40 to < 65, ≥65

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 PASI score (by median)

Psoriatic arthritis (yes, no)

Prior systemic treatment (0, ≥1)
Age ≥65 years or BMI ≥30 subgroups will be combined with their adjacent subgroup when having fewer 
than 10% subjects.
7.5 Statistical Analyses for Safety
All safety analyses will be performed among the Safety Populations.  Subjects will be analyzed based on 
the first dose of treatment received after randomization or re-randomization.  A treatment-emergent 
adverse event (TEAE) in each analysis period is defined as follows:
A TEAE in Period A is defined as any AE with an onset date on or after the first dose of study drug in 
Period A and 
1.
within the minimum of 140 days after the last dose of RZB in Period A and first dose of study 
drug in Period B for subjects who receive RZB at Baseline and
2.
within the minimum of 28 days after the last dose of APR in Period A and first dose of study drug 
in Period B for subjects who receive APR at Baseline.
A TEAE in Period B is defined as any AE with an onset date on or after the first dose of study drug in 
Period B and 
1.
within 140 days after the last dose of RZB in Period B for subjects who receive RZB in Period B 
and
2.
within the minimum of 28 days after the last dose of APR in Period B, first dose of rescue 
risankizumab (if any) for subjects who receive APR in Period B.
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A TEAE during the administration of rescue risankizumab is defined as any AE with an onset date on or 
after the first dose of rescue risankizumab and within 140 days after the last dose of rescue 
risankizumab.
A TEAE during the administration of risankizumab (i.e., among the ALL_RZB Population) is defined as any 
AE with an onset date on or after the first dose of RZB and within 140 days after the last dose of RZB.
The number and percentage of subjects experiencing TEAEs will be tabulated using the Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term, by severity, and 
by relationship to the study drug as assessed by the investigator.  Summaries (including percentages and 
events per 100 PYs) of SAEs, deaths, and AEs leading to discontinuation of study drug will be provided as 
well. Pre-treatment SAEs will be summarized separately.
For selected lab parameters, a listing of all subjects with any laboratory value that is above Grade 3 of 
Common Toxicity Criteria will be provided. Mean change in laboratory and vital signs variables will be
summarized. Additional details for the safety analysis are provided in the SAP.
7.6 Interim Analysis
No interim analysis is planned for this study.
7.7 Overall Type I Error Control
Overall type-I error for Period A will be controlled by testing the co-primary endpoints, followed by the 
ranked and only secondary endpoint, in a hierarchical order as described in Section 3.2 and Section 3.3.
Overall type-I error for Period B will be controlled 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
This study plans to enroll a total of N = 330 subjects, to be sufficiently powered to detect the treatment 
difference between RZB and APR with respect to the co-primary endpoints in Period A, as well as 
between APR/RZB and APR/APR with respect to the primary endpoint in Period B:

Assuming that 50% of APR-PASI75NR subjects in the APR/RZB group and 20% of APR-PASI75NR 
subjects in the APR/APR group will achieve PASI 90 at Week 52 in Period B, the sample size of 
120 re-randomized APR-PASI75NR subjects (60 subjects per group) will have more than 90%
power to detect the treatment difference between APR/RZB and APR/APR, using a Chi-square 
test with a 2-sided significance level of 0.05.

Assuming 55% of subjects initially randomized to APR will be re-randomized at Week 16 under 
the APR-PASI75NR (as defined by the PASI 75 response at Week 16) stratum, the total sample 
size for the initial APR group is 120/55% = 220.  Assuming the treatment difference is at least 
40% with respect to the co-primary endpoints of PASI 90 and sPGA of 0 or 1 at Week 16 in 
Period A, the total sample size of N = 330 subjects (RZB:  110, APR:  220) will also provide more 
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than 90% power to detect the treatment difference between RZB and APR, using a Chi-square 
test with a 2-sided significance level of 0.05.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
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).
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 and geo-political conflict in Ukraine and surrounding 
impacted regions, remote monitoring of data may be employed if allowed by the local regulatory 
authority, IRB/IEC, and the study site.
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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
START AND COMPLETION OF THE STUDY
The start-of-study is defined as the date of the first site activated.
The end-of-study is defined as the date of end of study participation by the last subject in the last 
country where the study was conducted.
12
REFERENCES
1.
World Health Organization. Global report on psoriasis. Geneva, Switzerland: WHO; 2016 [cited 2017 
Sep 17]. Available from: http://apps.who.int/iris/handle/10665/204417.
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.
6.
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.
7.
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.
8.
AbbVie. Risankizumab Investigator's Brochure Edition 6. 11 May 2020.
9.
Warren RB, Blauvelt A, Poulin Y, et al. Efficacy and safety of risankizumab vs. secukinumab in 
patients with moderate-to-severe plaque psoriasis (IMMerge): results from a phase III, randomized, 
open-label, efficacy-assessor-blinded clinical trial. Br J Dermatol. 2021;184(1):50-9.
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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
10. 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.
11. O'Garra A, Redford PS, McNab FW, et al. The immune response in tuberculosis. Annu Rev Immunol. 
2013;31:475-527.
12. 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.
13. 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.
14. 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.
15. Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 
2006;442(7101):461-5.
16. AbbVie. Data on File, RRT165055.
17. Otezla (apremilast) [US Prescribing Information]. Thousand Oaks, CA: Amgen Inc.; 2020.
18. Agency EM. Otezla (apremilast) [SmPC]. Thousand Oaks, CA: Amgen Inc.; 2020.
19. US Department of Health and Human Services NIoH, National Cancer Institute. Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 2017 [cited 10 Feb 2020]. Available 
from: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refer
ence_8.5x11.pdf.
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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AAC
Anaphylaxis Adjudication Committee
Ab
Antibody
ADA
Antidrug antibody
AE
Adverse event
ALL_RZB
All risankizumab treated population
ALT
Alanine aminotransferase/transaminase
APR
Apremilast
APR-PASI75NR
Apremilast PASI75 non-responders
APR-PASI75R
Apremilast PASI75 responders
ASI
Areas of safety interest/adverse events of safety interest
AST
Aspartate aminotransferase/transaminase
BCG
Bacille Calmette-Guérin
BID
Twice daily
BMI
Body mass index
BSA
Body surface area
CAC
Cardiovascular Adjudication Committee
CBC
Complete blood count
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus disease of 2019
CTCAE
Common Terminology Criteria for Adverse Events
DLQI
Dermatology Life Quality Index
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
FSH
Follicle-stimulating hormone
GCP
Good clinical practice
HB
Hepatitis B
HBV
Hepatitis B virus
HCV
Hepatitis C virus
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
HIV
Human immunodeficiency virus
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-23
Interleukin-23
IMP
Investigational Medicinal Product
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent to treat
ITT_A
Intent to Treat Population in Period A
ITT_B_Combined
Intent to Treat Population for Period B combined Population
ITT_LT
Intent to Treat Population for Long-term Efficacy
ITT_Res
Intent to Treat Population for Rescued Population
MACE
Major adverse cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effect Model Repeat Measurement
nAb
Neutralizing antibody
NAPSI
Nail Psoriasis Severity Index
NCI
National Cancer Institute
NMSC
Non-melanoma skin cancer
NRI-MI
Non-Responder Imputation incorporating multiple imputation
OC
Observed case
PASI
Psoriasis Area and Severity Index
PCR
Polymerase chain reaction
PD
Premature Discontinuation
PFS
Pre-filled syringe
PK
Pharmacokinetic(s)
PPD
Purified protein derivative (tuberculin)
ppIGA
Palmoplantar Investigator's Global Assessment
PRO
Patient-reported outcome
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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
PsA
Psoriatic arthritis
PsO
Psoriasis
PSS
Psoriasis Symptoms Scale
PSSI
Psoriasis Scalp Severity Index
PT
Preferred term
PY
Patient year
q12w
Every 12 weeks
QTcF
QT interval corrected for heart rate using Fridericia's formula
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 Global Assessment
SUSAR
Suspected unexpected serious adverse reactions
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
TEAE
Treatment emergent adverse event
TSQM-9
Treatment Satisfaction Questionnaire for Medication version 9
ULN
Upper limit of normal
US
United States
WPAI
Work Productivity and Activity Impairment
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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M20-326:  A Phase 4 Multicenter, Randomized, Open-label, Efficacy Assessor-blinded Study of 
Risankizumab Compared to Apremilast for the Treatment of Adult Subjects with Moderate Plaque Psoriasis who 
are Candidates for Systemic Therapy
Protocol Date:  10 November 2022
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and local laws and 
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, (within 1 calendar day) to AbbVie, the ethics committees/institutional review boards 
(as required) and other appropriate individuals (e.g., coordinating investigator, institution director): 

