Clinical trial NCT03777436
Conditions: Psoriasis
Keywords: Genital Psoriasis CC-10004 Apremilast Plaque Psoriasis
Sponsor: Amgen
Start date: 2019-02-11; Completion date: 2022-02-09
Enrollment: 289 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 multicenter, randomized, placebo-controlled, double-blind study is designed to evaluate the efficacy and safety of apremilast in subjects with moderate to severe genital psoriasis (modified sPGA-G ≥3, moderate or severe).

Approximately 286 subjects with moderate to severe genital psoriasis will be randomized 1:1 to receive either apremilast 30 mg BID or placebo for the first 16 weeks.

Detailed description:
The study will consist of four phases:

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

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

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

Arms: arm 1: 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 arm 2: 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
Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: Oral intervention 2: Oral

Protocol documents:
Prot_000.pdf: 
Apremilast 
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TITLE PAGE 
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 GENITAL PSORIASIS 
 
PROTOCOL NUMBER: 
 
CC-10004-PSOR-025 
ORIGINAL DATE: 
 
31 Oct 2018 
AMENDMENT No. 1.0 DATE: 
 
22 May 2019 
AMENDMENT No. 2.0 DATE: 
 
01 May 2020 
AMENDMENT No. 3.0 DATE 
 
03 Mar 2021 
EudraCT NUMBER: 
 
2018-002608-15 
NCT NUMBER: 
 
NCT03777436 
IND NUMBER: 
 
070270 
SPONSOR NAME/ ADDRESS: 
 
Amgen Inc. 
One Amgen Drive 
Thousand Oaks, CA 91320 
 
CONFIDENTIALITY NOTICE 
This document contains confidential information of Amgen. This document 
must not be disclosed to anyone other than the site study staff and members of 
the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. The information in this document cannot 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Amgen. If you have 
questions regarding how this document may be used or shared, call the Amgen 
Medical Information number: 1- 800-77-AMGEN 


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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION  
 
Contact Information:  
Name: 
, MD, PhD 
Title: Clinical Research Medical Director 
Address: Amgen Inc. 
 
 
 
One Amgen Center Drive, Thousand Oaks, CA 91320 
Phone: 
 
E-mail:  
 
 
Note: Only call Amgen Medical Information, if you are not able to reach the Clinical 
Research Physician(s) or Medical Monitor or designee for emergency calls.  
Amgen Medical Information:  1-800-77-AMGEN (1-800-772-6436) 
 
 


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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
Signature of Site Principal Investigator 
 
dd mmm yyyy 
 
 
Printed Name of Site Principal Investigator 
Institution Name:____________________________________ 
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Amgen 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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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
Signature of Coordinating Principal Investigator 
 
dd mmm yyyy 
 
 
Printed Name of Coordinating Principal Investigator 
Institution Name:____________________________________ 
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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Protocol Summary 
Study Title 
A Phase 3, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study of the Efficacy 
and Safety of Apremilast (CC-10004) in Subjects with Moderate to Severe Genital Psoriasis  
Indication 
The indication is moderate to severe genital psoriasis. 
Objectives 
Primary Objective 
 To evaluate the clinical efficacy of oral apremilast 30 mg twice daily (BID), compared to 
placebo, in subjects with moderate to severe genital psoriasis during the 16-week 
Placebo-controlled Phase. 
Secondary Objectives 
 To evaluate the safety and tolerability of apremilast 30 mg BID, compared with placebo, 
in subjects with moderate to severe genital psoriasis 
 To evaluate the effect of apremilast 30 mg BID compared with placebo on genital 
psoriasis symptoms 
 To evaluate the effect of apremilast 30 mg BID compared with placebo on Health-related 
Quality of Life (HRQoL) 
Study Design 
This Phase 3, multicenter, randomized, placebo-controlled, double-blind study is designed to 
evaluate the efficacy and safety of apremilast (CC-10004) in subjects with moderate to severe 
genital psoriasis (modified Static Physician Global Assessment of Genitalia (sPGA-G)  3, 
moderate or severe). 
Approximately 286 subjects will be enrolled and randomized 1:1 to receive either apremilast 
30 mg BID or placebo for the first 16 weeks. Subjects will be randomized based on a permuted 
block randomization using a centralized Interactive Response Technology (IRT).  
 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 


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 Subjects will be randomly assigned in a 1:1 ratio to either apremilast 30 mg BID 
or placebo.   
 Apremilast Extension Phase – Weeks 16 to 32 
 All subjects will be switched to (or continue to) receive apremilast 30 mg BID.  
All subjects will maintain this dosing through Week 32. 
 Observational Follow-up Phase – 4 weeks 
 Four-week Post-Treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue the study prematurely. 
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 and a Week 16 
Clinical Study Report (CSR) will be generated. However, unblinded data will only be made 
available to select Sponsor and Contract Research Organization (CRO) team members involved 
with analysis of the data and preparation of the Week 16 CSR. All other Sponsor, site, and CRO 
personnel directly involved with the conduct of the study, will remain blinded to treatment 
assignments until the final database lock at the conclusion of the study. 
The study will be conducted in compliance with International Council on Harmonisation (ICH) 
Good Clinical Practices (GCPs). 
Study Population 
Approximately 286 adult subjects  18 years of age with chronic moderate to severe genital 
psoriasis (modified sPGA-G 3 [moderate or severe]) will be randomized.  Only subjects who 
are inadequately controlled with or intolerant of topical therapies for the treatment of genital 
psoriasis will be eligible for the study. 
Length of Study 
The study is designed as a 32-week study with a Four-week Post-treatment Observational 
Follow-up Visit and consists of 4 phases as described above.  Please refer to Section 1.3.2 for 
details. 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date. 
Study Treatments 
The chemical name of apremilast (CC-10004) is acetamide, N-[2-[(1S)-1-(3-ethoxy-4- 
methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]. 
From Weeks 0 to 16, subjects will be dispensed blister cards with 10, 20, or 30 mg apremilast 
tablets or identically appearing 10, 20, or 30 mg placebo tablets. 
Investigational product will be taken orally twice daily, approximately 12 hours apart, without 
restriction of food or drink. As in prior Phase 3 studies, dose titration will be implemented in 
order to mitigate potential gastrointestinal-related adverse events (AEs).  During Week 0 
(Days 1-7), subjects will be dispensed dose titration blister cards with 10, 20, and 30 mg 


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apremilast tablets or identically appearing placebo for the dose titration.  Starting at Week 16, 
subjects originally randomized to apremilast will continue with apremilast.  Subjects originally 
randomized to placebo at Week 0 will be switched to apremilast 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. Starting at the Week 20 Visit through Week 32, all subjects will 
receive open-label apremilast (APR) 30 mg BID tablets in high-density polyethylene (HDPE) 
bottles.  
Dose modifications are not permitted in this study. 
Overview of Key Efficacy Assessments 
Primary Efficacy Assessment 
 Modified Static Physician Global Assessment of Genitalia (sPGA-G) 
Additional Efficacy Assessments 
 Static Physician Global Assessment (sPGA) 
 Body Surface Area (BSA) 
 Genital Psoriasis Symptoms Scale (GPSS) 
 Genital Psoriasis Itch Numeric Rating Scale (GPI-NRS) 
 Dermatology Life Quality Index (DLQI) 
Overview of Key Safety Assessments 
Safety assessments will include: 
 Adverse events  
 Vital signs 
 Pregnancy tests for females of childbearing potential (FCBP) 
 Clinical laboratory tests 
Statistical Methods 
It is assumed that modified sPGA-G response will be similar to historic sPGA response. With a 
total of approximately 286 subjects and a randomization ratio of 1:1, Study PSOR-025 will 
randomize approximately 143 subjects to apremilast (APR) 30 BID and 143 subjects to placebo. 
This sample size will provide 85 power to detect a treatment difference of 15 at Week 16 
(25 for APR 30 BID and 10 for placebo) for the primary endpoint using a chi-square test at a 
2-sided significance level of 0.05 after adjusting for a 20 dropout rate.  
The analyses of efficacy endpoints will be based on the intent-to-treat (ITT) population, defined 
as all subjects who are randomized. Statistical comparisons will be made between APR 30 BID 
and placebo for the Placebo-controlled Phase (Weeks 0 to 16). All statistical tests will be at the 
2-sided 0.05 significance level and the corresponding p-values will be reported. 


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The treatment difference for the primary endpoint will be compared between APR 30 BID and 
placebo using a Cochran Mantel–Haenszel (CMH) test adjusting for the stratification factor. 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 stratification factor with the CMH 
weights, along with the associated 2-sided 95 confidence intervals (CIs) using a normal 
approximation to the weighted average will be provided. Missing values at Week 16 will be 
imputed using multiple imputation (MI) as the primary method, with sensitivity analysis using 
the nonresponder imputation (NRI) method. 
The continuous endpoints will be analyzed using a mixed-effect model for repeated measures 
(MMRM) as the primary method. The MMRM model will use the change or percent change 
from baseline as the response variable and include treatment group, visit time, treatment-by-time 
interaction, and stratification factor as fixed effects, and the baseline value as a covariate. An 
unstructured covariance matrix will be used to model the correlation among repeated 
measurements. The Kenward-Roger adjustment will be used with restricted maximum likelihood 
(REML) to make proper statistical inference. Within-group least-squares (LS) means and the 
associated standard errors (SEs) and 2-sided 95 CIs, treatment differences in LS means and the 
associated 2-sided 95 CIs and 2-sided p-values will be derived from the MMRM model. A 
sensitivity analysis will be conducted using the analysis of covariance (ANCOVA) model with 
treatment and stratification factor as the fixed effects, the baseline value as the covariate and the 
last observation carried forward (LOCF) method to impute the missing data at Week 16.  
The other binary endpoints will be analyzed similarly as the primary endpoint using the CMH 
test.  
To control the overall type I error rate, a fixed-sequence testing procedure will be used to test the 
primary and secondary endpoints in a predefined order. The test will be performed in sequence 
and significance of all preceding endpoints is required in order to proceed to the next one. The 
proposed sequence of testing for the primary and secondary efficacy endpoints is specified in 
Section 9.6.1.3. 
The safety analyses will be performed using the safety population, defined as all subjects who 
are randomized and receive at least one dose of investigational product. Safety will be assessed 
by clinical review of all relevant parameters including treatment-emergent adverse events 
(TEAEs), laboratory tests, and vital signs; no inferential testing for statistical significance will be 
performed. 
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. All TEAEs will be summarized by system organ class, 
preferred term, severity and relationship to investigational product. TEAEs leading to death or to 
discontinuation from treatment and serious adverse events (SAEs) will be summarized and listed 
separately. 
Data from other safety assessments will be summarized descriptively. Shift tables for laboratory 
parameters showing the number of subjects with values low, normal, and high comparing with 
the normal reference ranges pre-treatment versus post treatment will be provided. 
To account for the different exposure to the investigational product, AEs or marked laboratory 
abnormalities will also be summarized using the exposure adjusted incidence rate, in addition to 
the simple incidence rates. 


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TABLE OF CONTENTS 
TITLE PAGE 
 ............................................................................................................. 1 
Protocol Summary .......................................................................................................... 5 
1. 
Introduction .......................................................................................................... 15 
1.1. 
Disease Background ................................................................................. 15 
1.2. 
Compound Background ............................................................................ 15 
1.3. 
Rationale .................................................................................................. 16 
1.3.1. 
Study Rationale and Purpose .................................................... 16 
1.3.2. 
Rationale for the Study Design .................................................. 16 
1.3.3. 
Rationale for Dose, Schedule and Regimen Selection .............. 18 
1.3.4. 
Rationale for Choice of Comparator Compounds ...................... 18 
1.3.5. 
Rationale for Pharmacodynamics and Potential Predictive 
Biomarkers ............................................................................... 19 
2. 
Study Objectives and endpoints ........................................................................... 20 
3. 
Overall Study Design ............................................................................................ 22 
3.1. 
Study Design ............................................................................................ 22 
3.2. 
Study Duration for Subjects ...................................................................... 23 
3.3. 
End of Trial ............................................................................................... 23 
4. 
Study Population .................................................................................................. 24 
4.1. 
Number of Subjects .................................................................................. 24 
4.2. 
Inclusion Criteria ....................................................................................... 24 
4.3. 
Exclusion Criteria ...................................................................................... 25 
5. 
Table of Events .................................................................................................... 28 
6. 
Procedures ........................................................................................................... 31 
6.1. 
Screening Period ...................................................................................... 31 
6.2. 
Treatment Period ...................................................................................... 32 
6.2.1. 
End of Treatment ...................................................................... 33 
6.3. 
Observational Follow-up Period ................................................................ 34 
6.4. 
Efficacy Assessments ............................................................................... 34 
6.5. 
Safety Assessments ................................................................................. 35 
................... 37 
6.7. 
Subject Reported Outcomes ..................................................................... 38 
6.7.1. 
Genital Psoriasis Symptoms Scale (GPSS) .............................. 38 
6.7.2. 
Dermatology Life Quality Index (DLQI) ...................................... 38 
6.8. 
Photography ............................................................................................. 39 
7. 
Description of study treatments ............................................................................ 40 
7.1. 
Description of Investigational Product(s) ................................................... 40 


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7.2. 
Treatment Administration and Schedule ................................................... 43 
7.3. 
Overdose .................................................................................................. 43 
7.4. 
Method of Treatment Assignment ............................................................. 43 
7.5. 
Packaging and Labeling ........................................................................... 43 
7.6. 
Investigational Product Accountability and Disposal ................................. 44 
7.7. 
Investigational Product Compliance .......................................................... 44 
8. 
Concomitant Medications and Procedures ........................................................... 45 
8.1. 
Permitted Concomitant Medications and Procedures ................................ 45 
8.2. 
Concomitant Medications Not Recommended .......................................... 45 
8.3. 
Prohibited Concomitant Medications and Procedures ............................... 45 
8.4. 
Required Concomitant Medications and Procedures ................................ 46 
9. 
Statistical considerations ...................................................................................... 47 
9.1. 
Overview .................................................................................................. 47 
9.2. 
Study Population Definitions ..................................................................... 47 
9.3. 
Sample Size and Power Considerations ................................................... 47 
9.4. 
Background and Demographic Characteristics ......................................... 48 
9.5. 
Subject Disposition ................................................................................... 48 
9.6. 
Efficacy Analysis ....................................................................................... 48 
9.6.1. 
Efficacy Evaluation for the Placebo-controlled Phase (Weeks 
0 to 16) ..................................................................................... 48 
9.6.1.1. 
Primary Efficacy Endpoint ....................................... 48 
9.6.1.2. 
Secondary Efficacy Endpoints ................................ 48 
9.6.1.3. 
Multiplicity Adjustment ............................................ 49 
9.6.1.4. 
Exploratory Endpoints ............................................. 50 
9.6.1.5. 
Subgroup Analysis .................................................. 50 
9.6.2. 
Efficacy Evaluation – Apremilast Extension Phase (Weeks 16 
to 32) ........................................................................................ 50 
9.7. 
Safety Analysis ......................................................................................... 50 
9.8. 
Interim Analysis ........................................................................................ 51 
9.9. 
Other Topics ............................................................................................. 51 
.................................................. 51 
9.9.2. 
Investigational Product Compliance .......................................... 51 
9.9.3. 
Concomitant Therapy ................................................................ 51 
10. 
Adverse Events .................................................................................................... 52 
10.1. 
Monitoring, Recording and Reporting of Adverse Events .......................... 52 
10.2. 
Evaluation of Adverse Events ................................................................... 52 
10.2.1. 
Seriousness .............................................................................. 52 
10.2.2. 
Severity/Intensity ....................................................................... 54 
10.2.3. 
Causality ................................................................................... 55 
10.2.4. 
Duration .................................................................................... 55 


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10.2.5. 
Action Taken ............................................................................. 55 
10.2.6. 
Outcome ................................................................................... 55 
10.3. 
Abnormal Laboratory Values .................................................................... 55 
10.4. 
Pregnancy ................................................................................................ 56 
10.4.1. 
Females of Childbearing Potential – Collection of Pregnancy 
Information ................................................................................ 56 
10.4.2. 
Male Subjects With Partners Who Become Pregnant ................ 57 
10.4.3. 
Collection of Lactation Information ............................................ 57 
10.5. 
Reporting of Serious Adverse Events ....................................................... 57 
10.5.1. 
Safety Queries .......................................................................... 58 
10.6. 
Expedited Reporting of Adverse Events .................................................... 58 
11. 
Discontinuations ................................................................................................... 60 
11.1. 
Treatment Discontinuation ........................................................................ 60 
11.2. 
Study Discontinuation ............................................................................... 60 
12. 
Emergency Procedures ........................................................................................ 62 
12.1. 
Emergency Contact .................................................................................. 62 
12.2. 
Emergency Identification of Investigational Products ................................ 62 
13. 
Regulatory Considerations ................................................................................... 63 
13.1. 
Good Clinical Practice .............................................................................. 63 
13.2. 
Investigator Responsibilities ..................................................................... 63 
13.3. 
Subject Information and Informed Consent ............................................... 64 
13.4. 
Confidentiality ........................................................................................... 64 
13.5. 
Protocol Amendments .............................................................................. 64 
13.6. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................... 64 
13.7. 
Ongoing Information for Institutional Review Board/ Ethics Committee ..... 65 
13.8. 
Termination of the Study ........................................................................... 65 
14. 
Data handling and recordkeeping ......................................................................... 66 
14.1. 
Data/Documents ....................................................................................... 66 
14.2. 
Data Management .................................................................................... 66 
14.3. 
Record Retention ...................................................................................... 66 
15. 
Quality Control and Quality Assurance ................................................................. 68 
15.1. 
Study Monitoring and Source Data Verification ......................................... 68 
15.2. 
Audits and Inspections .............................................................................. 68 
15.3. 
Product Complaint .................................................................................... 68 
16. 
Publications .......................................................................................................... 70 
17. 
References ........................................................................................................... 71 
18. 
Appendices .......................................................................................................... 73 


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Appendix A. 
The Modified Static Physician Global Assessment of Genitalia 
(spgA-G)  ........................................................................................................... 76 
Appendix B. 
Static Physician Global Assessment (spgA) of Whole Body 
Psoriasis  ........................................................................................................... 77 
Appendix C. 
The Dermatology Life Quality Index (DLQI) ......................................... 78 
Appendix D. 
Genital psoriasis symptoms scale (Gpss) ............................................ 80 
Appendix E. 
Titration Blister Card Configuration ..................................................... 82 
Appendix F. 
Active Treatment Dummy Titration Blister Card Configuration ............. 83 
Appendix G. 
Placebo Treatment Blister Card Configuration .................................... 84 
Appendix H. 
Sample Serious Adverse Event Report Form ...................................... 85 
Appendix I. 
Pregnancy Notification Form ............................................................... 88 
Appendix J. 
Lactation Notification Form .................................................................. 89 
 
 


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LIST OF TABLES 
Table 1: 
Study Objectives .................................................................................... 20 
Table 2: 
Study Endpoints ..................................................................................... 20 
Table 3: 
Table of Events ...................................................................................... 28 
Table 4: 
Treatment Schema for Dose Titration at Visit 2 (Week 0) ....................... 41 
Table 5: 
Treatment Schema for Dose Titration at Visit 7 (Week 16) ..................... 42 
Table 6: 
Abbreviations and Specialist Terms ....................................................... 73 
 


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LIST OF FIGURES 
Figure 1: 
Study Design .......................................................................................... 23 
 


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1. 
INTRODUCTION  
1.1. 
Disease Background  
Psoriasis is a chronic, systemic, immunological disease involving the skin and/or joints that may 
profoundly affect quality of life and result in a significant socioeconomic burden (World Health 
Organization [WHO] Global Report on Psoriasis, 2016; Van Voorhees, 2016). Genital psoriasis, 
defined as psoriasis in the peri-vaginal region, penis, scrotum and perineum (Menter, 2018) has 
been reported as the most stigmatizing form of psoriasis, regardless of overall disease severity 
(Schmid-Ott, 1999).  Genital involvement has been shown to have a profound impact on quality 
of life and sexual health (Meeuwis, 2011; Meeuwis, 2015; Ryan, 2015).  In addition, patients 
with genital psoriasis report high levels of itching, pain and discomfort (Meeuwis, 2011; Ryan, 
2015). 
Involvement of genital skin has been reported to occur in 29-46 of psoriasis patients 
(Meeuwis, 2015), but underreporting of genital skin involvement has been a concern.  In an 
observational, multicenter study of 354 consecutive psoriasis patients by Ryan (2015), 63 of 
patients reported genital involvement currently and/or previously during the course of their 
disease.  
Genital psoriasis is characterized as plaque psoriasis, although lesions may differ in appearance 
from those in other body areas.  Genital plaques are more likely to be thinner and less scaly than 
psoriatic plaques located elsewhere (Menter, 2008; Papp, 2009; Committee for Medicinal 
Products for Human Use (CHMP) Guideline on Clinical Investigation of Medicinal Products 
Indicated for the Treatment of Psoriasis, 2005).   Local conditions in the genital area such as 
warmth, moisture and friction from clothing may lead to maceration, fissuring and chafing, and 
may impede both accurate diagnosis and treatment as well as healing (Guglielmetti, 2012).   
1.2. 
Compound Background  
Apremilast (CC-10004) is a specific phosphodiesterase type 4 (PDE4) inhibitor under 
development for use in the treatment of inflammatory conditions.  The PDE4 is one of the major 
phosphodiesterases expressed in leukocytes. PDE4 inhibition by apremilast elevates cyclic 
adenosine monophosphate (cAMP) levels in immune cells, which in turn down-regulates the 
inflammatory response by reducing the expression of pro-inflammatory mediators such as tumor 
necrosing factor (TNF) , 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 50 countries worldwide for the treatment 
of adult patients with active psoriatic arthritis and the treatment of adult patients with moderate 
to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Apremilast 
is also approved in several countries for the treatment of adult patients with oral ulcers 
associated with Behçet’s disease. 


