Clinical trial NCT03930186
Conditions: Plaque Psoriasis
Sponsor: Amgen
Start date: 2019-06-17; Completion date: 2020-09-25
Enrollment: 152 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to assess the efficacy and safety of the combination of apremilast plus topical therapies for the treatment of adults with plaque psoriasis who have not achieved an adequate response with topicals alone.

Detailed description:
Participants will be enrolled at 28 sites in Japan. The study consists of 4 phases: a screening phase (4 weeks), an open-label combination therapy phase (16 weeks), an open-label combination therapy phase with optional topical reduction (16 weeks), and a post-treatment observational follow-up phase (4 weeks).

Arms: arm 1: After a 5-day titration, participants received 30 mg apremilast tablets orally twice daily (BID) for up to 32 weeks in addition to their existing topical therapy. At week 16 participants were permitted to decrease their use of topical therapy at their own discretion under the direction of their physician.
Interventions: intervention 1: Apremilast intervention 2: Topical Therapy
Intervention descriptions: intervention 1: Tablets for oral administration intervention 2: Participants continued to use their existing topical treatment for psoriasis for the first 16 weeks. After 16 weeks, participants could decrease the use of topical therapy at their discretion under the direction of their physician.

Protocol documents:
Prot_000.pdf: 
Study Identifier: CC-10004-PSOR-023 
NCT number: NCT03930186 
 
Official Title on page 1 of the Protocol: OPEN-LABEL, SINGLE-ARM STUDY OF THE 
EFFICACY AND SAFETY OF APREMILAST, IN SUBJECTS WITH PLAQUE 
PSORIASIS THAT IS NOT ADEQUATELY CONTROLLED BY TOPICAL THERAPY 
 
Official Title on page 5 of the Protocol: A PHASE 3B, OPEN-LABEL, SINGLE-ARM 
STUDY OF THE EFFICACY AND SAFETY OF APREMILAST, IN SUBJECTS WITH 
PLAQUE PSORIASIS THAT IS NOT ADEQUATELY CONTROLLED BY TOPICAL 
THERAPY 
 
Official Title in the Statistical Analysis Plan (SAP): A PHASE 3B MULTI-CENTER, 
OPENLABEL, SINGLE-ARM STUDY OF THE EFFICACY AND SAFETY OF 
APREMILAST, IN SUBJECTS WITH PLAQUE PSORIASIS THAT IS NOT 
ADEQUATELY CONTROLLED BY TOPICAL THERAPY 
 
Note: The official title in the Protocol (page 1 and 5) and Statistical Analysis Plan (SAP) are 
slightly different but these documents pertain to the same study CC-10004-PSOR-023.    
This cover page has been appended to the document for purpose of posting on 
Clinicaltrials.gov. 
 


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TITLE PAGE 
OPEN-LABEL, SINGLE-ARM STUDY OF THE 
EFFICACY AND SAFETY OF APREMILAST, IN 
SUBJECTS WITH PLAQUE PSORIASIS THAT IS NOT 
ADEQUATELY CONTROLLED BY TOPICAL 
THERAPY
PROTOCOL NUMBER: 
CC-10004-PSOR-023
DATE FINAL: 
30 Jan 2019
AMENDMENT DATE FINAL 
28 Apr 2020
EudraCT NUMBER: 
Not Applicable
IND NUMBER: 
N/A
SPONSOR NAME/ ADDRESS: 
Amgen Inc.
One Amgen Center Drive Thousand
Oaks, CA 91320, US
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  
NCT Number: NCT03930186
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information: 
Amgen K.K. Clinical Research Physician/Medical Monitor 
Name: 
 MD 
Title: 
Associate Medical Director, Inflammation and Immunology, 
Amgen K.K. 
Address: 
9-7-1 Akasaka
Minato-ku Tokyo 107-6239
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: +1-800-772-6436 


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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE 
{See appended electronic signature page} 
Signature of Celgene Therapeutic Area Head 
dd mmm yyyy 
 Vice President 
Printed Name of Celgene Therapeutic Area Head and Title 
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.   


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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 Conference on 
Harmonisation Good Clinical Practices Guidelines, and local regulations governing the 
conduct of clinical studies. 


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PROTOCOL SUMMARY 
Study Title 
A Phase 3B, open-label, single-arm study of the efficacy and safety of apremilast, in subjects 
with plaque psoriasis that is not adequately controlled by topical therapy 
Indication 
Psoriasis vulgaris is a chronic inflammatory immunologic disorder which manifests primarily in 
the skin. It is characterized by sharply demarcated areas of affected skin which appear thickened, 
red, and scaly. The scalp, elbows, knees, lower back, hands, and feet are commonly affected 
sites. About 80% of affected patients complain of pruritus (Gottlieb, 1998). The psoriatic 
appearance of the skin is initiated by an antigen presenting cell (APC) – T-cell interaction 
leading to the release of multiple inflammatory cytokines (Nestle, 2009). In time, this leads to an 
increased rate of epidermal proliferation with impaired differentiation of keratinocytes, resulting 
in a thickened epidermis covered by a thickened, parakeratotic stratum corneum. Dermal 
capillaries become tortuous and dilated, and there is infiltration of both epidermis and dermis 
with immunologically active cells (Lowes, 2007). 
Psoriasis is a disease that requires long-term treatment, ideally with effective agents that offer 
convenient dosing and a low incidence of adverse events. The American Academy of Dermatology 
recommends use of topical treatments for patients with localized disease; however, their 
effectiveness is limited by the inconvenience associated with application and low adherence rates 
(Menter, 2008). Moderate psoriasis is often inadequately treated and there remains an unmet 
medical need for an effective convenient agent that is well tolerated and less immunosuppressive 
than the currently available treatment options (Armstrong, 2013). 
While the Japanese Phase 2b study (PSOR-011) with apremilast in psoriasis was conducted in 
subjects with moderate to severe disease, the mean Psoriasis Area Severity Index (PASI) was 22 
and the mean body surface area (BSA) was 30%. Over 30% of subjects had a static Physician’s 
Global Assessment (sPGA) of ≥ 4 or a PASI > 20 in PSOR-011, with 60% or more of the subjects 
having a BSA involvement of > 20%. In addition, 32.3% of subjects were treated with previous 
conventional systemic therapy and 3.5% were treated with prior biologics.  This would suggest 
that there was a high proportion of subjects with severe disease in this study (Ohtsuki, 2017). This 
Phase 3B study is designed to focus on the efficacy and safety of apremilast added to topicals in 
subjects with plaque psoriasis who have not responded adequately to topical therapies. 
A significant proportion of patients with mild or moderate plaque psoriasis still have active disease 
despite treatment with topical therapies.  Topical treatments, although safe and effective, are 
limited by inconvenience and poor adherence.  This study would generate data to help understand 
the impact of apremilast when added to background topical therapy, which is an important 
scientific data gap in Japan.  In addition, the usage of topical therapies would also be collected to 
help understand if the addition of apremilast to the therapeutic regimen for plaque psoriasis could 
reduce the usage of topical therapies. 


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Objectives 
Primary Objective 
• The primary objective of the study is to assess the efficacy and safety of the combination 
of apremilast plus topical therapies for the treatment of subjects with plaque psoriasis who 
have not achieved an adequate response with topicals alone.  
Secondary Objective(s) 
The secondary objectives of the study are: 
• To assess the efficacy of the combination of apremilast plus topical therapies for the 
treatment of subjects with scalp psoriasis who have not achieved an adequate response 
with topicals alone. 
• To assess the impact on quality of life for the combination of apremilast plus topical 
therapies for the treatment of subjects with plaque psoriasis who have not achieved an 
adequate response with topicals alone. 
 
Study Design 
This is a Phase 3B, multi-center, open-label, single arm study of the efficacy and safety of the 
combination of apremilast and topical therapy in subjects with plaque psoriasis that have not 
responded adequately to topical treatments alone. 
Approximately 150 subjects will be enrolled at approximately 30 sites in Japan.  After a 5-day 
titration, subjects will receive apremilast 30 mg tablets orally twice daily (BID) for 32 weeks in 
addition to their existing topical therapy.  Beginning at Week 16, subjects will be permitted to 
decrease the use of topical therapy at their discretion. 
The study will consist of four phases: 
• Screening Phase – Week -4 ± 1 week 
• Open-label Combination Therapy Phase – Weeks 0 to 16 
Subjects will receive treatment with 
− apremilast 30 mg tablets orally BID, AND 
− existing topical therapy 
• Open-label Combination Therapy Phase with Optional Topical Reduction – Weeks 16 
to 32 
− All subjects will continue to receive apremilast 30 mg tablets orally BID AND 
existing topical therapy 
− Subjects will be permitted to decrease the use of topical therapy at their own 
discretion 
• Post-treatment Observational Follow-up Phase – Week 36 


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− Four-week post-treatment observational follow-up phase for all subjects who 
complete the study or discontinue from the study early.  Subjects who transition to 
commercial supply of apremilast after the week 32 visit are not required to attend 
the post-treatment observational follow-up visit. 
The study will be conducted in compliance with International Conference on Harmonisation 
(ICH) Good Clinical Practices (GCPs). 
Study Population 
Approximately 150 subjects with plaque psoriasis who have not achieved an adequate response 
from topical treatment alone (according to Investigator’s discretion) will be enrolled in the study 
across multiple centers in Japan. 
Length of Study 
The study is designed as a 32-week study.  Visits will be scheduled at Screening (Week -4 ± 1), 
Week 0 (Baseline), Weeks 2, 4, 8, 16, 24, and 32.   
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary, and/or exploratory analysis, as pre-specified in the protocol, whichever is 
the later date.  
Study Treatments 
During Week 0 (Days 1 to 7), subjects will be dispensed blister cards with 10, 20, and 30 mg 
apremilast tablets for the dose titration.  The treatment schema for dose titration at Baseline is 
shown in Table 4. 
All subjects will maintain this dosing through Week 32.   
Apremilast tablets will be taken orally twice daily (BID), approximately 12 hours apart, through 
the last treatment visit. 
Overview of Key Efficacy Assessments 
Primary Efficacy Endpoint 
The primary endpoint will be the proportion of subjects that achieve static Physicians Global 
Assessment score of 0 (clear) or 1 (almost clear) at week 16. 
Secondary Efficacy Endpoints 
• Scalp Physicians Global Assessment (ScPGA) 
• Dermatology Life Quality Index (DLQI) 
• Treatment Satisfaction Questionnaire for Medication (TSQM) Version II 
Exploratory Endpoints 


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Overview of Key Safety Assessments 
Safety assessments will include: 
• Adverse Events (AEs) 
• Pregnancy tests for females of childbearing potential (FCBP) 
• Vital signs  
• Clinical laboratory tests 
• Body weight  
Statistical Methods 
This study will enroll 150 subjects to apremilast 30 mg BID combined with topical therapy. It 
will support a 95% confidence interval with at least 80% probability that the length of the 
interval is within 13%, assuming the expected response rate of 15% [8.5% -21.5%] at Week 16 
and allows for a 10% discontinuation rate prior to week 16. The sample size calculation is based 
on nQuery software version 7.0, and the 80% probability supporting the margin of error is based 
on simulation results. 
The primary analysis for the primary endpoint will be analyzed using descriptive statistics which 
involve the sample size, the number of responders, point estimate of proportion of responders 
along with the associated two-sided 95% confidence intervals.  
All reasonable attempts will be made to prevent missing data from occurring in this study, 
especially through Week 16. However, in the case of missing data at Week 16, multiple 
imputation (MI) method will be incorporated into the primary analysis. The aim of the multiple 
imputation approach is to incorporate a representative random sample in place of the missing 
data such that unbiased estimation can be made.  


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL SUMMARY ...............................................................................................................5 
1. 
INTRODUCTION ......................................................................................................14 
1.1. 
Disease Background ...................................................................................................14 
1.2. 
Study Drug ..................................................................................................................14 
1.3. 
Rationale .....................................................................................................................15 
1.3.1. 
Study Rationale and Purpose ......................................................................................15 
1.3.2. 
Rationale for the Study Design ...................................................................................15 
1.3.3. 
Rationale for Choice of Combination Compounds ....................................................15 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................16 
3. 
OVERALL STUDY DESIGN ....................................................................................19 
3.1. 
Study Design ...............................................................................................................19 
3.2. 
Study Duration for Subjects ........................................................................................20 
3.3. 
End of Trial .................................................................................................................20 
4. 
STUDY POPULATION .............................................................................................21 
4.1. 
Number of Subjects ....................................................................................................21 
4.2. 
Inclusion Criteria ........................................................................................................21 
4.3. 
Exclusion Criteria .......................................................................................................22 
5. 
TABLE OF EVENTS .................................................................................................24 
6. 
PROCEDURES ..........................................................................................................28 
6.1. 
Screening Period .........................................................................................................28 
6.2. 
Treatment Period ........................................................................................................29 
6.2.1. 
End of Treatment ........................................................................................................30 
6.3. 
Follow-up Period ........................................................................................................30 
6.3.1. 
Post-Treatment Observational Follow-up...................................................................30 
6.4. 
Efficacy Assessments .................................................................................................30 
6.4.1. 
Static Physician Global Assessment (sPGA) ..............................................................31 
6.4.2. 
Body Surface Area (BSA) ..........................................................................................31 
6.4.3. 
Scalp Physicians Global Assessment ..........................................................................31 
6.4.4. 
Pruritus VAS ...............................................................................................................31 
6.4.5. 
Nail Assessments/Nail Psoriasis Severity Index (NAPSI) .........................................31 


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6.4.6. 
Psoriasis Area Severity Index (PASI).........................................................................31 
6.4.7. 
DLQI ...........................................................................................................................32 
6.4.8. 
Shiratori’s Pruritus Severity Score .............................................................................32 
6.4.9. 
Treatment Satisfaction Questionnaire for Medication Version II ..............................32 
6.4.10. 
Patient Benefit Index (PBI) ........................................................................................32 
6.4.11. 
Photographs ................................................................................................................32 
6.4.12. 
Subject Diary ..............................................................................................................33 
.............................................................................................................33 
6.5. 
Safety Assessments .....................................................................................................33 
6.5.1. 
Serum and Urine Pregnancy Tests for Females of Childbearing Potential ................33 
6.5.2. 
Vital Signs, Height and Weight ..................................................................................33 
6.5.3. 
Clinical Laboratory Evaluations .................................................................................34 
6.5.4. 
Adverse Events ...........................................................................................................34 
..............................................34 
7. 
DESCRIPTION OF STUDY TREATMENTS ..........................................................35 
7.1. 
Description of Investigational Product(s) ...................................................................35 
7.2. 
Treatment Administration and Schedule ....................................................................35 
7.3. 
Method of Treatment Assignment ..............................................................................35 
7.4. 
Packaging and Labeling ..............................................................................................35 
7.5. 
Investigational Product Accountability and Disposal .................................................36 
7.6. 
Investigational Product Compliance ...........................................................................36 
7.7. 
Overdose .....................................................................................................................36 
8. 
CONCOMITANT MEDICATIONS AND PROCEDURES ......................................37 
8.1. 
Permitted Concomitant Medications and Procedures .................................................37 
8.2. 
Prohibited Concomitant Medications and Procedures ................................................37 
8.3. 
Required Concomitant Medications and Procedures ..................................................38 
9. 
STATISTICAL CONSIDERATIONS .......................................................................39 
9.1. 
Overview .....................................................................................................................39 
9.2. 
Study Population Definitions ......................................................................................39 
9.3. 
Sample Size and Power Considerations .....................................................................39 
9.4. 
Background and Demographic Characteristics ..........................................................39 
9.5. 
Subject Disposition .....................................................................................................39 
9.6. 
Efficacy Analysis ........................................................................................................40 


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9.6.1. 
Primary Endpoint ........................................................................................................40 
9.6.2. 
Secondary and Exploratory Efficacy Endpoints .........................................................40 
9.7. 
Safety Analysis ...........................................................................................................40 
9.8. 
Interim Analysis ..........................................................................................................41 
10. 
ADVERSE EVENTS..................................................................................................42 
10.1. 
Monitoring, Recording and Reporting of Adverse Events .........................................42 
10.2. 
Evaluation of Adverse Events ....................................................................................42 
10.2.1. 
Seriousness .................................................................................................................42 
10.2.2. 
Severity/Intensity ........................................................................................................44 
10.2.3. 
Causality .....................................................................................................................45 
10.2.4. 
Duration ......................................................................................................................45 
10.2.5. 
Action Taken ..............................................................................................................45 
10.2.6. 
Outcome ......................................................................................................................45 
10.3. 
Abnormal Laboratory Values .....................................................................................45 
10.4. 
Pregnancy ...................................................................................................................46 
10.4.1. 
Females of Childbearing Potential– Collection of Pregnancy Information ................46 
10.5. 
Reporting of Serious Adverse Events .........................................................................47 
10.5.1. 
Safety Queries .............................................................................................................48 
10.6. 
Expedited Reporting of Adverse Events .....................................................................48 
11. 
DISCONTINUATIONS .............................................................................................50 
12. 
EMERGENCY PROCEDURES ................................................................................51 
12.1. 
Emergency Contact .....................................................................................................51 
12.2. 
Emergency Identification of Investigational Products ...............................................51 
13. 
REGULATORY CONSIDERATIONS......................................................................52 
13.1. 
Good Clinical Practice ................................................................................................52 
13.2. 
Investigator Responsibilities .......................................................................................52 
13.3. 
Subject Information and Informed Consent ...............................................................53 
13.4. 
Confidentiality ............................................................................................................53 
13.5. 
Protocol Amendments ................................................................................................53 
13.6. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval .....................................................................................................................53 
13.7. 
Ongoing Information for Institutional Review Board/ Ethics Committee .................54 
13.8. 
Termination of the Study ............................................................................................54 


