Conditions: Psoriasis
Keywords: Phase 3 Double-Blind Efficacy Safety Apremilast Otezla CC-10004 Plaque Psoriasis Mild Moderate Scalp Nail Itch
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 595
Healthy volunteers: no

Brief summary:
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study designed to evaluate the efficacy and safety of apremilast (CC-10004) in subjects with mild to moderate plaque psoriasis.

Approximately 574 subjects with mild to moderate plaque psoriasis will be randomized 1:1 to receive either apremilast 30 mg BID or placebo for the first 16 weeks.

Detailed description:
The study will consist of four phases:

* Screening Phase - up to 35 days
* Double-blind Placebo-controlled Phase - Weeks 0 to 16

  \- Subjects will be randomly assigned to either apremilast 30 mg tablets orally BID or placebo tablets (identical in appearance to apremilast 30 mg tablets) orally BID.
* Apremilast Extension Phase - Weeks 16 to 32

  \- All subjects will be switched to (or continue with) apremilast 30 mg BID. All subjects will maintain this dosing through Week 32.
* Observational Follow-up Phase - 4 weeks - Four-week Post-Treatment Observational Follow-up Phase for all subjects who complete the study or discontinue the study early.

Arms:
arm 1: Participants received placebo as oral tablets twice daily (BID) for up to 16 weeks (Week 0 to Week 16). arm 2: Participants received apremilast 30 mg as oral tablets BID for up to 16 weeks (Week 0 to Week 16). arm 3: Eligible participants who completed the placebocontrolled phase entered the extension phase and received apremilast 30 mg as oral tablets BID for up to an additional 16 weeks (Week 16 to Week 32).

Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: Apremilast, oral, twice daily intervention 2: Placebo, oral, twice daily

Protocol document:
Prot_000.pdf: 
EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
1
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
TITLE PAGE
A PHASE 3, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY OF 
THE EFFICACY AND SAFETY OF APREMILAST (CC-
10004) IN SUBJECTS WITH MILD TO MODERATE
PLAQUE PSORIASIS
PROTOCOL NUMBER:
CC-10004-PSOR-022
DATE FINAL:
26 June 2018
AMENDMENT 1 FINAL:
08 Oct 2018
AMENDMENT 2 FINAL:
21 Nov 2018
EudraCT NUMBER:
Not applicable
IND NUMBER:
IND 070270
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
NCT Number: NCT03721172
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
, MD
Title: Director, Clinical Research and Development
          Inflammation and Immunology
Address: Celgene Corporation
                86 Morris Avenue
                Summit, NJ 07901
Phone:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: +1-877-501-7738


EDMS Doc. Number: 23137123 - 22819879
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, MD, Vice President, Clinical Research and Development 
Inflammation and Immunology
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  


EDMS Doc. Number: 23137123 - 22819879
Apremilast
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.


EDMS Doc. Number: 23137123 - 22819879
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PROTOCOL SUMMARY
Study Title
A Phase 3, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study of the Efficacy 
and Safety of Apremilast (CC-10004) in Subjects with Mild to Moderate Plaque Psoriasis
Indication
The indication is mild to moderate plaque psoriasis.
Objectives
Primary Objective

To evaluate the clinical efficacy of oral apremilast 30 mg twice daily (BID), compared to 
placebo, in subjects with mild to moderate plaque psoriasis during the 16-week Placebo-
controlled Phase.
Secondary Objectives

To evaluate the safety and tolerability of apremilast 30 mg BID, compared with placebo, 
in subjects with mild to moderate plaque psoriasis

To evaluate the effect of apremilast 30 mg BID compared with placebo on itch over the 
whole body caused by plaque psoriasis

To evaluate the effect of apremilast 30 mg BID compared with placebo on Health-related 
Quality of Life (HRQoL)
Study Design
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study designed to 
evaluate the efficacy and safety of apremilast (CC-10004) in subjects with mild to moderate 
plaque psoriasis. 
Approximately 574 subjects will be enrolled and randomized 1:1 to receive either apremilast 30 
mg BID or placebo for the first 16 weeks. Subjects will be randomized based on a permuted 
block randomization using a centralized Interactive Response Technology (IRT). Randomization 
to apremilast arm or placebo arm will be stratified by baseline static Physician Global 
Assessment (sPGA) score (mild [2] or moderate [3]). Approximately 30% of subjects 
randomized will have a baseline sPGA score of mild (2) and approximately 70% of subjects will 
have a baseline sPGA score of moderate (3).

Subjects randomized to the apremilast 30 mg BID treatment group will receive 
apremilast 30 mg tablets orally twice daily for the first 16 weeks

Subjects randomized to the placebo treatment group will receive placebo tablets 
(identical in appearance to apremilast 30 mg tablets) orally twice daily for the first 16 
weeks

All subjects will receive apremilast 30 mg tablets orally twice daily after the Week 16 
Visit through the end of the Apremilast Extension Phase of the study


EDMS Doc. Number: 23137123 - 22819879
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The study will consist of four phases:

Screening Phase – up to 35 days

Double-blind Placebo-controlled Phase – Weeks 0 to 16

Subjects will be randomly assigned in a 1:1 ratio to either apremilast 30 mg BID 
or placebo.  

Apremilast Extension Phase – Weeks 16 to 32

All subjects will be switched to (or continue with) apremilast 30 mg BID.  All 
subjects will maintain this dosing through Week 32.

Observational Follow-up Phase – 4 weeks

Four-week Post-Treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue the study early
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed; the primary data analysis will be conducted and a Week 
16 Clinical Study Report (CSR) will be generated. However, unblinded data will only be made 
available to select Sponsor and Contract Research Organization (CRO) team members involved 
with analysis of the data and preparation of the Week 16 CSR. All other Sponsor, site, and CRO 
personnel directly involved with the conduct of the study, will remain blinded to treatment 
assignments until the final database lock at the conclusion of the study.
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
Approximately 574 adult subjects ≥ 18 years of age with mild to moderate plaque psoriasis will 
be randomized.  Only subjects who don’t have prior exposure to biologics for the treatment of 
psoriatic arthritis, psoriasis, or any other indication that could impact the assessment of psoriasis
and who are inadequately controlled with or intolerant of topical therapies (including topical 
corticosteroids, topical retinoids or vitamin D analog preparations, calcipotriene and 
betamethasone dipropionate ointment or foam, tacrolimus, pimecrolimus, or anthralin/dithranol)
for the treatment of psoriasis will be eligible for the study.
Length of Study
The study is designed as a 32-week study with a Four-week Post-treatment Observational 
Follow-up Visit and consists of 4 phases as described above.  Please refer to Section 1.3.2 for 
details.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
The chemical name of apremilast (CC-10004) is acetamide, N-[2-[(1S)-1-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl].


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All study medication will be provided in blister cards throughout the entire study.  Apremilast 
will be provided as 10, 20, or 30 mg tablets by the study Sponsor, Celgene Corporation.  Placebo 
will be provided as identically appearing 10, 20, or 30 mg tablets.
Investigational product will be taken orally twice daily, approximately 12 hours apart, without 
restriction of food or drink. As in the prior Phase 3 studies, dose titration will be implemented in 
order to mitigate potential gastrointestinal-related adverse events (AEs).  During Week 0 (Days 1
to 7), subjects will be dispensed placebo or 30 mg BID titration and treatment blister cards with 
10, 20, and 30 mg apremilast tablets or identically appearing placebo for the dose titration.  
Starting at Week 16, all subjects will be switched to, or will continue with apremilast.  Subjects 
originally randomized to placebo at Week 0 will be switched to apremilast at Week 16.  The 30 
mg BID titration and treatment blister cards will be used for subjects switching from placebo to 
apremilast; dummy titration blister cards will be used for subjects initially randomized to receive 
apremilast 30 mg BID. At all other visits during the Apremilast Extension Phase, all subjects will 
receive apremilast 30 mg tablets which are to be taken twice daily. 
Dose modifications are not permitted in this study.
Overview of Key Efficacy Assessments
Primary Efficacy Assessment

sPGA
Additional Efficacy Assessments

Body Surface Area (BSA)

Psoriasis Area Severity Index (PASI) 

Whole Body Itch Numeric Rating Scale (NRS) 

Scalp PGA (ScPGA)

Dermatological Life Quality Index (DLQI)

Nail Psoriasis Severity Index (NAPSI)
Overview of Key Safety Assessments
Safety assessments will include:

Adverse events (AE)

Vital signs

Pregnancy tests for females of childbearing potential (FCBP)

Clinical laboratory tests

Columbia-Suicide Severity Rating Scale (C-SSRS)
Statistical Methods
The sample size estimation is based on the results of the Phase 3 and 4 studies with apremilast. 
With a total of approximately 574 subjects and a randomization ratio of 1:1, the study will 
randomize approximately 287 subjects to apremilast 30 mg BID and 287 subjects to placebo. 


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This sample size will provide more than 90% power to detect a 15% difference between the two 
treatment groups for the primary endpoint at a two-sided significance level of 0.05. The 
calculation is based on a chi-square test assuming 15% response rate for placebo and adjusting 
for a 20% dropout rate. 
For the Placebo-controlled Phase (Weeks 0 to 16), the analyses for efficacy endpoints will be 
based on the intent-to-treat (ITT) population, defined as all subjects who are randomized. 
Statistical comparisons will be made between apremilast 30 mg BID and placebo. All statistical 
tests will be at the two-sided 0.05 significance level and the corresponding p-values and 95% 
confidence intervals (CIs) will be reported.
The treatment difference for the primary endpoint will be compared between apremilast 30 mg 
BID and placebo using a Cochran Mantel–Haenszel (CMH) test adjusting for the stratification 
factor. The two-sided p-values from the CMH test, the adjusted treatment difference in 
proportion using the weighted average of the treatment differences across the stratification factor 
with the CMH weights, along with the associated two-sided 95% CIs using a normal 
approximation to the weighted average will be provided. Missing values at Week 16 will be 
imputed using multiple imputation (MI) as the primary method, with sensitivity analysis using 
the non-responder imputation (NRI) method and the tipping point analysis.  
The continuous endpoints will be analyzed using a mixed-effect model for repeated measures 
(MMRM) as the primary method. The MMRM model will use the change from baseline as the 
response variable and include treatment group, visit time, treatment-by-time interaction, and 
stratification factor as fixed effects, and the baseline value as a covariate. An unstructured 
covariance matrix will be used to model the correlation among repeated measurements. The 
Kenward-Roger adjustment will be used with restricted maximum likelihood (REML) to make 
proper statistical inference. Within-group least-squares (LS) means and the associated standard 
errors (SEs) and two-sided 95% CIs, treatment differences in LS means and the associated two-
sided 95% CIs and two-sided p-values will be derived from the MMRM model. A sensitivity 
analysis will be conducted using the analysis of covariance (ANCOVA) model with treatment 
and stratification factor as the fixed effects, the baseline value as the covariate and the LOCF 
method to impute the missing data.
The other binary endpoints will be analyzed similarly as the primary endpoint using the CMH 
test.
To control the overall type I error rate, a fixed-sequence testing procedure will be used to test the 
primary and secondary endpoints in a predefined order. The test will be performed in sequence 
and significance of all preceding endpoints is required in order to proceed to the next one. The
proposed sequence of testing for the primary and secondary efficacy endpoints is listed below.

Proportion of subjects with sPGA score of clear (0) or almost clear (1) with at least a 
2-point reduction from baseline at Week 16

Proportion of subjects who improved ≥ 75% in BSA from baseline

Change from baseline in affected BSA at Week 16

Change from baseline in total PASI score at Week 16


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
In subjects with BSA > 3% at baseline, proportion of subjects who achieved BSA ≤
3% at Week 16

In subjects with whole body Itch NRS score ≥ 4 at baseline, proportion of subjects 
with ≥4-point reduction (improvement) from baseline in the whole body itch NRS 
score at Week 16

In subjects with ScPGA score ≥ 2 at baseline, proportion of subjects with ScPGA 
score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline at 
Week 16

Change from baseline in DLQI total score at Week 16
The safety analyses will be performed using the safety population, defined as all subjects who 
are randomized and receive at least one dose of investigational product. Safety will be assessed 
by clinical review of all relevant parameters including treatment emergent adverse events 
(TEAEs), laboratory tests, and vital signs; no inferential testing for statistical significance will be 
performed.
Adverse events will be classified using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) classification system.  All TEAEs will be summarized by system organ class, 
preferred term, severity and relationship to investigational product.  TEAEs leading to death or to 
discontinuation from treatment and serious adverse events (SAEs) will be summarized and listed 
separately.
Data from other safety assessments will be summarized descriptively.  Shift tables for laboratory 
parameters showing the number of subjects with values low, normal, and high comparing with 
the normal reference ranges pre-treatment versus post treatment will be provided.
To account for the different exposure to the investigational product, AEs or marked laboratory 
abnormalities will also be summarized using the exposure adjusted incidence rate, in addition to 
the simple incidence rates.


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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................5
1.
INTRODUCTION..................................................................................................16
1.1.
Disease Background ...............................................................................................16
1.2.
Compound Background ..........................................................................................16
1.3.
Rationale ................................................................................................................17
1.3.1.
Study Rationale and Purpose ..................................................................................17
1.3.2.
Rationale for the Study Design ...............................................................................17
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................19
1.3.4.
Rationale for Choice of Comparator Compounds....................................................19
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................21
3.
OVERALL STUDY DESIGN ................................................................................24
3.1.
Study Design ..........................................................................................................24
3.2.
Study Duration for Subjects....................................................................................25
3.3.
End of Trial ............................................................................................................25
4.
STUDY POPULATION.........................................................................................26
4.1.
Number of Subjects ................................................................................................26
4.2.
Inclusion Criteria....................................................................................................26
4.3.
Exclusion Criteria...................................................................................................27
5.
TABLE OF EVENTS.............................................................................................29
6.
PROCEDURES......................................................................................................32
6.1.
Screening Period.....................................................................................................32
6.2.
Treatment Period ....................................................................................................33
6.2.1.
End of Treatment....................................................................................................34
6.3.
Observational Follow-up Period .............................................................................35
6.3.1.
Safety Follow-up ....................................................................................................35
6.3.2.
Efficacy Follow-up.................................................................................................36
6.4.
Efficacy Assessments .............................................................................................36
6.5.
Safety Assessments.................................................................................................37
6.6.
Pharmacokinetics....................................................................................................39


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6.8.
Subject Reported Outcomes or Health-related Quality of Life Assessment..............41
6.8.1.
Whole Body Itch Numeric Rating Scale Assessment ..............................................41
6.8.2.
Dermatology Life Quality Index .............................................................................41
7.
DESCRIPTION OF STUDY TREATMENTS........................................................42
7.1.
Description of Investigational Product(s)................................................................42
7.2.
Treatment Administration and Schedule .................................................................45
7.3.
Overdose ................................................................................................................45
7.4.
Method of Treatment Assignment...........................................................................45
7.5.
Packaging and Labeling..........................................................................................45
7.6.
Investigational Product Accountability and Disposal ..............................................46
7.7.
Investigational Product Compliance........................................................................46
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................47
8.1.
Permitted Concomitant Medications and Procedures...............................................47
8.2.
Prohibited Concomitant Medications and Procedures..............................................47
8.3.
Required Concomitant Medications and Procedures................................................48
9.
STATISTICAL CONSIDERATIONS ....................................................................49
9.1.
Overview................................................................................................................49
9.2.
Study Population Definitions ..................................................................................49
9.3.
Sample Size and Power Considerations...................................................................49
9.4.
Background and Demographic Characteristics........................................................49
9.5.
Subject Disposition.................................................................................................50
9.6.
Efficacy Analysis....................................................................................................50
9.6.1.
Efficacy Evaluation for the Placebo-controlled Phase (Weeks 0 to 16)....................50
9.6.1.1.
Primary Efficacy Endpoint......................................................................................50
9.6.1.2.
Secondary Efficacy Endpoints ................................................................................51
9.6.1.3.
Multiplicity Adjustment..........................................................................................51
9.6.1.4.
Exploratory Endpoints............................................................................................52
9.6.1.5.
Subgroup Analysis..................................................................................................52
9.6.2.
Efficacy Evaluation – Apremilast Extension Phase (Weeks 16 to 32)......................52
9.7.
Safety Analysis.......................................................................................................53
9.8.
Interim Analysis .....................................................................................................53
9.9.
Other Topics...........................................................................................................53


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9.9.1.
Pharmacodynamic Analysis....................................................................................53
9.9.2.
Investigational Product Compliance........................................................................54
9.9.3.
Concomitant Therapy .............................................................................................54
10.
ADVERSE EVENTS..............................................................................................55
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................55
10.2.
Evaluation of Adverse Events.................................................................................55
10.2.1.
Seriousness.............................................................................................................55
10.2.2.
Severity/Intensity....................................................................................................57
10.2.3.
Causality ................................................................................................................58
10.2.4.
Duration .................................................................................................................58
10.2.5.
Action Taken..........................................................................................................58
10.2.6.
Outcome.................................................................................................................58
10.3.
Abnormal Laboratory Values..................................................................................58
10.4.
Pregnancy...............................................................................................................59
10.5.
Reporting of Serious Adverse Events......................................................................59
10.5.1.
Safety Queries ........................................................................................................60
10.6.
Expedited Reporting of Adverse Events..................................................................60
11.
DISCONTINUATIONS .........................................................................................61
11.1.
Treatment Discontinuation......................................................................................61
11.2.
Study Discontinuation ............................................................................................61
12.
EMERGENCY PROCEDURES.............................................................................63
12.1.
Emergency Contact.................................................................................................63
12.2.
Emergency Identification of Investigational Products .............................................63
13.
REGULATORY CONSIDERATIONS...................................................................64
13.1.
Good Clinical Practice............................................................................................64
13.2.
Investigator Responsibilities ...................................................................................64
13.3.
Subject Information and Informed Consent.............................................................65
13.4.
Confidentiality........................................................................................................65
13.5.
Protocol Amendments.............................................................................................65
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................65
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................66
13.8.
Termination of the Study ........................................................................................66


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14.
DATA HANDLING AND RECORDKEEPING.....................................................67
14.1.
Data/Documents .....................................................................................................67
14.2.
Data Management...................................................................................................67
14.3.
Record Retention....................................................................................................67
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................69
15.1.
Study Monitoring and Source Data Verification......................................................69
15.2.
Audits and Inspections............................................................................................69
15.3.
Product Quality Complaint .....................................................................................69
16.
PUBLICATIONS ...................................................................................................71
17.
REFERENCES.......................................................................................................72
18.
APPENDICES........................................................................................................75
Appendix A:
Table of Abbreviations ......................................................................................75
Appendix B:
Static Physician Global Assessment (sPGA) of Whole Body Psoriasis...............78
Appendix C:
Psoriasis Area and Severity Index (PASI) ..........................................................79
Appendix D:
Scalp Physician Global Assessment (ScPGA)....................................................80
Appendix E:
Nail Psoriasis Severity Index (NAPSI)...............................................................81
Appendix F:
Columbia-Suicide Severity Rating Scale ............................................................83
Appendix G:
Whole Body Itch Numeric Rating Scale (NRS)..................................................87
Appendix H:
The Dermatology Life Quality Index (DLQI) ....................................................88
Appendix I:
Titration Blister Card Configuration....................................................................89
Appendix J:
Active Treatment Dummy Titration Blister Card Configuration..........................90
Appendix K:
Placebo Treatment Blister Card Configuration...................................................91


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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................21
Table 2:
Study Endpoints .....................................................................................................22
Table 3:
Table of Events.......................................................................................................29
Table 4:
Treatment Schema for Dose Titration at Visit 2 (Week 0).......................................43
Table 5:
Treatment Schema for Dose Titration at Visit 7 (Week 16).....................................44
Table 6:
Abbreviations and Specialist Terms........................................................................75


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LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................25


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1.
INTRODUCTION
1.1.
Disease Background
Psoriasis is a chronic, immune-mediated disorder.  Plaque psoriasis, the most common form of 
psoriasis, is typically characterized by raised, demarcated erythematous plaques covered by a 
silvery scale (Lebwohl, 2003a). Psoriasis affects 2-3% of the population, with approximately 
80% of patients experiencing mild to moderate disease (Menter, 2009). Psoriasis is associated 
with a range of comorbidities that have been demonstrated in subjects regardless of psoriatic 
disease severity (Ahlehoff, 2011, 2013).  
Treatment guidelines categorize therapy by extent of psoriatic disease based on the amount of 
affected body surface area (BSA).  Limited involvement or mild disease, defined as 0-3% BSA 
(National Psoriasis Foundation [NPF]) or ≤5% (American Academy of Dermatology [AAD], 
[Menter, 2008]) can be treated with topical therapies. However, treatment satisfaction remains 
low in patient using topical therapies compared to systemic or phototherapy (Cranenburgh, 
2013). In a recently published comparison of combination calcipotriene and betamethasone 
(Enstilar®) with the individual component therapies in a 4-week treatment period, about half of 
the subjects in this treatment group did not achieve a meaningful reduction of their plaque 
psoriasis, and even higher numbers of subjects failed to achieve response with calcipotriene or 
betamethasone treatment alone (Stein Gold, 2016). Additionally, topical therapies may not be 
adequate for subjects with less than 5% BSA affected with psoriasis in vulnerable areas such as 
the face, genitals, hands and feet, scalp, or intertriginous areas (Menter, 2011). Treatment of nail 
psoriasis with topical therapies also poses a clinical challenge and may not be adequate for 
subject with significant skin and nail disease (Crowley, 2015; Pasch, 2016).
Extensive disease or moderate to severe disease, established by health authorities as BSA ≥ 10%, 
Psoriasis Area Severity Index (PASI) ≥12 and static Physician Global Assessment (sPGA) ≥ 3 
(moderate or greater) can be treated with systemic therapies, but biologics and oral therapies 
such as methotrexate may be limited by safety concerns and the need for careful laboratory 
monitoring.  Consequently, subjects with mild to moderate psoriasis, represent an underserved 
population.  There remains an unmet medical need for an effective, convenient treatment of mild 
to moderate psoriasis that is well tolerated compared to the currently available treatment options 
(Armstrong, 2013).
1.2.
Compound Background 
Apremilast (CC-10004) is a specific phosphodiesterase type 4 (PDE4) inhibitor under 
development for use in the treatment of inflammatory conditions.  The PDE4 is one of the major 
phosphodiesterases expressed in leukocytes. PDE4 inhibition by apremilast elevates cyclic 
adenosine monophosphate (cAMP) levels in immune cells, which in turn down-regulates the 
inflammatory response by reducing the expression of pro-inflammatory mediators such as tumor 
necrosing factor (TNF)-α, interleukin (IL)-23, IL-17, and other inflammatory cytokines, and 
increasing the production of anti-inflammatory mediators. 
In completed Phase 3 studies in subjects with moderate to severe plaque psoriasis and active 
psoriatic arthritis, treatment with apremilast was associated with statistically significant and 
clinically meaningful improvements in multiple efficacy measures. On the basis of these studies, 


EDMS Doc. Number: 23137123 - 22819879
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Protocol CC-10004-PSOR-022
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17
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
apremilast (OTEZLA®) is approved in approximately 50 countries worldwide for the treatment 
of adult patients with active psoriatic arthritis and the treatment of patients with moderate to 
severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Apremilast remains under further clinical development for the treatment of inflammatory/ 
autoimmune disorders including Behçet’s disease, and ulcerative colitis. Further studies within 
the approved indications of plaque psoriasis and psoriatic arthritis are also ongoing.
Please refer to the current Investigator’s Brochure (IB) for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) 
profile of the investigational product (IP).
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
Treatment of mild to moderate plaque psoriasis can be challenging, and patient satisfaction and 
compliance with current treatment modalities are often low, particularly with topical therapies 
(Cranenburgh, 2013; Duffin, 2014).  Low satisfaction with treatment options can lead to poor 
adherence and suboptimal response.
There remains an unmet medical need for an effective, convenient treatment of mild to moderate 
psoriasis that is well tolerated compared to the currently available treatment options (Armstrong, 
2013). Currently approved topical corticosteroids and vitamin D analogues may be limited by 
short treatment durations, poor treatment compliance and significant adverse effects such as 
tachyphylaxis, skin atrophy, striae, telangiectasia, and hypothalamic-pituitary-adrenal (HPA) 
axis suppression (Chan, 2009; Kragballe, 2013).  Other topical therapies, such as coal tar and 
anthralin preparations have cosmetically unappealing formulations, foul odor, limited efficacy, 
and potential carcinogenic risk (Chan, 2009). Systemic therapies including conventional 
therapies such as methotrexate, retinoids and cyclosporine or the biologics, have been approved 
for moderate to severe plaque psoriasis, and are associated with dose limiting effects such as 
hepatotoxicity, teratogenicity, nephrotoxicity and increased risk of malignancy or severe 
infection. In addition, careful laboratory monitoring for infections, reactivation of latent 
tuberculosis, hypersensitivity reactions and malignancies (Menter, 2009; Nast, 2012) may be 
required with these agents.
Apremilast (APR, OTEZLA®) is a drug that is taken orally (by mouth [PO]).  Apremilast inhibits 
the enzyme PDE4, which is a cAMP-specific PDE and the dominant PDE in inflammatory cells.  
By inhibiting PDE4, apremilast elevates intracellular cAMP levels, which in turn modulates a 
network of pro- and anti-inflammatory mediators and reduces the inflammatory response.
The proposed Phase 3 study is intended to assess the safety and efficacy of apremilast 30 mg 
twice daily (BID) in the treatment of subjects with mild to moderate plaque psoriasis who are not 
adequately controlled by topical therapies.
1.3.2.
Rationale for the Study Design
Study CC-10004-PSOR-012 was a randomized, double-blind, placebo-controlled Phase 4 trial, in 
which the efficacy and safety of apremilast was evaluated in 221 subjects with moderate plaque 
psoriasis defined as BSA of 5-10% and sPGA of 3 (moderate).  In addition, eligible subjects had 