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated
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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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Therapeutic Area Medical Director
Medical Affairs, Immunology
Director, Statistics
Data and Statistical Sciences
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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
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 
are described in detail in the Operations Manual.  Allowed modifications due to COVID-19 and/or the 
geo-political conflict in Ukraine and surrounding impacted regions are detailed within the Operations 
Manual.
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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
BSA = body surface area; CBC= complete blood count; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IGRA = interferon gamma release assay; IRT = interactive response technology; NAPSI = Nail Psoriasis Severity Index; PASI = Psoriasis Area and Severity 
Index; PPD = purified protein derivative (tuberculin); ppIGA = Palmoplantar Investigator's Global Assessment; PSSI = Psoriasis Scalp Severity Index; SARS-CoV-2 = Severe acute 
respiratory syndrome coronavirus 2; sPGA = static Physician Global Assessment; TB = tuberculosis; US = United States
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STUDY M20-326  |  Version 2.0  |  EudraCT 2020-005512-21
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
29 March 2021
Administrative Change 1
15 April 2021
Administrative Change 2
17 February 2022
The purpose of Protocol Version 2.0 is to capture Administrative Changes 1 and 2, and update text for 
Primary Analysis for Period B. Administrative Change 1, which changed the study phase from Phase 4 to 
Phase 3b, was not incorporated into Protocol Version 2.0. The study drug, risankizumab 150 mg/ml, has 
now been approved in all study countries, and the study phase is re-confirmed as Phase 4.
Protocol Version 2.0 also incorporates necessary protocol modifications in the protocol template and 
new safety information as follows:
Protocol

Text was updated throughout the Protocol to align with revisions in the protocol template and 
changes due to new safety information available.

Protocol sections include:  Section 2.2, Section 4.1, Section 5.1, Section 5.4, Section 5.5, 
Section 5.6, Section 6.1, Section 9, Section 11, Appendix B, Appendix C, Appendix D, and
Appendix E.

Protocol Section 7.1: added the interim lock for primary analysis for Period B.

Administrative Change 2: Update the Sponsor/Emergency Medical Contact information to 
 as Sponsor/Emergency Medical Contact.

Rationale:  Reflects a change in the Sponsor/Emergency Medical Contact for the study.
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.

Operations Manual sections include:  Section 1, Section 2.1, Section 3.1, Section 3.12, 
Section 3.13, Section 4.1, Section 4.3, Section 6.3, and Section 8.7.

Administrative Change 2: Update the Sponsor/Emergency Medical Contact information to 
 as Sponsor/Emergency Medical Contact.

Rationale:  Reflects a change in the Sponsor/Emergency Medical Contact for the study.
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SAP_001.pdf: 
Risankizumab
M20-326 – Statistical Analysis Plan
Version 3.0 –
1
Statistical Analysis Plan for Study M20-326
Plaque Psoriasis: A Phase 4 Multicenter, 
Randomized, Open-label, Efficacy Assessor-blinded-
Study of Risankizumab Compared to Apremilast for 
the Treatment of Adult Subjects with Moderate 
Plaque Psoriasis who are Candidates for Systemic 
Therapy
Date:  26 February 2023
Version 3.0
 
NCT04908475


Risankizumab
M20-326 – Statistical Analysis Plan
Version 3.0 –
2
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.......................................................................... 8
2.3
Treatment Assignment and Blinding....................................................... 9
2.4
Sample Size Determination .................................................................. 10
3.0
Endpoints.............................................................................11
3.1
Primary Endpoints................................................................................ 11
3.2
Secondary Endpoints............................................................................ 11
3.3
Other Efficacy Endpoints ..................................................................... 12
3.4
Safety Endpoints .................................................................................. 13
3.5
Additional Endpoints............................................................................ 13
4.0
Analysis Populations ...........................................................13
5.0
Subject Disposition..............................................................15
6.0
Study Drug Duration and Compliance ..............................16
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................17
7.1
Demographics and Baseline Characteristics.......................................... 17
7.2
Medical History.................................................................................... 18
7.3
Prior and Concomitant Medications...................................................... 18
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints ............................19
9.0
Efficacy Analyses.................................................................20
9.1
General Considerations......................................................................... 20
9.2
Handling of Missing Data..................................................................... 22
9.2.1
Categorical Endpoints .......................................................................... 23
9.2.2
Continuous Endpoints .......................................................................... 24
9.3
Primary Efficacy Endpoints and Analyses ............................................ 25
9.3.1
Primary Efficacy Endpoints.................................................................. 25
9.3.2
Main Analysis of Primary Efficacy Endpoints ...................................... 26
 


Risankizumab
M20-326 – Statistical Analysis Plan
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3
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoints ............................................................................................. 28
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 28
9.4.1
Key Secondary Efficacy Endpoints....................................................... 28
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints .......................... 28
9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints ............................................................................... 30
9.5
Additional Efficacy Analyses ............................................................... 30
9.6
Efficacy Subgroup Analyses................................................................. 30
10.0
Safety Analyses....................................................................31
10.1
General Considerations......................................................................... 31
10.2
Adverse Events..................................................................................... 31
10.2.1
Treatment-Emergent Adverse Events.................................................... 31
10.2.2
Adverse Event Overview...................................................................... 32
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 33
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 33
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 35
10.2.6
Safety Topics of Interest....................................................................... 35
10.3
Analysis of Laboratory Data................................................................. 36
10.4
Analysis of Vital Signs......................................................................... 38
10.5
Safety Subgroup Analyses.................................................................... 38
10.6
Other Safety Analyses .......................................................................... 38
11.0
Other Analyses ....................................................................38
12.0
Interim Analyses..................................................................39
12.1
Data Monitoring Committee................................................................. 39
13.0
Overall Type-I Error Control.............................................39
14.0
Version History ...................................................................40
15.0
References............................................................................40
 


Risankizumab
M20-326 – Statistical Analysis Plan
Version 3.0 –
4
List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoints ............................................................................................. 27
Table 2.
Summary of the Estimand Attributes of the Key Secondary 
Efficacy Endpoints ............................................................................... 29
Table 3.
SAP Version History Summary ............................................................ 40
List of Figures
Figure 1.
Study Schematic..................................................................................... 9
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 41
Appendix B.
Definition of Safety Topics of Interest.................................................. 42
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 43
Appendix D.
Non-Responder Imputation Incorporating Multiple Imputation to 
Handle Missing Data Due to COVID-19 Pandemic for 
Dichotomized Outcome Variables ........................................................ 45
 


