Clinical trial NCT03123471
Conditions: Psoriasis
Keywords: Plaque Psoriasis Scalp Double-Blind Efficacy Safety CC-10004 Apremilast Otezla Itch Head
Sponsor: Amgen
Start date: 2017-05-16; Completion date: 2019-01-09
Enrollment: 303 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Approximately 300 subjects with moderate to severe plaque psoriasis of the scalp will be randomized 2:1 to receive either apremilast 30 mg twice daily (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 receive treatment with one of the following:

  * 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 who had received placebo during the placebo-controlled phase will be switched to apremilast 30 mg BID (or continue with) apremilast. At Week 16, all subjects will maintain this dosing through Week 32.
* Observational Follow-up Phase

  * Four-week Post-Treatment Observational Follow-up Phase for all subjects who complete the study or discontinue from the study early.

Arms: arm 1: Apremilast 30 mg tablets orally twice daily (BID) during Weeks 0 to 32 arm 2: Placebo tablets BID during weeks 0 to 16; at week 16, placebo participants were switched to apremilast 30 mg tablets BID for 16 weeks (from Week 16 to Week 32)
Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: Apremilast 30 mg tablets BID from weeks 0 to 32. intervention 2: Placebo tablets twice daily (BID) for 16 weeks; placebo participants were switched to apremilast 30 mg at week 16.

Protocol documents:
Prot_000.pdf: 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
1
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
TITLE PAGE
A PHASE 3, MULTI-CENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY OF 
THE EFFICACY AND SAFETY OF APREMILAST (CC-
10004) IN SUBJECTS WITH MODERATE TO SEVERE 
PLAQUE PSORIASIS OF THE SCALP
PROTOCOL NUMBER:
CC-10004-SPSO-001
DATE FINAL:
29 Mar 2017
AMENDMENT 1 FINAL:
30 Nov 2017
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.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
2
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:  
Title:  
           
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.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
3
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
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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.  
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
4
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
5
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
6
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
PROTOCOL SUMMARY
Study Title
A Phase 3, Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study of the Efficacy 
and Safety of Apremilast (CC-10004) in Subjects with Moderate to Severe Plaque Psoriasis of 
the Scalp
Indication
The indication is moderate to severe plaque psoriasis of the scalp.
Objectives
Primary Objective
!
To evaluate the clinical efficacy of apremilast 30 mg twice daily (BID) compared 
with placebo, in subjects with moderate to severe plaque psoriasis of the scalp, at 
Week 16
Secondary Objective(s)
!
To evaluate the safety and tolerability of apremilast 30 mg BID compared with 
placebo, in subjects with moderate to severe plaque psoriasis of the scalp.
!
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 itch 
associated with plaque psoriasis of the scalp
!
To evaluate the onset of effect on itch over the whole body caused by plaque psoriasis 
with apremilast 30 mg BID compared with placebo
!
To evaluate the onset of effect on itch associated with plaque psoriasis of the scalp 
with apremilast 30 mg BID compared with placebo
!
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 of the 
efficacy and safety of apremilast (CC-10004) in subjects with moderate to severe plaque 
psoriasis of the scalp.
Approximately 300 subjects will be randomized 2:1 to receive either apremilast
30 mg BID or placebo for the first 16 weeks.  Randomization will be stratified by baseline Scalp 
Physician Global Assessment (ScPGA) score (moderate [3], severe [4]) to ensure balance 
between treatment arms with respect to baseline severity of scalp psoriasis.
!
Subjects randomized to the apremilast 30 mg BID treatment group will receive 
apremilast 30 mg tablets orally twice daily for the first 16 weeks
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
7
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
!
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:
!
Screening Phase – up to 35 days
!
Double-blind Placebo-controlled Phase – Weeks 0 to 16
Subjects will receive treatment with one of the following:  
∀
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 at 
Week 16. All subjects will maintain this dosing through Week 32.
!
Observational Follow-up Phase
∀
Four-week Post-treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue from the study early.
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database lock will be performed; the primary data analysis will be conducted 
 
.  However, unblinded data will only be made available 
to select Sponsor and Contract Research Organization (CRO) team members involved with 
analysis of the data 
.  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, ie, when all subjects have also completed (or have been discontinued) the Apremilast
Extension Phase (Weeks 16 to 32) and the Observational Follow-up Phase, the final analysis will 
be performed and a final Clinical Study Report will be generated.
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.
Study Population
Adult subjects ≥ 18 years of age with moderate to severe plaque psoriasis (Psoriasis Area and 
Severity Index [PASI] ≥ 12, and Body Surface Area [BSA] ≥ 10%, and Static Physician Global 
Assessment [sPGA] ≥ 3 [moderate or greater]) who also have moderate to severe plaque 
psoriasis of the scalp (Scalp Physician Global Assessment ≥ 3 [moderate or greater], and Scalp 
Surface Area ≥ 20%, and having had an inadequate response or intolerance to at least one topical 
therapy [for example, potent or super potent topical corticosteroids, vitamin D analogs, and 
combination products] for plaque psoriasis of the scalp).
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235


EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
8
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 3 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 pre-specified in the protocol, 
whichever is the later date.
Study Treatments
All IP 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 (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 and at Week 16 for subjects initially 
randomized to placebo when they switch to apremilast 30 mg BID treatment.  
During Week 0 (Days 1 to 7), subjects will be dispensed dose titration 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 in the Placebo-controlled 
Treatment Phase.  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.
!
Weeks 16 to 32: Apremilast Extension Phase: Apremilast 30 mg BID.
∀
Week 16 to 17: subjects will be dose titrated as described below.
At Visit 2 (Week 0), subjects who meet entry criteria will be randomized using a permuted block 
randomization in parallel 2:1 to receive either apremilast 30 mg BID or placebo, using a 
centralized Interactive Response Technology (IRT). 
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 (see Table 5 Treatment Schema for Dose Titration at Visit 7 [Week 16]) which details 
the titration supplies from Day 1 to Day 7 in the Apremilast Extension Phase. Dose titration 
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.
Dose modifications are not permissible in this study.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
9
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Overview of Key Efficacy Assessments
Primary Efficacy Assessment
!
Scalp Physician Global Assessment (ScPGA)
Additional Efficacy Assessments
!
Subject’s Assessment of Whole Body Itch numeric rating scale (NRS)
!
Subject’s Assessment of Scalp Itch NRS
!
!
!
!
!
Health-Related Quality of Life (HRQoL) questionnaires
∀
Dermatology Life Quality Index (DLQI)
∀
Overview of Key Safety Assessments
Safety assessments will include:
!
Adverse events (AE)
!
12-lead electrocardiograms (ECG)
!
Chest radiographs (CXR)
!
Physical examinations
!
Vital signs
!
Pregnancy tests for females of childbearing potential (FCBP)
!
Clinical laboratory tests
Statistical Methods
The study will randomize approximately 300 subjects in a 2:1 ratio to apremilast 30 mg BID or 
placebo arms stratified by baseline ScPGA score (moderate [3], severe [4]). With this sample 
size, a chi-square test at the 2-sided 0.05 significance level will have 90% power to detect a 
minimum treatment difference of 18% (38% for apremilast 30 mg BID versus 20% for placebo) 
between the two arms for proportions of subjects achieving ScPGA response at Week 16 
(defined as ScPGA score of clear [0] or almost clear [1] with at least a 2 point reduction from 
baseline at Week 16).
Analyses for efficacy endpoints will be mainly on the intent-to-treat (ITT) population, defined as 
all randomized subjects. Statistical comparisons will be made between the two treatment arms.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
10
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
All statistical tests will be at the 2-sided 0.05 significance level and the corresponding p-values 
and confidence intervals will be reported. 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 2-sided 0.05 significance level. 
The primary endpoint, the proportion of subjects who achieved ScPGA response at Week 16 
between apremilast 30 mg BID and placebo, will be compared using Cochran–Mantel–Haenszel 
(CMH) test adjusted by stratification factors in randomization. Missing values at Week 16 will 
be imputed using the multiple imputation (MI) method as the primary analysis. Sensitivity 
analyses will be performed using the last observation carried forward (LOCF) method and the 
non-responder imputation (NRI) method. The binary secondary efficacy endpoints will be 
analyzed similarly as the primary endpoint. 
The analysis for the continuous secondary endpoint will be performed using the analysis of 
covariance (ANCOVA) model. The ANCOVA model will use the change from baseline as the 
dependent variable and will include treatment group and stratification factor as independent 
variables and the baseline value as a covariate variable.
All efficacy endpoints will be summarized by study visit for both the Placebo-controlled Phase 
(Weeks 0 to 16) and Apremilast Extension Phase (Weeks 16 to 32). When appropriate, 
exploratory endpoints at Week 16 will also be analyzed using CMH or ANCOVA methods 
similar to the primary and secondary endpoints.
The safety analyses will be performed using the safety population defined as all subjects who 
received at least one dose of IP. Safety will be assessed by clinical review of all relevant 
parameters including treatment-emergent adverse events (TEAEs), laboratory tests, vital signs, 
and electrocardiogram (ECG) measurements. Data from safety assessments will be summarized 
descriptively for the Placebo-controlled Phase (Weeks 0 to 16) and the Apremilast Exposure 
Period. Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. All TEAEs will be summarized by system organ class, 
preferred term, severity, and relationship to IP.  TEAEs leading to death or to IP withdrawal and 
serious TEAEs will also be summarized and listed separately.  
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
11
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................17
1.1.
Disease Background ...............................................................................................17
1.2.
Compound Background ..........................................................................................17
1.3.
Rationale ................................................................................................................18
1.3.1.
Study Rationale and Purpose ..................................................................................18
1.3.2.
Rationale for the Study Design ...............................................................................18
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................19
1.3.4.
Rationale for Choice of Comparator .......................................................................19
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................21
3.
OVERALL STUDY DESIGN ................................................................................24
3.1.
Overall 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.............................................................................................30
6.
PROCEDURES......................................................................................................33
6.1.
Screening Period.....................................................................................................33
6.2.
Treatment Period ....................................................................................................34
6.2.1.
End of Treatment....................................................................................................35
6.3.
Follow-up Period....................................................................................................36
6.4.
Efficacy Assessments .............................................................................................37
6.5.
Safety Assessments.................................................................................................39
6.7.
Patient Reported Outcomes.....................................................................................42
6.8.
Photography ...........................................................................................................43
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
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CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
7.
DESCRIPTION OF STUDY TREATMENTS........................................................44
7.1.
Description of Investigational Product(s)................................................................44
7.2.
Treatment Administration and Schedule .................................................................47
7.3.
Overdose ................................................................................................................47
7.4.
Method of Treatment Assignment...........................................................................47
7.5.
Packaging and Labeling..........................................................................................47
7.6.
Investigational Product Accountability and Disposal ..............................................48
7.6.1.
Record of Administration .......................................................................................48
7.7.
Investigational Product Compliance........................................................................48
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................49
8.1.
Permitted Concomitant Medications and Procedures...............................................49
8.2.
Prohibited Concomitant Medications and Procedures..............................................49
8.3.
Required Concomitant Medication..........................................................................50
9.
STATISTICAL CONSIDERATIONS ....................................................................51
9.1.
Overview................................................................................................................51
9.2.
Study Population Definitions ..................................................................................51
9.3.
Sample Size and Power Considerations...................................................................51
9.4.
Background and Demographic Characteristics........................................................52
9.5.
Subject Disposition.................................................................................................52
9.6.
Efficacy Analysis....................................................................................................52
9.6.1.
Efficacy Evaluation for the Placebo-controlled Phase (Weeks 0 to 16)....................52
9.6.1.1.
Primary Efficacy Endpoint......................................................................................52
9.6.1.2.
Secondary Efficacy Endpoints ................................................................................53
9.6.1.3.
Multiplicity Adjustment..........................................................................................54
9.6.1.4.
Exploratory Endpoints............................................................................................55
9.6.1.5.
Subgroup Analysis..................................................................................................55
9.6.2.
Efficacy Evaluation – Apremilast Extension Phase (Weeks 16 to 32)......................55
9.7.
Safety Analysis.......................................................................................................55
9.8.
Interim Analysis .....................................................................................................56
9.9.
Other Topics...........................................................................................................56
9.9.1.
Investigational Product Compliance (Tablets).........................................................56
9.9.2.
Concomitant Therapy .............................................................................................56
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
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Confidential and Proprietary
13
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
9.9.3.
Steering Committee ................................................................................................56
9.9.4.
Internal Celgene Safety Monitoring During the Apremilast Program: Role of 
the Safety Management Team.................................................................................57
10.
ADVERSE EVENTS..............................................................................................58
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................58
10.2.
Evaluation of Adverse Events.................................................................................58
10.2.1.
Seriousness.............................................................................................................58
10.2.2.
Severity/Intensity....................................................................................................60
10.2.3.
Causality ................................................................................................................60
10.2.4.
Duration .................................................................................................................61
10.2.5.
Action Taken..........................................................................................................61
10.2.6.
Outcome.................................................................................................................61
10.3.
Abnormal Laboratory Values..................................................................................61
10.4.
Pregnancy...............................................................................................................62
10.5.
Reporting of Serious Adverse Events......................................................................62
10.5.1.
Safety Queries ........................................................................................................63
10.6.
Expedited Reporting of Adverse Events..................................................................63
11.
DISCONTINUATIONS .........................................................................................64
11.1.
Treatment Discontinuation......................................................................................64
11.2.
Study Discontinuation ............................................................................................64
12.
EMERGENCY PROCEDURES.............................................................................66
12.1.
Emergency Contact.................................................................................................66
12.2.
Emergency Identification of Investigational Products .............................................66
13.
REGULATORY CONSIDERATIONS...................................................................67
13.1.
Good Clinical Practice............................................................................................67
13.2.
Investigator Responsibilities ...................................................................................67
13.3.
Subject Information and Informed Consent.............................................................68
13.4.
Confidentiality........................................................................................................68
13.5.
Protocol Amendments.............................................................................................68
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................68
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................69
13.8.
Termination of the Study ........................................................................................69
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
14
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
14.
DATA HANDLING AND RECORDKEEPING.....................................................70
14.1.
Data/Documents.....................................................................................................70
14.2.
Data Management...................................................................................................70
14.3.
Record Retention....................................................................................................70
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................72
15.1.
Study Monitoring and Source Data Verification......................................................72
15.2.
Audits and Inspections............................................................................................72
16.
PUBLICATIONS ...................................................................................................73
17.
REFERENCES.......................................................................................................74
18.
APPENDICES........................................................................................................76
Appendix A:
Table of Abbreviations ......................................................................................76
Appendix B:
Scalp Physician Global Assessment (ScPGA)....................................................79
Appendix C:
Modified Whole Body Itch Numeric Rating Scale (NRS) ..................................80
Appendix D:
Scalp Itch Numeric Rating Scale (NRS).............................................................81
Appendix F:
The Dermatology Life Quality Index (DLQI).....................................................84
Appendix K:
Treatment Schema for Dose Titration at Baseline ..............................................94
Appendix L:
Treatment Schema for Dose Titration at Week 16 ..............................................95
Appendix M:
Titration Blister Card Configuration..................................................................96
Appendix N:
Active Treatment Blister Card Configuration.....................................................97
Appendix O:
Placebo Treatment Blister Card Configuration...................................................98
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
15
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................21
Table 2:
Study Endpoints .....................................................................................................22
Table 3:
Table of Events.......................................................................................................30
Table 4:
Treatment Schema for Dose Titration at Visit 2 (Week 0).......................................45
Table 5:
Treatment Schema for Dose Titration at Visit 7 (Week 16).....................................46
Table 6:
Abbreviations and Specialist Terms........................................................................76
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
16
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................25
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
17
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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).  The scalp is the most frequent area affected by plaque psoriasis, 
occurring in up to 80% of patients (van de Kerkhof, 1998).  These lesions can affect the hair-
bearing areas of the scalp, extending past the hair line, as well as in the retroauricular area and on 
the neck.  The lesions and associated flaking can be visible as well as highly pruritic, causing a 
negative impact on the patient’s quality of life (Kragballe, 2013; Szepietowski, 2016). 
The presence of scalp hair makes application of topical therapies or use of phototherapy difficult 
and inconvenient, limiting their effectiveness as well as compliance (Warren, 2008; Feldman,
2003). Currently approved topical corticosteroids and calcipotriene preparations may be limited 
by short treatment durations and poor treatment compliance.  In addition, potent topical 
corticosteroid therapies can be associated with side effects such as tachyphylaxis, skin atrophy, 
striae, telangiectasia, and hypothalamic-pituitary-adrenal (HPA) axis suppression (van der 
Vleuten, 2001; Hogan, 1989).  Other topical therapies, such as coal tar and anthralin preparations 
have cosmetically unappealing formulations, foul odor, limited efficacy, and potential 
carcinogenic risk (Chan, 2009).  Second-line therapies such as phototherapy and systemic 
medications have been used, however, safety and efficacy data from controlled clinical trials for 
these agents is limited (Chan, 2009).  Efficacy data from controlled clinical trials involving 
treatment with biologics, such as ixekizumab has only recently been published (Reich, 2016).  
Thus, there remains an unmet medical need in treating plaque psoriasis of the scalp, particularly 
in patients with moderate to severe plaque psoriasis of the scalp.
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.  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, 
apremilast (OTEZLA®) is approved in approximately forty 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.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
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CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Please refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP).
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
Plaque psoriasis of the scalp is often challenging to treat.  Scalp skin is also relatively 
inaccessible, making topical therapies difficult to apply and inconvenient to use (Ortonne, 2009).  
Given the visibility of the lesions and the scaling/flaking as well as the itch associated with the 
disease, patients with plaque psoriasis of the scalp often experience considerable physical, 
psychological and social impacts to quality of life.
There remains an unmet medical need in treating plaque psoriasis of the scalp as currently 
approved topical corticosteroids and calcipotriene preparations may be limited by short treatment 
durations, poor treatment compliance, limited efficacy, and cosmetic appeal. As well, potent 
topical corticosteroid therapies can be associated with side effects such as tachyphylaxis, skin 
atrophy, striae, telangiectasia, and hypothalamic-pituitary-adrenal (HPA) axis suppression. Other 
topical therapies, such as coal tar and anthralin preparations, have the additional risk of 
carcinogenesis. Second-line therapies for plaque psoriasis of the scalp include phototherapy and 
systemic medications, however safety and efficacy data from controlled clinical trials for most of 
these agents is limited.  Efficacy data from controlled clinical trials involving treatment with 
biologics, such as ixekizumab has only recently been published.
Apremilast (CC-10004) is a specific phosphodiesterase type 4 (PDE4) inhibitor approved for the 
treatment of both psoriasis and psoriatic arthritis.  In Phase 2 and Phase 3 trials, apremilast 
demonstrated efficacy in treating subjects with moderate to severe plaque psoriasis.  
Furthermore, exploratory analyses performed in these studies showed that apremilast also 
provided significant benefit in the treatment of moderate to severe plaque psoriasis of the scalp.
This study is intended to directly assess the safety and efficacy of apremilast 30 mg twice daily 
(BID) in the treatment of subjects with moderate to severe plaque psoriasis of the scalp.
1.3.2.
Rationale for the Study Design
Exploratory analyses from the two pivotal Phase 3 studies of apremilast in subjects with 
moderate to severe plaque psoriasis (Study PSOR-008 and Study PSOR-009) demonstrated that 
apremilast 30 mg BID provided a treatment benefit in the subset of subjects who also presented 
with plaque psoriasis of the scalp of moderate or greater severity at baseline using a six-point 
Scalp Physician Global Assessment (ScPGA).  The 6-point ScPGA scale ranged from 0 (clear), 
1 (minimal), 2 (mild), 3 (moderate), 4 (severe), to 5 (very severe).
This study will directly investigate the safety and efficacy of apremilast 30 mg BID, compared 
with placebo, in the treatment of subjects with moderate to severe plaque psoriasis of the scalp.  
The primary endpoint will be the proportion of subjects who achieved ScPGA response at 
Week 16 (defined as ScPGA score of clear (0) or almost clear (1) with at least a 2-point 
reduction from baseline at Week 16), based on the intent-to-treat (ITT) population.  Based on 
Health Authority feedback, this study will use a 5-point ScPGA scale ranging from 0 (clear), 
1 (almost clear), 2 (mild), 3 (moderate), to 4 (severe), instead of the 6-point scale used in prior 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
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CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
studies.  This modified 5-point ScPGA scale is static, limited in the number of categories, and 
has categorical descriptions that are distinct and non-overlapping.
The primary endpoint will be assessed at Week 16 as results from prior studies suggest that a 
treatment effect over placebo can be demonstrated by this time point. The use of placebo for 16 
weeks has been acceptable in moderate to severe plaque psoriasis clinical trials. A total treatment 
duration of 32 weeks was selected in order to assess longer term effect of apremilast in the 
treatment of moderate to severe scalp psoriasis.
The study will also investigate the efficacy of apremilast 30 mg BID, compared with placebo, in 
the improvement of itch.  The data from the two pivotal Phase 3 studies of apremilast in subjects 
with moderate to severe plaque psoriasis (Study PSOR-008 and Study PSOR-009) demonstrated 
improvement in itch severity using a Visual Analog Scale (VAS). In this study, improvement of 
itch will be assessed using Numeric Rating Scales (NRS) as these are considered to have better 
reliability and precision, and lesser potential for missing values, than the VAS (Phan, 2012). The 
first secondary endpoint will be the proportion of subjects with ≥4-point reduction 
(improvement) from baseline in the Whole Body Itch NRS score at Week 16.  It is anticipated 
that approximately 80% of the subjects would be evaluable for this analysis, based on prior 
experience in Studies PSOR-008 and PSOR-009 as well as other clinical trials in moderate to 
severe plaque psoriasis (Griffiths, 2015).
Eligible subjects will be randomized 2:1 to receive either apremilast 30 mg BID or placebo in
order to reduce exposure to placebo without greatly increasing numbers of subjects exposed to 
IP, while maintaining the statistical power of the study.  Randomization will be stratified by 
baseline ScPGA score in order to ensure balance between treatment arms with respect to baseline 
severity of scalp psoriasis.
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
Exploratory analyses from the two pivotal Phase 3 studies (PSOR-008 and PSOR-009)
demonstrated that apremilast 30 mg BID provided a treatment benefit in subjects with plaque 
psoriasis of the scalp of moderate or greater severity.  This study will directly investigate the 
safety and efficacy of this dosing regimen in the treatment of subjects with moderate to severe 
plaque psoriasis of the scalp.
1.3.4.
Rationale for Choice of Comparator 
A randomized, double-blind placebo-controlled design was chosen in order to measure the 
absolute treatment effect of apremilast 30 mg BID in moderate to severe plaque psoriasis of the 
scalp.  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). 
 