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14. 
DATA HANDLING AND RECORDKEEPING .......................................................55 
14.1. 
Data/Documents .........................................................................................................55 
14.2. 
Data Management .......................................................................................................55 
14.3. 
Record Retention ........................................................................................................55 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................57 
15.1. 
Study Monitoring and Source Data Verification ........................................................57 
15.2. 
Audits and Inspections ................................................................................................57 
15.3. 
Product Complaint ......................................................................................................57 
16. 
PUBLICATIONS .......................................................................................................59 
17. 
REFERENCES ...........................................................................................................60 
18. 
APPENDICES ............................................................................................................62 
Appendix A: Table of Abbreviations and Specialist Terms ........................................................62 
Appendix B: Static Physician’s Global Assessment (sPGA) ......................................................64 
Appendix C: Scalp Physicians Global Assessment (ScPGA) .....................................................65 
Appendix D: Pruritus Visual Analog Scale (VAS) .....................................................................66 
Appendix E: Nail Psoriasis Severity Index (NAPSI) ..................................................................67 
Appendix F: Psoriasis Area Severity Index (PASI) ....................................................................68 
Appendix G: The Dermatology Life Quality Index (DLQI) .......................................................69 
Appendix H: Shiratori’s Pruritus Severity Score ........................................................................70 
Appendix I: Treatment Satisfaction Questionnaire for Medication (TSQM)  Version II ...........71 
Appendix J: Patient Needs Questionnaire (PNQ) .......................................................................74 
Appendix K: Patient Benefit Questionnaire (PBQ) ....................................................................75 
Appendix L: Waist Circumference Measurement .......................................................................76 
Appendix M: Subject Diary ........................................................................................................77 
Appendix N: SAMPLE SERIOUS ADVERSE EVENT REPORT FORM................................78 
Appendix O: PREGNANCY NOTIFICATION FORM .............................................................81 
Appendix P: LACTATION NOTIFICATION FORM ...............................................................82 
 
 
 


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LIST OF TABLES 
Table 1: 
Study Objectives .........................................................................................................16 
Table 2: 
Study Endpoints ..........................................................................................................16 
Table 3: 
Table of Events ...........................................................................................................24 
Table 4: 
Treatment Schema for Dose Titration At Baseline .....................................................35 
 
LIST OF FIGURES 
Figure 1: Overall Study Design .....................................................................................................20 
 


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1. 
INTRODUCTION  
1.1. 
Disease Background  
Psoriasis vulgaris is a chronic inflammatory immunologic disorder which manifests primarily in 
the skin. It is characterized by sharply demarcated areas of affected skin which appear thickened, 
red, and scaly. The scalp, elbows, knees, lower back, hands, and feet are commonly affected 
sites. About 80% of affected subjects complain of pruritus (Gottlieb, 1998). The psoriatic 
appearance of the skin is initiated by an antigen presenting cell (APC) – T-cell interaction 
leading to the release of multiple inflammatory cytokines (Nestle, 2009). In time, this leads to an 
increased rate of epidermal proliferation with impaired differentiation of keratinocytes, resulting 
in a thickened epidermis covered by a thickened, parakeratotic stratum corneum. Dermal 
capillaries become tortuous and dilated, and there is infiltration of both epidermis and dermis 
with immunologically active cells (Lowes, 2007).  
Psoriasis is a chronic disease that requires long-term treatment, ideally with effective agents that 
offer convenient dosing and a low incidence of adverse events.  The American Academy of 
Dermatology recommends use of topical treatments for subjects with localized disease and 
recognizes that the systemic options for subjects with more severe psoriasis are limited by 
potential risks of organ toxicities and immunosuppression (Menter, 2008).   
Mild or moderate psoriasis is often treated with topical therapy only.  However, a significant 
proportion of subjects with mild or moderate plaque psoriasis still have active disease despite 
treatment with topical therapies.  Topical treatments, although safe and effective, are limited by 
inconvenience and poor adherence.  Therefore, there remains an unmet medical need for an 
effective convenient agent that is well tolerated and less immunosuppressive than the currently 
available treatment options (Armstrong, 2013). 
1.2. 
Study Drug 
Apremilast (CC-10004) is a specific phosphodiesterase type 4 (PDE4) inhibitor (Schafer, 2010) 
under development for use in the treatment of inflammatory conditions.  PDE4 is one of the 
major phosphodiesterases expressed in leukocytes. PDE4 inhibition by apremilast elevates cyclic 
adenosine monophosphate levels in immune cells, which in turn down-regulates the 
inflammatory response by reducing the expression of pro-inflammatory mediators such as 
TNF-α, 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 the US, Canada, Europe, Japan, and Latin America for both 
moderate to severe plaque psoriasis and active psoriatic arthritis.  A Phase 2B study (PSOR-011) 
was conducted in Japan in subjects with moderate to severe plaque psoriasis, and also included 
subjects with active psoriatic arthritis, which supported the approval of apremilast for plaque 
psoriasis and psoriatic arthritis in Japan. 


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Apremilast remains under further clinical development for the treatment of Behçet’s disease. 
Further studies within the approved indications of plaque psoriasis and psoriatic arthritis are also 
ongoing. 
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP). 
1.3. 
Rationale 
1.3.1. 
Study Rationale and Purpose 
While the Japanese Phase 2b study (PSOR-011) with apremilast in psoriasis was conducted in 
subjects with moderate to severe disease, the mean Psoriasis Area Severity Index (PASI) was 22 
and the mean BSA was 30%. Over 30% of subjects had a static Physician Global Assessment 
(sPGA) of  ≥ 4 or a PASI > 20 in PSOR-011, with 60% or more of the subjects having a BSA 
involvement of  > 20%. In addition, 32.3% of subjects were treated with previous conventional 
systemic therapy and 3.5% were treated with prior biologics.  This would suggest that there was 
a high proportion of subjects with severe disease in this study. This Phase 3B study is designed 
with a specific focus on the efficacy and safety of apremilast added to topicals in subjects with 
plaque psoriasis who have not responded adequately to topical therapies. 
A significant proportion of subjects with mild or moderate plaque psoriasis still have active 
disease despite treatment with topical therapies.  Topical treatments, although safe and effective, 
are limited by inconvenience and poor adherence.  This study would generate data to help 
understand the impact of apremilast when added to background topical therapy, which is an 
important scientific data gap in Japan.  In addition, the usage of topical therapies would also be 
collected to help understand if the addition of apremilast to the therapeutic regimen for plaque 
psoriasis could reduce the usage of topical therapies. 
1.3.2. 
Rationale for the Study Design 
This will be a multi-center, open-label, single-arm study of the efficacy and safety of apremilast 
in combination with existing topical therapy in subjects who have not achieved an adequate 
response to topical therapy alone.  A placebo control is not necessary because apremilast will be 
added to a therapy which is not adequately controlling the disease.  In addition, the proportion of 
subjects that achieve sPGA 0 or 1 with placebo is historically low (~5%), reducing the need for a 
placebo control.  Finally, a 32 week study is sufficient to assess the efficacy and safety of 
apremilast in combination with topical therapy and the impact of apremilast on the use of topical 
therapy. 
1.3.3. 
Rationale for Choice of Combination Compounds 
Subjects will be required to remain on their existing topical therapy through the Open-label 
Combination Therapy Phase (Weeks 0 to 16).  After Week 16, subjects may decrease or 
discontinue the use of topical therapies at their discretion.  


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
Table 1: 
Study Objectives 
Primary Objective 
The primary objective of the study is to assess the efficacy and safety of the combination of 
apremilast plus topical therapies for the treatment of subjects with plaque psoriasis who have not 
achieved an adequate response with topicals alone.  
Secondary Objective(s) 
The secondary objectives of the study are: 
• To assess the efficacy of the combination of apremilast plus topical therapies for 
the treatment of subjects with scalp psoriasis who have not achieved an adequate 
response with topicals alone. 
• To assess the impact on quality of life for the combination of apremilast plus 
topical therapies for the treatment of subjects with plaque psoriasis who have not 
achieved an adequate response with topicals alone. 
Exploratory Objective(s) 
The exploratory objectives of the study are: 
Data from the exploratory objectives may not be included in the clinical study report. 
 
Table 2: 
Study Endpoints 
Endpoint 
Name 
Description 
Timeframe 
Primary  
static Physicians Global 
Assessment (sPGA) 
Proportion of subjects who achieve 
sPGA 0 or 1  
Week 16 
 


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Table 2: 
Study Endpoints (Continued) 
Endpoint 
Name 
Description 
Timeframe 
Secondary  
static Physicians Global 
Assessment (sPGA) 
Proportion of subjects who achieve sPGA 
0 or 1 
Week 32 
Scalp Physicians Global 
Assessment (ScPGA) 
Proportion of subjects who achieve 
ScPGA score of 0 or 1 
Weeks 16, 32 
Body Surface Area (BSA) 
Mean percent change from baseline in 
psoriasis-affected BSA 
Weeks 16, 32 
Pruritus Visual Analog 
Scale (VAS) 
Mean percent change from baseline 
Weeks 2, 16, 32 
Shiratori’s Pruritus 
Severity Score 
Mean change in severity score from 
baseline 
Weeks 2, 16, 32 
Nail Psoriasis Severity 
Index (NAPSI) 
Proportion of subjects that achieve a ≥ 
50% reduction from baseline in NAPSI 
score (NAPSI-50) at Week 32 among 
subjects with NAPSI ≥ 1 at baseline 
Weeks 16, 32 
Dermatology Life Quality 
Index (DLQI) 
Mean change from baseline 
Weeks 16, 32 
Psoriasis Area and 
Severity Index (PASI) 
• 
Mean percentage change from 
baseline 
• 
Proportion of subjects who achieve ≥ 
75% reduction from baseline (PASI-
75) 
• 
Proportion of subjects who achieve ≥ 
50% reduction from baseline (PASI-
50) 
Weeks 16, 32 
Treatment Satisfaction 
Questionnaire for 
Medication (TSQM) 
Mean overall score and mean score in 
sub-domains 
Weeks 0, 16, 32 
Patient Benefit Index 
(PBI) 
Proportion of subjects who achieve PBI ≥ 
1 
Weeks 16, 32 
Exploratory 
Safety 
Adverse Events 
Type, frequency, severity, and 
relationship of adverse events (AEs) to 
apremilast 
Throughout 
study duration 


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Endpoint 
Name 
Description 
Timeframe 
Discontinuation due to 
AEs 
Number of subjects who discontinue 
apremilast due to any AE 
Throughout 
study duration 
BSA = body surface area; DLQI = The Dermatology Life Quality Index; 
 
; NAPSI = Nail Psoriasis Severity Index; PASI = Psoriasis Area Severity Index; PBI = Patient 
Benefit Index; 
; ScPGA = Scalp Physician Global Assessment; sPGA = 
Static Physician’s Global Assessment; TSQM = Treatment Satisfaction Questionnaire for Medication; VAS = 
Visual Analog Scale. 
 


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3. 
OVERALL STUDY DESIGN  
3.1. 
Study Design 
This is a Phase 3B multi-center, open-label, single-arm study of the efficacy and safety of 
apremilast, in subjects with plaque psoriasis that is not adequately controlled by topical therapy. 
Approximately 150 subjects will be enrolled at approximately 30 sites in Japan.  After a 5-day 
titration, subjects will receive apremilast 30 mg tablets orally twice daily (BID) for 32 weeks in 
addition to their existing topical therapy.  Beginning at Week 16, subjects will be permitted to 
decrease the use of topical therapy at their discretion. 
The study will consist of four phases: 
• Screening Phase – Week -4 ± 1 week 
• Open-label Combination Therapy Phase – Weeks 0 to 16 
Subjects will receive treatment with:  
− apremilast 30 mg tablets orally BID, AND 
− existing topical therapy 
• Open-label Combination Therapy Phase with Optional Topical Reduction – Weeks 16 
to 32 
− All subjects will continue to receive apremilast 30 mg tablets orally BID AND 
existing topical therapy 
− Subjects will be permitted to decrease the use of topical therapy at their own 
discretion 
• Post-treatment Observational Follow-up Phase 
− Four-week Post-treatment Observational Follow-up Phase for all subjects who 
complete the study or discontinue from the study early.  Subjects who transition to 
commercial supply of apremilast after the week 32 visit are not required to attend 
the post-treatment observational follow-up visit. 
The study will be conducted in compliance with the International Council on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements. 
 
 


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Figure 1: Overall Study Design 
 
3.2. 
Study Duration for Subjects  
The study is designed as a 32-week study with a 4-week Post-treatment Observational Follow-up 
Phase.  Visits will be scheduled at Screening (Week -4 ± 1 week), Week 0 (Baseline), Weeks 2, 
4, 8, 16, 24, and 32.  A follow-up visit will be conducted at Week 36 or in the case of subjects 
withdrawing prior to Week 32, 4 weeks after investigational product (IP) discontinuation.  
Subjects who transition to commercial supply of apremilast after the week 32 visit are not 
required to attend the post-treatment observational follow-up visit. 
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 150 subjects with plaque psoriasis who have not achieved an adequate response 
from topical treatment (according to Investigator’s discretion) will be enrolled in the study across 
multiple centers in Japan. 
4.2. 
Inclusion Criteria 
Subjects must satisfy the following criteria to be enrolled in the study: 
1. Subject is ≥ 20 years of age at the time of signing the informed consent form (ICF) with 
plaque psoriasis.  
2. Subject has understood and voluntarily signed an informed consent document prior to any 
study related assessments/procedures being conducted. 
3. Subject is able to adhere to the study visit schedule and other protocol requirements. 
4. Subject has chronic plaque psoriasis based on a diagnosis for at least 6 months prior to 
Baseline. 
5. Subject has psoriasis with sPGA = 2 or 3 at screening and baseline. 
6. Subject is currently treated for psoriasis with topical therapies only for at least 4 weeks 
prior to Baseline.   
7. Subject has inadequate response to current topical therapy as per Investigator’s discretion. 
8. Subject is naïve to all biologic therapies for psoriasis vulgaris. 
9. Subject must be in general good health (except for psoriasis) as judged by the 
Investigator, based on medical history, physical examination, and clinical laboratories. 
(NOTE: The definition of good health means a subject does not have uncontrolled 
significant co-morbid conditions).   
10. Subjects that are females of childbearing potential (FCBP)† must have a negative 
pregnancy test at Screening and Baseline.  While on investigational product and for at 
least 28 days after taking the last dose of investigational product, FCBP who engage in 
activity in which conception is possible must use one of the approved contraceptive§ 
options described below: 
Option 1:  Any one of the following highly effective methods:  hormonal contraception 
(oral, injection, implant, transdermal patch, vaginal ring); intrauterine device; tubal 
ligation; or partner’s vasectomy; 
                                                             
† A female of childbearing potential is defined as 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 enrolled into 
the study (for example, hormonal contraception should be initiated at least 28 days before enrollment). 


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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 condition, including other inflammatory diseases or dermatologic 
conditions, which confounds the ability to interpret data from the study, including other 
types of psoriasis (ie, pustular, inverse, erythrodermic, or guttate), other than plaque 
psoriasis. 
2. Subject has psoriatic arthritis that requires systemic therapy. 
3. Subject has history of drug-induced psoriasis. 
4. Subject has had prior treatment with biologic therapies for psoriasis. 
5. Subject has used phototherapy or conventional systemic therapy for psoriasis within 8 
weeks prior to baseline and during the study (including but not limited to cyclosporine, 
corticosteroids, methotrexate, oral retinoids, mycophenolate, thioguanine, hydroxyurea, 
sirolimus, sulfasalazine, azathioprine). 
6. Subject has worsening of psoriasis indicated by an increase in sPGA of ≥ 1 from 
Screening to Baseline. 
7. Subject cannot avoid excessive sun exposure or use of tanning booths for at least 8 weeks 
prior to Baseline and during the study. 
8. Subject is currently enrolled in any other clinical trial involving an investigational 
product. 
9. Subject has other than psoriasis, any clinically significant (as determined by the 
Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, 
hematologic, immunologic disease, or other major disease that is currently uncontrolled. 
10. Subject has malignancy or history of malignancy or myeloproliferative or 
lymphoproliferative disease within the past 3 years, except for treated (ie, cured) basal 
cell or squamous cell in situ skin carcinomas.  
11. Subject has received a live vaccine within 3 months of baseline or plans to do so during 
study. 
12. Subject is pregnant or breastfeeding (lactating) women. 
13. 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 and the infection cured, at least 4 weeks prior 
to Screening and no new or recurrent infections prior to the Baseline Visit. 