Risankizumab
M20-326 – Statistical Analysis Plan
Version 3.0 –
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for risankizumab 
Study M20-326, Plaque Psoriasis: A Phase 4 Multicenter, Randomized, Open-label, 
Efficacy Assessor-blinded-Study of Risankizumab Compared to Apremilast for the 
Treatment of Adult Subjects with Moderate Plaque Psoriasis who are Candidates for 
Systemic Therapy.
Study M20-326 examines the efficacy and safety of risankizumab in adult subjects with 
moderate plaque psoriasis who are candidates for systemic therapy.
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 objective of the study is to evaluate the efficacy and safety of risankizumab (RZB) 
versus apremilast (APR) for the treatment of adult subjects with moderate plaque psoriasis 
(PsO) who are candidates for systemic therapy.
In addition, the study aims to evaluate the efficacy and safety of switching to RZB versus 
continuing on APR for subjects with moderate plaque PsO who do not achieve PASI 75 
(defined as ≥75% reduction from Baseline in Psoriasis Area and Severity Index [PASI]) 
after 16 weeks of treatment with APR.
Primary Efficacy Objective:
The primary efficacy objective in Period A is to demonstrate a higher rate of a) PASI 90 
(defined as ≥90% reduction from Baseline in PASI) and b) static Physicians Global 
 


Risankizumab
M20-326 – Statistical Analysis Plan
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Assessment (sPGA) 0 or 1 with at least 2-grade improvement from Baseline after
16 weeks of treatment with RZB when compared to APR based on Intent to Treat (ITT) 
Population in Period A (ITT_A), which consists of all randomized subjects.
The hypotheses corresponding to the co-primary efficacy objective and endpoints in 
Period A are:
●
The proportion of subjects achieving PASI 90 in the RZB group is greater than 
that in the APR group at Week 16, among the ITT_A Population.
●
The proportion of subjects achieving sPGA 0 or 1 with at least 2-grade 
improvement from Baseline in the RZB group is greater than that in the APR 
group at Week 16, among the ITT_A Population.
The estimands corresponding to the co-primary efficacy objectives in Period A are
defined as follows:
●
Difference in the percentage of subjects achieving PASI 90 at Week 16 without 
receiving alternative PsO treatment regardless of premature discontinuation of 
study drug, in the RZB group in comparison to the APR group among the 
ITT_A population, and
●
Difference in the percentage of subjects achieving sPGA of 0 or 1 with at least 
two grades of reduction from Baseline at Week 16 without receiving alternative 
PsO treatment regardless of premature discontinuation of study drug, in the 
RZB group in comparison to the APR group among the ITT_A population.
The primary efficacy objective in Period B is to demonstrate a higher rate of PASI 90 
after switching the treatment at Week 16 from APR to RZB for 36 weeks (APR/RZB) 
when compared to continuing with APR (APR/APR) based on the Intent to Treat 
Population in Period B for Week 16 APR-PASI75NRs (ITT_B_NR), which consists of 
subjects randomized to APR at Baseline, failed to achieve PASI 75 at Week 16 and are 
re-randomized.
The hypothesis corresponding to the primary objective and endpoint in Period B is:
 


Risankizumab
M20-326 – Statistical Analysis Plan
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7
●
The proportion of APR-PASI75NR subjects achieving PASI 90 in the 
APR/RZB group is greater than that in the APR/APR group at Week 52, among 
the ITT_B_NR Population.
The estimand corresponding to the primary efficacy objective in Period B is defined as 
follows:
●
Difference in the percentage of subjects achieving PASI 90 at Week 52 without 
satisfying the rescue criteria or receiving the rescue medication, and without 
receiving alternative PsO treatment regardless of premature discontinuation of 
study drug, in the APR/RZB group in comparison to the APR/APR group 
among the ITT_B_NR population
Key Secondary Efficacy Objective:
The key secondary efficacy objective in Period A is to demonstrate higher efficacy of 
treatment with RZB when compared to APR with respect to the ranked and only 
secondary endpoint in Period A among the ITT_A Population, as specified in Section 3.2
below.
The hypothesis corresponding to the ranked and only secondary efficacy objective and
endpoint in Period A is:
●
The proportion of subjects achieving PASI 75 in the RZB group is greater than 
that in the APR group at Week 16, among the ITT_A Population.
The estimand corresponding to the ranked and only secondary efficacy objective in 
Period A is defined as follows:
●
Difference in the percentage of subjects achieving PASI 75 from Baseline at 
Week 16 without receiving alternative PsO treatment, regardless of premature 
discontinuation of study drug, in the RZB group in comparison to the APR
group among the ITT_A population.
 


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The key secondary efficacy objectives in Period B are to demonstrate higher efficacy of 
treatment with APR/RZB when compared to APR/APR among the ITT_B_NR 
Population, with respect to the key secondary endpoints in a ranked order in Period B, as 
specified in Section 3.2 below.
The hypotheses corresponding to the ranked secondary efficacy objective and endpoints in 
Period B are:
●
The proportion of APR-PASI75NR subjects achieving PASI 75 in the 
APR/RZB group is greater than that in the APR/APR group at Week 52, among 
the ITT_B_NR Population.
●
The proportion of APR-PASI75NR subjects achieving sPGA 0 or 1 with at 
least 2-grade improvement from Baseline in the APR/RZB group is greater than 
that in the APR/APR group at Week 52, among the ITT_B_NR Population.
The estimands corresponding to the ranked secondary efficacy objectives in Period B are
defined as follows:
●
Difference in the percentage of subjects achieving PASI 75 at Week 52 without 
satisfying the rescue criteria or receiving the rescue medication, and without 
receiving alternative PsO treatment regardless of premature discontinuation of 
study drug, in the APR/RZB group in comparison to the APR/APR group 
among the ITT_B_NR population, and
●
Difference in the percentage of subjects achieving sPGA of 0 or 1 with at least 
two grades of reduction from Baseline at Week 52 without satisfying the rescue 
criteria or receiving the rescue medication, and without receiving alternative 
PsO treatment regardless of premature discontinuation of study drug in the 
APR/RZB group in comparison to the APR/APR group among the ITT_B_NR
population.
2.2
Study Design Overview
The schematic of the study is shown in Figure 1.
 


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M20-326 – Statistical Analysis Plan
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Figure 1.
Study Schematic
BID = twice daily; PASI = Psoriasis Area Severity Index; SC = subcutaneous
2.3
Treatment Assignment and Blinding
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.
In Period A (Baseline to Week 16), subjects will be centrally randomized to risankizumab 
(Arm 1) or apremilast (Arm 2) in a 1:2 ratio at Baseline.  Randomization will be stratified 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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by Baseline body weight (≤ 100 kg, > 100 kg) and prior exposure to any systemic and/or 
biologic treatment for Po (0, ≥ 1).
In Period B (Week 16 to Week 52), subjects initially randomized to risankizumab (Arm 1) 
will continue to receive risankizumab.  Subjects initially randomized to apremilast 
(Arm 2) will be centrally re-randomized at the Week 16 visit in a 1:1 ratio to receive 
either risankizumab (Arm 2a) or apremilast (Arm 2b).  Re-randomization will be stratified 
by PASI 75 response (responder, non-responder) at Week 16.  Rescue risankizumab will 
be offered to subjects who are re-randomized to apremilast (Arm 2b) and are PASI 50 
non-responders at Week 28 (Arm 3a) or Week 40 (Arm 3b).
This is an open-label study; however, the efficacy assessor will remain blinded to each 
subject's treatment, clinical laboratory results, and all subject safety data during the course 
of the study.
2.4
Sample Size Determination
This study plans to enroll a total of N = 330 subjects, to be sufficiently powered to detect 
the treatment difference between risankizumab (RZB) and apremilast (APR) with respect 
to the co-primary endpoints in Period A, as well as between APR/RZB and APR/APR 
with respect to the primary endpoint in Period B:
●
Assuming that 50% of APR-PASI75NR subjects in the APR/RZB group and 
20% of APR-PASI75NR subjects in the APR/APR group will achieve PASI 90 
at Week 52 in Period B, the sample size of 120 re-randomized APR-PASI75NR 
subjects (60 subjects per group) will have more than 90% power to detect the 
treatment difference between APR/RZB and APR/APR, using a Chi-square test 
with a 2-sided significance level of 0.05.
●
Assuming 55% of subjects initially randomized to APR will be re-randomized 
at Week 16 under the APR-PASI75NR (as defined by the PASI 75 response at 
Week 16) stratum, the total sample size for the initial APR group is 
120/55% = 220.  Assuming the treatment difference is at least 40% with respect 
to the co-primary endpoints of PASI 90 and sPGA of 0 or 1 at Week 16 in 
Period A, the total sample size of N = 330 subjects (RZB: 110, APR: 220) will 
 