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
18
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
no prior exposure to systemic therapy (conventional or biologic), and no concurrent topical 
therapy for psoriasis was permitted during the study, with the exception of an unmedicated 
moisturizer such as Eucerin®.  Subjects were treated with APR 30 BID or placebo for 16 weeks 
during the Placebo-controlled Phase.  At the end of the Placebo-controlled Phase at Week 16, 
subjects entered the Apremilast Extension Phase and received APR 30 BID up to study Week 52.
Analyses of the proportion of subjects who achieved an sPGA score of 0 (clear) or 1 (almost 
clear) with at least a 2-point reduction from baseline at Week 16, demonstrated statistically 
significant benefit with APR 30 BID compared to placebo in the treatment of subjects with 
plaque psoriasis of moderate severity.  These results from the CC-10004-PSOR-12 study are 
consistent with results from the pivotal Phase 3 studies CC-10004-PSOR-008 and CC-10004-
PSOR 009, which were conducted in subjects with moderate to severe psoriasis.
This study will directly investigate the safety and efficacy of apremilast 30 mg BID, compared 
with placebo, in the treatment of subjects with mild to moderate plaque psoriasis. While PASI-75 
has been the standard primary efficacy endpoint to measure disease severity in subjects with 
moderate to severe plaque psoriasis (BSA ≥10%), the utility of PASI is limited by its decreased 
sensitivity in moderate disease (BSA < 10%) where the general degree of improvement is 
underestimated (Spuls, 2010; Menter, 2008).  The PASI scoring system combines the severity of 
the psoriatic lesion and BSA involvement into a single score of 0-72.  Assessment of PASI 
includes the scoring of affected skin based on categories of involved BSA, with the lowest score 
covering a BSA of < 10%. As the extent of the psoriatic lesion decreases, the score is 
increasingly dependent on plaque severity.  Consequently, in subjects with a baseline BSA of 
< 10%, the PASI score can no longer account for changes in affected skin surface area, but only 
plaque severity.
The primary endpoint will be the proportion of subjects with an sPGA score of 0 (clear) or 1 
(almost clear) at Week 16 with at least a 2-point reduction from baseline.  The sPGA is a 5-point 
scale ranging from 0 (clear) to 4 (severe), incorporating an assessment of the severity of the 3 
primary signs of the disease: erythema, scaling and plaque elevation (Feldman, 2005).  This 
assessment has been used routinely in pivotal studies evaluating response to investigational 
psoriasis therapies and has been used in all clinical psoriasis trials with apremilast.  In the 
proposed study population of subjects with a baseline of sPGA of mild (2) or moderate (3), in 
whom topicals are inadequate, inappropriate or contraindicated, Celgene believes that achieving 
an sPGA score of clear (0) or almost clear (1) with at least a 2-point at Week 16 will represent a 
clinically meaningful benefit in patients with limited treatment options. 
Secondary endpoints of response will include, at Week 16, proportion of subjects who improved 
≥ 75% in BSA, change from baseline in affected BSA, PASI score, proportion of subjects who 
achieved BSA ≤ 3%, proportion of subjects with ≥4-point reduction (improvement) in the whole 
body itch numeric rating scale (NRS) score among subjects with baseline whole body itch NRS 
≥ 4, proportion of subjects with Scalp Physician Global Assessment (ScPGA) score of clear (0) 
or almost clear (1) and with at least a 2-point reduction among subjects with baseline ScPGA 
score ≥ 2, and Dermatology Life Quality Index (DLQI) total score.
Eligible subjects will be randomized 1:1 to receive either apremilast 30 mg BID or placebo.
Randomization will be stratified by baseline sPGA score (mild [2] or moderate [3]) to ensure 
balance between treatment arms with respect to baseline severity of psoriasis. Approximately 


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
19
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
30% of subjects randomized will have baseline sPGA score of mild (2) and approximately 70% 
of subjects will have a baseline sPGA score of moderate (3).
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
In addition to subgroup analysis of Phase 3 pivotal studies of CC-10004-PSOR-008 and CC-
10004-PSOR-009, Study CC-10004-PSOR-012, a randomized, double-blind, placebo-controlled 
Phase 4 study, demonstrated that apremilast 30 mg BID provided a treatment benefit in subjects 
with moderate plaque psoriasis. This study will directly investigate the safety and efficacy of this 
dosing regimen in the treatment of subjects with mild to moderate plaque psoriasis.
1.3.4.
Rationale for Choice of Comparator Compounds
A randomized, double-blind placebo-controlled design was chosen in order to measure the 
absolute treatment effect of apremilast 30 mg BID in mild to moderate plaque psoriasis.  The 
placebo-controlled design also minimizes subject and investigator bias in evaluating the efficacy 
and safety of apremilast in the selected patient population (Food and Drug Administration [FDA] 
Guidance for Industry E10 [FDA, 2016]).


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
20
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
21
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the clinical efficacy of oral apremilast 30 mg twice daily 
(BID), compared to placebo, in subjects with mild to moderate plaque psoriasis during the 16-week 
Placebo-controlled Phase.
Secondary Objectives
The secondary objectives are:

To evaluate the safety and tolerability of apremilast 30 mg BID, compared with placebo, in 
subjects with mild to moderate plaque psoriasis

To evaluate the effect of apremilast 30 mg BID compared with placebo on itch over the whole 
body caused by plaque psoriasis

To evaluate the effect of apremilast 30 mg BID compared with placebo on Health-related Quality 
of Life (HRQoL) 
Exploratory Objective(s)
The exploratory objectives are:


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Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Static Physician Global 
Assessment (sPGA) 0/1
Proportion of subjects with an 
sPGA score of clear (0) or almost 
clear (1) and with at least a 2-point 
reduction from baseline
Week 16
Secondary 
Body Surface Area (BSA)
Proportion of subjects who 
improved ≥ 75% in BSA from 
baseline
Week 16
BSA
Change from baseline in affected 
BSA.
Week 16
Psoriasis Area and Severity 
Index (PASI)
Change from baseline in total 
PASI score
Week 16
BSA
Proportion of subjects who 
achieved BSA ≤ 3% for subjects 
with baseline BSA > 3%
Week 16
Whole body itch numeric 
rating scale (NRS)
Proportion of subjects with ≥4-
point reduction (improvement) 
from baseline in the whole body 
itch NRS score among subjects 
with baseline whole body itch 
NRS ≥ 4
Week 16
Scalp Physician Global 
Assessment (ScPGA)
Proportion of subjects with a 
ScPGA score of clear (0) or almost 
clear (1) with at least a 2-point 
reduction from baseline among 
subjects with baseline ScPGA 
score ≥ 2
Week 16
Dermatology Life Quality 
Index (DLQI)
Change from baseline in DLQI 
total score
Week 16
Safety
Type, frequency, severity and 
relationship of adverse events to 
investigational product (IP)
Throughout study 
(Day 0 to end of 
Observational 
Follow-up Phase)


EDMS Doc. Number: 23137123 - 22819879
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CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Exploratory


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Celgene Corporation
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CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study designed to 
evaluate the efficacy and safety of apremilast (CC-10004) in subjects with mild to moderate 
plaque psoriasis. 
Approximately 574 subjects will be enrolled and randomized 1:1 to receive either apremilast 30 
mg BID or placebo for the first 16 weeks. Subjects will be randomized based on a permuted 
block randomization using a centralized Interactive Response Technology (IRT). Randomization 
to apremilast arm or placebo arm will be stratified by baseline sPGA score (mild [2] or moderate 
[3]).  Approximately 30% of subjects randomized will have a baseline sPGA score of mild (2) 
and approximately 70% of subjects will have a baseline sPGA score of moderate (3).

Subjects randomized to the apremilast 30 mg BID treatment group will receive 
apremilast 30 mg tablets orally twice daily for the first 16 weeks

Subjects randomized to the placebo treatment group will receive placebo tablets 
(identical in appearance to apremilast 30 mg tablets) orally twice daily for the first 16 
weeks

All subjects will receive apremilast 30 mg tablets orally twice daily after the Week 16 
Visit through the end of the Apremilast Extension Phase of the study
The study will consist of four phases (Figure 1):

Screening Phase – up to 35 days

Double-blind Placebo-controlled Phase – Weeks 0 to 16

Subjects will be randomly assigned in a 1:1 ratio to either apremilast 30 mg BID 
or placebo.  

Apremilast Extension Phase – Weeks 16 to 32

All subjects will be switched to (or continue with) apremilast 30 mg BID.  All 
subjects will maintain this dosing through Week 32.

Observational Follow-up Phase – 4 weeks

Four-week Post-Treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue the study early
The blind should be maintained for persons responsible for the ongoing conduct of the study. 
Blinded persons may include but are not limited to: Clinical Research Physician, Clinical 
Research Scientist, Clinical Trial Manager, Study Statistician, Data Manager, Programmers, 
Clinical Research Associates.
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed; the primary data analysis will be conducted and a Week 
16 Clinical Study Report (CSR) will be generated. However, unblinded data will only be made 


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
25
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
available to select Sponsor and Contract Research Organization (CRO) team members involved 
with analysis of the data and preparation of the Week 16 CSR. All other Sponsor, site, and CRO 
personnel directly involved with the conduct of the study, will remain blinded to treatment 
assignments until the final database lock at the conclusion of the study.
Figure 1:
Study Design
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
3.2.
Study Duration for Subjects 
Subjects who complete the entire study will spend a total of approximately 41 weeks in this 
clinical trial:

Up to 35 days (5 weeks) in the Screening Phase

Weeks 0 to 16 (16 weeks) in the Double-blind Placebo-controlled Phase

Weeks 16 to 32 (16 weeks) in the Apremilast Extension Phase

Four-week (4 weeks) Post-treatment Observational Follow-up Phase
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
26
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 574 subjects with mild to moderate plaque psoriasis will be enrolled and 
randomized from investigator sites in Canada and the United States of America (USA).
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject must be male or female, ≥18 years of age at the time of signing the informed 
consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments / procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. Subject must have a diagnosis of chronic plaque psoriasis for at least 6 months prior to 
signing the ICF.
5. Subject must have a diagnosis of mild to moderate plaque psoriasis at both Screening and 
Baseline as defined by: 
a.
sPGA score of 2-3 (mild to moderate)
b. BSA 2-15% 
c.
PASI score 2-15
6. Subject must be inadequately controlled with, or intolerant of at least one topical therapy
(including topical corticosteroids, topical retinoids or vitamin D analog preparations,
calcipotriene and betamethasone dipropionate ointment or foam, tacrolimus, 
pimecrolimus, or anthralin/dithranol) for the treatment of psoriasis at both Screening and 
Baseline.
7. Subject has not had prior exposure to biologics for the treatment of psoriatic arthritis, 
psoriasis, or any other indication that could impact the assessment of psoriasis.
8. Subject must be in good health (except for psoriasis) as judged by the investigator, based 
on medical history, physical examination, clinical laboratories, and urinalysis.
9. Subject must meet the following laboratory criteria:
a.
White blood cell count ≥3000/mm3 (≥3.0 x 109/L) and < 14,000/mm3 (< 14 x 109/L)
b. Platelet count ≥100,000/μL (≥100 x 109/L)
c.
Serum creatinine ≤1.5 mg/dL (≤132.6 μmol/L)
d. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase 
[SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase 
[SGPT]) ≤2 x upper limit of normal (ULN)
e.
Total bilirubin ≤ 2 mg/dL (34 μmol/L)


EDMS Doc. Number: 23137123 - 22819879
Apremilast
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Confidential and Proprietary
27
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
10. Females of childbearing potential (FCBP)1 must have a negative pregnancy test at 
Screening and Baseline.  While on investigational product and for at least 28 days after 
taking the last dose of investigational product, FCBP who engage in activity in which 
conception is possible must use one of the approved contraceptive2 options described 
below: 
Option 1: Any one of the following highly effective methods: hormonal contraception 
(oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); 
tubal ligation; or partner’s vasectomy;
OR
Option 2: Male or female condom (latex condom or nonlatex condom NOT made out 
of natural [animal] membrane [for example, polyurethane]; PLUS one additional 
barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or 
(c) contraceptive sponge with spermicide.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
2. Subjects has any condition, including the presence of laboratory abnormalities, which 
would place the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject is pregnant or breast feeding.
5. Subject has hepatitis B surface antigen or anti-hepatitis C antibody positive at Screening.
6. Subject has active tuberculosis (TB) or a history of incompletely treated TB.
7. Subject has history of positive human immunodeficiency virus (HIV), or has congenital 
or acquired immunodeficiency (eg, common variable immunodeficiency disease).
8. Subject has active substance abuse or a history of substance abuse within 6 months prior 
to signing the ICF.
9. Subject has bacterial infections requiring treatment with oral or injectable antibiotics, or 
significant viral or fungal infections, within 4 weeks of signing the ICF.  Any treatment 
for such infections must have been completed at least 4 weeks prior to randomization.
10. Subject has malignancy or history of malignancy except for: 
a.
treated (ie, cured) basal cell or squamous cell in situ skin carcinomas; 
                                               
1 A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24 
consecutive months).
2 The female subject’s chosen form of contraception must be effective by the time the female subject is randomized 
into the study (for example, hormonal contraception should be initiated at least 28 days before randomization).


EDMS Doc. Number: 23137123 - 22819879
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Celgene Corporation
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28
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
b. treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in situ of the 
cervix with no evidence of recurrence.
11. Subject has prior history of suicide attempt at any time in the subject’s life time prior to 
signing the informed consent and randomization, or major psychiatric illness requiring 
hospitalization within the last 3 years prior to signing the informed consent.
12. Subject has psoriasis flare/rebound (defined as a sudden worsening of psoriasis which 
requires administration of prohibited medications) within 4 weeks of signing the ICF or 
between the Screening and Baseline Visit.
13. Subject has current or planned concurrent use of the following therapies that may have a 
possible effect on psoriasis during the course of the treatment phase of the trial:
a.
Topical therapy within 2 weeks of randomization (including but not limited to 
topical corticosteroids, topical retinoid or vitamin D analog preparations, 
tacrolimus, pimecrolimus, or anthralin/dithranol). An unmedicated skin 
moisturizer (eg, Eucerin®) will be also permitted for body lesions only.  Subjects 
should not use these topical treatments within 24 hours prior to the clinic visit. 
b. Conventional systemic therapy for psoriasis within 4 weeks prior to 
randomization (including but not limited to cyclosporine, corticosteroids, 
methotrexate, oral retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, 
sulfasalazine, azathioprine, or fumaric acid esters).
c.
Phototherapy treatment of body within 4 weeks prior to randomization (ie, 
ultraviolet B [UVB], psoralen and ultraviolet A [PUVA] radiation).
d. Use of any investigational drug beginning 4 weeks prior to randomization, or 5 
pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer).
14. Subject has evidence of skin conditions that would interfere with clinical assessments.
15. Subject has prolonged sun exposure or use of tanning booths or other ultraviolet (UV) 
light sources.
16. Subject had prior treatment with apremilast.
17. Subject has history of allergy or hypersensitivity to any components of the investigational 
product (IP).


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5.
TABLE OF EVENTS
Table 3:
Table of Events
Screening
Placebo-controlled Treatment Phase
Apremilast Extension Phase
Observational 
Follow-up
Visit Number
1
Baselinea
2
3
4
5
6
7
8
9
10/ETb
11
Week
-5 to 0
0
(Day 1)
2
(± 4 days)
4
(± 4 days)
8
(± 4 days)
12
(± 4 days)
16
(± 4 days)
20
(± 4 days)
24
(± 4 days)
32
(± 4 days)
4 Weeks 
After Last Dose
(± 2 weeks)c
Administrative/Demographics
Informed consentd
X
-
-
-
-
-
-
-
-
-
-
Optional consent for researchd
X
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
Inclusion / Exclusion criteria
X
X
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
-
Prior psoriasis medication
X
-
-
-
-
-
-
-
-
-
-
Prior / concomitant medications or 
therapies
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
Height 
X
-
-
-
-
-
-
-
-
-
-
Weight 
X
X
X
X
X
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination 
X
-
-
-
-
-
-
-
-
X
-
Pregnancy Test for FCBP and 
Contraception Educatione
X
X
-
X
X
X
X
X
X
X
-
Hepatitis B and Cf
X
-
-
-
-
-
-
-
-
-
-
Clinical Laboratory Evaluationsg
X
X
-
-
X
-
X
-
X
X
-


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CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
Table 3:
Table of Events (Continued)
Screening
Placebo-controlled Treatment Phase
Apremilast Extension Phase
Observational 
Follow-up
Visit Number
1
Baselinea
2
3
4
5
6
7
8
9
10/ETb
11
Week
-5 to 0
0
(Day 1)
2
(± 4 days)
4
(± 4 days)
8
(± 4 days)
12
(± 4 days)
16
(± 4 days)
20
(± 4 days)
24
(± 4 days)
32
(± 4 days)
4 Weeks 
After Last Dose
(± 2 weeks)c
C-SSRS screening
X
-
-
-
-
-
-
-
-
-
-
C-SSRS since last visit
-
X
X
X
X
X
X
X
X
X
X
Psychiatric evaluationh
-
-
-
-
-
-
-
-
-
-
-
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Psoriasis Flare Assessmenti
-
-
-
-
-
-
-
-
-
-
-
Clinical Efficacy Assessments
sPGA
X
X
X
X
X
X
X
X
X
X
X
BSA
X
X
X
X
X
X
X
X
X
X
X
PASI
X
X
X
X
X
X
X
X
X
X
X
ScPGAj
X
X
X
X
X
X
X
X
X
X
X
NAPSIj
-
X
-
-
X
-
X
-
-
X
-
Subject Rated Outcomes or Health-related Quality of Life Assessment
Whole body itch NRS
-
X
X
X
X
X
X
X
X
X
-
DLQI
-
X
X
X
X
X
X
-
-
X
-
Pharmacodynamic Assessments (optional for subjects)
Inflammatory Protein Biomarkers
-
X
-
-
-
-
X
-
-
-
-


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Table 3:
Table of Events (Continued)
Screening
Placebo-controlled Treatment Phase
Apremilast Extension Phase
Observational 
Follow-up
Visit Number
1
Baselinea
2
3
4
5
6
7
8
9
10/ETb
11
Week
-5 to 0
0
(Day 1)
2
(± 4 days)
4
(± 4 days)
8
(± 4 days)
12
(± 4 days)
16
(± 4 days)
20
(± 4 days)
24
(± 4 days)
32
(± 4 days)
4 Weeks 
After Last Dose
(± 2 weeks)c
Dosing
Dispense IP
-
X
-
X
X
X
X
X
X
-
-
Return and count IP tablets
-
-
-
X
X
X
X
X
X
X
-
BSA = body surface area; C-SSRS = Columbia-Suicide Severity Rating Scale; DLQI = Dermatology Life Quality Index; ET = Early Termination Visit; FCBP = females of 
childbearing potential; IP = investigational product; NAPSI = Nail Psoriasis Severity Index; NRS = Numeric Rating Scale; ScPGA = Scalp Physician Global Assessment; RNA = 
ribonucleic acid; sPGA = Static Physician Global Assessment.
a All baseline assessments must be completed prior to randomization and dispensing of IP.
b Visit 10 will serve as the Early Termination Visit for any subject who prematurely discontinues from the study.
c All subjects who complete the study or discontinue the study early will be asked to enter the Four-week Post-Treatment Observational Follow-up Phase.
d Written informed consent will be obtained by the Principal Investigator or designee prior to performing any study assessments.  Optional consents for research include: RNA 
Gene Expression, 
sub-studies. 
e FCBP:  Serum pregnancy tests will be performed at the Screening and Early Termination/Visit 10.  Urine dipstick pregnancy test will be performed at baseline, prior to dosing
and at Visits 4, 5, 6, 7, 8, and 9.  An unscheduled serum pregnancy test should be administered if the subject has missed a menstrual period or has a positive urine dipstick test.  
The investigator will educate all FCBP about the options for and correct use of contraceptive methods at the Screening and Baseline Visits and at any time when a FCBP’s 
contraceptive measures or ability to become pregnant changes.
f Hepatitis B surface antigen and anti-hepatitis C antibody.  
g Refer to Section 6.5, Clinical Laboratory Evaluations for details regarding hematology, clinical chemistries, and urinalysis parameters to be tested.
h Should be performed at any time during the study when suicidal thoughts or a suicide attempt is identified.  See Section 6.5, Psychiatric Evaluation.
i At any time during the study, a psoriasis flare may be reported as an adverse event, provided it meets the protocol definition.  See Section 6.5, Psoriasis Flare Assessments.
j Post-baseline NAPSI and ScPGA assessments will only be performed for subjects with nail and/or scalp involvement, respectively, at Baseline.


EDMS Doc. Number: 23137123 - 22819879
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6.
PROCEDURES
The following administrative/demographic procedures will be conducted as outlined in the Table 
of Events, Table 3.
Informed Consent
An informed consent form (ICF) must be signed by the subject before any study-related 
assessments are performed.  Details of the informed consent process may be found in 
Section 13.3.
The appropriate optional consent form(s) for research must be signed by the subject before any 
sub-study sampling takes place.  
Inclusion/Exclusion Criteria
Subjects must meet all inclusion criteria (Section 4.2) and must not have any of the conditions 
specified in the exclusion criteria (Section 4.3) to qualify for participation in the study.  The 
subject’s source documents must support his/her qualifications for the study (eg, if a female 
subject does not require pregnancy testing and birth control because of a hysterectomy, the date 
of the hysterectomy must be included in the medical history).
Medical and Disease History
Relevant medical history, as defined in the electronic Case Report Form (eCRF) Completion 
Guidelines, should be recorded, including smoking and alcohol history, as well as previous 
relevant surgeries (please refer to the eCRF Completion Guidelines for further details).  Disease 
history includes history of psoriasis.
Prior/Concomitant Medications and Therapies
All medications and therapies being taken/used by the subject at the time of consent or at any 
time during the study should be recorded.  Other key medications and therapies, such as previous 
treatment for TB or relevant diseases, should be recorded.  Please refer to the eCRF Completion 
Guidelines and the Study Manual for additional instructions and for further details.
All medications and therapies for psoriasis, including topicals (used within the last 5 years prior 
to randomization), systemics, and all medications and therapies for psoriatic arthritis, should be 
recorded.  The stop dates for all medications and therapies prohibited in the study should be 
recorded.  Responses to prior psoriasis therapies should also be recorded.  Please refer to the 
eCRF Completion Guidelines for additional instructions.
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 35 days of screening unless noted otherwise below. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.


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Safety laboratory analyses and all assessments will be performed by the central laboratory. 
Screening laboratory values must demonstrate subject eligibility, but exclusionary results may be 
re-tested one time within the screening window, without Celgene Medical Monitor approval.
Subjects who fail initial screening may re-screen one additional time for the study. 
Efficacy assessments may be performed by the investigator or qualified designee at any time 
during the Screening Visit.  However, when conducting the efficacy assessments, the 
investigator must complete these assessments in the following order: 1) sPGA; 2) BSA; 3) PASI; 
4) ScPGA.
The following assessments will be performed at screening as specified in the Table of Events, 
Table 3, after informed consent has been obtained:

Optional consents for research sub-studies

Columbia-Suicide Severity Rating Scale (C-SSRS)

Demographics (initials, date of birth, sex, race, and ethnicity-if allowed by local 
regulations)

Prior disease therapies: includes topical, systemic, and phototherapies

Complete medical history (all relevant medical conditions diagnosed/ occurring prior 
to screening should also be included)

Height

Weight

Complete physical examination

Vital signs (including blood pressure, temperature, and heart rate)

Efficacy assessments (see Section 6.4)

Hematology panel 

Chemistry panel (including 

Urinalysis

Hepatitis B and C screening 

Serum pregnancy test is required for all female subjects of childbearing potential.  
Counseling about pregnancy precautions and the potential risks of fetal exposure 

Adverse event assessment (begins when the subject signs the informed consent form)

Prior/concomitant medications
6.2.
Treatment Period
The subject will begin treatment upon confirmation of eligibility. For visits within the Placebo-
controlled Phase and Apremilast Extension Phase, an administrative window of ± 4 days is 
permitted.