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14. Subject is hepatitis B surface antigen positive or hepatitis B core antibody positive at 
screening. 
15. Subject is positive for antibodies to hepatitis C at screening. 
16. Subject has any condition, including the presence of laboratory abnormalities, which 
would place the subject at unacceptable risk if he/she were to participate in the study. 
17. Subject has prior history of suicide attempt at any time in the subject’s life time prior to 
signing the informed consent and enrollment, or major psychiatric illness requiring 
hospitalization within the last 3 years prior to signing the informed consent. 
18. Subject has active substance abuse or a history of substance abuse within 6 months prior 
to signing the informed consent. 
19. Subject has prior treatment with apremilast or participation in a clinical study involving 
apremilast. 


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5. 
TABLE OF EVENTS 
Table 3: 
Table of Events 
 
Screening 
Open-label Combination Phasea 
Open-label Combination 
with Optional Topical 
Reduction Phaseb 
Early Terminationc 
Post-Treatment 
Observational 
Follow-Upk 
Visit Number 
1 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-4 
(± 7 days) 
0 
(Day 1) 
2 
(± 3 days) 
4 
(± 3 days) 
8 
(± 3 days) 
16 
(± 3 days) 
24 
(± 4 days) 
32 
(± 4 days) 
36 (or 4 weeks after 
investigational 
product (IP) 
discontinuation) 
Informed consentd 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion / Exclusion criteria 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Prior / concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Review Diaries 
- 
- 
X 
X 
X 
X 
X 
X 
X 
- 
Clinical and Laboratory Assessments 
Adverse events/Serious Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test and contraception 
educatione 
X 
X 
- 
- 
- 
- 
- 
X 
X 
X 
Hepatitis B and C 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Height 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Waist Circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Physical Examination 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 


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Screening 
Open-label Combination Phasea 
Open-label Combination 
with Optional Topical 
Reduction Phaseb 
Early Terminationc 
Post-Treatment 
Observational 
Follow-Upk 
Visit Number 
1 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-4 
(± 7 days) 
0 
(Day 1) 
2 
(± 3 days) 
4 
(± 3 days) 
8 
(± 3 days) 
16 
(± 3 days) 
24 
(± 4 days) 
32 
(± 4 days) 
36 (or 4 weeks after 
investigational 
product (IP) 
discontinuation) 
Clinical laboratory evaluationsf 
X 
X 
- 
- 
- 
X 
- 
X 
X 
- 
Table 3: 
Table of Events (Continued) 
 
Screening 
Open-label Combination Phasea 
Open-label Combination 
with Optional Topical 
Reduction Phaseb 
Early Terminationc 
Post-Treatment 
Observational 
Follow-Upk 
Visit Number 
1 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-4 
(± 7 days) 
0 
(Day 1) 
2 
(± 3 days) 
4 
(± 3 days) 
8 
(± 3 days) 
16 
(± 3 days) 
24 
(± 4 days) 
32 
(± 4 days) 
36 (or 4 weeks after 
investigational 
product (IP) 
discontinuation) 
Efficacy Assessment(s) 
 
 
 
 
 
 
 
 
 
 
sPGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
BSA 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Pruritus VAS 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Shiratori’s Pruritus Severity Score 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
PASI 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
ScPGA 
- 
X 
- 
X 
X 
X 
X 
X 
X 
- 
NAPSI 
- 
X 
- 
- 
X 
X 
X 
X 
X 
- 
TSQM 
- 
X 
- 
X 
- 
X 
X 
X 
X 
- 
PNQj 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
PBQj 
- 
- 
- 
X 
- 
X 
X 
X 
X 
- 


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Screening 
Open-label Combination Phasea 
Open-label Combination 
with Optional Topical 
Reduction Phaseb 
Early Terminationc 
Post-Treatment 
Observational 
Follow-Upk 
Visit Number 
1 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-4 
(± 7 days) 
0 
(Day 1) 
2 
(± 3 days) 
4 
(± 3 days) 
8 
(± 3 days) 
16 
(± 3 days) 
24 
(± 4 days) 
32 
(± 4 days) 
36 (or 4 weeks after 
investigational 
product (IP) 
discontinuation) 
Photographsi 
- 
X 
- 
- 
- 
X 
- 
X 
X 
- 
Health-related Quality of Life Assessment(s) 
 
 
 
 
 
 
DLQI 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Table 3: 
Table of Events (Continued) 
 
Screening 
Open-label Combination Phasea 
Open-label Combination 
with Optional Topical 
Reduction Phaseb 
Early Terminationc 
Post-Treatment 
Observational 
Follow-Upk 
Visit Number 
1 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
-4 
(± 7 days) 
0 
(Day 1) 
2 
(± 3 days) 
4 
(± 3 days) 
8 
(± 3 days) 
16 
(± 3 days) 
24 
(± 4 days) 
32 
(± 4 days) 
36 (or 4 weeks after 
investigational 
product (IP) 
discontinuation) 
Dosing 
Dispense IP 
- 
X 
- 
X 
X 
X 
X 
- 
- 
- 
Return and count IP tablets 
- 
- 
-h 
X 
X 
X 
X 
X 
X 
- 


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Abbreviations:  BSA = body surface area; DLQI = The Dermatology Life Quality Index; FCBP = female of childbearing potential; IP = investigational product; 
 
; NAPSI = Nail Psoriasis Severity Index; PASI = Psoriasis Area Severity Index; PBQ = Patient Benefit Questionnaire; 
 
; PNQ = Patient Needs Questionnaire; ScPGA = Scalp Physician Global Assessment; sPGA = Static Physician’s Global Assessment; TSQM = 
Treatment Satisfaction Questionnaire for Medication ver II; VAS = Visual Analog Scale. 
a Visits in the Open-label Combination Phase to be performed ± 3 days. 
b Visits in the Open-label Combination with Optional Topical Reduction Phase to be performed ± 4 days. 
c Subjects who discontinue before week 32 will be asked to attend an Early Termination Visit. 
d Written informed consent will be obtained by the Principal Investigator or designee prior to initiation of any study procedures, including washouts from prior medications. 
e Females of child bearing potential (FCBPs) only.  Serum pregnancy tests are performed at Screening, Baseline, Early Termination Visit/Last Treatment Visit and 4 weeks 
thereafter (Observational Follow-up Visit).  Urine pregnancy test kit will also be provided to the site and performed at baseline prior to enrollment.  The Investigator will educate 
all FCBP about the different options of contraceptive methods and their correct use at Screening and Baseline visits.  The subject will be reeducated every time their 
contraceptive measures/methods or their ability to become pregnant changes.  A pregnancy test(s) should be administered if the FCBP subject misses a menstrual period. 
f Laboratory assessments will include routine/standard chemistry and hematology panel of tests, hs-CRP, and urinalysis. A lipid panel will be included in the standard chemistry 
panel. 
h There will be no drug return at week 2. 
i Photographs are optional and will only be collected in subjects who consent. 
j The Patient Benefit Index represents the subject benefits (PBQ) realized as a function of most important subject needs (PNQ). 
k Subjects who transition to commercial supply of apremilast after the week 32 visit are not required to attend the post-treatment observational follow-up visit. 
 


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6. 
PROCEDURES 
6.1. 
Screening Period 
An Informed Consent Document must be signed by the subject before any study-related 
assessments are performed. Details of the informed consent process are found in Section 13.3. 
Screening evaluations, including assessment of inclusion and exclusion criteria, will be 
performed for all subjects to determine study eligibility. These evaluations must be completed 3 
to 5 weeks prior to enrollment.  Subjects who do not meet eligibility criteria for the study may 
not be re-screened. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances. 
Safety laboratory analyses and all assessments will be performed (locally/centrally). Screening 
laboratory values must demonstrate subject eligibility, but may be repeated within the Screening 
window, if necessary. 
The following will be performed at Screening as specified in the Table of Events, after informed 
consent has been obtained: 
• Demographics (Initials, date of birth, sex, race, and ethnicity-if allowed by local 
regulations, will be collected)  
• Complete medical history 
• Prior and concomitant medications 
• Physical examination, height, weight, waist circumference (see Appendix L), body 
mass index  
• Vital signs (including blood pressure and heart rate) 
• Urinalysis 
• Hepatitis testing will include hepatitis B surface antigen, anti-hepatitis B core 
antibody, and anti-hepatitis C antibody. 
• Hematology panel including complete blood count with differential, including red 
blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, RBC morphology, mean corpuscular 
volume, white blood cell count (with differential), and platelet count. 
• Chemistry panel including sodium, potassium, calcium, chloride, blood urea nitrogen, 
creatinine, glucose, hemoglobin A1c, albumin, total protein, alkaline phosphatase, 
bilirubin (total and direct), aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase, alanine aminotransferase/serum glutamic pyruvic transaminase, 
gamma-glutamyl transferase, lactate dehydrogenase. A lipid panel will be included in 
the standard chemistry panel.  Fasting is not required. However, if significant 
elevation of serum lipid(s) is observed, a fasting re-test should be requested to 
determine whether or not the elevation was caused by food. 


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• High-sensitivity C-reactive protein (hs-CRP) 
• Pregnancy test is required for all female subjects of childbearing potential. Serum 
beta human chorionic gonadotropin (β-hCG) pregnancy test will be performed at 
Screening. Urine (or serum) pregnancy test will be performed to assess subject 
eligibility within 72 hours prior to the first administration of IP, if the initial serum 
pregnancy test did not already occur with 72 hours of dosing (negative results 
required for IP administration). 
• Contraception education will be performed by the Investigator at Screening for 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. 
− A pregnancy test should be performed if the FCBP subject has missed a menstrual 
period or the contraception method has changed 
− Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted.  
• Adverse event/Serious Adverse event assessment begins when the subject signs the 
informed consent form 
• Assessment of sPGA to determine study eligibility and Investigator’s assessment of 
response to existing topical therapy 
6.2. 
Treatment Period 
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment 3 to 5 weeks after signing the ICF. An administrative window of ± 3 days is permitted 
for Visits 3 through 6 and ± 4 days is permitted for Visits 7 and 8.  
The following procedures will be conducted as outlined in the Table of Events, Table 3. The 
evaluations should be performed prior to dosing on the visit day, unless otherwise specified. 
• Inclusion/Exclusion criteria (Baseline/Visit 2) 
• Concomitant medications evaluation 
• Vital signs 
• Weight, waist circumference 
• Adverse event/Serious Adverse Event evaluation (continuously and through 28 days 
after last dose of apremilast).  Subjects who transition to commercial supply of 
apremilast after the week 32 visit are not required to attend the post-treatment 
observational follow-up visit. 
• Clinical laboratory evaluations [For subjects who are not of child bearing potential, if 
screening laboratory assessments are within 7 days of Baseline (Week 0), laboratory 
assessment does not need to be repeated at Baseline (Week 0)] 
• Efficacy assessments (see Section 6.4) 


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• Dispense IP 
• Return and count IP tablets 
• Urine (or serum) pregnancy test (prior to dosing on Day 1) 
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 8) assessments will also be performed for 
subjects who complete the study. 
The following evaluations will be performed as specified in the Table of Events: 
• 
Weight, waist circumference 
• 
Vital signs 
• 
Concomitant medications evaluation 
• 
Adverse event/Serious Adverse Event evaluation (through 28 days after last dose of 
apremilast).  Subjects who transition to commercial supply of apremilast after the week 32 visit 
are not required to attend the post-treatment observational follow-up visit. 
• 
Clinical laboratory evaluations 
• 
Urine/Serum pregnancy test for females of childbearing potential (β-subunit of human 
chorionic gonadotropin [Serum β-hCG]) 
• 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted 
• 
Return and count IP tablets 
• 
Efficacy assessment 
6.3. 
Follow-up Period 
6.3.1. 
Post-Treatment Observational Follow-up 
All subjects will be followed for 28 days after the last dose of apremilast for AE reporting, as 
well as any SAEs made known to the Investigator at any time thereafter, as described in Section 
10.1. A 4-week post-treatment observational follow-up visit will be conducted for subjects who 
complete the 32-week study treatment.  Subjects who transition to commercial supply of 
apremilast after the week 32 visit are not required to attend the post-treatment observational 
follow-up visit and will not have a 28-day follow-up. 
6.4. 
Efficacy Assessments 
The following assessment will be conducted as outlined in the Table of Events, Table 3.  


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6.4.1. 
Static Physician Global Assessment (sPGA) 
The sPGA is the assessment by the Investigator of the overall disease severity at the time of 
evaluation. The National Psoriasis Foundation Psoriasis Score version of a static PGA is 
calculated by averaging the total body erythema, induration, and desquamation scores. Erythema 
(E), induration (I), and desquamation (D) are scored on a 5-point scale, ranging from 0 (clear) to 
4 (severe).  See Appendix B for grading criteria.  
6.4.2. 
Body Surface Area (BSA) 
BSA is a measurement of involved skin. The overall BSA affected by psoriasis is estimated based 
on the palm area of the subject’s hand, which equates to approximately 1% of total body surface 
area. 
6.4.3. 
Scalp Physicians Global Assessment 
The ScPGA will assess scalp involvement, if present at Baseline. See Appendix C for grading 
criteria.  The 5-point ScPGA scale ranges from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), 
to 4 (severe). 
6.4.4. 
Pruritus VAS 
The Pruritus VAS assessment will be conducted as outlined in the Table of Events. The subject 
will be asked to place a vertical stroke on a 100 mm VAS on which the left-hand boundary 
represents no itch, and the right-hand boundary represents itch as severe as can be imagined. The 
distance from the mark to the left-hand boundary will be recorded.  See Appendix D for grading 
criteria. 
6.4.5. 
Nail Assessments/Nail Psoriasis Severity Index (NAPSI) 
The number of fingers with psoriasis nail involvement will be counted, if present at Baseline.   
The NAPSI will assess one target thumb nail or fingernail representing the worst nail psoriasis 
involvement at Baseline.  See Appendix E for grading criteria. 
6.4.6. 
Psoriasis Area Severity Index (PASI) 
The PASI is a measure of psoriatic disease severity taking into account qualitative lesion 
characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on 
defined anatomical regions. The PASI is a validated instrument that has become standard in clinical 
trials for psoriasis. 
The PASI scores range from 0 to 72, with higher scores reflecting greater disease severity 
(Frederiksson, 1978). Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very 
severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of 
involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 
(90% to 100% involvement). The total qualitative score (sum of erythema, thickness, and scaling 
scores) is multiplied by the degree of involvement for each anatomic region and then multiplied 
by a constant. These values for each anatomic region are summed to yield the PASI score.  See 
Appendix F for grading criteria. 


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6.4.7. 
DLQI 
The DLQI (Finlay, 1994) will be assessed by the subject upon arrival at the site before any other 
procedures or assessments are performed.  The instrument contains 10 items pertaining to 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 
quality of life, and 0 corresponding to the best score. The developers suggest that the DLQI can 
be grouped into six subscales: symptoms and feelings, daily activities, leisure, work/school, 
personal relationships, and treatment. Scores for four of the subscales (symptoms and feelings, 
daily activities, leisure, and personal relationships) range from 0 to 6; scores for two of the 
subscales (work/school and treatment) range from 0 to 3. Higher scores correspond to poorer 
quality of life.  See Appendix G for grading criteria. 
6.4.8. 
Shiratori’s Pruritus Severity Score 
Shiratori’s Pruritus Severity Score is a pruritus severity assessment tool used in Japan.  Symptom 
severity is assessed for daytime and nighttime symptoms, separately, on a 5-point scale (0, No 
Symptoms; 1, Minimal; 2, Mild; 3, Moderate; 4, Severe).  See Appendix H for grading criteria. 
6.4.9. 
Treatment Satisfaction Questionnaire for Medication Version II 
The TSQM version II is an 11-question self-administrated instrument to understand a subject’s 
satisfaction on the current therapy (Atkinson, 2005). See Appendix I for questionnaire. 
6.4.10. 
Patient Benefit Index (PBI) 
The PBI is a validated patient-reported instrument to assess patient-relevant benefits of psoriasis 
treatment (Feuerhahn, 2012). Prior to starting therapy, subjects are asked to assess their treatment 
expectations by completing the Patient Needs Questionnaire (PNQ) (See Appendix J). After a 
period of treatment, subjects are then asked to assess the benefits of treatment by completing the 
Patient Benefit Questionnaire (PBQ) (See Appendix K). The Patient Benefit Index represents the 
subject benefits realized as a function of most important subject needs. The PBI score ranges 
from 0 (no benefit) to 4 (maximum benefit). 
6.4.11. 
Photographs 
Photographs will be collected only in subjects who consent, and will be considered as supportive 
evidence of efficacy, but these will not be addressed in the statistical analysis plan (SAP) or 
included in the clinical study report.   
Photographs will be taken of affected locations of plaque psoriasis at Weeks 0, 16, and 32.  
Appropriate protective mechanisms shall be implemented to ensure that the photographs do not 
contain any subject-specific identifiers (such as tattoos, scars, etc) when shared with the Sponsor. 