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Apremilast remains under further clinical development for the treatment of inflammatory/ 
autoimmune disorders. Further studies within the approved indications of plaque psoriasis, 
psoriatic arthritis, and Behçet’s disease are also ongoing. 
Please refer to the current Investigator’s Brochure (IB) for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) 
profile of the investigational product (IP). 
1.3. 
Rationale 
1.3.1. 
Study Rationale and Purpose 
Topical therapies are the first line of treatment for genital psoriasis. However, topical treatment 
may be limited by short treatment durations, poor treatment compliance, limited efficacy and 
significant adverse effects such as tachyphylaxis, skin atrophy, striae, telangiectasia, and 
hypothalamic-pituitary-adrenal (HPA) axis suppression (Chan, 2009; Kragballe, 2013).  
Evaluation of systemic therapies for the treatment of genital psoriasis has been limited 
(Guglielmetti, 2012; Meeuwis 2015).  To date only the IL-17 inhibitor ixekizumab has 
demonstrated both dermatologic and psychosocial improvements in patients with moderate to 
severe genital psoriasis (Ryan, 2017; Cather, 2018).  Other systemic therapies used to treat 
moderate to severe plaque psoriasis have not been studied in moderate to severe genital psoriasis.  
Therefore, the benefit-risk profile of these agents in patients with genital psoriasis has not been 
well defined.  
There remains an unmet medical need for an effective, convenient treatment for moderate to 
severe genital psoriasis that is well tolerated compared to the currently available treatment 
options.   
Apremilast (APR, OTEZLA) is a drug that is taken orally (by mouth [PO]).  Apremilast inhibits 
the enzyme PDE4, which is a cAMP-specific PDE and the dominant PDE in inflammatory cells.  
By inhibiting PDE4, apremilast elevates intracellular cAMP levels, which in turn modulates a 
network of pro- and anti-inflammatory mediators and reduces the inflammatory response.  
Evaluation of apremilast in a randomized clinical study of genital psoriasis will provide robust 
analysis of the benefit-risk of a systemic therapy in this difficult to treat population. Apremilast 
may offer patients with moderate to severe genital psoriasis an effective oral therapy with a 
novel mechanism of action and a favorable safety profile. 
1.3.2. 
Rationale for the Study Design 
This Phase 3, multicenter, randomized, placebo-controlled, double-blind study is designed to 
evaluate the efficacy and safety of apremilast (CC-10004) in subjects with moderate to severe 
genital psoriasis, who are inadequately controlled with or intolerant of topical therapy. The 
enrolled adult subjects will have a modified static Physician Global Assessment of Genitalia 
(sPGA-G) score of  3 (moderate or severe) and evidence of plaque psoriasis (Body Surface 
Area [BSA]  1) in a non-genital region and static Physician Global Assessment (sPGA)  3 
(moderate or severe).  This is a 32-week study comprised of a 16-week Placebo-controlled Phase 
followed by a 16-week Apremilast Extension Phase where all subjects will receive apremilast 
(APR) 30 twice daily (BID).  The primary endpoint is the proportion of subjects with a modified 


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sPGA-G score of 0 (clear) or 1 (almost clear) with at least a 2-point reduction from baseline at 
Week 16.   
The efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis have 
been demonstrated across multiple clinical trials.  In the pivotal Phase 3 studies (PSOR-008 and 
PSOR-009), significant improvement in difficult to treat areas of psoriasis such as nail, scalp and 
palmoplantar were observed in subjects treated with apremilast, however, genital manifestations 
were not assessed in these trials.  Study PSOR-025 will be the first study to investigate use of 
apremilast in the treatment of moderate to severe genital psoriasis.   
The sample size estimation of approximately 286 subjects with a randomization ratio of 1:1 is 
based on extrapolation of results from Phase 3 and 4 studies with apremilast, where an sPGA 
treatment effect of 
 compared to placebo was demonstrated. 
Study PSOR-025 will enroll adult subjects with chronic plaque psoriasis of at least 6 months 
duration, and evidence of plaque psoriasis BSA  1 in a non-genital region and sPGA  3 
(moderate or severe).  Subjects will have moderate or severe genital psoriasis with a modified 
sPGA-G score of  3 (moderate or severe), who are inadequately controlled with or intolerant of 
topical therapy.  Prior treatment for psoriasis will be stopped for specified durations before 
randomization as follows: Topical therapy at least 2 weeks, phototherapy and conventional 
systemic therapy at least 4 weeks, biologic therapy with a TNF or IL-17 blocker at least 
12 weeks and anti-IL-12 or IL-23 monoclonal antibodies at least 24 weeks before randomization, 
and no concomitant psoriasis therapy (topical, photo or systemic) will be permitted during the 
active treatment period of the study (except for a non-medicated moisturizer such as Eucerin or 
non-medicated shampoo). 
The primary endpoint will be the proportion of subjects with a modified sPGA-G score of 0 
(clear) or 1 (almost clear) with at least a 2-point reduction from baseline at Week 16. Based on 
health authority feedback, the sPGA-G described by Merola has been modified from a 6-point to 
a 5-point scale ranging from 0 (clear) to 4 (severe).  The modified sPGA-G score incorporates an 
assessment of the severity of the 3 primary signs of the disease: erythema, scaling and plaque 
elevation at a given time point, and was developed as an efficacy outcome measure in the clinical 
assessment of the severity of genital psoriasis, based on sPGA scales used in clinical studies 
(Merola, 2017; Menter, 2018).  Assessment of sPGA-G response was the primary endpoint in a 
recent ixekizumab genital psoriasis study (Cather, 2018).  
In the proposed study population of subjects with a baseline of modified sPGA-G of  3 
(moderate or severe), who are inadequately controlled with or intolerant of topical therapy. 
Amgen believes that achieving a modified sPGA-G score of clear (0) or almost clear (1) with at 
least a 2-point reduction from baseline at Week 16 will represent a clinically meaningful benefit 
in subjects with limited treatment options.   
Further supporting the decision to use modified sPGA-G, the CHMP Guidelines (2005) 
recognize that Psoriasis Area and Severity Index (PASI) has not been adapted for difficult to 
treat manifestations of psoriasis such as the scalp or in the genital region and recommend the use 
of a PGA to assess efficacy.  Similar to the development of a Scalp Physician Global Assessment 
(ScPGA), the modified sPGA-G serves as a clinical outcome measure of severity in genital 
psoriasis. 


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Study PSOR-025 will enroll subjects with total body plaque psoriasis ranging in skin 
involvement (BSA  1).  Unlike the PASI scoring system, modified sPGA-G is not limited by 
a decrease in sensitivity in less extensive disease.  Stratification by psoriasis-affected BSA will 
be performed (BSA  10 or  10) and the strata with BSA  10 will take  40 of the 
total enrollment to allow an assessment of efficacy in subjects with greater or lesser overall skin 
involvement.   
The first secondary endpoint will be proportion of subjects achieving an overall sPGA score of 
clear (0) or almost clear (1) with at least a 2-point reduction from baseline.  
Other secondary endpoints of response will include the proportion of subjects with a 4-point 
reduction (improvement) from baseline in the Genital Psoriasis Itch Numeric Rating Scale 
(GPI-NRS) score at Week 16.  The GPI-NRS is one of eight components of the validated Genital 
Psoriasis Symptoms Scale (GPSS) which was developed to assess symptoms that are particularly 
burdensome to subjects with genital psoriasis (Gottlieb, 2018).  The GPSS was modeled after the 
Whole Body Itch numeric rating scale (NRS) instrument, which has been previously validated in 
subjects with moderate to severe plaque psoriasis (Naegeli, 2015).  While all eight components 
of the GPSS and total symptoms score will be included as a secondary endpoint, the significant 
impact of itch on quality of life in subjects with genital psoriasis warrants additional attention.  
Pruritus is a common and frequently reported symptom of plaque psoriasis, occurring on a daily 
basis in 77 of subjects with extensive psoriasis (Yosipovitch, 2000).  In an observational, 
multicenter study of 354 subjects with current and/or previous genital psoriasis, itch was reported 
by 86 of participants (Ryan, 2015).  In study PSOR-025, assessment of genital itch will be 
conducted from baseline (Visit 2) through the Apremilast Extension Phase. In addition to 
GPI-NRS, change from baseline in affected BSA, change from baseline in Dermatology Life 
Quality Index (DLQI) total score, and change from baseline in GPSS total score and individual 
items scores will be assessed at Week 16. 
1.3.3. 
Rationale for Dose, Schedule and Regimen Selection  
In a Phase 2 dose finding study (CC-10004-PSOR-005), a clear dose response was demonstrated 
with statistically significant improvement in apremilast 30 mg BID, but not the apremilast 10 mg 
BID treatment groups, compared with placebo. The safety and tolerability profiles of the 
apremilast 30 mg BID treatment group were acceptable with no clinically significant safety 
signals. The apremilast 30 mg BID dose was evaluated in two large pivotal Phase 3 studies 
(studies CC-10004-PSOR-008 and CC-10004-PSOR-009) and was subsequently approved for 
use in adult subjects with moderate to severe plaque psoriasis who are candidates for 
phototherapy or systemic therapy.  Since the outcome of apremilast treatment on genital psoriasis 
has not been evaluated previously, this study will directly investigate the safety and efficacy of 
this dosing regimen in the treatment of subjects with moderate to severe genital psoriasis. 
1.3.4. 
Rationale for Choice of Comparator Compounds 
A randomized, double-blind placebo-controlled design was chosen in order to measure the 
absolute treatment effect of apremilast 30 mg BID in moderate to severe genital psoriasis.  The 
placebo-controlled design also minimizes subject and investigator bias in evaluating the efficacy 
and safety of apremilast in the selected patient population (Food and Drug Administration [FDA] 
Guidance for Industry E10). 


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1.3.5. 
Rationale for Pharmacodynamics and Potential Predictive Biomarkers 
Phosphodiesterase 4 (PDE4) is the predominant cyclic adenosine monophosphate (cAMP)-
selective phosphodiesterase that regulates intracellular cAMP levels and gene expression in cells 
of the immune system. PDE4 is highly overexpressed in the peripheral blood of a subset of 
psoriasis subjects (Schafer, 2016). Apremilast has been found to reduce Th17 and Th22 cytokine 
expression in the lesional skin and peripheral blood of psoriasis subjects (Gottlieb, 2013; 
Krueger, 2016). In subjects with moderate to severe psoriasis, treatment with apremilast is 
associated with significant reductions in plasma levels of interleukin (IL)-17F, IL-17A, IL-22, 
and tumor necrosis factor- (TNF-) compared with placebo as early as Week 4; decreases in 
cytokine levels were sustained with continued treatment. These in vitro and clinical data 
demonstrate that the beneficial effects of apremilast on known inflammatory mediators are 
associated with its clinical efficacy. However, the efficacy of apremilast has not yet been tested 
in the moderate to severe genital psoriasis population, and predictors of clinical response to 
apremilast have not yet been identified. 
 
 
 These data will define the mechanism of action of apremilast in subjects with moderate to 
severe genital psoriasis and may inform on the subset of subjects who are responding well to 
apremilast treatment. 
Psoriasis is driven in part by genetic factors, including HLA-Cw6, TNF-, LCE3B/3C, IL12B, 
IL23A, IL23R, LCE, TNIP1, IFHIH1, and NFKBIA. Apremilast has been shown to inhibit the 
expression of some of these genes, including TNF-, IL12B, and IL23A (Gottlieb, 2013). 
Therefore, clinical response to apremilast may be dependent upon the underlying genetic drivers 
in some psoriasis subjects. 
 
 
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
Table 1: 
Study Objectives 
Primary Objective 
The primary objective of the study is to evaluate the clinical efficacy of oral apremilast 30 mg 
BID, compared to placebo, in subjects with moderate to severe genital psoriasis during the 16-
week Placebo-controlled Phase. 
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 genital psoriasis 
 
To evaluate the effect of apremilast 30 mg BID compared with placebo on genital 
psoriasis symptoms 
 
To evaluate the effect of apremilast 30 mg BID, compared with placebo, on Health-
related Quality of Life (HRQoL) 
Exploratory Objective(s) 
The exploratory objectives are: 
Table 2: 
Study Endpoints 
Endpoint 
Name 
Description 
Timeframe 
Primary  
Static Physician Global 
Assessment of Genitalia 
(sPGA-G) 0/1 (modified) 
Proportion of subjects with a 
modified sPGA-G score of clear 
(0) or almost clear (1) with at least 
a 2-point reduction from baseline 
Week 16 
 
Secondary 
Static PGA (sPGA) 0/1 
Proportion of subjects achieving 
an overall sPGA score of clear (0) 
or almost clear (1) with at least a 
2-point reduction from baseline 
Week 16 
 
Genital Psoriasis Itch 
Numeric Rating Scale 
(GPI-NRS) 
Proportion of subjects with at least 
a 4-point improvement in GPI-
NRS item score within the Genital 
Psoriasis Symptoms Scale (GPSS) 
for subjects with a baseline score 
of  4  
Week 16 
 
 
Body Surface Area (BSA) 
Change from baseline in affected 
BSA 
Week 16 
 
 


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Table 2: 
Study Endpoints (Continued) 
Endpoint 
Name 
Description 
Timeframe 
 
Dermatology Life Quality 
Index (DLQI) 
Change from baseline in DLQI 
total score 
Week 16 
 
Genital Psoriasis 
Symptoms Scale (GPSS) 
Change from baseline in GPSS 
total score and individual items 
scores 
Week 16 
Exploratory 
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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3. 
OVERALL STUDY DESIGN  
3.1. 
Study Design 
This Phase 3 multicenter, randomized, placebo-controlled, double-blind study is designed to 
evaluate the efficacy and safety of apremilast over 32 weeks of treatment in approximately 
286 subjects with moderate to severe genital psoriasis (modified sPGA-G  3, moderate or 
severe).  Subjects will be randomized 1:1 based on a permuted block randomization using a 
centralized Interactive Response Technology (IRT). Randomization to apremilast arm or placebo 
arm will be stratified by baseline psoriasis-involved body surface area (BSA) ( 10 or  10). 
No more than 60 of subjects with BSA  10 will be enrolled.  
 Subjects randomized to the apremilast 30 mg BID treatment group will receive 
apremilast 30 mg tablets orally twice daily for the first 16 weeks 
 Subjects randomized to the placebo treatment group will receive placebo tablets 
(identical in appearance to apremilast 30 mg tablets) orally twice daily for the first 
16 weeks 
 All subjects will receive apremilast 30 mg tablets orally twice daily after the Week 16 
Visit through the end of the Apremilast Extension Phase of the study 
The study will consist of four phases (Figure 1): 
 Screening Phase – up to 35 days 
 Double-blind Placebo-controlled Phase – Weeks 0 to 16 
 Subjects will be randomly assigned in a 1:1 ratio to either apremilast 30 mg BID 
or placebo.   
 Apremilast Extension Phase – Weeks 16 to 32 
 All subjects will be switched to (or continue to) receive apremilast 30 mg BID.  
All subjects will maintain this dosing through Week 32. 
 Observational Follow-up Phase – 4 weeks 
 Four-week Post-Treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue the study early 
The blind should be maintained for persons responsible for the ongoing conduct of the study. 
Blinded persons may include but are not limited to: Clinical Research Physician, Clinical 
Research Scientist, Clinical Trial Manager, Study Statistician, Data Manager, Programmers, and 
Clinical Research Associates. 
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 and a Week 16 
Clinical Study Report (CSR) will be generated. However, unblinded data will only be made 
available to select Sponsor and Contract Research Organization (CRO) team members involved 
with analysis of the data and preparation of the Week 16 CSR. All other Sponsor, site, and CRO 
personnel directly involved with the conduct of the study, will remain blinded to treatment 
assignments until the final database lock at the conclusion of the study. 


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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. 
Figure 1: Study Design 
 
3.2. 
Study Duration for Subjects 
Subjects who complete the entire study will spend a total of approximately 41 weeks in this 
clinical trial: 
 Up to 35 days (5 weeks) in the Screening Phase 
 Weeks 0 to 16 (16 weeks) in the Double-blind Placebo-controlled Phase 
 Weeks 16 to 32 (16 weeks) in the Apremilast Extension Phase 
 Four-week (4 weeks) Post-treatment Observational Follow-up Phase 
3.3. 
End of Trial 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date. 
 


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4. 
STUDY POPULATION 
4.1. 
Number of Subjects  
Approximately 286 adult subjects  18 years of age with moderate to severe genital psoriasis 
will be randomized worldwide. 
4.2. 
Inclusion Criteria 
Subjects must satisfy the following criteria to be enrolled in the study: 
1. Subject is  18 years of age at the time of signing the informed consent form (ICF). 
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted.  
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements. 
4. Subject must have a diagnosis of chronic plaque psoriasis for at least 6 months prior to 
signing the ICF. 
5. Subject must have a diagnosis of moderate or severe psoriasis of the genital area at 
Screening and Baseline as defined by having a modified sPGA-G score of  3 (moderate or 
severe). 
6. Subject must have a diagnosis of moderate or severe psoriasis at Screening and Baseline 
as defined by having a sPGA score of  3. 
7. Subject must have plaque psoriasis (BSA  1) in a non-genital area at both Screening 
and Baseline.  
8. Subject must have been inadequately controlled with or intolerant of topical therapy for 
the treatment of psoriasis affecting the genital area.  
9. Subject must be in good health (except for psoriasis) as judged by the investigator, based 
on medical history, physical examination, clinical laboratories, and urinalysis. 
10. Subject must meet the following laboratory criteria:  
a. White blood cell count  3000/mm3 ( 3.0 x 109/L) and  14,000/mm3 
( 14 x 109/L) 
b. Platelet count  100,000/μL ( 100 x 109/L) 
c. Serum creatinine  1.5 mg/dL ( 132.6 μmol/L) 
d. Total bilirubin  2 mg/dL (34 μmol/L) 
e. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase 
[SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic 
transaminase [SGPT])  2 x upper limit of normal (ULN) 
11. 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 


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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. Subject has any significant medical condition or laboratory abnormality, that would 
prevent the subject from participating in the study. 
2. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study. 
3. Subject has any condition that confounds the ability to interpret data from the study. 
4. Subject is pregnant or breast feeding. 
5. Subject has positive Hepatitis B surface antigen or anti-hepatitis C antibody at 
Screening. 
6. Subject has active tuberculosis (TB) or a history of incompletely treated TB. 
7. Subject has history of positive human immunodeficiency virus (HIV), or has 
congenital or acquired immunodeficiency (eg, common variable immunodeficiency 
disease). 
8. Subject has active substance abuse or a history of substance abuse within 6 months 
prior to Screening. 
9. Subject has bacterial infections requiring treatment with oral or injectable antibiotics, 
or significant viral or fungal infections, within 4 weeks of Screening.  Any treatment 
for such infections must have been completed at least 4 weeks prior to Screening. 
 
 
____________________________________________________________ 
†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). 
*Option 2 may not be an acceptable contraception option in all countries per local guidelines/regulations. 
 


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10. Subject has malignancy or history of malignancy (except for treated [ie, cured] basal 
cell or squamous cell in situ skin carcinomas and treated [ie, cured] cervical 
intraepithelial neoplasia [CIN] or carcinoma in situ of the cervix with no evidence of 
recurrence). 
11. Subject has prior history of suicide attempt at any time in the subject’s life time prior 
to signing the informed consent and randomization, or major psychiatric illness 
requiring hospitalization within the last 3 years prior to signing the informed consent. 
12. Subject has psoriasis flare/rebound (defined as a sudden worsening of body psoriasis 
or psoriasis of the genitalia which requires administration of prohibited medications) 
within 4 weeks of Screening or between the Screening and Baseline Visit. 
13. Subject has current or planned concurrent use of the following therapies that may 
have a possible effect on psoriasis of the body and/or genital area during the course of 
the treatment phase of the trial: 
a. Topical therapy within 2 weeks prior to randomization (including but not 
limited to topical corticosteroids, vitamin D analog preparations, calcineurin 
inhibitors).   
- 
Exceptions: unmedicated emollients (eg, Eucerin) for body and 
genital lesions and non-medicated shampoos for scalp lesions 
(Subjects should not use these topical treatments within 24 hours prior 
to the clinic visit.) 
b. Conventional systemic therapy for psoriasis within 4 weeks prior to 
randomization (including but not limited to cyclosporine, corticosteroids, 
methotrexate, oral retinoids, mycophenolate, thioguanine, hydroxyurea, 
sirolimus, sulfasalazine, azathioprine, fumaric acid esters). 
c. Phototherapy treatment of body within 4 weeks prior to randomization (ie, 
ultraviolet B [UVB], psoralen and ultraviolet A radiation [PUVA]). 
d. 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 
e. Use of any investigational drug beginning 4 weeks prior to randomization, or 
5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is 
longer). 
14. Subject has evidence of skin conditions that would interfere with clinical assessments. 
15. Subject has prolonged sun exposure or use of tanning booths or other ultraviolet (UV) 
light sources. 


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16. Subject had prior treatment with apremilast. 
17. Subject has history of allergy or hypersensitivity to any components of the IP. 
 