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During the treatment period, subjects must complete the itch NRS and subject questionnaires 
prior to any other study procedure being performed. The subject should complete the 
questionnaires in the following order when applicable: 1) whole body itch NRS; 2) DLQI. 
During the treatment period, efficacy assessments may be performed by the investigator or 
qualified designee at any time during a study visit. The investigator performing efficacy 
assessments shall make independent observations at a given study visit and shall not review 
previous assessments or subject-derived data in advance of conducting the assessments.  When 
conducting the efficacy assessments, the investigator must complete these assessments in the 
following order: 1) sPGA; 2) BSA; 3) PASI; 4) ScPGA; 5) NAPSI.
The following evaluations/assessments will be performed at the frequency specified in the Table 
of Events, Table 3:

Subject reported outcomes or health-related quality of life (HRQoL)

Concomitant medications or therapies evaluation

Vital signs

Weight 

Biomarker and Pharmacodynamic sampling

Hematology panel 

Chemistry panel (including 

Urinalysis

C-SSRS

Adverse event evaluation (continuously)

Efficacy assessments (see Section 6.4)

Urine pregnancy test and contraception education (prior to dosing on Day 1)

IP dispense, return, and IP tablets count
6.2.1.
End of Treatment
An end of treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made.  The end of treatment (Visit 10) assessments will also be performed for 
subjects who complete the study.
Subjects must complete the itch NRS and subject questionnaires prior to any other study 
procedure being performed. The subject should complete the questionnaires in the following 
order when applicable: 1) whole body itch NRS; 2) DLQI.
The investigator performing efficacy assessments shall make independent observations at a given 
study visit and shall not review previous assessments or subject-derived data in advance of 
conducting the assessments.  When conducting the efficacy assessments, the investigator must 


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
35
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
complete these assessments in the following order: 1) sPGA; 2) BSA; 3) PASI; 4) ScPGA; 5) 
NAPSI.
The following evaluations will be performed as specified in the Table of Events, Table 3:

Subject reported outcomes or health-related quality of life (HRQoL)

Concomitant medications or therapies evaluation

Complete physical exam

Vital signs

Weight 

Hematology panel 

Chemistry panel (including 

Urinalysis

C-SSRS

Adverse event evaluation (continuously)

Efficacy assessments (see Section 6.4)

Serum pregnancy test

IP return and IP tablets count
6.3.
Observational Follow-up Period
For visits within the Observational Follow-up Phase, an administrative window of ± 2 weeks 
from the last dose of IP is permitted.
6.3.1.
Safety Follow-up
All subjects will be followed for 28 days after the last dose of IP for AE reporting, as well as 
serious adverse events (SAEs) made known to the Investigator at any time thereafter that are 
suspected of being related to IP, as described in Section 10.1.
The following evaluations will be performed at the Follow-up Visit as specified in the Table of 
Events,Table 3.

Concomitant medications or therapies evaluation

Weight

Vital signs

Adverse event evaluation

C-SSRS


EDMS Doc. Number: 23137123 - 22819879
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6.3.2.
Efficacy Follow-up
During the follow-up period, efficacy assessments may be performed by the investigator or
qualified designee at any time during a study visit.  The investigator performing efficacy 
assessments shall make independent observations at a given study visit and shall not review 
previous assessments in advance of conducting the assessments.  When conducting the efficacy 
assessments, the investigator must complete these assessments in the following order: 1) sPGA; 
2) BSA; 3) PASI; 4) ScPGA.
6.4.
Efficacy Assessments
The following assessments will be conducted as outlined in the Table of Events, Table 3

static Physician Global Assessment
The sPGA is the assessment by the Investigator of the overall disease severity at the 
time of evaluation.  The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), 
incorporating an assessment of the severity of the three primary signs of the disease: 
erythema, scaling and plaque elevation.  When making the assessment of overall 
severity, the Investigator should factor in areas that have already been cleared (ie, 
have scores of 0) and not just evaluate remaining lesions for severity, ie, the severity 
of each sign is averaged across all areas of involvement, including cleared lesions. 
In the event of different severities across disease signs, the sign that is the 
predominant feature of the disease should be used to help determine the sPGA score.
See (Appendix B) grading criteria.

Body Surface Area
The BSA is a measurement of involved skin over the whole body.  The overall BSA 
affected by psoriasis is estimated based on the palm area of the subject’s hand.  The 
surface area of the whole body is made up of approximately 100 palms or 
“handprints” (each entire palmar surface or “handprint” equates to approximately 1% 
of total body surface area).

Psoriasis Area and Severity Index 
The PASI will be determined for all subjects throughout the study.  The PASI 
calculation is described in Appendix C.
The PASI is a measure of psoriatic disease severity taking into account qualitative 
lesion characteristics (erythema, thickness, and scaling) and degree of skin surface 
area involvement on defined anatomical regions.  The PASI is a validated instrument 
that has become standard in clinical trials for psoriasis.
Psoriasis Area Severity Index scores range from 0 to 72, with higher scores reflecting 
greater disease severity (Fredriksson, 1978).  Erythema, thickness, and scaling are 
scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: 
head, trunk, upper limbs, and lower limbs.  Degree of involvement on each of the 
4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% 
involvement).  The total qualitative score (sum of erythema, thickness, and scaling 
scores) is multiplied by the degree of involvement for each anatomic region and then 


EDMS Doc. Number: 23137123 - 22819879
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Confidential and Proprietary
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CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
multiplied by a constant.  These values for each anatomic region are summed to yield 
the PASI score.

Scalp Physician Global Assessment 
The ScPGA is a measurement of overall scalp involvement by the Investigator at the 
time of evaluation.  The ScPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), 
incorporating an assessment of the severity of the three primary signs of the disease: 
erythema, scaling and plaque elevation.  When making the assessment of overall 
scalp severity, the Investigator should factor in areas that have already been cleared 
(ie, have scores of 0) and not just evaluate remaining lesions for severity, ie, the 
severity of each sign is averaged across all areas of involvement, including cleared 
lesions.  
In the event of different severities across signs of psoriasis, the sign that is the 
predominant feature of psoriasis should be used to help determine the ScPGA score. 
See Appendix D for grading criteria.

Nail Assessments/Nail Psoriasis Severity Index
The number of fingers with psoriasis nail involvement will be counted. The NAPSI 
will assess one target thumb nail or fingernail representing the worst nail psoriasis 
involvement at baseline.  See Appendix E for grading criteria.
6.5.
Safety Assessments 

Contraception Education
The risks to a fetus or to a nursing child from apremilast are not known at this time.  
Results of animal and in vitro studies can be found in the current IB.
All FCBP must use one of the approved contraceptive options as described in 
Section 4.2 while on IP and for at least 28 days after administration of the last dose of 
the IP.  The female subject’s chosen form of contraception must be effective by the 
time the female subject is randomized into the study (for example, hormonal 
contraception should be initiated at least 28 days before randomization).
At screening and at baseline, and at any time during the study when a female subject 
of childbearing potential’s contraceptive measures or ability to become pregnant 
changes, the Investigator will educate the subject regarding contraception options and 
correct and consistent use of effective contraceptive methods in order to successfully 
prevent pregnancy.

Serum and Urine Pregnancy Tests for Females of Childbearing Potential
A serum pregnancy test with a sensitivity of ≤ 25 mIU/mL will be required for FCBP 
subjects at screening and at the Early Termination Visit or Visit 10.  In addition, a 
local urine pregnancy test kit will be provided by the central laboratory and will be 
performed at the site on all FCBP subjects at the Baseline Visit, prior to dosing, and 
at Visits 4, 5, 6, 7, 8, and 9.  An unscheduled serum pregnancy test should be 
performed if the FCBP subject has missed a menstrual period or has a positive urine 
dipstick test.


EDMS Doc. Number: 23137123 - 22819879
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Confidential and Proprietary
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CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018

Hepatitis B and C
Hepatitis testing will include hepatitis B surface antigen and anti-hepatitis C antibody.

Vital Signs, Height, and Weight
Vital signs, including temperature, pulse, and seated blood pressure, will be taken 
during the visits indicated in Table 3.  Height will be measured and recorded at 
Screening; weight will also be measured and recorded at screening and then as 
indicated in Table 3.  Body mass index (BMI) will be calculated at Screening.

Complete Physical Examination
A complete physical examination includes evaluations of skin, nasal cavities, eyes, 
ears, lymph nodes, and respiratory, cardiovascular, gastrointestinal, neurological, and 
musculoskeletal systems.  The complete physical examination is done at screening 
and at the Early Termination or Last Treatment Visit (Visit 10).

Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS (Posner, 2007) is a scale that captures the occurrence, severity, and
frequency of suicide-related ideations and behaviors during the assessment period
(Appendix F). The C-SSRS must be administered by appropriately trained site 
personnel. The C-SSRS will be completed at all study visits. At Visit 1 (Screening) 
the C-SSRS will be completed for the subject’s lifetime history of suicidal ideation 
and behavior. At all other visits the C-SSRS will be completed for ideation and 
behavior since the previous visit.

Psychiatric Evaluation
Apremilast prescriber information (eg, Summary of Product Characteristics, Package 
Insert) includes a warning regarding depression and suicidal thoughts. Patients with 
chronic diseases may be prone to depression. The risks and benefits of starting or 
continuing treatment with apremilast should be carefully assessed if patients report 
previous or existing psychiatric symptoms or if concomitant treatment with other 
medicinal products likely to cause psychiatric events is intended. At any time during 
the study, subjects who have suicidal thoughts or behavior should be evaluated. If the 
psychiatrist deems the subject not to be a risk for suicide, the subject may remain in 
the study, but if a risk of suicide is confirmed, the subject must be discontinued from 
the study. If the subject is discontinued during the treatment phase of the study, the 
subject should return for the Observational Follow-up Visit.
A copy of the psychiatric evaluation report must be in the subject’s source 
documentation, especially if the subject is confirmed not to be at risk for suicide and 
is continuing in the study.

Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed by a central laboratory and as 
indicated in Table 3.  Clinical laboratory evaluations include complete blood count 
(red blood cell [RBC] count, hemoglobin, hematocrit, white blood cell [WBC] count 
and differential, absolute WBC counts, platelet count); serum chemistries (total 


EDMS Doc. Number: 23137123 - 22819879
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protein, albumin, calcium, phosphorous, glucose, total cholesterol [TC], triglycerides, 
high-density lipoprotein [HDL], high-density lipoprotein cholesterol [HDL-C], low-
density lipoprotein cholesterol [LDL-C], uric acid, total bilirubin, alkaline 
phosphatase, aspartate aminotransferase [AST; serum glutamic-oxaloacetic 
transaminase, SGOT], alanine aminotransferase [ALT; serum glutamic pyruvic 
transaminase, SGPT], sodium, potassium, chloride, bicarbonate [carbon dioxide, 
CO2], blood urea nitrogen, creatinine, lactate dehydrogenase [LDH], and 
magnesium); as well as 
and dipstick urinalysis (specific gravity, 
pH, glucose, ketones, protein, blood, bilirubin, leukocyte esterase, nitrite, and 
urobilinogen).  Dipstick urinalysis will be performed by the central laboratory; 
microscopic urinalysis (epithelial cells, RBC, WBC, and casts) will be performed 
only if the dipstick urinalysis is abnormal.
Fasting is not required.  However, if significant elevation of serum lipid(s) is 
observed, a fasting retest should be requested to determine whether or not elevation 
was caused by eating.  

Psoriasis Flare Assessments
Psoriasis flare represents an atypical or unusual worsening of disease during 
treatment (Carey, 2006).  It is defined as a sudden intensification of psoriasis 
requiring medical intervention or a diagnosis of new generalized erythrodermic, 
inflammatory, or pustular psoriasis.  A more typical, gradual worsening of plaque 
psoriasis would not be recorded as an AE. 

Adverse Events
Details of AE reporting may be found in Section 10.1.
6.6.
Pharmacokinetics
Not Applicable.  


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
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CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018


EDMS Doc. Number: 23137123 - 22819879
Apremilast
Protocol CC-10004-PSOR-022
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Confidential and Proprietary
41
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
6.8.
Subject Reported Outcomes or Health-related Quality of Life 
Assessment
6.8.1.
Whole Body Itch Numeric Rating Scale Assessment
Prior to any other procedures or assessments being performed during the treatment 
period, the subject will be asked to assess whole body itch and select a number on a 
scale of 0-10, where “0” represents no itch, and “10” represents the worst imaginable 
itch.  The number selected by the subject will be recorded in the database.  See 
Appendix G.
The Whole Body Itch NRS scale has been validated among patients with moderate to 
severe plaque psoriasis, and a 4-point change from baseline was shown to be optimal 
for demonstrating a level of clinically meaningful improvement in itch severity
(Kimball, 2016).
6.8.2.
Dermatology Life Quality Index 
The DLQI was developed as a simple, compact, and practical questionnaire for use in 
a dermatology clinical setting to assess limitations related to the impact of skin 
disease (Finlay, 1994).  The instrument contains 10 items dealing with the subject’s 
skin.  With the exception of Item Number 7, the subject responds on a four-point 
scale, ranging from “Very Much” to “Not at All.”  Item Number 7 is a multi-part 
item, the first part of which ascertains whether the subject’s skin prevented them from 
working or studying (Yes or No), and if “No,” then the subject is asked how much of 
a problem the skin has been at work or study over the past week, with response 
alternatives being “A lot,” “A little,” or “Not at all.”  
The DLQI Total score has a possible range from 0 to 30, with 30 corresponding to the 
worst health-related quality of life, and 0 corresponding to the best score.  The 
developers suggest that the DLQI can be grouped into six subscales: symptoms and 
feelings; daily activities; leisure; work/school; personal relationships; and treatment.  
Scores for four of the subscales (symptoms and feelings, daily activities, leisure, and 
personal relationships) range from 0 to 6; scores for two of the subscales 
(work/school and treatment) range from 0 to 3.  Higher scores correspond to poorer 
health-related quality of life.  See Appendix H.


EDMS Doc. Number: 23137123 - 22819879
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
The chemical name of apremilast (CC-10004) is acetamide, N-[2-[(1S)-1-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl].
Apremilast will be supplied by the Sponsor, Celgene Corporation, and labeled appropriately as 
investigational product for this study.  
All IP will be provided in blister cards throughout the entire study.  Apremilast will be provided 
as 10, 20, or 30 mg tablets.  Placebo will be provided as identically appearing 10, 20, or 30 mg 
tablets. Apremilast, the investigational product (IP), will be taken orally twice daily, 
approximately 12 hours apart, without restriction of food or drink.  To mitigate potential 
gastrointestinal (GI) side effects, dose titration will be implemented in the first week of this study 
(see Table 4).
During Week 0 (Days 1 to 7), subjects will be dispensed placebo or 30 mg BID titration and 
treatment blister cards with 10, 20, and 30 mg apremilast tablets or identically appearing placebo 
tablets.  The blister cards will contain all IP required for 4 weeks of treatment, with the first 7 
days containing the titration supplies or matching placebo (see Table 4 Treatment Schema for 
Dose Titration at Visit 2 [Week 0] which details the titration supplies from Day 1 to Day 7).
At Visit 2 (Week 0), subjects who meet entry criteria will be randomized using a permuted block 
randomization in parallel 1:1 to receive either apremilast 30 mg BID or placebo, using a 
centralized Interactive Response Technology (IRT).  Treatment assignment will be stratified by 
baseline sPGA score [mild (2), or moderate (3)]. Approximately 30% of subjects randomized 
will have baseline sPGA score of mild (2) and approximately 70% of subjects will have a 
baseline sPGA score of moderate (3). The IRT system will monitor the total enrollment of each 
strata and screening will close once the approximate percentages are reached. IP will be 
dispensed as indicated below. 

Weeks 0 to 16: Double-blind, Placebo-controlled Treatment Phase: Apremilast 30 mg 
BID or placebo BID. 

Week 0 to 1: subjects will be dose titrated as described above and detailed in 
Table 4.

Weeks 16 to 32: Apremilast Extension Phase: Apremilast 30 mg BID. 

Week 16 to 17: subjects will be dose titrated as described below and detailed in 
Table 5.
Starting at Week 16, all subjects will be switched to, or will continue with apremilast. Subjects 
originally randomized to placebo at Week 0 will be switched to apremilast 30 mg BID at 
Week 16. The 30 mg BID titration and treatment blister cards will be used for subjects switching 
from placebo to apremilast; dummy titration blister cards (dosing at 30 mg BID directly) will be 
used for subjects initially randomized to receive apremilast 30 mg BID. At all other visits during 
the Apremilast Extension Phase, all subjects will receive apremilast 30 mg tablets which are to 
be taken twice daily.


EDMS Doc. Number: 23137123 - 22819879
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The treatment schema for dose titration at baseline is shown in Table 4.
Table 4:
Treatment Schema for Dose Titration at Visit 2 (Week 0)
Week 0
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6-7
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Apremilast 
30 mg BID
10 mg A
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg A
20 mg P 
30 mg P
10 mg A
20 mg P 
30 mg P
10 mg A
20 mg P 
30 mg P
10 mg P
20 mg A 
30 mg P
10 mg P
20 mg A 
30 mg P
10 mg P
20 mg A 
30 mg P
10 mg P
20 mg A 
30 mg P
10 mg P
20 mg P 
30 mg A
30 mg A
30 mg A
Placebo
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
30 mg P
30 mg P
A = Apremilast; BID = twice daily; P = Placebo.
During Weeks 16 to 32, the IP will remain blinded, to prevent study personnel and subjects from knowing the IP assignment in the 
Placebo-controlled Treatment Phase and to maintain the blind regarding the initial treatment assignment, all subjects will receive dose 
titration cards at Visit 7 (Week 16).  Although only subjects initially randomized to placebo will be dose titrated during their first 
week of the Apremilast Extension Phase, all subjects entering the Apremilast Extension Phase will receive identically-appearing 
titration/treatment cards as shown in Table 5.


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Table 5:
Treatment Schema for Dose Titration at Visit 7 (Week 16)
Week 16
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6-7
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Apremilast 
30 mg BID
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
10 mg P
20 mg P 
30 mg A
30 mg A
30 mg A
Placebo to 
APR 30 
BID
10 mg A
20 mg P 
30 mg P
10 mg P
20 mg P 
30 mg P
10 mg A
20 mg P 
30 mg P
10 mg A
20 mg P 
30 mg P
10 mg A
20 mg P 
30 mg P
10 mg P
20 mg A 
30 mg P
10 mg P
20 mg A 
30 mg P
10 mg P
20 mg A 
30 mg P
10 mg P
20 mg A 
30 mg P
10 mg P
20 mg P 
30 mg A
30 mg A
30 mg A
A = Apremilast; BID = twice daily; P = Placebo.


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7.2.
Treatment Administration and Schedule
Investigational product will be taken orally twice daily, approximately 12 hours apart, without 
restriction of food or drink.  To mitigate potential gastrointestinal (GI) side effects, dose titration 
will be implemented in this study.  During Week 0 (Days 1 to 7) and Week 16 (when placebo 
subjects are switched to receive apremilast 30 mg BID), subjects will be dispensed blister cards 
with 10, 20, and 30 mg apremilast tablets or identically appearing placebo tablets for the dose 
titration.  At all other visits where IP is dispensed, apremilast will be provided in blister cards as 
10, 20, and 30 mg tablets or identically appearing placebo tablets.  The treatment schema for 
dose titration at baseline and Week 16 is shown in Table 4 and Table 5.  Blister card 
configurations are pictured in Appendix I, Appendix J, and Appendix K.
7.3.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the investigational 
product(s) only.  Therefore, for a drug to be subject to the overdose definition it must be both 
required and an investigational drug.  In this study the only required and investigational drug is 
apremilast and the control arm drug (ie, placebo), hence the overdose definition will apply to 
only apremilast (or matching placebo).  Other required or optional non-IP intended for 
prophylaxis of certain side effects are excluded from this definition.
Overdose for this protocol, on a per dose basis, is defined as ingestion of 4 or more 30 mg 
apremilast (or matching placebo) tablets in any 24-hour period whether by accident or 
intentionally. On a schedule or frequency basis, an overdose is defined as dosing more than 4 
times during any 24-hour period.
7.4.
Method of Treatment Assignment
At Visit 2 (Week 0), subjects who meet entry criteria will be randomized using a permuted block 
randomization in parallel 1:1 to receive either apremilast 30 mg BID or placebo, using a 
centralized Interactive Response Technology (IRT).  Designated research personnel at the 
investigational sites will be assigned password protected, coded identification numbers, which 
gives them authorization to enter the IRT to randomize subjects.  
The system will present a menu of questions by which the research center personnel will identify 
the subject and confirm eligibility. When all questions have been answered and the subject 
deemed eligible, the IRT will assign a randomization identification number.  
Confirmation of the randomization will be sent to the investigational site, Celgene, and/or its 
representative. The confirmation reports should be maintained as source documents.  During the 
study visits, the pharmacy or authorized study personnel at the investigational site will dispense 
coded IP kits in accordance with the randomization number assigned by the IRT.
7.5.
Packaging and Labeling
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 


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applicable. Additional information may be included on the label as applicable per local 
regulations.
7.6.
Investigational Product Accountability and Disposal 
The Investigator(s) or designee(s) is responsible for accounting for all IP that is issued to and 
returned by the subject during the course of the study.
The Investigator(s) or designee(s) is responsible for taking an inventory of each shipment of IP 
received, and comparing it with the accompanying IP accountability form.  The Investigator(s) or 
Pharmacist(s) will verify the accuracy of the information on the form, sign and date it, retain a 
copy in the study file, and return a copy to Celgene.
At the study site, all IP will be stored in a locked, safe area to prevent unauthorized access.
The IP should be stored as directed on the package label.
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for investigational product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
7.7.
Investigational Product Compliance
Study personnel will review the instructions printed on the package with the study subjects prior 
to dispensing the IP.  Investigational product will be dispensed as noted in the Table of Events, 
Table 3.  The subjects will be instructed to return the IP containers, including any unused 
medication, to the study site at each visit for tablet counts and reconciliation.  Subjects will be 
asked whether they have taken their IP as instructed at each study visit.  Any problems with IP 
compliance will be reviewed with the subject.  If a subject misses 4 or more consecutive days of 
dosing, Celgene should be contacted to decide whether dosing should resume or whether the 
subject should be terminated from the Treatment Phase of the study, and enter into the 
Observational Follow-up Phase.
Gross compliance problems (eg, missing 4 or more consecutive days of dosing or taking less 
than 75% or more than 120% of the doses between study visits) are protocol deviations and 
should be discussed with Celgene.  Overall compliance with the study treatment regimen is 
defined as taking between 75% and 120% of the expected doses during a subject’s participation 
while in the treatment phases (Placebo-controlled Phase and Apremilast Extension Phases) of the 
study.


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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression. 
Supportive care, including but not limited to antiemetic medications, may be administered at the 
discretion of the Investigator. 
All concomitant treatments, including blood and blood products, used from 28 days prior to first 
dose of IP until 28 days after the last dose of IP, must be reported on the CRF. 
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the current Investigators Brochure and/or local 
package insert.
8.1.
Permitted Concomitant Medications and Procedures
Subjects may take any medication that is not restricted by the protocol and would not be 
expected to interfere with the conduct of the study or affect assessments.  Chronic medication 
should be dosed on a stable regimen.
All medications (prescription and non-prescription), treatments and therapies taken by the 
subject from screening throughout their entire participation in the study, including those initiated
prior to the start of the study, must be recorded on the subject’s source document and on the 
appropriate page of the eCRF.  The dose, unit, frequency, route, indication, the date the 
medication was started and the date the medication was stopped (if not ongoing) must be 
recorded.  The recording of any permitted topical medications taken for psoriasis should also 
include the area of the body to which they are applied and the frequency of application.
The following topical therapies will be permitted during the study:

For body lesions: unmedicated emollients

For scalp lesions: non-medicated shampoos
8.2.
Prohibited Concomitant Medications and Procedures
The following psoriasis medications cannot be administered for the duration of the study:

Topical therapy

Topical therapy, including, but not limited to, topical corticosteroids, retinoids or 
vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin/dithranol 
for body lesions; coal tar, salicylic acid preparations, or medicated shampoos for 
scalp lesions, or as specified in Section 8.1.