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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 in the main study 
will be asked to enrol at selected photography sites and will be asked to sign a separate consent 
form specific to photography at Visit 1 (Screening Visit), prior to being photographed. 
6.4.12. 
Subject Diary 
Subjects will be instructed to record their daily usage of topical medication in a standardized 
diary (Appendix M).  Subjects will record the quantity of topical medication used compared to 
the previous day as “Decreased”, “No change”, or “Increased”.  The subject diary will be 
provided to subjects at the baseline visit and subjects will be instructed to bring the diary to visits 
3 through 8 (or Early Termination visit). 
6.5. 
Safety Assessments 
In addition to daily safety monitoring conducted by Investigators and individual study personnel, 
AEs, serious adverse events (SAEs), discontinuations and laboratory findings will be reviewed 
by the study team. The review follows the Council for International Organizations for Medical 
Sciences, Working Group VI (CIOMS VI) recommendations. 
The study will be conducted in compliance with the ICH of Technical Requirements for 
Registration of Pharmaceuticals for Human Use/GCP and applicable regulatory requirements. 
The following assessments will be conducted as outlined in Table 3, Table of Events. 
6.5.1. 
Serum and Urine Pregnancy Tests for Females of Childbearing Potential 
A serum pregnancy test with a sensitivity of ≤ 15 mIU/mL will be required for FCBP subjects at 
Screening and the Week 32 Visit (or at the Early Termination Visit for subjects who prematurely 
discontinue from the study). Urine pregnancy test will be performed on all FCBP subjects at the 
Baseline Visit, prior to enrollment. A urine pregnancy test kit will be provided by the central 
laboratory. Pregnancy tests should be performed if the FCBP subject has missed a menstrual 
period or the contraception method has changed. 
6.5.2. 
Vital Signs, Height and Weight 
Vital signs, including temperature, pulse, and seated blood pressure, will be taken during the 
visits indicated in Table 3, Table of Events. Height will be measured and recorded at Screening; 


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weight will also be measured and recorded at the Screening Visit and then as indicated in the 
Table of Events, Body mass index (BMI) will be calculated programmatically. 
6.5.3. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed as indicated in Table 3, Table of Events. These 
include complete blood count with differential, including red blood cell (RBC) count, 
hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, RBC morphology, mean corpuscular volume, white blood cell count (with 
differential), platelet count and serum chemistries including sodium, potassium, calcium, 
chloride, blood urea nitrogen, creatinine, glucose, albumin, total protein, alkaline phosphatase, 
bilirubin (total and direct), aspartate aminotransferase/serum glutamic oxaloacetic transaminase, 
alanine aminotransferase/serum glutamic pyruvic transaminase, gamma-glutamyl transferase, 
lactate dehydrogenase. A lipid panel will be included in the standard chemistry panel.     
6.5.4. 
Adverse Events 
All subjects will be monitored for adverse events (AEs) during the study. Assessments may 
include monitoring of any or all of the following parameters: the subject’s clinical symptoms, 
laboratory findings, physical examination findings, or other appropriate tests and procedures. 
All AEs will be recorded by the Investigator from the time the subject signs informed consent to 
28 days after the last dose of IP. Adverse events and serious adverse events (SAEs) will be 
recorded on the AE page of the electronic case report form (eCRF) and in the subject’s source 
documents. All SAEs must be reported  immediately (ie, within 24 hours of the Investigator’s 
knowledge of the event) by facsimile, or other appropriate method, using the SAE Report Form, 
or approved equivalent form. 
Details of AE reporting can be found in Section 10 of the protocol. It should be noted that 
worsening of a subject’s psoriasis should be considered as worsening of disease under study and 
should not be captured as an adverse event. 


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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 provided by  Amgen Corporation as 10, 20, or 30 mg tablets in blister cards 
for dose titration purposes.  Apremilast will also be provided as 30 mg tablets in blister cards for 
the Maintenance Phase of the study. 
7.2. 
Treatment Administration and Schedule 
During Week 0 (Days 1 to 7), subjects will be dispensed blister cards with 10, 20, and 30 mg 
apremilast tablets for the dose titration.  The treatment schema for dose titration at Baseline is 
shown in Table 4.  All subjects will maintain this dosing through Week 32. 
Apremilast tablets will be taken orally twice daily (BID), approximately 12 hours apart, through 
the last treatment visit. 
Table 4: 
Treatment Schema for Dose Titration At Baseline 
Dose 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Days 6 -7 
Group 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
30 mg 
apremilast 
(titration) 
10 mg 
apremilast 
 
10 mg 
apremilast 
10 mg 
apremilast 
10 mg 
apremilast 
20 mg 
apremilast 
20 mg 
apremilast 
20 mg 
apremilast 
20 mg 
apremilast 
30 mg 
apremilast 
30 mg 
apremilast 
30 mg 
apremilast 
7.3. 
Method of Treatment Assignment 
After the informed consent is signed, subjects will be assigned a subject identification number 
using a centralized interactive web response system (IWRS). 
Designated study personnel at the investigational sites will be assigned password protected, 
coded identification numbers, which give them authorization to call into the IWRS.  The system 
will present a menu of questions by which the study personnel will identify the subject and 
confirm eligibility.  When all questions have been answered, the IWRS will assign an enrollment 
number.  Confirmation of the enrollment will be sent electronically to the investigational site, 
Amgen and/or its representative. 
7.4. 
Packaging and Labeling 
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations. 
All IP tablets will be supplied by Amgen.  Investigational product (IP) for dose titration at 
baseline and through Week 32 will be supplied in blister cards. 


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7.5. 
Investigational Product Accountability and Disposal 
The Investigator, or designee, is responsible for taking an inventory of each shipment of oral IP 
received, and comparing it with the accompanying IP shipping order/packing list.  
The Investigator, or designee, will verify the accuracy of the information on the form, sign and 
date it, retain a copy in the study file, and record the information in the IRT. 
Investigational product will be stored per the storage conditions identified on drug label.  At the 
study site, all IP will be stored in a locked, safe area to prevent unauthorized access. 
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). 
7.6. 
Investigational Product Compliance 
Study personnel will review the instructions printed on the package with the study subjects prior 
to dispensing the IP in tablet form.  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.  At 
each study visit, subjects will be asked whether they have taken their IP as instructed.  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 Post-treatment 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) should be discussed with Amgen.  Compliance is 
defined as taking between 75% and 120% of dispensed IP. 
7.7. 
Overdose 
Overdose for this protocol, on a per dose basis, is defined as ingestion of 4 or more 30 mg 
apremilast 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.  
Adverse Events associated with an overdose must be collected on the Adverse Events page of the 
electronic case report form (eCRF) (see Section 10.1) for all overdosed subjects, but the 
overdose itself is not considered an AE. 


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8. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
8.1. 
Permitted Concomitant Medications and Procedures 
Subjects must remain on their existing topical therapy from at least 4 weeks prior to baseline 
through week 16 of the study.  Principal Investigator or Sub-investigator will instruct subjects to 
continue to apply their existing topical therapy without a change in quantity or frequency through 
week 16.  After week 16, subjects are permitted to decrease the use of their existing topical 
therapy, in consultation with the principal Investigator or Sub-investigator. 
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 signing the informed consent throughout their entire participation in the study, 
including those initiated prior to signing the informed consent and continued through 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. 
During the study, the initiation of new concomitant medications or a change of existing 
concomitant medications may potentially indicate the presence of a new adverse event or the 
worsening of an existing condition.  If appropriate, such events should be recorded in the eCRF. 
8.2. 
Prohibited Concomitant Medications and Procedures 
The following psoriasis medications cannot be administered for the duration of the study. 
• Systemic therapy 
− Systemic therapy including but not limited to cyclosporine, corticosteroids, 
methotrexate, retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, 
sulfasalazine, azathioprine, fumaric acid esters 
• Phototherapy 
− Ultraviolet light B or psoralens and long-wave ultraviolet radiation 
• Biologic agents, including: 
− Adalimumab, etanercept, infliximab, or certolizumab pegol 
− Ustekinumab 
− Secukinumab, ixekizumab, or brodalumab 
− Guselkumab, risankizumab, or tildrakizumab 
• Use of any investigational drug or device 


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• Prolonged sun exposure or use of tanning booths, which may confound the ability to 
interpret data from the study 
8.3. 
Required Concomitant Medications and Procedures 
Existing topical therapy used for the treatment of plaque psoriasis is required from at least Week 
-4 to Week 16 of the treatment period.  Beginning at Week 16, subjects will be permitted to 
decrease the use of topical therapy at their discretion. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Overview 
The objective of this study is to assess the efficacy and safety of the combination of apremilast 
plus topical therapies for the treatment of subjects with plaque psoriasis who have not achieved 
an adequate response with topicals alone. 
9.2. 
Study Population Definitions 
The safety population will consist of all subjects who received at least one dose of study 
medication (IP). 
The Enrolled population will consist of all subjects who receive a IWRS identification number 
and are enrolled into the study. This will be the population for all efficacy analyses. 
The per protocol (PP) population will consist of all subjects included in the enrolled population 
who have both baseline sPGA and at least one post-baseline sPGA evaluation and no important 
protocol deviations. 
9.3. 
Sample Size and Power Considerations 
The primary endpoint of this study is the proportion of subjects who achieve a static Physicians 
Global Assessment (sPGA) score of 0 or 1 at Week 16, in subjects on combined therapy of 
apremilast and topicals. Because there is no control arm for the study, if the lower bound of the 
95% confidence interval (CI) of the observed response rate is above 8% (ie, the upper bound of 
95% CI of the response rate from the placebo group in pooled Phase III studies, namely, PSOR-
008 and PSOR-009), one can safely conclude that the treatment effect from the combined 
therapy is real. A sample size of 150 subjects will support a 95% confidence interval (CI) with at 
least 80% probability that the length of the interval is within 13%, assuming the expected 
response rate of 15% [8.5% to 21.5%] (conservatively estimated based on data of Phase III 
clinical trials). This sample size allows for a 10% discontinuation rate prior to week 16. The 
sample size calculation is based on nQuery software version 7.0, and the 80% probability 
supporting the margin of error is based on simulation results. 
9.4. 
Background and Demographic Characteristics 
Subjects’ age, height, weight, waist circumference, and baseline characteristics will be 
summarized using descriptive statistics, while gender, race, and other categorical variables will 
be provided using frequency tabulations.  The disease characteristics at baseline will also be 
summarized using appropriate descriptive statistics. Medical history data will be summarized 
using frequency tabulations by MedDRA system organ class and preferred term. 
9.5. 
Subject Disposition 
The distribution of enrollment by site will be provided.  Subject disposition (analysis population 
allocation, entered, completed, discontinued, along with primary reason for discontinuation) will 
be summarized using frequency and percent for the Open-label Combination Therapy Phase 
(Week 0 to 16) and for the Open-label Combination Therapy Phase with Optional Topical 


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Reduction Phase (Week 16 to 32). Protocol deviations will be summarized using frequency 
tabulations. 
9.6. 
Efficacy Analysis 
No statistical comparisons will be made for this single-arm study. 
9.6.1. 
Primary Endpoint 
The primary endpoint is the proportion of subjects that achieve sPGA score of 0 (clear) or 1 
(almost clear) at Week 16. It will be analyzed using the Enrolled population. In addition, a 
supplemental analysis will be performed using the PP population. 
The primary endpoint will be analyzed using descriptive statistics which involve the sample size, 
the number of responders, point estimate of proportion of responders along with the associated 
two-sided 95% confidence intervals (CI).  
All reasonable attempts will be made to prevent missing data from occurring in this study, 
especially through Week 16. However, in the case of missing data at Week 16, multiple 
imputation method will be incorporated into the primary analysis. The aim of the multiple 
imputation approach is to incorporate a representative random sample in place of the missing 
data such that an unbiased estimation can be made.  
Sensitivity analysis will be conducted to account for missing data using the last observation 
carried forward (LOCF) method and the non-responder imputation method. 
9.6.2. 
Secondary and Exploratory Efficacy Endpoints 
The secondary and exploratory efficacy endpoints will be analyzed based on the Enrolled 
population. 
The continuous endpoints will be analyzed using a mixed-effect model for repeated measures 
(MMRM) as the primary method. The MMRM model will use the change from baseline as the 
response variable and include visit time as a fixed effect, and the baseline value as a covariate. 
Within-group least-squares means and the associated standard errors and two-sided 95% CIs will 
be derived from the MMRM model. A sensitivity analysis will be conducted using LOCF 
method to impute the missing data. For discrete endpoints, similar analysis conducted for the 
primary endpoint will be performed for the secondary and exploratory endpoints. 
9.7. 
Safety Analysis 
The safety analyses will be performed using the Safety populations as defined in Section 9.2. 
Adverse events will be classified using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) classification system.  Adverse events will be tabulated by study phase (Open-label 
Combination Therapy Phase [Week 0 to 16] and for the Open-label Combination Therapy Phase 
with Optional Topical Reduction Phase [Week 16 to 32]).  All treatment-emergent AEs will be 
summarized by system organ class, preferred term, severity, and relationship to IP.  Adverse 
events leading to death or to discontinuation from treatment and serious AEs will also be 
summarized and listed separately.   


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Laboratory data will be summarized using shift tables showing the number of subjects with low, 
normal, and high values based on the normal ranges, pretreatment versus post-treatment.   
Vital sign measurements, including weight, will be summarized by visit descriptively (count, 
mean, median, standard deviation, and range).  In addition, shift tables showing the number of 
subjects with values below, within and above the normal reference ranges pre-treatment versus 
post-treatment will be provided.  
9.8. 
Interim Analysis 
No interim analysis is planned for this study. 
 


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10. 
ADVERSE EVENTS 
10.1. 
Monitoring, Recording and Reporting of Adverse Events 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the eCRF 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 eCRF (see Section 7.7 for definition of overdose).  Any sequela of an 
accidental or intentional overdose of an investigational product should be reported as an AE on 
the AE eCRF.  If the sequela of an overdose is an SAE, then the sequela must be reported on the 
paper SAE report form and on the AE eCRF.  The overdose resulting in the SAE should be 
identified as the cause of the event on the paper SAE report form and AE CRF but should not be 
reported as an SAE itself.  
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for apremilast overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician. 
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures. 
All AEs (non-serious and serious) will be recorded by the Investigator from the time the subject 
signs informed consent until 28 days after the last dose of IP as well as those SAEs made known 
to the Investigator at any time following the protocol-required reporting period or after end of 
study.  Subjects who transition to commercial supply of apremilast after the week 32 visit are not 
required to attend the post-treatment observational follow-up visit.  All adverse events 
(serious/non-serious) will be recorded on the CRF and in the subject’s source documents.  All 
SAEs must be reported to Amgen Global Patient Safety within 24 hours of the Investigator’s 
knowledge of the event using the paper Serious Adverse Event Report Form (refer to Appendix 
O) by facsimile/email of the paper SAER Form 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: 


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• Results in death; 
• 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. 
If an AE is considered serious, both the AE page/screen of the CRF and the paper Serious 
Adverse Event Report Form in English language (refer to Appendix O) must be completed and 


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must be reported to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of the event using the paper Serious Adverse Event Report Form by facsimile 
or email of this form directly to Amgen Global Patient Safety. 
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome. 
10.2.2. 
Severity/Intensity 
For both AEs and SAEs, 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 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 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 both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event. 
10.2.5. 
Action Taken 
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or dose reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
10.2.6. 
Outcome 
The Investigator will report the outcome of the event for both AEs and SAEs. 
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE). 
10.3. 
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• results in discontinuation from the study; 
• requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or 


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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 on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets). 
10.4. 
Pregnancy 
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events. 
10.4.1. 
Females of Childbearing Potential– Collection of Pregnancy Information 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events.  IP is to be discontinued 
immediately. A female subject with suspected pregnancy may resume IP after a confirmed negative 
pregnancy test and consultation with the Sponsor. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Amgen Global Patient Safety, or designee, immediately by 
facsimile, or other appropriate method, using the Pregnancy Notification Form, or approved 
equivalent form in English language (refer to Appendix O).  The Pregnancy Notification Form in 
English language 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 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 female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation. The Investigator will monitor the progress of the 
pregnancy of a female subject, 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 or therapeutic 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 via the 
paper Serious Adverse Event Report Form in English language within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form in English language. 
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 


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by facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the paper SAE Report Form in English language. 
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 in English 
language. The form must be submitted to Amgen Global Patient Safety with 24 hours of the 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,     
  
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 in English language (refer 
to Appendix P) 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 (refer   to exclusion criterion # 12).  
• 
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 AE/SAE page/screen 
of the eCRF and the completion of the paper Serious Adverse Event Report Form in English 
language (refer to Appendix N). All SAEs must be reported to Amgen Global Patient Safety by 
facsimile or email via the paper Serious Adverse Event Report form within 24 hours of the 
Investigator’s knowledge of the event. This instruction pertains to initial SAE reports as well as 
any follow-up reports.  
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) or any 
SAE made known to the Investigator at any time following the protocol-required reporting 


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period or after end of study.  Serious adverse events occurring prior to treatment (after signing 
the ICF) will be collected/recorded/reported. 
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Amgen Global 
Patient Safety as soon as these become available.  Any follow-up data should be detailed in a 
subsequent paper SAE Report Form, or approved equivalent form, and sent to Amgen Global 
Patient Safety jn English language.   
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene/Amgen and the IRB/EC. 
 