 
 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
20
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
 
 
 
 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
21
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the clinical efficacy of apremilast 30 mg twice daily
(BID) compared with placebo, in subjects with moderate to severe plaque psoriasis of the scalp, at 
Week 16.
Secondary Objective(s)
The secondary objectives are:
!
To evaluate the safety and tolerability of apremilast 30 mg BID compared with placebo, in 
subjects with moderate to severe plaque psoriasis of the scalp.
!
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 itch associated with 
plaque psoriasis of the scalp
!
To evaluate the onset of effect on itch over the whole body caused by plaque psoriasis with 
apremilast 30 mg BID compared with placebo
!
To evaluate the onset of effect on itch associated with plaque psoriasis of the scalp with 
apremilast 30 mg BID compared with placebo
!
To evaluate the effect of apremilast 30 mg BID compared with placebo on health-related quality 
of life
Exploratory Objective(s)
The exploratory objectives are:
 
 
 
!
To evaluate the effect of apremilast 30 mg BID compared to placebo on Dermatological Life 
Quality Index (DLQI)
 
 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
22
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Scalp Physician Global 
Assessment (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. 
Week 16
Secondary 
Itch Numeric Rating 
Scale (NRS) [whole
body]
Proportion of subjects with ≥4-point 
reduction (improvement) from 
baseline in the whole body itch NRS 
score 
Week 16
Itch NRS (Scalp)
Proportion of subjects with ≥4-point 
reduction (improvement) from 
baseline in the scalp itch NRS score 
Week 16
Onset of effect on itch
NRS (whole body)
Proportion of subjects with ≥4-point 
reduction (improvement) from 
baseline in the whole body itch NRS 
score
By Visit in 
Placebo-controlled 
Phase (Week 12, 
Week 8, Week 4, 
Week 2)
Onset of effect on itch
NRS (Scalp)
Proportion of subjects with ≥4-point 
reduction (improvement) from 
baseline in the scalp itch NRS score
By Visit in 
Placebo-controlled 
Phase (Week 12, 
Week 8, Week 4, 
Week 2)
Dermatological Life 
Quality Index (DLQI)
Change from baseline in DLQI total 
score 
Week 16
Exploratory
 
 
ScPGA
Proportion of subjects with ScPGA 
score of clear (0) or almost clear (1) 
with at least a 2-point reduction from 
baseline 
By Visit 
Itch NRS (whole body)
Proportion of subjects with ≥4-point 
reduction (improvement) from 
baseline in the whole body itch NRS 
score
By Visit in 
Apremilast 
Extension Phase
Itch NRS (Scalp)
Proportion of subjects with ≥4-point 
reduction (improvement) from 
baseline in the scalp itch NRS score
By Visit in 
Apremilast 
Extension Phase
 
 
 
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
23
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Table 2:
Study Endpoints (Continued)
Endpoint
Name 
Description
Timeframe
 
 
 
 
 
DLQI
Change from baseline in DLQI total 
score
Weeks 4, 8, 16 and 
32
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety
Type, frequency, 
severity, and 
relationship of adverse 
events to IP
Day 0 through end of Observational 
Follow-Up
Study duration
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
24
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
3.
OVERALL STUDY DESIGN
3.1.
Overall Study Design
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study of the 
efficacy and safety of apremilast (CC-10004) in subjects with moderate to severe plaque 
psoriasis of the scalp.
Approximately 300 subjects with moderate to severe plaque psoriasis of the scalp will be 
randomized 2:1 to receive either apremilast 30 mg BID or placebo for the first 16 weeks.  
Randomization will be stratified by baseline Scalp Physician Global Assessment (ScPGA) score 
(moderate [3], severe [4]) to ensure balance between treatment arms with respect to baseline 
severity of scalp psoriasis.
!
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:
!
Screening Phase – up to 35 days
!
Double-blind Placebo-controlled Phase – Weeks 0 to 16
Subjects will receive treatment with one of the following:  
!
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 at 
Week 16. All subjects will maintain this dosing through Week 32.
!
Observational Follow-up Phase
!
Four-week Post-treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue from the study early.
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database lock will be performed; the primary data analysis will be conducted 
 
.  However, unblinded data will only be made available 
to select Sponsor and Contract Research Organization (CRO) team members involved with 
analysis of the data 
.  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 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
25
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Extension Phase (Weeks 16 to 32) and the Observational Follow-up Phase, the final analysis will 
be performed and a final Clinical Study Report will be generated.
Figure 1:
Study Design
Abbreviation:  BID = twice daily.
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 pre-specified in the protocol, 
whichever is the later date.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
26
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 300 subjects with moderate to severe plaque psoriasis of the scalp will be 
enrolled and randomized from investigator sites in Canada and the USA.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Males or females, ≥ 18 years of age at the time of signing the informed consent document
2. Understand and voluntarily sign an informed consent form (ICF) prior to any study-
related assessments/procedures being conducted. 
3. Be willing and able to adhere to the study visit schedule and other protocol requirements.
4. Have a diagnosis of moderate to severe plaque psoriasis of the scalp at screening and 
baseline as defined by:
a.
ScPGA (See Appendix B) score of ≥3 (moderate or severe) and,
b. Scalp Surface Area (SSA) involvement of ≥20% and,
c.
Inadequate response or intolerance to at least one topical therapy (for example, 
potent or super potent topical corticosteroids, vitamin D analogs, and combination 
products) for plaque psoriasis of the scalp.
5. Must be a candidate for phototherapy and/or systemic therapy for either body or scalp 
psoriasis lesions.  
6. Have moderate to severe plaque psoriasis at screening and baseline as defined by:
a.
Psoriasis Area and Severity Index (PASI) (
) score ≥12 and,
b. Body Surface Area (BSA) ≥10% and,
c.
Static Physician Global Assessment (sPGA) (
) ≥3 (moderate)
7. Must be in good health (except for psoriasis) as judged by the Investigator, based on 
medical history, physical examination, 12-lead electrocardiogram (ECG), clinical 
laboratories, and urinalysis
8. 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)
f.
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L)
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
27
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
g. Hemoglobin A1c ∃9.0%
9. Females of childbearing potential (FCBP)† 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 contraceptive§ 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. Other than psoriasis, history of any clinically significant (as determined by the 
Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, 
hematologic, immunologic disease, or other major uncontrolled disease.
2. 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. Any condition that confounds the ability to interpret data from the study.
4. Pregnant or breast feeding
5. Hepatitis B surface antigen positive at Screening
6. Anti-hepatitis C antibody positive at Screening
7. AST (SGOT) and/or ALT (SGPT) > 1.5 X ULN and total bilirubin > ULN and/or 
albumin < lower limit of normal (LLN)
8. Active tuberculosis (TB) or a history of incompletely treated TB
                                                            
† 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).
§ 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).
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onsecutive 


EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
28
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
9. Clinically significant abnormality on 12-lead ECG at screening
10. Clinically significant abnormality based upon chest radiograph with at least a posterior to 
anterior (PA) view (radiograph must be taken within 12 weeks prior to screening or 
during the Screening Visit).  An additional lateral view is strongly recommended but not 
required.
11. History of positive human immunodeficiency virus (HIV), or have congenital or acquired 
immunodeficiency (eg, common variable immunodeficiency disease)
12. Active substance abuse or a history of substance abuse within 6 months prior to signing 
the informed consent form.
13. Bacterial infections requiring treatment with oral or injectable antibiotics, or significant 
viral or fungal infections, within 4 weeks of signing the informed consent form.  Any 
treatment for such infections must have been completed at least 4 weeks prior to 
randomization.
14. Malignancy or history of malignancy, except for:
a.
treated (ie, cured) basal cell or squamous cell in situ skin carcinomas; 
b. treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in situ of 
the cervix with no evidence of recurrence within 5 years of signing the informed 
consent.
15. 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.
16. Psoriasis flare/rebound (defined as a sudden worsening of body plaque psoriasis or 
plaque psoriasis of the scalp which requires administration of prohibited medications) 
within 4 weeks of signing the informed consent form or between the Screening and 
Baseline Visits.
17. Current or planned concurrent use of the following therapies that may have a possible 
effect on psoriasis of the body and/or scalp during the course of the treatment phase of 
the trial:
a.
Topical therapy, including medicated shampoos, coal tar and salicylic acid 
preparations, within 2 weeks prior to randomization (including but not limited to 
topical corticosteroids, topical retinoid or vitamin D analog preparations, 
tacrolimus, pimecrolimus, or anthralin/dithranol).  
i. Exceptions:  
1. non-medicated shampoos for scalp lesions
2. unmedicated emollients for body lesions
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).
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
29
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
c.
Intralesional corticosteroids on the scalp within 2 weeks prior to randomization
d. Phototherapy treatment of body or scalp psoriasis lesions within 4 weeks prior to 
randomization (ie, ultraviolet B (UVB), psoralen and ultraviolet A radiation
[PUVA])
e.
Biologic therapy:
i. TNF or IL-17 blockers such as adalimumab, brodalumab, certolizumab 
pegol, etanercept, infliximab, ixekizumab, secukinumab (or biosimilars for 
each) within 12 weeks prior to randomization
ii. Anti-IL-12 or anti-IL-23 monoclonal antibodies such as ustekinumab, 
guselkumab, or tildrakizumab, within 24 weeks prior to randomization
f.
Use of any investigational drug beginning 4 weeks prior to randomization, or 5 
pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer)
18. Evidence of scalp and/or skin conditions that would interfere with clinical assessments
19. Prolonged sun exposure or use of tanning booths or other ultraviolet (UV) light sources
20. Prior treatment with apremilast
21. History of allergy or hypersensitivity to any components of the IP
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
30
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
Inclusion / Exclusion
X
X
-
-
-
-
-
-
-
-
-
Medical and Disease History
X
-
-
-
-
-
-
-
-
-
-
Prior / Concomitant Medications 
and Therapies
X
X
X
X
X
X
X
X
X
X
X
Safety Assessment(s)
Height, BMI
X
-
-
-
-
-
-
-
-
-
-
CXRe
X
-
-
-
-
-
-
-
-
-
-
Hepatitis B and C, TBf
X
-
-
-
-
-
-
-
-
-
-
Hemoglobin A1C
X
-
-
-
-
-
-
-
-
-
-
Weight
X
X
-
-
X
-
X
-
X
X
X
Complete Physical Exam
X
-
-
-
-
-
-
-
X
-
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test for FCBP and 
Contraception Educationg
X
X
-
-
-
-
-
-
-
X
-
12-lead ECG
X
-
-
-
-
-
-
-
-
-
-
Clinical Laboratory Evaluationsh
X
X
-
-
-
-
X
-
-
X
-
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
31
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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
Vasculitis Assessment i
-
-
-
-
-
-
-
-
-
-
-
Psychiatric Evaluation j
-
-
-
-
-
-
-
-
-
-
-
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Psoriasis Flare Assessment k
-
-
-
-
-
-
-
-
-
-
-
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Whole Body Itch NRSm
-
X
X
X
X
X
X
X
X
X
-
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-
X
X
X
X
X
X
X
X
X
-
ScPGA
X
X
X
X
X
X
X
X
X
X
X
Patient Reported Outcomes
DLQI
-
X
-
X
X
-
X
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-
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
32
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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
Optional Assessment(s) at Selected Investigative Sites
Photographso
-
X
-
-
X
-
X
-
-
X
-
Dosing
Dispense IP
-
X
-
X
X
X
X
X
X
-
-
Return and count IP tablets
-
-
-
X
X
X
X
X
X
X
-
Abbreviations: BMI = body mass index; 
; CXR = Chest Radiograph; DLQI = The Dermatology Life Quality Index; ECG = Electrocardiogram; ET = 
Early Termination Visit; FCBP = females of childbearing potential; 
 
 IP = Investigational Product; NRS = Numeric Rating Scale; 
; ScPGA = Scalp Physician Global 
Assessment; 
 TB = tuberculosis testing; 
 
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.
e CXRs taken within 12 weeks prior to screening will be accepted.  CXRs should be performed as indicated by local treatment guidelines or practice for monitoring while on 
immunosuppressive/immunomodulatory therapy.  If such guidelines are not available/applicable, routine CXRs should be performed as per the Table of Events or when 
clinically indicated.
f The QuantiFERON® Gold test should be used for TB testing in lieu of the tuberculin skin test (TST) or purified protein derivative (PPD) test, if possible.
g FCBP:  Serum pregnancy tests will be performed at the Screening and Early Termination/Last Treatment Visit.  Urine dipstick pregnancy test(s) will be performed at baseline, 
prior to dosing.  An unscheduled pregnancy test should be administered if the subject has missed a menstrual period.  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.
h Refer to Section 6.5, Procedures, for details regarding hematology, clinical chemistries, and urinalysis parameters to be tested.
i At any time vasculitis is suspected.  See Section 6.5, Procedures
j At any time when suicidal thoughts or a suicide attempt is identified.  See Section 6.5, Procedures
k At any time, a psoriasis flare may be reported as an adverse event, provided it meets the protocol definition.  See Section 6.5, Procedures
l Clinician assessments are to be performed after subject completes numeric rating scales and patient reported outcomes questionnaires as scheduled in the Table of Events.  
Clinician assessments must be done in the following order: ScPGA, 
.
m Subject assessment of whole body itch must be performed prior to scalp itch assessment.
n Subject assessments must be completed in the following order: whole body itch NRS, scalp itch NRS,
 DLQI, 
 as scheduled in the Table of Events.
o Photographs will be obtained from subjects who provide separate consent to be photographed and at select sites only.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
33
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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.
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 and the Study Manual, should be recorded, including smoking and alcohol history, as 
well as previous relevant surgeries (please refer to the eCRF Completion Guidelines and the 
Study Manual for further details).  Disease history includes history of psoriasis and psoriatic 
arthritis.
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 tuberculosis (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 and the Study Manual 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 randomization unless noted otherwise below. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
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.
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
34
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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) ScPGA; 
 
The following assessments will be performed at screening as specified in the Table of Events, 
Table 3, after informed consent has been obtained:
!
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)
!
Chest radiograph (historic scans within 12 weeks of screening are allowed)
!
12-lead electrocardiogram (ECG)
!
Scalp Physician Global Assessment
 
!
Hematology panel 
!
Chemistry panel (including Hemoglobin A1C)
!
Urinalysis
!
Hepatitis B and C screening
!
TB testing
!
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)
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 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
35
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
permitted.  For visits within the Observational Follow-up Phase, an administrative window of ± 2
weeks from the last dose of IP is permitted.  
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) scalp itch
NRS, 
 4) DLQI,
 
During the treatment period, efficacy assessments may be performed by the investigator or 
qualified designee at any time during a study visit, but only after the subject has completed the 
NRS and health-related quality of life (HRQoL) assessments, when required.  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) ScPGA;
. 
The following evaluations/assessments will be performed at the frequency specified in the Table 
of Events, Table 3.
!
Patient reported outcomes or health-related quality of life (HRQoL)
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Vital signs
!
12-lead electrocardiogram (ECG)
!
Weight 
!
!
Hematology panel 
!
Chemistry panel 
!
Urinalysis
!
Adverse event evaluation (continuously)
!
Efficacy assessments (see Section 6.4)
!
Urine pregnancy test (prior to dosing on Day 1)
!
IP dispense and return
!
Photography (select sites and involving subjects signing a separate photography ICF)
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.
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235


EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
36
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
During the end of treatment visit, subjects must complete the itch NRS and subject 
questionnaires prior to any other study procedure being performed.  The subject must complete 
the questionnaires in the following order: 1) body itch NRS, 2) scalp itch NRS, 3) DLQI, 
 
.
During the end of treatment visit, efficacy assessments may be performed by the investigator or 
qualified designee at any time during a study visit, but only after the subject has completed the 
NRS and HRQoL assessments, when required.  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) ScPGA, 
.
The following evaluations will be performed as specified in the Table of Events, Table 3:
!
Patient reported outcomes or health-related quality of life (HRQoL)
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Complete physical exam
!
Vital signs
!
Weight 
!
Hematology panel 
!
Chemistry panel 
!
Urinalysis
!
Adverse event evaluation (continuously)
!
Efficacy assessments (see Section 6.4)
!
Serum pregnancy test 
!
IP return
!
Photography (select sites and involving subjects signing a separate photography ICF)
6.3.
Follow-up Period 
All subjects should be followed for 28 days after the last dose of IP for AE reporting, as well as 
SAEs made known to the Investigator at any time thereafter that are suspected of being related to 
IP, as described in Section 10.1.
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) ScPGA,
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
37
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
The following evaluations will be performed at the Observational Follow-up Visit as specified in 
the Table of Events,Table 3.
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Weight
!
Vital signs
!
Adverse event evaluation 
!
Efficacy assessments (ScPGA, 
)
6.4.
Efficacy Assessments
The following assessments will be conducted as outlined in the Table of Events, Table 3:
!
Numeric Rating Scale Assessments
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 C.
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).
Scalp Itch Numeric Rating Scale Assessment
After completing the Whole Body Itch NRS, the subject will be asked to assess scalp 
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 D.
The Scalp Itch NRS was derived from the Whole Body Itch NRS. 
 
 
!
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.  
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
38
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 B for grading criteria.
!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
39
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
 
 
 
 
 
  
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 IB.
All females of childbearing potential (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 
(FCBP)
A serum pregnancy test with a sensitivity of ≤ 25 mIU/mL will be required for FCBP 
subjects at screening and at the Early Termination or Last Treatment Visit.  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.  An unscheduled pregnancy test should be performed if the FCBP subject has 
missed a menstrual period.
!
Chest Radiograph (CXR)
A CXR is required during Screening.  A PA view is required; an additional lateral 
view is strongly recommended but not required.  Alternatively, PA or PA/lateral 
radiographs that were taken within the 12 weeks prior to screening will be accepted.  
Chest radiographs should be performed as indicated by local treatment guidelines or 
practice for monitoring while on immunosuppressive/immunomodulatory therapy.  If 
such guidelines are not available/applicable, routine CXRs should be performed when 
clinically indicated.
!
Hepatitis B and C
Hepatitis testing will include hepatitis B surface antigen and anti-hepatitis C antibody.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
40
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
!
TB Testing
The QuantiFERON®-TB Gold test should be used in lieu of the tuberculin skin test 
(TST) or purified protein derivative (PPD) skin test if possible.  This test result must 
be negative within one month prior to first administration of IP or prior completed 
treatment was documented.  
!
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).
!
Vasculitis Assessment
The PDE4 inhibitors, including apremilast, have been shown to produce 
inflammatory perivascular histopathological changes in animal studies (eg, rodent 
toxicology studies).  The Investigator should be watchful for any signs and symptoms 
of vasculitis at all times.  Any suspicion of vasculitis must be thoroughly investigated 
by taking pertinent patient history, doing a physical examination, reviewing adverse 
events, and performing diagnostic procedures, as clinically indicated.  A subject with 
signs and symptoms of possible vasculitis should receive a thorough evaluation as 
described above, be managed as medically appropriate, and continued with follow-up 
until the signs and symptoms of vasculitis have resolved.
!
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 (post-randomization), 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, 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.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
41
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
!
Twelve-lead Electrocardiogram
A 12-lead ECG will be performed after the subject has been supine for approximately 
3 minutes.  ECGs will be performed at screening as indicated in Table 3.  ECGs will 
be evaluated by a central reader.
!
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 
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], adiponectin, 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 Hemoglobin A1C at the Screening Visit, 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 re-test 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 adverse event (AE). 
!
Adverse Events
Details of AE reporting may be found in Section 10.1.
 
 
 
 
 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
42
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
 
 
 
 
6.7.
Patient Reported Outcomes
Questionnaires should be completed by the subject after the whole body itch NRS and 
scalp itch NRS efficacy assessments and in the order that they are described below 
and as indicated in Table 3.
!
 
 
!
Dermatology Life Quality Index (DLQI)
During the treatment phase (see Table 3), DLQI (Finlay, 1994) will be assessed by 
the subject upon arrival at the site, after completing the Whole Body Itch NRS, Scalp 
Itch NRS, 
 and prior to any other procedures or assessments 
being performed.  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 F.
 