Intralesional corticosteroid injections for psoriasis lesions 

Conventional systemic therapy

Systemic therapy including but not limited to cyclosporine, corticosteroids, 
methotrexate, retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, 
sulfasalazine, azathioprine, or fumaric acid esters


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
Phototherapy

UVB or PUVA 

Biologic agents, including:

TNF or IL-17 blockers, anti-IL-12 or anti-IL-23 monoclonal antibodies or 
biosimilars for each

Use of any investigational drug or device

Prolonged sun exposure or any use of tanning booths or other ultraviolet light sources
8.3.
Required Concomitant Medications and Procedures
Not Applicable


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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study of the 
efficacy and safety of apremilast (CC-10004) in subjects with mild to moderate plaque psoriasis. 
Treatment assignment will be stratified by baseline sPGA score [mild (2), or moderate (3)]. 
Approximately 30% of subjects randomized will have baseline sPGA score of mild (2) and 
approximately 70% of subjects will have a baseline sPGA score of moderate (3).
The objective of the statistical analysis will be to evaluate the efficacy and safety of apremilast 
30 mg BID versus placebo for 16 weeks, and to evaluate the effects of apremilast 30 mg BID as 
a treatment for up to 32 weeks in subjects with mild to moderate plaque psoriasis.
After all subjects have completed the Placebo-controlled Phase (Weeks 0 to 16), the primary 
analysis will be performed.  At the study completion, ie, when all subjects have also completed 
the Apremilast Extension Phase (Weeks 16 to 32) and the Observational Follow-up Phase, the 
final analysis will be performed. To maintain the blind at the site and subject level, the individual 
subject treatment assignments will not be revealed to the investigators until after the final 
database lock following the study completion.
9.2.
Study Population Definitions
The intent-to-treat (ITT) population will consist of all subjects who are randomized. Subjects 
will be included in the treatment group to which they are randomized.
The safety population will consist of all subjects who are randomized and receive at least one 
dose of IP (IP).  Subjects will be included in the treatment group corresponding to the IP they 
actually receive.
The per protocol (PP) population will consist of all subjects included in the ITT population who 
receive at least one dose of IP (IP), have both baseline and at least one post-treatment sPGA 
evaluation, and have no important protocol deviations which may affect analyses in the Placebo-
controlled Phase
9.3.
Sample Size and Power Considerations
The sample size estimation is based on the results of the Phase 3 and 4 studies with apremilast. 
With a total of approximately 574 subjects and a randomization ratio of 1:1, the study will 
randomize approximately 287 subjects to apremilast 30 mg BID and 287 subjects to placebo. 
This sample size will provide more than 90% power to detect a 15% difference between the two 
treatment groups for the primary endpoint at a two-sided significance level of 0.05. The 
calculation is based on a chi-square test assuming 15% response rate for placebo and adjusting 
for a 20% dropout rate.
9.4.
Background and Demographic Characteristics
Subject’s age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while sex, race and other categorical variables will be provided using frequency 


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tabulations.  Medical history data will be summarized using frequency tabulations by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency tabulations and percent for the 
Placebo-controlled Phase (Weeks 0 to 16) and the Apremilast Extension Phase (Weeks 16 to 32).  
A summary of subjects enrolled by site will be provided. Protocol deviations will be summarized 
using frequency distributions.
9.6.
Efficacy Analysis
9.6.1.
Efficacy Evaluation for the Placebo-controlled Phase (Weeks 0 to 16)
For the Placebo-controlled Phase (Weeks 0 to 16), the analyses for efficacy endpoints will be 
based on the intent-to-treat (ITT) population, defined as all subjects who are randomized. 
Statistical comparisons will be made between apremilast 30 mg BID and placebo. All statistical 
tests will be at the two-sided 0.05 significance level and the corresponding p-values and 95% 
confidence intervals (CIs) will be reported.
9.6.1.1.
Primary Efficacy Endpoint
The primary endpoint is the proportions of subjects who achieving sPGA response at Week 16 
(defined as sPGA score of clear [0] or almost clear [1] and with at least a 2-point reduction from 
baseline at Week 16). It will be analyzed using the ITT population. A sensitivity analysis will be 
performed using the PP population.
The primary endpoint will be analyzed using the Cochran–Mantel–Haenszel (CMH) test 
adjusting for the stratification factor at randomization. The two-sided p-values from the CMH 
test, the adjusted treatment difference in proportion using the weighted average of the treatment 
differences across the strata with the CMH weights, along with the associated two-sided 95% CIs 
using a normal approximation to the weighted average will be provided. 
Missing values at Week 16 will be imputed using the multiple imputation (MI) method (SAS 
Institute Inc., 2011) based on similar subjects who remained in the study as the primary method. 
Sensitivity analysis will be conducted to account for missing data using the non-responder 
imputation (NRI) method and the tipping point analysis.  Details of the NRI method and the 
tipping point analysis will be provided in the Statistical Analysis Plan (SAP).
For the multiple imputation method, the SAS procedure MI will be used to impute missing sPGA 
scores at the scheduled analysis visits in the Placebo-controlled Phase (Weeks 0 to 16) to create 
M=50 complete data sets. The missing data patterns will be checked at the scheduled analysis 
visits, ie, Baseline (Week 0), and Weeks 2, 4, 8, 12 and 16. If there are non-monotone missing 
patterns, two steps will be used to complete the imputation process. 
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used with a single 
chain to impute missing scores by treatment and stratification factor to create M=50 imputed data 
sets with monotone missing patterns. In case there are convergence issues, a simple model will 
be used to impute the missing scores by treatment, with further simplification by dropping both 


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treatment and stratification factor in imputation model if necessary. The seed will be set to 
17813721. The imputed scores will be rounded to the nearest integer. The minimum and the 
maximum values for imputation will be 0 and 4, which correspond to the lowest and the highest 
sPGA scores.
In the second step, the predictive mean matching method will be used to impute the remaining 
missing scores for the 50 data sets with monotone missing patterns. The imputation procedure 
will use monotone statement to create one complete data set for each of the monotone data set 
from the first step, and the variables will include treatment arm, stratification factor, and sPGA 
scores at scheduled analysis visits from baseline to Week 16. The seed will be set to 55218163.
After the completion of imputation, sPGA response at Week 16 will be derived based on both 
observed and imputed scores. The same CMH method will be used to analyze the 50 complete 
data sets and the SAS procedure MIANALYZE will be used to combine the results for the 
statistical inferences. 
9.6.1.2.
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be analyzed based on the ITT population. The two-sided 
p-values and two-sided 95% confidence intervals (CIs) will be reported for treatment difference 
between apremilast and placebo arms. Multiplicity adjustment will be specified in the next 
section.
The continuous endpoints will be analyzed using a mixed-effect model for repeated measures 
(MMRM) as the primary method. The MMRM model will use the change from baseline as the 
response variable and include treatment group, visit time, treatment-by-time interaction, and 
stratification factor as fixed effects, and the baseline value as a covariate. An unstructured 
covariance matrix will be used to model the correlation among repeated measurements. The 
Kenward-Roger adjustment will be used with restricted maximum likelihood (REML) to make 
proper statistical inference. Within-group least-squares (LS) means and the associated standard 
errors (SEs) and two-sided 95% CIs, treatment differences in LS means and the associated two-
sided 95% CIs and two-sided p-values will be derived from the MMRM model. A sensitivity 
analysis will be conducted using the analysis of covariance (ANCOVA) model with treatment 
and stratification factor as the fixed effects, the baseline value as the covariate and the LOCF 
method to impute the missing data.
The binary endpoints will be analyzed similarly as the primary endpoint using the CMH test
adjusting for the stratification factor at randomization. The two-sided p-values from the CMH 
test, the adjusted treatment difference in proportion using the weighted average of the treatment 
differences across the strata with the CMH weights, along with the associated two-sided 95% CIs 
using a normal approximation to the weighted average will be provided. Missing values at Week 
16 will be imputed using the multiple imputation (MI) method (SAS Institute Inc., 2011) based 
on similar subjects who remained in the study as the primary method. Sensitivity analysis will be 
conducted to account for missing data using the last observation carried forward (LOCF) method 
and the non-responder imputation (NRI) method. 
9.6.1.3.
Multiplicity Adjustment
The primary and secondary efficacy endpoints will be hierarchically ranked for testing in order 
to control the overall type I error rate in claiming statistical significance at the two-sided 0.05 


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significance level. Specifically, for the primary efficacy endpoint (sPGA response at Week 16), 
if the two-sided p-value from the comparison between apremilast arm and placebo arm is below 
0.05, the outcome will be considered statistically significant and apremilast will be declared 
effective. For any secondary endpoint, statistical significance will be claimed only if its two-
sided p-value is below 0.05 and tests for the primary endpoint and all previous secondary 
endpoints are significant at the two-sided 0.05 level. The proposed test sequence for the primary 
and secondary efficacy endpoints is listed as the following:

Proportion of subjects with sPGA score of clear (0) or almost clear (1) and with at 
least a 2-point reduction from baseline at Week 16

Proportion of subjects who improved ≥ 75% in BSA from baseline

Change from baseline in affected BSA at Week 16

Change from baseline in total PASI score at Week 16

In subjects with BSA > 3% at baseline, proportion of subjects who achieved BSA ≤
3% at Week 16

In subjects with whole body Itch NRS score ≥ 4 at baseline, proportion of subjects 
with ≥4-point reduction (improvement) from baseline in the whole body itch NRS 
score at Week 16

In subjects with ScPGA score ≥ 2 at baseline, proportion of subjects with ScPGA 
score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline at 
Week 16

Change from baseline in DLQI total score at Week 16
9.6.1.4.
Exploratory Endpoints
9.6.1.5.
Subgroup Analysis 
Subgroup analyses for sPGA response at Week 16 based upon baseline demographic (age, 
gender, race, etc.) or baseline disease characteristics will be provided to determine the robustness 
of the treatment effect.
9.6.2.
Efficacy Evaluation – Apremilast Extension Phase (Weeks 16 to 32)
Efficacy endpoints for time points beyond Week 16 will be summarized according to the 
treatment assigned at randomization. For all subjects, changes in measurements will be 
calculated relative to measurements obtained at baseline (Week 0). Descriptive summary 
statistics or proportion of subjects achieving specified criteria will be summarized by treatment 
group. For continuous variables, descriptive statistics for baseline and changes or percent 
changes from baseline will be provided. Categorical variables will be summarized with 
frequency tabulations.  Two-sided 95% confidence intervals will be provided for changes or 
percent changes and response rates.


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9.7.
Safety Analysis
The safety analyses will be performed using the safety population, defined as all subjects who 
are randomized and receive at least one dose of investigational product. Safety will be assessed 
by clinical review of all relevant parameters including treatment emergent adverse events 
(TEAEs), laboratory tests, and vital signs; no inferential testing for statistical significance will be 
performed. Data from safety assessments will be summarized descriptively for the Placebo-
controlled Phase (Weeks 0 to 16) and the Apremilast Exposure Period when subjects receive 
apremilast treatment. For safety analyses in the Placebo-controlled Phase, baseline will be 
relative to the first dose date following randomization at Week 0. For safety analyses in 
Apremilast Exposure Period, baseline will be relative to the first apremilast dose date at Week 0 
for subjects initially randomized to apremilast or Week 16 for subjects initially randomized to 
placebo and switched to apremilast in the Apremilast Extension Phase (Weeks 16 to 32).
Adverse events will be classified using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) classification system.  All TEAEs will be summarized by system organ class, 
preferred term, severity and relationship to investigational product.  TEAEs leading to death or to 
discontinuation from treatment and SAEs will be summarized and listed separately.
Data from other safety assessments will be summarized descriptively.  Shift tables for laboratory 
parameters showing the number of subjects with values low, normal, and high compare to the 
normal reference ranges pretreatment versus post treatment will be provided.
To account for the different exposure to the investigational product, AEs or marked laboratory 
abnormalities will also be summarized using the exposure adjusted incidence rate, in addition to 
the simple incidence rates.
9.8.
Interim Analysis
No interim analysis will be conducted.
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed, the primary data analysis will be conducted and a Week 
16 CSR will be generated.  However, unblinded data will only be made available to select 
Sponsor and Contract Research Organization (CRO) team members involved with analysis of the 
data and preparation of the Week 16 CSR.  All other Sponsor, site, and CRO personnel directly 
involved with the conduct of the study, will remain blinded to treatment assignments until the 
final database lock at the conclusion of the study.  At the end of the study, after all subjects have 
completed, or have been discontinued from the Apremilast Extension Phase (Weeks 16 to 32) 
and the Observational Follow-up Phase, the final analysis will be performed and a final CSR will 
be generated.
9.9.
Other Topics
9.9.1.
Pharmacodynamic Analysis


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9.9.2.
Investigational Product Compliance
Investigational product record information will be summarized.  Overall compliance will be 
estimated by the proportion of subjects who take between 75% and 120% of the intended 
quantity of IP.
9.9.3.
Concomitant Therapy
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations. The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health 
Organization (WHO) will be used to group medications into relevant categories for these 
tabulations.


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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 7.3 for the definition of overdose.) Any sequela of 
an accidental or intentional overdose of an investigational product which meets the definition of 
an adverse event, should be reported as an AE on the CRF. If the sequela of an overdose meets 
serious criteria, then it must be marked as serious on the CRF. The overdose itself should not be 
reported as an AE.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for apremilast overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP as well as those SAEs made known to the Investigator at 
any time thereafter that are suspected of being related to IP. All adverse events (serious/non-
serious) will be recorded on the CRF and in the subject’s source documents.  All SAEs must be 
reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by 
recording on the CRF and transmitting the data electronically.  In the event the CRF is not 
available for transmission, a paper SAE Report Form will be sent directly to Celgene Drug 
Safety.  The event must also be reported on the CRF once available.
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:

Results in death;


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
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
All SAEs must be reported to Celgene Drug Safety within 24 hours of the Investigator’s 
knowledge of the event by recording them on the CRF, or other appropriate method as directed.


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For each AE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For all AEs, the Investigator must assess the severity/ intensity of the event. 
Mild

Asymptomatic or mild symptoms; clinical or diagnostic observations only

Intervention not indicated

Activities of daily life (ADLs) minimally or not affected

No or minimal intervention/therapy may be required 
Moderate 

Symptom(s) cause moderate discomfort

Local or noninvasive intervention indicated

More than minimal interference with ADLs but able to carry out daily social and 
functional activities.

Drug therapy may be required
Severe (could be non-serious or serious) 

Symptoms causing severe discomfort/pain

Symptoms requiring medical/surgical attention/intervention

Interference with ADLs including inability to perform daily social and functional 
activities (eg, absenteeism and/or bed rest)

Drug therapy is required
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory reporting obligations.


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10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the AE to IP administration is unlikely 
or remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the 
observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the AE.  ‘Reasonable possibility’ means there is 
evidence to suggest a causal relationship between the IP and the 
AE.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For each AE, the Investigator will provide a record of the start and stop dates of the event.
10.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of each AE, as applicable (eg, 
discontinuation, interruption, or dose modification, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for each AE.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or


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
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded as the AE on the CRF.  If the abnormality was not a part of a 
diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in a female subject of childbearing potential
are immediately reportable events.  
Pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 28 days of the subject’s last dose of IP, are considered immediately reportable 
events.  Investigational product is to be discontinued immediately and the subject instructed to 
return any unused portion of the IP to the Investigator. The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Celgene Drug Safety immediately by email, phone or 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form.  
The Investigator will follow the female subject until completion of the pregnancy and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of the relevant CRFs. All 
SAEs must be reported to Celgene Drug Safety by recording them on the CRF and transmitting 
the data electronically within 24 hours of the Investigator’s knowledge of the event. In the event 
the CRF is not available for transmission, a paper SAE Report Form will be sent directly to 
Celgene Drug Safety.  The event must also be reported on the CRF once available.  This 


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instruction pertains to the initial reporting of an SAE as well as reporting any follow-up 
information.
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) or any 
SAE made known to the Investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the ICF) will be captured
within the CRF but will not be transmitted electronically to Celgene Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
source documents and all correspondence with the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be generated from Celgene Drug Safety to the site via the CRF.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to apremilast based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
Celgene or its authorized representative shall notify the Investigator of the following information 

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with the IRB/EC.  (See Section 14.3 for record retention information).


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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):

Adverse Event

Lack of efficacy

Withdrawal by subject

Death

Lost to follow-up

Non-compliance with IP

Protocol deviation

Pregnancy

Physician decision

Study terminated by Sponsor

Subjects with a BMI < 18.5 kg/m2 at baseline who lose ≥ 5% of their baseline weight

Other (to be specified on the CRF)
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents.
When a subject is discontinued from treatment, the Investigator should make every attempt 
possible to have the subject evaluated at the Early Termination Visit within 4 days of the last 
intake of IP.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting
documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure

Adverse event

Withdrawal by subject

Death

Lost to follow-up


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
Protocol deviation

Pregnancy

Physician decision

Study terminated by Sponsor

Other (to be specified on the CRF)
The reason for study discontinuation should be recorded in the CRF and in the source 
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the Investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. 
The Investigator should ensure that the code is broken only in accordance with the protocol. The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the Investigator through the IRT by using an 
emergency unblinding personal identification number (PIN), and the Investigator should call IRT 
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Council for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.


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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 


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Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected AEs as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.


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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene SOPs. This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in the 
database.  An audit trail within the system will track all changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 

All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).


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The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.


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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives.  The Investigator should make every effort to be available 
for the audits and/or inspections.  If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.
15.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness,
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution.  PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the subject.  
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
seal/packaging breach, product missing/short/overage, contamination, suspected falsified, 


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tampered, diverted or stolen material, and general product/packaging damage. If you become 
aware of a suspected PQC, you are obligated to report the issue immediately.  You can do so by 
emailing customercomplaints@celgene.com or by contacting the Celgene Customer Care Center 
(1-888-423-5436).


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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.


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17.
REFERENCES
Ahlehoff O, Gislason GH, Charlot M, Jørgensen CH, Lindhardsen J, Olesen JB, et al.  Psoriasis 
is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study J 
Int Med 2011;270:147–157.
Ahlehoff O, Skov L, Gislason G, Lindhardsen J, Kristensen SL, Iversen L, et al.  Cardiovascular 
disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory 
drugs: a Danish real-world cohort study. J Int Med 2013;273:197-204.
Armstrong AW, Robertson AD, Wu J., Schupp C, Lebwohl MG. Undertreatment, Treatment 
Trends and Treatment Dissatisfaction Among Patients with Psoriasis and Psoriatic Arthritis in 
the United States: findings from the National Psoriasis Foundation surveys, 2003-2011. JAMA 
Dermatol. 2013;149(10):1180-5. Erratum in: JAMA Dermatol. 2014 Mar;150(3):337. Erratum in 
JAMA Dermatol. 2014 Jan;150(1):103.
Carey W, Glazer S, Gottlieb AB, Lebwohl M, Leonardi C, Menter A, et al.  Relapse, rebound 
and psoriasis adverse events: An advisory group report.  J Am Acad Dermatol.  2006;54:S171-
81.
Chan CS, Van Voorhees AS, Lebwohl MG, Korman NJ, Young M, Bebo BF Jr, et al. Treatment 
of severe scalp psoriasis: From the Medical Board of the National Psoriasis Foundation. J Am 
Acad Dermatol 2009;60(6):963-71.
Crowley JJ, Weinberg JM, Wu JJ, Robertson AD, Van Voorhees AS, National Psoriasis 
Foundation. Treatment of nail psoriasis: best practice recommendations from the Medical Board 
of the National Psoriasis Foundation. JAMA Dermatol. 2015 Jan;151(1):87-94.
Duffin KC, Yeung H, Takeshita J, Krueger GG, Robertson AD, Troxel AB, et al. Patient 
satisfaction with treatments for moderate-to-severe plaque psoriasis in clinical practice. Br J 
Dermatol 2014;70:672–680.
Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis 
2005;64(suppl II):ii65–ii68. 
Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI): a simple practical measure for 
routine clinical use.  Clin Exp Dermatol.  1994;19:210-6.
FDA Guidance for Industry E10.  Choice of control group and related issues in clinical trials.  
May 2001.
FDA, The Voice of the Patient: Psoriasis. Report dated Nov 2016.
Fredriksson T, Pettersson U. Severe psoriasis: oral therapy with a new retinoid.  Dermatologica.  
1978;157:238-44.
Gottlieb AB, Matheson RT, Menter A, Leonardi CL, Day RM, Hu C, et al. Efficacy, tolerability, 
and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. 
J Drugs Dermatol. 2013 Aug;12(8):888-97.
Kimball AB, Luger T, Gottlieb A, Puig L, Kaufmann R, Nikai E,et al.  Impact of ixekizumab on 
psoriasis itch severity and other psoriasis symptoms: Results from 3 phase III psoriasis clinical 
trials.  J Am Acad Dermatol.  2016 Dec;75(6):1156-61.


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Kragballe K, Menter A, Lebwohl M, Tebbey PW, van de Kerkhof PC. International Psoriasis 
Council. Long-term management of scalp psoriasis: perspectives from the International Psoriasis 
Council. J Dermatolog Treat 2013;24(3):188-92.
Krueger JG, Ohtsuki M, Garcet S, da Rosa JC, Gonzalez J, Li X, et al. Apremilast Reduces IL-
17F, IL-17A, IL-22, and TNF-α Plasma Protein Levels in Patients With Moderate to Severe 
Plaque Psoriasis: Similar Pharmacodynamic and Correlative Results From a Phase 3 Study in 
North America and Europe and a Phase 2b Study in Japan. European Academy of Dermatology 
and Venereology. 2016 Sep 29 –Oct 02; Vienna, Austria.
Langan EA, Griffiths CEM, Solbach W, Knobloch JK, Zillikens D, Thaçi D. The role of the 
microbiome in psoriasis: moving from disease description to treatment selection. Br J Dermatol. 
2018 May;278(5):1020-27.
Lebwohl M. Psoriasis. Lancet 2003a;361:1197-204.
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi C, Gordon KB, et al. 
Guidelines of care for the management of psoriasis and psoriatic arthritis Section 1. Overview of 
psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad 
Dermatol 2008;58:826-50.
Menter A, Korman NJ, Elmets C, Feldman SR, Gelfand JM, Gordon KB, et al. Guidelines of 
care for the management of psoriasis and psoriatic arthritis Section 4. Guidelines of care for the 
management and treatment of psoriasis with traditional systemic agents.  J Am Acad Dermatol 
2009;61:451-85.
Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordan KB, et al. Guidelines of 
care for the management of psoriasis and psoriatic arthritis: Section 6. Guidelines of care for the 
treatment of psoriasis and psoriatic arthritis: Case-based presentations and evidence-based 
conclusions. J Am Acad Dermatol 2011;65:137-74.
Nast A, Boehncke WH, Mrowietz U, Ockenfels HM, Philipp S, Reich K, et al. German S3-
guidelines on the treatment of psoriasis vulgaris (short version). Arch Dermatol Res 
2012;304:87-113.
Pasch MC. Nail psoriasis: A review of treatment options. Drugs. 2016 Apr;76(6):675–705.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal 
risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-43.
Rich P, Scher RK.  Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis.  
J Am Acad Dermatol 2003;49(2):206-12.
SAS Institute Inc. 2011. SAS/STAT® 9.3 User’s Guide. Cary, NC: SAS Institute Inc.
Schafer PH, Truzzi F, Parton A, Wu L, Kosek J, et al. Phosphodiesterase 4 in inflammatory 
diseases: Effects of apremilast in psoriatic blood and in dermal myobibroblasts through the 
PDE4/CD271 complex. Cell Signal. 2016 Jul;28(7):753-63.
Spuls PI, Lecluse L, Poulsen ML, Bos JD, Stern RS, Nijsten T.  How good are clinical severity 
and outcome measures for psoriasis?: Quantitative evaluation in a systematic review. J Invest 
Dermatol 2010;130:933-34.


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Stein Gold L, Lebwohl M, Menter A, et al. Aerosol Foam Formulation of Fixed Combination 
Calcipotriene Plus Betamethasone Dipropionate is Highly Efficacious in Patients With Psoriasis 
Vulgaris: Pooled Data From Three Randomized Controlled Studies. J Drugs Dermatol. 
2016;15(8):951-7.
van Cranenburgh OD, de Korte J, Sprangers MA, de Rie MA, Smets EM. Satisfaction with 
Treatment Among Patients with psoriasis: a web-based survey study. Br J Derm 2013;169:398-
405.