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5. 
TABLE OF EVENTS 
Table 3: Table of Events 
 
Screening 
Placebo-controlled Treatment Phase 
Active Treatment 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 criteria 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Prior psoriasis medications 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Prior / concomitant medications or 
therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical and Laboratory Assessments 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric evaluatione 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Pregnancy test and contraception 
educationf 
X 
X 
- 
- 
- 
- 
- 
- 
- 
X 
- 
Hepatitis B and C g 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Vital signs 
X 
X 
- 
X 
X 
- 
X 
- 
- 
X 
- 
Height  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Weight 
X 
X 
- 
- 
X 
- 
X 
- 
X 
X 
X 
Complete physical examination 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 


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Table 3: 
Table of Events (Continued) 
 
Screening 
Placebo-controlled Treatment Phase 
Active Treatment 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 
Clinical laboratory evaluationsh 
X 
X 
- 
- 
- 
- 
X 
- 
- 
X 
- 
Psoriasis Flare Assessmenti 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Subject Rated Outcome and Health-related 
Quality of Life Assessment 
 
 
 
 
 
 
 
 
 
 
 
Optional Assessment(s) at Selected Investigative Sites 
 
 
 
 
 
 
 
 
Photographs 
- 
X 
- 
- 
X 
- 
X 
- 
- 
X 
- 
IP 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IP 
- 
X 
- 
X 
X 
X 
X 
X 
X 
- 
- 
Return and count IP tablets 
- 
- 
- 
X 
X 
X 
X 
X 
X 
X 
- 


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Abbreviations:
 ET  Early Termination Visit; FCBP  females of childbearing potential; IP  investigational product;
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 
Should be performed at any time during the study when suicidal thoughts or a suicide attempt is identified.  See Section 6.5 Psychiatric Evaluation  
f 
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 the site 
at baseline, prior to dosing.  An unscheduled serum pregnancy test should be administered if the subject has missed a menstrual period or a positive urine dipstick test.  The 
investigator will educate all FCBP about the options for and correct use of contraceptive methods at the Screening and Baseline Visits and at any time when a FCBP’s 
contraceptive measures or ability to become pregnant changes. 
g 
Hepatitis B surface antigen and anti-hepatitis C antibody. 
h 
Refer to Section 6.5, Clinical Laboratory Evaluations for details regarding hematology, clinical chemistries, and urinalysis parameters to be tested. 
i 
At any time during the study, a psoriasis flare may be reported as an adverse event, provided it meets the protocol definition. See Section 6.5, Psoriasis Flare Assessments. 
 


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6. 
PROCEDURES 
The following administrative/demographic procedures will be conducted as outlined in the 
Table of Events, Table 3. 
Informed Consent 
An informed consent form (ICF) must be signed by the subject before any study-related 
assessments are performed.  For study-related assessments that are optional, additional ICFs will 
also be signed before these 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, should be recorded, including smoking and alcohol history, as well as previous 
relevant surgeries (please refer to the eCRF Completion Guidelines for further details).  Disease 
history includes history of psoriasis 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 TB or relevant diseases, should be recorded.  Please refer to the eCRF Completion 
Guidelines for additional instructions and for further details. 
All medications and therapies for psoriasis, including topicals (used within the last 5 years prior 
to randomization), systemics, and all medications and therapies for psoriatic arthritis, should be 
recorded.  The stop dates for all medications and therapies prohibited in the study should be 
recorded.  Responses to prior psoriasis therapies should also be recorded.  Please refer to the 
eCRF Completion Guidelines for additional instructions. 
6.1. 
Screening Period 
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 35 days of screening unless noted otherwise below.  
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances. 
Safety laboratory analyses 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 Amgen Medical Monitor approval. 


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Subjects who fail initial screening may re-screen one additional time for the study, after 
re-consenting to the study.  
Efficacy assessments may be performed by the investigator or qualified designee at any time 
during the Screening Visit.   
The following assessments will be performed at screening as specified in the Table of Events, 
Table 3, after informed consent has been obtained: 
 Demographics (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) 
 Modified sPGA-G 
 sPGA 
 BSA  
 Hematology panel  
 Chemistry panel 
 Urinalysis 
 Hepatitis B and C screening  
 Serum pregnancy test is required for all female subjects of childbearing potential.  
Counseling about pregnancy precautions and the potential risks of fetal exposure  
 Adverse event assessment (begins when the subject signs the informed consent form) 
6.2. 
Treatment Period 
The subject will begin treatment upon confirmation of eligibility. For visits within the 
Placebo-controlled Phase and Apremilast Extension Phase, an administrative window of  4 days 
is permitted.  For the Observational Follow-up visit, an administrative window of  2 weeks 
from the last dose of investigational product (IP) is permitted.   
During the treatment period, every effort must be made to ensure that subjects complete the 
subject questionnaires prior to any other study procedure being performed. Subjects 
questionnaires must always be completed prior to any efficacy assessments by the investigator or 
qualified designee.  
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 


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GPSS and DLQI), 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.   
The following evaluations/assessments will be performed at the frequency specified in the 
Table of Events, Table 3: 
 Subject reported outcomes or health-related quality of life (HRQoL) 
 Concomitant medications and therapies evaluation 
 Vital signs 
 Weight  
 Pharmacodynamic blood sampling 
 Hematology panel  
 Chemistry panel  
 Urinalysis 
 Adverse event assessments (continuously) 
 Efficacy assessments (see Section 6.4)  
 Urine dipstick pregnancy test and contraception education (prior to dosing on Day 1) 
 IP dispense, return, and IP tablets count 
 Photographs (optional, refer to Section 6.8) 
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. 
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.   
The following evaluations will be performed as specified in the Table of Events, Table 3: 
 Subject reported outcomes or health-related quality of life (HRQoL) 
 Concomitant medications and therapies evaluation 
 Complete physical examination 
 Vital signs 
 Weight  
 Hematology panel  
 Chemistry panel  


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 Urinalysis 
 Adverse event evaluation  
 Efficacy assessments (see Section 6.4)  
 Serum pregnancy test 
 IP return and IP tablets count 
 Photographs (optional, refer to Section 6.8) 
6.3. 
Observational Follow-up Period 
All subjects will be followed for 28 days after the last dose of IP for AE reporting, as well as any 
serious adverse events (SAEs) made known to the investigator at any time following the 
protocol-required reporting period or end of study-, as described in Section 10.1. 
The following evaluations will be performed at the Follow-up Visit as specified in the Table of 
Events, Table 3. 
 Concomitant medications or therapies evaluation 
 Weight 
 Adverse event evaluation 
6.4. 
Efficacy Assessments  
 Modified static Physician Global Assessment of Genitalia (sPGA-G) 
The modified sPGA-G is the assessment by the investigator of the subject’s psoriasis 
lesions’ overall severity in the genital area (labia majora, labia minora, and perineum 
in females; penis, scrotum, and perineum in males) at the time of evaluation. The 
modified sPGA-G is a 5-point scale ranging from 0 (clear) to 4 (severe), 
incorporating an assessment of the severity of the 3 primary signs of the disease: 
erythema, plaque elevation, and scaling. It is not necessary that all 3 criteria be 
fulfilled. The sPGA of Genitalia score is based on a combination of erythema and the 
secondary features (plaque elevation and/or scale).  Since erythema is the most robust 
finding, it should be the dominant feature influencing the sPGA of Genitalia rating in 
the majority of cases (Merola, 2017). See Appendix A for grading criteria. 
 static Physician Global Assessment (sPGA) 
The sPGA is the assessment by the investigator of the overall disease severity at the 
time of evaluation.  The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), 
incorporating an assessment of the severity of the three primary signs of the disease: 
erythema, scaling and plaque elevation.  When making the assessment of overall 
severity, the investigator should factor in areas that have already been cleared (ie, 
have scores of 0) and not just evaluate remaining lesions for severity, ie, the severity 
of each sign is averaged across all areas of involvement, including cleared lesions.  


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In the event of different severities across disease signs, the sign that is the 
predominant feature of the disease should be used to help determine the sPGA score. 
See (Appendix B) for grading criteria.  
 Body Surface Area (BSA) 
Body surface area is a measurement of involved skin over the whole body.  The 
overall BSA affected by psoriasis is estimated based on the palm area of the subject’s 
hand.  The surface area of the whole body is made up of approximately 100 palms or 
“handprints” (each entire palmar surface or “handprint” equates to approximately 1 
of total body surface area). 
6.5. 
Safety Assessments 
 Contraception Education 
The risks to a fetus or to a nursing child from apremilast are not known at this time.  
Results of animal and in vitro studies can be found in the current IB. 
All 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 Visit or Visit 10.  In addition, a 
local urine pregnancy test kit will be provided by the central laboratory and will be 
performed at the site on all FCBP subjects at the Baseline Visit, prior to dosing. An 
unscheduled serum pregnancy test should be performed if the FCBP subject has 
missed a menstrual period or has a positive urine dipstick test. 
 Hepatitis B and C 
Hepatitis testing will include hepatitis B surface antigen and anti-hepatitis C antibody. 
 Vital Signs, Height, and Weight 
Vital signs, including temperature, pulse, and seated blood pressure, will be taken 
during the visits indicated in Table 3.  Height will be measured and recorded at 
Screening; weight will also be measured and recorded at screening and then as 
indicated in Table 3. Body mass index (BMI) will be calculated at Screening. 


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 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). 
 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. 
 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], 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 dipstick urinalysis (specific gravity, pH, glucose, ketones, 
protein, blood, bilirubin, leukocyte esterase, nitrite, and urobilinogen).  Dipstick 
urinalysis will be performed by the central laboratory; microscopic urinalysis 
(epithelial cells, RBC, WBC, and casts) will be performed only if the dipstick 
urinalysis is abnormal. 
Fasting is not required.  However, if significant elevation of serum lipid(s) is 
observed, a fasting retest should be requested to determine whether or not elevation 
was caused by eating.   


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 Psoriasis Flare Assessments 
Psoriasis flare represents an atypical or unusual worsening of disease during 
treatment (Carey, 2006).  It is defined as a sudden intensification of psoriasis 
requiring medical intervention or a diagnosis of new generalized erythrodermic, 
inflammatory, or pustular psoriasis.  A more typical, gradual worsening of plaque 
psoriasis would not be recorded as an AE.  
 Adverse Events 
Details of AE reporting may be found in Section 10.1. 


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6.7. 
Subject Reported Outcomes  
6.7.1. 
Genital Psoriasis Symptoms Scale (GPSS) 
The GPSS is a patient-administered assessment of 8 symptoms:  itch, pain, 
discomfort, stinging, burning, redness, scaling, and cracking.  Respondents are asked 
to answer the questions based on their psoriasis symptoms in the genital area.   
Numeric rating scales (NRS) are used to assess the self-reported overall severity of 
each of the 8 symptoms individually in the genital area on an 11-point horizontal 
scale anchored at 0 (no) and 10 (worst imaginable).  The overall severity for each 
individual symptom from patient's genital psoriasis is indicated by selecting the 
number from 0 to 10 that best describes the worst level of each symptom in the genital 
area in the past 24 hours. The symptom severity scores, ranging from 0 to 10, are the 
values of the selected numbers indicated by the patient on the instrument’s horizontal 
scale.  Each of the 8 individual items will receive a score of 0 to 10 and will be 
reported as item scores for itch, pain, discomfort, stinging, burning, redness, scaling, 
and cracking.  In addition, a total score ranging from 0 (no genital psoriasis 
symptoms) to 80 (worst imaginable genital psoriasis symptoms) will be reported 
(Gottlieb, 2018). See (Appendix D). 
6.7.2. 
Dermatology Life Quality Index (DLQI)  
The DLQI was developed as a simple, compact, and practical questionnaire for use in 
a dermatology clinical setting to assess limitations related to the impact of skin 
disease (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 


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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 C. 
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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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, Amgen Inc., and labeled appropriately as 
investigational product for this study.   
Apremilast will be provided as 10, 20, or 30 mg tablets in blister cards through Week 20.  
Placebo will be provided as identically appearing 10, 20, or 30 mg tablets in blister cards. 
Beginning at Week 20, apremilast will be provided as 30 mg tablets in high-density polyethylene 
(HDPE) bottles with child-resistant caps. 
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 1:1 to receive either apremilast 30 mg BID or placebo, using a 
centralized Interactive Response Technology (IRT).  Randomization to apremilast arm or 
placebo arm will be stratified by baseline psoriasis-involved body surface area (BSA) ( 10 or 
 10). No more than 60 of subjects with BSA  10 will be enrolled. 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.  Beginning with the Week 20 visit, all 
subjects will receive high-density polyethylene (HDPE) bottles containing APR 30 mg tablets. 
All subjects will receive open-label APR 30 mg BID from Week 20 through Week 32. 


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The treatment schema for dose titration at baseline is shown in Table 4. 
Table 4: 
Treatment Schema for Dose Titration at Visit 2 (Week 0) 
 
Week 0 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6-7 
 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Apremilast 
30 mg BID 
10 mg A 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg P 
30 mg A 
 
 
30 mg A 
 
 
30 mg A 
Placebo 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
 
 
30 mg P 
 
 
30 mg P 
A  Apremilast; BID  twice daily; P  Placebo. 
 
 
 


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


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7.2. 
Treatment Administration and Schedule 
Investigational product will be taken orally twice daily, approximately 12 hours apart, without 
restriction of food or drink.  To mitigate potential gastrointestinal (GI) side effects, dose titration 
will be implemented in this study.  During Week 0 (Days 1-7) 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.  
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 E, Appendix F and Appendix G. 
At Week 20 through Week 32, all subjects will receive apremilast 30 mg tablets in open-label 
HDPE bottles with child-resistant caps. 
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 1:1 to receive either apremilast 30 mg BID or placebo, using a 
centralized Interactive Response Technology (IRT).  Randomization to apremilast arm or 
placebo arm will be stratified by baseline psoriasis-involved body surface area (BSA) ( 10 or 
 10). No more than 60 of subjects with BSA  10 will be enrolled.  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, Amgen, and/or its 
representative. The confirmation reports should be maintained as source documents.  During the 
study visits, the pharmacy or authorized study personnel at the investigational site will dispense 
coded IP kits in accordance with the randomization number assigned by the IRT. 
7.5. 
Packaging and Labeling 
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 


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number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations. 
All IP tablets, including apremilast and identically-appearing placebo, will be supplied by 
Amgen. Investigational product for dose titration at Baseline and at Week 16 will be supplied in 
blister cards. Investigational product tablets at Week 20 and through Week 32 will be supplied in 
open-label HDPE bottles with child-resistant caps. 
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 record a copy in the IRT. 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. 
Amgen (or designee) will review with the investigator and relevant site personnel the process for 
investigational product return, disposal, and/or destruction including responsibilities for the site 
versus Amgen (or designee). 
7.7. 
Investigational Product Compliance 
Study personnel will review the instructions printed on the package with the study subjects prior 
to dispensing the IP.  Investigational product will be dispensed as noted in the Table of Events, 
Table 3.  The subjects will be instructed to return the IP containers, including any unused 
medication, to the study site at each visit for tablet counts and reconciliation as indicated in the 
Table of Events, Table 3.  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, Amgen 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 
Amgen.  Overall compliance with the study treatment regimen is defined as taking between 75 
and 120 of the expected doses during a subject’s participation while in the treatment phases 
(Placebo-controlled Phase and Apremilast Extension Phases) of the study. 


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8. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments. Supportive care may be 
administered at the discretion of the investigator.  
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigators Brochure and/or local package insert. 
8.1. 
Permitted Concomitant Medications and Procedures 
Subjects may take any medication that is not restricted by the protocol and would not be 
expected to interfere with the conduct of the study or affect assessments.  Chronic medication 
should be dosed on a stable regimen. 
All medications (prescription and non-prescription), treatments and therapies taken by the 
subject from screening throughout their entire participation in the study, including those initiated 
prior to the start of the study, must be recorded on the subject’s source document and on the 
appropriate page of the eCRF.  The dose, unit, frequency, route, indication, the date the 
medication was started and the date the medication was stopped (if not ongoing) must be 
recorded.  The recording of any permitted topical medications taken for psoriasis should also 
include the area of the body to which they are applied and the frequency of application. 
The following topical therapies will be permitted during the study: 
 For body and genital lesions: unmedicated emollients 
 For scalp lesions: non-medicated shampoos 
8.2. 
Concomitant Medications Not Recommended 
Co-administration of the strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, 
resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy 
of apremilast. Therefore, the use of strong CYP3A4 enzyme inducers (eg, rifampicin, 
phenobarbital, carbamazepine, phenytoin and St. John’s Wort) with apremilast is not 
recommended during the study. 
8.3. 
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. 


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 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  
 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 
Note: During the Placebo-controlled Phase, the use of antifungal and antiseptic treatment for the 
genital area is prohibited. 
8.4. 
Required Concomitant Medications and Procedures 
Not applicable 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Overview 
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study of the 
efficacy and safety of apremilast (CC-10004) in subjects with moderate to severe genital 
psoriasis (modified sPGA-G  3, moderate or severe). Treatment assignment will be stratified by 
baseline psoriasis-involved body surface area (BSA) ( 10 or  10). No more than 60 of 
subjects with BSA  10 will be enrolled.  
The objective of the statistical analysis is 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 genital psoriasis. 
After all subjects have completed the Placebo-controlled Phase (Weeks 0 to 16), the primary 
analysis will be performed.  At the study completion, ie, when all subjects have also completed 
the Apremilast Extension Phase (Weeks 16 to 32) and the Observational Follow-up Phase, the 
final analysis will be performed. To maintain the blind at the site and subject level, the individual 
subject treatment assignments will not be revealed to the investigators until after the final 
database lock following the study completion. 
9.2. 
Study Population Definitions 
The intent-to-treat (ITT) population will consist of all subjects who are randomized. Subjects 
will be included in the treatment group to which they are randomized. 
The safety population will consist of all subjects who are randomized and received at least one 
dose of IP.  Subjects will be included in the treatment group corresponding to the IP they actually 
receive. 
The per protocol (PP) population will consist of all subjects included in the ITT population who 
receive at least one dose of IP, have both baseline and at least one post-treatment modified 
sPGA-G evaluation, and have no important protocol deviations which may affect analyses in the 
Placebo-controlled Phase. 
9.3. 
Sample Size and Power Considerations 
With a 
total of approximately 286 subjects and a randomization ratio of 1:1, Study PSOR-025 will 
randomize approximately 143 subjects to APR 30 BID and 143 subjects to placebo. This sample 
size will provide 85 power to detect a minimum treatment difference of 15 at Week 16 (25 
for APR 30 BID and 10 for placebo) for the primary endpoint using a chi-square test at a 
2-sided significance level of 0.05 after adjusting for a 20 dropout rate. The sample size 
calculation was done using nQuery. 
 


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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 and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations. 
9.6. 
Efficacy Analysis 
9.6.1. 
Efficacy Evaluation for the Placebo-controlled Phase (Weeks 0 to 16) 
For the Placebo-controlled Phase (Weeks 0-16), the analyses for efficacy endpoints will be based 
on the intent-to-treat (ITT) population, defined as all subjects who are randomized. Statistical 
comparisons will be made between apremilast 30 mg BID and placebo. All statistical tests will 
be at the 2-sided 0.05 significance level and the corresponding p-values and 95 confidence 
intervals (CIs) will be reported. 
9.6.1.1. 
Primary Efficacy Endpoint 
The primary endpoint is the proportions of subjects who achieve modified sPGA-G response at 
Week 16 (defined as modified sPGA-G 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 primary endpoint will be analyzed using the 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., 2011) based on similar subjects who remained in the study as the primary method. 
Details of the MI method will be provided in the Statistical Analysis Plan (SAP). Sensitivity 
analysis will be conducted to account for missing data using the non-responder imputation (NRI) 
method. The last observation carried forward (LOCF) method will only be used for the 
exploratory purpose.  
9.6.1.2. 
Secondary Efficacy Endpoints  
The secondary efficacy endpoints will be analyzed based on the ITT population. The 2-sided 
p-values and 2-sided 95 confidence intervals (CIs) will be reported for treatment difference 
between apremilast and placebo arms. Multiplicity adjustment will be specified in the next 
section. 