Serious Adverse Event Reporting via paper Serious Adverse Event Report Form:   
• 
Facsimile transmission of the Serious Adverse Event Report Form in English language is 
the preferred method to transmit this information. If facsimile is unavailable, the email method 
to transmit this information is acceptable (refer to Appendix N).      
• 
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 N).      
 
10.5.1. 
Safety Queries 
Queries pertaining to SAEs will be communicated 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. 
Amgen  or its authorized representative shall notify the Investigator of the following information. 
In Japan, Amgen KK shall notify the Heads of the Institutes in addition to the Investigators: 
• Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR); 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 


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• In Japan, measures taken in foreign countries to ensure subject safety, study reports 
that indicate potential risk of cancer, etc., or annual SAE report according to the local 
regulations. 
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects. 
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene/Amgen and the IRB/EC.  (See Section 14.3 for record retention 
information). 
Amgen Global Patient Safety Contact Information: 
For Amgen Global Patient Safety contact information, please refer to the Serious Adverse Event 
Report Form (refer to Appendix N), Pregnancy Notification  Form (refer to Appendix 
O) and/or the Lactation Notification Form (refer to Appendix P). 


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11. 
DISCONTINUATIONS 
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study: 
• Adverse event 
• Lack of efficacy  
• Non-compliance with investigational product 
• Withdrawal by subject 
• Death 
• Lost to follow-up 
• Protocol violation 
• Pregnancy 
• Physician decision 
• Study terminated by Sponsor 
• Other (to be specified on the eCRF)) 
Subjects have the right to withdraw from the study at any time and for any reason.  The reason 
for discontinuation should be recorded in the eCRF and in the source documents. 
The decision to discontinue a subject 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 or designee and forward appropriate supporting 
documents for review and discussion. 


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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-
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 
This is an open-label study; therefore, IP will be identified on the package labeling. 


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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 
Harmonization (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 eCRFs 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 Sponsor'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/IEC approval but will be submitted to the IRB/IEC 
for information purposes. 
13.6. 
Institutional Review Board/Independent Ethics Committee Review 
and Approval 
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements. 
IP can only be supplied to an Investigator by 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 eCRFs or CD-ROM. 
14.2. 
Data Management 
Data will be collected via eCRF 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 for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The Investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer. Essential documents include, but are not limited to, the following: 
• Signed ICFs for all subjects; 
• Subject identification code list, screening log (if applicable), and enrollment log; 
• Record of all communications between the Investigator and the IRB/EC; 
• Composition of the IRB/EC; 
• Record of all communications between the Investigator, Celgene/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 eCRFs (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. 
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, a 
Amgen representative will review the protocol, eCRFs, 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, eCRFs, 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 eCRFs 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 eCRFs 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 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, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, PMDA, FDA, EMA, Health 
Canada) and company authorized representatives.  The Investigator should make every effort to 
be available for the audits and/or inspections.  If the Investigator is contacted by any regulatory 
authority regarding an inspection, he/she should contact 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 product.  Any product 


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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 PC to Amgen.  Please report in English language:  
  
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 Phase2 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 
Armstrong AW, Robertson AD, Wu J, Schupp C, Lebwohl, MG. Undertreatment, treatment 
trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the 
United States. findings from the National Psoriasis Foundation surveys 2003-2011. JAMA 
Dermatol 2013;149(10):1180-5. 
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. 
Feuerhahn J, Blome C, Radtke M, Augustin M. Validation of the patient benefit index for the 
assessment of patient-relevant benefit in the treatment of psoriasis. Arch Dermatol Res. 
2012;304(6):433–41. 
Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI): a simple practical measure for 
routine clinical use.  Clin Exp Dermatol 1994;19:210-6. 
Frederiksson T, Pettersson U.  Severe psoriasis - oral therapy with a new retinoid.  
Dermatologica 1978;157:238-44. 
Gottlieb AB, Psoriasis – Enhanced epidermal differentiation and reduced cell-mediated 
inflammation are unexpected outcomes. Dis Manag Clin Outcomes 1998;1(6):195-202. 
Lowes MA, Bowcock AM, Krueger JG.  Pathogenesis and therapy of psoriasis.  Nature  
2007;445(7130):866-73. 
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. 
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361(5):496-509. 
Ohtsuki M, Okubo Y, Komine M, Imafuku S, Day RM, Chen P et al.  Apremilast, an oral 
phosphodiesterase 4 inhibitor, in the treatment of Japanese patients with moderate to severe 
plaque psoriasis:  Efficacy, safety and tolerability results from a phase 2b randomized controlled 
trial.  J Dermatology 2017;44(8):  873-884. 
Rich P, Scher RK.  Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis.  
J Am Acad Dermatol  2003;49(2):206-12. 
Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, et al.  Apremilast, a cAMP 
phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of 
psoriasis.  Brit J Pharmacol  2010;159:842-55. 
Shiratori A., Efficacy of Mequitazine (LM-209) on pruritus’ skin disease.  West Japan 
Dermatology 1983;45:470-473. 
The Practical Guide, Identification, Evaluation, and Treatment of Overweight and Obesity in 
Adults. NHLBI Obesity Education Initiative, October 2000: 
https://www.nhlbi.nih.gov/files/docs/guidelines/prctgd_c.pdf. Accessed on April 23, 2018. 


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Walsh JA, McFadden M, Woodcock J, Clegg DO, Helliwell P, Dommasch E, et al.  Product of 
the Physician Global Assessment and body surface area: a simple static measure of psoriasis 
severity in a longitudinal cohort. J Am Acad Dermatol 2013;69(6):931-7. 
 


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18. 
APPENDICES 
Appendix A: Table of Abbreviations and Specialist Terms 
Abbreviation or 
Specialist Term 
Explanation 
ADL 
Activity of daily life 
AE 
Adverse event 
ANC 
Absolute neutrophil count 
APC 
Antigen presenting cell 
β-hCG 
β-subunit of human chorionic gonadotropin 
BID 
Twice daily 
BSA 
Body surface area 
CI 
Confidence interval 
CRF 
Case report form 
DLQI 
Dermatology Life Quality Index 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetretraacetic acid 
EOT 
End of treatment 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
NAPSI 
Nail Psoriasis Severity Index of target nail 


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Abbreviation or 
Specialist Term 
Explanation 
PBI 
Patient Benefit Index 
PBQ 
Patient Benefit Questionnaire 
PDE4 
Phosphodiesterase type 4 
PASI 
Psoriasis Area Severity Index 
PNQ 
Patient Needs Questionnaire  
PC 
Product Complaint 
RBC 
Red blood cell count 
SAE 
Serious adverse event 
ScPGA 
Scalp Physician Global Assessment 
sPGA 
static Physician’s Global Assessment  
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TSQM 
Treatment Satisfaction Questionnaire for Medication (TSQM) Version II 
VAS 
Pruritis Visual Analog Scale 
 


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Appendix B: Static Physician’s Global Assessment (sPGA) 
The sPGA is the assessment by the Investigator of the overall disease severity at the time of 
evaluation. 
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) 
Source: Walsh, 2013. 
 
 


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


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Appendix D: Pruritus Visual Analog Scale (VAS) 
Subject’s assessment of pruritus (Itch) 
On average, how much itch have you had because of your condition in the past week? 
 
Please note: VAS above is not drawn to scale and is for illustrative purposes only. 
 
 
No itch at all
Worst itch imaginable
0 mm
100 mm
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Appendix E: Nail Psoriasis Severity Index (NAPSI) 
 
The target thumb or finger nail which represents the worst nail 
psoriasis is graded for nail matrix psoriasis and nail bed psoriasis.  
The sum of these two scores is the total score for that nail. 
Evaluation 1: Nail matrix. In each quadrant of 
the nail, nail matrix psoriasis is evaluated by 
presence of any of the nail matrix features 
(pitting, leukonychia red spots in the lunula, 
crumbling): 
 
Score for nail matrix psoriasis  _____________ 
 
0 = none 
1 = present in 1/4 nail 
2 = present in 2/4 nail 
3 = present in 3/4 nail 
4 = present in 4/4 nail 
Evaluation 2: Nail bed. Nail bed psoriasis is 
evaluated by the presence of any of the nail bed 
features (onycholysis, splinter hemorrhages, 
subungual hyperkeratosis, “oil drop” (salmon 
patch dyschroma):  
 
Score for nail bed psoriasis  _____________ 
 
0 = none 
1 = present in 1/4 nail 
2 = present in 2/4 nail 
3 = present in 3/4 nail 
4 = present in 4/4 nail 
TOTAL FOR NAIL___________  (0-8) 
Source:  Rich, 2003. 


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Appendix F: 
Psoriasis Area Severity Index (PASI) 
* Round all calculations to 1 decimal place. 
 
Source:  Frederiksson, 1978. 
 
 


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Appendix G: The Dermatology Life Quality Index (DLQI) 
Please check/tick (√) 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 garden?  
_ Very much _ 
A lot _ A little _ 
Not at all  
 
_ Not relevant  
 
4. Over the last week, how much has your skin 
influenced the clothes you wear?  
_ Very much _ 
A lot _ A little _ 
Not at all  
 
_ Not relevant  
 
5. Over the last week, how much has your skin affected 
any social or leisure activities?  
_ Very much _ 
A lot _ A little _ 
Not at all  
 
_ Not relevant  
 
6. Over the last week, how much has your skin made it 
difficult for you to do any sport?  
_ Very much _ 
A lot _ A little _ 
Not at all  
 
_ Not relevant  
 
7. Over the last week, has your skin prevented you 
from working or studying?  
_ Yes _ No  
_ Not relevant  
If “No”, over the last week how much has your skin 
been a problem at work or studying?  
_ A lot _ A little 
_ Not at all  
 
 
8. Over the last week, how much has your skin created 
problems with your partner or any of your close 
friends or relatives?  
_ Very much _ 
A lot _ A little _ 
Not at all 
 
_ Not relevant 
 
9. Over the last week, how much has your skin caused 
any sexual difficulties? 
_ Very much _ 
A lot _ A little _ 
Not at all 
 
_ Not relevant 
 
10. Over the last week, how much of a problem has the 
treatment for your skin been, for example, by 
making your home messy, or by taking up time? 
_ Very much _ 
A lot _ A little _ 
Not at all 
 
_ Not relevant 
 
 
Source:  Finlay, 1994. 
 
 


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Appendix H: Shiratori’s Pruritus Severity Score 
 
 
Severity 
Day Time Symptom 
Night Time Symptom 
0 
Nothing 
Little or not at all feel the itch. 
Little or not at all feel the itch. 
1 
Minimal 
Sometimes feel creepy, but able to 
endure it without scratching. 
Feel slight itching at bedtime, but not 
particularly scratched by consciousness. 
Sleep well. 
2 
Mild 
Sometimes hands go up, getting 
scratched slightly but it does not bother 
much. 
There is somewhat itching, but after 
scratching, it will relent. Not to be 
awakened by itching. 
3 
Moderate 
Feel pretty itchy and scratches even in 
public. Irritated due to itching, scratching 
constantly. 
Awoke due to itching. Scratch for a while 
and fall in sleep, but scratch unconsciously 
while asleep. 
4 
Severe 
Can’t endure itching. Even if scratch, 
itchiness does not relent, it becomes 
more and neither work nor study can get 
it on my hands. 
Hardly sleep due to itchiness. Often 
scratching, but it becomes itching more 
and more. 
Source:  Shiratori, 1983. 
 
 


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Appendix I: Treatment Satisfaction Questionnaire for Medication (TSQM)  
Version II 
 
Instructions:  Please take some time to think about your level of satisfaction or dissatisfaction 
with the medication you are taking in this clinical trial.  We are interested in your evaluation of 
the effectiveness, side effects, and convenience of the medication over the last two to three 
weeks, or since you last used it.  For each question, please place a single check mark next to the 
response that most closely corresponds to your own experiences. 
 
1. How satisfied or dissatisfied are you with the ability of the medication to prevent or treat your 
condition?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
2. How satisfied or dissatisfied are you with the way the medication relieves your symptoms?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
3. As a result of taking this medication, do you experience any side effects at all? 
□1   Yes 
□0   No 
 
4. How dissatisfied are you by side effects that interfere with your physical health and ability to 
function (e.g., strength, energy levels)? 
□1   A Great Deal 
□2   Quite a Bit 
□3   Somewhat  
□4   Minimally 
□5   Not at All  


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5. How dissatisfied are you by side effects that interfere with your mental function (e.g., ability 
to think clearly, stay awake)? 
□1   A Great Deal 
□2   Quite a Bit 
□3   Somewhat  
□4   Minimally 
□5   Not at All  
 
6. How dissatisfied are you by side effects that interfere with your mood or emotions (e.g., 
anxiety/fear, sadness, irritation/anger)? 
□1   A Great Deal 
□2   Quite a Bit 
□3   Somewhat  
□4   Minimally 
□5   Not at All  
 
7. How satisfied or dissatisfied are you with how easy the medication is to use?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
8. How satisfied or dissatisfied are you with how easy it is to plan when you will use the 
medication each time?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 


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9. How satisfied or dissatisfied are you by how often you are expected to use/take the 
medication? 
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
10. How satisfied are you that the good things about this medication outweigh the bad things?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
11. Taking all things into account, how satisfied or dissatisfied are you with this medication?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
Source: Atkinson, 2005. 
 
 


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Appendix J: 
Patient Needs Questionnaire (PNQ) 
 
With the help of the following questions, we’d like to know how important the below mentioned 
goals are to you personally in the current treatment of your skin disease. 
For each of the following statements, please mark how important this treatment goal is to you.  
If a statement does not apply to you, e.g. because you do not have pain, please mark “does not 
apply to me”.  
 
 
Source: Feuerhahn, 2012. 
 
 


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Appendix K: Patient Benefit Questionnaire (PBQ) 
 
At the start of the treatment, you indicated in a questionnaire how important various goals were 
in the treatment of your skin disease. 
Please mark each of the following statements according to the extent that these treatment goals 
were achieved, thereby indicating if the treatment has benefitted you. If a statement did not 
apply to you, e.g. because you had no pain, please mark “did not apply to me”. 
 
 
Source: Feuerhahn, 2012. 
 
 


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Appendix L: Waist Circumference Measurement 
 
Measuring Tape Position for Waist (Abdominal) Circumference 
 
How to Measure Waist Circumference 
a. Place a tape measure around subject’s waist above the tip  
of hipbone. 
b. Ask the subject to exhale. 
c. Measure the waist after exhaling. 
 
Sources: NHLBIObesity. 
 