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18.
APPENDICES
Appendix A:
Table of Abbreviations
Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADLs
Activities of daily life
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase (SGOT)
ATC
Anatomical Therapeutic Chemical
BID
Twice daily
BMI
Body mass index
BSA
Body Surface Area
cAMP
cyclic adenosine monophosphate
CI
Confidence Interval
CIN
Cervical intraepithelial neoplasia
CMH
Cochran-Mantel-Haenzel
CO2
Carbon dioxide
CRO
Contract Research Organization
CRF
Case report form
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
DLQI
Dermatology Life Quality Index
DNA
Deoxyribonucleic acid
EC
Ethics Committee
eCRF
Electronic case report form
EMA
European Medicines Agency
EOT
End of treatment
FAS
Full analysis set
FCBP
Females of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice


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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
GI
Gastrointestinal
HDL
High-density lipoproteins
HIV
Human immunodeficiency virus
HPA
Hypothalamic-pituitary-adrenal
HRQoL
Health-Related Quality of Life
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IL
Interleukin
IND
Investigational New Drug
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
IUD
Intrauterine device
LDH
Lactate dehydrogenase
LOCF
Last observation carried forward
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed-effect model for repeated measures
NAPSI
Nail psoriasis severity index
NPF
National Psoriasis Foundation
NRI
Non-responder imputation
NRS
Numeric rating scale
PASI
Psoriasis Area and Severity Index
PDE4
Phosphodiesterase type 4
PP
Per protocol
PQC
Product Quality Complaint
PUVA
Psoralen and ultraviolet A


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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
RBC
Red blood cell 
REML
restricted maximum likelihood
RNA
Ribonucleic acid
SAE
Serious adverse event
SGOT
Serum glutamic oxaloacetic transaminase 
ScPGA
Scalp Physician Global Assessment
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
sPGA
Static Physician Global Assessment
SUSAR
Suspected unexpected serious adverse reaction
SE
Standard error
TB
Tuberculosis
TC
Total cholesterol
TEAE
Treatment-emergent adverse event
TNF
Tumor necrosing factor
ULN
Upper limit of normal
USA
United States of America
UV
Ultraviolet
UVB
Ultraviolet B
WBC
White blood cell
WHO
World Health Organization


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Appendix B:
Static Physician Global Assessment (sPGA) of Whole Body 
Psoriasis
Score
Category
Description
0
Clear
Plaque Elevation = 0 (no elevation over normal skin)
Scaling = 0 (no evidence of scaling)
Erythema = 0 (except for residual hyperpigmentation/ 
hypopigmentation)
1
Almost Clear
Plaque Elevation = ± (possible but difficult to ascertain whether 
there is a slight elevation above normal skin)
Scaling = ± (surface dryness with some desquamation)
Erythema = ± (faint, diffuse pink or slight red coloration)
2
Mild
Plaque Elevation = slight (slight but definite elevation, typically 
edges are indistinct or sloped)
Scaling = fine (fine scale partially or mostly covering lesions)
Erythema = mild (light red coloration)
3
Moderate
Plaque Elevation = marked (marked definite elevation with rough 
or sloped edges)
Scaling = coarser (coarser scale covering most or all of the 
lesions)
Erythema = moderate (definite red coloration)
4
Severe
Plaque Elevation = marked (marked elevation typically with hard 
or sharp edges)
Scaling = coarser (coarse, non tenacious scale predominates 
covering most or all of the lesions)
Erythema = severe (very bright red coloration)


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Appendix C:
Psoriasis Area and Severity Index (PASI)
* Round all calculations to 1 decimal place
STEP A.  Please write in the appropriate number for rows 1 - 3 using the scale 
below:
    0 = None    1 = Slight    2 = Moderate    3 = Severe    4 = Very Severe
HEAD
TRUNK
UPPER 
LIMBS
LOWER 
LIMBS
1. Erythema
2. Thickness
3. Scaling
4. TOTAL Each Column
STEP B.  Enter the number of hands the psoriasis covers on each body area
HEAD
TRUNK
UPPER 
LIMBS
LOWER 
LIMBS
5. Number of Hands
6. Area (% of total BSA)
10
30
20
40
STEP C. Calculate % of involvement: 
7. % of each region involved [(Row 5 ÷ Row 6) x 100*]
8. TOTAL BSA (sum of # of hands from row 5)
STEP D. Select Degree of Involvement using value in Row 7:
          0 = No involvement
          1 = <10%
          2 = 10 < 30%
          3 = 30 < 50%
          4 = 50 < 70%
          5 = 70 < 90%
          6 = 90 < 100%
9. Degree of Involvement (0-6) of each region
STEP E.  Calculate PASI (Row 4 x Row 6 x Row 9) ÷ 100*
10. PASI for each body region
11. TOTAL PASI (sum of Row 10 subscores)


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Appendix D:
Scalp Physician Global Assessment (ScPGA)
Score
Category
Description
0
Clear
Scalp Plaque Elevation = 0 (no elevation over normal skin)
Scalp Scaling = 0 (no evidence of scaling)
Scalp Erythema = 0 (except for residual hyperpigmentation/ 
hypopigmentation)
1
Almost Clear
Scalp Plaque Elevation = ± (possible but difficult to ascertain whether 
there is a slight elevation above normal skin)
Scalp Scaling = ± (surface dryness with some desquamation)
Scalp Erythema = ± (faint, diffuse pink or slight red coloration)
2
Mild
Scalp Plaque Elevation = slight (slight but definite elevation, typically 
edges are indistinct or sloped)
Scalp Scaling = fine (fine scale partially or mostly covering lesions)
Scalp Erythema = mild (light red coloration)
3
Moderate
Scalp Plaque Elevation = marked (marked definite elevation with rough 
or sloped edges)
Scalp Scaling = coarser (coarser scale covering most or all of the lesions)
Scalp Erythema = moderate (definite red coloration)
4
Severe
Scalp Plaque Elevation = marked (marked elevation typically with hard 
or sharp edges)
Scalp Scaling = coarser (coarse, non tenacious scale predominates 
covering most or all of the lesions)
Scalp Erythema = severe (very bright red coloration)


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Appendix E:
Nail Psoriasis Severity Index (NAPSI)
Nail Psoriasis Severity Index (NAPSI) (Version 1.00)
Complete at VISIT 2 only: Circle the number of the thumb or fingernail that will be used 
as the target nail (i.e. the nail that has the worst nail psoriasis) for the NAPSI calculation 
for this subject during the study:
1 = Right Thumb
2 = Right Index Finger
3 = Right 3rd Finger
4 = Right 4th Finger
5 = Right 5th Finger
6 = Left Thumb
7 = Left Index Finger
8 = Left 3rd Finger
9 = Left 4th Finger
10 = Left 5th Finger
11 = No Nail Psoriasis
Complete at EVERY VISIT:  Enter the number of nails that have nail psoriasis.
Number of thumb and fingernails with psoriasis:_____________________


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The target thumb or finger nail which represents the worst nail psoriasis is graded for 
nail matrix psoriasis and nail bed psoriasis.  The sum of these two scores is the total score 
for that nail.
Evaluation 1: Nail matrix. In each quadrant of the nail, nail 
matrix psoriasis is evaluated by presence of any of the nail 
matrix features (pitting, leukonychia red spots in the lunula, 
crumbling):
Score for nail matrix psoriasis  _____________
0 = none
1 = present in 1/4 nail
2 = present in 2/4 nail
3 = present in 3/4 nail
4 = present in 4/4 nail
Evaluation 2: Nail bed. Nail bed psoriasis is evaluated by the 
presence of any of the nail bed features (onycholysis, splinter 
hemorrhages, subungual hyperkeratosis, “oil drop” (salmon 
patch dyschroma): 
Score for nail bed psoriasis  _____________
0 = none
1 = present in 1/4 nail
2 = present in 2/4 nail
3 = present in 3/4 nail
4 = present in 4/4 nail
TOTAL FOR NAIL___________  (0-8)
Rich, 2003.


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Appendix F:
Columbia-Suicide Severity Rating Scale
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Baseline Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended for use by trained clinicians. The questions contained in the Columbia-
Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the 
presence of suicidality depends on clinical judgment.
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk 
factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@childpsych.columbia.edu


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SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 
2 is “yes,” ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of 
Ideation” section below. 
Lifetime:
Time He/She 
Felt Most 
Suicidal 
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.
Have you wished you were dead or wished you could go to sleep and not wake up?
If yes, describe: 
Yes No
□ □
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing myself”) 
without thoughts of ways to kill oneself/associated methods, intent, or plan.
Have you actually had any thoughts of killing yourself?
If yes, describe: 
Yes No
□ □
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different 
than a specific plan with time, place or method details worked out (e.g. thought of method to kill self but not a specific 
plan). Includes person who would say, “I thought about taking an overdose but I never made a specific plan as to when, 
where or how I would actually do it…..and I would never go through with it”.
Have you been thinking about how you might do this?
If yes, describe: 
Yes No
□ □
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I 
have the thoughts but I definitely will not do anything about them”.
Have you had these thoughts and had some intention of acting on them?
If yes, describe: 
Yes No
□ □
5. Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
If yes, describe: 
Yes No
□ □
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, 
with 1 being the least severe and 5 being the most severe ). Ask about time he/she was feeling the most 
suicidal.
_____ _________________________________________________
Most Severe Ideation:
Type # (1-5) Description of Ideation 
Most Severe 
Frequency
How many times have you had these thoughts?
(1) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or almost daily (5) Many times each day 
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes (4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time 
____
Controllability
Could /can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts (4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty (5) Unable to control thoughts
(3) Can control thoughts with some difficulty (0) Does not attempt to control thoughts 
____


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Deterrents
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from wanting 
to die or acting on thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide (4) Deterrents most likely did not stop you
(2) Deterrents probably stopped you (5) Deterrents definitely did not stop you
(3) Uncertain that deterrents stopped you (0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the 
pain or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you 
were feeling) or was it to get attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others. (4) Mostly to end or stop the pain (you               
(2) Mostly to get attention, revenge or a reaction from others.            couldn’t go on living with the pain or
                                                                                                                how you were feeling).
(3) Equally to get attention, revenge or a reaction from others        (5) Completely to end or stop the pain      and to end/stop 
the pain.                                                                       (you couldn’t go on living with the          
(0) Does not apply                                                                                   pain or how you were feeling).
____
SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of 
as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it 
can be considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or 
harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred 
(e.g. gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought 
that what they did could be lethal, intent may be inferred.
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life?
Did you want to die (even a little) when you_____?
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, 
feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes No
□ □
Total # of
Attempts
______
Yes No
□ □ 
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, 
actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather 
than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is 
somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: 
Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet 
started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something stopped 
you before you actually did anything?
If yes, describe: 
Yes No
□ □
Total # of 
interrupted
______ 


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Aborted Attempt:
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged 
in any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, 
instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself 
before you actually did anything?
If yes, describe: 
Yes No
□ □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or 
thought, such as assembling a specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide 
(e.g. giving things away, writing a suicide note).
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting 
pills, getting a gun, giving valuables away or writing a suicide note)?
If yes, describe: 
Yes No
□ □ 
Suicidal Behavior:
Suicidal behavior was present during the assessment period? 
Yes No
□ □ 
Answer for Actual Attempts Only 
Most 
Recent
Attempt
Date:
Most 
Lethal
Attempt
Date:
Initial/First
Attempt
Date:
Actual Lethality/Medical Damage:
0. No physical damage or very minor physical damage (e.g. surface scratches).
1. Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains).
2. Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat 
responsive; second-degree burns; bleeding of major vessel).
3. Moderately severe physical damage; medical hospitalization and likely intensive care 
required (e.g. comatose with reflexes intact; third-degree burns less than 20% of body; 
extensive blood loss but can recover; major fractures).
4. Severe physical damage; medical hospitalization with intensive care required (e.g. comatose 
without reflexes; third-degree burns over 20% of body; extensive blood loss with unstable vital 
signs; major damage to a vital area).
5. Death 
Enter 
Code
______ 
Enter 
Code
______ 
Enter Code
______
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having 
no actual medical damage, had potential for very serious lethality: put gun in mouth and pulled 
the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming 
train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter 
Code
______ 
Enter 
Code
______ 
Enter Code
______


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Appendix G:
Whole Body Itch Numeric Rating Scale (NRS)
ITCH NUMERIC RATING SCALE
Please rate the itching severity due to your psoriasis by circling the number that best describes 
your worst level of itching in the past 24 hours.
0        1        2        3        4        5        6        7        8        9        10
0 = No itching
     10 = Worst itch imaginable
Naegeli, 2015.


EDMS Doc. Number: 23137123 - 22819879
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Appendix H:
The Dermatology Life Quality Index (DLQI)
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE 
LAST WEEK.  Please check one box for each question.
1. 
Over the last week, how itchy, sore, painful or stinging has 
your skin been? 
_ Very much _ A lot _ 
A little _ Not at all 
2. 
Over the last week, how embarrassed or self conscious have 
you been because of your skin? 
_ Very much _ A lot _ 
A little _ Not at all 
3. 
Over the last week, how much has your skin interfered with 
you going shopping or looking after your home or yard? 
_ Very much _ A lot _ 
A little _ Not at all 
_ Not relevant 
4. 
Over the last week, how much has your skin influenced the 
clothes you wear? 
_ Very much _ A lot _ 
A little _ Not at all 
_ Not relevant 
5. 
Over the last week, how much has your skin affected any 
social or leisure activities? 
_ Very much _ A lot _ 
A little _ Not at all 
_ Not relevant 
6. 
Over the last week, how much has your skin made it difficult 
for you to do any sport? 
_ Very much _ A lot _ 
A little _ Not at all 
_ Not relevant 
7. 
Over the last week, has your skin prevented you from 
working or studying? 
_ Yes _ No 
_ Not relevant 
If “No”, over the last week how much has your skin been a 
problem at work or studying? 
_ A lot _ A little _ Not 
at all 
8. 
Over the last week, how much has your skin created problems 
with your partner or any of your close friends or relatives? 
_ Very much _ A lot _ 
A little _ Not at all
_ Not relevant
9. 
Over the last week, how much has your skin caused any 
sexual difficulties?
_ Very much _ A lot _ 
A little _ Not at all
_ Not relevant
10.
Over the last week, how much of a problem has the 
treatment for your skin been, for example, by making your 
home messy, or by taking up time?
_ Very much _ A lot _ 
A little _ Not at all
_ Not relevant
Finlay, 1994.


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Appendix I:Titration Blister Card Configuration


EDMS Doc. Number: 23137123 - 22819879
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Appendix J: Active Treatment Dummy Titration Blister Card Configuration


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Appendix K:
Placebo Treatment Blister Card Configuration


EDMS Doc. Number: 23137123 - 22819879
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  VP, Clinical R&D
Date: Sunday, 25 November 2018, 05:40 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================


EDMS Doc. Number: 23034655 - 23034089
Apremilast
Summary of Changes CC-10004-PSOR-022
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CC-10004-PSOR-022 Amendment 1 Final: 08 Oct 2018
1.
JUSTIFICATION FOR AMENDMENT
Changes included in this amendment are summarized below:

Provided clarification to Sections 6.1, 6.2 and 6.5
 

Provided clarification to Sections 5 and 6.5 Safety Assessments, Serum and Urine 
Pregnancy Tests for Females of Childbearing Potential to further specify that an 
unscheduled serum pregnancy test should be performed if the FCBP subject has missed a 
menstrual period or has a positive urine dipstick test. 

Modified Sections 4.3, 5, 6.1, and 6.5 to include hepatitis C testing to be consistent with 
apremilast historical studies. 

Modified Section 10 Adverse Events to reflect the process by which adverse events are to 
be reported.


EDMS Doc. Number: 23137123 - 23034089
Apremilast
Protocol CC-10004-PSOR-022
Celgene Corporation
Confidential and Proprietary
4
CC-10004-PSOR-022 Amendment 2 Final: 21 Nov 2018
1.
JUSTIFICATION FOR AMENDMENT
Changes included in this amendment are summarized below:

In the Protocol Summary, provided clarifications regarding the approximate enrollment 
limits in Study Design and topical psoriasis preparations in Study Population; included 
Columbia Suicide Severity Rating Scale (C-SSRS) in Overview of Key Safety 
Assessment and tipping point analysis in Statistical Method based on FDA 
recommendation.

Provided clarification in Section 3.1 regarding the approximate enrollment limits as 
determined by baseline sPGA scores of mild (2) or moderate (3). 

Provided clarification in Section 4.2 Inclusion Criteria #6 to define topical psoriasis 
preparations.

Modified Section 5 Table of Events to include Optional Consent for Research based on 
new protocol template; to include C-SSRS, additional body weight measures, additional 
clinical laboratory evaluations, and urine pregnancy tests based on FDA 
recommendations; and to include clarifications on the footnotes.

Modified Sections 5, 6.1, and 6.3.2 to update the NAPSI assessment schedule.   

Provided clarification in Section 6 Procedures under Medical and Disease History to 
remove psoriatic arthritis.  Clarified the need for subjects to sign optional consents for 
research before any sub-study sampling may be performed.

Modified Section 6.1 to include options consents for research being presented to subjects, 
and to review prior/concomitant medications during the screening period. 

Modified Sections 6.1, 6.2, 6.3, 6.5, 17, Appendix A, and Appendix F to reflect the 
addition of C-SSRS based on FDA recommendation. 

Modified Section 6.5 with additional time points for urine pregnancy testing for FCBP 
subjects.

Provided clarification in Section 6.7 to reflect the sub-studies are optional. 

Modified reference in Sections 6.8, 7.2 to reflect the addition of C-SSRS as an appendix.  

Provided modification in Section 7.7 investigational Product Compliance to include 
upper range of > 120% compliance between visits as meeting definition of a gross 
compliance problem. 

Provided clarification in Section 9.6.1.1 Primary Efficacy Endpoint where reference to 
LOCF was replaced with “tipping point analysis” based on FDA recommendation.

Provided clarification in Section 11.1 Treatment Discontinuation to include the following 
reason: “Subjects with BMI < 18.5 kg/m2 at baseline who lose ≥ 5% of their baseline 
weight, based on FDA recommendation.

Provided clarification to Appendix E to include a count of the number of nails with 
psoriasis involvement.

Appendices F, G, H, I, J were modified to reflect the addition of C-SSRS as an appendix.

SAP_001.pdf: 
Celgene Corporation
Protocol: CC-10004-PSOR-022
Statistical Analysis Plan
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 3, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY OF 
THE EFFICACY AND SAFETY OF APREMILAST (CC-
10004) IN SUBJECTS WITH MILD TO MODERATE 
PLAQUE PSORIASIS
INVESTIGATIONAL PRODUCT (IP):
Apremilast (CC-10004)
PROTOCOL NUMBER:
CC-10004-PSOR-022
DATE FINAL:
12MAR2020
Prepared by:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
The information contained in this document is regarded as confidential and, 
except to the extent necessary to obtain informed consent, may not be disclosed to 
another party unless such disclosure is required by law or regulations.  Persons to 
whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them.
NCT Number: NCT03721172
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov




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Protocol: CC-10004-PSOR-022
Statistical Analysis Plan
Confidential and Proprietary
3
TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION....................................................................................................9
3.
STUDY OBJECTIVES STUDY OBJECTIVES.....................................................10
3.1.
Primary Objective...................................................................................................10
3.2.
Secondary Objectives .............................................................................................10
3.3.
Exploratory Objectives ...........................................................................................10
4.
INVESTIGATIONAL PLAN .................................................................................11
4.1.
Overall Study Design and Plan ...............................................................................11
4.2.
Study Endpoints .....................................................................................................12
4.2.1.
Primary Endpoint....................................................................................................12
4.2.2.
Secondary Endpoints ..............................................................................................12
4.2.3.
Exploratory Efficacy Endpoints ..............................................................................13
4.2.4.
Exploratory Pharmacokinetic Endpoints .................................................................13
4.2.5.
Exploratory Pharmacodynamics Endpoints.............................................................13
4.2.6.
Safety Endpoints.....................................................................................................13
4.2.7.
Derivations of Efficacy Endpoints ..........................................................................13
4.2.8
Derivations of Safety Endpoints..............................................................................15
4.2.9
Derivations of Pharmacokinetic Endpoints..............................................................16
4.2.10
Derivations of Pharmacodynamic Endpoints...........................................................16
4.3.
Randomization, Stratification, and Blinding............................................................17
4.4.
Sample Size Determination.....................................................................................17
5.
ANALYSIS PHASES OR PERIODS, DEFINITION OF ANALYSIS 
POPULATIONS, BASELINE AND TIME POINTS ..............................................18
5.1.
Analysis Phases or Periods .....................................................................................18
5.1.1.
Analysis Phases ......................................................................................................18
5.1.2.
Apremilast-exposure Period for Safety Analysis .....................................................19
5.1.3.
Treatment Arms in Analysis Phases........................................................................19
5.2.
Definition of analysis populations...........................................................................20
5.2.1.
Intent-to-treat Population........................................................................................20
5.2.2.
Per-protocol Population ..........................................................................................20


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5.2.3.
Safety Population....................................................................................................20
5.3.
Baseline Definitions ...............................................................................................20
5.4.
Time Points ............................................................................................................20
6.
STATISTICAL METHODOLOGY FOR EFFICACY............................................23
6.1.
General Approaches to Efficacy Analysis ...............................................................23
6.2.
Multiplicity Adjustment..........................................................................................23
6.3.
Analyses of the Primary Efficacy Endpoint.............................................................24
6.4.
Analyses of the Secondary Efficacy Endpoints .......................................................25
6.4.1.
Binary Variables.....................................................................................................25
6.4.2.
Continuous Variables..............................................................................................26
6.5.
Analyses of Exploratory Efficacy Endpoints...........................................................26
6.5.1.
NAPSI....................................................................................................................27
6.5.2.
BSA........................................................................................................................27
6.6.
Subgroup Analysis..................................................................................................27
6.7.
Assessing Study Site Effect ....................................................................................28
6.8.
Interim Analysis .....................................................................................................29
6.9.
Analysis of Pharmacokinetic Endpoints..................................................................29
6.10.
Analysis of Pharmacodynamic Endpoints ...............................................................29
7.
SUMMARY OF SUBJECT DISPOSITION ...........................................................31
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................33
8.1.
Demographics.........................................................................................................33
8.2.
Baseline or Disease Characteristics.........................................................................33
8.3.
Medical History......................................................................................................34
8.4.
Prior and Concomitant Procedures..........................................................................34
8.5.
Prior and Concomitant Medications........................................................................34
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................36
9.1.
Treatment Duration.................................................................................................36
9.1.1.
Placebo-controlled Phase (Weeks 0 to 16) ..............................................................36
9.1.2.
Apremilast Extension Phase (Weeks 16 to 32)........................................................36
9.1.3.
Apremilast-exposure Period....................................................................................36
9.2.
Treatment Compliance............................................................................................36
9.2.1.
Placebo-controlled Phase (Weeks 0 to 16) ..............................................................37


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9.2.2.
Apremilast Extension Phase (Weeks 16 to 32)........................................................37
9.2.3.
Apremilast-exposure Period....................................................................................37
10.
PROTOCOL DEVIATIONS AND IMPORTANT PROTOCOL 
DEVIATIONS........................................................................................................38
11.
SAFETY ANALYSIS ............................................................................................39
11.1.
Adverse Events.......................................................................................................40
11.1.1.
Overall Summary of TEAEs ...................................................................................40
11.1.2.
All TEAEs..............................................................................................................40
11.1.3.
Common TEAEs ....................................................................................................41
11.1.4.
Drug-related TEAEs...............................................................................................41
11.1.5.
TEAEs by Maximum Severity................................................................................41
11.1.6.
Serious TEAEs .......................................................................................................41
11.1.7.
TEAEs Leading to Drug Interruption and Drug Withdrawal ...................................41
11.1.8.
Deaths ....................................................................................................................41
11.1.9.
Onset/Duration of TEAEs for Selected PT..............................................................41
11.1.10.
Adverse Events of Special Interest..........................................................................42
11.2.
Vital Signs and Weight...........................................................................................42
11.3.
Clinical Laboratory Evaluations..............................................................................42
11.4.
Columbia Suicide Severity Rating Scale (C-SSRS).................................................43
APPENDIX A1 – CONVENTIONS RELATED TO DATES....................................................44
11.5.
A1.1 Guideline of Partially Missing Date Imputation..............................................44
A1.1.1 Adverse Events..............................................................................................................44
A1.1.2 Prior/Concomitant Medications/Procedures ...................................................................46
A.1.1.3 Medical History............................................................................................................46
A1.1.4 Treatment Duration........................................................................................................46
APPENDIX A2 – LABORATORY MARKED ABNORMALITIES CRITERIA......................47
APPENDIX A3– REPORTING CONVENTIONS....................................................................50


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LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2: 
Table for Visit Mapping for by Time Point Analysis...............................................21
Table 3:
Adjustment and Mapping of Study Weeks for Placebo Subjects Who Are 
Treated with Apremilast 30 mg BID after Week 16 in Summary of Safety 
Data over Time.......................................................................................................22
Table 4:
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially...................................................................44
Table 5:
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Placebo Initially........................................................................45
Table 6:
Laboratory Marked Abnormalities Criteria .............................................................47
LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................12


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Statistical Analysis Plan
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1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
Adverse Event
ANCOVA
Analysis of Covariance (model)
ATC
Anatomical-Therapeutic-Chemical
BID
Twice Daily
BMI
Body Mass Index
BSA
Body Surface Area (%) Affected by Psoriasis
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
CRF or eCRF
(electronic) Case Report Form
CRO
Contract Research Organization 
CRP
Clinical Research Physician
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
DAO
Data As Observed
DLQI
Dermatological Life Quality Index
EAIR
Exposure Adjusted Incidence Rate
HRQoL
Health-Related Quality of Life
IP
Investigational Product
IRT
Interactive Response Technology
ITT
Intent-to-Treat
LS Mean
Least Squares Mean
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
MMRM
Mixed-effect Model for Repeated Measures
NAPSI
Nail Psoriasis Severity Index


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Statistical Analysis Plan
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NRI
Non-responder Imputation 
NRS
Numeric Rating Scale
PASI
Psoriasis Area and Severity Index
PD
Pharmacodynamic
PG
Pharmacogenetic
PK
Pharmacokinetic
PP
Per-Protocol (population)
PT
Preferred Term
REML
Restricted Maximum Likelihood
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
ScPGA
Scalp Physician Global Assessment
SD 
Standard Deviation
SE
Standard Error 
SI
Standard International (unit)
sPGA
Static Physician Global Assessment
SOC
System Organ Class
TEAE
Treatment-emergent Adverse Event
USA
United States of America
WHODD
World Health Organization Drug Dictionary


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Statistical Analysis Plan
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2.
INTRODUCTION 
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-10004-PSOR-022, “A phase 3, multi-center, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of apremilast (CC-10004) in subjects with 
mild to moderate plaque psoriasis”.
After all subjects have completed or have been discontinued from the Double-blind Placebo-
controlled Phase (Weeks 0 to 16), a Week 16 database restriction will be performed; the primary 
data analysis will be conducted and a Week 16 Clinical Study Report will be generated. No interim 
analysis is planned prior to this primary data analysis. At the end of the study, after all subjects 
have completed or have been discontinued from the Apremilast Extension Phase (Weeks 16 to 32) 
and the Observational Follow-up Phase, the final database lock and analysis will be performed and 
the final Clinical Study Report (CSR) will be generated.
No pharmacokinetic (PK) analyses will be done for this study. The details of the pharmacodynamic 
(PD) analyses except biomarker analysis for plasma proteins assessments will be specified in a 
separate PD analysis plan.
This SAP provides a more technical and detailed elaboration of the statistical analyses as outlined 
and/or specified in the study protocol amendment 2 dated 21Nov2018. The SAP will be finalized 
and signed prior to the unblinding of the Week 16 database. All statistical analyses detailed in this 
SAP will be conducted using SAS® Version 9.3 or higher.