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The continuous endpoints will be analyzed using a mixed-effect model for repeated measures 
(MMRM) as the primary method. The MMRM model will use the change or percent change 
from baseline as the response variable and include treatment group, visit time, treatment-by-time 
interaction, and stratification factor as fixed effects, and the baseline value as a covariate. An 
unstructured covariance matrix will be used to model the correlation among repeated 
measurements. The Kenward-Roger adjustment will be used with restricted maximum likelihood 
(REML) to make proper statistical inference. Within-group least-squares (LS) means and the 
associated SEs and 2-sided 95 CIs, treatment differences in LS means and the associated 
2-sided 95 CIs and 2-sided p-values will be derived from the MMRM model. A sensitivity 
analysis will be conducted using the analysis of covariance (ANCOVA) model with treatment 
and stratification factor as the fixed effects, the baseline value as the covariate and the LOCF 
method to impute the missing data. 
The binary endpoints will be analyzed similarly as the primary endpoint using the CMH test 
adjusting for the stratification factor at randomization. The 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., 2011) 
based on similar subjects who remained in the study as the primary method. Sensitivity analysis 
will be conducted to account for missing data using the last observation carried forward (LOCF) 
method and the non-responder imputation (NRI) method.  
9.6.1.3. 
Multiplicity Adjustment 
The primary and secondary efficacy endpoints will be hierarchically ranked for testing in order 
to control the overall type I error rate in claiming statistical significance at the 2-sided 0.05 
significance level. Specifically, for the primary efficacy endpoint (modified sPGA-G response at 
Week 16), if the 2-sided p-value from the comparison between apremilast arm and placebo arm 
is below 0.05, the outcome will be considered statistically significant and apremilast will be 
declared effective. For any secondary endpoint, statistical significance will be claimed only if its 
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 modified sPGA-G score of clear (0) or almost clear (1) 
with at least a 2-point reduction from baseline at Week 16 
 Proportion of subjects achieving an overall sPGA score of clear (0) or almost clear (1) 
with at least a 2-point reduction from baseline at Week 16 
 Proportion of subjects with at least a 4-point improvement in GPI-NRS item score 
within the GPSS for subjects with a baseline score of  4 at Week 16 
 Change from baseline in affected BSA at Week 16 
 Change from baseline in DLQI total score at Week 16 
 Change from baseline in GPSS total score and individual items scores at Week 16 


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9.6.1.4. 
Exploratory Endpoints 
9.6.1.5. 
Subgroup Analysis  
Subgroup analyses for modified sPGA-G response at Week 16 based upon baseline demographic 
(age, gender, race, etc.) or baseline disease characteristics will be provided to determine the 
robustness of the treatment effect. 
9.6.2. 
Efficacy Evaluation – Apremilast Extension Phase (Weeks 16 to 32) 
Efficacy endpoints for time points beyond Week 16 will be summarized according to the 
treatment assigned at randomization. For all subjects, changes in measurements will be 
calculated relative to measurements obtained at baseline (Week 0). Descriptive summary 
statistics or proportion of subjects achieving specified criteria will be summarized by treatment 
group. For continuous variables, descriptive statistics for baseline and changes or percent 
changes from baseline will be provided. Categorical variables will be summarized with 
frequency tabulations.  Two-sided 95 confidence intervals will be provided for changes or 
percent changes and response rates. 
9.7. 
Safety Analysis 
The safety analyses will be performed using the safety population, defined as all subjects who 
are randomized and receive at least one dose of investigational product. Safety will be assessed 
by clinical review of all relevant parameters including treatment-emergent adverse events 
(TEAEs), laboratory tests, and vital signs; no inferential testing for statistical significance will be 
performed. Data from safety assessments will be summarized descriptively for the Placebo-
controlled Phase (Weeks 0 to 16) and the Apremilast Exposure Period when subjects receive 
apremilast treatment. For safety analyses in the Placebo-controlled Phase, baseline will be 
relative to the first dose date following randomization at Week 0. For safety analyses in 
Apremilast Exposure Period, baseline will be relative to the first apremilast dose date at Week 0 
for subjects initially randomized to apremilast or Week 16 for subjects initially randomized to 
placebo and switched to apremilast in the Apremilast Extension Phase (Weeks 16-32). 
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 investigational product. TEAEs leading to death or to 
discontinuation from treatment and serious adverse events will be summarized and listed 
separately. 
Data from other safety assessments will be summarized descriptively. Shift tables for laboratory 
parameters showing the number of subjects with values low, normal, and high comparing with 
the normal reference ranges pre-treatment versus post treatment will be provided. 
To account for the different exposure to the investigational product, adverse events or marked 
laboratory abnormalities will also be summarized using the exposure adjusted incidence rate, in 
addition to the simple incidence rates. 


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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 
data restriction will be performed, the primary data analysis will be conducted and a Week 16 
Clinical Study Report will be generated. However, unblinded data will only be made available to 
select Sponsor and Contract Research Organization (CRO) team members involved with analysis 
of the data and preparation of the Week 16 Clinical Study Report. All other Sponsor, site, and 
CRO personnel directly involved with the conduct of the study, will remain blinded to treatment 
assignments until the final database lock at the conclusion of the study.  At the end of the study, 
after all subjects have completed, or have been discontinued from the Apremilast Extension 
Phase (Weeks 16 to 32) and the Observational Follow-up Phase, the final analysis will be 
performed and a final Clinical Study Report will be generated. 
9.9. 
Other Topics 
9.9.2. 
Investigational Product Compliance 
Investigational product record information will be summarized.  Overall compliance will be 
estimated by the proportion of subjects who take between 75 and 120 of the intended 
quantity of IP. 
9.9.3. 
Concomitant Therapy 
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations. The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health 
Organization (WHO) will be used to group medications into relevant categories for these 
tabulations. 
 


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10. 
ADVERSE EVENTS 
10.1. 
Monitoring, Recording and Reporting of Adverse Events 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE/SAE 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 which meets the definition of 
an adverse event, should be reported as an AE on the CRF. If the sequela of an overdose meets 
serious criteria, then it must be marked as serious on the CRF and the paper SAE report form. 
The overdose itself should not be reported as an AE. 
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for apremilast overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician. 
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures. 
All AEs will be recorded by the investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP as well as all SAEs made known to the investigator at any 
time following the protocol-required reporting period or after end of study.  All adverse events 
(serious/non-serious) will be recorded on the CRF, the paper SAE report form (for SAEs) and in 
the subject’s source documents.  All SAEs must be reported to Amgen Global Patient Safety 
within 24 hours of the Investigator’s knowledge of the event by recording on the CRF and 
submitting the SAE information using the paper Serious Adverse Event Report Form by 
facsimile/email directly to Amgen Global Patient Safety.   
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; 


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


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


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10.2.3. 
Causality 
The investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected: 
a causal relationship of the 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 
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 
non-IP that has not been manufactured or provided by Amgen, please provide the name of the 
manufacturer when reporting the event. 
10.2.4. 
Duration 
For each AE, the investigator will provide a record of the start and stop dates of the event. 
10.2.5. 
Action Taken 
The investigator will report the action taken with IP as a result of each AE, as applicable 
(eg, discontinuation, interruption, or dose modification, as appropriate) and report if concomitant 
and/or additional treatments were given for the event.  
10.2.6. 
Outcome 
The investigator will report the outcome of the event for each AE. 
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE). 
10.3. 
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
 results in discontinuation from the study; 
 requires treatment, modification/ interruption of IP dose, or any other therapeutic 
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 is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity or is an exacerbation or worsening of an existing 
condition. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded as the AE on the CRF.  If the abnormality was not a part of a 
diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets). 
10.4. 
Pregnancy 
All pregnancies or suspected pregnancies occurring in females of childbearing potential are 
immediately reportable events.   
10.4.1. 
Females of Childbearing Potential – Collection of Pregnancy Information 
Pregnancies and suspected pregnancies (including elevated -subunit of human chorionic 
gonadotropin [-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 
Amgen Global Patient  Safety immediately by email or facsimile, or other appropriate method, 
using the Pregnancy Notification Form or approved equivalent form (refer to Appendix I).  The 
Pregnancy Notification Form must be submitted to Amgen Global Patient Safety within 24 hours 
of learning of a subject’s pregnancy. (Note:  Sites are not required to provide any information on 
the Pregnancy Notification Form that violates the country or regions local privacy laws).  
After obtaining the female subject’s signed consent for release of pregnancy and infant health 
information, the investigator will collect pregnancy and infant health information and complete 
the pregnancy questionnaire for any female subject who becomes pregnant while taking IP 
through 28 days of the subject’s last dose of IP. This information will be forwarded to Amgen 
Global Patient Safety. Generally, infant follow-up will be conducted 12 months after the birth of 
the child (if applicable). 
The investigator will follow the female subject until completion of the pregnancy and must 
notify Amgen Global Patient Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome).  
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 Amgen Global Patient Safety by facsimile, email or 
other appropriate method, within 24 hours of the investigator’s knowledge of the event using the 
paper SAE Report Form. 


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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 Amgen Global Patient Safety 
by facsimile, email, or other appropriate method, within 24 hours of the investigator’s knowledge 
of the event using the paper SAE Report Form. 
10.4.2. 
Male Subjects With Partners Who Become Pregnant  
In the event a male subject fathers a child during treatment, and for an additional 28 days after 
discontinuing IP, the information will be recorded on the Pregnancy Notification Form (refer to 
Appendix I). The form must be submitted to Amgen Global Patient Safety with 24 hours of the 
investigator’s/site’s awareness of the pregnancy (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions local 
privacy laws).  
The investigator will attempt to obtain a signed consent for release of pregnancy and infant 
health information directly from the pregnant female partner to obtain additional pregnancy 
information.    
After obtaining the female partner’s signed consent for release of pregnancy and infant health 
information the investigator will collect pregnancy outcome and infant health information on the 
pregnant partner and her baby and complete the pregnancy questionnaires. This information will 
be forwarded to Amgen Global Patient Safety. 
Generally, infant follow-up will be conducted up to 12 months after the birth of the child (if 
applicable).  
Any termination of the pregnancy will be reported to Amgen Global Patient Safety regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.    
10.4.3. 
Collection of Lactation Information  
 Investigator will collect lactation information on any female subject who breastfeeds 
while taking IP through 28 days post last dose of IP.   
 Information will be recorded on the Lactation Notification Form (refer to Appendix J) 
and submitted by facsimile or email to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  
 Study treatment will be discontinued if female subject breastfeeds during the study. 
With the female subjects signed consent for release of mother and infant health information, the 
investigator will collect mother and infant health information and complete the lactation 
questionnaire on any female subject who breastfeeds while taking IP through 28 days after 
discontinuing IP.  
10.5. 
Reporting of Serious Adverse Events 
Any AE that meets any criterion for an SAE requires the completion of the relevant CRFs and 
the paper SAE report form. All SAEs must be reported to Amgen Global Patient Safety by 
recording them on the CRF and sending the SAE data/information using the paper SAE report 


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form within 24 hours of the Investigator’s knowledge of the event. In This instruction pertains to 
the initial reporting of an SAE as well as reporting any follow-up information. 
The investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) and all 
SAEs made known to the Investigator at any time following the protocol-required reporting 
period or after end of study.   Serious adverse events occurring prior to treatment (after signing 
the ICF) will be collected/recorded and reported.   
Where required by local legislation, the investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
source documents and all correspondence with the IRB/EC. 
Serious Adverse Event Reporting transmitted via paper Serious Adverse Event Report 
Form:  
 Facsimile transmission of the Serious Adverse Event Report Form is the preferred 
method to transmit this information. If facsimile is unavailable, the email method to 
transmit this information is acceptable (refer to Appendix H).  
 In rare circumstances and in the absence of facsimile equipment, this form may be sent 
via email, or notification by telephone is acceptable with a copy of the Serious Adverse 
Event Report Form in English language sent by overnight mail or courier service. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated 
reporting timeframes.   
 Once the study has ended, serious adverse events (regardless of causality) should be 
reported to Amgen Global Patient Safety if the investigator becomes aware of them and 
may use the paper Serious Adverse Event Report Form (refer to Appendix H). 
10.5.1. 
Safety Queries 
Queries pertaining to SAEs will be communicated/generated from Amgen Global Patient Safety 
to the site via Amgen’s safety query paper process or other appropriate method.   
10.6. 
Expedited Reporting of Adverse Events 
For the purpose of regulatory reporting, Amgen Global Patient Safety will determine the 
expectedness of events suspected of being related to apremilast based on the Investigator’s 
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. 
Amgen or its authorized representative shall notify the investigator of the following information 
 Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR); 


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 Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects. 
The investigator must keep copies of all pertinent safety information on file including 
correspondence with the IRB/EC.  (See Section 14.3 for record retention information). 
Amgen Global Patient Safety Contact Information (fax/email): 
For Amgen Global Patient Safety contact information, please refer to your site’s paper Serious 
Adverse Event Report Form, paper Pregnancy Notification Form and/or paper Lactation 
Notification Form (Appendix H, Appendix I, Appendix J). 
 


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11. 
DISCONTINUATIONS 
11.1. 
Treatment Discontinuation 
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s): 
 Adverse Event 
 Lack of efficacy 
 Withdrawal by subject 
 Death 
 Lost to follow-up 
 Non-compliance with IP 
 Protocol deviation 
 Pregnancy 
 Physician decision 
 Study terminated by Sponsor 
 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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 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. 
 


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12. 
EMERGENCY PROCEDURES 
12.1. 
Emergency Contact 
In emergency situations, the investigator should use their medical judgement to provide 
appropriate medical care of clinical trial subjects.  The Investigator may also 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, the investigator may also contact the Amgen Medical Information number at 1- 800-77-
AMGEN (1 800-772-6436). The representatives are responsible for obtaining your call-back 
information and contacting the on-call Amgen/contract research organization Medical Monitor, 
who will then contact you promptly. 
12.2. 
Emergency Identification of Investigational Products 
The blind must not be broken during the course of the study unless in the opinion of the 
investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the investigator, continuing IP can negatively affect the outcome of the subject’s treatment.   
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, the investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject.  
The investigator should ensure that the code is broken only in accordance with the protocol.  The 
investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the investigator in the 
subject’s source documentation. 
Emergency unblinding should only be performed by the investigator through the IRT by using an 
emergency unblinding personal identification number (PIN), and the investigator should call IRT 
for unblinded dose information. 
 


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13. 
REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Amgen, its authorized representative, and 
investigator abide by Good Clinical Practice (GCP), as described in International Conference on 
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.  Amgen 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 Amgen 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 Amgen on public registry websites) is considered Amgen confidential 
information.  Only information that is previously disclosed by Amgen on a public registry 
website may be freely disclosed by the investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Amgen 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 Amgen.  Information proposed for posting on the investigator’s or their 
institution’s website must be submitted to Amgen 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, Amgen will provide 
investigators with a summary of the results that is written for the lay person.  The investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject. 


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13.3. 
Subject Information and Informed Consent 
The investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures. 
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the investigator’s 
study files and a copy given to the study subject. 
13.4. 
Confidentiality 
Amgen 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). Amgen requires 
the investigator to permit Amgen '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 Amgen 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/EC approval but will be submitted to the IRB/EC 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 Amgen or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 


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Amgen 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 Amgen 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 
Amgen 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 Amgen has the right to discontinue a single site at any time during 
the study for medical or administrative reasons such as: 
 Unsatisfactory enrollment; 
 GCP noncompliance; 
 Inaccurate or incomplete data collection; 
 Falsification of records; 
 Failure to adhere to the study protocol. 
 


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14. 
DATA HANDLING AND RECORDKEEPING  
14.1. 
Data/Documents 
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM. 
14.2. 
Data Management 
Data will be collected via CRF and entered into the clinical database per Amgen standard 
operating procedures (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, Amgen, 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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 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 Amgen 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 Amgen prior to destruction of any records. 
If the investigator is unable to meet this obligation, the investigator must ask Amgen 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. The 
investigator or institution should take measures to prevent accidental or premature destruction of 
these documents. 
 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
All aspects of the study will be carefully monitored by Amgen 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 
Amgen 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, an 
Amgen 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 Amgen 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 Quality, Compliance & Audit, Learning & 
Performance unit exists within Amgen.  Representatives of this unit will conduct audits of 
clinical research activities in accordance with Amgen 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 Amgen 
immediately. 
15.3. 
Product Complaint 
A product complaint (PC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product or device after they are released for distribution to 
market or clinic by either Amgen or by distributors, and partners with whom Amgen 
manufactures the material.  This includes any drugs, devices, or combination products 
provisioned and/or repackaged/modified by Amgen.  Drugs or devices include investigational 


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product.  Any product complaints associated with an investigational product, or non-
investigational products or devices supplied by Amgen are to be reported according to the 
instructions provided in the Investigational Product Instruction Manual or equivalent.  
If you become aware of a suspected PC, you are obligated to report the issue within 24 hours of 
discovery or notification of the concern or irregularity.  Amgen requires notification of any 
concern or irregularity at any stage of the study. 
 
How to Report a Product Complaint to Amgen:   
Complete Amgen’s paper Clinical Product Complaint Intake Form and email the form to the 
following Amgen email address: Clinical-Complaint-Intake@amgen.com 
 


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16. 
PUBLICATIONS 
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Amgen on public registry websites, is considered 
Amgen confidential information and is not to be used in any publications.  Amgen protocol-
related information proposed for use in a publication must be submitted to Amgen for review and 
approval and should not be utilized in a publication without express written approval from 
Amgen, or as described in the Clinical Trial Agreement. 
Amgen will ensure Amgen -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 2 and 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 authorship will be in alignment with ICMJE authorship criteria and be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, and contribution to abstract, presentation 
and/or publication development. 
 


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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. 
Cather J, Meeuwis K, Burge R, Bleakman AP, Lin CY, Ryan C. Ixekizumab provides greater 
improvement versus placebo on the impact of genital psoriasis on sexual activity for patients 
with moderate-to-severe genital psoriasis in a randomized, double-blind phase 3b clinical trial. 
Presented at: American Academy of Dermatology Annual Meeting; February 16-20, 2018; San 
Diego, CA.  
Chan CS, Van Voorhees AS, Lebwohl MG, Korman NJ, Young M, Bebo BF Jr, et al. Treatment 
of severe scalp psoriasis: From the Medical Board of the National Psoriasis Foundation. J Am 
Acad Dermatol. 2009;60(6):962-71.  
Committee for Medicinal Products for Human Use (CHMP) Guideline on Clinical Investigation 
of Medicinal Products Indicated for the Treatment of Psoriasis, 2005 (CHMP/EWP/2454/02 
corr). 
Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI): a simple practical measure for 
routine clinical use.  Clin Exp Dermatol.  1994;19(3):210-6. 
Gottlieb AB, Matheson RT, Menter A, Leonardi CL, Day RM, Hu C, et al. Efficacy, tolerability, 
and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. 
J Drugs Dermatol. 2013;12(8):888-97. 
Gottlieb A, Kirby B, Ryan C, Naegeli A, Burge R, Potts Bleakman A, et al. The development of 
the genital psoriasis sexual frequency questionnaire (GenPs-SFQ) to assess the impact of genital 
psoriasis on sexual health.  Dermatol Ther (Heidelb). 2018;8(1):33-44.  
Gottlieb A, Kirby B, Ryan C, Naegeli A, Burge R, Potts Bleakman A, et al. The development of 
a patient-reported outcome measure for assessment of genital psoriasis symptoms: The Genital 
Psoriasis Symptoms Scale (GPSS). Dermatol Ther (Heidelb). 2018;8(1):45-56. 
Guglielmetti A, Conlledo R, Bedoya J, Ianiszewski F, Correa J. Inverse psoriasis involving 
genital skin folds: successful therapy with dapson. Dermatol Ther (Heidelb). 2012;2(1):15. 
Kragballe K, Menter A, Lebwohl M, Tebbey PW, van de Kerkhof PC, International Psoriasis 
Council. Long-term management of scalp psoriasis: perspectives from the International Psoriasis 
Council. J Dermatolog Treat. 2013;24(3):189-92. 
Meeuwis KA, De Hullu JA, Massuger LF, Van de Kerkhoff PC, Van Rossum MM. Genital 
Psoriasis: A systematic literature review on this hidden skin disease. Acta Derm Venereol. 
2011;91(1):5-11.  


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Meeuwis KA, De Hullu JA, Inthout J, Hendriks IM, Sparreboom EE, Massuger LF, et al. Genital 
psoriasis awareness program: Physical and psychological care for patients with genital psoriasis. 
Acta Derm Venereol. 2015;95(2):211-6. 
Menter A. The treatment of genital psoriasis. S026: Presented at: American Academy of 
Dermatology Annual Meeting; February 16-20, 2018; San Diego, CA. 
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, et al. 
Guidelines of care for the management of psoriasis and psoriatic arthritis Section 1. Overview of 
psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad 
Dermatol. 2008;58(5):826-50.  
Merola JF, Bleakman AP, Gottlieb AB, Menter A, Naegeli AN, Bissonnette R, et al. The static 
physician’s global assessment of genitalia: a clinical outcome measure for the severity of genital 
psoriasis. J Drugs Dermatol. 2017;16(8):793-799. 
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(6):715-22. 
Papp K, Canadian Psoriasis Guidelines Committee. Canadian Guidelines for the Management 
of Plaque Psoriasis, June 2009. 
Ryan C, Sadlier M, de Vol E, Patel M, Lloyd AA, Day A, et al. Genital psoriasis is associated 
with significant impairment in quality of life and sexual functioning. J Am Acad Dermatol 
2015;72(6):978-83. 
Ryan C, Menter A, Guenther L, Blauvelt A, Bissonnette R, Yang FE, et al.  Efficacy and Safety 
of Ixekizumab in a randomized, double-blinded, placebo-controlled, Phase 3b clinical trial in 
patients with moderate to severe genital psoriasis. Presented at the European Academy of 
Dermatology and Venereal Disease: September 13-17, 2017; Geneva, Switzerland. 
SAS Institute Inc. 2011. SAS/STAT 9.3 User’s Guide. Cary, NC: SAS Institute Inc. 
Schmid-Ott G, Kuensebeck HW, Jaeger B. Validity study for the stigmatization experience in 
atopic dermatitis and psoriasis. Acta Derm Venereol. 1999;79(6):443-7. 
Van Voorhees AS, Feldman SR, Koo JYM, Lebwohl M, Menter A, Ritchlin C, et al. The 
Psoriasis and Psoriatic Arthritis Pocket Guide: Treatment Algorithms and Management Options 
(4th ed) 2016, National Psoriasis Foundation. www.psoriasis.org. 
WHO Global Report on Psoriasis 2016. www.who.int. 
Yosipovitch G, Goon A, Wee J, Chan YH, Goh CL. The prevalence and clinical characteristics 
of pruritus among patients with extensive psoriasis. Br J Dermatol. 2000;143(5):969-73. 