 
 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
43
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
 
6.8.
Photography
Photographic assessments will be done at selected sites to provide supportive 
evidence of efficacy as scheduled in Table 3.  The procedure for taking the 
photographs and processing and shipping photographs will be described in a separate 
procedure manual distributed to investigational sites performing photographic 
assessments.
Photographic assessments are an optional part of this study.  Subjects enrolled at the 
selected photography sites will be asked to provide separate consent prior to being 
photographed. 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
44
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 1-7), subjects will be dispensed dose titration 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 2:1 to receive either apremilast 30 mg BID or placebo, using a 
centralized Interactive Response Technology (IRT).  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. Dose titration 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.
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
45
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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
10mg A
20mg P 
30mg P
10mg P
20mg P 
30mg P
10mg A
20mg P 
30mg P
10mg A
20mg P 
30mg P
10mg A
20mg P 
30mg P
10mg P
20mg A 
30mg P
20mg A 
30mg P
20mg A 
30mg P
20mg A 
30mg P
20mg P 
30mg A
20mg P 
30mg A
20mg P 
30mg A
Placebo
10mg P
20mg P 
30mg P
10mg P
20mg P 
30mg P
10mg P
20mg P 
30mg P
10mg P
20mg P 
30mg P
10mg P
20mg P 
30mg P
10mg P
20mg P 
30mg P
20mg P 
30mg P
20mg P 
30mg P
20mg P 
30mg P
20mg P 
30mg P
20mg P 
30mg P
20mg P 
30mg 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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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
46
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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
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10mg P
20mg P 
30mg A
10mg P
20mg P 
30mg A
10mg P
20mg P 
30mg A
10mg P
20mg P 
30mg A
10mg P
20mg P 
30mg A
10mg P
20mg P 
30mg A
20mg P 
30mg A
20mg P 
30mg A
20mg P 
30mg A
20mg P 
30mg A
20mg P 
30mg A
20mg P 
30mg A
Placebo to 
APR 30 
BID
10mg A
20mg P 
30mg P
10mg P
20mg P 
30mg P
10mg A
20mg P 
30mg P
10mg A
20mg P 
30mg P
10mg A
20mg P 
30mg P
10mg P
20mg A 
30mg P
20mg A 
30mg P
20mg A 
30mg P
20mg A 
30mg P
20mg P 
30mg A
20mg P 
30mg A
20mg P 
30mg A
A=Apremilast; BID= twice daily; P= Placebo.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
47
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 1 (Days 1-7) 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 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 M, Appendix N, and Appendix O.
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 overdose definition will apply to only 
apremilast (or matching placebo).  Other required or optional non-IP intended for prophylaxis of 
certain side effects, etc, 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 2:1 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 may include, but may not be limited to, 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 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
48
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
regulatory statements as 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 IP return, disposal, and/or destruction including responsibilities for the site versus Celgene 
(or designee). 
7.6.1.
Record of Administration
Accurate recording of all IP administration (including dispensing and dosing) will be made in the 
appropriate section of the subject’s eCRF and source documents.
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% 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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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
49
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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. 
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics (PK), or excretion, please see the Investigator’s 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
!
Phototherapy
!
UVB or PUVA 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
50
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
!
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 Medication
Not applicable.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
51
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 3, multi-center, randomized, placebo-controlled, double-blind study of the 
efficacy and safety of apremilast (CC-10004) in subjects with moderate to severe plaque 
psoriasis of the scalp. Treatment assignment will be stratified by baseline ScPGA score 
[moderate (3), or severe (4)]. 
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 moderate to severe plaque psoriasis of the scalp.
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 safety population will consist of all subjects who are randomized and received at least one 
dose of IP (IP).  Subjects will be included in the treatment group corresponding to the IP they 
actually receive.
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 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 ScPGA 
evaluation, and have no 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 3b studies, including CC-
10004-PSOR-008, PSOR-009 and PSOR-010 which demonstrated positive treatment effects
between apremilast 30 mg BID and placebo in the proportion of subjects achieving ScPGA 
response at Week 16 (range 18% to 29%). Approximately 300 subjects will be randomized in a 
2:1 ratio to apremilast 30 mg BID or placebo. With this sample size, a chi-square test at the 2-
sided 0.05 significance level will have 90% power to detect a minimum treatment difference of 
18% (38% for apremilast 30 mg BID versus 20% for placebo) between the two arms for 
proportions of subjects achieving ScPGA response at Week 16 (defined as ScPGA score of clear 
[0] or almost clear [1] with at least a 2 point reduction from baseline at Week 16).
If at least 60% of the approximate 300 randomized subjects would be evaluable for the whole 
body itch NRS analysis, the subset sample size of 180 subjects will provide 90% power to detect 
a treatment difference of 25% (45% for apremilast 30 mg BID and 20% for placebo) in the 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
52
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
proportion of subjects with ≥4-point improvement from baseline in the whole body itch NRS 
score.
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 
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)
Statistical comparisons will be made between apremilast 30 mg BID and placebo. All statistical 
tests will be at the 2-sided 0.05 significance level and the corresponding p-values will be 
reported. Data summaries will be provided for the two randomized treatment arms (apremilast 30 
mg BID and placebo).
9.6.1.1.
Primary Efficacy Endpoint
The primary endpoint is the proportions of subjects who achieving ScPGA response at Week 16 
(defined as ScPGA score of clear [0] or almost clear [1] 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 treatment difference between apremilast 30 mg BID and placebo will be compared using 
CMH (Cochran–Mantel–Haenszel) test adjusting for the stratification factor at randomization. 
The 2-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 2-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. 2008) as the primary analysis, with sensitivity analysis using the last 
observation carried forward (LOCF) method and the non-responder imputation (NRI) method.
The SAS procedure MI will be used to impute missing ScPGA scores at the scheduled 
assessments in the Placebo-controlled Phase (Weeks 0-16) to create M=25 complete data sets. 
The missing data patterns will be checked by treatment and stratification factor at 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. 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
53
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used to impute missing 
scores by treatment and stratification factor to create M=25 imputed data sets with monotone 
missing patterns. The minimum and the maximum values for imputation will be 0 and 4, which 
correspond to the lowest and the highest ScPGA scores. The seed will be set to 804529, the 
imputed values will be rounded to integers and a single chain will be used to produce
imputations.
In the second step, the predictive mean matching method will be used to impute the remaining 
missing values for the 25 data sets with monotone missing patterns. The MONOTONE 
REGPMM statement will be used with seed 447159. The missing values at each visit will be 
imputed based on treatment, stratification factor, and ScPGA scores at baseline and previous 
visits. The number of closest observations to be used in the selection will be K=2. 
After the completion of imputation, the same CMH method will be used to analyze the 25 
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 
For the binary endpoints defined as ≥4-point reduction (improvement) from the baseline visit in 
either the whole body pruritus NRS score or the scalp pruritus NRS score at post-baseline visits, 
the analyses will be based on subjects in the ITT population with baseline whole body pruritus 
NRS score ≥4 or baseline scalp pruritus NRS score ≥4, respectively. For the continuous 
secondary endpoint (ie, change from baseline in DLQI total score at Week 16), the analyses will 
be based on ITT population. Unadjusted 2-sided p-values and 2-sided 95% confidence intervals 
(CIs) will be reported.
In order to evaluate the onset of effect of apremilast 30 mg BID compared to placebo for itch, the 
following secondary endpoints are specified (Section 2):
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 16
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 16
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
overall body itch NRS score at Week 12, Week 8, Week 4, and Week 2
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 12, Week 8, Week 4, and Week 2
Statistical analyses for the ten endpoints will be performed one by one downward from Week 16 
to Week 2. Multiplicity adjustment is specified in Section 9.6.1.3. 
The binary endpoints will be analyzed similarly as the primary endpoint. The treatment 
difference at each time point between apremilast 30 mg BID and placebo will be compared using 
CMH (Cochran–Mantel–Haenszel) test adjusting for the stratification factor at randomization.
The 2-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 2-sided 95% CIs using a normal approximation to the weighted average will 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
54
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
be provided. Missing values will be imputed using the similar MI method as the primary 
endpoint, with sensitivity analysis using the LOCF method and NRI method.
The continuous endpoint (ie, change from baseline in DLQI total score at Week 16) will be 
analyzed based on the ITT population using the analysis of covariance (ANCOVA) model. The 
ANCOVA model will use the change from baseline as the dependent variable and will include 
treatment group and stratification factor as independent variables and the baseline value as a 
covariate variable. Within-group least-squares (LS) mean changes from baseline at Week 16, the 
associated standard errors (SEs) and 2-sided 95% CIs, treatment differences in LS mean changes 
from baseline, and the associated 2-sided 95% CIs and p-values, will be derived from the 
ANCOVA model. Missing values at Week 16 will be imputed using the MI method, with 
sensitivity analysis using the LOCF 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 2-sided 0.05 
significance level.  Specifically, for the primary efficacy endpoint (ScPGA response at Week 
16), if the 2-sided p-value from the comparison between apremilast 30 mg BID and placebo is 
below 0.05, the outcome will be considered statistically significant and apremilast 30 mg BID 
will be declared effective. For any secondary endpoint, statistical significance will be claimed 
only if its 2-sided p-value is below 0.05 and tests for the primary endpoint and all previous 
secondary endpoints are significant at the 2-sided 0.05 level. The proposed test sequence for the 
primary and secondary efficacy endpoints is listed as the following:
!
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
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 16
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 16
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 12
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 12
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 8
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 8
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 4
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 4
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
55
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
!
Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 2
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Proportion of subjects with ≥4 point reduction (improvement) from baseline in the 
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!
Change from baseline in Dermatology Life Quality Index total score at Week 16
9.6.1.4.
Exploratory Endpoints 
Descriptive summary statistics or proportion of subjects achieving specified criteria will be 
summarized by treatment group. When appropriate, exploratory endpoints at Week 16 will also 
be analyzed using CMH or ANCOVA methods similar to the primary and secondary endpoints.
9.6.1.5.
Subgroup Analysis 
Subgroup analyses for ScPGA response at Week 16 and proportions of subjects with ≥4-point 
reduction (improvement) from baseline in the whole body itch NRS or scalp itch NRS scores at 
post baseline time points 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. 2-sided 95% confidence intervals will be provided for changes or percent 
changes and response rates.
9.7.
Safety Analysis
The safety analyses will be performed using the safety population as defined in Section 9.2. 
Safety will be assessed by clinical review of all relevant parameters including 
treatment-emergent adverse events (TEAEs), laboratory tests, vital signs, and ECG 
measurements; no inferential testing for statistical significance will be performed.
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. Adverse events will be tabulated for the Placebo-controlled 
Phase (Weeks 0 to 16) and the Apremilast Exposure Phase in the study. All TEAEs will be 
summarized by system organ class, preferred term, severity, and relationship to IP.  Adverse 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
56
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
events leading to death or to IP withdrawal and serious AEs will also 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 compared with the 
normal reference ranges pre-treatment versus post-treatment will be provided.
To account for the different exposure to the investigational product, adverse events or marked 
laboratory abnormalities will also be summarized using the exposure adjusted incidence rate, in 
addition to the simple incidence rates. 
By-subject listings will be provided for all relevant safety data.
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 lock will be performed, the primary data analysis will be conducted 
 
.  However, unblinded data will only be made available 
to select Sponsor and Contract Research Organization (CRO) team members involved with 
analysis of the data 
  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 Clinical Study Report will be generated.
9.9.
Other Topics
9.9.1.
Investigational Product Compliance (Tablets)
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.
9.9.2.
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.
9.9.3.
Steering Committee 
Guidance in protocol development and interpretation of data analysis will be provided by a 
scientific steering committee (SSC).  Details for the SSC are pre-specified in a separate SSC 
charter.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
57
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
9.9.4.
Internal Celgene Safety Monitoring During the Apremilast Program: Role of the 
Safety Management Team 
In addition to daily safety monitoring conducted by investigators and individual study personnel, 
cumulative and interval blinded adverse events (AEs), serious adverse events (SAEs),
discontinuations, and laboratory findings are reviewed internally by a Safety Management Team
(SMT) at Celgene. The review follows the Council for International Organizations for Medical 
Sciences, Working Group VI (CIOMS VI) recommendations. The SMT is comprised of lead 
representatives from multiple Celgene functions engaged in the apremilast development 
program. The scope, conduct, processes, and accountabilities of the SMT are specified in the
SMT charter.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
58
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 case report form (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 should be reported as an AE 
on the AE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported on 
an SAE report form and on the AE CRF. The overdose resulting in the SAE should be identified 
as the cause of the event on the SAE report form and CRF but should not be reported as an SAE 
itself.
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.  AEs and SAEs will be recorded on 
the AE page of 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 facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
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!
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.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
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10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event based on 
the descriptions listed below. 
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 obligations.
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 adverse event 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 adverse event.  ‘Reasonable possibility’ means there 
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EDMS Doc. Number:
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Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
61
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
is evidence to suggest a causal relationship between the IP and 
the adverse event.
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 both AEs and SAEs, 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 an AE or SAE, as applicable 
(eg, discontinuation, interruption, or dose reduction of IP, 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 both AEs and SAEs.
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
!
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 serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of 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).
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
62
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 β-subunit of human chorionic 
gonadotropin [β-hCG] 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 female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
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 an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form.  This instruction pertains to initial SAE reports as well as any follow-up reports.
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.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
63
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent 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 
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
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 (eg, 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 Celgene and the IRB/EC.  (See Section 14.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
64
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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
!
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
!
Protocol deviation
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
65
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
!
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 
documents.
CCI
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
66
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 contact
IRT for unblinded dose information.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
67
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
68
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
69
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 adverse events 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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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
70
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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 compact disc, read only memory device (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.); 
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EDMS Doc. Number:
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!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
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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EDMS Doc. Number:
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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 standard operating procedures (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, European Medicines 
Agency [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.
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EDMS Doc. Number:
Apremilast
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CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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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EDMS Doc. Number:
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17.
REFERENCES
 
 
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, et al.  Treatment of 
severe scalp psoriasis: From the medical board of the National Psoriasis Foundation.  J Am Acad 
Dermatol. 2009;6:962-71.
FDA Guidance for Industry E10.  Choice of control group and related issues in clinical trials.  
May 2001.
Feldman SR, Housman TS.  Patients’ vehicle preference for corticosteroid treatments of scalp 
psoriasis.  Am J Clin Dermatol.  2003;4(4):221-4.
Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI): a simple practical measure for 
routine clinical use.  Clin Exp Dermatol.  1994;19:210-6.
  
 
Griffiths, CE, Reich K, Lebwohl M, Kerkhof P, Paul C, Menter A, Cameron, GS, Erickson J, 
Zhang L, Secrest RJ, Ball S, Braun DK, Osuntokun OO, Heffernan MP, Nickoloff BJ, Papp K. 
Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis 
(UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials Lancet 2015; 
386:541-51.
Hogan DJ, Rooney ME.  Facial telangiectasia associated with long-term application of a topical 
corticosteroid to the scalp.  J Am Acad Dermatol 1989;20:1129-30.
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;75(6):1156-61.
Kragballe K, Menter A, Lebwohl M, Tebbey PW, van der Kerkhof PC.   Long-term management 
of scalp psoriasis: perspectives from the International Psoriasis Council.  J Dermatol Treat.  
2013;24:188-92.
 