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3.
  STUDY OBJECTIVES STUDY OBJECTIVES
3.1.
Primary Objective

To evaluate the clinical efficacy of oral apremilast 30 mg twice daily (BID), 
compared to placebo, in subjects with mild to moderate plaque psoriasis during the 
16-week Placebo-controlled Phase
3.2.
Secondary Objectives
The secondary objectives are:

To evaluate the safety and tolerability of apremilast 30 mg BID, compared with 
placebo, in subjects with mild to moderate plaque psoriasis

To evaluate the effect of apremilast 30 mg BID compared with placebo on itch over 
the whole body caused by plaque psoriasis

To evaluate the effect of apremilast 30 mg BID compared with placebo on Health-
related Quality of Life (HRQoL)
3.3.
Exploratory Objectives
The exploratory objectives are:


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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study designed to 
evaluate the efficacy and safety of apremilast (CC-10004) in subject with mild to moderate 
plaque psoriasis. 
Approximately 574 subjects will be enrolled and randomized 1:1 to receive either apremilast 30 
mg BID or placebo for the first 16 weeks. Subjects will be randomized based on a permuted 
block randomization using a centralized Interactive Response Technology (IRT). Randomization 
to apremilast arm or placebo arm will be stratified by baseline Static Physician Global 
Assessment (sPGA) score (mild [2] or moderate [3]). Approximately 30% of subjects with mild 
plaque psoriasis will be enrolled in the study.

Subjects randomized to the apremilast 30 mg BID treatment group will receive 
apremilast 30 mg tablets orally twice daily for the first 16 weeks

Subjects randomized to the placebo treatment group will receive placebo tablets 
(identical in appearance to apremilast 30 mg tablets) orally twice daily for the first 16 
weeks

All subjects will receive apremilast 30 mg tablets orally twice daily after the Week 16 
Visit through the end of the Apremilast Extension Phase of the study
The study will consist of four phases (Figure 1):

Screening Phase – up to 35 days

Double-blind Placebo-controlled Phase – Weeks 0-16
-
Subjects will be randomly assigned in a 1:1 ratio to either apremilast 30 mg BID 
or placebo. 

Apremilast Extension Phase – Weeks 16-32
-
All subjects will be switched to (or continue with) apremilast 30 mg BID. All
subjects will maintain this dosing through Week 32.

Observational Follow-up Phase – 4 weeks
-
Four-week Post-Treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue the study early
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed; the primary data analysis will be conducted and a Week 
16 Clinical Study Report (CSR) will be generated. However, unblinded data will only be made 
available to select Sponsor and Contract Research Organization (CRO) team members involved 
with analysis of the data and preparation of the Week 16 CSR. All other Sponsor, site, and CRO 
personnel directly involved with the conduct of the study, will remain blinded to treatment 
assignments until the final database lock at the conclusion of the study.


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Figure 1:
Study Design
4.2.
Study Endpoints
The endpoints of the study are listed below.
4.2.1.
Primary Endpoint

Static PGA (sPGA) 0/1: Proportion of subjects with an sPGA score of clear (0) or almost
clear (1) with at least a 2-point reduction from baseline at Week 16
4.2.2.
Secondary Endpoints

BSA-75: Proportion of subjects who improved ≥ 75% in BSA (BSA-75) from baseline at 
Week 16

BSA: Change from baseline in affected BSA at Week 16

PASI: Change from baseline in total PASI score at Week 16

BSA ≤ 3%: Proportion of subjects who achieved BSA ≤ 3% for subjects with baseline 
BSA > 3% at Week 16

Itch NRS: Proportion of subjects with ≥4-point reduction (improvement) from baseline in 
the whole body itch NRS score at Week 16, among subjects with baseline whole body 
itch NRS ≥ 4

ScPGA: Proportion of subjects with ScPGA score of clear (0) or almost clear (1) with at 
least a 2-point reduction from baseline at Week 16, among subjects with baseline ScPGA 
score ≥ 2

DLQI: Change from baseline in DLQI total score at Week 16


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4.2.3.
Exploratory Efficacy Endpoints
4.2.4.
Exploratory Pharmacokinetic Endpoints
Not applicable.
4.2.5.
Exploratory Pharmacodynamics Endpoints
4.2.6.
Safety Endpoints 
Safety endpoints will include:

Adverse events (AEs): Type, frequency, severity, seriousness, and relationship of AEs to 
IP 

Death

Clinical laboratory evaluations

Vital signs and weight

Columbia Suicide Severity Rating Scale (C-SSRS)
4.2.7.
Derivations of Efficacy Endpoints
The derivation of efficacy endpoints is described below in separate sections. Baseline definition 
for all efficacy endpoints is given in Section 5.3. Change from baseline is calculated as post-
baseline visit value minus the baseline value. Percent change from baseline is defined as 100* 
Change from baseline/Baseline value (%). Handling of time points is described in Section 5.4.
4.2.7.1.
Static Physician Global Assessment (sPGA)
The sPGA is the assessment of whole body psoriasis by the investigator of the overall disease 
severity at the time of evaluation.  The sPGA is a 5-point scale ranging from clear (0), almost 


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clear (1), mild (2), moderate (3), to severe (4), incorporating an assessment of the severity of the 
three primary signs of the disease: erythema, scaling and plaque elevation.  
The sPGA response at a post-baseline visit is defined as achieving sPGA score of clear (0) or 
almost clear (1) with at least a 2-point reduction from baseline.
4.2.7.2.
Body Surface Area (BSA)
BSA is a measurement of involved skin over the whole body. The overall BSA affected by 
psoriasis is estimated based on the palm area of the subject’s hand. The surface area of the whole
body is made up of approximately 100 palms or “handprints” (each entire palmar surface or 
“handprint” equates to approximately 1% of total body surface area).
BSA scores will be presented with one digit after the decimal point. For post-baseline visits, 
BSA score change and percent change from baseline will be derived. BSA score percent change 
will be rounded to integers.
4.2.7.3.
Psoriasis Area and Severity Index (PASI) 
The PASI is a measure of psoriatic disease severity taking into account qualitative lesion 
characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on 
defined anatomical regions. Psoriasis Area and Severity Index scores range from 0 to 72, with 
higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a 
scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, 
and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 
0 (no involvement) to 6 (90% to 100% involvement).  The total qualitative score (sum of 
erythema, thickness, and scaling scores) is multiplied by the degree of involvement for each 
anatomic region and then multiplied by a constant.  These values for each anatomic region are 
summed to yield the PASI score. The PASI score will be set to missing if any severity score or 
degree of involvement is missing. 
PASI scores will be presented with one digit after the decimal point. For post-baseline visits, 
PASI score change and percent change from baseline will be derived. PASI score percent change 
will be rounded to integers.
4.2.7.4.
Whole Body Itch Numeric Rating Scale (NRS) Assessment
The whole body itch NRS assessment is a tool designed to measure the amount of whole body 
itch due to psoriasis by circling a number on a scale from 0 to 10. Subjects will be asked to 
assess their worst level whole body itch in the past 24 hours and select a number on a scale of 0
to 10, where “0” represents no itching, and “10” represents the worst itch imaginable.
For a post baseline visit, the whole body itch NRS response is defined as ≥ 4 points reduction 
(improvement) from baseline in the NRS score for subjects with baseline score 4 or higher.  
Change from baseline in the NRS score will also be derived. 


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4.2.7.5.
Scalp Physician Global Assessment (ScPGA)
The ScPGA is a measurement of overall scalp involvement. The ScPGA is a 5-point scale that 
assesses three dimensions (Plaque Elevation, Scaling, and Erythema) on a scale of 0 (clear), 1
(almost clear), 2 (mild), 3 (moderate), to 4 (severe).
For a post baseline visit, the ScPGA response is defined as achieving ScPGA global assessment 
of 0 (clear) or 1 (almost clear) with at least a 2-point reduction from baseline among subjects 
with baseline ScPGA score ≥ 2. Change from baseline in the ScPGA score will also be derived.
4.2.7.6.
Dermatology Life Quality Index (DLQI)
The DLQI was developed as a simple, compact, and practical questionnaire for use in a 
dermatology clinical setting to assess limitations related to the impact of skin disease.  The 
instrument contains 10 items dealing with the subject’s skin. With the exception of Item Number 
7, the subject responds on a four-point scale, ranging from “Very Much” (score 3) to “Not at 
All” or “Not relevant” (score 0). Item Number 7 is a multi-part item, the first part of which 
ascertains whether the subject’s skin prevented them from working or studying (Yes or No, 
scores 3 or 0 respectively), and if “No,” then the subject is asked how much of a problem the 
skin has been at work or study over the past week, with response alternatives being “A lot,” “A 
little,” or “Not at all” (scores 2, 1, or 0 respectively). The DLQI total score is derived by 
summing all item scores, which has a possible range of 0 to 30, with 30 corresponding to the 
worst quality of life, and 0 corresponding to the best.
If one of the 10 items is left unanswered, it is scored 0 and the scores are summed and expressed 
as usual out of a maximum of 30. If two or more of the ten items are left unanswered, DLQI total 
score will be left missing. When using sub-scales, if the answer to one item in a sub-scale is 
missing, the score is set to missing for that sub-scale.
DLQI total score and change from baseline will be derived.
4.2.8
Derivations of Safety Endpoints
Baseline definition for all safety endpoints is given in Section 5.3. Change from baseline is 
calculated as post-baseline visit value minus the baseline value. Handling of time points is 
described in Section 5.4.
4.2.8.1.
Treatment-emergent Adverse Event
An AE is a treatment-emergent AE (TEAE) if the AE start date is

On or after the date of the first dose of investigational product (IP) and no later than 28 
days after the last dose of IP for subjects who have completed study treatment or have 
discontinued early by the time of database cut, or

On or after the date of the first dose of IP for subjects who are ongoing with study 
treatment at the time of database cut.
If the treatment-emergent status of an AE is unclear due to a missing/incomplete start date, it will 
always be considered treatment-emergent, unless shown otherwise by data. Date imputation rules 
for missing AE start dates are described in Appendix A1.


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Adverse event started more than 28 days after the last dose of IP will not be considered as a 
treatment-emergent AE.
4.2.8.2.
Treatment-emergent Adverse Event Leading to Drug Withdrawal, Drug 
Interruption, or Death, and Drug-related Treatment-emergent Adverse Event
A TEAE leading to drug withdrawal is a TEAE for which the investigator indicates that the 
action taken with respect to IP is withdrawn permanently. A TEAE leading to drug interruption 
is a TEAE for which the investigator indicates that the action taken with respect to IP is 
interrupted. A TEAE leading to death is a TEAE for which the outcome is fatal. Relationship to 
IP is based on the investigator's causality judgment; that is, a drug-related AE is an AE indicated 
by the investigator to have a suspected relationship to IP.
4.2.8.3.
Vital Signs and Weight
Vital signs and weight endpoints include: 

Observed value and change from baseline over time in vital signs (temperature, pulse, 
and blood pressure)

Observed value, change and percent change from baseline over time in weight

Shifts from baseline to post-baseline timepoints and to the worst post-baseline value in 
terms of normal/abnormal in pulse and blood pressure (normal ranges are defined as: 60-
100 beats/minute for pulse, 90-140 mmHg for systolic blood pressure, and 60-90 mmHg 
for diastolic blood pressure)
4.2.8.4.
Clinical Laboratory Evaluations
Laboratory evaluations include: 

Observed value and change from baseline over time in hematology and serum chemistry 
parameters

Laboratory marked abnormalities (see Appendix A2)

Shifts from baseline to post-baseline time points and to the worst post-baseline value in 
terms of normal/abnormal (low or high) in hematology and serum chemistry parameters
4.2.9
Derivations of Pharmacokinetic Endpoints
Not applicable.
4.2.10 Derivations of Pharmacodynamic Endpoints
Blood samples will be collected at Visit 2 (Baseline) and Week 16. Plasma proteins will be 
evaluated, such as but not limited to: IL-17A, IL-17F, and IL-22, as well as other markers for 
psoriasis and the mechanism of action for apremilast. The endpoints include observed values, 
changes and percent changes from baseline in biomarkers.


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Derivations of rest of the pharmacodynamic endpoints including peripheral blood RNA gene 
expression, pharmacogenetic assessment and microbiome skin swab data will be specified in a 
PD analysis plan separately.
4.3.
Randomization, Stratification, and Blinding
Approximately 574 subjects will be enrolled and randomized 1:1 to receive either apremilast 30 
mg BID or placebo for the first 16 weeks. Subjects will be randomized based on a permuted 
block randomization using a centralized Interactive Response Technology (IRT). Randomization 
to apremilast arm or placebo arm will be stratified by baseline sPGA score (mild [2] or moderate 
[3]). Approximately 30% of subjects will be with sPGA score of mild (2) and approximately 
70% of subjects will be with sPGA score of moderate (3). The IRT system will monitor the total 
enrollment of each stratum and screening will close once the approximate percentages are 
reached.
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed; the primary data analysis will be conducted and a Week 
16 CSR will be generated. However, unblinded data will only be made available to select CRO 
team members involved with analysis of the data and preparation of the Week 16 CSR. All other 
Sponsor, site, and CRO personnel directly involved with the conduct of the study will remain 
blinded to treatment assignments until the final database lock at the conclusion of the study.
4.4.
Sample Size Determination
The sample size estimation is based on the results of the Phase 3 and 4 studies with apremilast. 
With a total of approximately 574 subjects and a randomization ratio of 1:1, the study will 
randomize approximately 287 subjects to apremilast 30 mg BID and 287 subjects to placebo. 
This sample size will provide more than 90% power to detect a 15% difference between the two 
treatment groups for the primary endpoint at a two-sided significance level of 0.05. The 
calculation is based on a chi-square test assuming 15% response rate for placebo and adjusting 
for a 20% dropout rate.


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5.
ANALYSIS PHASES OR PERIODS, DEFINITION OF 
ANALYSIS POPULATIONS, BASELINE AND TIME POINTS
5.1.
Analysis Phases or Periods
For efficacy analysis, different phases will be used. For safety analysis, Placebo-controlled Phase 
and Apremilast-exposure Period will be used.
5.1.1.
Analysis Phases
Per protocol specification, data summary and analysis will be provided for the following phases.

Placebo-controlled Phase – Weeks 0 to 16
This phase starts on the day of randomization (Week 0/Visit 2), and stops on either: (1) 
the day the first IP for the next phase is dispensed at Week 16/Visit 7; or (2) the day of 
the discontinuation visit if the subject discontinued prior to or at Week 16/Visit 7; or (3) 
the last known study day if the subject is lost to follow-up prior to Week 16/Visit 7 
during the phase.
For safety analysis in subjects who continued treatment in Apremilast Extension Phase 
(Weeks 16 to 32), the phase stopped one day prior to the first dose date in Apremilast 
Extension Phase. 
For the analysis of measured (ie, visit-based) safety data (ie, labs, vital signs, and ECG), 
this period is exclusive of the date of the first dose of IP and inclusive of the date of the 
first Week 16 dose of Apremilast.
At the time of the Week 16 analysis, if the date of the first Week 16 dose of Apremilast 
(derived from the Study Drug Exposure eCRF which may not be entered by sites until the 
next visit after Week 16) is not yet available for subjects with Apremilast dispensed at 
Week 16 and on or before the (possibly derived) date of the last dose of IP as of the time 
of analysis (ie, no evidence that the subject has discontinued without receiving at least 
one dose of Apremilast after Week 16), the date of Apremilast dispensing at Week 16 
will replace the date of the first Week 16 dose of Apremilast in the above definition for 
these subjects.

Apremilast Extension Phase – Weeks 16 to 32
This phase starts on the day after the first IP is dispensed for the phase at Week 16/Visit 
7, and stops on either: (1) the day of Week 32/Visit 10; or (2) the day of the 
discontinuation visit if the subject discontinued prior to or at Week 32/Visit 10; or (3) the 
last known study day if the subject is lost to follow-up prior to Week 32/Visit 10 during 
the phase.
For safety analysis, the phase started at the first dose date in the phase and ended at the 
last dose date + 1.

Observational Follow-up Phase – 4 weeks


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Subjects who complete the study or discontinue the study early, will be followed up for 
28 days after the last dose of IP.
5.1.2.
Apremilast-exposure Period for Safety Analysis
Apremilast-exposure Period will be used for safety analyses.

Apremilast-exposure Period:
This period starts on the date of either: (1) the first dose of IP following randomization 
(Week 0/Visit 2) for subjects who are treated with apremilast from Week 0; or (2) the 
first dose of IP from the IP dispensed at Week16/Visit 7 for subjects who were originally 
treated with placebo and are treated with apremilast at Week 16.
This period stops on either: (1) data cut-off date; or (2) the end of the study.
5.1.3.
Treatment Arms in Analysis Phases
In general, the treatment arms used in the analyses and summaries in each phase are described 
below in this section unless otherwise specified. 

Placebo-controlled Phase (Weeks 0 to 16)
-
Placebo
-
Apremilast 30 mg BID
-
Total (optional, not for the efficacy analysis)

Apremilast Extension Phase (Weeks 16 to 32)
Subjects who entered the extension phase will be included in analysis, i.e, subjects who 
were initially randomized to apremilast and continued at Week 16 or who were initially 
randomized to placebo and switched to apremilast at Week 16. 
-
Placebo/30 mg BID
-
30 mg BID/30 mg BID
-
Total

Apremilast-exposure Period
Subjects who are treated with at least one dose of apremilast will be included here, which 
includes all subjects who are randomized to (at Week 0/Visit 2) or switched to (at Week 
16/Visit 7) apremilast, and receive at least one dose of apremilast after randomization or
Week 16. 
-
Placebo/30 mg BID
-
30 mg BID as Initiated
-
30 mg BID as Treated

Observational Follow-up Phase (4 weeks)
For subjects who entered Follow-up Phase from Placebo-controlled Phase, summaries 
will be provided by their initial treatment arm: 


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-
Placebo
-
30 mg BID
For subjects who entered Follow-up Phase from Apremilast Extension Phase, summaries 
will be provided by their treatment sequence: 
-
Placebo/30 mg BID
-
30 mg BID/30 mg BID
5.2.
Definition of analysis populations
5.2.1.
Intent-to-treat Population
The intent-to-treat (ITT) population will consist of all subjects who are randomized regardless of 
whether or not the subject received IP. Subjects will be included in the treatment group to which 
they are randomized.
5.2.2.
Per-protocol Population
The per protocol (PP) population will consist of all subjects included in the ITT population who 
receive at least one dose of IP, have both baseline and at least one post-treatment sPGA 
assessment, and have no important protocol deviations which may affect efficacy assessments in 
the Placebo-controlled Phase.
5.2.3.
Safety Population
The safety population will consist of all subjects who are randomized and received at least one 
dose of investigational product (IP).  Subjects will be included in the treatment group 
corresponding to the IP they actually received (apremilast or placebo) for the analyses and 
summaries using the safety population.  
5.3.
Baseline Definitions
For efficacy analysis and summary of baseline disease characteristics data, baseline is defined as 
the last value measured prior to or at the randomization date.
For safety analyses in the Placebo-controlled Phase, baseline will be relative to the first dose date 
following randomization at Week 0. It is the last value measured prior to or on the day of the first 
dose of IP.
For safety analyses in Apremilast Exposure Period, baseline will be relative to the first 
apremilast dose date at Week 0 for subjects initially randomized to apremilast or Week 16 for 
subjects initially randomized to placebo and switched to apremilast in the Extension Phase. It is 
the last value measured prior to or at the first apremilast dose date. 
5.4.
Time Points
Time points in all analyses are based on the remapped visits/study weeks using the following 
visit mapping algorithm, which may or may not be the same as the visits/study weeks as 
recorded in the database.