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18. 
APPENDICES 
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 
APR 
Apremilast 
AST 
Aspartate aminotransferase (SGOT) 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice daily 
BSA 
Body surface area 
cAMP 
Cyclic adenosine monophosphate 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 
CIN 
Cervical intraepithelial neoplasia 
CMH 
Cochran-Mantel-Haenzel 
CO2 
Carbon dioxide 
CRO 
Contract research organization 
eCRF 
Electronic case report form 
CRF 
Case report form 
CSR 
Clinical Study Report 
CYP3A4 
Cytochrome P450 3A4 
DLQI 
Dermatology Life Quality Index 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOT 
End of treatment 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


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Abbreviation or 
Specialist Term 
Explanation 
GI 
Gastrointestinal 
GPI-NRS 
Genital Psoriasis Itch Numeric Rating Scale 
GPSS 
Genital Psoriasis Symptoms Scale 
HDPE 
High-density polyethylene 
HDL 
High-density lipoprotein 
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 on Harmonisation 
IL 
Interleukin 
IND 
Investigational New Drug 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Integrated Response Technology 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
LDH 
Lactate dehydrogenase 
LOCF 
Last observation carried forward 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MMRM 
Mixed-effect model for repeated measures 
NRI 
Non-responder imputation 
NRS 
Numeric rating scale 
PASI 
Psoriasis Area and Severity Index 
PDE4 
Phosphodiesterase type 4 
PO 
By mouth 
PP 
Per protocol 
PC 
Product Complaint 


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Abbreviation or 
Specialist Term 
Explanation 
PUVA 
Psoralen and ultraviolet A 
RBC 
Red blood cell count 
REML 
Restricted maximum likelihood 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
ScPGA 
Scalp Physician Global Assessment 
SE 
Standard error 
SGOT 
Serum glutamic oxaloacetic transaminase  
SGPT 
Serum glutamic pyruvic transaminase 
sPGA-G 
Static Physician Global Assessment of Genitalia 
sPGA 
Static Physician Global Assessment 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TNF 
Tumor necrosing factor 
TNF- 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
UV 
Ultraviolet 
UVB 
Ultraviolet B 
WBC 
White blood cell count 
WHO 
World Health Organization 
 


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APPENDIX A. THE MODIFIED STATIC PHYSICIAN GLOBAL 
ASSESSMENT OF GENITALIA (sPGA-G) 
 
Score 
Category 
Category Description 
0 
Clear 
Erythema: no erythema (except for residual 
hyperpigmentation/hypopigmentation) 
Plaque elevation: no elevation 
Scaling: no scale 
1 
Almost clear 
Erythema: faint, light pink erythema 
Plaque elevation: elevation is very slight and difficult 
to confirm 
Scaling: some fine, white surface dryness 
2 
Mild 
Erythema: mild, pink erythema 
Plaque elevation: slight elevation with sloped edges 
Scaling: fine scale on some or most lesions 
3 
Moderate 
Erythema: moderate, red erythema 
Plaque elevation: moderate elevation with definite 
edges that are either sloped or rough  
Scaling: coarse scale on most lesions 
4 
Severe 
Erythema: severe, bright red or deep red erythema  
Plaque elevation: substantial elevation, hard and sharp 
edges 
Scaling: coarse scale on most to all lesions 
 
Adapted from source: Merola, 2017. 


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APPENDIX B. STATIC PHYSICIAN GLOBAL ASSESSMENT (sPGA) OF 
WHOLE BODY PSORIASIS 
 
Score 
Category 
Description 
0 
Clear 
Plaque Elevation  0 (no elevation over normal skin) 
Scaling  0 (no evidence of scaling) 
Erythema  0 (except for residual hyperpigmentation/ 
hypopigmentation) 
1 
Almost Clear 
Plaque Elevation   (possible but difficult to ascertain 
whether there is a slight elevation above normal skin) 
Scaling   (surface dryness with some desquamation) 
Erythema   (faint, diffuse pink or slight red coloration) 
2 
Mild 
Plaque Elevation  slight (slight but definite elevation, 
typically edges are indistinct or sloped) 
Scaling  fine (fine scale partially or mostly covering 
lesions) 
Erythema  mild (light red coloration) 
3 
Moderate 
Plaque Elevation  marked (marked definite elevation 
with rough or sloped edges) 
Scaling  coarser (coarser scale covering most or all of the 
lesions) 
Erythema  moderate (definite red coloration) 
4 
Severe 
Plaque Elevation  marked (marked elevation typically 
with hard or sharp edges) 
Scaling  coarser (coarse, non-tenacious scale 
predominates covering most or all of the lesions) 
Erythema  severe (very bright red coloration) 
 
 


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APPENDIX C. THE DERMATOLOGY LIFE QUALITY INDEX (DLQI) 
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE 
LAST WEEK.  Please check one box for each question. 
1.  Over the last week, how itchy, sore, painful or stinging 
has your skin been?  
_ Very much _ A 
lot _ A little _ Not 
at all  
 
2.  Over the last week, how embarrassed or self 
conscious have you been because of your skin?  
_ Very much _ A 
lot _ A little _ Not 
at all  
 
3.  
Over the last week, how much has your skin interfered 
with you going shopping or looking after your home or 
yard?  
_ Very much _ A 
lot _ A little _ Not 
at all  
 
_ Not relevant  
4.  Over the last week, how much has your skin influenced 
the clothes you wear?  
_ Very much _ A 
lot _ A little _ Not 
at all  
 
_ Not relevant  
5.  Over the last week, how much has your skin affected any 
social or leisure activities?  
_ Very much _ A 
lot _ A little _ Not 
at all  
 
_ Not relevant  
6.  Over the last week, how much has your skin made it 
difficult for you to do any sport?  
_ Very much _ A 
lot _ A little _ Not 
at all  
 
_ Not relevant  
7.  Over the last week, has your skin prevented you from 
working or studying?  
_ Yes _ No  
_ Not relevant  
 
If “No”, over the last week how much has your skin been 
a problem at work or studying?  
_ A lot _ A little 
_ Not at all  
 
 
 
 


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8.  
Over the last week, how much has your skin created 
problems with your partner or any of your close friends 
or relatives?  
_ Very much _ A 
lot _ A little _ Not 
at all 
 
_ Not relevant 
9.  
Over the last week, how much has your skin caused any 
sexual difficulties? 
_ Very much _ A 
lot _ A little _ Not 
at all 
 
_ Not relevant 
10.  
Over the last week, how much of a problem has the 
treatment for your skin been, for example, by making 
your home messy, or by taking up time? 
_ Very much _ A 
lot _ A little _ Not 
at all 
 
_ Not relevant 
Finlay, 1994. 
 


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APPENDIX D. GENITAL PSORIASIS SYMPTOMS SCALE (GPSS) 
Please answer the questions based on your psoriasis symptoms in the genital area within the 
past 24 hours. Genital area is defined as the labia majora (outer lip), labia minora (inner lip), 
and perineum (area between vagina and anus) for females; penis, scrotum, and perineum (are 
between the penis and anus) for males. 
1. Please rate your itching severity due to your genital psoriasis by selecting 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 
No itch 
 
 
 
 
 
 Worst itch  
imaginable 
 
2.  Please rate your pain severity due to your genital psoriasis by selecting the number that best 
describes your worst level of pain in the past 24 hours. 
 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
 9 
10 
No pain 
 
 
 
 
 
Worst pain  
imaginable 
 
3.  Please rate your discomfort severity due to your genital psoriasis by selecting the number 
that best describes your worst level of discomfort in the past 24 hours. 
 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
 9 
10 
   No  
discomfort 
 
 
 
 
 
    Worst  
 discomfort  
 imaginable 
 
 
 
 
 
 
 
 
4.  Please rate your stinging severity due to your genital psoriasis by selecting the number that 
best describes your worst level of stinging in the past 24 hours. 
 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
 9 
10 
   No  
stinging 
 
 
 
 
 
    Worst  
   stinging  
 imaginable 
5.  Please rate your burning severity due to your genital psoriasis by selecting the number that 
best describes your worst level of burning in the past 24 hours. 


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    0 
1 
2 
3 
4 
5 
6 
7 
8 
 9 
10 
   No  
burning 
 
 
 
 
 
    Worst 
   burning 
 imaginable 
 
6.  Please rate your redness severity due to your genital psoriasis by selecting the number that 
best describes your worst level of redness in the past 24 hours. 
 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
 9 
10 
   No  
redness 
 
 
 
 
 
    Worst  
   redness  
 imaginable 
 
7.  Please rate your scaling severity due to your genital psoriasis by selecting the number that 
best describes your worst level of scaling in the past 24 hours. 
 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
 9 
10 
   No  
scaling 
 
 
 
 
 
    Worst  
   scaling  
 imaginable 
 
8.  Please rate your cracking severity due to your genital psoriasis by selecting the number that 
best describes your worst level of cracking in the past 24 hours. 
 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
 9 
10 
   No  
cracking 
 
 
 
 
 
     Worst  
   cracking  
  imaginable 
Gottlieb, 2018 
 
 
 
 
 
 


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APPENDIX E. TITRATION BLISTER CARD CONFIGURATION 
 


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APPENDIX F. ACTIVE TREATMENT DUMMY TITRATION BLISTER 
CARD CONFIGURATION 
 


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APPENDIX G. PLACEBO TREATMENT BLISTER CARD 
CONFIGURATION 
 
 
 
 
 
 
 


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APPENDIX H. SAMPLE SERIOUS ADVERSE EVENT REPORT FORM 
 
 
 
 


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APPENDIX I. PREGNANCY NOTIFICATION FORM 
 
 
 
 
 
 
 
 


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APPENDIX J. LACTATION NOTIFICATION FORM 
 


Apremilast 
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CC-10004-PSOR-025 Amendment 3.0 Final:  03 March 2021 
– SUMMARY OF CHANGES – 
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 GENITAL PSORIASIS 
AMENDMENT NO. 3.0 
PROTOCOL NUMBER: 
 
CC-10004-PSOR-025  
ORIGINAL DATE: 
 
31 Oct 2018 
AMENDMENT No. 1.0 DATE: 
 
22 May 2019 
AMENDMENT No. 2.0 DATE: 
 
01 May 2020 
AMENDMENT No. 3.0 DATE: 
 
03 Mar 2021 
EudraCT NUMBER: 
 
2018-002608-15 
NCT NUMBER: 
 
NCT03777436 
IND NUMBER:  
 
070270  
Contact Information:  
 
 Name: 
, MD, PhD 
 Title: 
Clinical Research Medical Director 
 Address:  
One Amgen Center Drive, Thousand Oaks, CA 
91320 
 Phone: 
 
 E-mail: 
 
Note: Only call Amgen Medical Information if you are not able to reach the Clinical 
Research Physician(s) or Medical Monitor or designee for emergency calls. 
CONFIDENTIALITY NOTICE 
This document contains confidential information of Amgen. This document must not be 
disclosed to anyone other than the site study staff and members of the institutional review 
board/independent ethics committee/institutional scientific review board or equivalent.  
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen. If you have any questions regarding how this document may be used or shared, 
call the Amgen Medical Information number: 1-800-77-AMGEN. 
Amgen Medical Information: 1- 800-77-AMGEN (1-800-772-6436) 


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JUSTIFICATION FOR AMENDMENT 
The purpose of this amendment is to facilitate study enrollment.  The following changes were 
made to the protocol, dated 03 March 2021: 
 Specified that the strata with BSA  10 will take  40 of the total enrollment in 
Section 1.3.2 Rationale for the Study Design 
 Updated  of subjects with BSA  10 that will be enrolled in Section 3.1 Study 
Design, Section 7.1 Description of Investigational Product(s), Section 7.4 Method of 
Treatment Assignment, and Section 9.1 Overview 
 Updated sample size in Section 1.3.2 Rationale for the Study Design, Section 3.1 Study 
Design, Section 4.1 Number of Subjects, and Section 9.3 Sample Size and Power 
Considerations 
 Updated the approximate number of subjects that will be randomized to each treatment 
group based on the revised sample size and how the sample size calculation was done in 
Section 9.3 Sample Size and Power Considerations  
 Updated the power calculation based on the change in sample size in Section 9.3 Sample 
Size and Power Considerations 
 Provided minor updates to Section 1.2 Compound Background 
 Provided updates to the Medical Monitor/Emergency Contact Information  
 Deleted Celgene Therapeutic Area Head Signature Page to conform to the Amgen 
template 
 Grammatical and typographical changes were made throughout the protocol. 


EDMS Doc. Number: 24687252 - 23738481
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CC-10004-PSOR-025 Amendment 2.0 Final:  01 May 2020
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 2.0
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 GENITAL PSORIASIS
INVESTIGATIONAL PRODUCT (IP):
CC-10004 (apremilast)
PROTOCOL NUMBER:
CC-10004-PSOR-025
ORIGINAL DATE:
31 Oct 2018
AMENDMENT No. 1.0 DATE:
22 May 2019
AMENDMENT No. 2.0 DATE:
01 May 2020
EudraCT NUMBER:
2018-002918-12
NCT NUMBER:
NCT03777436
IND NUMBER: 
070270
Contact Information: 
Name:
, MD
Title:
Senior Director, Global Development
Address: 
One Amgen Center Drive, Thousand Oaks, CA 91320
Phone:
E-mail:
Note: Only call Amgen Medical Information if you are not able to reach the Clinical 
Research Physician(s) or Medical Monitor or designee for emergency calls.
CONFIDENTIALITY NOTICE
This document contains confidential information of Amgen. This document must not be 
disclosed to anyone other than the site study staff and members of the institutional review 
board/independent ethics committee/institutional scientific review board or equivalent.  
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen. If you have any questions regarding how this document may be used or shared, 
call the Amgen Medical Information number: 1-800-77-AMGEN.
Amgen Medical Information: 1- 800-77-AMGEN (1-800-772-6436)


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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, MD – VP and Head of Immunology & Fibrosis Clinical 
Development
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.
NOTE: Signed by Celgene based on approval from Amgen Therapeutic Head, Primal 
Kaur


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CC-10004-PSOR-025 Amendment 2.0 Final:  01 May 2020
JUSTIFICATION FOR AMENDMENT
The purpose of this amendment is to update the change in Sponsor, as well as key contact and 
emergency information, and to update safety reporting and product complaints to align with 
Amgen processes.
Significant changes included in this amendment are summarized below:

All references to “Celgene Corporation” were removed and replaced with “Amgen Inc.” 
and “Celgene” changed to “Amgen” throughout the protocol. 

Cover Pages were updated with Amgen contact information

Section 6 Procedures was updated to align with Amgen Global Drug Safety processes

Section 10.1 Monitoring, Recording and Reporting of Adverse Events was updated to 
align with Amgen Global Drug Safety processes. 

Section 10.4 Pregnancy was modified according to the Amgen Global Drug Safety 
process:
o
Collection of Pregnancy Information and Infant Health Information
o
Collection of information: Male Subjects with Partners Who Become Pregnant 
o
Collection of Lactation Information

Section 10.5 Reporting of Serious Adverse Events was updated to include instructions for 
paper reporting of SAEs 

Section 12.1 Emergency Contact was updated with Amgen emergency contact 
information.

Section 15.3 Product Complaint section was modified according to the Amgen product 
complaint reporting process
The amendment also includes addition of forms, minor clarifications and corrections to 
align with Amgen processes:

Section 7.6 Investigational Product Accountability and Disposal

Section 15.2 Audits and Inspections

Section 16 Publications

Appendix H Sample Serious Adverse Event Form was added

Appendix I Pregnancy Notification Form was added 

Appendix J Lactation Notification Form was added


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CC-10004-PSOR-025 Amendment 1.0 Final: 22 May 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 1.0
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 GENITAL PSORIASIS
INVESTIGATIONAL PRODUCT (IP):
CC-10004 (apremilast)
PROTOCOL NUMBER:
CC-10004-PSOR-025
ORIGINAL DATE:
31 Oct 2018
AMENDMENT No. 1.0 DATE:
22 May 2019
EudraCT NUMBER:
2018-002608-15
IND NUMBER: 
070270
Contact Information: 
Name:
, MD
Title:
Senior Director, Clinical Research and Development
Address: 
86 Morris Avenue, Summit, NJ 07901
Phone:
E-mail:
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.


EDMS Doc. Number: 23738290 - 23738481
Apremilast
Summary of Changes CC-10004-PSOR-025
Celgene Corporation
Confidential and Proprietary
2
CC-10004-PSOR-025 Amendment 1.0 Final: 22 May 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, MD     Vice President, Clinical Research and Development
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.


EDMS Doc. Number: 23738290 - 23738481
Apremilast
Summary of Changes CC-10004-PSOR-025
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PSOR-025 Amendment 1.0 Final: 22 May 2019
1.
JUSTIFICATION FOR AMENDMENT
In addition to administrative updates, changes in this amendment include requests from the 
Federal Institute for Drugs and Medical Devices (Bundesinstitut fur Arzeneimittel und 
Medizinprodukte [BfArM]) that are summarized below:

Administrative change to be consistent with the document
Revised Section: Protocol Summary, Study Population

Revised sentence to reflect citations.
Revised Section: Section 1.3.1 Study Rationale and Purpose

Removed wording “for whom topical therapy is inappropriate”
Revised Sections: Section 1.3.2, Rationale for Study Design and Section 4.2, 
Inclusion Criterion 8

Removed reference to a Study Manual
Revised Section: Section 6, Procedures

Added a footnote for contraception Option 2 which states that Option 2 may not be an 
acceptable contraception option in all countries per local guidelines/regulations
Revised Section: Section 4.2, Inclusion Criterion 11

Added section to include language about strong cytochrome P450 3A4 inducers
Added Section: Section 8.2, Concomitant Medications Not Recommended

Removed blinded language in reference to the Apremilast Extension Phase and added
dispensation of bottles at Week 20
Revised Sections: Protocol Summary, Section 7.1, Description of Investigational 
Product; Section 7.2, Treatment Administration and Schedule; and Section 7.5, 
Packaging and Labeling

Added note to include prohibitive use of antifungal and antiseptic treatment in the 
genital area
Revised Section: Section 8.3, Prohibited Concomitant Medications and Procedures

Removed ‘non-adherent’
Revised Appendix A, The Modified Static Physician Global Assessment of Genitalia 
(sPGA-G)

SAP_001.pdf: 
Product:  AMG407   
Protocol Number:  20200063 
Date:  22 October 2021 
Page 1 of 51 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
Phase 3, Multicenter, Randomized, Placebo-
Controlled, Double-Blind Study of the Efficacy and 
Safety of Apremilast in Subjects with Moderate to 
Severe Genital Psoriasis 
Short Protocol Title: 
Not Applicable 
Protocol Number: 
20200063 
NCT Number: 
 Enter NCT Number
Authors: 
Sponsor: 
AMGEN INC. 
One Amgen Center Drive, Thousand Oaks, CA 
91320, United States 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
22 October 2021 
NCT Number: NCT03777436
This NCT number has been applied to the document 
for the purposes of posting on clinicaltrials.gov


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CONFIDENTIAL  
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
22OCT2021 
N/A 
 


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Table of Contents 
1. 
Introduction ........................................................................................................... 10 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 10 
2.1 
Objectives and Endpoints .......................................................................... 10 
2.2 
Hypotheses and/or Estimations ................................................................. 12 
3. 
Study Overview .................................................................................................... 12 
3.1 
Study Design ............................................................................................. 12 
3.2 
Sample Size .............................................................................................. 14 
3.3 
Adaptive Design ........................................................................................ 14 
4. 
Covariates and Subgroups ................................................................................... 14 
4.1 
Planned Covariates ................................................................................... 14 
4.2 
Subgroups ................................................................................................. 14 
5. 
Definitions ............................................................................................................. 15 
5.1 
Derivations of Efficacy Endpoints .............................................................. 15 
5.1.1 
Modified static Physician Global Assessment of 
Genitalia (sPGA-G) ................................................................... 15 
5.1.2 
Static Physician Global Assessment (sPGA) ............................. 15 
5.1.3 
Genital Psoriasis Symptoms Scale (GPSS) ............................... 15 
5.1.4 
Genital Psoriasis Itch Numeric Rating Scale (GPI-
NRS) ......................................................................................... 16 
5.1.5 
Body Surface Area (BSA) .......................................................... 16 
5.1.6 
Dermatology Life Quality Index (DLQI) ...................................... 16 
5.2 
Derivations of Safety Endpoints ................................................................ 17 
5.2.1 
Treatment-emergent Adverse Event .......................................... 17 
5.2.2 
Treatment-emergent Adverse Event Leading to Drug 
Withdrawal, Drug Interruption, or Death, and Drug-
related Treatment-emergent Adverse Event .............................. 17 
5.2.3 
Vital Signs and Weight .............................................................. 18 
5.2.4 
Clinical Laboratory Evaluations ................................................. 18 
............. 18 
5.4 
Baseline Definitions ................................................................................... 19 
5.5 
Time Points ............................................................................................... 19 
6. 
Analysis Sets ........................................................................................................ 19 
6.1 
Intent-to Treat Analysis Set ....................................................................... 19 
6.1.1 
Primary Analysis Set ................................................................. 19 
6.2 
Safety Analysis Set ................................................................................... 19 
6.3 
Per Protocol Set(s) .................................................................................... 19 
6.4 
Health-related Quality-of-Life or Health Economics Analyses 
Set(s) ........................................................................................................ 20 
............ 20 