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also provide more than 90% power to detect the treatment difference between 
RZB and APR, using a Chi-square test with a 2-sided significance level of 0.05.
3.0
Endpoints
3.1
Primary Endpoints
The co-primary endpoints of this study in Period A are:
●
Achievement of PASI 90 at Week 16, among subjects in the ITT_A Population.
●
Achievement of sPGA 0 or 1 with at least 2-grade improvement from Baseline 
at Week 16, among subjects in the ITT_A Population.
The primary endpoint of this study in Period B is:
●
Achievement of PASI 90 at Week 52, among subjects in the ITT_B_NR 
Population.
3.2
Secondary Endpoints
The ranked and only secondary endpoint of this study in Period A is:
1.
Achievement of PASI 75 at Week 16, among subjects in the ITT_A Population.
The ranked secondary endpoints of this study in Period B are:
1.
Achievement of PASI 75 at Week 52, among subjects in the ITT_B_NR 
Population.
2.
Achievement of sPGA 0 or 1 with at least 2-grade improvement from Baseline at 
Week 52, among subjects in the ITT_B_NR Population.
 


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3.3
Other Efficacy Endpoints
All variables listed in Section 3.1 and Section 3.2 as primary or ranked secondary 
endpoints will also be analyzed at all other visits collected.  Additionally, the following 
endpoints will be evaluated at all visits collected:
●
Achievement of 100% reduction from Baseline in PASI (PASI 100)
●
Achievement of sPGA 0
●
Change from Baseline in PASI
●
Percent change from Baseline in PASI
●
Change from Baseline in body surface area (BSA)
●
Achievement of Palmoplantar Investigator's Global Assessment (ppIGA) 0 or 
1, among subjects with Baseline ppIGA of at least 3
●
Change from Baseline in Psoriasis Scalp Severity Index (PSSI), among subjects 
with Baseline scores > 0
●
Change from Baseline in Nail Psoriasis Severity Index (NAPSI), among 
subjects with Baseline scores > 0
●
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
●
Change from Baseline in Work Productivity and Activity Impairment (WPAI) 
scores
●
Treatment Satisfaction Questionnaire for Medication version 9 (TSQM-9) 
scores (at each post-Baseline visit in Period A)
●
Change from Entry of Period B in TSQM-9 scores, among subjects who are re-
randomized at Week 16
●
Change from Baseline in Psoriasis Symptoms Scale (PSS) scores
●
Percentage change from Baseline in PSS, among subjects with baseline scores 
> 0
●
Achievement of PSS 0
 


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●
Achievement of PSS 0 or 1
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 (hematology and chemistry)
3.5
Additional Endpoints
Not applicable.
4.0
Analysis Populations
The following analysis populations will be used for the analyses.
The Intent to Treat Population in Period A (ITT_A) includes all randomized subjects.  The 
ITT_A Population will be used for all efficacy analyses in Period A.
The Intent to Treat Population for APR-PASI75NRs in Period B (ITT_B_NR) includes 
subjects randomized at Baseline (Day 1), fail to achieve PASI 75 at Week 16 and are re-
randomized.  The ITT_B_NR Population will be used for the analysis comparing switch-
to-RZB (APR/RZB) vs. continue-with-APR (APR/APR) among APR-PASI75NRs in 
Period B.
The Intent to Treat Population for APR-PASI75 responders in Period B (ITT_B_R) 
includes subjects randomized to APR at baseline, achieve PASI 75 at Week 16 and are re-
randomized (APR-PASI75Rs).  The ITT_B_R Population will be used for the summary of 
efficacy for APR/RZB and APR/APR among APR-PASI75Rs in Period B.
 


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The Intent to Treat Population for Period B combined Population (ITT_B_Combined) 
includes subjects randomized to APR at Baseline and are re-randomized at Week 16.  The 
ITT_B_Combined Population will be used for combined analysis (APR-PASI75NRs and 
APR-PASI75Rs) between subjects re-randomized to APR/RZB and APR/APR in 
Period B.
The Intent to Treat Population for Long Term Efficacy (ITT_LT) includes subjects 
randomized to receive continuous RZB (i.e., all subjects randomized to RZB at Baseline) 
and subjects randomized and re-randomized to receive continuous APR, including half of 
the subjects randomized to APR at Baseline and prematurely discontinued from study 
before entering Period B. The ITT_LT Population will be used for the analysis comparing
long term efficacy between continuous treatment of RZB/RZB and APR/APR in 
Period B. Of note, the algorithm to select half of the subjects randomized to APR at 
Baseline and prematurely discontinued from study before entering Period B is defined as 
follow:
1.
Rank all such subjects by their subject ID in ascending order (as 1, 2, 3...).
2.
Select subjects whose ranks are even numbers.
The Intent to Treat Population for Rescued Population (ITT_Res) includes subjects who 
are re-randomized to APR at Week 16, fail to achieve PASI 50 at Week 28 and/or
Week 40, and receive RZB as the rescue medication.  The ITT_Res Population will be 
used for the summary of efficacy after being rescued with RZB.
Each ITT Population will have a corresponding Safety Population, consists of subjects 
who received at least one dose of study drug during the specific Study Period.  In 
addition, an all risankizumab treated (ALL_RZB) Population will be utilized for a 
comprehensive safety summary of RZB.  The ALL_RZB Population is defined as all 
subjects who receive at least one dose of RZB as the study drug.
 


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5.0
Subject Disposition
A summary of subject disposition in Period A will be provided among the ITT_A 
Population, where the number of subjects in each of the following categories will be 
summarized for each treatment group:
●
Subjects randomized in the study;
●
Subjects who took at least one dose of study drug in Period A;
●
Subjects who completed protocol-specified treatment in Period A;
●
Subjects who prematurely discontinued study drug in Period A (by reasons);
●
Subjects who completed Period A
Summaries of subject disposition in Period B will be provided among the ITT_B_R and 
the ITT_B_NR Populations, as well as the RZB group in the ITT_LT Population, where 
the number of subjects in each of the following categories will be summarized for each 
treatment group:
●
Subjects re-randomized in Period B (or Subjects who entered Period B among 
the ITT_LT Population);
●
Subjects who took at least one dose of study drug in Period B;
●
Subjects who received RZB as the rescue medication (not applicable to the 
ITT_LT Population);
●
Subjects who completed protocol-specified treatment in Period B;
●
Subjects who prematurely discontinued study drug in Period B (by reasons);
●
Subjects who completed the study.
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.
 