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All visit-based data, except for those with the recorded visit being a follow-up visit, will be 
assigned to analysis visits based on study day (the date of assessment/collection relative to the 
reference date) and the defined analysis visit windows (Table 2), rather than the recorded visit. 
The only exception is that data with the recorded visit being a follow-up visit will be assigned to 
the analysis visit corresponding to the follow-up visit.
Table 2:
Table for Visit Mapping 
Analysis Visit
Target Day
Visit Window
  Week 0 (Baseline)
1
≤ 1
Placebo-controlled Phase
Week 2
15
2 – 21
Week 4
29
22 – 42
Week 8
57
43 – 70
Week 12
85
71 – 98
Week 16
113
99 – End of Phase
Apremilast Extension Phase
Week 20
141
Start of Phase – 154
Week 24
169
155 – 196
Week 32
225
197 – End of Phase
Note: Target day and visit window are relative to the date of Visit 2/Week 0 (Day 1) 
randomization date. For efficacy and safety analysis, definitions for start or end dates for a phase 
or period are specified in Section 5.1 and Baselines are specified in Section 5.3.
Time points in the analyses or summaries of efficacy data over time include the scheduled study 
weeks per protocol, the end of a study phase, and the observational follow-up visit when 
applicable. It is possible that multiple assessment values will fall into the same visit window. The 
following rule may be used to select the unique value for that analysis visit: 
1. Among all assessments in the same visit window for the analysis visit, select the value 
with the assessment date closest to the target day of the analysis visit;
2. If the relative days from 2 assessments are equally close to, but on different sides of the 
target day, then the latter assessment will be used for that analysis visit;


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3. If multiple assessments are available on the same relative day, the duplicated values will 
be suppressed; otherwise, the highest value of these assessments will be used for that 
relative day.
For the Apremilast-exposure Period, the scheduled study weeks for placebo subjects who are 
treated with apremilast 30 mg BID at Week 16/Visit 7 are shown below for summaries of safety 
data (laboratory parameters, vital signs, etc) over time. 
Table 3:
Analysis Visit for Placebo Subjects Who Are Treated with Apremilast 30 mg 
BID after Week 16 in the Apremilast-exposure Period
Original Visit
Analysis Visit
Week 16
Week 0 (Baseline)
Week 20
Week 4
Week 24
Week 8
Week 32
Week 16


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6.
STATISTICAL METHODOLOGY FOR EFFICACY
6.1.
General Approaches to Efficacy Analysis
The intent-to-treat principle will be used in statistical analyses for efficacy endpoints. For the 
Placebo-controlled Phase (Weeks 0-16), efficacy evaluations will be conducted using the intent-
to-treat (ITT) population defined as all randomized subjects. Statistical comparisons will be 
made between the two treatment arms (placebo or apremilast). For the Apremilast Extension 
Phase (Weeks 16-32), efficacy evaluations will be conducted using subjects who entered the 
phase from both treatment arms.
Descriptive statistics (n, mean, SD, median, Q1, Q3, min, max) will be presented for appropriate 
endpoints at specified time points. Specifically, for continuous variables, descriptive statistics for 
assessment values and change (plus percentage change when specified) from baseline will be 
provided. Binary variables will be summarized with frequency tabulations. 
Statistical comparisons will be made between placebo arm and apremilast arm; the null 
hypothesis is that the effects of the two treatment arms (i.e., placebo vs. apremilast) have no 
difference. Statistical tests will be at the two-sided 0.05 significance level and the corresponding 
p-values and two-sided 95% confidence intervals (CIs) will be reported.
In the data as observed (DAO) analyses, only subjects with sufficient data at the time point under 
consideration will be included.
6.2.
Multiplicity Adjustment
The primary and secondary efficacy endpoints will be hierarchically ranked for testing to control 
the overall type I error rate in claiming statistical significance at the two-sided 0.05 significance 
level. Specifically, for the primary efficacy endpoint (sPGA response at Week 16), if the two-
sided p-value from the comparison between apremilast arm and placebo arm is below 0.05, the 
outcome will be considered statistically significant and apremilast will be declared effective. For 
any secondary endpoint, statistical significance will be claimed only if its two-sided p-value is 
below 0.05 and tests for the primary endpoint and all previous secondary endpoints are 
significant at the two-sided 0.05 level. The proposed test sequence for the primary and secondary 
efficacy endpoints is listed as the following:

Proportion of subjects with an sPGA score of clear (0) or almost clear (1) with at least a 2-
point reduction from baseline at Week 16

Proportion of subjects who improved ≥ 75% in BSA (BSA-75) from baseline at Week 16

Change from baseline in affected BSA at Week 16

Change from baseline in total PASI score at Week 16

Proportion of subjects who achieved BSA ≤ 3% for subjects with baseline BSA > 3% at 
Week 16

Proportion of subjects with ≥4-point reduction (improvement) from baseline in the whole 
body itch NRS score at Week 16, among subjects with baseline whole body itch NRS ≥ 4


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
Proportion of subjects with ScPGA score of clear (0) or almost clear (1) with at least a 2-
point reduction from baseline at Week 16, among subjects with baseline ScPGA score ≥2

Change from baseline in DLQI total score at Week 16
6.3.
Analyses of the Primary Efficacy Endpoint
The primary endpoint is the proportion of subjects who achieve sPGA response at Week 16 
(defined as sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from 
baseline at Week 16). 
The primary endpoint will be analyzed using the CMH (Cochran–Mantel–Haenszel) test 
adjusting for the stratification factor at randomization (mild vs. moderate sPGA). The two-sided 
p-values from the CMH test, the adjusted treatment difference in proportion using the weighted 
average of the treatment differences across the strata with the CMH weights, along with the 
associated two-sided 95% CIs using a normal approximation to the weighted average will be 
provided.
Missing values at Week 16 for this endpoint will be imputed using the multiple imputation (MI) 
method (SAS Institute Inc. 2011) based on similar subjects who remained in the study as the 
primary method. The SAS procedure MI will be used to impute missing sPGA scores at the 
scheduled analysis visits in the Placebo-controlled Phase (Weeks 0-16) to create M=50 complete 
datasets. The missing data patterns will be checked at the scheduled analysis visits, i.e., Baseline 
(Week 0), and Weeks 2, 4, 8, 12 and 16. If there are non-monotone missing patterns, two 
separate imputation procedures will be used to complete the imputation process. 
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used with a single 
chain to impute missing scores by treatment and stratification factor to create M=50 imputed
datasets with monotone missing patterns.  In case there are convergence issues, a simpler model 
will be used to impute the missing scores by treatment, with further simplification by dropping 
both treatment and stratification factor from the imputation model if necessary. The seed will be 
set to 17813721. The imputed scores will be rounded to the nearest integer. The minimum and 
the maximum values for imputation will be 0 and 4, which correspond to the lowest and the 
highest sPGA scores. 
In the second step, the predictive mean matching method will be used to impute the remaining 
missing scores for the 50 datasets with monotone missing patterns. The imputation procedure 
will use the monotone statement to create one complete dataset for each of the monotone datasets
from the first step, and the variables will include treatment arm, stratification factor, and sPGA 
scores at scheduled analysis visits from baseline to Week 16. The seed will be set to 55218163. 
The number of closest observations to be used in the selection will be set to 2. 
After the completion of imputation, sPGA response at Week 16 will be derived based on both 
observed and imputed scores. The same CMH method will be used to analyze the 50 complete 
datasets. The SAS procedure MIANALYZE will be used to combine the results for the statistical 
inferences. 
Sensitivity analysis will be conducted to account for missing data using the NRI (Non-responder 
Imputation) method and the tipping point analyses. 


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By NRI, subjects who have insufficient data for response determination for the time point under 
consideration will be considered non-responders for that time point. Insufficient data, including 
missing data at baseline (if the binary endpoint assesses change from baseline) or a post-baseline 
time point, will be determined after the handling of time points as described in Section 5.4.
For the tipping point analyses, let M1 and M2 be the total number of subjects with missing data 
of primary endpoint in Apremilast and Placebo. There are overall (M1+1)*(M2 +1) possible 
ways for imputing missing data as responders or non-responders in statistical analysis, ranging 
from imputing all missing values as non-responders to imputing all missing values as responders 
in each of the two arms. For each of the (M1+1)*(M2 +1) different imputation patterns, the Chi-
square test will be used for testing statistical significance and the output will be plotted in a 
rectangle for inspection. The staircase region that separates significant and non-significant 
outcomes forms the tipping-point boundary.
A supplementary analysis using the PP population will also be performed. 
The primary endpoint will be assessed for site effect as specified in Section 6.7.
6.4.
Analyses of the Secondary Efficacy Endpoints
For the analyses of the secondary efficacy endpoints, the two-sided p-values and two-sided 95% 
CIs will be reported for the treatment difference between placebo arm and apremilast arm.
Details for multiplicity adjustment are described in Section 6.2.
6.4.1.
Binary Variables
The binary variables for secondary endpoints include the following:

Proportion of subjects who improved ≥ 75% in BSA (BSA-75) from baseline at Week 
16

Proportion of subjects who achieved BSA ≤ 3% for subjects with baseline BSA > 3%
at Week 16

Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 16, among subjects with baseline whole body 
itch NRS ≥ 4

Proportion of subjects with ScPGA score of clear (0) or almost clear (1) with at least 
a 2-point reduction from baseline at Week 16, among subjects with baseline ScPGA 
score ≥ 2
For these binary endpoints, the treatment difference between apremilast arm and placebo arm 
will be compared using CMH test adjusting for the stratification factor at randomization. The 
two-sided p-values from the CMH test, the adjusted treatment difference in proportion using the 
weighted average of the treatment differences across the strata with the CMH weights, along 
with the associated two-sided 95% CIs using a normal approximation to the weighted average 
will be provided.


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Missing values will be imputed using the similar MI method as the primary endpoint, with 
sensitivity analysis using the NRI method as described in section 6.3. 
Further, analyses of the following secondary endpoints will be performed for the subjects with 
baseline sPGA =2 (mild psoriasis) and sPGA = 3 (moderate psoriasis):

Proportion of subjects who improved ≥ 75% in BSA (BSA-75) from baseline at Week 
16

Proportion of subjects who achieved BSA ≤ 3% for subjects with baseline BSA > 3% 
at Week 16

Proportion of subjects who achieved BSA ≤ 1% for subjects with baseline BSA > 1% 
at Week 16
The treatment difference between apremilast arm and placebo arm will be compared using Chi-
squared test. The two-sided p-values from the Chi-squared test, the treatment difference in 
proportion, along with the associated two-sided 95% CIs will be provided.
6.4.2.
Continuous Variables
The continuous variables for secondary endpoints include the following:

Change from baseline in affected BSA at Week 16

Change from baseline in total PASI score at Week 16

Change from baseline in DLQI total score at Week 16
The continuous efficacy endpoints will be analyzed based on the ITT population using a mixed-
effect model for repeated measures (MMRM) as the primary method. The MMRM model will 
use the change from baseline as the response variable and include treatment group, visit time, 
treatment-by-time interaction, and stratification factor as fixed effects, and the baseline value as 
a covariate. An unstructured covariance matrix will be used to model the correlation among 
repeated measurements. The Kenward-Roger adjustment will be used with restricted maximum 
likelihood (REML) to make proper statistical inference. Within-group least-squares (LS) means 
and the associated SEs and 2-sided 95% CIs, treatment differences in LS means and the 
associated 2-sided 95% CIs and 2-sided p-values will be derived from the MMRM model.
The continuous efficacy endpoints will also be analyzed based on the baseline sPGA categories 
(sPGA = 2 and sPGA =3) using the similar analysis method specified for the ITT population. For 
the subjects with baseline sPGA = 2 (mild psoriasis) and sPGA = 3 (moderate psoriasis), the 
MMRM model will use the change from baseline as the response variable and include treatment 
group, visit time, and treatment-by-time interaction as fixed effects, and the baseline value as a 
covariate.
6.5.
Analyses of Exploratory Efficacy Endpoints


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6.5.1.
NAPSI
The endpoints include the following:

Change from baseline in NAPSI at Week 16 and Week 32

Proportion of subjects with NAPSI score of 0 at Week 16 and Week 32
For summary and analyses, only subjects with nail psoriasis at baseline will be included.
6.5.2.
BSA
The endpoint is proportion of subjects who achieved BSA ≤ 1% at Week 16.
6.6.
Subgroup Analysis
Subgroup analysis will be carried out for sPGA response at Week 16 in the Placebo-controlled 
Phase based upon baseline demographics and disease characteristics. Summary and analysis will 
be based on ITT population and missing values will be imputed using MI method. Treatment 
difference of response rates will be reported with two-sided 95% CI.
Forest plots for the treatment differences in proportions by subgroup will be provided.
The following subgroup variables will be used: 

Baseline sPGA score: 2 (mild), 3 (moderate)

Sex (Male, Female)

Race (White, Non-white)

Age category (<65 years, ≥65 years) 

Alcohol usage (Yes, No)

Tobacco usage (Current user, Past user, Never used)

Baseline weight category < 70, ≥ 70 to < 85, ≥ 85 to < 100, ≥100 kg) 

Baseline BMI category < 25, ≥25 to < 30, ≥ 30 to < 35, ≥ 35 to < 40, ≥ 40 kg/m2) 

Duration of plaque psoriasis categories (< 10, ≥ 10 to < 20, ≥ 20 years) 


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
Geographical region (USA, Canada)

Baseline PASI score category (≤7, >7)

Baseline BSA (%) category (≤5, >5)

Prior conventional systemic therapies (Used or Never used)

Prior phototherapies (Used or Never used)
6.7.
Assessing Study Site Effect
This study is a multicenter study and planned to have 65 study sites to enroll 574 subjects. A 
single site may not have sufficient number of subjects to allow meaningful within-site analysis if 
treatment effects stratified by baseline sPGA score; therefore, study sites effect will be assessed 
by pooling sites on geographic basis to help interpret the results. 
In pooling sites for analysis, the minimum cell size of 5 randomized subjects per treatment arm 
(placebo arm or apremilast arm) per stratum of baseline sPGA score (mild [2] or moderate [3])
will be used. The pooling strategy is described as follows: 1) Sites will be pooled within each 
country (USA or Canada) according to their rank based on site-specific sample size, starting with 
the smallest sites; i.e., within a country, the smallest sites will first be pooled until the pooled site 
has a minimum cell size of 5 for each of the four cells. 2) The remaining un-pooled sites will 
then be pooled within the country with the smallest pooled site. 3) In the rare case that all sites
pooled together in a country does not satisfy the above condition (a minimum cell size of 5 for 
each of the four cells), all sites in the country will be pooled together with the smallest pooled 
site of the other country.
Sites will be pooled together as described above in order to assess the site effect and site by 
treatment interaction on the primary efficacy endpoint listed below.

Proportion of subjects with an sPGA score of clear (0) or almost clear (1) with at least a 2-
point reduction from baseline at Week 16
For the pooled sites, summary and analyses will be based on ITT population using MI imputation 
for missing values. Study site effect will be assessed for the primary endpoint by stratifying the 
analysis based on pooled site in addition to the stratification factor at randomization and 
examining whether the treatment differences adjusted for both stratification factor and pooled 
site are consistent with those from the primary analysis.
In addition, the consistency of the treatment effect across individual study sites (or pooled sites) 
will be assessed by performing a subgroup-type analysis with respect to the endpoints, with 
individual study sites (or pooled sites) treated as subgroups. Listings of response rates will be 
provided by individual study site and by pooled site. The treatment difference for each of the
individual study sites (or pooled sites) will be reviewed to determine the effect among the
individual study sites (or pooled sites).


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6.8.
Interim Analysis
No interim analysis will be conducted.
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed; the primary data analysis will be conducted.  However, 
unblinded data will only be made available to selected Sponsor and CRO team members 
involved with analysis of the data and preparation of the Week 16 Clinical Study Report.  All 
other Sponsor, site, and CRO personnel directly involved with the conduct of the study will 
remain blinded to treatment assignments until the final database lock at the conclusion of the 
study.  At the end of the study, after all subjects have completed or have been discontinued from 
the Apremilast Extension Phase (Weeks 16 to 32) and the Observational Follow-up Phase, the 
final analysis will be performed and a final CSR will be generated.
6.9.
Analysis of Pharmacokinetic Endpoints
Not applicable.
6.10.
Analysis of Pharmacodynamic Endpoints
Biomarker analysis for plasma proteins assessments will be conducted to explore the effects of 
apremilast on concentrations of a select set of interleukins and cytokines and the relationship 
between biomarker concentrations and clinical efficacy of apremilast. Proteins will be evaluated, 
such as but not limited to: IL-17A, IL-17F, and IL-22, as well as other biomarkers for psoriasis 
and the mechanism of action for apremilast. 
Biomarker analysis will be conducted based on the Biomarker subset, which includes all subjects 
who are randomized and receive at least one dose of IP, have a baseline value and at least one 
post-baseline value for any biomarker of plasma proteins. 
In the biomarker analysis, the endpoints (biomarkers) will be summarized at both baseline and 
Week 16. Observed values, changes and percent changes from baseline in biomarkers will be 
summarized. At Week 16 of the above DAO summaries, distribution-free 2-sided 95% CIs for 
medians using the binomial distribution will be provided for change and percent change from 
baseline. P-values for testing within-group change and percent change from baseline (against no 
change) will be calculated by the Wilcoxon signed-rank test. 
At Week 16, between-group differences in change and percent change from baseline will also be 
estimated using the Hodges-Lehmann estimate of location shift and its asymptotic (or exact 
where appropriate) 2-sided 95% CI based on the Wilcoxon rank-sum test. P-values for the 
between-group differences (between apremilast and placebo) in change and percent change will 
be calculated by a nonparametric method using an ANCOVA model on rank-transformed data. 
The model will use the van der Waerden normal score of the change or percent change from 
baseline as the response variable, and include treatment group and randomization stratification 
factors as factors, and the van der Waerden normal score of the baseline value as a covariate.


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An association between the primary efficacy endpoint, sPGA response at Week 16, and the 
biomarkers (IL-17A, IL-17F, IL-22) will be explored. The association will be explored by a 
logistic regression of the sPGA response on the biomarker (the absolute value, change from 
baseline, or percent change from baseline), treatment group, the biomarker-by-treatment group 
interaction, randomization stratification factors, and baseline biomarker. The odds ratio, 2-sided 
95% CI, and 2-sided p-value associated with the biomarker for each treatment group, as well as 
the 2-sided p-value for the biomarker-by-treatment group interaction will be calculated from this 
model. The common odds ratio, 2-sided 95% CI, and 2-sided p-value associated with the 
biomarker across the overall data will also be calculated from a similar model without the 
biomarker-by-treatment group interaction; these results are meaningful when there is no 
evidence of the biomarker-by-treatment group interaction (p > 0.1000). In addition, Pearson and 
Spearman point-biserial partial correlation coefficients, controlling for randomization 
stratification factors, and baseline biomarker, will be provided for each treatment group and 
across the overall data (the latter will additionally control for treatment group), along with the 
associated 2-sided 95% CI and 2-sided p-value. All tests are not adjusted by multiplicity. The 
analyses will be performed with missing data for biomarkers and sPGA responses handled in 
DAO (see Section 6.1 for missing data handling).
A listing of biomarker values for subjects in Biomarker subset will be provided. For each 
biomarker, a bar chart for percent change from baseline at Week 16 (Mean ± standard error of 
the mean), by treatment group, will be provided. An asterisk will be added to indicate significant 
treatment differences between APR 30 BID and placebo groups at Week 16 (DAO). 
Pharmacodynamic peripheral blood RNA gene expression, pharmacogenetic assessment and 
microbiome skin swab data will be documented in a separate PD analysis plan.


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7.
SUMMARY OF SUBJECT DISPOSITION
The number of subjects screened, the number and percentage of subjects randomized (as 
recorded in the IVRS database) will be summarized. The failed inclusion/exclusion criteria of 
subjects who were screened and not randomized will be included in the summary. The above 
percentages will be based on the number of subjects screened.
The number and percentage of subjects randomized will be tabulated by treatment arm, study 
site, and country. The percentages will be based on the number of subjects randomized.
Subject disposition will be provided by treatment arm and phase:

Placebo-controlled Phase – Weeks 0 to 16
Summary will be based on subjects who are randomized. Tabulation of subjects included 
in the ITT, PP, and Safety populations, subjects who completed and entered the next 
phase (Weeks 16 to 32), completed but did not enter the next phase, and discontinued 
early will be provided. The primary reasons for early discontinuation will also be 
tabulated. Subjects who complete and entered the next phase include subjects who have 
IP dispensed at Week 16/Visit 7, subjects who completed but did not enter the next phase 
include subjects who have either a Week 16 visit or a termination visit no earlier than the 
Week 16 visit window, and discontinued early subjects include those who discontinued 
prior to the Week 16 visit window.

Apremilast Extension Phase – Weeks 16 to 32
Summary will be based on subjects who entered the Apremilast Extension Phase, i.e., 
who had IP dispensed for the Phase. Subjects who entered the phase, took at least one 
dose of IP, completed, discontinued early, and primary reason for discontinuation will be 
provided.

Observational Follow-up Phase (4 weeks) 
Summary will include subjects who entered Follow-up Phase. Subjects who entered the 
phase, completed, discontinued early, and primary reason for discontinuation will be 
provided.
Primary reasons for discontinuation in the Placebo-controlled, Apremilast Extension and Follow-
up phases collected on the Disposition eCRF pages will be summarized with the following 
categories:

Death

AEs

Pregnancy

Lack of efficacy 

Non-compliance with study drug 

Lost to follow-up

Protocol deviation


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
Physician decision

Study terminated by sponsor

Withdrawal by subject

Other
Listings will be provided for randomized subjects who early discontinued during the treatment 
period with primary reason for discontinuation. Listing of subjects excluded from PP population, 
with the reasons for exclusions, will be provided.


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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics, baseline characteristics, prior medication/procedure, and 
concomitant medications/procedure will be presented by treatment group and overall for the ITT 
population, as well as for the mild psoriasis subjects (defined as baseline sPGA =2) and moderate 
psoriasis subjects (defined as baseline sPGA =3). Subject data listings will also be provided.
8.1.
Demographics
Summary statistics will be provided for the following continuous variables:

Age (years)

Weight (kg)

Height (cm)

Baseline Body Mass Index (BMI; kg/m2)
Number and percentage will be provided for the following categorical variables:

Sex (Male, Female)

Age category (< 65, ≥ 65 years; < 40, ≥ 40 to < 65, ≥ 65 to < 75, ≥ 75 to < 85, ≥ 85 years)

Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islanders, White, Not Collected or Unknown)

Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not reported, Unknown)

Baseline weight category (< 70, ≥ 70 to < 85, ≥ 85 to < 100, ≥100 kg) 

Baseline BMI category (< 25, ≥25 to < 30, ≥ 30 to < 35, ≥ 35 to < 40, ≥ 40 kg/m2) 

Geographical region (USA, Canada)

Alcohol usage (Yes, No)

Tobacco usage (Current user, Past user, Never used)
8.2.
Baseline or Disease Characteristics
Baseline clinical characteristics will be summarized descriptively by treatment group, which will 
include the following:

Duration of plaque psoriasis (from date of diagnosis to the date of informed consent; 
year, presented one digit after the decimal point)

Duration of plaque psoriasis categories (< 10, ≥ 10 to < 20, ≥ 20 years)

Baseline sPGA score: Mild (2), Moderate (3)

Baseline psoriatic involved BSA (%)


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
Baseline BSA (%) category (≤5%, >5%)

Baseline PASI score

Baseline PASI score category (≤7, >7)

Baseline DLQI total score

Baseline whole body itch NRS

Baseline whole body itch NRS category (0 to 4, 5 to 10, ≥ 4)

Number of prior phototherapies 

Number of prior biologic therapies

Number of prior conventional systemic therapies

Number of prior systemic therapies 

Number of failed prior phototherapies for subjects who had prior phototherapies 

Number of failed prior conventional systemic therapies for subjects who had prior 
conventional systemic therapies

Number of failed prior systemic therapies for subjects who had prior systemic therapies
8.3.
Medical History
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) version 21.0 or higher. A frequency summary (counts and percentage) of medical 
history will be presented by treatment group, system organ class (SOC), and preferred term (PT)
for ITT population.  A listing of medical history will be provided for the ITT population. 
8.4.
Prior and Concomitant Procedures
Prior and concomitant procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.0 or higher. Frequency summaries of prior and concomitant 
procedures will be provided for the safety population by treatment group, SOC, and PT. 
Prior procedures are defined as those started before the first dose of IP. A concomitant procedure 
is defined similarly as a TEAE. Concomitant procedures will be summarized for (1) Placebo-
controlled Phase (Weeks 0 to16), (2) Apremilast Extension Phase (Weeks 16 to 32).
8.5.
Prior and Concomitant Medications
Prior and concomitant medication will be coded using the Anatomical Therapeutic Chemical 
(ATC) coding scheme of the World Health Organization Drug Dictionary (WHO DD version 
March 2018 or higher). Prior medications will be summarized by treatment group (and overall), 
ATC2 level, and preferred name for the ITT population. Concomitant medications will be 


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summarized by treatment group, ATC2 level, and preferred name for the placebo-controlled 
phase for the safety population, and for the Apremilast-exposure periods for the Apremilast 30 
mg BID subjects as treated population. Frequency summaries will be provided by treatment 
group, ATC 2 level, and standardized medication name for the safety population.
Prior medications are defined as those started before the first dose of IP. Prior medications that 
continue after the first dose of IP will also be reported as concomitant medications.
For each of the treatment phases, Concomitant medications are defined as non-study medications 
started during the phase, or non-study medications started before the phase and ended or 
remained ongoing during the phase. The treatment phase for concomitant medications will start 
on the first dose date and end on the last dose date.
Medications in the Follow-up Phase will include those medications started after the date of last 
dose of investigational product.
Summaries will be provided for prior psoriasis medications and prior medications, as well as for 
concomitant medications in: (1) Placebo-controlled Phase (Weeks 0 to16), (2) Apremilast 
Extension Phase (Weeks 16 to 32), and (3) Observational Follow-up Phase (4 weeks).