Lebwohl M. Psoriasis.  Lancet.  2003a;361:1197-204.
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Naegeli, AN, Flood, E, Tucker J, Devlen J, Edson-Heredia E.  The Worst Itch Numeric Rating 
Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis.  Int J Dermatol 
2015;54:715-22.
Ortonne JP, Chimenti S, Luger T, Puig L, Reid F, Trϋeb RM. Scalp psoriasis: European 
consensus on grading and treatment algorithm. JEADV 2009;23:1435-44.
Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, Augustin M, Szepietowski JC, Ständer S. 
Assessment of pruritus intensity: prospective study on validity and reliability of the visual 
analogue scale, numeric rating scale and verbal rating scale in 471 patients with chronic pruritus. 
Acta Derm Venereol. 2012; 92:502-7.
Reich K, Leonardi C, Lebwohl M, Kerdel F, Okubo Y, Romiti R, Goldblum O, Dennehy EB, 
Kerr L, Sofen H. Sustained response with ixekizumab treatment of moderate-to-severe psoriasis 
with scalp involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2, 
UNCOVER-3). J Dermatolog Treat. 2016 Nov 13:1-6. [Epub ahead of print]
SAS Institute Inc. 2008. SAS/STAT® 9.2 User’s Guide. Cary, NC: SAS Institute Inc.
Szepietowski, JC, Reich, A.  Itch-in Psoriasis Management.  Curr Probl Dermatol. Basel, Karger,
2016;50:102-10.
van de Kerkhof PC, de Hoop D, de Korte J, Kuipers MV.  Scalp psoriasis, clinical presentations 
and therapeutic management.  Dermatology. 1998;197:326-34.
van der Vleuten CJ, van de Kerkhof PC.  Management of scalp psoriasis: guidelines for 
corticosteroid use in combination treatment.  Drugs. 2001;61:1593-8.
Warren RB, Brown BC, Griffiths CE.  Topical treatments for scalp psoriasis.  Drugs.  
2008;68:2293-302.
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EDMS Doc. Number:
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18.
APPENDICES
Appendix A:
Table of Abbreviations
Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADL
Activity 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
CI
Confidence Interval
CIN
Cervical intraepithelial neoplasia
CD-ROM
Compact disc, read only memory device
CIOMS
Council for International Organization of Medical Sciences
CMH test
Cochran-Mantel-Haenzel test
CO2
Carbon dioxide
CRO
Contract Research Organization
CRF
Case report form
CXR
Chest radiograph
DLQI
Dermatology Life Quality Index
EC
Ethics Committee
ECG
Electrocardiogram
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
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
GCP
Good Clinical Practice
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
LLN
Lower level of normal
LOCF
Last observation carried forward
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
NRI
Non-responder imputation
NRS
Numeric Rating Scale
PA
Posterior to anterior
PDE4
Phosphodiesterase type 4
PP
Per protocol
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EDMS Doc. Number:
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Protocol CC-10004-SPSO-001
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CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
PUVA
Psoralens ultraviolet A
RBC
Red blood cell 
SAE
Serious adverse event
ScPGA
Scalp Physician Global Assessment
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SMT
Safety Management Team
SOP
Standard Operating Procedure
SSC
Scientific steering committee
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TC
Total cholesterol
TEAE
Treatment-emergent adverse event
TNF
Tumor necrosing factor
TST (PPD)
Tuberculin sensitivity test (purified protein derivative)
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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EDMS Doc. Number:
Apremilast
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Appendix B:
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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EDMS Doc. Number:
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Appendix C: Modified Whole Body Itch Numeric Rating Scale (NRS)
Instruction: Please think about your whole body (including your scalp) when answering the 
question below.
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
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Naegeli, 2015.
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EDMS Doc. Number:
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Appendix D:
Scalp Itch Numeric Rating Scale (NRS)
Please rate the itching severity of your scalp due to your psoriasis by circling the number that 
best describes your worst level of itching in the past 24 hours.
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EDMS Doc. Number:
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82
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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Appendix F:
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.
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
85
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Appendix F: Dermatology Life Quality Index (DLQI) (Continued)
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
86
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
87
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
88
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
89
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
CCI
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
90
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
CCI
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
91
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
CCI
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
92
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
93
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
CCI
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
94
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Appendix K:
Treatment Schema for Dose Titration at Baseline
Dose
Day 1
Day 2
Day 3
Day 4
Day 5
Days 6 -7
Group
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Placebo 
(dummy 
titration)
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
20 mg 
placebo
+ 30 mg 
placebo
20 mg 
placebo
+ 30 mg 
placebo
20 mg 
placebo
+ 30 mg 
placebo
20 mg 
placebo
+ 30 mg 
placebo
20 mg 
placebo
+ 30 mg 
placebo
20 mg 
placebo
+ 30 mg 
placebo
30 mg
apremilast
(titration)
10 mg 
apremilast 
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilast 
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilast + 
20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilas
t
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
apremilast 
+ 30 mg 
placebo
20 mg 
apremilast 
+ 30 mg 
placebo
20 mg 
apremilast 
+ 30 mg 
placebo
20 mg 
apremilast 
+ 30 mg 
placebo
20 mg 
placebo
+ 30 mg 
apremilast
20 mg 
placebo
+ 30 mg 
apremilast
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+ 30 mg 
apremilast
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EDMS Doc. Number: 
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
95
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Appendix L:
Treatment Schema for Dose Titration at Week 16
Dose
Day 112
Day 113
Day 114
Day 115
Day 116
Days 117 through 118
Group
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
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30 mg
apremilast 
(titration)
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+ 30 mg 
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
96
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Appendix M: Titration Blister Card Configuration
CCI
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EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
97
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Appendix N:
Active Treatment Blister Card Configuration
CCI
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
Apremilast
Protocol CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
98
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
Appendix O:
Placebo Treatment Blister Card Configuration
CCI
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EDMS Doc. Number:
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.
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EDMS Doc. Number:
Apremilast
Summary of Changes CC-10004-SPSO-001
Celgene Corporation
Confidential and Proprietary
3
CC-10004-SPSO-001 Amendment 1 Final: 30 Nov 2017
1.
JUSTIFICATION FOR AMENDMENT
Changes included in this amendment are summarized below:
!
Modified Section 4.2 Inclusion Criteria 9 such that approved contraceptive options 
includes 2 options to reflect the standard contraception language for all Apremilast 
studies. 
!
In Section 6.4 Efficacy Assessment: added instructional text to Scalp Physician Global 
Assessment to guide investigators on method of assessment.
!
Provided clarification to Section 6.5 Safety Assessment that subjects with positive TB 
testing at screening who have documentation of completed TB treatment will qualify for 
the study. This is in line with the Exclusion Criteria 8.
!
Modified Sections 9.2, 9.5, 11.1 and 11.2 by changing protocol violations to protocol 
deviations to reflect current sponsor standards. 
!
Modified Section 8.2 Prohibited Concomitant Medications and Procedures: Topical 
therapy. Replaced acetylsalicylic acid with salicylic acid preparations. This is in line with 
Exclusion Criteria 17.
!
Provided updates to the following appendices to reflect the validated and IRB approved
questionnaires that were provided to the subjects since the initiation of the study: 
o
Appendix C: Modified Whole Body Itch Numeric Rating Scale;
o
Appendix D: Scalp Itch Numeric Rating Scale;
o
Appendix F: The Dermatology Life Quality Index;
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 3, MULTI-CENTER, RANDOMIZED, PLACEBO-
CONTROLLED, DOUBLE-BLIND STUDY OF THE EFFICACY 
AND SAFETY OF APREMILAST (CC-10004) IN SUBJECTS WITH 
MODERATE TO SEVERE PLAQUE PSORIASIS OF THE SCALP
INVESTIGATIONAL PRODUCT (IP):
Apremilast (CC-10004)
PROTOCOL NUMBER:
CC-10004-SPSO-001
DATE FINAL:
29 Mar 2017
Prepared by:
on behalf of
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.
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
4
TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................10
3.
STUDY OBJECTIVES...........................................................................................11
3.1.
Primary Objective...................................................................................................11
3.2.
Secondary Objectives .............................................................................................11
3.3.
Exploratory Objectives ...........................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.2.
Study Endpoints .....................................................................................................13
4.2.1.
Primary Endpoint....................................................................................................13
4.2.2.
Secondary Endpoints ..............................................................................................13
4.2.3.
Exploratory Endpoints............................................................................................14
4.2.6.
Safety Endpoints.....................................................................................................14
4.2.7.
Derivations of Efficacy Endpoints ..........................................................................15
4.2.9.
Derivations of Safety Endpoints..............................................................................18
4.3.
Randomization, Stratification, and Blinding............................................................19
4.4.
Sample Size Determination.....................................................................................19
5.
ANALYIS PHASES OR PERIODS, DEFINITION OF ANALYSIS 
POPULATIONS, BASELINE AND TIME POINTS ..............................................21
5.1.
Analysis Phases or Periods .....................................................................................21
5.1.1.
Analysis Phases ......................................................................................................21
5.1.2.
Apremilast-exposure Period for Safety Analysis .....................................................21
5.2.
Definition of analysis populations...........................................................................22
5.2.1.
Intent-to-treat Population........................................................................................22
5.2.2.
Per-protocol Population ..........................................................................................22
5.2.3.
Safety Population....................................................................................................22
5.3.
Baseline Definitions ...............................................................................................22
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
5
5.4.
Time Points ............................................................................................................23
6.
STATISTICAL METHODOLOGY FOR EFFICACY............................................25
6.1.
General Approaches to Efficacy Analysis ...............................................................25
6.2.
Multiplicity Adjustment..........................................................................................25
6.3.
Analyses of Primary Efficacy Endpoint ..................................................................26
6.4.
Analyses of Secondary Efficacy Endpoint...............................................................27
6.4.1.
Whole Body Itch Numeric Rating Scale (NRS) and Scalp Itch Numeric 
Rating Scale (NRS) Assessments............................................................................28
6.4.2.
Change from Baseline in Dermatology Life Quality Index (DLQI) Total 
Score at Week 16....................................................................................................29
6.5.
Analyses of Exploratory Efficacy Endpoints...........................................................30
6.5.1.
Study Phases...........................................................................................................30
 
6.5.3.
Dermatology Life Quality Index (DLQI) ................................................................31
6.5.4.
Whole Body Itch and Scalp Itch Numeric Rating Scale (NRS) Assessment.............31
6.5.6.
Scalp Physician Global Assessment (ScPGA) and 
 
................................................................................................32
6.6.
Subgroup Analysis..................................................................................................32
6.9.
Assessing Study Site Effect ....................................................................................33
6.10.
Interim Analysis .....................................................................................................34
7.
SUMMARY OF SUBJECT DISPOSITION ...........................................................35
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................37
8.1.
Demographics.........................................................................................................37
8.2.
Baseline or Disease Characteristics.........................................................................37
8.3.
Medical History......................................................................................................38
8.4.
Prior and Concomitant Procedures..........................................................................39
8.5.
Prior and Concomitant Medications........................................................................39
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................40
9.1.
Treatment Duration.................................................................................................40
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
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9.1.1.
Placebo-controlled Phase – Weeks 0 to 16..............................................................40
9.1.2.
Apremilast Extension Phase – Weeks 16 to 32........................................................40
9.1.3.
Apremilast-exposure Period....................................................................................40
9.2.
Treatment Compliance............................................................................................40
9.2.1.
Placebo-controlled Phase – Weeks 0 to16...............................................................41
9.2.2.
Apremilast Extension Phase – Weeks 16 to 32........................................................41
9.2.3.
Apremilast-exposure Period....................................................................................41
10.
PROTOCOL DEVIATIONS AND IMPORTANT PROTOCOL 
DEVIATIONS........................................................................................................42
11.
SAFETY ANALYSIS ............................................................................................43
11.1.
Adverse Events.......................................................................................................44
11.1.1.
Overall Summary of TEAEs ...................................................................................44
11.1.2.
All TEAEs..............................................................................................................44
11.1.3.
Common TEAEs ....................................................................................................45
11.1.4.
Drug-related TEAEs...............................................................................................45
11.1.5.
TEAEs by Maximum Severity................................................................................45
11.1.6.
Serious TEAEs.......................................................................................................45
11.1.7.
TEAEs Leading to Drug Interruption and TEAEs Leading to Drug 
Withdrawal.............................................................................................................45
11.1.8.
Deaths ....................................................................................................................45
11.2.
Psoriasis Flare ........................................................................................................45
11.3.
Clinical Laboratory Evaluations..............................................................................46
11.4.
Vital Signs and Weight...........................................................................................46
11.5.
Physical Examination .............................................................................................47
REFERENCES .........................................................................................................................48
APPENDIX A1
– CONVENTIONS RELATED TO DATES.................................................49
A1.1
GUIDELINE OF PARTIALLY MISSING DATE IMPUTATION .........................49
A1.1.1
Adverse Events.......................................................................................................49
A1.1.2
Prior/Concomitant Medications/Procedures ............................................................51
A1.1.3
Medical History......................................................................................................51
A1.1.4
Treatment Duration.................................................................................................51
APPENDIX A2
–LABORATORY MARKED ABNORMALITIES CRITERIA ....................52
APPENDIX A3
–REPORTING CONVENTIONS .................................................................54
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
7
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2: 
Table for Visit Mapping for by Time Point Analysis...............................................23
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.......................................................................................................24
Table 4:
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially...................................................................49
Table 5:
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Placebo Initially........................................................................50
Table 6:
Imputation Rules for Partially Missing AE Start Dates for Subjects who 
were Treated with Placebo Initially Laboratory Marked Abnormalities 
Criteria ...................................................................................................................52
LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................13
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
8
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
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
CRF or eCRF
(electronic) Case Report Form
CRO
Contract Research Organization 
CRP
Clinical Research Physician
DLQI
Dermatology Life Quality Index
FCBP
Female of Childbearing Potential
 
HRQoL
Health-Related Quality of Life
IP
Investigational Product
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IVRS
Interactive Voice Response System
LOCF
Last Observation Carried Forward
LS Mean
Least Square Mean
 
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
NRI
Non-responder Imputation 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
9
NRS
Numeric Rating Scale
PP
Per-Protocol (population)
PRO
Patient Reported Outcome
PT
Preferred Term
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
ScPGA
Scalp Physician Global Assessment
SD or STDEV
Standard Deviation
SE
Standard Error 
SI
Standard International (unit)
SOC
System Organ Class
TEAE
Treatment-emergent Adverse Event
US
United States
WHODD
World Health Organization Drug Dictionary
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Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-10004-SPSO-001, “A Phase 3, Multi-Center, Randomized, Placebo-Controlled, 
Double-Blind Study of the Efficacy and Safety of Apremilast (CC-10004) in Subjects with 
Moderate to Severe Plaque Psoriasis of the Scalp”.
An interim analysis is not planned. After all subjects have completed the Week 16 Visit (or 
discontinued from the study), a Week 16 data restriction will be performed, the primary data 
analysis will be conducted 
.  However, 
unblinded data will only be made available to select Sponsor and Contract Research 
Organization (CRO) team members involved with analysis of the data 
 
.  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 data base lock and analysis will be performed 
and a final Clinical Study Report will be generated.
 