 


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Appendix M: 
Subject Diary 
 
mm/dd 
(a day of the week) 
Application quantity compared with the previous day 
□decrease 
□no change 
□increase 
mm/dd 
(a day of the week) 
Application quantity compared with the previous day 
□decrease 
□no change 
□increase 
mm/dd 
(a day of the week) 
Application quantity compared with the previous day 
□decrease 
□no change 
□increase 
mm/dd 
(a day of the week) 
Application quantity compared with the previous day 
□decrease 
□no change 
□increase 
mm/dd 
(a day of the week) 
Application quantity compared with the previous day 
□decrease 
□no change 
□increase 
mm/dd 
(a day of the week) 
Application quantity compared with the previous day 
□decrease 
□no change 
□increase 
mm/dd 
(a day of the week) 
Application quantity compared with the previous day 
□decrease 
□no change 
□increase 
 
 
 


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Appendix N: 
SAMPLE SERIOUS ADVERSE EVENT REPORT FORM 
 


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Appendix O: 
PREGNANCY NOTIFICATION FORM 
 
 
 


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Appendix P: 
LACTATION NOTIFICATION FORM 
  
 


EDMS Doc. Number: 24661141 - 23129988
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  Vice President and Head of Immunology & Fibrosis Clinical Develo
Date: Tuesday, 28 April 2020, 10:04 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================


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TITLE PAGE 
– SUMMARY OF CHANGES – 
AMENDMENT NO. 1 
OPEN-LABEL, SINGLE-ARM STUDY OF THE 
EFFICACY AND SAFETY OF APREMILAST, IN 
SUBJECTS WITH PLAQUE PSORIASIS THAT IS NOT 
ADEQUATELY CONTROLLED BY TOPICAL 
THERAPY 
 
INVESTIGATIONAL PRODUCT (IP): 
 
Apremilast (CC-10004) 
PROTOCOL NUMBER: 
 
CC-10004-PSOR-023  
ORIGINAL DATE: 
 
30 Jan 2019  
AMENDMENT No.1 DATE: 
 
28 Apr 2020  
EudraCT NUMBER: 
 
Not Applicable  
IND NUMBER:  
 
Not Applicable  
 
Contact Information:  
 
 
Name: 
, M.D., Ph.D. 
 
Title: 
Associate Medical Director, Inflammation and 
Immunology 
 
Address:  
9-7-1 Akasaka Minato-ku Tokyo 107-6239, Japan 
 
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. 


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AMGEN THERAPEUTIC AREA HEAD SIGNATURE PAGE 
 
 
{See appended electronic signature page} 
 
 
Signature of Amgen Therapeutic Area Head 
 
dd mmm yyyy 
 
 Vice President 
Printed Name of Amgen Therapeutic Area Head and Title 
 
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.  
 
 
 


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Summary of Changes CC-10004-PSOR-023 
 
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Confidential and Proprietary 
3 
CC-10004-PSOR-023 Amendment 1 Final: 28 April 2020 
1. 
JUSTIFICATION FOR AMENDMENT 
      Those changes are not significant but administrative changes for sponsor name change , 
related sentences and other minor change. 
 
1. Change of sponsor name from ‘Celgene’ to ‘Amgen’ and related function name. 
Rationale: Because sponsor is changed from Celgene to Amgen 
 
2. Change of ‘Confidential’ Box in Page 1 
Rationale: Change to Amgen wordings from Celgene’s 
 
3. Revise ‘EMERGENCY CONTACT INFORMATION’ in Page 2. 
Rationale: Change to Amgen wordings from Celgene’s 
 
4. Change of CELGENE THERAPEUTIC AREA HEAD signer in Page 3 
Rationale: According to sponsor change, signer is changed 
 
5. Revise of description for SAE, AE and the reporting and pregnancy and lactation 
related sentence in Sections 5, 6, 10  
Rationale: Revised to adjust to global standard for Otezla study protocol in Amgen 
 
6. Revise of description for ‘Section 9.1 and 9.2 
Rationale: To clear inappropriate description 
 
7. Revise ‘Section 12.1 Emergency Contact’ 
Rationale: Change to Amgen standard wordings from Celgene’s 
 
8. Revise ‘Section 15. Quality Control and Quality Assurance’ 
Rationale: According to sponsor change, revised to Amgen policy 
 
9. Revise ‘Section 16. Publications’ 
Rationale: Change to Amgen standard wordings from Celgene’s 


Apremilast (CC-10004) 
Summary of Changes CC-10004-PSOR-023 
 
Amgen Inc. 
Confidential and Proprietary 
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CC-10004-PSOR-023 Amendment 1 Final: 28 April 2020 
 
10. Add Appendix N, O, P 
Rationale: Add Amgen standard forms 
 
 
 


Approval Signatures
Document Name:
Protocol-Published Amendment  apremilast 20200062 1
Document Description:
Document Number:
CLIN-000275771
Approval Date:
26 Aug 2021
Type of Study Protocol:
Amendment
Protocol Amendment No.: 1
Document Approvals
Reason for Signing: Functional Area
Name: Hernan Picard
Date of Signature: 26-Aug-2021 16:01:35 GMT+0000

SAP_001.pdf: 
Study Identifier: CC-10004-PSOR-023 
NCT number: NCT03930186 
 
Official Title on page 1 of the Protocol: OPEN-LABEL, SINGLE-ARM STUDY OF THE 
EFFICACY AND SAFETY OF APREMILAST, IN SUBJECTS WITH PLAQUE 
PSORIASIS THAT IS NOT ADEQUATELY CONTROLLED BY TOPICAL THERAPY 
 
Official Title on page 5 of the Protocol: A PHASE 3B, OPEN-LABEL, SINGLE-ARM 
STUDY OF THE EFFICACY AND SAFETY OF APREMILAST, IN SUBJECTS WITH 
PLAQUE PSORIASIS THAT IS NOT ADEQUATELY CONTROLLED BY TOPICAL 
THERAPY 
 
Official Title in the Statistical Analysis Plan (SAP): A PHASE 3B MULTI-CENTER, 
OPENLABEL, SINGLE-ARM STUDY OF THE EFFICACY AND SAFETY OF 
APREMILAST, IN SUBJECTS WITH PLAQUE PSORIASIS THAT IS NOT 
ADEQUATELY CONTROLLED BY TOPICAL THERAPY 
 
Note: The official title in the Protocol (page 1 and 5) and Statistical Analysis Plan (SAP) are 
slightly different but these documents pertain to the same study CC-10004-PSOR-023.    
This cover page has been appended to the document for purpose of posting on 
Clinicaltrials.gov. 
 


Apremilast
Statistical Analysis Plan. Protocol CC-10004-PSOR-023
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STATISTICAL ANALYSIS PLAN
A PHASE 3B MULTI-CENTER, OPEN-LABEL, SINGLE-ARM 
STUDY OF THE EFFICACY AND SAFETY OF APREMILAST, IN 
SUBJECTS WITH PLAQUE PSORIASIS THAT IS NOT 
ADEQUATELY CONTROLLED BY TOPICAL THERAPY
STUDY DRUG:
Apremilast (CC-10004)
PROTOCOL NUMBER:
CC-10004-PSOR-023
DATE FINAL:
30APR2020
Prepared by:
Amgen K.K.
Midtown Tower, 9-7-1 Akasaka Minato-ku
Tokyo 107-6239 Japan
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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NCT Number: NCT03930186
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


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TABLE OF CONTENTS
SIGNATURE PAGE .......................................................................................................................6
1.
LIST OF ABBREVIATIONS....................................................................................8
2.
INTRODUCTION ....................................................................................................10
3.
STUDY OBJECTIVES ............................................................................................11
3.1.
Primary Objective.......................................................................................................11
3.2.
Secondary Objectives .................................................................................................11
3.3.
Exploratory Objectives...............................................................................................11
4.
INVESTIGATIONAL PLAN ..................................................................................12
4.1.
Overall Study Design and Plan...................................................................................12
4.2.
Study Endpoints..........................................................................................................13
4.2.1.
Primary Efficacy Endpoint(s).....................................................................................13
4.2.2.
Secondary Efficacy Endpoint(s).................................................................................13
4.2.3.
Exploratory Endpoint(s) .............................................................................................14
4.2.4.
Safety Endpoints.........................................................................................................14
4.2.5.
Assessments and Derivations of Efficacy Endpoints .................................................15
4.3.
Stratification, Randomization, and Blinding. .............................................................18
4.4.
Sample Size Determination ........................................................................................18
5.
GENERAL STATISTICAL CONSIDERATIONS ...............................................19
5.1.
Reporting Conventions...............................................................................................19
5.2.
Analysis Phases or Periods.........................................................................................19
5.2.1.
Open-label Combination Therapy Phase – Weeks 0 to 16.........................................19
5.2.2.
Open-label Combination Therapy Phase with Optional Topical Reduction –
Weeks 16 to 32 ...........................................................................................................19
5.2.3.
Post-Treatment Observational Follow-Up................................................................20
5.3.
Analysis Populations ..................................................................................................20
5.3.1.
Enrolled Population ....................................................................................................20
5.3.2.
Per-Protocol Population..............................................................................................20
5.3.3.
Safety Population........................................................................................................20
5.4.
Definition of baseline and day 1.................................................................................20
5.5.
Time Points.................................................................................................................20
6.
SUBJECT DISPOSITION.......................................................................................22
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7.
PROTOCOL DEVIATIONS...................................................................................23
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS............................24
8.1.
Demographics.............................................................................................................24
8.2.
Baseline Disease Characteristics and Baseline Summary of Efficacy 
Variables.....................................................................................................................24
8.3.
Medical History ..........................................................................................................25
8.4.
Prior and Concomitant Procedures.............................................................................25
8.5.
Prior and Concomitant Medications...........................................................................25
9.
STUDY TREATMENTS..........................................................................................27
9.1.
Study Treatment Duration ..........................................................................................27
9.2.
Treatment Compliance................................................................................................27
10.
EFFICACY ANALYSIS ..........................................................................................28
10.1.
General Approaches to Efficacy Analysis..................................................................28
10.2.
Multiplicity .................................................................................................................28
10.3.
Analysis of Primary Efficacy Endpoint......................................................................28
10.4.
Analyses of Secondary and Exploratory Efficacy Endpoints.....................................29
10.4.1.
Binary/Categorical Variables......................................................................................29
10.4.2.
Continuous Variables..................................................................................................30
10.5.
Subgroup Analysis......................................................................................................31
11.
SAFETY ANALYSIS ...............................................................................................32
11.1.
Adverse Events...........................................................................................................32
11.1.1.
Overall Summary of TEAEs.......................................................................................32
11.1.2.
All TEAEs ..................................................................................................................33
11.1.3.
Common TEAEs.........................................................................................................33
11.1.4.
Drug-related TEAEs ...................................................................................................33
11.1.5.
TEAEs by Maximum Severity....................................................................................33
11.1.6.
Serious TEAEs............................................................................................................33
11.1.7.
TEAEs Leading to Drug Interruption and TEAEs Leading to Drug 
Withdrawal .................................................................................................................34
11.1.8.
Deaths .........................................................................................................................34
11.2.
Clinical Laboratory Evaluations.................................................................................34
11.3.
Vital Sign, Weight, and Waist Circumference Measurements...................................34
12.
INTERIM ANALYSIS .............................................................................................35
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13.
APPENDICES...........................................................................................................36
13.1.
Handling of Dates.......................................................................................................36
13.1.1.
Calculation Using Dates .............................................................................................36
13.2.
Date Imputation Guideline .........................................................................................36
13.2.1.
Adverse Events...........................................................................................................36
13.2.2.
Prior/Concomitant Medications/Procedures...............................................................37
13.2.3.
Medical History ..........................................................................................................37
13.2.4.
Treatment Duration.....................................................................................................37
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LIST OF TABLES
Table 1: 
Abbreviations and Specialist Terms .............................................................................8
Table 2:  
Table for Visit Mapping for by Time Point Analysis.................................................20
Table 3:  
Imputation Rules for Partially Missing AE Start Dates..............................................37
LIST OF FIGURES
Figure 1: 
Study Design...............................................................................................................13
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SIGNATURE PAGE
STATISTICAL ANALYSIS PLAN (SAP) AND SAP AMENDMENT APPROVAL SIGNATURE PAGE 
SAP TITLE
Statistical Analysis Plan for A Phase 3B multi-center, open-label, single-arm 
study of the efficacy and safety of apremilast, in subjects with plaque psoriasis 
that is not adequately controlled by topical therapy
SAP VERSION, DATE
Version 1.0, 30APR2020
SAP AUTHOR
Associate Manager, Biostatistics
Printed Name and Title
Signature and Date
PROTOCOL TITLE
A Phase 3B multi-center, open-label, single-arm study of the efficacy and safety of 
apremilast, in subjects with plaque psoriasis that is not adequately controlled by 
topical therapy
INVESTIGATIONAL 
PRODUCT
Apremilast (CC-10004)
PROTOCOL NUMBER
CC-10004-PSOR 023
PROTOCOL 
VERSION, 
DATE
1.0, 30JAN2019; 2.0, 28APR2020
SIGNATURE 
STATEMENT
By my signature, I indicate I have reviewed this SAP and find its contents to be 
acceptable.
Statistical Therapeutic Area Head
Signature
Printed Name
Lead Clinical Research Physician / Clinical Research Physician
Signature
Printed Name
Lead Product Safety Physician
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Digitally signed by 
 
Date: 2020.05.01 
01:39:27 +09'00'
Digitally signed by
DN: cn=
 
Date: 2020.05.01 12:40:14 -04'00'


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Signature
Printed Name
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Digitally signed by 
DN: cn=
Date: 2020.04.30 13:52:37 -04'00'


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1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical 
BID
Twice Daily
BMI
Body Mass Index
BSA
Body Surface Area
CI
Confidence Interval
CRF
Case Report Form
CRO
Contract Research Organization 
DLQI
Dermatology Life Quality Index
EAIR
Exposure-Adjusted Incidence Rate
FCBP
Females of Childbearing Potential
GCP
Good Clinical Practice
ICH
International Council for Harmonization
IP
Investigational Product
IWRS
Interactive Web Response System
LOCF
Last Observation Carried Forward
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Affairs
MI
Multiple Imputation
MMRM
Mixed-effect Model for Repeated Measures
NA
Not Applicable
NAPSI
Nail Psoriasis Severity Index
NRI
Non-responder Imputation
PASI
Psoriasis Area and Severity Index
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PBI
Patient Benefit Index 
PBQ
Patient Benefit Questionnaire
PNQ
Patient Needs Questionnaire
PP
Per-Protocol
PsA
Psoriatic Arthritis
PT
Preferred Term
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
ScPGA
Scalp Physician Global Assessment
SI
Standard International (unit)
SOC
System Organ Class 
sPGA
Static Physician Global Assessment
STDEV
Standard Deviation
TEAE
Treatment Emergent Adverse Event
TSQM
Treatment Satisfaction Questionnaire for Medication
VAS
Visual Analog Scale
WHO DD
World Health Organization Drug Dictionary 
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2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Amgen’s 
protocol CC-10004-PSOR-023 “A Phase 3B multi-center, open-label, single-arm study of the 
efficacy and safety of apremilast, in subjects with plaque psoriasis that is not adequately controlled 
by topical therapy”.
The objective of this study is to assess the efficacy and safety of the combination of apremilast
plus topical therapies for the treatment of subjects with plaque psoriasis who have not achieved
an adequate response with topicals alone.
This SAP provides a more technical and detailed elaboration of the statistical analyses as outlined 
and/or specified in the study protocol. All statistical analyses detailed in this SAP will be conducted 
using SAS® Version 9.3 or higher.
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3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective of the study is to assess the efficacy and safety of the combination of 
apremilast plus topical therapies for the treatment of subjects with plaque psoriasis who have not 
achieved an adequate response with topicals alone.
3.2.
Secondary Objectives
The secondary objectives are:
y
To assess the efficacy of the combination of apremilast plus topical therapies for the 
treatment of subjects with scalp psoriasis who have not achieved an adequate response with 
topicals alone.
y
To assess the impact on quality of life for the combination of apremilast plus topical therapies 
for the treatment of subjects with plaque psoriasis who have not achieved an adequate response 
with topicals alone.
3.3.
Exploratory Objectives
The exploratory objectives are:
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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a phase 3B multi-center, open-label, single-arm study of the efficacy and safety of 
apremilast, in subjects with plaque psoriasis that is not adequately controlled by topical therapy.
Approximately 150 subjects will be enrolled at approximately 30 sites in Japan. After a 5-day
titration, subjects will receive apremilast 30 mg tablets orally twice daily (BID) for 32 weeks in
addition to their existing topical therapy. Beginning at Week 16, subjects will be permitted to
decrease the use of topical therapy at their discretion.
The study consists 4 phases:
x
Screening Phase – Week -4 ± 1 week 
x
Open-label Combination Therapy Phase – Weeks 0 to 16 
Subjects will receive treatment with: 

apremilast 30 mg tablets orally BID, AND 

existing topical therapy 
x
Open-Label Combination Therapy Phase with Optional Topical Reduction – Weeks 16
to 32 

All subjects will continue to receive apremilast 30 mg tablets orally BID AND
existing topical therapy 

Subjects will be permitted to decrease the use of topical therapy at their own
discretion
x
Post-treatment Observational Follow-up Phase 

Four-week Post-treatment Observational Follow-up Phase for all subjects who
complete the study or discontinue from the study early. Subjects who transition to
commercial supply of apremilast after the Week 32 visit are not required to attend
the post-treatment observational follow-up visit
 