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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Treatment duration will be summarized by treatment group for the analysis phases and for the 
Apremilast-exposure Period (Section 5.1). Subjects who are treated in the corresponding phases 
or period will be used, i.e., the safety population for Placebo-controlled Phase (Weeks 0 to 16), 
subjects who are treated in Apremilast Extension Phase (Weeks 16 to 32), and the apremilast 
subjects as treated population for the Apremilast-exposure Period.
Summary statistics for treatment duration (in weeks), as well as a frequency summary of 
treatment duration categories (e.g., < 4, ≥ 4 - < 8 weeks, etc.), will be provided.
9.1.1.
Placebo-controlled Phase (Weeks 0 to 16)
Treatment duration (in weeks) is calculated from the date of the first dose of IP at Week 0/Visit 2 
to either the date one day prior to the first dose date in the Apremilast Extension phase for the IP 
dispense at Week 16/Visit 7, or the date of the last dose of IP in the study for subjects who 
discontinue in the phase. Imputation rule for partially or completely missing last dose date is 
specified in Appendix A1.1.4.
Treatment duration will be summarized by actual treatment (placebo or apremilast) for the safety 
population. 
9.1.2.
Apremilast Extension Phase (Weeks 16 to 32)
Treatment duration is calculated from the first dose date in the Apremilast Extension phase for 
the IP dispense at Week 16/Visit 7 to the date of the last dose of IP in the study for subjects who 
discontinue in the phase or who complete the study at Week 32/Visit 10. Imputation rule for 
partially or completely missing last dose date is specified in Appendix A1.1.4. 
9.1.3.
Apremilast-exposure Period
Treatment duration for Apremilast-exposure Period (Section 5.1) is calculated from the date of 
the first dose of apremilast, which is the date of the first dose of apremilast after randomization at 
Week 0/Visit 2 or switched to apremilast at Week 16/Visit 7, to the last apremilast dose date for 
subjects who discontinue in the first 32 weeks or who complete the study at Week 32/Visit 10.  
Imputation rule for partially or completely missing last dose date is specified in Appendix 
A1.1.4.
9.2.
Treatment Compliance 
As part of the routine recording of the amount of IP taken by each subject, the numbers of tablets 
dispensed and/or returned will be recorded at visits in treatment phases. These records will be 
used to calculate treatment compliance. 
The treatment compliance (in %) for each subject will be computed as 100 times the total 
number of tablets taken (the total number of tablets dispensed minus the total number of tablets 
returned) over the analysis phase or period divided by the intended total number of tablets that 
should have been taken over the same phase or period.


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Summary statistics for compliance (%) will be provided by treatment arm for each analysis phase 
or period. Frequency summary tables of compliance will also be presented with the following 
categories: < 75%, ≥75% - ≤120%, and > 120%. A subject data listing of drug accountability 
records will be provided.
9.2.1.
Placebo-controlled Phase (Weeks 0 to 16)
Treatment compliance will be calculated for the treatment duration in the phase specified in 
Section 9.1.1 and will be summarized by treatment arm for ITT population.
9.2.2.
Apremilast Extension Phase (Weeks 16 to 32)
Treatment compliance will be calculated for the treatment duration in the phase specified in 
Section 9.1.2 and will be summarized by treatment arm for the subjects who were treated in the 
phase.
9.2.3.
Apremilast-exposure Period
Treatment compliance will be calculated for the treatment duration in the period specified in 
Section 9.1.3 and will be summarized by treatment arm for apremilast as treated population.


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10.
PROTOCOL DEVIATIONS AND IMPORTANT PROTOCOL 
DEVIATIONS
Protocol deviations will be classified as protocol deviations or important protocol deviations 
according to Celgene or CRO’s standard procedure. A list of protocol deviations and important 
protocol deviations for all subjects for week 16 analysis will be defined prior to the Week 16 
data restriction and unblinding (i.e., prior to the unblinding of double-blind placebo-controlled 
phase data). The list of protocol deviations and important protocol deviations for all subjects for 
final analysis will be finalized prior to the final database lock. This listing of important protocol 
deviations for week 16 analysis will also identify which subjects are to be excluded from the per-
protocol population.
Protocol deviations and important protocol deviations by treatment group and overall will be 
provided for the placebo-controlled phase for the ITT population, and for the Apremilast 
extension phase for subjects who receive at least one dose of IP during the phase. Summary 
tables showing the number and percent of subjects with at least one protocol deviation and 
important protocol deviations and by each category of protocol deviations and important protocol 
deviations will be provided. Listings of subjects with protocol deviations and important protocol 
deviations will also be provided. 


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11.
SAFETY ANALYSIS 
Safety will be assessed via descriptive statistics. Unless otherwise specified, all safety analyses 
described in this section will be performed for both the Placebo-controlled Phase and the 
Apremilast-exposure Period. The safety analyses for the Placebo-controlled Phase will be based 
on the safety population and presented by treatment group (placebo arm or apremilast arm), and 
the safety analyses for the Apremilast-exposure Period will be based on the apremilast subjects 
as treated population and presented by treatment group (Placebo/30 mg BID, 30 mg BID as 
Initiated and 30 mg BID as Treated).
For the analyses of AEs and lab marked abnormalities, the following endpoints will also be 
summarized:

Subject incidence: Subject incidence (i.e., percentage [%] used in a frequency summary) 
is defined as the number of subjects with the specific event divided by the number of 
subjects included in the analysis. Subjects with multiple occurrences of the specific event 
in the specific analysis period will be counted only once in the numerator.

Exposure-adjusted incidence rate (EAIR) per 100 subject-years: The EAIR per 100 
subject-years is defined as 100 times the number of subjects with the specific event 
divided by the total exposure time (in years) among subjects included in the analysis. 
Subjects with multiple occurrences of the specific event in the specific analysis period 
will be counted only once in the numerator. The exposure time for a subject without the 
specific event is the treatment duration, whereas the exposure time for a subject with the 
specific event is the treatment duration up to the start date (inclusive) of the first
occurrence of the specific event. The total exposure time in years is calculated by 
dividing the sum of exposure time in days over all subjects included in the analysis by 
365.25. The EAIR per 100 subject-years is interpreted as the expected number of subjects 
with at least one occurrence of the specific event per 100 subject-years of exposure to the 
IP.
AEs and lab marked abnormalities will be summarized by subject incidence and EAIR for the 
Placebo-controlled Phase (Weeks 0 to 16) and for the Apremilast-exposure Period. In addition, 
selected summaries for the Apremilast Extension Phase (Weeks 16 to 32) and the Observational 
Follow-up Phase (4 weeks) may be presented if deemed necessary.
Descriptive statistics will be provided for vital signs, weight, height and BMI, laboratory values 
(continuous measurements) by treatment and visit, including the end of treatment visits. The 
baseline value, value at the time point, and change from baseline will be summarized for subjects 
who have values at baseline and at the time point.
Shift tables, that is, tables that summarize the baseline categories (normal, abnormal) versus the 
category at the end of the respective periods or versus the worst post-baseline category, include 
subjects who have values at baseline and at least one post-baseline value. Similarly, in frequency 
summaries of shifts from baseline at scheduled study weeks per protocol, only subjects who have 
values at baseline and at the time point will be included.


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11.1.
Adverse Events
AEs will be coded according to the MedDRA version 21.0 or higher. Unless otherwise specified, 
AEs will be summarized by SOC and PT, with SOCs presented in the standard international 
order and PTs within SOCs will be presented in descending order of subject incidence.
11.1.1.
Overall Summary of TEAEs
An overall summary of the following TEAE categories will be provided for the Placebo-
controlled Phase (Weeks 0 to 16) for subjects with:

Any TEAE

Any drug-related TEAE

Any severe TEAE

Any serious TEAE

Any serious drug-related TEAE

Any TEAE leading to drug interruption

Any TEAE leading to drug withdrawal

Any TEAE leading to death
In addition, for Apremilast Exposure Period overall summary of TEAEs will also be provided.
11.1.2.
All TEAEs
All TEAEs will be summarized by SOC and PT as well as by PT only (in descending order of 
subject incidence for the Placebo-controlled Phase (Weeks 0 to 16) and the Apremilast-exposure 
Period. 
New events of all TEAEs by exposure interval (≤ 1, > 1 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12 and > 12 
Weeks) will be summarized for the Placebo-controlled Phase. Each subject is counted once for 
either subject incidence or EAIR for each applicable specific TEAE in each exposure interval 
where an event started. The denominator of a subject incidence is the number of subjects with 
the exposure time reaching the lower bound of the particular exposure interval, and the 
denominator of an EAIR is the sum of the exposure time during the exposure interval (up to the 
start date [inclusive] of the first occurrence of the specific event for each subject reporting the 
event in the interval) among the same number of subjects as in the denominator of the 
corresponding subject incidence.
In addition, new events of all TEAEs by exposure interval (≤ 1, > 1 to ≤ 8, > 8 to ≤ 16, > 16 to ≤ 
24, > 24 to ≤ 32, > 32 Weeks) will be summarized for the Apremilast-exposure Period.
All TEAEs will be summarized by age category (< 65, ≥ 65 years), sex, race (white vs. non-
white), baseline sPGA categories (sPGA =2; sPGA =3) and, if deemed necessary, by 
prior/concomitant psoriasis medication usage or baseline disease characteristics.


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11.1.3.
Common TEAEs
TEAEs with subject incidence ≥ 5% (or another cut-off if justified) in any treatment group will 
be summarized by SOC and PT as well as by PT only in descending order of subject incidence.
11.1.4.
Drug-related TEAEs
Drug-related TEAEs will be summarized and new events of drug-related TEAEs by exposure 
interval (see Section 11.1.2) will be summarized.
11.1.5.
TEAEs by Maximum Severity
All TEAEs will be summarized by maximum severity (mild, moderate, severe, and, if needed, 
missing; EAIR will not be provided for this summary). If a subject reports multiple occurrences 
of a specific event within a specific analysis phase or period, the subject will be counted only 
once by the maximum severity. If the severity is missing for one or more of the occurrences, the 
maximum severity of the remaining occurrences will be used. If the severity is missing for all of 
the occurrences, the subject will be counted only once in the “missing” category of severity.
TEAE by maximum severity will be summarized for the Placebo-controlled Phase (Weeks 0 to 
16) and Apremilast-exposure Period.
In addition, severe TEAE will be summarized for the Placebo-controlled Phase (Weeks 0 to 16), 
the Apremilast Extension Phase (Weeks 16 to 32), and Apremilast-exposure Period.
11.1.6.
Serious TEAEs
Serious TEAEs and serious drug-related TEAEs will be summarized. 
New events of serious TEAEs and serious drug-related TEAEs by exposure interval will be 
summarized for Placebo-controlled Phase (Weeks 0 to16).
Serious TEAEs will be summarized by age category (< 65, ≥ 65 years), sex and race.
A subject data listing of all serious AEs (both TEAEs and non-TEAEs) will be provided.
11.1.7.
TEAEs Leading to Drug Interruption and Drug Withdrawal
TEAEs leading to drug interruption and TEAEs leading to drug withdrawal will be summarized.
TEAEs leading to drug withdrawal will also be summarized by age category (< 65, ≥ 65 years), 
sex and race.
A subject data listing of TEAEs leading to drug withdrawal will be provided.
11.1.8.
Deaths
TEAEs leading to death will be summarized. A subject data listing of all deaths will be provided.
11.1.9.
Onset/Duration of TEAEs for Selected PT
Onset and duration (Days) of diarrhea, nausea, headache, vomiting and tension headache will be 
summarized for the Placebo-controlled Phase (Weeks 0 to 16) and Apremilast-exposure Period. 


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11.1.10.
Adverse Events of Special Interest
Summary tables and listings may be provided for the AESIs if deemed necessary.
11.2.
Vital Signs and Weight
The endpoints for vital signs and weight include:

Observed value and change from baseline over time in vital signs (temperature, pulse, 
and blood pressure)

Shifts from baseline to post-baseline time points and to the worst post-baseline value in 
terms of normal/abnormal in pulse and blood pressure (normal ranges are defined as: 60-
100 beats/minute for pulse, 90-140 mmHg for systolic blood pressure, and 60-90 mmHg 
for diastolic blood pressure)

Observed value, change and percent change from baseline over time in weight
Summary statistics of observed values and changes from baseline in vital signs (including 
weight, for which percent change from baseline will also be summarized) will be provided over 
time. Frequency summaries (shift tables) of shifts from baseline to post-baseline time points and 
to the worst post-baseline value in terms of normal/abnormal will be provided for pulse and 
blood pressure.
Frequency summaries of change and percent change in weight from baseline to the end of the 
period will be provided by baseline BMI category (< 25, ≥ 25 to < 30, ≥ 30 to < 35, ≥35 to < 40, 
and ≥40 kg/m2) and by baseline weight category (< 70, ≥ 70 to < 85, ≥85 to < 100, and ≥100 kg). 
The categories of weight change (kg) and percent change (%) are < -20, ≥-20 to < -10, ≥-10 to < 
-5, ≥-5 to < 0, 0, > 0 to ≤ 5, > 5 to ≤ 10, > 10 to ≤ 20, and > 20. The end-of-period or end-of-
phase value is the last post-baseline value in the analysis period or phase (excluding the value 
obtained at the follow-up visit, if applicable) up to 28 days after the last dose of IP in the study.
A subject data listing of all vital signs and weight data will be provided.
11.3.
Clinical Laboratory Evaluations
The endpoints for clinical laboratory evaluations include:
-
Laboratory marked abnormalities (see Appendix A2)
-
Observed value and change from baseline over time in the following laboratory 
parameters including but not limited to

Complete blood count: red blood cell [RBC] count, hemoglobin, hematocrit, white 
blood cell [WBC] count and differential, absolute WBC counts, platelet count

Serum chemistry: total protein, albumin, calcium, phosphorous, glucose, total 
cholesterol [TC], triglycerides, high-density lipoprotein [HDL], high-density 
lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], uric 


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acid, total bilirubin, alkaline phosphatase, aspartate aminotransferase [AST; serum 
glutamic-oxaloacetic transaminase, SGOT], alanine aminotransferase [ALT; serum 
glutamic pyruvic transaminase, SGPT], sodium, potassium, chloride, bicarbonate 
[carbon dioxide, CO2], blood urea nitrogen, creatinine, lactate dehydrogenase 
[LDH], and magnesium

Dipstick urinalysis: specific gravity, pH, glucose, ketones, protein, blood, bilirubin, 
leukocyte esterase, nitrite, and urobilinogen
-
Shifts from baseline to post-baseline time points and to the worst post-baseline value in 
terms of normal/abnormal (low or high) in the above hematology and serum chemistry 
parameters
Summary statistics of observed values and changes from baseline in laboratory parameters will 
be provided over time. Frequency summaries (shift tables) of shifts from baseline to post-
baseline time points and to the worst post-baseline value in terms of normal/abnormal will be 
provided.
Laboratory marked abnormalities will be summarized; subject incidence and EAIR for each 
abnormality will be calculated based on subjects with a baseline value and at least one post-
baseline value for criteria requiring baseline or subjects with at least one post-baseline value for 
criteria not requiring baseline. A subject data listing of laboratory marked abnormalities will be 
provided. Laboratory marked abnormalities will also be summarized for subjects with normal 
values at baseline and for subjects with abnormal values at baseline separately. For the purposes 
of these summaries, subjects with abnormal (normal) values at baseline are defined as those 
whose baseline value is low (not low) for criteria concerning low values and those whose 
baseline value is high (not high) for criteria concerning high values; both low and high are 
relative to the laboratory normal range.
A subject data listing of all laboratory data, including urinalysis, will be provided.
11.4.
Columbia Suicide Severity Rating Scale (C-SSRS)
All subjects will complete the Columbia-Suicide Severity Rating Scale (C-SSRS) assessment at 
all study visits. C-SSRS is a scale that captures the occurrence, severity, and frequency of 
suicide-related ideations and behaviors during the assessment period (Posner, 2007). At Visit 1 
(Screening) the C-SSRS will be completed for the subject’s lifetime history of suicidal ideation 
and behavior. At all other visits the C-SSRS will be completed for ideation and behavior since 
the previous visit.
A summary and subject data listing of psychiatric evaluation results will be provided.


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APPENDIX A1 – CONVENTIONS RELATED TO DATES
Following are the general conventions for various computations and imputations for references. 
Users may need to consult with study team for specific study practices or regulatory guidelines.
11.5.
A1.1 Guideline of Partially Missing Date Imputation
A1.1.1 Adverse Events
Partially missing AE start dates will be imputed in the ADaM dataset for AEs, but partially 
missing AE end dates will not be imputed in the same dataset. If the AE end date is complete
with no missing year, month, or day, and the partially missing start date imputed by the rules 
below is after the AE end date, then the start date will be imputed by the AE end date.
Subjects who were treated with apremilast at Week 0/Visit 2
The principle of the imputation rules for subjects who were treated with apremilast initially is to 
treat the AE as treatment-emergent, i.e., occurring on or after the date of the first dose of IP, if 
possible.
Let an AE start date be represented as “DEvent/MEvent/YEvent”, and the date of the first dose of IP as 
“DIP/MIP/YIP”. The following table gives the imputation rules for partially missing AE start dates 
for subjects who were treated with apremilast initially.
Table 4:
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially
Scenario
Condition
Imputation Rule
Partially missing date includes year only (both month and day are missing)
1
YEvent < YIP
12/31/YEvent
2
Otherwise, i.e., YIP ≤ YEvent
Max (date of first dose of IP, 1/1/YEvent)
Partially missing date includes both year and month (only day is missing)
1
YEvent < YIP, or (YEvent = YIP and MEvent < MIP)
Last date of MEvent/YEvent
2
Otherwise, i.e., YIP < YEvent, or (YIP = YEvent
and MIP ≤ MEvent) 
Max (date of first dose of IP, 1/MEvent/YEvent)
Subjects who were treated with placebo at Week 0/Visit 2
The principle of the imputation rules for subjects who were treated with placebo initially and 
started apremilast treatment at Week 16 is to consider the AE starting on or after the date of the 
first dose of apremilast, if possible; if the partially missing start date suggests that it is prior to 
the date of the first dose of apremilast, the AE will be considered starting on or after the date of 
the first dose of IP, if possible.
The following are 4 scenarios considered in the imputation rules:
1. The partially missing AE start date suggests the date is prior to the date of the first dose 
of IP: impute it by the latest possible date (determined by the non-missing field of the 
date);


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2. The partially missing AE start date suggests the date is after the date of the first dose of 
apremilast following Week 16: impute it by the earliest possible date (determined by the 
non-missing field of the date);
3. The partially missing AE start date is in the same year (if both month and day are 
missing), or the same year/month (if only day is missing) of the first dose of apremilast 
following Week 16: impute it by the date of the first dose of apremilast;
4. The partially missing AE start date suggests the date is no earlier than the date of the first 
dose of IP but prior to the date of the first dose of apremilast following Week 16: impute 
it by the date of the first dose of IP, or the earliest possible date (determined by the non-
missing field of the date), whichever occurs later.
Let an AE start date be represented as “DEvent/MEvent/YEvent”, the date of the first dose of IP as 
“DIP/MIP/YIP”, and the date of the first dose of apremilast following Week 16 as
“DAPR/MAPR/YAPR”. The following table gives the imputation rules for partially missing AE start 
dates.
Table 5:
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Placebo Initially
Scenario
Condition
Imputation Rule
Partially missing date includes year only (both month and day are missing)
1
YEvent < YIP
12/31/YEvent
2
YEvent > YAPR
1/1/YEvent
3
YEvent = YAPR
Date of first dose of apremilast following 
Week 16
4
Otherwise, i.e., YIP ≤ YEvent< YAPR
Max (date of first dose of IP, 1/1/YEvent)
Partially missing date includes both year and month (only day is missing)
1
YEvent < YIP, or (YEvent = YIP and MEvent < MIP )
Last date of MEvent/YEvent
2
YEvent > YAPR, or (YEvent = YAPR and MEvent > 
MAPR)
1/MEvent/YEvent
3
YEvent = YAPR and MEvent = MAPR
Date of first dose of apremilast following 
Week 16
4
Otherwise, i.e., YIP < YEvent < YAPR, or 
(YIP = YEvent < YAPR and MIP ≤ MEvent), or 
(YIP = YEvent = YAPR and MIP ≤ MEvent < MAPR), 
or (YIP < YEvent = YAPR and MEvent < MAPR)
Max (date of first dose of IP, 1/MEvent/YEvent)


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A1.1.2 Prior/Concomitant Medications/Procedures
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset for 
prior/concomitant medications/procedures. For prior/concomitant medications, if the stop date is 
complete with no missing year, month, or day, and the partially missing start date imputed by the 
rule below is after the stop date, then the start date will be imputed by the stop date.
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date.
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date. If the imputed start date is after the stop date, the 
start date will be imputed as the stop date – 1.
A.1.1.3 Medical History
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history (for the purposes of calculating durations of PsA and psoriasis). The 16th of the month 
will be used to impute a partially missing start date that has only the day missing, and July 1st
will be used to impute a partially missing start date that has both the month and day missing.
If the imputed start date is after the stop date, the start date will be imputed as the stop date – 1.
A1.1.4 Treatment Duration
Partially or completely missing last dose dates will be imputed in the ADaM dataset for 
treatment duration. 
When partially missing last dose date is available, set last dose date to the maximum of [the 
earliest possible date given the non-missing field(s) of last dose date, the minimum of (the latest 
possible date given the non-missing field(s) of last dose date, last known date in database, first 
non-missing Early Termination (ET) visit date)]
When last dose date is completely missing, set last dose date to the minimum of (last known date 
in database, first non-missing Early Termination (ET) visit date)
Last known date in database is defined as maximum of (last visit date, lab, vital signs, ECG 
assessment date, AE start or end dates, concomitant medications start or end dates, concomitant 
procedure date, last dose date from 'Disposition- Treatment' page, treatment exposure start or end 
dates where doses were completely or partially taken, death date).


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APPENDIX A2 – LABORATORY MARKED ABNORMALITIES 
CRITERIA
Table 6:
Laboratory Marked Abnormalities Criteria


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Category / Analyte
SI Units 
Criteria 
Chemistry/
  Alanine Aminotransferase (SGPT)
U/L
> 2*ULN
  Albumin
Kg/m3
< 25
  Alkaline Phosphatase
U/L
> 400
  Aspartate Aminotransferase (SGOT)
U/L
> 2*ULN
 Total Bilirubin
µmol/L
> 2*ULN
 Total Bilirubin and Alanine 
  Aminotransferase /Aspartate 
  Aminotransferase 
µmol/L and 
U/L
Bilirubin Value > 2xULN with (ALT 
or AST value > 2xULN)
 Blood Urea Nitrogen
mmol/L
> 24
 Calcium
mmol/L
< 1.8
> 3.0
 Cholesterol
mmol/L
> 7.8
 Creatinine 
µmol/L 
> 1.5*ULN
 Glucose
mmol/L
< 2.8
> 13.9
 Hemoglobin A1C
%
> 6.5
 Lactate Dehydrogenase (LDH)
U/L
> 2*ULN
 Magnesium
mmol/L
> 1.2
 Phosphate
mmol/L
<1.03
>1.94
 Potassium
mmol/L
<3.0
>5.4
 Sodium
mmol/L
<132
>147
 Triglycerides
mmol/L
> 3.4


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 Urate
umol/L
Male: > 480
Female: > 480
Hematology/
  Hemoglobin
g/L
Female <110, Male <110
Female >150, Male >150
 Leukocytes
10^9/L 
< 2.0
 Lymphocytes
10^9/L
< 1.0
 Neutrophils
10^9/L
< 1.5
 Platelets
10^9/L
<100
>500


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APPENDIX A3– REPORTING CONVENTIONS

Statistical test of the treatment difference will use two-sided significance level 0.05 
for significance or nominal significance. 

P-values will be rounded to 4 decimal places. p-values that round to 0.0000 will be 
presented as ‘<0.0001’ and p-values that round to 1.000 will be presented as 
‘>0.9999’;

Confidence intervals (CIs) will be presented as two-sided 95% CIs unless specified 
differently in specific analysis;

Summary statistics will consist of the number and percentage of subjects in each 
category for discrete variables, the sample size, mean, median, standard deviation 
(SD), minimum, and maximum for continuous variables, the 25th (Q1) and 75th (Q3) 
percentiles will also be applied to efficacy continuous variables;

Mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
places than the measured value. Minimum and maximum values will be presented to 
the same number of decimal places as the measured value;

Percentages will be rounded to one decimal place. The number and percentage of 
responses will be presented in the form xx (xx.x), where the percentage is in the 
parentheses;

Analysis and summary tables will have the analysis population sample size (i.e., 
number of subjects) in the column header;

Subject data listings will be provided to support the tables and graphs. Listings will 
be sorted for presentation in order of subject number and date of procedure or event.