 
 
This SAP provides a more technical and detailed elaboration of the statistical analyses as 
outlined and/or specified in the study protocol final version dated 29 Mar 2017 and final version 
of Amendment 1 dated 30 Nov 2017. 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 the 
responsibility of the Biostatistics & Programming department of 
 and will be conducted 
using SAS® Version 9.3 or higher.
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
11
3.
STUDY OBJECTIVES
3.1.
Primary Objective
!
To evaluate the clinical efficacy of apremilast 30 mg twice daily (BID) compared 
with placebo, in subjects with moderate to severe plaque psoriasis of the scalp, at 
Week 16
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 moderate to severe plaque psoriasis of the scalp
!
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 itch 
associated with plaque psoriasis of the scalp
!
To evaluate the onset of effect on itch over the whole body caused by plaque psoriasis 
with apremilast 30 mg BID compared with placebo
!
To evaluate the onset of effect on itch associated with plaque psoriasis of the scalp 
with apremilast 30 mg BID compared with placebo
!
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:
 
 
 
!
To evaluate the effect of apremilast 30 mg BID compared to placebo on 
Dermatological Life Quality Index (DLQI)
 
 
 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
12
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study of the 
efficacy and safety of apremilast (CC-10004) in subjects with moderate to severe plaque 
psoriasis of the scalp.
Approximately 300 subjects with moderate to severe plaque psoriasis of the scalp will be 
randomized 2:1 to receive either apremilast 30 mg BID or placebo for the first 16 weeks.  
Randomization will be stratified by baseline Scalp Physician Global Assessment (ScPGA) score 
(moderate [3], severe [4]) to ensure balance between treatment arms with respect to baseline 
severity of scalp psoriasis.
!
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:
!
Screening Phase – up to 35 days
!
Double-blind Placebo-controlled Phase – Weeks 0 to 16
Subjects will receive treatment with one of the following:  
!
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 at 
Week 16. All subjects will maintain this dosing through Week 32.
!
Observational Follow-up Phase
!
Four-week Post-treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue from the study early.
After all subjects have completed the Week 16 Visit (or discontinued from the study), a 
Week 16 data restriction will be performed; the primary data analysis will be conducted 
 
.  However, unblinded data will only be 
made available to select Sponsor and Contract Research Organization (CRO) team members 
involved with analysis of the data 
.  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 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
13
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 Clinical Study Report will be 
generated.
Figure 1:
Study Design
Abbreviation:  BID = twice daily.
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.
4.2.
Study Endpoints
The endpoints of the study are listed below:
4.2.1.
Primary Endpoint
!
Scalp Physician Global Assessment (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
4.2.2.
Secondary Endpoints
!
Itch NRS (Whole Body): Proportion of subjects with ≥4-point reduction (improvement) 
from baseline in the whole body itch NRS score at Week 16
!
Itch NRS (Scalp): Proportion of subjects with ≥4-point reduction (improvement) from 
baseline in the scalp itch NRS score at Week 16
!
Onset of effect on itch NRS (Whole Body): Proportion of subjects with ≥4-point 
reduction (improvement) from baseline in the whole body itch NRS score by visit in 
placebo-controlled phase (Week 12, Week 8, Week 4, Week 2)
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
14
!
Onset of effect on itch NRS (Scalp): Proportion of subjects with ≥4-point reduction 
(improvement) from baseline in the scalp itch NRS score by visit in placebo-controlled 
phase (Week 12, Week 8, Week 4, Week 2)
!
DLQI: Change from baseline in DLQI total score at Week 16
4.2.3.
Exploratory Endpoints
!
ScPGA: Proportion of subjects with ScPGA score of clear (0) or almost clear (1) with at 
least a 2-point reduction from baseline by visit
!
Itch NRS (Whole Body): Proportion of subjects with ≥4-point reduction (improvement) 
from baseline in the whole body itch NRS score by visit in apremilast extension phase
!
Itch NRS (Scalp): Proportion of subjects with ≥4-point reduction (improvement) from 
baseline in the scalp itch NRS score by visit in apremilast extension phase
 
!
DLQI: Change from baseline in DLQI total score at Weeks 4, 8, 16 and 32
 
 
 
 
4.2.6.
Safety Endpoints 
Safety endpoints will include:
!
Adverse Events (AEs)
-
Type, frequency, severity, seriousness, and relationship of adverse events to apremilast
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
15
-
Number of subjects who prematurely discontinue investigational product (IP) due to an 
adverse event
!
Death
!
Psoriasis flare
!
Clinical laboratory evaluations
!
Vital signs and weight
!
Physical examinations
!
Pregnancy tests for females of child bearing potential (FCBP)
4.2.7.
Derivations of Efficacy Endpoints
The derivation of each efficacy endpoint is described below in separate sections. Baseline 
definition for all efficacy endpoints is given in Section 5.3. Change from baseline is calculated as 
on-treatment 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.
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). The ScPGA scores will be collected on the 
eCRF directly at each visit.
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.
4.2.7.2.
Whole Body Itch Numeric Rating Scale (NRS) Assessment
Prior to any other procedures or assessments being performed during the treatment period, the 
subject will be asked to assess their worst level whole body itch (including the scalp) over 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. The number selected by the subject will be recorded in 
the database.
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.
For a post baseline visit, the whole body itch NRS response is defined as achieving ≥ 4-point
reduction (improvement) from baseline in the NRS score.  
4.2.7.3.
Scalp Itch Numeric Rating Scale (NRS) Assessment  
After completing the Whole Body Itch NRS, the subject will be asked to assess the severity of 
their worst level of scalp itch over the past 24 hours and select a number on a scale of 0 to 10, 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
16
where “0” represents no scalp itch, and “10” represents the worst scalp itch imaginable. The 
number selected by the subject will be recorded in the database.
For a post baseline visit, the scalp itch NRS response is defined as achieving ≥ 4-point reduction 
(improvement) from baseline in the NRS score.
4.2.7.4.
Dermatology Life Quality Index (DLQI)
During the treatment phase, DLQI will be assessed by the subject upon arrival at the site, after 
completing the Whole Body Itch NRS, Scalp Itch NRS, 
 and prior to
any other procedures or assessments being performed. 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.
The developers suggest that the DLQI can be grouped into 6 subscales: symptoms and feelings; 
daily activities; leisure; work/school; personal relationships; and treatment.  Scores for 4 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 HRQoL.
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 form baseline will be derived, where change = visit value − 
baseline value.
  
 
 