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6.6 
Interim Analyses Set(s) ............................................................................. 20 
6.7 
Study-specific Analysis Sets...................................................................... 20 
7. 
Planned Analyses ................................................................................................. 20 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 20 
7.2 
Primary Analysis ....................................................................................... 20 
7.3 
Final Analysis ............................................................................................ 20 
7.4 
Analysis Phases/Period ............................................................................. 21 
7.4.1 
Analysis Phases ........................................................................ 21 
7.4.1.1 
Placebo-controlled Phase – Weeks 0 to 16 ............. 21 
7.4.1.2 
Apremilast Extension Phase – Weeks 16 
to 32 ........................................................................ 22 
7.4.1.3 
Observational Follow-up Phase – 4 weeks .............. 22 
7.4.2 
Apremilast-exposure Period for Safety Analysis ........................ 22 
7.5 
Treatment arms ......................................................................................... 22 
7.5.1.1 
Placebo-controlled Phase (Weeks 0 to 16) .............. 23 
7.5.1.2 
Apremilast Extension Phase (Weeks 16 to 
32) ........................................................................... 23 
7.5.1.3 
Apremilast-exposure Period .................................... 23 
7.5.1.4 
Observational Follow-up Phase (4 weeks) .............. 23 
8. 
Data Screening and Acceptance ........................................................................... 23 
8.1 
General Principles ..................................................................................... 23 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 24 
8.3 
Handling of Missing and Incomplete Data ................................................. 24 
8.3.1 
Efficacy endpoints ..................................................................... 24 
8.3.2 
Partially Missing Date Imputation for Adverse Events ................ 25 
8.3.3 
Prior Concomitant Medications/Procedures ............................... 27 
8.3.4 
Medical History .......................................................................... 27 
8.3.5 
Treatment Duration.................................................................... 27 
8.4 
Detection of Bias ....................................................................................... 28 
8.5 
Outliers ..................................................................................................... 28 
8.6 
Distributional Characteristics ..................................................................... 28 
8.7 
Validation of Statistical Analyses ............................................................... 28 
9. 
Statistical Methods of Analysis.............................................................................. 29 
9.1 
General Considerations ............................................................................. 29 
9.1.1 
General Approaches to Efficacy Analysis .................................. 29 
9.1.2 
Multiplicity Adjustment ............................................................... 30 
9.2 
Subject Accountability ............................................................................... 30 
9.3 
Important Protocol Deviations ................................................................... 30 
9.4 
Demographic and Baseline Characteristics ............................................... 31 
9.4.1 
Demographics ........................................................................... 31 
9.4.2 
Baseline or Disease Characteristics .......................................... 32 


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9.4.3 
Medical History .......................................................................... 33 
9.4.4 
Prior and Concomitant Procedures ............................................ 33 
9.4.5 
Prior and Concomitant Medications ........................................... 33 
9.5 
Efficacy Analyses ...................................................................................... 34 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 34 
9.5.1.1 
Assessing Study Site Effect ..................................... 36 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 37 
9.5.2.1 
Binary Variables ...................................................... 37 
9.5.2.2 
Continuous Variables .............................................. 37 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 38 
9.6 
Safety Analyses ........................................................................................ 38 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 38 
9.6.2 
Adverse Events ......................................................................... 40 
9.6.2.1 
Overall Summary of TEAEs ..................................... 40 
9.6.2.2 
All TEAEs ................................................................ 40 
9.6.2.3 
Common TEAEs ..................................................... 41 
9.6.2.4 
Drug-related TEAEs ................................................ 41 
9.6.2.5 
TEAEs by Maximum Severity .................................. 41 
9.6.2.6 
Serious TEAEs ........................................................ 41 
9.6.2.7 
TEAEs Leading to Drug Interruption and 
Drug Withdrawal ...................................................... 42 
9.6.2.8 
Deaths..................................................................... 42 
9.6.2.9 
Adverse Events of Special Interests ........................ 42 
9.6.3 
Laboratory Test Results ............................................................ 42 
9.6.4 
Vital Signs ................................................................................. 43 
9.6.5 
Physical Measurements ............................................................ 43 
9.6.6 
Electrocardiogram ..................................................................... 43 
9.6.7 
Antibody Formation ................................................................... 44 
9.6.8 
Exposure to Investigational Product .......................................... 44 
9.6.9 
Exposure to Non-investigational Product ................................... 44 
9.6.10 
Exposure to Other Protocol-required Therapy ........................... 44 
9.6.11 
Exposure to Concomitant Medication ........................................ 44 
9.7 
Other Analyses ......................................................................................... 44 
9.7.1 
Analyses of COVID-19 impacted data ....................................... 44 
.................. 45 
9.7.3 
Analyses of Clinical Outcome Assessments .............................. 45 
9.7.4 
Analyses of Health Economic Endpoints ................................... 45 
....................................... 45 
9.7.6 
Analyses of COVID-19 impacted data ....................................... 47 
10. 
Changes From Protocol-specified Analyses.......................................................... 47 
11. 
Literature Citations / References ........................................................................... 47 


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12. 
Prioritization of Analyses....................................................................................... 48 
13. 
Data Not Covered by This Plan............................................................................. 48 
14. 
Appendices ........................................................................................................... 49 
Appendix A.  Analytical Windows .............................................................. 49 
Appendix B. Laboratory Marked Abnormalities Criteria ............................. 51 
 
List of Table 
Table 1. Summary of  missing data handling method applied to the analysis for each 
efficacy endpoint ............................................................................................. 24 
Table 2: Imputation Rules for Partially Missing AE Start Dates for Subjects Who Were 
Treated with Apremilast Initially ....................................................................... 25 
Table 3: Imputation Rules for Partially Missing AE Start Dates for Subjects Who Were 
Treated with Placebo Initially ........................................................................... 26 
Table 4. Table for Visit Mapping for by Time Point Analysis .......................................... 49 
Table 5. Analysis Visit for Placebo Subjects Who Are Treated with Apremilast 30 mg BID 
after Week 16 in the Apremilast-exposure Period ........................................... 51 
  
List of Figures 
Figure 1: Study Design................................................................................................... 13 
 
List of Appendices 
Appendix A. Analytical Windows.................................................................................... 49 
Appendix B. Laboratory Marked Abnormalities Criteria .................................................. 51 
 


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List of Abbreviations 
 
Abbreviation 
Explanation 
AE 
Adverse Event 
ADaM 
Analysis Data Model 
ALT 
Alanine aminotransferase (SGPT)  
ANCOVA 
Analysis of Covariance (model) 
AST 
Aspartate aminotransferase (SGOT) 
ATC 
Anatomical-Therapeutic-Chemical 
BID 
Twice Daily 
BMI 
Body Mass Index 
BSA 
Body Surface Area (%) Affected by Psoriasis 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Corona Virus Disease 2019 
CRO 
Contract Research Organization  
CRP 
Clinical Research Physician 
CSR 
Clinical Study Report 
DAO 
Data As Observed 
DLQI 
Dermatological Life Quality Index 
EAIR 
Exposure-adjusted incidence rate 
ET 
Early Termination 
EU 
Europe 
GPI-NRS 
Genital Psoriasis Itch Numeric Rating Scale 
GPSS 
Genital Psoriasis Symptoms Scale 
GSO-DM 
Global Study Operations-Data Management 
HRQoL 
Health-Related Quality of Life 
IL 
Interleukin 
IP 
Investigational Product 


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IPD 
Important Protocol Deviation 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
LS Mean 
Least Squares Mean 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed-effect Model for Repeated Measures 
NRI 
Non-responder Imputation  
PK 
Pharmacokinetic 
PP 
Per-Protocol (population) 
PsA 
Psoriatic arthritis 
PT 
Preferred Term 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD  
Standard Deviation 
SE 
Standard Error  
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SI 
Standard International (unit) 
sPGA 
static Physician Global Assessment 
sPGA-G 
static Physician Global Assessment of Genitalia 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
ULN 
Upper Limit of Normal 


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USA 
United States of America 
WHODD 
World Health Organization Drug Dictionary 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 3 for study 20200063, 
AMG407 dated 03 Mar 2021.  The scope of this plan includes the primary analysis and 
final analysis that is planned and will be executed by the Amgen Global Biostatistical 
Science department unless otherwise specified. 
The SAP will be finalized and signed prior to the unblinding of the Week 16 database. All 
statistical analyses detailed in this SAP will be conducted using SAS® Version 9.4 or 
higher. 
 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the clinical efficacy of 
oral apremilast 30 mg twice daily 
(BID), compared to placebo, in 
subjects with moderate to severe 
genital psoriasis during the 16-week 
Placebo-controlled Phase. 
 
Modified static Physician Global 
Assessment of Genitalia (sPGA-G) 
0/1 : Proportion of subjects with a 
modified sPGA-G score of clear (0) or 
almost clear (1) with at least a 2-point 
reduction from baseline at Week 16  
Secondary 
 
To evaluate the safety and 
tolerability of apremilast 30 mg BID, 
compared with placebo, in subjects 
with moderate to severe genital 
psoriasis during the 16-week Placebo-
controlled Phase. 
 
static Physician Global 
Assessment (sPGA) 0/1: Proportion of 
subjects achieving an overall sPGA 
score of clear (0) or almost clear (1) 
with at least a 2-point reduction from 
baseline at Week 16  
 
To evaluate the effect of 
apremilast 30 mg BID compared with 
placebo on genital psoriasis 
symptoms during the 16-week 
Placebo-controlled Phase. 
 
Genital Psoriasis Itch Numeric 
Rating Scale (GPI-NRS): Proportion 
of subjects with at least a 4-point 
improvement in GPI-NRS item score 
within the Genital Psoriasis Symptoms 
Scale (GPSS) for subjects with a 
baseline score of ≥ 4 at Week 16 
 
BSA: Change from baseline in 
affected BSA at Week 16 
 
GPSS: Change from baseline in 
GPSS total score and individual items 
scores at Week 16 


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 
To evaluate the effect of 
apremilast 30 mg BID compared with 
placebo on Health-related Quality of 
Life (HRQoL) during the 16-week 
Placebo-controlled Phase. 
 
Dermatology Life Quality Index 
(DLQI): Change from baseline in DLQI 
total score at Week 16  
 
 
 
Exploratory 


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2.2 
Hypotheses and/or Estimations 
The primary hypothesis for this study is: Apremilast monotherapy is superior to placebo 
in subjects with moderate to severe genital psoriasis as measured by proportion of 
subjects with a modified sPGA-G score of clear (0) or almost clear (1) with at least a 2-
point reduction from baseline at Week 16. 
H0: the difference in proportion of subjects who achieved a modified sPGA-G score of 
clear (0) or almost clear (1) with at least a 2-point reduction from baseline at Week 16 in 
apremilast and in that of placebo = 0. 
H1: the difference in proportion of subjects who achieved a modified sPGA-G score of 
clear (0) or almost clear (1) with at least a 2-point reduction from baseline at Week 16 in 
apremilast and in that of placebo ≠ 0. 
 
3. 
Study Overview 
3.1 
Study Design 
This Phase 3 multicenter, randomized, placebo-controlled, double-blind study is 
designed to evaluate the efficacy and safety of apremilast over 32 weeks of treatment in 
approximately 286 subjects with moderate to severe genital psoriasis (modified sPGA-G 
≥ 3, moderate or severe). Subjects will be randomized 1:1 based on a permuted block 
randomization using a centralized Interactive Response Technology (IRT). 
Randomization to apremilast arm or placebo arm will be stratified by baseline psoriasis-
involved body surface area (BSA) (< 10% or ≥ 10%). No more than 60% of subjects with 
BSA < 10% will be enrolled.  
 
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 


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The study will consist of four phases (Figure 1): 
1. Screening Phase – up to 35 days 
2. Double-blind Placebo-controlled Phase – Weeks 0 to 16 
 
Subjects will be randomly assigned in a 1:1 ratio to either apremilast 30 
mg BID or placebo.   
3. Apremilast Extension Phase – Weeks 16 to 32 
 
All subjects will be switched to (or continue with) apremilast 30 mg BID.  
All subjects will maintain this dosing through Week 32. 
4. Observational Follow-up Phase – 4 weeks 
 
Four-week Post-Treatment Observational Follow-up Phase for all subjects 
who complete the study or discontinue the study early 
After all subjects have completed the Week 16 Visit (or discontinued from the study), a 
Week 16 database restriction will be performed; the primary data analysis will be 
conducted. However, unblinded data will only be made available to select Sponsor and 
Contract Research Organization (CRO) team members involved with analysis of the 
data and preparation of the regulatory submission activities. All other Sponsor, site, and 
CRO personnel directly involved with the conduct of the study, will remain blinded to 
treatment assignments until the final database lock at the conclusion of the study. 
Figure 1. Study Design 
 
 


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3.2 
Sample Size 
 
 
 It is assumed that modified sPGA-G response will be similar 
to historic sPGA response. With a total of approximately 286 subjects and a 
randomization ratio of 1:1, this study will randomize approximately 143 subjects to the 
apremilast 30 BID group and 143 subjects to the placebo group. This sample size will 
provide 85% power to detect a minimum treatment difference of 15% at Week 16 (25% 
for apremilast 30 BID and 10% for placebo) for the primary endpoint using a chi-square 
test at a 2-sided significance level of 0.05 after adjusting for a 20% dropout rate. The 
sample size calculation was done using nQuery. 
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Covariates includes but not be limited to baseline value for each measured endpoint.  
4.2 
Subgroups 
Subgroup analysis will be carried out for modified sPGA-G response at Week 16 based 
upon baseline demographics and disease characteristics. Summary and analysis will be 
based on ITT population and missing values will be imputed using MI method. 
The following subgroup variables will be used:  
 
Baseline BSA (%) category (<10%, ≥10%) 
 
Baseline modified sPGA-G score (moderate [3] or severe [4]) 
 
Sex (Male, Female) 
 
Race (White, Non-white) 
 
Age category (<65 years, ≥ 65 years)  
 
Alcohol usage (Yes, No) 
 
Tobacco usage (Current user, Past user, Never used) 
 
Geographical region (USA/Canada, EU) 
 
Baseline weight category (< 50, ≥ 50 to < 60, ≥ 60 to < 70, ≥ 70 to < 85, ≥ 85 kg)  


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 
Baseline BMI category (< 18.5, ≥ 18.5 to < 25, ≥25 to < 30, ≥ 30 to < 35, ≥ 35 to 
< 40, ≥ 40 kg/ m2)  
 
Duration of genital psoriasis categories (<2, ≥2 to <5, ≥5 to < 10, ≥ 10 to < 20, ≥ 
20 years)  
 
Prior conventional systemic therapies (Used or Never used) 
 
Prior phototherapies (Used or Never used) 
 
Prior biologic therapy (Used or Never used) 
5. 
Definitions 
5.1 
Derivations of Efficacy Endpoints 
5.1.1 
Modified static Physician Global Assessment of Genitalia (sPGA-G) 
The modified sPGA-G is the assessment by the investigator of the subject’s psoriasis 
lesions’ overall disease severity in the genital area at the time of evaluation. The 
modified sPGA-G is a 5-point scale ranging from clear (0), almost clear (1), mild (2), 
moderate (3), to severe (4), incorporating an assessment of the severity of the three 
primary signs of the disease: erythema, plaque elevation, and scaling. It is not necessary 
that all three criteria be fulfilled. The modified sPGA-G is based on a combination of 
erythema and the secondary features (plaque elevation and/or scale).  
The modified sPGA-G response at a post-baseline visit is defined as achieving modified 
sPGA-G score of clear (0) or almost clear (1) with at least a 2-point reduction from 
baseline. 
5.1.2 
Static Physician Global Assessment (sPGA) 
The sPGA is the assessment of whole body psoriasis by the investigator of the overall 
disease severity at the time of evaluation.  The sPGA is a 5-point scale ranging from 
clear (0), almost clear (1), mild (2), moderate (3), to severe (4), incorporating an 
assessment of the severity of the three primary signs of the disease: erythema, scaling 
and plaque elevation.   
The sPGA response at a post-baseline visit is defined as achieving sPGA score of clear 
(0) or almost clear (1) with at least a 2-point reduction from baseline. 
5.1.3 
Genital Psoriasis Symptoms Scale (GPSS)  
The GPSS is a patient-administered assessment of eight symptoms: itch, pain, 
discomfort, stinging, burning, redness, scaling, and cracking. Respondents are asked to 
answer the questions based on their psoriasis symptoms in the genital area. Numeric 


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rating scales (NRS) are used to assess the self-reported overall severity of each of the 
eight symptoms individually in the genital area on an 11-point horizontal scale anchored 
at 0 (no) and 10 (worst imaginable). The overall severity for each individual symptom 
from patient's genital psoriasis is indicated by selecting the number from 0 to 10 that 
best describes the worst level of each symptom in the genital area in the past 24 hours. 
Each of the eight individual items will receive a score of 0 to 10 and will be reported as 
item scores for itch, pain, discomfort, stinging, burning, redness, scaling, and cracking.  
In addition, a total score ranging from 0 (no genital psoriasis symptoms) to 80 (worst 
imaginable genital psoriasis symptoms) will be reported. 
5.1.4 
Genital Psoriasis Itch Numeric Rating Scale (GPI-NRS)  
The GPI-NRS is one of eight components of the validated GPSS which was developed 
to assess symptoms that are particularly burdensome to subjects with genital psoriasis. 
Patient self-reported severity score of itch in the genital area on an 11-point horizontal 
scale anchored at 0 (no) and 10 (worst imaginable) will be reported.  
For a post baseline visit, the GPI-NRS response is defined as ≥ 4 points reduction 
(improvement) from baseline in the GPI-NRS score for subjects with baseline score of ≥ 
4. Change from baseline in the GPI-NRS score will also be derived.  
5.1.5 
Body Surface Area (BSA)  
BSA is a measurement of involved skin over the whole body. The overall BSA affected 
by psoriasis is estimated based on the palm area of the subject’s hand. The surface area 
of the whole body is made up of approximately 100 palms or “handprints” (each entire 
palmar surface or “handprint” equates to approximately 1% of total body surface area).  
BSA scores will be presented with one digit after the decimal point. For post-baseline 
visits, BSA score change and percent change from baseline will be derived. BSA score 
percent change will be rounded to integers. 
5.1.6 
Dermatology Life Quality Index (DLQI) 
The DLQI was developed as a simple, compact, and practical questionnaire for use in a 
dermatology clinical setting to assess limitations related to the impact of skin disease.  
The instrument contains 10 items dealing with the subject’s skin. With the exception of 
Item Number 7, the subject responds on a four-point scale, ranging from “Very Much” 
(score 3) to “Not at All” or “Not relevant” (score 0). Item Number 7 is a multi-part item, 
the first part of which ascertains whether the subject’s skin prevented them from working 
or studying (Yes or No, scores 3 or 0 respectively), and if “No,” then the subject is asked 


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how much of a problem the skin has been at work or study over the past week, with 
response alternatives being “A lot,” “A little,” or “Not at all” (scores 2, 1, or 0 
respectively). The DLQI total score is derived by summing all item scores, which has a 
possible range of 0 to 30, with 30 corresponding to the worst quality of life, and 0 
corresponding to the best. 
If one of the 10 items is left unanswered, it is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. If two or more of the ten items are left 
unanswered, DLQI total score will be left missing. When using sub-scales, if the answer 
to one item in a sub-scale is missing, the score is set to missing for that sub-scale. 
DLQI total score and change from baseline will be derived.  
5.2 
Derivations of Safety Endpoints 
Baseline definition for all safety endpoints is given in Section 5.4. Change from baseline 
is calculated as post-baseline visit value minus the baseline value. Handling of time 
points is described in Section 5.5.  
5.2.1 
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 study treatment or have 
discontinued early by the time of database cut, or 
 
On or after the date of the first dose of IP for subjects who are ongoing with study 
treatment at the time of database cut. 
If the treatment-emergent status of an AE is unclear due to a missing/incomplete start 
date, it will always be considered treatment-emergent, unless shown otherwise by data. 
Date imputation rules for missing AE start dates are described in section 8.3.2.  
Adverse event started more than 28 days after the last dose of IP will not be considered 
as a treatment-emergent AE.  
5.2.2 
Treatment-emergent Adverse Event Leading to Drug Withdrawal, 
Drug Interruption, or Death, and Drug-related Treatment-emergent 
Adverse Event 
A TEAE leading to drug withdrawal is a TEAE for which the investigator indicates that 
the action taken with respect to IP is withdrawn permanently. A TEAE leading to drug 
interruption is a TEAE for which the investigator indicates that the action taken with 
respect to IP is interrupted. A TEAE leading to death is a TEAE for which the outcome is 


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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.  
5.2.3 
Vital Signs and Weight 
Vital signs and weight endpoints include:  
 
Observed value and change from baseline over time in vital signs (temperature, 
pulse, and blood pressure)  
 
Shifts from baseline to post-baseline time points and to the worst post-baseline 
value in terms of normal/abnormal in pulse and blood pressure (normal ranges 
are defined as: 60-100 beats/minute for pulse, 90-140 mmHg for systolic blood 
pressure, and 60-90 mmHg for diastolic blood pressure) 
 
Observed value, change and percent change from baseline over time in weight 
5.2.4 
Clinical Laboratory Evaluations  
Laboratory evaluations include:  
 
Observed value and change from baseline over time in hematology and serum 
chemistry parameters 
 
Laboratory marked abnormalities and by baseline laboratory category will be 
analyzed for selected analytes (Appendix B).  
 