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6.0
Study Drug Duration and Compliance
Duration of treatment will be summarized by treatment groups among the Safety_A, 
Safety_B_R, Safety_B_NR, and Safety_Res Populations as well as the RZB group in the 
Safety_LT Population.  In addition, duration of any RZB will be summarized among the 
ALL_RZB Population.
The duration of RZB 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 for Period A + 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 for Period B + 1 day]) minus 
the first dose date in Period B.
Rescue RZB:  the minimum of (the last dose date of rescue risankizumab + 84 days, the 
end of study date +1 day [and cutoff date during the Primary Analysis for Period B + 1 
day]) minus the first dose date of rescue risankizumab.
ALL_RZB:  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 for Period B + 1 day]) 
minus the first dose date of risankizumab.
The duration of APR for each period is defined as follows:
Period A:  the minimum of (the last dose date in Period A + 1 day, 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 for Period A + 1 day]) minus the first dose date in Period A.
Period B:  the minimum of (the last dose date in Period B + 1 day, the start date of rescue 
RZB if applicable, and the end of study date + 1 day [and cutoff date during the Primary 
Analysis for Period B + 1 day]) minus the first dose date in Period B.
 


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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_A, 
Safety_B_R, Safety_B_NR, and Safety_Res Populations as well as the RZB group in the 
Safety_LT Population.
The compliance for RZB will be summarized by the percentage of planned injections 
which are administered in each analysis period.  The compliance for APR will be 
summarized by the number of APR tablets actually taken (i.e., the difference between the 
number of tablets dispensed and the number of tablets returned) by the subject divided by 
the number of tablets planned to be taken by the subject in each analysis period.  When 
computing the compliance 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.  For subjects who prematurely discontinued the study drug, the planned 
injections/tablets will only be counted prior to that scheduled visit of discontinuation. For 
subjects who are rescued, the planned APR tablets will only be counted prior to the first 
dose date of rescue RZB.
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).
 


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Baseline disease characteristics include history of psoriatic arthritis (yes, no), Baseline 
ppIGA categories, Baseline sPGA categories, Baseline PASI, Baseline NAPSI, Baseline 
PSSI, Baseline BSA, Baseline WPAI, Baseline PSS and Baseline DLQI.
Demographics and baseline disease characteristics will be summarized among the ITT_A,
ITT_B_R, ITT_B_NR, and ITT_Res Populations, 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 group. The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC. Subjects reporting more than one condition/diagnosis will be 
counted only once in each row (SOC or preferred term).
Medical history will be summarized among the ITT_A, ITT_B_R, and ITT_B_NR
Populations.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name. A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug. A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the minimum of {the date of the last dose of RZB plus 140 days, the date of the last 
 


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dose of APR plus 28 days}. The number and percentage of subjects taking medications 
will be summarized by generic drug name based on the World Health Organization 
(WHO) Drug Dictionary for both prior and concomitant medications.
In addition, subjects' prior biologic therapy for psoriasis will also be summarized by the 
reason for discontinuation.
Prior and concomitant medications will be summarized among the ITT_A, ITT_B_R, and 
ITT_B_NR Population as well as the RZB group in the ITT_LT Population.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
The primary efficacy endpoints (defined in Section 3.1) and the ranked secondary 
endpoint (defined in Section 3.2) in Period A will be analyzed in the ITT_A Population 
and the following method will be used to address the potential intercurrent event:
●
Subjects who receive alternative PsO treatment regardless of premature 
discontinuation of study drug before Week 16 will be counted as non-
responders. 
The primary efficacy endpoint (defined in Section 3.1) and ranked secondary endpoints
(defined in Section 3.2) in Period B will be analyzed in the ITT_B_NR Population and the 
following method will be used to address the potential intercurrent events:
●
Subjects who receive alternative PsO treatment regardless of premature 
discontinuation of study drug before Week 52 will be counted as non-
responders.
●
Subjects who satisfy rescue criteria or receive the rescue medication at 
Week 28 or Week 40 will be counted as non-responders.
 


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9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted among the ITT Population in each analysis period.
All tests will be 2-sided at an alpha level of 0.05.
The Primary Analysis for Period A will be performed after all ongoing subjects have 
completed Week 16 and all data pertaining to Period A are cleaned. This will be the only 
and final analysis for efficacy in Period A.
The Primary Analysis for Period B will be performed after all ongoing subjects have 
completed Week 52 and all data pertaining to Period B are cleaned. This will be the only 
and final analysis for efficacy in Period B.
The final analysis will be performed upon study completion.
Categorical Endpoints:
For categorical endpoints, the number and proportion of subjects who achieved the 
endpoint, as well as the 95% confidence interval (CI) of that proportion, will be provided 
by each treatment group among all ITT Populations. 
In addition, comparisons between treatment groups will be made in the following 
analyses, with the estimated treatment difference, as well as the corresponding 95% CI 
and the p-value provided among the following populations:
●
ITT_A Population: Comparisons in Period A will be made between RZB and 
APR using the Cochran-Mantel-Haenszel (CMH) test, adjusting for the actual 
values of stratification factors at Baseline: Baseline body weight (≤ 100 kg, 
> 100 kg) and prior exposure to any systemic and/or biologic treatment for 
psoriasis (0, ≥ 1). In case of any stratum with zero subject in either treatment 
group, no stratification factor will be controlled.
●
ITT_B_NR Population: Comparisons in Period B will be made between 
APR/RZB and APR/APR using the chi-square test.
 


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●
ITT_B_Combined Population: Comparisons in Period B will be made between 
APR/RZB and APR/APR using the CMH test, adjusting for the actual values of 
the stratification factor of re-randomization: PASI 75 response status at Week 
16 (Yes/No).  In case of any stratum with zero subject in either treatment 
group, no stratification factor will be controlled.
●
ITT_LT Population: Comparisons in Period B will be made between RZB/RZB 
and APR/APR using the Cochran-Mantel-Haenszel (CMH) test, adjusting for 
the actual values of stratification factors at Baseline: Baseline body weight 
(≤100 kg, > 100 kg) and prior exposure to any systemic and/or biologic 
treatment for psoriasis (0, ≥ 1). In case of any stratum with zero subject in 
either treatment group, no stratification factor will be controlled.
Continuous Endpoints:
For continuous endpoints, the Baseline mean, visit mean, as well as the Least Square (LS) 
mean, 95% confidence interval (CI) and Standard Error (SE) of that mean, will be 
provided by each treatment group among all ITT Populations.
In addition, comparisons between treatment groups will be made in the following 
analyses, with the estimated treatment difference, as well as the corresponding 95% CI, 
SE and the p-value will be provided among the following populations:
●
ITT_A Population: Comparisons in Period A will be made between RZB and 
APR 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 at Baseline, visit and treatment-
by-visit interaction as covariates.
●
ITT_B_NR Population: Comparisons in Period B comparisons will be made 
between APR/RZB and APR/APR 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 after 
Entry of Period B, adjusting for the fixed effects of treatment, visit and 
treatment-by-visit interaction as covariates.
 


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●
ITT_Combined Population: Comparisons in Period B comparisons will be 
made between APR/RZB and APR/APR 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 after 
Entry of Period B, adjusting for the fixed effects of treatment, actual values of 
stratification factor at re-randomization, visit and treatment-by-visit interaction
as covariates.
●
ITT_LT Population: Comparisons in Period B comparisons will be made 
between RZB/RZB and APR/APR 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 after 
Entry of Period B, adjusting for the fixed effects of treatment, actual values of 
stratification factor at Baseline, visit and treatment-by-visit interaction as 
covariates.
"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.
"Entry of Period B" refers to the last non-missing observation on or before:
●
The first dose date on or after re-randomization, or the date of re-randomization 
if no study drug is administered in Period B, for subjects who are randomized 
to APR at Baseline.
●
The first dose date on or after Week 16, or the first visit date on or after 
Week 16 if no study drug is administered in Period B, for subjects who are 
randomized to RZB at Baseline.
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.
 