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Figure 1:
Study Design
The study will be conducted in compliance with the International Council for Harmonization (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements.
4.2.
Study Endpoints
4.2.1.
Primary Efficacy Endpoint(s)
The primary endpoint is the proportion of subjects who achieve static Physicians Global 
Assessment (sPGA) score of 0 (clear) or 1 (almost clear) at week 16. 
4.2.2.
Secondary Efficacy Endpoint(s)
The secondary endpoints include below.
Name
Description
Timeframe
Static Physicians Global 
Assessment (sPGA)
Proportion of subjects who achieve sPGA 0 or 
1
Week 32
Scalp Physicians Global 
Assessment (ScPGA)
Proportion of subjects who achieve ScPGA 
score of 0 or 1
Weeks 16, 32
Body Surface Area (BSA)
Mean percent change from baseline in 
psoriasis-affected BSA
Weeks 16, 32
Pruritus 
Visual 
Analog 
Scale (VAS)
Mean percent change from baseline
Weeks 2, 16, 32
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Name
Description
Timeframe
Shiratori’s 
Pruritus 
Severity Score
Mean change in severity score from baseline
Weeks 2, 16, 32
Nail 
Psoriasis 
Severity 
Index (NAPSI)
Proportion of subjects that achieve a ≥50% 
reduction from baseline in NAPSI score 
(NAPSI-50) at Week 32 among subjects with 
NAPSI ≥1 at baseline
Weeks 16, 32
Dermatology Life Quality 
Index (DLQI)
Mean change from baseline
Weeks 16, 32
Psoriasis Area and Severity 
Index (PASI)
y
Mean percentage change from baseline
y
Proportion of subjects who achieve ≥75% 
reduction from baseline (PASI-75)
y
Proportion of subjects who achieve ≥50% 
reduction from baseline (PASI-50)
Weeks 16, 32
Treatment 
Satisfaction 
Questionnaire
for 
Medication (TSQM)
Mean score in domains
Weeks 0, 16, 32
Patient Benefit Index (PBI)
Proportion of subjects who achieve PBI ≥1
Weeks 16, 32
4.2.3.
Exploratory Endpoint(s)
The exploratory efficacy endpoints include:
4.2.4.
Safety Endpoints
Safety endpoints will include:
x
Adverse Events (AEs)

Type, frequency, severity, and relationship of AEs to apremilast

Number of subjects who discontinue apremilast due to any AE
x
Pregnancy tests for females of childbearing potential (FCBP)
x
Vital signs and body weight
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x
Clinical laboratory tests
4.2.5.
Assessments and Derivations of Efficacy Endpoints
The assessment and derivation of each efficacy endpoint is described below. Baseline definition 
for all efficacy endpoints is given in Section 5.4. Change from baseline is calculated as on-
treatment value minus the baseline value. Percent change from baseline is defined as 100* Change 
from baseline/Baseline value (%). Handling of time points is described in Section 5.5.
4.2.5.1.
Static Physician Global Assessment (sPGA)
The sPGA is the assessment by the Investigator of the overall disease severity at the time of
evaluation. The National Psoriasis Foundation Psoriasis Score version of a sPGA is a 5-point 
scale ranging from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), to 4 (severe), incorporating 
an assessment of the severity of the three primary signs of the disease: erythema, scaling and 
plaque elevation.
4.2.5.2.
Scalp Physicians Global Assessment (ScPGA)
The ScPGA is a measurement of overall scalp involvement. The ScPGA is a 5-point scale that 
assesses three dimensions (Plaque Elevation, Scaling, and Erythema) on a scale of 0 (clear), 1 
(almost clear), 2 (mild), 3 (moderate), to 4 (severe).
4.2.5.3.
Body Surface Area (BSA)
BSA is a measurement of involved skin. The overall BSA affected by psoriasis is estimated
based on the palm area of the subject’s hand (entire palm surface or “handprint”), which equates
to approximately 1% of total body surface area.
4.2.5.4.
Pruritus Visual Analog Scale (VAS) 
The Pruritus VAS is a continuous scale comprised of a vertical line range from 0 to 100 mm on
which the left-hand boundary (0 mm) represents no itch and the right-hand boundary (100 mm) 
represents itch as severe as can be imagined. The distance from the mark to the left-hand 
boundary will be recorded.
4.2.5.5.
Shiratori’s Pruritus Severity Score
Shiratori’s Pruritus Severity Score is assessment tool for daytime and nighttime symptoms, 
separately, on a 5-point scale (0, Nothing; 1, Minimal; 2, Mild; 3, Moderate; 4, Severe).
4.2.5.6.
Nail Assessments/Nail Psoriasis Severity Index (NAPSI)
The NAPSI will assess one target thumb nail or fingernail representing the worst nail psoriasis 
involvement at baseline. The target nail is graded for nail matrix psoriasis and nail bed psoriasis, 
both ranges from 0 to 4 for numbers of involved nail quadrants. The sum of these scores is the 
total NAPSI score for the target nail, which range from 0 to 8 (worst).
Subject whose NAPSI score is reduced by at least 50% (percent change ranges from −100% to 
−50%) are classified as having achieved NAPSI-50 response.
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4.2.5.7.
DLQI
The DLQI is questionnaire for use in a dermatology clinical setting to assess limitations related 
to the impact of skin disease. The instrument contains 10 items pertaining to the subject’s skin. 
With the exception of Item Number 7, the subject responds on a four-point scale, ranging from 
“Very Much” (score 3) to “Not at All” or “Not relevant” (score 0). Item Number 7 is a multi-part 
item, the first part of which ascertains whether the subject’s skin prevented them from working 
or studying (Yes or No, scores 3 or 0 respectively), and if “No,” then the subject is asked how 
much of a problem the skin has been at work or study over the past week, with response 
alternatives being “A lot,” “A little,” or “Not at all” (scores 2, 1, or 0 respectively). The DLQI 
total score is derived by summing all item scores, which has a possible range of 0 to 30, with 30 
corresponding to the worst quality of life, and 0 corresponding to the best.
The DLQI can be grouped into six subscales: symptoms and feelings; daily activities; leisure;
work/school; personal relationships; and treatment. Scores for four of the subscales (symptoms
and feelings, daily activities, leisure, and personal relationships) range from 0 to 6; scores for
two of the subscales (work/school and treatment) range from 0 to 3. Higher scores correspond to
poorer quality of life.
4.2.5.8.
Psoriasis Area Severity Index (PASI)
The PASI is a measure of psoriatic disease severity taking into account qualitative lesion
characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on
defined anatomical regions.
The PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. 
Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 
anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement 
on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% 
involvement). The total qualitative score (sum of erythema, thickness, and scaling scores) is 
multiplied by the degree of involvement for each anatomic region and then multiplied by a 
constant. These values for each anatomic region are summed to yield the PASI score. 
A subject is classified as having achieved PASI-75 (PASI-75 response) if the PASI score is
reduced by at least 75% from baseline, which is equivalent to a percent change from baseline
ranging from −100% to −75%. PASI-50 is similarly defined except the percent changes that must 
be achieved are at least −50%.
4.2.5.9.
Treatment Satisfaction Questionnaire for Medication (TSQM) Version II
The TSQM version II is an 11-question self-administrated instrument to understand a subject’s
satisfaction on the current therapy. The TSQM comprises 11 items across 4 domains focusing on 
effectiveness (Item 1 and 2), side effects (Item 4 to 6), convenience (Item 7 to 9), and global 
satisfaction (Item 10 and 11). With the exception of Item 3 (experience any side effects; yes or 
no), all items have five or seven responses. Item 4 to 6 have five responses (1, A Great Deal; 2, 
Quite a Bit; 3, Somewhat; 4, Minimally; 5, Not at All) and the other items (1 and 2, and 7 to 11)
have seven responses (1, Extremely Dissatisfied; 2, Very Dissatisfied; 3, Dissatisfied; 4, 
Somewhat Satisfied; 5, Satisfied; 6, Very Satisfied; 7, Extremely Satisfied). Item scores are 
summed to give four domain scores, which are in turn transformed to a scale of 0-100 as below.
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y
EFFECTIVENESS: ([(Item 1 + Item 2) − 2] divided by 12) × 100
y
SIDE EFFECTS: ([(Sum of Item 4 to Item 6) − 3] divided by 12) × 100

If one item is missing: ([(Sum of the two completed items) − 2] divided by 8) × 100
y
CONVENIENCE: ([(Sum of Item 7 to Item 9) − 3] divided by 18) × 100