Shifts from baseline to post-baseline time points and to the worst post-baseline 
value in terms of normal/abnormal (low or high) in hematology and serum 
chemistry parameters 


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5.4 
Baseline Definitions 
For efficacy analysis and summary of baseline disease characteristics data, baseline is 
defined as the last value measured prior to or at the randomization date. 
For safety analyses in the Placebo-controlled Phase, baseline will be relative to the first 
dose date following randomization at Week 0. It is the last value measured prior to or on 
the day of the first dose of IP.  
For safety analyses in Apremilast Exposure Period, baseline will be relative to the first 
apremilast dose date at Week 0 for subjects initially randomized to apremilast or Week 
16 for subjects initially randomized to placebo and switched to apremilast in the 
Extension Phase. It is the last value measured prior to or at the first apremilast dose 
date.  
5.5 
Time Points 
Time points in all analyses are based on the remapped visits/study weeks using the visit 
mapping algorithm (Appendix A), which may or may not be the same as the visits/study 
weeks as recorded in the database.  
6. 
Analysis Sets 
6.1 
Intent-to Treat Analysis Set 
The intent-to-treat (ITT) analysis set will consist of all subjects who are randomized 
regardless of whether the subject received IP. Subjects will be included in the treatment 
group to which they are randomized. 
6.1.1 
Primary Analysis Set 
The primary analysis set is the intent-to-treat analysis set, and will be based on week 16 
database.  
6.2 
Safety Analysis Set 
The safety analysis set will consist of all subjects who are randomized and received at 
least one dose of investigational product (IP).  Subjects will be included in the treatment 
group corresponding to the IP they actually received (apremilast or placebo) for the 
analyses and summaries using the safety analysis set.   
6.3 
Per Protocol Set(s) 
The per protocol (PP) analysis set will consist of all subjects included in the ITT analysis 
set who receive at least one dose of IP, have both baseline and at least one post-
baseline modified sPGA-G assessment, and have no important protocol deviations 
which may affect efficacy assessments in the Placebo-controlled Phase. 


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6.4 
Health-related Quality-of-Life or Health Economics Analyses Set(s) 
Not applicable. 
Not applicable. 
6.6 
Interim Analyses Set(s) 
Not applicable. 
6.7 
Study-specific Analysis Sets 
Not applicable. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis will be conducted. 
After all subjects have completed the Week 16 Visit (or discontinued from the study), a 
Week 16 database restriction will be performed, the primary data analysis will be 
conducted. However, unblinded data will only be made available to selected Sponsor 
and Contract Research Organization (CRO) team members involved with analysis of the 
data and preparation of the regulatory submission activities.  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. 
7.2 
Primary Analysis 
The primary analysis will be performed after all subjects have had the opportunity to 
complete the week 16 visit. 
The primary analysis will present data from the completed placebo-controlled phase of 
the study, including the primary, secondary, and exploratory endpoints, and safety 
results at week 16.  In addition, the primary analysis will present cumulative safety data 
up to the report’s data cutoff date for the active treatment phase, including exposure 
from both the completed placebo-controlled phase and the ongoing active treatment 
phase. 
7.3 
Final Analysis 
The final analysis will occur after all subjects have had the opportunity to complete the 
study (ie, completion of the observational follow-up phase or discontinued the study).  


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The scope of the final analysis is the evaluation of the remaining efficacy data and final 
safety data. 
7.4 
Analysis Phases/Period  
For efficacy analysis, different phases will be used; For safety analysis, Placebo-
controlled Phase and Apremilast-exposure Period will be used.  
7.4.1 
Analysis Phases 
Per protocol specification, data summary and analysis will be provided for the following 
phases:  
7.4.1.1 
Placebo-controlled Phase – Weeks 0 to 16 
This phase starts on the day of randomization (Week 0/Visit 2), and stops on either: (1) 
the day the first IP for the next phase is dispensed at Week 16/Visit 7; or (2) the day of 
the discontinuation visit if the subject discontinued prior to or at Week 16/Visit 7; or (3) 
the last known study day if the subject is lost to follow-up prior to Week 16/Visit 7 during 
the phase. 
For safety analysis in subjects who continued treatment in Apremilast Extension Phase 
(Weeks 16 to 32), the phase stopped one day prior to the first dose date in Apremilast 
Extension Phase.  
For analysis of adverse events, TEAEs in the phase including those with start date at the 
first IP dose date through either: (1) one day prior to the first IP dose date in Apremilast 
Extension Phase (Weeks 16 to 32); or (2) 28 days after the last IP dose date for subjects 
who discontinue after only receiving treatment in the Placebo-controlled Phase.  
For safety analysis of visit-based data (ie, laboratory parameters, vital signs, etc), the 
post-baseline data in the phase including those with assessments dates after the first IP 
dose date (exclusive) and through either: (1) the first IP dose date (inclusive) in 
Apremilast Extension Phase (Weeks 16 to 32); or (2) the last visit date within 28 days of 
the last IP dose date (prior to the first Follow-up Visit) for subjects who discontinue after 
only receiving treatment in the Placebo-controlled Phase.  
At the time of the Week 16 analysis, if the date of the first IP dose date in Apremilast 
Extension Phase is not available in data base and the subject has not discontinued, the 
first IP dispensing date will be used instead.  


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7.4.1.2 
Apremilast Extension Phase – Weeks 16 to 32 
This phase starts on the day after the first IP is dispensed for the phase at Week 16/Visit 
7, and stops on either: (1) the day of Week 32/Visit 10; or (2) the day of the 
discontinuation visit if the subject discontinued prior to or at Week 32/Visit 10; or (3) the 
last known study day if the subject is lost to follow-up prior to Week 32/Visit 10 during 
the phase. 
For safety analysis, the phase started at the first dose date in the phase and ended at 
the last dose date.  
For analysis of adverse events, TEAEs in the phase including those starts at the first IP 
dose date in the phase through 28 days after the last IP dose date for subjects who 
completed or discontinued treatment in the phase.  
For safety analysis of visit-based data (ie, laboratory parameters, vital signs, etc), data in 
the phase starts at the first IP dose date (exclusive) and stops on the last visit date 
within 28 days of the last IP dose date (prior to the first Follow-up visit). 
7.4.1.3 
Observational Follow-up Phase – 4 weeks 
Subjects who complete the study or discontinue the study early, will be followed up for 
28 days after the last dose of IP.  
TEAEs in the Follow-up Phase will include adverse events started after and within 28 
days of the last dose date. Those TEAEs will also be summarized in one of the two 
treatment phases.  
7.4.2 
Apremilast-exposure Period for Safety Analysis 
This period starts on the date of either: (1) the first dose of IP following randomization 
(Week 0/Visit 2) for subjects who are treated with apremilast from Week 0; or (2) the first 
dose of IP from the IP dispensed at Week16/Visit 7 for subjects who were originally 
treated with placebo and are treated with apremilast at Week 16. 
This period stops on either: (1) 28 days after the last IP dose date for subjects 
completed or discontinued treatment from the study; or (2) data cut-off date for ongoing 
subjects. 
7.5 
Treatment arms 
In general, the treatment arms used in the analyses and summaries in each phase are 
described below in this section unless otherwise specified.  


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7.5.1.1 
Placebo-controlled Phase (Weeks 0 to 16) 
 
Placebo 
 
Apremilast 30 mg BID 
 
Total (optional, not for the efficacy analysis) 
7.5.1.2 
Apremilast Extension Phase (Weeks 16 to 32) 
Subjects who entered the extension phase will be included in analysis, ie, who were 
initially randomized to apremilast and continued at Week 16 and who were initially 
randomized to placebo and switched to apremilast at Week 16.  
 
Placebo/30 mg BID 
 
30 mg BID/30 mg BID 
7.5.1.3 
Apremilast-exposure Period 
Subjects who are treated with at least one dose of apremilast will be included here, 
which includes all subjects who are randomized to (at Week 0/Visit 2) or switched to (at 
Week 16/Visit 7) apremilast, and receive at least one dose of apremilast after 
randomization or Week 16.  
 
30 mg BID as Treated 
7.5.1.4 
Observational Follow-up Phase (4 weeks) 
For subjects who entered Follow-up Phase from Placebo-controlled Phase, summaries 
will be provided by their initial treatment arm:  
 
Placebo 
 
30 mg BID 
For subjects who entered Follow-up Phase from Apremilast Extension Phase, 
summaries will be provided by their treatment sequence:  
 
Placebo/30 mg BID  
 
30 mg BID/30 mg BID 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 


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8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
8.3.1 
Efficacy endpoints 
Missing data handling methods applied to the analysis for each efficacy endpoints is 
summarized as below:  
Table 1. Summary of missing data handling method applied to the analysis for 
each efficacy endpoint 
Analysis Set [a] 
Week 
Endpoint  
Imputation  
Method [b] 
ITT, PP 
0-16 
Modified sPGA-G response  
MI, NRI, DAO 
ITT 
0-16 
sPGA response  
MI, NRI, DAO 
ITT 
0-16 
GPI-NRS response  
MI, NRI, DAO 
ITT 
0-16 
BSA change and percent change from 
baseline 
MMRM 
ITT 
0-16 
DLQI change from baseline 
MMRM 
ITT 
0-16 
GPSS total score change from baseline 
MMRM 
ITT 
0-16 
GPSS individual items scores change from 
baseline 
MMRM 
ITT 
0-16 
DLQI-Q#9 change from baseline 
MMRM 
ITT (Subjects 
entered 
extension phase) 
16-32 
sPGA-G response, sPGA response, GPI-
NRS response 
NRI, DAO 
ITT (Subjects 
entered 
extension phase) 
16-32 
BSA change and percent change from 
baseline, DLQI change from baseline, 
GPSS total score change from baseline, 
GPSS individual items scores change from 
baseline, GPI-NRS change from baseline, 
DLQI-Q#9 change from baseline 
DAO 
Note: MI = Multiple Imputation; NRI = Non-responder imputation; DAO = Data as 
Observed; MMRM= Mixed-effect model for repeated measures 
[a] See Section 6 
[b] See Section 9.5 
 


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8.3.2 
Partially Missing Date Imputation for 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 2. Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially 
Scenario 
Condition 
Imputation Rule 
Partially missing date includes year only (both month and day are missing) 
1 
YEvent < YIP 
12/31/YEvent 
2 
Otherwise, i.e., YIP ≤ YEvent 
Max (date of first dose of IP, 
1/1/YEvent) 
 Partially missing date includes both year and month (only day is missing) 
1 
YEvent < YIP, or (YEvent = YIP and MEvent 
< MIP) 
Last date of MEvent/YEvent 
2 
Otherwise, i.e., YIP < YEvent, or (YIP = 
YEvent and MIP ≤ MEvent)  
Max (date of first dose of IP, 
1/MEvent/YEvent) 
Subjects who were treated with placebo at Week 0/Visit 2 
The principle of the imputation rules for subjects who were treated with placebo initially 
and started apremilast treatment at Week 16 is to consider the AE starting on or after the 
date of the first dose of apremilast, if possible; if the partially missing start date suggests 
that it is prior to the date of the first dose of apremilast, the AE will be considered starting 
on or after the date of the first dose of IP, if possible. 
The following are 4 scenarios considered in the imputation rules: 
1. The partially missing AE start date suggests the date is prior to the date of the 
first dose of IP: impute it by the latest possible date (determined by the non-
missing field of the date); 


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2. The partially missing AE start date suggests the date is after the date of the first 
dose of apremilast following Week 16: impute it by the earliest possible date 
(determined by the non-missing field of the date); 
3. The partially missing AE start date is in the same year (if both month and day are 
missing), or the same year/month (if only day is missing) of the first dose of 
apremilast following Week 16: impute it by the date of the first dose of apremilast; 
4. The partially missing AE start date suggests the date is no earlier than the date 
of the first dose of IP but prior to the date of the first dose of apremilast following 
Week 16: impute it by the date of the first dose of IP, or the earliest possible date 
(determined by the non-missing field of the date), whichever occurs later. 
Let an AE start date be represented as “DEvent/MEvent/YEvent”, the date of the first dose of 
IP as “DIP/MIP/YIP”, and the date of the first dose of apremilast following Week 16 as 
“DAPR/MAPR/YAPR”. The following table gives the imputation rules for partially missing AE 
start dates. 
Table 3．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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8.3.3 
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. 
8.3.4 
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. 
8.3.5 
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, 
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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8.4 
Detection of Bias 
This study has been designed to minimize potential bias by the use of randomization of 
subjects into treatment groups and the use of blinding. Other factors that may bias the 
results of the study include: 
 
Major protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints 
 
Subject level unblinding before final database lock and formal unblinding 
Important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints will be tabulated in the Clinical Study Report (CSR).  
Any unblinding of individual subjects prior to formal unblinding of the study will be 
documented in the CSR. The impact of such unblinding on the results observed will be 
assessed.  
Additional sensitivity analyses may be included to assess the impact of potential biases 
on the primary endpoint. If any sensitivity analyses are required to evaluate potential 
biases in the study’s conclusions, then the sources of the potential biases and results of 
the sensitivity analyses will be documented in the CSR. 
8.5 
Outliers 
Extreme data points will be identified during the blinded review of the data prior to 
database lock. Such data points will be reviewed with clinical data management to 
ensure accuracy. The primary analyses will include outliers in the data. Sensitivity 
analyses may be undertaken if extreme outliers for a variable are observed. 
8.6 
Distributional Characteristics 
Distributional assumptions for the primary and secondary endpoints will be assessed If 
the assumptions are not met, then alternative methods will be utilized. The use of 
alternative methods will be fully justified in the CSR. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   


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The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
9.1.1 
General Approaches to Efficacy Analysis 
The intent-to-treat principle will be used in statistical analyses for efficacy endpoints. For 
the Placebo-controlled Phase (Weeks 0-16), efficacy evaluations will be conducted using 
the intent-to-treat (ITT) analysis set defined as all randomized subjects. Statistical 
comparisons will be made between the two treatment arms (placebo or apremilast). For 
the Apremilast Extension Phase (Weeks 16-32), efficacy evaluations will be conducted 
using subjects who entered the phase from both treatment arms. 
Descriptive statistics (n, mean, SD, SE, median, Q1, Q3, min, max) will be presented for 
appropriate endpoints at specified time points. Specifically, for continuous variables, 
descriptive statistics for assessment values and change (plus percentage change when 
specified) from baseline will be provided. Binary variables will be summarized with 
frequency tabulations; shift tables will be provided when appropriate. 
Statistical comparisons will be made between placebo arm and apremilast arm; the null 
hypothesis is that the effects of the two treatment arms (i.e., placebo vs. apremilast) 
have no difference. Statistical tests will be at the two-sided 0.05 significance level and 
the corresponding p-values and two-sided 95% confidence intervals will be reported. 
Baseline definition for all efficacy endpoints is given in Section 5.4. Change from 
baseline is calculated as post-baseline visit value minus the baseline value. Percent 
change from baseline is defined as 100* Change from baseline/Baseline value (%). 
Handling of time points is described in Section 5.5. 
In the event that any site errors are made in specifying the stratification factor (baseline 
BSA <10% or BSA ≥10%) for randomization, the classification of the stratification factor 
in all efficacy analyses will be based on the actual classification according to the clinical 
database. 
In the data as observed (DAO) analyses, only subjects with sufficient data at the time 
point under consideration will be included. 


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9.1.2 
Multiplicity Adjustment 
The primary and secondary efficacy endpoints will be hierarchically ranked for testing to 
control the overall type I error rate in claiming statistical significance at the two-sided 
0.05 significance level. Specifically, for the primary efficacy endpoint (modified sPGA-G 
response at Week 16), if the two-sided p-value from the comparison between apremilast 
arm and placebo arm is below 0.05, the outcome will be considered statistically 
significant and apremilast will be declared effective. For any secondary endpoint, 
statistical significance will be claimed only if its two-sided p-value is below 0.05 and tests 
for the primary endpoint and all previous secondary endpoints are significant at the two-
sided 0.05 level. The proposed test sequence for the primary and secondary efficacy 
endpoints is listed as the following: 
 
Proportion of subjects with modified sPGA-G score of clear (0) or almost clear (1) 
with at least a 2-point reduction from baseline at Week 16  
 
Proportion of subjects achieving an overall sPGA score of clear (0) or almost 
clear (1) with at least a 2-point reduction from baseline at Week 16 
 
Proportion of subjects with at least a 4-point improvement in GPI-NRS item score 
within the GPSS for subjects with a baseline score of ≥ 4 at Week 16 
 
Change from baseline in affected BSA at Week 16  
 
Change from baseline in DLQI total score at Week 16  
 
Change from baseline in GPSS total score and individual items scores at Week 
16  
9.2 
Subject Accountability 
The number of subjects screened, randomized, receiving IP, and completing the study 
will be summarized. Key study dates for the first subject enrolled, last subject enrolled 
and last subject’s end of study will be presented.  
Study discontinuation and IP discontinuation will be tabulated separately by reasons for 
discontinuation.  
The number and percent of subjects randomized will be tabulated by the stratification 
factor.  
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 


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prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 
Protocol deviations and important protocol deviations will be categorized by the 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 excluded from the per-protocol population. 
Protocol deviations and important protocol deviations by treatment group and overall will 
be provided for the placebo-controlled phase for the ITT analysis set, and for the 
Apremilast extension phase for subjects who receive at least one dose of IP during the 
phase. Summary tables showing the number and percent of subjects with at least one 
protocol deviation and important protocol deviations and by each category of protocol 
deviations and important protocol deviations will be provided. Listings of subjects with 
protocol deviations and important protocol deviations will also be provided.  
Additionally, protocol deviations and important protocol deviations related to COVID-19 
will be summarized. 
9.4 
Demographic and Baseline Characteristics 
Summaries for the demographics, baseline characteristics, prior medication/procedure, 
and concomitant medications/procedure will be presented for the ITT analysis set by 
treatment group and overall. Subject data listings will also be provided.  
9.4.1 
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: 


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 
Sex (Male, Female) 
 
Age category (< 65, ≥ 65 years; < 40, ≥ 40 to < 65, ≥ 65 to < 75, ≥ 75 to < 85, ≥ 
85 years) 
 
Race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islanders, White, Not Collected or Unknown) 
 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not reported, Unknown) 
 
Baseline weight category (< 50, ≥ 50 to < 60, ≥ 60 to < 70, ≥ 70 to < 85, ≥ 85 kg)  
 
Baseline BMI category (< 18.5, ≥ 18.5 to < 25, ≥ 25 to < 30, ≥ 30 to <35, ≥ 35 to 
< 40, ≥ 40 kg/m2)  
 
Geographical region (USA/Canada, EU) 
 
Alcohol usage (Yes, No) 
 
Tobacco usage (Current user, Past user, Never used) 
9.4.2 
Baseline or Disease Characteristics 
Baseline clinical characteristics will be summarized descriptively by treatment group, 
which will include the following: 
 
Duration of genital psoriasis (from date of diagnosis to the date of informed 
consent; year, presented one digit after the decimal point) 
 
Duration of genital psoriasis categories (<2, ≥2 to <5, ≥5 to < 10, ≥ 10 to < 20, ≥ 
20 years) 
 
Baseline modified sPGA-G score: Moderate (3), Severe (4) 
 
Baseline sPGA score: Moderate (3), Severe (4) 
 
Baseline psoriatic involved BSA (%) 
 
Baseline BSA (%) category (<10%, ≥10%) 
 
Baseline DLQI total score 
 
Number of prior phototherapies  
 
Number of failed prior phototherapies for subjects who had prior phototherapies  
 
Number of prior conventional systemic therapies  


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 
Number of failed prior conventional systemic therapies for subjects who had prior 
conventional systemic therapies   
 
Number of prior biologic therapies  
 
Number of failed prior biologic therapies for subjects who had prior biologic 
therapies  
 
Number of prior systemic therapies  
 
Number of failed prior systemic therapies for subjects who had prior systemic 
therapies  
9.4.3 
Medical History 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.1 or higher. A frequency summary (counts and percentage) of 
medical history will be presented by treatment group, system organ class (SOC), and 
preferred term (PT). 
9.4.4 
Prior and Concomitant Procedures 
Prior and concomitant procedures will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 24.1 or higher. Frequency summaries of prior 
and concomitant procedures will be provided for the safety population by treatment 
group, SOC, and PT. 
Prior procedures are defined as those started before the first dose of IP (whether or not 
ended before the first dose of IP). Concomitant procedures will be summarized for (1) 
Placebo-controlled Phase (Weeks 0 to16), (2) Apremilast Extension Phase (Weeks 16 to 
32), and (3) Observational Follow-up Phase (4 weeks). The concomitant procedures will 
be similarly analyzed as concomitant medications in the next section.  
9.4.5 
Prior and Concomitant Medications 
The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health 
Organization Drug Dictionary (WHO DD version March 2020 or higher) will be used to 
group prior and concomitant medications and prior psoriasis medications into relevant 
categories. Frequency summaries will be provided by treatment group, ATC 2 level, and 
standardized medication name for the safety population. 
Prior medications are defined as those started before the first dose of IP (whether or not 
ended before the first dose of IP). Prior medications that continue after the first dose of 
IP will also be reported as concomitant medications. 