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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.  
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-MI) will be the approach for handling missing data in the 
analysis of categorical endpoints among all ITT Populations except for the ITT_Res 
Population.  The NRI-MI 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 receive alternative PsO treatment regardless of premature discontinuation of 
study drug or receive RZB as the rescue medication 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 D.
 


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Of note, during the Primary Analysis for Period A upon completion of Week 16, the 
NRI-MI analysis will only be performed at all visits up to Week 16.
Observed Cases (OC) will be the approach for handling missing data in the analysis of 
categorical endpoints among the ITT_Res Population.  The OC analysis will not impute 
values for missing evaluations, and thus a subject who does not have an evaluation on a 
scheduled visit will be excluded from the OC analysis for that visit.  OC will exclude 
values after a subject receive alternative PsO treatment regardless of premature 
discontinuation of study drug.
9.2.2
Continuous Endpoints
Mixed-Effect Model Repeat Measurement (MMRM) will be the primary and only 
approach to handle missing data for continuous endpoints among all ITT Populations 
except for the ITT_Res Population.  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 (but not all) post-baseline visits during the analysis period.  Subjects' 
observations after the use of alternative PsO treatment regardless of premature 
discontinuation of study drug or after the use of RZB as the rescue medication 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.
●
Comparison of additional endpoints among the ITT_A and ITT_LT Populations
will be made adjusting for treatment, visit and treatment-by-visit interaction, 
actual values of stratification factors at Baseline, and baseline value (if not 
duplicating the stratification factors).
●
Comparison of additional endpoints among the ITT_B_NR Population will be 
made adjusting for treatment, visit and treatment-by-visit interaction and 
baseline value.
 


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●
Comparison of additional endpoints among the ITT_B_Combined Population 
will be made adjusting for treatment, visit and treatment-by-visit interaction, 
actual values of stratification factors at re-randomization, and baseline value (if 
not duplicating the stratification factors).
●
Summary statistics will be provided for additional endpoints among the 
ITT_B_R Population, adjusting for treatment, visit and treatment-by-visit 
interaction and baseline value.
Of note, during the Primary Analysis for Period A upon completion of Week 16, the 
MMRM analysis will only be performed at all visits up to Week 16.
Observed Cases (OC) will be the approach for handling missing data in the analysis of 
continuous endpoints among the ITT_Res Population: The OC analysis will not impute 
values for missing evaluations, and thus a subject who does not have an evaluation on a 
scheduled visit will be excluded from the OC analysis for that visit.  OC will exclude 
values after a subject receive alternative PsO treatment regardless of premature 
discontinuation of study drug.
9.3
Primary Efficacy Endpoints and Analyses
9.3.1
Primary Efficacy Endpoints
The co-primary endpoints of this study in Period A are:
●
Achievement of PASI 90 at Week 16, among subjects in the ITT_A Population.
●
Achievement of sPGA 0 or 1 with at least 2-grade improvement from Baseline 
at Week 16, among subjects in the ITT_A Population.
The primary endpoint of this study in Period B is:
●
Achievement of PASI 90 at Week 52, among subjects in the ITT_B_NR 
Population.
 


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9.3.2
Main Analysis of Primary Efficacy Endpoints
The primary efficacy endpoints will be analyzed as specified in Section 9.1.
The attributes of the estimands corresponding to the primary efficacy endpoints in 
Period A and Period B are summarized in Table 1.
 


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Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoints
Estimand 
Label
Attributes of the Estimands
Treatment
Endpoint
Population
Handling of Intercurrent 
Events
Statistical 
Summary
PASI 90 
at 
Week 16
RZB and 
APR
PASI 90 at 
Week 16
ITT_A

Subjects who receive 
alternative PsO 
treatment regardless 
of premature 
discontinuation of 
study drug before 
Week 16 will be 
considered as non-
responders
Difference in 
the percentage 
of subjects 
achieving 
PASI 90 at 
Week 16 in 
RZB group in 
comparison with 
APR group
sPGA 0/1 
at 
Week 16
sPGA 0/1 
with at least 
2-grade 
improvement 
from 
Baseline at 
Week 16
Difference in 
the percentage 
of subjects 
achieving sPGA 
0/1 with at least 
2-grade 
improvement 
from Baseline at 
Week 16 in 
RZB group in 
comparison with 
APR group
PASI 90 
at 
Week 52
APR/RZB 
and 
APR/APR
PASI 90 at 
Week 52
ITT_B_NR

Subjects who receive 
alternative PsO
treatment regardless 
of premature 
discontinuation of 
study drug before 
Week 52 will be 
considered as non-
responders

Subjects who satisfy 
rescue criteria or 
receive the rescue 
medication at Week 
28 or Week 40 will 
be considered as non-
responders
Difference in 
the percentage 
of subjects 
achieving 
PASI 90 at 
Week 52 in 
APR/RZB 
group in 
comparison with 
APR/APR 
group
 


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9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoints
There will be no sensitivity analysis for the primary efficacy endpoints.
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.
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints
The secondary efficacy endpoints will be analyzed as specified in Section 9.1.
The attributes of the estimands corresponding to the key secondary efficacy endpoints are 
summarized in Table 2.
 


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Table 2.
Summary of the Estimand Attributes of the Key Secondary Efficacy 
Endpoints
Estimand 
Label
Attributes of the Estimands
Treatment
Endpoint
Population
Handling of Intercurrent 
Events
Statistical 
Summary
PASI 75 
response 
at 
Week 16
RZB and 
APR
PASI 75 
response at 
Week 16
ITT_A

Subjects who receive 
alternative PsO 
treatment regardless 
of premature 
discontinuation of 
study drug before 
Week 16 will be 
considered as non-
responders
Difference in the 
percentage of 
subjects 
achieving 
PASI 75 response 
at Week 16 in 
RZB group in 
comparison with 
APR group
PASI 75 
at 
Week 52
APR/RZB 
and 
APR/APR
PASI 75 
response at 
Week 16
ITT_B_NR

Subjects who receive 
alternative PsO 
treatment regardless 
of premature 
discontinuation of 
study drug before 
Week 52 will be 
considered as non-
responders

Subjects who satisfy 
rescue criteria or 
receive the rescue 
medication at Week 
28 or Week 40 will 
be considered as non-
responders
Difference in the 
percentage of 
subjects 
achieving 
PASI 75 at 
Week 52 in 
APR/RZB group 
in comparison 
with APR/APR 
group
sPGA 0/1 
at 
Week 52
sPGA 0/1 
with at least 
2-grade 
improvement 
from 
Baseline at 
Week 52
Difference in the 
percentage of 
subjects 
achieving sPGA 
0/1 with at least 
2-grade 
improvement 
from Baseline at 
Week 52 in 
APR/RZB group 
in comparison 
with APR/APR 
group
 


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9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints
There will be no sensitivity analysis for the ranked secondary efficacy endpoints.
9.5
Additional Efficacy Analyses
All additional efficacy endpoints will be analyzed as specified in Section 9.1.
Period A: Additional efficacy endpoints will be compared between the RZB and APR
treatment groups among the ITT_A Population at each visit.
Period B: Additional efficacy endpoints will be compared between the APR/RZB and 
APR/APR treatment groups among the ITT_B_NR and ITT_B_Combined Populations, 
and between the RZB/RZB and APR/APR treatment groups among the ITT_LT
Population, at each visit in Period B.
Additional efficacy endpoints will also be summarized by the APR/RZB and APR/APR
treatment groups among the ITT_B_R Population at each visit in Period B.
During the Period of Rescue RZB: Additional efficacy endpoints will be summarized 
among the ITT_Res Population at each visit after the use of Rescue RZB.
9.6
Efficacy Subgroup Analyses
Subgroup analysis will be performed on co-primary endpoints in Period A based on the 
following subgroups, among the ITT_A Population:
●
Age group:  < 40, ≥40 to < 65, ≥65
●
Sex (male, female)
●
Race (white, non-white)
●
Smoking (current, ex or never)
●
Body mass index (normal:  < 25, overweight:  ≥25 to < 30, obese:  ≥30)
●
Baseline PASI score (by median)
●
Psoriatic arthritis (yes, no)
 