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Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
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Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
18
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2.9.
Derivations of Safety Endpoints
Baseline definition for all safety endpoints is given in Section 5.3. Change from baseline is 
calculated as on-treatment value minus the baseline value. Handling of time points is described 
in Section 5.4.
4.2.9.1.
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 IP and no later than 28 days after the last dose of 
IP for subjects who have completed the study or have discontinued early by the time of 
database cut, or
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.9.1.
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
19
!
On or after the date of the first dose of IP for subjects who are ongoing 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 Appendices Appendix A1A1.1.1 .
4.2.9.2.
Treatment-emergent Adverse Events Leading to Drug Withdrawal, Leading to 
Drug Interruption, and Leading to Death, and Drug-related Treatment-emergent 
Adverse Events
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.
4.3.
Randomization, Stratification, and Blinding
At Visit 2 (Week 0), subjects who meet entry criteria will be randomized using a permuted block 
randomization in parallel 2:1 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.  Treatment assignment will be 
stratified by baseline ScPGA score [moderate (3), or severe (4)].
All subjects will receive apremilast 30 mg BID in the Apremilast Extension Phase.
The original treatment assignments (apremilast 30 mg BID or placebo) will remain blinded until 
all subjects have completed their Week 16 visit (or have discontinued). After Week 16 data
restriction, unblinded data will only be made available to select Sponsor and CRO team members 
involved with analysis of the data 
.  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.
4.4.
Sample Size Determination
The sample size estimation is based on the results of the Phase 3 and 3b studies, including CC-
10004-PSOR-008, PSOR-009 and PSOR-010 which demonstrated positive treatment effects
between apremilast 30 mg BID and placebo in the proportion of subjects achieving ScPGA 
response at Week 16 (range 18% to 29%).  Approximately 300 subjects will be randomized in a 
2:1 ratio to apremilast 30 mg BID or placebo. With this sample size, a chi-square test at the 2-
sided 0.05 significance level will have 90% power to detect a minimum treatment difference of 
18% (38% for apremilast 30 mg BID versus 20% for placebo) between the two arms for 
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Protocol: CC-10004-SPSO-001
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20
proportions of subjects achieving ScPGA response at Week 16 (defined as ScPGA score of clear 
[0] or almost clear [1] with at least a 2 point reduction from baseline at Week 16).
If at least 60% of the approximate 300 randomized subjects would be evaluable for the whole 
body itch NRS analysis, the subset sample size of 180 subjects will provide 90% power to detect 
a treatment difference of 25% (45% for apremilast 30 mg BID and 20% for placebo) in the 
proportion of subjects with ≥4-point improvement from baseline in the whole body itch NRS 
score.
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Celgene Corporation
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21
5.
ANALYIS 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, different phases 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 to16
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. 
!
Apremilast Extension Phase – Weeks 16 to 32
This phase starts on the next day that 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 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. 
!
Observational Follow-up Phase – 4 weeks
For all subjects who complete the study or discontinue the study early, the Four-week 
Observational Follow-up Phase starts on the next day of the completion or discontinuation 
visit and stops at the follow-up visit or the last assessment date.
5.1.2.
Apremilast-exposure Period for Safety Analysis
In addition to the above defined phases, 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 30 mg BID first; 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 30 mg BID at Week 16.
This period stops on either: (1) data cut-off date; or (2) the day of the treatment 
discontinuation if the subject discontinued prior to or at Week 32/Visit 10; or (3) the last 
g phases.
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
22
known study day if the subject lost to follow-up prior to Week 32/Visit 10; or (4) Week 
32/Visit 10 visit date.
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. 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 ScPGA 
evaluation, and have no important protocol deviations which may affect analyses in the Placebo-
controlled Phase.
5.2.3.
Safety Population
5.2.3.1.
Placebo-controlled Phase (Weeks 0 to16)
Safety analyses will be based on the safety population, which will include all subjects who are 
randomized and receive at least one dose of IP. Subjects will be included in the treatment group 
corresponding to the IP they actually received (apremilast 30 mg BID or placebo) for the 
analyses and summaries using the safety population. 
5.2.3.2.
Apremilast Extension Phase (Weeks 16 to 32)
Safety analyses will be based on subjects who are treated in the phase. At Week 16, subjects will 
continue 30 mg BID treatment or will switch to 30 mg BID from placebo.
5.2.3.3.
Apremilast-exposure Period
The safety analyses for the Apremilast-exposure Period will be based on the apremilast subjects 
as treated population, which includes all subjects who are randomized to (at Week 0/Visit 2) or 
treated with (at Week 16/Visit 7) apremilast 30 mg BID, and receive at least one dose of 
apremilast after randomization or Week 16. All subjects will be included in apremilast 30 mg 
BID dose group. 
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 visit.
For safety analysis, baseline is defined as the last value measured prior to or on the day of the 
first dose of IP in the summaries for the Placebo-controlled Phase, and defined as the last value 
measured prior to or on the start day (defined in Section 5.1, ie, the first apremilast dose date) of 
the Apremilast-exposure Period in the summaries for the Apremilast-exposure Period. For 
subjects who are randomized but do not take any study medication, baseline for the Placebo-
controlled Phase is defined as the last value measured prior to or on the day of the 
randomization.   
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
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23
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.
Post baseline time points in all analyses will be captured based on analysis visit window (range 
of study days) around the target day for each analysis visit, based on the actual day of evaluation 
relative to a reference date. Appropriate dates will be used to calculate the study day, e.g., date of 
measurement or date of specimen collection will first be used, and then the date of visits/study 
weeks as recorded in the database will be used. If there are multiple measurements within a time 
point based on the study day, then the non-missing value from the closest measurement to the 
planned study day will be used for that visit. If the value at a scheduled visit is missing and there 
is no value available within the time window based on the study day, the value at the study week 
will be missing.
Table 2:
Table for Visit Mapping for by Time Point Analysis
Analysis Visit
Target Day
Visit Window
  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) for randomization. 
Definitions for baseline and start or end of the phases are specified in Section 5.1 and 5.3 for both 
efficacy and safety analysis. 
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. Appropriate 
dates (e.g., date of measurement or date of specimen collection) will first be used to ensure only 
data (including data from scheduled, unscheduled, discontinuation, and observational follow-up 
visits) measured or collected within the specific analysis phase (as defined in Section 5.1) being 
analyzed or summarized are included, and then the visits/study weeks as recorded in the database 
will be used to assign one value (possibly missing) to each time point at the subject level. 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;
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
24
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;
3. If multiple assessments are available on the same relative day, then the highest value of 
these assessments will be used for that relative day.
The time points for summaries of safety data (laboratory parameters, vital signs and weight) are 
based on study week/visit for the Placebo-controlled Phase. 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 will be mapped to reflect the study weeks relative to the first dose of apremilast
(see table below).
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
Original Visit
Re-Mapped Visit for subjects initially 
randomized to placebo
Week 16 (Visit 7)
Week 0 (Baseline)
Week 20 (Visit 8)
Week 4
Week 24 (Visit 9)
Week 8
Week 32 (Visit 10)
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
25
6.
STATISTICAL METHODOLOGY FOR EFFICACY 
6.1.
General Approaches to Efficacy Analysis
All efficacy evaluations will be conducted using the ITT population. Supportive analysis of the 
primary efficacy endpoint using the PP population will be conducted. 
The summary and analyses of the primary and secondary endpoints evaluated at or prior to Week 
16 will be performed by treatment (placebo vs. apremilast 30 mg BID). Statistical comparisons 
will be made between apremilast 30 mg BID and placebo; the null hypothesis is that the effects 
of the two treatments (i.e., placebo vs. apremilast 30 mg BID) have no difference.
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 
baseline and change (or percentage change) from baseline will be provided. Categorical variables 
will be summarized with frequency tabulations; shift tables will be provided when appropriate.
For discrete variables, the response rate and its 95% confidence interval (CI) will be calculated 
by treatment. Treatment difference will be tested using the Cochran-Mantel-Haenszel (CMH) 
test adjusting for the stratification factor at randomization (baseline ScPGA score moderate (3) 
or severe (4)) for the Double-blind Placebo-controlled Phase. The difference of response rate 
(apremilast 30 mg BID - placebo) and its 95% CI as well as the p-value will be produced using 
CMH method.
The continuous endpoints will be analyzed using the analysis of covariance (ANCOVA) model 
with treatment group and stratification factor as independent variables and the baseline value as a 
covariate variable. SAS Proc Mixed will be used for the analysis. The least square means (LS 
mean) with 95% CI for each treatment and difference of LS mean (apremilast 30 mg BID -
placebo) with 95% CI as well as the p-value will be provided. 
For the primary and the secondary efficacy endpoints, the primary approach in handling missing 
data will be the multiple imputation (MI) methods. Statistical outputs from the imputed complete 
data sets will be combined in making statistical inferences. 
Efficacy results will be considered statistically significant after consideration of the strategy for 
controlling the Type I error rate that is described in Section 6.2. All statistical tests will be two-
sided and be conducted at the 0.05 significance level, and p-values will be reported.
6.2.
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 2-sided 0.05 
significance level.  Specifically, for the primary efficacy endpoint (ScPGA response at Week 
16), if the 2-sided p-value from the comparison between apremilast 30 mg BID and placebo is 
below 0.05, the outcome will be considered statistically significant and apremilast 30 mg BID 
will be declared effective. For any secondary endpoint, statistical significance will be claimed 
only if its 2-sided p-value is below 0.05 and tests for the primary endpoint and all previous 
secondary endpoints are significant at the 2-sided 0.05 level. The proposed test sequence for the 
primary and secondary efficacy endpoints is listed as the following:
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Celgene Corporation
Protocol: CC-10004-SPSO-001
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26
!
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
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 16
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 16
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 12
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 12
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 8
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 8
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 4
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 4
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
whole body itch NRS score at Week 2
!
Proportion of subjects with ≥4-point reduction (improvement) from baseline in the 
scalp itch NRS score at Week 2
!
Change from baseline in DLQI total score at Week 16
6.3.
Analyses of Primary Efficacy Endpoint
The primary endpoint is the proportions of subjects who achieving ScPGA response at Week 16 
(defined as ScPGA 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 ITT population. A 
sensitivity analysis will be performed using the PP population. 
The treatment difference between apremilast 30 mg BID and placebo will be compared using 
CMH test adjusting for the stratification factor at randomization. The 2-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 2-sided 
95% CIs using a normal approximation to the weighted average will be provided (Mehrotra and 
Railkar, 2000). Missing values at Week 16 will be imputed using the multiple imputation (MI) 
method (SAS Institute Inc. 2011) as the primary analysis, with sensitivity analysis using the last 
observation carried forward (LOCF) method and the non-responder imputation (NRI) method.
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Celgene Corporation
Protocol: CC-10004-SPSO-001
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The SAS procedure MI will be used to impute missing ScPGA scores at the scheduled analysis 
visits  in the Placebo-controlled Phase (Weeks 0 to16) to create M=25 complete data sets. The 
missing data patterns will be checked by treatment and stratification factor at 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 to impute missing 
scores by treatment and stratification factor to create M=25 imputed data sets with monotone 
missing patterns. The minimum and the maximum values for imputation will be 0 and 4, which 
correspond to the lowest and the highest ScPGA scores. The seed will be set to 804529, the 
imputed values will be rounded to integers and a single chain will be used to produce 
imputations. 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 treatment and 
stratification factor in imputation model if necessary.
In the second step, the predictive mean matching method will be used to impute the remaining 
missing values for the 25 data sets with monotone missing patterns. The MONOTONE 
REGPMM statement will be used with seed 447159. The missing values at each visit will be 
imputed based on treatment, stratification factor, and ScPGA scores at baseline and previous 
visits. The number of closest observations to be used in the selection will be K=2. 
After the completion of imputation, the same CMH method will be used to analyze the 25 
complete data sets and the SAS procedure MIANALYZE will be used to combine the results for 
the statistical inferences.
In summary, the primary analysis will be performed for ITT population using the MI method for 
treating missing values. Supportive analyses will be performed for: (1) ITT population treating 
missing values using the LOCF method, (2) ITT population treating missing values using the 
NRI method, (3) PP population using the MI method for treating missing values. In addition, 
analyses using CMH test adjusting for the stratification factor at randomization and pooled site 
will be performed for ITT population using MI method for imputing missing values. 
6.4.
Analyses of Secondary Efficacy Endpoint
For the binary endpoints defined as ≥4-point reduction (improvement) from the baseline visit in 
either the whole body itch NRS score or the scalp itch NRS score at post-baseline visits, the 
analyses will be based on subjects in the ITT population with baseline whole body itch NRS 
score ≥4 or baseline scalp itch NRS score ≥4, respectively. For the continuous secondary 
endpoint (i.e. change from baseline in DLQI total score at Week 16), the analyses will be based 
on ITT population. Unadjusted 2-sided p-values and 2-sided 95% confidence intervals (CIs) (ie, 
without multiplicity adjustment) will be reported.
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
28
6.4.1.
Whole Body Itch Numeric Rating Scale (NRS) and Scalp Itch Numeric Rating 
Scale (NRS) Assessments
In order to evaluate the onset of effect of apremilast 30 mg BID compared to placebo for itch, the 
following secondary endpoints are specified.
!
Whole Body Itch NRS Response: Proportion of subjects with ≥4-point reduction 
(improvement) from baseline in the whole body itch NRS score at Week 16
!
Scalp Itch NRS Response: Proportion of subjects with ≥4-point reduction 
(improvement) from baseline in the scalp itch NRS score at Week 16
!
Whole Body Itch NRS Response: Proportion of subjects with ≥4-point reduction 
(improvement) from baseline in the whole body itch NRS score at Week 12, Week 8, 
Week 4, and Week 2
!
Scalp Itch NRS Response: Proportion of subjects with ≥4-point reduction 
(improvement) from baseline in the scalp itch NRS score at Week 12, Week 8, Week 
4, and Week 2
Statistical analyses for the 10 endpoints will be performed 1 by 1 downward from Week 16 to 
Week 2. Multiplicity adjustment is specified in Section 6.2. 
These binary endpoints will be analyzed similarly as the primary endpoint. The treatment 
difference between apremilast 30 mg BID and placebo will be compared using CMH test 
adjusting for the stratification factor at randomization. The 2-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 2-sided 95% CIs 
using a normal approximation to the weighted average will be provided.
The SAS procedure MI will be used to impute missing whole body itch NRS score (or scalp itch 
NRS score) at the scheduled analysis visits in the Placebo-controlled Phase (Weeks 0 to16) to 
create M=25 complete data sets. The missing data patterns will be checked by treatment and 
stratification factor at 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 to impute missing 
scores by treatment and stratification factor to create M=25 imputed data sets with monotone 
missing patterns. The minimum and the maximum values for imputation will be 0 and 10, which 
correspond to the lowest and the highest whole body itch NRS score (or scalp itch NRS score). 
The seed will be set to 804529, the imputed values will be rounded to integers and a single chain 
will be used to produce imputations. 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 
treatment and stratification factor in imputation model if necessary.
In the second step, the predictive mean matching method will be used to impute the remaining 
missing values for the 25 data sets with monotone missing patterns. The MONOTONE 
REGPMM statement will be used with seed 447159. The missing values at each visit will be 
imputed based on treatment, stratification factor, and whole body itch NRS score (or scalp itch 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
29
NRS score) at baseline and previous visits. The number of closest observations to be used in the 
selection will be K=5. 
After the completion of imputation, the same CMH method will be used to analyze the 25 
complete data sets and the SAS procedure MIANALYZE will be used to combine the results for 
the statistical inferences.
In summary, the primary analysis of whole body Itch NRS response (or scalp Itch NRS response)
will be performed separately for each post baseline visit in the Placebo-controlled Phase for ITT 
population using MI method for treating missing values. Supportive analyses will be performed 
at Week 16 visit for: (1) ITT population treating missing values using the LOCF method, (2) ITT 
population treating missing values using NRI method. In addition, analyses using CMH test 
adjusting for the stratification factor at randomization and pooled site will be performed at Week 
16 for ITT population using MI method for imputing missing values. 
6.4.2.
Change from Baseline in Dermatology Life Quality Index (DLQI) Total Score at 
Week 16
Change from baseline in DLQI total score at Week 16 will be analyzed based on the ITT 
population using the analysis of covariance (ANCOVA) model. The ANCOVA model will use 
the change from baseline as the dependent variable and will include treatment group and 
stratification factor as independent variables and the baseline value as a covariate variable. 
Within-group least-squares (LS) mean changes from baseline at Week 16, the associated 
standard errors (SEs) and 2-sided 95% CIs, treatment differences in LS mean changes from 
baseline, and the associated 2-sided 95% CIs and p-values, will be derived from the ANCOVA 
model.
The SAS procedure MI will be used to impute missing DLQI total score at the scheduled 
analysis visits in the Placebo-controlled Phase (Weeks 0 to16) to create M=25 complete data 
sets. The missing data patterns will be checked by treatment and stratification factor at Baseline 
(Week 0), and Weeks 4, 8 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 to impute missing 
scores by treatment and stratification factor to create M=25 imputed data sets with monotone 
missing patterns. The minimum and the maximum values for imputation will be 0 and 30, which 
correspond to the lowest and the highest DLQI total score. The seed will be set to 804529, the 
imputed values will be rounded to integers and a single chain will be used to produce 
imputations. 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 treatment and 
stratification factor in imputation model if necessary.
In the second step, the predictive mean matching method will be used to impute the remaining 
missing values for the 25 data sets with monotone missing patterns. The MONOTONE 
REGPMM statement will be used with seed 447159. The missing values at each visit will be 
imputed based on treatment, stratification factor, and DLQI total score at baseline and previous 
visits. The number of closest observations to be used in the selection will be K=5. 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
30
After the completion of imputation, the same ANCOVA model will be used to analyze the 25 
complete data sets and the SAS procedure MIANALYZE will be used to combine the results for 
the statistical inferences.
In summary, the secondary analysis of change from baseline in DLQI total score at Week 16 will 
be performed for ITT population using MI method for treating missing values. Sensitivity 
analysis will be performed for ITT population treating missing values using the LOCF method,
6.5.
Analyses of Exploratory Efficacy Endpoints 
Descriptive summary statistics or proportion of subjects achieving specified criteria will be 
summarized by treatment group. When appropriate, exploratory endpoints at Week 16 will also 
be analyzed using CMH or ANCOVA methods similar to the primary and secondary endpoints
based on ITT population with missing values imputed using LOCF method.
6.5.1.
Study Phases
The subjects included and the treatment arms considered for statistical analyses and summaries 
in each phase are described below in this section. The specific summaries are discussed in the
following sections.
!
Placebo-controlled Phase (Weeks 0 to16)
The two treatment arms are 30 mg BID or Placebo, all subjects in the ITT population are to 
be included.
!
Apremilast Extension Phase (Weeks 16 to 32)
The two treatment arms are 30 mg BID/30 mg BID, and Placebo/30 mg BID. Subjects 
included are those in the ITT population who entered the Apremilast Extension Phase, either 
were initially randomized to 30 mg BID or placebo, respectively.
 
 
 
 
 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
31
6.5.3.
Dermatology Life Quality Index (DLQI)
The endpoints include:
!
Change from baseline in DLQI total score at Weeks 4, 8, 16 and 32
!
Change from baseline in DLQI subscale scores at Weeks 4, 8, 16 and 32
 
Mean change from baseline in DLQI total score and subscale scores will be summarized by 
treatment group and time point using descriptive statistics. Analysis for the Week 16 change 
from baseline in DLQI total score is presented in the secondary efficacy endpoint Section 6.4.2.
 
Week 16 DLQI 
response will be analyzed similarly as the primary and secondary binary endpoint. The treatment 
difference between apremilast 30 mg BID and placebo will be compared using CMH test 
adjusting for the stratification factor at randomization. The 2-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 2-sided 95% CIs 
using a normal approximation to the weighted average will be provided. The analysis will be 
based on ITT population with missing values imputed using the LOCF method.
6.5.4.
Whole Body Itch and Scalp Itch Numeric Rating Scale (NRS) Assessment
The endpoints include:
!
Whole body itch NRS score by visit
!
Scalp itch NRS score by visit
!
Change from baseline in whole body itch NRS score by visit
!
Change from baseline in scalp itch NRS score by visit
All endpoints will be summarized by treatment group and time point using descriptive statistics.
Shift tables for shifts from baseline to post-baseline visits and End of Phase (LOCF) will be 
provided by treatment and time point for whole body itch NRS score and scalp itch NRS score.
 
 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
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32
6.5.6.
Scalp Physician Global Assessment (ScPGA) 
The endpoints include:
!
ScPGA response defined as proportion of subjects with ScPGA score of clear (0) or 
almost clear (1) with at least a 2-point reduction from baseline by visit
 
These endpoints will be summarized by treatment group and time point. 
Analysis for the Week 16 ScPGA response is presented as the primary efficacy endpoint in 
Section 6.3.
 
 The treatment difference between apremilast 30 mg BID and placebo will be compared 
using CMH test adjusting for the stratification factor at randomization. The 2-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 2-
sided 95% CIs using a normal approximation to the weighted average will be provided. The 
analysis will be based on ITT population with missing values imputed using the LOCF method.
Shift tables for 
and ScPGA shifts from baseline to post-baseline visits and End of Phase 
(LOCF) will be provided by treatment and time point. 
6.6.
Subgroup Analysis 
Subgroup analyses for ScPGA response at Week 16 and proportions of subjects with ≥4-point 
reduction (improvement) from baseline in the whole body itch NRS or scalp itch NRS scores at 
post baseline time points based upon baseline demographic or baseline disease characteristics.
Summary and analysis will be based on ITT population and missing values will be imputed using 
MI method. Treatment-difference for response will be reported with 2-sided 95% CI.
The following subgroup variables will be considered and analyzed when appropriate:
!
Sex (Male, Female)
!
Race (White, Others)
!
Age category (< 65, ≥65) 
!
Baseline weight (< 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)
!
Alcoholic beverage drinking (Yes, No)
!
Tobacco use (Current user, Past user, Never used)
!
Duration of plaque psoriasis categories (< 10, ≥ 10 to < 20, ≥ 20 years)
!
Baseline ScPGA score: 3 (moderate), 4 (severe)
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
33
!
Baseline whole body itch NRS score (0 to 3, 4 to 6, 7 to 10)
!
Baseline scalp itch NRS score (0 to 3, 4 to 6, 7 to 10)
!
Number of prior conventional systemic therapies (0, ≥1)
!
Number of prior biologic therapies (0, ≥1)
!
Number of prior systemic therapies (0, ≥1)
!
Number of prior topical scalp psoriasis medications or shampoo treatments (1, ≥2)
!
Number of failed prior scalp psoriasis medications or shampoo treatments for subjects 
who had prior scalp psoriasis medications or shampoo treatments (0, ≥1)
 
 
 
 
 
 
 