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Prior psoriasis medications will be classified as phototherapies, biologic therapies, 
conventional systemic therapies, or systemic therapies through manual review by 
Clinical Research Physician (CRP). 
For each of the treatment phases, concomitant mediations are defined as non-study 
medications started during the phase, or non-study medications started before the phase 
and ended or remained ongoing during the phase. The treatment phase for concomitant 
medications will start on the first dose date and end one day prior to the last dose date.   
Medications in the Follow-up Phase will include those medications started from the date 
of last dose of investigational product. 
Summaries will be provided for prior psoriasis medications and prior medications, as well 
as for concomitant medications in: (1) Placebo-controlled Phase (Weeks 0 to16), (2) 
Apremilast Extension Phase (Weeks 16 to 32), and (3) Observational Follow-up Phase 
(4 weeks). 
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
The primary endpoint is the proportions of subjects who achieve modified sPGA-G 
response at Week 16 (defined as modified sPGA-G score of clear (0) or almost clear (1) 
with at least a 2-point reduction from baseline at Week 16). The main analysis for the 
primary efficacy endpoint will be based on the ITT analysis set. A sensitivity analysis 
using the PP analysis set will also be performed. 
The primary endpoint will be analyzed using the CMH (Cochran–Mantel–Haenszel) test 
adjusting for the stratification factor at randomization. The two-sided p-values from the 
CMH test, the adjusted treatment difference in proportion using the weighted average of 
the treatment differences across the strata with the CMH weights, along with the 
associated two-sided 95% CIs using a normal approximation to the weighted average 
will be provided. 
Missing values at Week 16 for this endpoint will be imputed using the multiple imputation 
(MI) method (SAS Institute Inc. 2011) based on similar subjects who remained in the 
study as the primary method. The SAS procedure MI will be used to impute missing 
modified sPGA-G scores at the scheduled analysis visits in the Placebo-controlled 
Phase (Weeks 0-16) to create M=50 complete data sets. The missing data patterns will 
be checked at the scheduled analysis visits, ie, Baseline (Week 0), and Weeks 2, 4, 8, 


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12 and 16. If there are non-monotone missing patterns, two separate imputation 
procedures will be used to complete the imputation process.  
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used with a 
single chain to impute missing scores by treatment and stratification factor to create 
M=50 imputed data sets with monotone missing patterns. In case there are convergence 
issues, a simple model will be used to impute the missing scores by treatment, with 
further simplification by dropping both treatment and stratification factor in imputation 
model if necessary. The seed will be set to 17813721. The imputed scores will be 
rounded to the nearest integer. The minimum and the maximum values for imputation 
will be 0 and 4, which correspond to the lowest and the highest modified sPGA-G 
scores.  
In the second step, the predictive mean matching method will be used to impute the 
remaining missing scores for the 50 data sets with monotone missing patterns. The 
imputation procedure will use monotone statement to create one complete data set for 
each of the monotone data set from the first step, and the variables will include 
treatment arm, stratification factor, and modified sPGA-G scores at scheduled analysis 
visits from baseline to Week 16. The seed will be set to 55218163. The number of 
closest observations to be used in the selection will be set to 2. 
After the completion of imputation, the modified sPGA-G response at Week 16 will be 
derived based on both observed and imputed scores. The same CMH method will be 
used to analyze the 50 complete data sets and the SAS procedure MIANALYZE will be 
used to combine the results for the statistical inferences.  
Shift table for shifts from baseline to post-baseline visits and End of Phase will be 
provided by treatment and time point for sPGA-G score. 
Additional sensitivity analysis will be conducted to account for missing data using the 
non-responder imputation (NRI) method and the tipping point analyses.  
For the tipping point analyses, let M1 and M2 be the total number of subjects with 
missing data of primary endpoint in Apremilast and Placebo. There are overall (M1 + 
1)*(M2 +1) possible ways for imputing missing data as responders or non-responders in 
statistical analysis, ranging from imputing all missing values as non-responders to 
imputing all missing values as responders in each of the two arms. For each of the (M1 + 
1)*(M2 +1) different imputation patterns, the Chi-square test will be used for testing 
statistical significance and the output can be plotted in a rectangle for inspection. The 


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staircase region that separates significant and non-significant outcomes forms the 
tipping-point boundary. 
9.5.1.1 
Assessing Study Site Effect 
The primary endpoint will be assessed for site effect.  
This study is a multicenter study and planned to have approximately 50 sites to enroll 
and randomize 286 subjects. A single site may not have sufficient number of subjects to 
allow meaningful within-site analysis of treatment effects stratified by baseline BSA 
category; therefore, study sites effect will be assessed by pooling sites on geographic 
basis to help interpret the results.  
In pooling sites for analysis, the minimum cell size of 5 randomized subjects per 
treatment arm (placebo arm or apremilast arm) per stratum of baseline BSA (%) 
category (< 10% or ≥ 10%) will be used. The pooling strategy is described as follows: 1) 
Sites will be pooled within each region (USA/Canada or EU) according to their rank 
based on site-specific sample size, starting with the smallest sites; i.e., within a region, 
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 
region with the smallest pooled site. 3) In the rare case that all site pooled together in a 
region does not satisfying the above condition (a minimum cell size of 5 for each of the 
four cells), all sites in the region will be pooled together with the smallest pooled site of 
the other region. 
Sites will be pooled together as described above in order to assess the site effect and 
site by treatment interaction on the primary efficacy endpoint.  
For the pooled sites, summary and analyses will be based on ITT analysis set using MI 
imputation for missing values. Study site effect will be assessed for the primary endpoint 
by stratifying the analysis based on pooled site in addition to the stratification factor at 
randomization and examining whether the treatment differences adjusted for both 
stratification factor and pooled site are consistent with those from the primary analysis. 
In addition, the consistency of the treatment effect across individual study sites (or 
pooled sites) will be assessed by performing a subgroup-type analysis with respect to 
the endpoints, with individual study sites (or pooled sites) treated as subgroups. Listings 
of response rates will be provided by individual study site and by pooled site. The 
treatment difference for each of the individual study sites (or pooled sites) will be 
reviewed to determine the effect among the individual study sites (or pooled sites). 


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9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The main analysis for the secondary efficacy endpoints will be based on the ITT analysis 
set. The two-sided p-values and two-sided 95% confidence intervals (CIs) will be 
reported for treatment difference between placebo arm and apremilast arm. Details for 
multiplicity adjustment are described in Section 9.1.2. 
9.5.2.1 
Binary Variables 
The binary variables for secondary endpoints include the following: 
 
Proportion of subjects achieving an overall sPGA score of clear (0) or almost 
clear (1) with at least a 2-point reduction from baseline at Week 16 
 
Proportion of subjects with at least a 4-point improvement in GPI-NRS item score 
within the GPSS for subjects with a baseline score of ≥ 4 at Week 16 
For these binary endpoints, the treatment difference between apremilast arm and 
placebo arm will be compared using CMH (Cochran–Mantel–Haenszel) test adjusting for 
the stratification factor at randomization. The two-sided p-values from the CMH test, the 
adjusted treatment difference in proportion using the weighted average of the treatment 
differences across the strata with the CMH weights, along with the associated two-sided 
95% CIs using a normal approximation to the weighted average will be provided. Missing 
values will be imputed using the similar MI method as the primary endpoint, with 
sensitivity analysis using the NRI method.  
9.5.2.2 
Continuous Variables 
The continuous variables for secondary endpoints include the following: 
 
Change from baseline in affected BSA at Week 16  
 
Change from baseline in DLQI total score at Week 16  
 
Change from baseline in GPSS total score and individual items scores at Week 
16 
The continuous efficacy endpoints will be analyzed based on the ITT analysis set using 
a mixed-effect model for repeated measures (MMRM) as the primary method. The 
MMRM model will use the change from baseline as the response variable and include 
treatment group, visit time, treatment-by-time interaction, and stratification factor as fixed 
effects, and the baseline value as a covariate. An unstructured covariance matrix will be 
used to model the correlation among repeated measurements. The Kenward-Roger 
adjustment will be used with restricted maximum likelihood (REML) to make proper 


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statistical inference. Within-group least-squares (LS) means and the associated SEs and 
2-sided 95% CIs, treatment difference in LS means and the associated SEs and 2-sided 
95% CIs and 2-sided p-values will be derived from the MMRM model for Week 16 and 
other scheduled visits (Week 2, 4, 8, and 12, if applicable) in the model.  
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Safety will be assessed via descriptive statistics. Unless otherwise specified, all safety 
analyses described in this section will be performed for both the Placebo-controlled 
Phase and the Apremilast-exposure Period. The safety analyses for the Placebo-
controlled Phase will be based on the safety population and presented by treatment 
group (placebo arm or apremilast arm), and the safety analyses for the Apremilast-
exposure Period will be based on the apremilast subjects as treated population and 


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


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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. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 or higher will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term with SOCs presented in the standard international order and PTs within 
SOCs will be presented in descending order of subject incidence. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, drug-related treatment-emergent adverse events, serious adverse 
events, adverse events leading to discontinuation of investigational product, fatal 
adverse events and adverse events of interest. 
9.6.2.1 
Overall Summary of TEAEs 
An overall summary of the following TEAE categories will be provided for the Placebo-
controlled Phase (Weeks 0 to 16) for subjects with: 
 
Any TEAE 
 
Any drug-related TEAE 
 
Any severe TEAE 
 
Any serious TEAE 
 
Any serious drug-related TEAE 
 
Any TEAE leading to drug interruption 
 
Any TEAE leading to drug withdrawal 
 
Any TEAE leading to death 
In addition, for Apremilast Exposure Period overall summary of TEAEs will also be 
provided. 
9.6.2.2 
All TEAEs 
All TEAEs will be summarized by SOC and PT as well as by PT only (in descending 
order of subject incidence for the Placebo-controlled Phase (Weeks 0 to 16) and the 
Apremilast-exposure Period.  


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New events of all TEAEs by exposure interval (≤ 1, > 1 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12, and 
> 12 Weeks) will be summarized for the Placebo-controlled Phase. Each subject is 
counted once for either subject incidence or EAIR for each applicable specific TEAE in 
each exposure interval where an event started. The denominator of a subject incidence 
is the number of subjects with 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, > 32 Weeks) will be summarized for the Apremilast-exposure 
Period. 
All TEAEs will be summarized by age category (< 65, ≥ 65 years), sex, race and, if 
deemed necessary, by prior/concomitant psoriasis medication usage or baseline disease 
characteristics. 
9.6.2.3 
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. 
9.6.2.4 
Drug-related TEAEs 
Drug-related TEAEs will be summarized and new events of drug-related TEAEs by 
exposure interval will be summarized. 
9.6.2.5 
TEAEs by Maximum Severity 
All TEAEs will be summarized by maximum severity (mild, moderate, severe, and, if 
needed, missing). If a subject reports multiple occurrence 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 the 
occurrences, the subject will be counted only once in the “missing” category of severity. 
9.6.2.6 
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 to 16). 


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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. 
9.6.2.7 
TEAEs Leading to Drug Interruption and Drug Withdrawal 
TEAEs leading to drug interruption and TEAEs leading to drug withdrawal will be 
summarized. 
TEAEs leading to drug withdrawal will also be summarized by age category (< 65, ≥ 65 
years), sex and race. 
A subject data listing of TEAEs leading to drug withdrawal will be provided. 
9.6.2.8 
Deaths 
TEAEs leading to death will be summarized. A subject data listing of all deaths will be 
provided. 
9.6.2.9 
Adverse Events of Special Interests 
Summary tables and listings may be provided for the AESIs if deemed necessary. 
9.6.3 
Laboratory Test Results 
The endpoints for clinical laboratory evaluations include: 
 
Laboratory marked abnormalities  
 
Observed value and change from baseline over time in the following laboratory 
parameters including but not limited to 
▪ 
Complete blood count: red blood cell [RBC] count, hemoglobin, hematocrit, 
white blood cell [WBC] count and differential, absolute WBC counts, platelet 
count 
▪ 
Serum chemistry: total protein, albumin, calcium, phosphorous, glucose, 
total cholesterol [TC], triglycerides, high-density lipoprotein [HDL], high-
density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol 
[LDL-C], uric acid, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase [AST; serum glutamic-oxaloacetic transaminase, SGOT], 
alanine aminotransferase [ALT; serum glutamic pyruvic transaminase, 
SGPT], sodium, potassium, chloride, bicarbonate [carbon dioxide, CO2], 
blood urea nitrogen, creatinine, lactate dehydrogenase [LDH], and 
magnesium 
▪ 
Dipstick urinalysis: specific gravity, pH, glucose, ketones, protein, blood, 
bilirubin, leukocyte esterase, nitrite, and urobilinogen 


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 
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. 
9.6.4 
Vital Signs 
The endpoints for vital signs 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) 
Summary statistics of observed values and changes from baseline in vital signs 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. 
9.6.5 
Physical Measurements 
The endpoints for physical measurements are Observed value, change and percent 
change from baseline over time in weight. Summary statistics of will be provided over 
time. 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/) 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. 
9.6.6 
Electrocardiogram 
 Not applicable.  


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9.6.7 
Antibody Formation 
Not applicable.  
9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. Compliance to each IP will also be summarized.  
The treatment compliance (in %) for each subject will be computed as 100 times the 
total number of tablets taken (the total number of tablets dispensed minus the total 
number of tablets returned) over the analysis phase or period divided by the intended 
total number of tablets that should have been taken over the same phase or period. 
Summary statistics for compliance (%) will be provided by treatment arm for each 
analysis phase or period. Frequency summary tables of compliance will also be 
presented with the following categories: < 75%, ≥ 75% - ≤120%, and > 120%. A subject 
data listing of drug accountability records will be provided. 
9.6.9 
Exposure to Non-investigational Product  
Not applicable.  
9.6.10 
Exposure to Other Protocol-required Therapy 
Not applicable.  
9.6.11 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category for each treatment group as coded by the 
World Health Organization Drug (WHODRUG) dictionary.   
9.7 
Other Analyses 
9.7.1 
Analyses of COVID-19 impacted data 
Analyses will be performed to assess the impact of COVID-19 on the amount of data 
collected for the study. These analyses include: 
 
Number and percent of subjects who are discontinued treatment/study due to 
COVID-19 
 
Number and percent of subjects with important protocol deviations and protocol 
deviations related to COVID-19 
 
Analysis of the primary endpoint and key secondary endpoints excluding COVID-
19 impacted subject data 


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 
Number and percent of subject study participation impacted by COVID-19 along 
with the listing 
 
Listing of subject efficacy related assessment impacted by COVID-19 
Listing of subject safety related assessment impacted by COVID-19  
9.7.3 
Analyses of Clinical Outcome Assessments 
Not applicable. 
9.7.4 
Analyses of Health Economic Endpoints 
Not applicable. 


Product:  AMG407   
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Product:  AMG407   
Protocol Number:  20200063 
Date:  22 October 2021 
 
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9.7.6 
Analyses of COVID-19 impacted data 
Analyses will be performed to assess the impact of COVID-19 on the amount of data 
collected for the study. These analyses include: 
 
Number and percent of subjects who are discontinued treatment/study due to 
COVID-19 
 
Number and percent of subjects with important protocol deviations and protocol 
deviations related to COVID-19 
 
Analysis of the primary endpoint and key secondary endpoints excluding COVID-
19 impacted subject data 
 
Number and percent of subject study participation impacted by COVID-19 along 
with the listing 
 
Listing of subject efficacy related assessment impacted by COVID-19 
 
Listing of subject safety related assessment impacted by COVID-19  
10. 
Changes From Protocol-specified Analyses 
During the initial development of this document, it was realized that there are protocol-
specified analyses that cannot be implemented/performed and the protocol is not 
required to be amended.  The following change(s) have been made to the statistical 
section of the protocol: 
 
The last observation carried forward (LOCF) method to impute the missing 
data as sensitivity analysis of efficacy is removed. 
These changes will also be documented in the Clinical Study Report. 
11. 
Literature Citations / References 
Cather J, Meeuwis K, Burge R, Bleakman AP, Lin CY, Ryan C. Ixekizumab provides 
greater improvement versus placebo on the impact of genital psoriasis on sexual activity 
for patients with moderate-to-severe genital psoriasis in a randomized, double-blind 
phase 3b clinical trial. Presented at: American Academy of Dermatology Annual 
Meeting; February 16-20, 2018; San Diego, CA.  
Gottlieb A, Kirby B, Ryan C, Naegeli A, Burge R, Potts Bleakman A, et al. The 
development of a patient-reported outcome measure for assessment of genital psoriasis 
symptoms: The Genital Psoriasis Symptoms Scale (GPSS). Dermatol Ther (Heidelb). 
2018; 8(1):45-56. Merola JF, Bleakman AP, Gottlieb AB, Menter A, Naegeli AN, 
Bissonnette R, et al. The static physician’s global assessment of genitalia: a clinical 
outcome measure for the severity of genital psoriasis. J Drugs Dermatol. 2017; 
16(8):793-799.  


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Date:  22 October 2021 
 
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Ryan C, Menter A, Guenther L, Blauvelt A, Bissonnette R, Yang FE, et al. Efficacy and 
Safety of Ixekizumab in a randomized, double-blinded, placebo-controlled, Phase 3b 
clinical trial in patients with moderate to severe genital psoriasis. Presented at the 
European Academy of Dermatology and Venereal Disease: September 13-17, 2017; 
Geneva, Switzerland.  
Atkinson MJ, Kumar R, Cappelleri JC, Hass SL.  Hierarchical construct validity of the 
treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
pharmacy consumers. Value Health 2005; 8 Suppl 1: S9-S24. 
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. 2008. SAS/STAT® 9.2 User’s Guide. Cary, NC: SAS Institute Inc. 
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. 
LaVange LM and Permutt T for the Missing Data Working Group. A regulatory 
perspective on missing data in the aftermath of the NRC report. Statist. Med., 2016; 
35(17):2853–2864.  
Permutt T. Missing Data Working Group. Sensitivity analysis for missing data in 
regulatory submissions. Statist. Med., 2016; 35(17): 2876–2879. 
12. 
Prioritization of Analyses 
Not applicable. 
13. 
Data Not Covered by This Plan 
Not applicable. 


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14. 
Appendices 
 
Appendix A.  Analytical Windows 
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.  
Table 4. Table for Visit Mapping for by Time Point Analysis 
Analysis Visit 
Target Day 
Visit Window (Days) 
  Week 0 (Baseline) 
1 
≤ 1 
Placebo-controlled Phase 
  Week 2 
15 
2 – 21 
  Week 4 
29 
22 – 42 
  Week 8 
57 
43 – 70 
  Week 12 
85 
71 – 98 
  Week 16 
113 
99 – End of Phase 
Apremilast Extension Phase 
  Week 20 
141 
Start of Phase – 154 
  Week 24 
169 
155 – 196 
  Week 32 
225 
197 – End of Phase 
Note: Target day and visit window are relative to the date of Visit 2/Week 0 (Day 1) 
randomization date. For efficacy and safety analysis, definitions for start or end dates for 
a phase or period are specified in Section 3.1 and Baselines are specified in Section 5.4 
. For endpoints that do not have week 12 assessment, the visit window for week 8 will be 
43 – 98 (Days). 
Time points in the analyses or summaries of efficacy data over time include the 
scheduled study weeks per protocol, the end of a study phase, and the observational 
follow-up visit when applicable. 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 3.1) 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 


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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; 
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. 
For the Apremilast-exposure Period, the study weeks relative to the first dose of 
apremilast (according to the baseline definition) for placebo subjects who are treated 
with apremilast 30 mg BID starting at Week 16/Visit 7 are shown below for summaries of 
safety data (laboratory parameters, vital signs, etc) over time.  
Table 5. Analysis Visit for Placebo Subjects Who Are Treated with Apremilast 30 
mg BID after Week 16 in the Apremilast-exposure Period 
Original Visit 
Analysis Visit for subjects initially 
randomized to placebo 
Week 16 
Week 0 (Baseline) 
Week 20 
Week 4 
Week 24 
Week 8 
Week 32 
Week 16 
Data collected in the observational Follow-up Phase will be summarized separately 
when applicable. 
 


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Appendix B. Laboratory Marked Abnormalities Criteria 
Category / Analyte 
SI Units  
 Criteria  
Chemistry/ 
  Alanine Aminotransferase 
(SGPT) 
U/L 
> 2*ULN 
  Albumin 
Kg/m3 
< 25 
  Alkaline Phosphatase 
U/L 
> 400 
  Aspartate Aminotransferase 
(SGOT) 
U/L 
> 2*ULN 
  Total Bilirubin 
µmol/L 
> 2*ULN 
  Total Bilirubin and Alanine  
  Aminotransferase /Aspartate  
  Aminotransferase  
µmol/L and 
U/L 
Bilirubin Value > 2xULN with (ALT 
or AST value > 2xULN) 
  Blood Urea Nitrogen 
mmol/L 
> 24 
  Calcium 
mmol/L 
< 1.8 
 > 3.0 
  Cholesterol 
mmol/L 
> 7.8 
  Creatinine  
µmol/L  
> 1.5*ULN 
  Glucose 
mmol/L 
< 2.8 
> 13.9 
  Hemoglobin A1C 
% 
> 6.5 
  Lactate Dehydrogenase (LDH) 
U/L 
> 2*ULN 
  Magnesium 
mmol/L 
> 1.2 
  Phosphate 
mmol/L 
<1.03 
>1.94 
  Potassium 
mmol/L 
<3.0 
>5.4 
  Sodium 
mmol/L 
<132 
>147 
  Triglycerides 
mmol/L 
> 3.4 
  Urate 
umol/L 
Male: > 480 
Female: > 480 
Hematology/ 
  Hemoglobin 
 
g/L 
 
Female <110, Male <110 
Female >150, Male >150 
  Leukocytes 
10^9/L  
< 2.0 
  Lymphocytes 
10^9/L 
< 1.0 
  Neutrophils 
10^9/L 
< 1.5 
  Platelets 
10^9/L 
<100  
>500