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Prior systemic (including biologic) treatment (0, ≥1)
Age ≥65 years or BMI ≥30 subgroups will be combined with their adjacent subgroup 
when having fewer than 10% subjects.
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized among the Safety_A, Safety_B_R, Safety_B_NR, and
Safety_LT Populations. Safety summaries will be presented by treatment group. For the 
safety analysis, subjects are analyzed based on the treatment actually received, determined 
by the first dose of study drug that the subject received during the specific analysis period.
The overview of TEAEs, and potentially clinically important (PCI) findings in laboratory 
variables and vital sign variables will also be summarized among the 
Safety_B_Combined, Safety_Res, and ALL_RZB Populations.
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 
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
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A TEAE in Period A is defined as any AE with an onset date on or after the first dose of 
study drug in Period A, and
●
Within the minimum of (i) 140 days after the last dose of RZB in Period A and 
(ii) the first dose date of study drug in Period B for subjects who receive RZB 
at Baseline.
●
Within the minimum of (i) 28 days after the last dose of APR in Period A and 
(ii) the first dose date of study drug in Period B for subjects who receive APR 
at Baseline.
A TEAE in Period B is defined as any AE with an onset date on or after the first dose of 
study drug in Period B and 
●
Within 140 days after the last dose of RZB in Period B for subjects who receive 
RZB in Period B.
●
Within the minimum of (i) 28 days after the last dose of APR in Period B and 
(ii) the first dose date of rescue risankizumab (if any) for subjects who receive 
APR in Period B.
A TEAE during the administration of rescue risankizumab is defined as any AE with an 
onset date on or after the first dose of rescue risankizumab and within 140 days after the 
last dose of rescue risankizumab.
A TEAE during the administration of risankizumab (i.e., among the ALL_RZB 
Population) is defined as any AE with an onset date on or after the first dose of 
risankizumab and within 140 days after the last dose of risankizumab.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories in each 
Safety Population:
●
Any treatment-emergent AE
 


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Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent Areas of Safety Interest, as defined in Appendix B.
All deaths will also be summarized:
●
Deaths occurring ≤140 days after last dose of RZB or ≤28 days after last dose 
of APR
●
Deaths occurring > 140 days after last dose of RZB or > 28 days after last dose 
of APR
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
The number and percentage of subjects experiencing TEAEs will be tabulated using the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and 
preferred term, by severity, and by relationship to the study drug as assessed by the 
investigator.  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 risankizumab group.
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Exposure-adjusted AEs per 100 patient-years will be provided, where AEs per 
100 patient-years of exposure are defined as the number of AEs divided by the total 
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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 
the same day for the same subject).  The exposure-adjusted TEAE rate per 100 patient-
years is calculated as:
100 × Number of TEAEs 
Total Patient Years,
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
RZB arm: 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 for Period A + 1 day]) minus the first dose date in Period A,
normalized by 365.25 and rounded to one decimal place.
APR arm: the minimum of (the last dose date in Period A + 28 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 for Period A + 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
RZB/RZB or APR/RZB arm: 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 for 
Period B + 1 day]) minus the first dose date in Period B, normalized by 365.25 and 
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APR/APR arm: the minimum of (the last dose date in Period B + 28 days, the first dose 
date of rescue RZB if not missing, and the end of study date + 1 day [and the cutoff date 
during the Primary Analysis for Period B + 1 day]) minus the first dose date in Period B, 
normalized by 365.25 and rounded to one decimal place.
Rescue RZB: the minimum of (the last dose date of rescue RZB + 140 days, and the end 
of study date + 1 day [and the cutoff date during the Primary Analysis for Period B + 
1 day]) minus the first rescue RZB dose date, 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 for Period A + 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 discontinuation of study 
drug 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.
10.2.6
Safety Topics of Interest
Safety Topics of Interest (STI) will be summarized according to the search criteria 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.
 


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Listings of selected Areas of safety interest will also 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 where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded. The 
clinical laboratory tests defined in the protocol operations manual (e.g., hematology and 
clinical chemistry) will be summarized.
Mean change from Baseline to each applicable post-baseline visit will be summarized for 
selected laboratory variables among the Safety_A, Safety_B_R, Safety_B_NR, and 
Safety_LT Populations.  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 among Safety_A, Safety_B_R and Safety_B_NR, and 
Safety_LT Populations categorized by the toxicity grade according to NCI CTCAE 
Version 4.031 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 will be summarized among 
all safety populations.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (Appendix C). For each laboratory PCI criterion, the number and 
percentage of subjects who have a laboratory value meeting the criteria will be 
summarized. Listings will be provided to summarize subject-level laboratory data for 
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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 
will be categorized as follows:
●
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× ULN and Total bilirubin > 1.5× ULN
●
ALT and/or AST > 3× ULN and Total bilirubin > 2× ULN
●
ALT > 3× ULN and Total bilirubin > 1.5× ULN
●
ALT > 3× ULN and Total bilirubin > 2× ULN
The listing will include all subjects who met any of the following four criteria:
●
ALT > 3 × ULN, or
●
AST > 3 × ULN, or
●
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.
 


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●
ALT of > 3 × ULN or AST of > 3 × ULN
●
Total bilirubin ≥ 2 × ULN
Urinalysis and pregnancy testing results will be provided in listings only.
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 among the Safety_A, Safety_B_R, Safety_B_NR, and Safety_LT 
Populations.  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 C) among all safety populations.  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
There will be no safety subgroup analyses for this study.
10.6
Other Safety Analyses
There will be no other safety analyses for this study.
11.0
Other Analyses
There will be no other safety analyses for this study.
 


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12.0
Interim Analyses
12.1
Data Monitoring Committee
There is no data monitoring committee for this open label study.
13.0
Overall Type-I Error Control
Overall type-I error for Period A will be controlled by testing the co-primary endpoints, 
followed by the ranked and only secondary endpoint, in a hierarchical order as described 
in Section 3.1 and Section 3.2.
Overall type-I error for Period B will be controlled by testing the primary endpoint, 
followed by the ranked secondary endpoints, in a hierarchical order as described in 
Section 3.1 and Section 3.2.
 


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14.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
28 July 2021
Original version
2.0
05 May 2022

Changed Area of safety interest (ASI) to Safety 
Topics of Interest (STI) to be aligned with the 
wording of PSSAP.

Changed liver function criteria in Section 10.3 to be 
aligned with PSSAP.

Changed 'Malignant Tumours' to 'Malignancies' in 
Appendix B to be consistent with the wording in 
PSSAP.
3.0
26 February 2023

Changed 'Phase 3b' to 'Phase 4' in the title and 
Section 1.0 to be consistent with the protocol. 

Added Primary Analysis for Period B in Section 9.1.

Added adjusting variables visit and treatment by visit
interaction in Mixed-effect Model Repeat 
Measurement (MMRM) in Section 9.2.2 to be 
consistent with Section 9.1.

Changed 'cutoff for Period A' to 'cutoff date for 
Period B' in Section 6.0 and Section 10.2.4.

Added '[and cutoff date during the Primary Analysis 
for Period B + 1 day]' to Rescue RZB duration in 
Section 6.0. 