6.9.
Assessing Study Site Effect
This multicenter study has approximately 46 study sites. As site enrollment caps are imposed, no 
single site will have sufficient number of subjects to allow a meaningful within-site analysis of 
treatment effects stratified by baseline ScPGA score; therefore, study site effect will be assessed 
by pooling sites on geographic basis to help interpret the results should potential site effect be 
suspected. 
In pooling sites for analysis purposes, a minimum of 5 randomized subjects per treatment group 
(apremilast 30 mg BID or placebo) per stratum of baseline ScPGA score (moderate [3], or severe 
[4]) will be used. The pooling strategy is described as follows: 1) Sites will be pooled within 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
34
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 site pooled together in a country does not satisfying 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 and major secondary efficacy endpoints as below:
!
ScPGA Response: 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
!
Whole Body Itch NRS Response: Proportion of subjects with ≥4-point reduction 
(improvement) from baseline in the whole body itch NRS score at Week 16
!
Scalp Itch NRS Response: Proportion of subjects with ≥4-point reduction (improvement) 
from baseline in the scalp itch NRS score 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 and the major secondary 
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 also be assessed by performing a subgroup-type analysis with respect to the endpoints, with 
individual study sites (or pooled sites) treated as subgroups (see Section 6.6). 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).
6.10.
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 
data restriction will be performed, the primary data analysis will be conducted 
.  However, unblinded data will only be made available 
to select Sponsor and Contract Research Organization (CRO) team members involved with 
analysis of the data 
.  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 Clinical Study Report will be generated.
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
35
7.
SUMMARY OF SUBJECT DISPOSITION
The number of subjects screened, the number and percentage of subjects randomized (as 
recorded in the IVRS database) and not randomized among all subjects screened 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 included in the ITT population, safety population, and PP 
population will be summarized by treatment arm; the percentages will be based on the number of 
subjects randomized.
For the Double-blind Placebo-controlled Phase, the number and percentage of subjects who 
entered, completed, and discontinued, as well as the number and percentage of primary reasons 
for discontinuation will be summarized.
All subjects who terminated early or completed the study treatment will be asked to continue into 
the Post-treatment Observational Follow-up Phase. The primary reasons for discontinuation are 
collected in the screening disposition, treatment disposition and follow-up disposition eCRF and 
will be summarized with the following categories:
!
Screen failure (screening only)
!
Death
!
Adverse event(s)
!
Pregnancy
!
Lack of efficacy (treatment disposition only)
!
Withdrawal by subject
!
Non-compliance with study drug (treatment disposition only)
!
Lost to follow-up
!
Study terminated by sponsor
!
Protocol deviation
!
Physician decision
!
Other
!
Site terminated by sponsor (treatment disposition only)
The number and percentage of subjects randomized will be tabulated by treatment and study site. 
The percentages will be based on the number of subjects randomized.
Subject disposition will be provided by treatment arm and protocol phase:
!
Placebo-controlled Phase – Weeks 0 to16: in addition to the tabulation of subjects who 
are randomized, or included in the ITT, PP, and Safety populations, the number and 
percent of 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 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
36
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: The number and percent of subjects who 
entered the phase, took at least one dose of IP, completed the phase, discontinued early, 
and primary reason for discontinuation will be provided.
!
Observational Follow-up Phase (4 weeks): Summary will include all subjects who 
entered Follow-up phase and whether completed Follow-up following the above phases.
The number and percentage of subjects randomized by study site and treatment group will be 
tabulated. The percentages will be calculated based on the number of subjects who are 
randomized.
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
37
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics, baseline characteristics, prior medication/procedure, and 
concomitant medications/procedure will be presented for the ITT population by treatment group 
and overall.  Individual subject 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:
!
Age category (< 65, ≥65)
!
Age category (< 40, ≥ 40 to < 65, ≥ 65 to < 75, ≥ 75 to < 85, ≥ 85 years)
!
Sex (Male, Female)
!
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islanders, White, Other)
!
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
!
Geographical region (USA, Canada)
!
Alcohol History (Yes, No)
!
Tobacco use (Never Smoked, Past Smoker, Current Smoker)
!
Baseline BMI category (< 18.5, ≥ 18.5 to < 25, ≥25 to < 30, ≥ 30 to < 35, ≥ 35 to < 40, ≥
40 kg/m2)
BMI will be calculated as follows: BMI (kg/m2) = Weight (kg)/ Height (m2). Other variables 
(i.e., age, weight, height, sex, race, ethnicity, geographical region, alcohol history and tobacco 
use history) will be summarized as recorded from the eCRF.
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 ScPGA score 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
38
!
Baseline whole body itch NRS score
!
Baseline scalp itch NRS score
!
Baseline DLQI total score
!
Baseline DLQI total score category (0 to 3, 4 to 10, 11 to 20, 21 to 30)
!
Number of prior phototherapies (0, 1, 2, ≥3)
!
Number of failed prior phototherapies for subjects who had prior phototherapies (0, 1, 2, 
≥3)
!
Number of prior conventional systemic therapies (0, 1, 2, ≥3)
!
Number of failed prior conventional systemic therapies for subjects who had prior 
conventional systemic therapies (0, 1, 2, ≥3)
!
Number of prior biologic therapies (0, 1, 2, ≥3)
!
Number of failed prior biologic therapies for subjects who had prior biologic therapies (0, 
1, 2, ≥3)
!
Number of prior systemic therapies (0, 1, 2, ≥3)
!
Number of failed prior systemic therapies for subjects who had prior systemic therapies
(0, 1, 2, ≥3)
!
Number of prior topical scalp psoriasis medications or shampoo treatments (0, 1, 2, ≥3)
!
Number of failed prior scalp psoriasis medications or shampoo treatments for subjects 
who had prior scalp psoriasis medications or shampoo treatments (0, 1, 2, ≥3)
8.3.
Medical History
A summary of relevant medical history and concomitant diseases will be presented by system 
organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory 
Affairs (MedDRA) version 20.0 or higher, using frequency distributions (counts and
percentages).  A similar summary will be generated for the currently active diagnosis only.
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Celgene Corporation
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39
8.4.
Prior and Concomitant Procedures
Prior procedures are defined as those started before the start of the study treatment (whether or 
not ended before the start of the study treatment).
For a study phase, concomitant procedures are defined as those started during the phase. Study 
phases are defined in Section 5.1.1. Prior procedures and concomitant procedures will be coded 
using the MedDRA dictionary Version 20.0 or higher.
A frequency tabulation of the number of subjects with each prior procedure will be given for the 
ITT population by treatment group, system organ class (SOC), and preferred term (PT). 
A frequency summary of concomitant procedures will be provided for the safety population by 
treatment group, SOC, and PT.
8.5.
Prior and Concomitant Medications
Prior medications are defined as medications that were started before the start of the study 
treatment and either ended before the start of the study treatment or continued after study 
treatment.
For a study phase, concomitant mediations are defined as non-study medications started during 
the phase, or started before the phase and ended or remain ongoing during the phase. Study 
phases are defined in Section 5.1.1. The Anatomical Therapeutic Chemical (ATC) coding 
scheme of the World Health Organization Drug Dictionary (WHO DD version DDE B2 March 
2017 or higher) will be used to group medications into relevant categories. A frequency
summary of prior medications will be provided by treatment group, ATC2 level, and 
standardized medication name for the safety population.
Prior psoriasis medications will be summarized with baseline characteristics.
Concomitant medications documented during the study will be summarized. The frequency 
tabulation will display the number (%) of subjects receiving at least one concomitant medication, 
the number (%) of subjects receiving at least one medication within a relevant category, and each 
concomitant medication by treatment group. The summaries will be provided for (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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40
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Treatment duration will be summarized by treatment group for the analysis phases (Section 
5.1.1) and for the Apremilast-exposure Period (Section 5.1.2). Subjects who are treated in the 
corresponding phases or period will be used, i.e., the safety population for Placebo-controlled 
Phase (Weeks 0 to16), and the apremilast subjects as treated population for the Apremilast-
exposure Period, etc.
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 A1A1.1.4 
Treatment duration will be summarized by actual treatment (placebo vs. apremilast 30 mg BID) 
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 A1A1.1.4
9.1.3.
Apremilast-exposure Period
Treatment duration for Apremilast-exposure Period (Section 5.1.2) is calculated from the date of 
the first dose of apremilast 30 mg BID, 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 A1A1.1.4
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 each visit (except Week 3/ Visit 1). 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 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
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41
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.
Summary statistics for compliance (%) will be provided by treatment 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 to16
Treatment compliance will be calculated for the treatment duration in the phase specified in 
Section 9.1.1 and will be summarized by treatment group 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 group for the subset of ITT population who 
entered 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.
Treatment compliance will be summarized for apremilast 30 mg BID treatment for apermilast as 
treated population.
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42
10.
PROTOCOL DEVIATIONS AND IMPORTANT PROTOCOL 
DEVIATIONS
Protocol deviations and important protocol deviations will be categorized by Clinical Research 
Physician (CRP). 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 removed from the per-protocol population.
Protocol deviations and important protocol deviations will be summarized by treatment. 
Summary tables showing the number and percent of subjects with at least one protocol 
deviation/important protocol deviation and by each protocol deviation/important protocol 
deviation will be provided. Listings of subjects with protocol deviations and important protocol 
deviations will also be provided. 
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Celgene Corporation
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11.
SAFETY ANALYSIS
Safety will be assessed via descriptive statistics and point estimates. 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, and apremilast 
30 mg BID), and the safety analyses for the Apremilast-exposure Period will be based on the 
apremilast subjects as treated population and presented by apremilast dose group (i.e., apremilast 
30 mg BID) irrespective of the start time of apremilast exposure (at Week 0 or 16).
For the analyses of AEs and marked abnormalities, the following point estimates are 
distinguished:
!
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 marked abnormalities will be summarized by subject incidence and EAIR for the 
Placebo-controlled Phase (Weeks 0 to16) 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) will be presented.
Descriptive statistics will be provided for vital signs, weight, 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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44
11.1.
Adverse Events
AEs will be coded according to the MedDRA version 18.0 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 to16):
!
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 Extension Phase (Weeks 16 to 32), Observational Follow-up Phase (4 
weeks) and 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). In addition to the Placebo-controlled Phase (Weeks 0 to16) and the 
Apremilast-exposure Period, summaries will also be provided for the Apremilast Extension
Phase (Weeks 16 to 32).
New events of all TEAEs by exposure interval (≤ 1, > 1 to ≤ 4, > 4 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 treatment duration 
exceeding the lower bound of the particular exposure interval, while the denominator of an EAIR 
is the sum of the exposure time during the exposure interval (up to the first event start date for 
subjects with at least one event starting 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 Weeks) will be summarized for the Apremilast-exposure Period.
All TEAEs will be summarized by age category (< 65, ≥ 65 years), sex, and race.
All TEAEs occurring after the date of the last dose of IP and up to 28 days after the last dose of 
IP will also be summarized by SOC and PT for subjects who enter the observational follow-up 
phase. The EAIR will not be provided in this summary.
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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). 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.
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 TEAEs Leading to 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.
11.2.
Psoriasis Flare
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. At any time, a
psoriasis flare may be reported as an adverse event, provided it meets the protocol definition. 
TEAEs in their coded terms containing psoriasis will be summarized. A subject data listing of all 
those adverse events will be provided.
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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

Hematology: hemoglobin, hematocrit, platelet, erythrocytes, leukocytes, 
basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, 
monocytes/leukocytes, neutrophils/leukocytes, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils

Serum chemistry: glucose, lactate dehydrogenase (LDH), bicarbonate, calcium, 
chloride, potassium, magnesium, phosphate, sodium, blood urea nitrogen, 
creatinine, urate, total cholesterol, high-density lipoprotein cholesterol (HDL-C), 
low-density lipoprotein cholesterol (LDL-C), triglycerides, alkaline phosphatase, 
AST (SGOT), ALT (SGPT), total bilirubin, albumin, and total protein
-
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.
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)
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!
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.
11.5.
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).
The protocol specified that physical examination findings of clinical significance (as defined by 
the investigator) are to be reported as AEs. No summary of physical examination findings will be 
provided.
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summary 


Celgene Corporation
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48
REFERENCES
 
 
Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI): a simple practical measure for 
routine clinical use.   Clin Exp Dermatol.  1994;19:210-6.
SAS Institute Inc. 2015. SAS/STAT® 14.1 User’s Guide. Cary, NC: SAS Institute Inc.
Naegeli, AN, Flood, E, Tucker J, Devlen J, Edson-Heredia E.  The Worst Itch Numeric Rating 
Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis.  Int J Dermatol 
2015; 54:715-22.
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.
Mehrotra, DV, and Railkar, R. Minimum risk weights for comparing treatments in stratified 
binomial trials. Statist. Med., 2000; 19: 811–825.
CCI
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Ratating 
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Derm
Dermatol
atol
Relapse, reb
Relapse, re
tol
tol.  2006;
.  2006;
g treatment
treatment


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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.
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:
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Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
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50
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);
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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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
51
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.
A1.1.3 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.
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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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
52
Appendix A2
–Laboratory Marked Abnormalities Criteria
Table 6:
Imputation Rules for Partially Missing AE Start Dates for Subjects who were 
Treated with Placebo Initially Laboratory Marked Abnormalities Criteria
Category / Analyte 
SI Units 
Criteria 
Chemistry/ 
Alanine Aminotransferase (SGPT) 
U/L 
> 3*ULN 
Albumin 
Kg/m3 
< 25 
Alkaline Phosphatase 
U/L 
> 400 
Aspartate Aminotransferase (SGOT) 
U/L 
> 3*ULN 
Total Bilirubin 
μmol/L 
> 1.8*ULN 
Blood Urea Nitrogen 
mmol/L 
> 15 
Calcium 
mmol/L 
1. < 1.8 
2. > 3.0 
Creatinine 
μmol/L 
> 1.7*ULN 
Glucose 
mmol/L 
< 2.8 
> 13.9 
Hemoglobin A1C 
% 
> 9 
Lactate Dehydrogenase 
U/L 
> 3*ULN 
Magnesium 
mmol/L 
>1.2 
Phosphate 
mmol/L 
1. < 0.64 
2. >1.60 
Potassium 
mmol/L 
< 3.0 
> 5.5 
Sodium 
mmol/L 
< 130 
> 150 
Triglycerides 
mmol/L 
> 3.4 
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
53
Category / Analyte 
SI Units 
Criteria 
Urate 
umol/L 
Male: > 590; Female: > 480 
Hematology/
Hemoglobin 
g/L 
Female < 8.5, Male < 10.5 
Female > 17, Male > 18.5 
Leukocytes 
10^9/L 
< 1.5 
Lymphocytes 
10^9/L 
< 0.8 
Neutrophils 
10^9/L 
< 1.0 
Platelets 
10^9/L 
1. < 75 
2. > 600 
Total cholesterol
mmol/L 
> 7.8
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Celgene Corporation
Protocol: CC-10004-SPSO-001
Statistical Analysis Plan
Confidential and Proprietary
54
Appendix A3
–Reporting conventions
!
Summary tabulation will be provided by treatment (e.g., placebo vs. apremilast 30 mg 
BID for Double-blind Placebo-controlled Phase; placebo/ apremilast 30 mg BID vs. 
apremilast 30 mg BID/30 mg BID for Apremilast Extension Phase; apremilast 30 mg 
BID for Apremilast-exposure Period);
!
All statistical tests of the treatment effect will preserve a significance level of 0.05 for 
2-sided tests;
!
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 2-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;
!
All 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;
!
All 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;
!
All analysis and summary tables will have the analysis population sample size (i.e., 
number of subjects) in the column header;
!
The day of the first dose of any study drug (i.e., apremilast or placebo) will be 
defined as Day 1; 
!
Subject data listings will be provided to support the tables and graphs. All listings 
will be sorted for presentation in order of treatment, subject, and date of procedure or 
event.
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