CMQ codes were revised for MedDRA 25.1 in 
Appendix B.
15.0
References
1.
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.
Definition of Safety Topics of Interest
Safety Topics of Interest (STI) will be identified using the following search criteria:
Safety Topics of Interest
Search Criteria
MACE
Adjudicated terms will be identified as described in PSSAP Table 4a using 
CECAT and CETERM from the CE SDTM dataset.
Extended MACE
Adjudicated terms will be identified as described in PSSAP Table 4a (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)
Malignancies
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, and the PCI criteria for vital sign findings are described in 
Table C-3.
Table C-1.
Criteria for Potentially Clinically Important Hematology Values
Hematology Variables
Units
Definition of Potentially Clinically Important
Current (Version 4) CTCAE Grade 3 or Greater
Very Low
Hemoglobin
g/dL
< 8.0
Platelets count
109/L
< 50.0
WBC count
109/L
< 2.0
Neutrophils
109/L
< 1.0
Lymphocytes
109/L
< 0.5
Note:
A post-baseline value must be more extreme than the baseline value 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 Current 
(Version 4) NCI CTCAE Grade 3 or Greater
Very Low
Very High
TBL
mcmol/L
> 3.0 × ULN
ALP
U/L
> 5.0 × ULN
SGOT/AST
U/L
> 5.0 × ULN
SGPT/ALT
U/L
> 5.0 × ULN
Albumin
g/L
< 20
Glucose
mmol/L
< 2.2
> 13.9
Triglycerides
mmol/L
> 5.7
Creatinine
mcmol/L
> 3.0 × ULN (> 3.0 × BL)
Sodium
mmol/L
< 130
> 155
Potassium
mmol/L
< 3.0
> 6.0
Calcium
mmol/L
< 1.75
> 3.1
CPK
U/L
> 5.0 × ULN
Total Cholesterol
mmol/L
> 10.34
GGT
> 5.0 × ULN
Note:
A post-baseline value must be more extreme than the baseline value to be considered a potentially clinically 
important finding.
Table C-3.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Signs Variables
Criterion
Definition of Potentially Clinically Important
Systolic Blood Pressure 
(mmHg)
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic Blood 
Pressure (mmHg)
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
 


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Appendix D.
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-MI)
2.1
Overall Description of the Method
For a dichotomized outcome variable with missing data, the NRI-MI 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 specific 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-MI) 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, PASI 90 
(at least a 90% reduction in PASI relative to Baseline), the multiple imputation will be 
applied to the original scale, PASI (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., PASI, the original scale of PASI 90, 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., PASI 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.  
●
For analyses for the ITT_A Population: Covariates included in the model are 
treatment group, Baseline body weight as a continuous variable, prior exposure 
to any systemic and/or biologic treatment for PsO (0, ≥ 1), Baseline and all 
post-baseline visits of the outcome variable up to the end of Period A.
●
For analyses for the ITT_B_Combined, ITT_B_NR and ITT_B_R Populations:  
Covariates included in the model are treatment group, PASI score at Baseline 
and at the Entry of Period B, and the outcome variable collected at the Entry of 
Period B and all later visits.
 


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●
For analyses for the ITT_LT Population: Covariates included in the model are 
treatment group, Baseline body weight as a continuous variable, prior exposure 
to any systemic and/or biologic treatment for PsO (0, ≥ 1), PASI score at 
Baseline and at the Entry of Period B, and the outcome variable collected at the 
Entry of Period B and all later visits.  Subjects randomized to RZB at Baseline 
and did not enter Period B will be included in the analysis and will be counted 
as non-responders.  To accommodate the 1:1 re-randomization, half (round 
down to integer) of the subjects randomized to APR at Baseline and did not 
enter Period B will be included in the analysis and will be counted as non-
responders. 
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)."
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 the same variables for each Population as listed in the 
augmentation step.  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. 
 


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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 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., PASI 90 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 
 


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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
For the ITT_A and ITT_LT Populations: The statistical analysis will use the Cochran-
Mantel-Haenszel (CMH) test adjusting for the actual values of stratification factors at 
Baseline: Baseline body weight (≤ 100 kg, > 100 kg), prior exposure to any systemic 
and/or biologic treatment for PsO (0, ≥ 1).
For the ITT_B_Combined Population: The statistical analysis will use the CMH test 
adjusting for the actual values of the stratification factor at re-randomization: PASI 75 
response status at the Entry of Period B (Yes/No).
For ITT_B_NR Population: The statistical analysis will use the Chi-square test. 
For ITT_B_R Population: Summary statistics will be calculated.  No statistical 
comparison is conducted.  
2.5.1
Analysis of Each Dataset
For each of the K 'complete' datasets, the statistical tests as specified above will be used to 
estimate the treatment difference between treatment groups and the corresponding 
standard error (except for ITT_B_R Population, in which only summary statistics of each 
group will be calculated).
 


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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:
 = 1
 ! ".
$
"%&
The estimated variance of θ ̃MI, is a combination of the between- and within-imputation 
variability as follows:
' = ( + (1 + 1
 ),
Where ( =
&
$ ∑
'"
$
"%&
is the within-imputation variability and, =
&
$.& ∑
(" −)0
$
"%&
is the between-imputation variance. 
It has been shown5 that the statistic
1 =  −
2'
 


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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*/
/*PASI 90 at Week 16 is used as an example in the sample code*/
/*PRE-AUGMENTATION – CREATE DUMMY FOR CATEGORICAL VARIABLES*/
/********************************************/
DATA PASI_2; SET PASI;
  /*THE MCMC STATMENT BELOW ASSUMES MULTI-VARIATE NORMAL*/
  IF TRT01PN=1 THEN TRT1=1; ELSE TRT1=0;
  /*BASELINE WEIGHT AND PRIOR BIO/SYS CATEGORY*/
  IF PSOBLGN
= 1 THEN REG1 = 1 ;ELSE REG1 = 0;
RUN;
/*AUGMENTATION STEP -- TO HAVE 30 MONOTONE MISSING DATASETS*/
PROC MI DATA= PASI 2 OUT= PASI MONO NIMPUTE=30 SEED= 12345 /*ACTUAL 
RANDOM SEED PRE-DEFINED AS THE NUMERICAL VALUE OF THE DATE OF FIRST 
SUBJECT FIRST DOSE*/
  ROUND=. . . 0.1 0.1 0.1 /*VALUE ROUND TO 1ST DECIMAL*/
  MIN=. . . 0 0 0
/*MINIMUM VALUE OF PASI IS 0*/
  MAX=. . . 72 72 72   /*MAXIMUM VALUE OF PASI 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 REG1 WTBL 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= PASI MONO OUT= PASI FULL NIMPUTE=1 SEED= 54321
/*ACTUAL 
RANDOM SEED PRE-DEFINED AS THE NUMERICAL VALUE OF THE DATE OF LAST 
SUBJECT FIRST DOSE */
  ROUND= =. . . 0.1 0.1 0.1 /*VALUE ROUND TO 1ST DECIMAL*/
  MIN=. . .  0 0 0
/*MINIMUM VALUE OF PASI IS 0*/
  MAX=. . .  72 72 72 /*MAXIMUM VALUE OF PASI IS 72*/
  MINMAXITER=1000;
  /*CLASS CATEGORICAL VARIABLES TRT1 AND REG2*/
  CLASS TRT1 REG1;
  VAR TRT1 REG1 WTBL 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, PASI 90 AT WEEK 16*/
DATA ALL; SET PASI FULL;
  IF 0<=WK16<=0.1*BASE THEN PASI90_16=1;
    ELSE PASI90_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 PASI90 NRI 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 PASI90_16= PASI90NRI_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* PASI90 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 PASI90_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. 
5.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data: a case 
study using agriculture industry codes.  J Am Stat Assoc.  1987;81:366-74.
6.
White IR, Royston P, Wood AM.  Multiple imputation using chained equations: 
Issues and guidance for practice.  Stat Med.  2011;30(4):377-99.