If one item is missing: ([(Sum of the two completed items) − 2] divided by 12) × 100
y
GLOBAL SATISFACTION: ([(Sum of Item 10 to Item 11) − 2] divided by 12) × 100
4.2.5.10.
Patient Benefit Index (PBI)
The PBI is a validated patient-reported instrument to assess patient-relevant benefits of psoriasis 
treatment and represents the subject benefits realized as a function of most important subject needs.
PBI consist of 2 questionnaires:
x
Patient Needs Questionnaire (PNQ): Prior to starting therapy, subjects are asked to assess 
their treatment expectations by completing the PNQ. Individual importance of treatment 
objectives is collected by marking the importance of a total of 25 treatment goal statements. 
The score ranges from 0 (not at all) to 4 (very) for each treatment objective will be recorded 
in the database. 
x
Patient Benefit Questionnaire (PBQ): After a period of treatment, subjects are then asked 
to assess the benefits of treatment by completing the PBQ with the same 25 treatment goal 
statements. The score ranges from 0 (not at all) to 4 (very) will be recorded in the database.
The PBI is calculated for each subject at a given visit by weighing the achievement values of the 
treatment objectives by their importance to the individual patient using the following Algorithm. 
The preferences before treatment (PNQ) and achieved benefit after treatment (PBQ) are 
converted into a weighted index value, the PBI. The PBI is calculated by taking the individually 
determined importance for each item (PNQ) divided by the sum of all individual importance and 
multiplied by the respective benefit achieved (PBQ). The sum of the resulting products is the PBI 
which can have a value between 0 (no benefit) up to 4 (maximal benefit).
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For score calculation, both “does/did not apply” and “question unanswered” will be treatment as 
missing values. The global score will be calculated using only the items pairs (i.e., importance 
item and benefit items) for which the patient has given a response other than “does/did not apply” 
in both PNQ and PBQ. For example, importance items for which the corresponding benefit item 
has been rated as “did not apply” (or vice versa) will not be included in the denominator within 
the algorithm.
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4.3.
Stratification, Randomization, and Blinding.
Not Applicable
4.4.
Sample Size Determination
The primary endpoint of this study is the proportion of subjects who achieve a static Physicians
Global Assessment (sPGA) score of 0 or 1 at Week 16, in subjects on combined therapy of
apremilast and topicals. Because there is no control arm for the study, if the lower bound of the
95% confidence interval (CI) of the observed response rate is above 8% (ie, the upper bound of
95% CI of the response rate from the placebo group in pooled Phase III studies, namely, PSOR-
008 and PSOR-009), one can safely conclude that the treatment effect from the combined
therapy is real. A sample size of 150 subjects will support a 95% confidence interval (CI) with at
least 80% probability that the length of the interval is within 13%, assuming the expected
response rate of 15% [8.5% to 21.5%] (conservatively estimated based on data of Phase III
clinical trials). This sample size allows for a 10% discontinuation rate prior to week 16. The
sample size calculation is based on nQuery software version 7.0, and the 80% probability
supporting the margin of error is based on simulation results.
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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
x
No statistical comparisons will be made for this single-arm study;
x
Confidence intervals (CIs) are presented as 2-sided 95% CIs;
x
Summary statistics consist of the number and percentage of subjects in each category 
for discrete variables, and the sample size, mean, median, Q1, Q3, Standard Deviation, 
minimum, and maximum for continuous variables;
x
All mean and median values are formatted to one more decimal place than the measured 
value, standard deviation values are formatted to two more decimal places than the 
measured value, minimum and maximum values are presented to the same number of 
decimal places as the measured value, the 95% CI are formatted to two more decimal 
places than the measured value;
x
All percentages are rounded to one decimal place. The number and percentage of 
responses are presented in the form XX (XX.X), where the percentage is in the
parentheses, the 95% CI are presented to two decimal places. Exact 100% that is not 
rounded from a percent >99.50% is presented in the format xx (100);
x
All analysis and summary tables have the analysis population sample size (i.e., number 
of subjects);
x
All laboratory data will be reported using standard international (SI) units;
x
All collected data will be listed and the listings are sorted for presentation in order of
subject, and date of procedure or event;
x
Summary table may not be provided if few data are obtained.
5.2.
Analysis Phases or Periods
Data summary and analysis will be provided for the following analysis phases/periods.
5.2.1.
Open-label Combination Therapy Phase – Weeks 0 to 16
This phase starts on the day of baseline visit (Week 0/Visit 2), and stops on either: (1) the day of
the first IP dispensed for the next phase at Week 16/Visit 6; or (2) the day of the discontinuation 
visit if the subject discontinues prior to or at Week 16/Visit 6; or (3) the last known study day if 
the subject is lost to follow-up prior to Week 16/Visit 6 during the phase.
5.2.2.
Open-label Combination Therapy Phase with Optional Topical Reduction –
Weeks 16 to 32
This phase starts on the next day of the first IP dispensed for the phase at Week 16/Visit 6, and 
stops on either: (1) the day of the discontinuation visit if the subject discontinued prior to or at 
Week 32/Visit 8; or (2) the last known study day if the subject lost to follow-up prior to Week 
32/Visit 8 during the phase.
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5.2.3.
Post-TreatmentObservationalFollow-Up
For all subjects who complete the study or discontinue the study early, the Four-week Post-
Treatment Observational Follow-Up starts at the completion or discontinuation visit and stops at 
the follow-up visit or the last assessment date. 
5.3.
Analysis Populations
5.3.1.
Enrolled Population
The Enrolled population will consist of all subjects who receive an IWRS identification number 
and are enrolled into the study. This will be the population for all efficacy analyses unless 
otherwise specified.
5.3.2.
Per-Protocol Population
The per protocol (PP) population will consist of all subjects included in the enrolled population
who have both baseline sPGA and at least one post-baseline sPGA evaluation and no important 
protocol deviations.
5.3.3.
Safety Population
The safety population will consist of all subjects who received at least one dose of study medication 
(IP). All safety endpoints, study treatment duration, and concomitant medication summaries are 
based on the safety population.
5.4.
Definition of baseline and day 1
Baseline is defined as the last value measured on or before the day of the first IP.
5.5.
Time Points
Time points in all analyses are based on the remapped visits/study weeks using the following visit 
mapping algorithm, which may or may not be the same as the visits/study weeks as recorded in 
the database.
All visit-based data, except for those with the recorded visit being a follow-up visit, will be 
assigned to analysis visits based on study day (the date of assessment/collection relative to the 
reference date) and the defined analysis visit windows (Table 2), rather than the recorded visit. The 
only exception is that data with the recorded visit being a follow-up visit will be assigned to the 
analysis visit corresponding to the follow-up visit.
Table 2:
Table for Visit Mapping for by Time Point Analysis
Analysis Visit
Target Day
Visit Window
Week 0 (Baseline)
1
≤ 1
Open-label Combination Therapy Phase
Week 2
15
2 – 21
Week 4
29
22 – 42
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Analysis Visit
Target Day
Visit Window
Week 8
57
43 – 84
Week 16
113
85 – End of Phase
Open-Label Combination Therapy Phase with Optional Topical Reduction
Week 24
169
Start of Phase – 196
Week 32
225
197 – End of Phase
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 post-treatment observational follow-up phase 
when applicable. It is possible that multiple assessment values will fall into the same visit window. 
The following rule may be used to select the unique value for that analysis visit: 
1. Among all assessments in the same visit window for the analysis visit, select the value with 
the assessment date closest to the target day of the analysis visit;
2. If the relative days from 2 assessments are equally close to, but on different sides of the 
target day, then the latter assessment will be used for that analysis visit;
3. If multiple assessments are available on the same relative day, then the worst value of these 
assessments will be used for that relative day.
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6.
SUBJECT DISPOSITION
The number and percentage of screened subjects will be summarized. The failed 
inclusion/exclusion criteria of subjects who are screened will be included in the summary. The 
percentages will be based on the number of subjects screened.
The number of subjects in the Enrolled population, PP population, and Safety population will be 
summarized.
The numbers and percentages of subjects who enrolled, completed, and discontinued the study
treatment and each protocol phase will also be summarized. The percentages will be based on the 
number of subjects entered in each phase.
The number and percentage of subjects enrolled by study site will be tabulated. The percentages 
will be calculated based on the number of the Enrolled population.
Listings will be provided for enrolled subjects, for the reason of treatment discontinuation, and for 
subjects excluded from the PP population along with the reason.
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7.
PROTOCOL DEVIATIONS
The protocol deviations and important protocol deviations are identified and assessed by clinical 
research physician or designee following company standard operational procedure. The protocol 
deviations and important protocol deviations will be summarized for the Enrolled population.
A by-subject listing of subjects with protocol deviations and important protocol deviations in the 
Enrolled population will be provided.
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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics, baseline characteristics, and prior medication/procedure will be 
presented for the Enrolled population. Summaries for the concomitant medication/procedure will 
be presented for the Safety population. Subject data listings will also be provided.
8.1.
Demographics
Summary statistics will be provided for the continuous variables include below:
x
Age (years)
x
Weight (kg)
x
Height (cm)
x
Baseline Body Mass Index (BMI; kg/m2), BMI will be calculated as: BMI (kg/m2) = 
Weight (kg)/ Height (m2)
x
Waist circumference (cm)
Number and percentage will be provided for categorical variables include below:
x
Age category (< 65, 65 to < 75, ≥ 75 years)
x
Sex (Male, Female)
x
Race
x
Baseline BMI category (<18.5, 18.5 to < 25, 25 to < 30, 30 to <35, 35 to <40, ≥ 40 kg/m2)
x
Weight category (< 40, 40 to < 55, 55 to < 70, 70 to < 85, 85 to < 100, ≥100 kg)
8.2.
Baseline Disease Characteristics and Baseline Summary of Efficacy 
Variables
Descriptive statistics will be provided for the following continuous variables:
x
Duration of psoriasis (from date of diagnosis to the date of informed consent; year, 
presented one digit after the decimal point)
x
Baseline BSA (%)
x
Baseline pruritus VAS score
x
Baseline Shiratori’s Pruritus Severity Score (Day and Night Time)
x
Baseline NAPSI score for the target nail 
x
Baseline DLQI total score 
x
Baseline PASI score
x
Baseline Treatment Satisfaction Questionnaire for Medication (TSQM) Version II and 4
domains (effectiveness, side effects, convenience, and global satisfaction).
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Number and percentage will be provided for the following categorical variables:
x
Duration of psoriasis category: < 5, ≥ 5 to < 10, ≥ 10 to < 20, ≥ 20 years
x
Baseline sPGA score: 0 (Clear), 1 (Almost Clear), 2 (Mild), 3 (Moderate), 4 (Severe)
x
Baseline ScPGA score: 0 (Clear), 1 (Almost Clear), 2 (Mild), 3 (Moderate), 4 (Severe)
x
Baseline Shiratori’s Pruritus Severity Score (Day/Night Time): 0 (Nothing), 1 (Minimal),
2 (Mild), 3 (Moderate), 4 (Severe)
x
Baseline NAPSI score for the target nail (0-8)
x
Baseline BSA (%):  <=5, >5 to <=10, >10 to <=15, >15
x
Baseline PNQ: the importance of each of the 25 treatment goals will be summarized with 
number and percentage
x
Baseline active psoriatic arthritis (PsA) (Yes, No).
8.3.
Medical History
A summary of relevant medical history and concomitant diseases will be presented by system 
organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory 
Affairs (MedDRA) version 21.0 or higher, using frequency distributions (counts and percentages).
8.4.
Prior and Concomitant Procedures
Prior and concomitant procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.0 or higher. Frequency summaries of prior and concomitant 
procedures will be provided by 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). A concomitant 
procedure is defined as non-study procedure started during the phase, or non-study procedure
started before the phase and ended or remained ongoing during the phase. 
8.5.
Prior and Concomitant Medications
The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health Organization 
Drug Dictionary (WHO DD version Global B3 March 2019 or higher) will be used to group prior 
and concomitant medications into relevant categories. Frequency summaries will be provided by 
ATC 2 level, and standardized medication name.
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.
Concomitant medications are defined as non-study medications started during the phase, or non-
study medications started before the phase and ended or remained ongoing during the phase. 
Medications in the Follow-up Phase will include those medications started after the date of last 
dose of IP.
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Prior medications and prior medications for psoriasis will be summarized. Summaries will be 
provided for concomitant medications as well as concomitant medications for psoriasis in each 
phase.
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9.
STUDY TREATMENTS 
Summaries of study treatment duration and treatment compliance will be based on the safety
population.
9.1.
Study Treatment Duration
Study treatment duration in weeks is calculated as (the date of the last dose of study treatment –
the date of the first dose of study treatment + 1) / 7 and rounded to one decimal place for each 
subject for a given analysis phase/period.
Descriptive statistics will also be provided for treatment duration.
Study treatment duration will be summarized using duration of IP exposure categories of < 2, 2 -
< 4, 4 -< 8, 8 - < 16, 16 - < 24, 24 - < 32, ≥32 weeks.
A subject data listing of study drug records including the reasons for missed dose will be provided.
9.2.
Treatment Compliance
Summaries on the compliance rate are provided for the Open-label Combination Therapy Phase,
for the Open-label Combination Therapy Phase with Optional Topical Reduction, and overall.
As part of the routine recording of the amount of IP taken by each subject, the numbers of tablets 
dispensed and/or returned will be recorded at visits. These records will be used to calculate 
treatment compliance.
The treatment compliance (in %) for each subject will be computed as 100 times the total number 
of tablets taken (the total number of tablets dispensed minus the total number of tablets returned) 
over the analysis phase or period divided by the intended total number of tablets that should have 
been taken over the same phase or period.
Summary statistics for compliance (%) will be provided. 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.
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10.
EFFICACY ANALYSIS
10.1.
General Approaches to Efficacy Analysis
All efficacy evaluations will be conducted using the Enrolled population. Supplemental analysis 
of the primary efficacy endpoint using the PP population will be conducted, if applicable.
Listings will be provided for efficacy endpoints.
10.2.
Multiplicity
There will be no multiplicity adjustment.
10.3.
Analysis of Primary Efficacy Endpoint
The primary endpoint is the proportion of subjects that achieve sPGA score of 0 (clear) or 1
(almost clear) at Week 16. It will be analyzed using descriptive statistics which involve the 
sample size, the number of responders, point estimate of proportion of responders along with the 
associated 95% confidence intervals (CI) using a normal approximation based on the Enrolled 
population. In addition, a supplemental analysis will be performed using the PP population, if 
applicable.
All reasonable attempts will be made to prevent missing data from occurring in this study, 
especially through Week 16. However, in the case of missing data at Week 16, multiple imputation 
method will be incorporated into the primary analysis. The aim of the multiple imputation 
approach is to incorporate a representative random sample in place of the missing data such that 
an unbiased estimation can be made.
The multiple imputation (MI) method will be used to impute missing sPGA score at Week 16 using 
an imputation model involving previous sPGA scores in the open-label combination therapy phase 
(Weeks 0-16). The SAS procedure MI will be used to create M=100 complete datasets. The missing 
data patterns will be checked at the scheduled analysis visits, i.e., Baseline (Week 0), and Weeks 
2, 4, 8 and 16. If there are non-monotone missing patterns, two separate imputation procedures 
will be used to complete the imputation process.
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used to impute missing 
scores to create M=100 imputed data sets with monotone missing patterns. The seed will be set to 
804529, the imputed values will be rounded to the nearest integers and a single chain will be used 
to produce imputations. The minimum and the maximum values for imputation will be 0 and 4, 
which correspond to the lowest and the highest sPGA scores.
In the second step, the predictive mean matching method will be used to impute the remaining 
missing scores for the 100 datasets with monotone missing patterns. The imputation procedure 
will use the monotone statement to create one complete dataset for each of the monotone datasets 
from the first step, and the variables will include sPGA scores at scheduled analysis visits from 
baseline to Week 16. The seed will be set to 55218163.
After the completion of imputation, sPGA response at Week 16 will be derived based on both 
observed and imputed scores. The SAS procedure MIANALYZE will be used to combine the 
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results for the statistical inferences.
Sensitivity analysis will be conducted to account for missing data using the NRI method and the 
LOCF method. A sensitivity analysis using the PP population will also be performed, if applicable.
10.4.
Analyses of Secondary and Exploratory Efficacy Endpoints
The analyses for the secondary endpoints are described below. All efficacy endpoints listed below
will be summarized at each applicable study visits including baseline and Week 16 based on the 
observed data.
10.4.1.
Binary/Categorical Variables
y
sPGA
-
sPGA score shift table
-
Proportion of subjects who achieve sPGA score improvement of ≥ 2 from baseline
y
ScPGA
-
Proportion of subjects who achieve ScPGA score of 0 or 1 among subjects with baseline 
ScPGA score of 2 or greater
-
ScPGA score shift table
y
Shiratori’s Pruritus Severity Score
-
Shiratori’s Pruritus Severity Score shift table in Day and Night time
y
NAPSI
-
Proportion of subjects that achieve ≥ 50% reduction from baseline in NAPSI score 
(NAPSI-50) among subjects with NAPSI ≥ 1 at baseline
-
NAPSI score shift table
y
DLQI
-
Proportion of subjects who achieve DLQI improvement of ≥ 5 from baseline
-
Proportion of subjects who achieved DLQI score of 0 or 1 among subjects with DLQI 
Score ≥2 at baseline
y
PASI
-
Proportion of subjects who achieve ≥ 50% reduction from baseline (PASI-50)
-
Proportion of subjects who achieve ≥ 75% reduction from baseline (PASI-75)
-
Proportion of subjects who achieve ≥ 90% reduction from baseline (PASI-90)
y
PBI
-
PNQ and PBQ: the importance of each of the 25 treatment goals will be summarized with 
number and percentage
-
Proportion of subjects who achieve PBI ≥ 1
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A similar MI method as the primary endpoint will be applied for binary variables. Sensitivity 
analysis will be conducted for binary variables using the NRI method and LOCF method. In the 
non-responder imputation (NRI) analyses, missing data will be imputed by the worst value of each 
efficacy assessment category. In the last observation carried forward (LOCF) analyses, missing 
data will be imputed by the last post-baseline non-missing observation. For an efficacy endpoint 
which consists of multiple individual sub-scores, the LOCF method will be applied to the 
individual sub-scores rather than directly to the endpoint, and then the endpoint will be calculated 
based on the observed or imputed sub-scores. The only NRI method will be applied for a subject 
with no post-baseline data.
10.4.2.
Continuous Variables
y
BSA (psoriasis-affected)
-
Mean change and percent change from baseline in psoriasis-affected BSA
y
Pruritus VAS
-
Mean change and mean percent change from baseline in Pruritus VAS
y
Shiratori’s Pruritus Severity Score
-
Mean change in severity score from baseline in Shiratori’s Pruritus Severity Score in 
Day time and Night time
y
NAPSI
-
Mean total score change and percent change from baseline for the target nail
y
DLQI
-
Mean total score change from baseline
y
PASI
-
Mean change and percentage change from baseline
y
TSQM
-
Mean score in domains
Continuous endpoints will be analyzed using a mixed-effect model for repeated measures 
(MMRM) as the primary method. The MMRM model will use the change from baseline as the 
response variable and include visit time as a fixed effect, subject as a random effect and the baseline 
value as a covariate. Within-group least-squares means and the associated standard errors and two-
sided 95% CIs will be derived from the MMRM model. A sensitivity analysis will be conducted
for continuous variables using LOCF method to impute the missing data.
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10.5.
Subgroup Analysis
Subgroup analysis will be carried out for sPGA response at Week 16. Summary and analysis will 
be based on Enrolled population and missing values will be imputed using MI method. The 
categorical groups of each subgroup may be pooled based on the number of observations available.
The following subgroup variables will be used: 
x
Baseline sPGA score: 2 (mild), 3 (moderate)
x
Sex (Male, Female)
x
Age (< 65, 65 to < 75, ≥ 75 years)
x
Baseline weight (< 40, 40 to < 55, 55 to < 70, 70 to < 85, 85 to < 100, ≥100 kg) 
x
Baseline BMI (<18.5, 18.5 to < 25, 25 to < 30, 30 to <35, 35 to <40, ≥ 40 kg/m2)
x
Duration of psoriasis (< 5, 5 to < 10, 10 to < 20, ≥ 20 years) 
x
Baseline PASI score (≤7, >7) 
x
Baseline BSA (%) (<=5, >5 to <=10, >10 to <=15, >15)
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11.
SAFETY ANALYSIS
Safety analyses will be performed based on the safety population.
For the analyses of AEs, the following endpoints will also be summarized:
x
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.
x
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.
Descriptive statistics will be provided for vital signs, weight, waist circumference, laboratory 
values (continuous measurements) by visit. The baseline value, value at the time point, and change 
from baseline (also percent change from baseline if applicable) 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, 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.
As necessity requires, additional safety information may be provided.
11.1.
Adverse Events
AEs will be coded according to the MedDRA version 21.0 or higher. Unless otherwise specified, 
AEs will be summarized by SOC and PT, with SOCs presented in the standard international order 
and PTs within SOCs will be presented in descending order of subject incidence.
An adverse event is a 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.
Unless otherwise specified, TEAEs summaries include new events of TEAE by exposure interval 
(≤1, 1 to ≤2, 2 to ≤4, 4 to ≤16, 16 to ≤32, > 32 weeks).
11.1.1.
Overall Summary of TEAEs
An overall summary of the following AE categories will be provided:
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x
Any TEAE
x
Any drug-related TEAE
x
Any severe TEAE
x
Any serious TEAE
x
Any severe drug-related TEAE
x
Any serious drug-related TEAE
x
Any TEAE leading to drug interruption
x
Any TEAE leading to drug withdrawal
x
Any TEAE leading to death
11.1.2.
All TEAEs
All TEAEs will be summarized by SOC and PT as well as by PT only (in descending order of 
subject incidence). All TEAEs occurring after the date of the last dose of IP and up to 28 days after 
the last dose of IP will also be summarized by SOC and PT for subjects who enter the observational 
follow-up phase. A listing of AEs including all TEAE will be provided.
11.1.3.
Common TEAEs
TEAEs with subject incidence ≥ 5% (or another cut-off if justified) will be summarized by SOC 
and PT as well as by PT only in descending order of subject incidence.
11.1.4.
Drug-related TEAEs
Drug-related TEAEs will be summarized. Serious drug-related TEAEs and severe drug-related 
TEAEs will be also summarized.
11.1.5.
TEAEs by Maximum Severity
All TEAEs will be summarized by maximum severity (mild, moderate, severe, and, if needed, 
missing). If a subject reports multiple occurrences of a specific event within a specific analysis 
phase or period, the subject will be counted only once by the maximum severity. If the severity is 
missing for one or more of the occurrences, the maximum severity of the remaining occurrences 
will be used. If the severity is missing for all of the occurrences, the subject will be counted only 
once in the “missing” category of severity.
11.1.6.
Serious TEAEs
Serious TEAEs and serious drug-related TEAEs will be summarized. A subject data listing of all 
serious AEs (both TEAEs and non-TEAEs) will be provided.
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11.1.7.
TEAEs Leading to Drug Interruption and TEAEs Leading to Drug Withdrawal
TEAEs leading to drug interruption and TEAEs leading to drug withdrawal will be summarized. 
Drug-related TEAEs leading to drug interruption and drug-related TEAEs leading to drug 
withdrawal will be summarized. A subject data listing of TEAEs leading to drug withdrawal will 
be provided.
11.1.8.
Deaths
TEAEs leading to death will be summarized. A subject data listing of all deaths will be provided. 
11.2.
Clinical Laboratory Evaluations
Summary statistics (N, Mean, Standard Deviations, Median, Q1, Q3, Minimum, and Maximum)
and the corresponding changes from baseline and frequency summaries of shifts from baseline to 
post-baseline time points in terms of normal/abnormal will be provided for the selected serum 
chemistry parameters.
A subject data listing of all laboratory data, including urinalysis, will be provided.
11.3.
Vital Sign, Weight, and Waist Circumference Measurements
The endpoints for vital sign parameters, weight, and waist circumference include:
x
Observed value and change from baseline over time in vital sign parameters including 
temperature, pulse, and blood pressure
x
Shifts from baseline to post-baseline time points 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)
x
Observed value, change and percent change from baseline over time in weight and waist 
circumference
Summary statistics (N, Mean, Standard Deviations, Median, Q1, Q3, Minimum, and Maximum) 
of observed values, changes from baseline, and percent change from baseline (applicable for 
weight and waist circumference) will be provided over time. Frequency summaries (shift tables) 
of shifts from baseline to post-baseline time points in terms of normal/abnormal will be provided 
for pulse and blood pressure.
Frequency summaries of percent change in weight from baseline to the end of the study
phase/period will be provided by baseline BMI category (<18.5, 18.5 to < 25, 25 to < 30, 30 to 
<35, 35 to <40, ≥40 kg/m2) and by baseline weight category (< 40, 40 to < 55, 55 to < 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.
A subject data listing of all vital sign parameters, weight and waist circumference data will be 
provided.
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12.
INTERIM ANALYSIS
No interim analysis will be conducted.
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13.
APPENDICES
13.1.
Handling of Dates
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS).   
13.1.1.
Calculation Using Dates
Calculations using dates (e.g., subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions: 
x
Study days after the start day of study drug will be calculated as the difference between 
the date of interest and the first date of dosing of study drug plus 1 day. The generalized 
calculation algorithm for relative day is the following: 
o
If TARGET DATE >= DSTART then STUDY DAY = (TARGET DATE –
DSTART) + 1; 
o
Else use STUDY DAY = TARGET DATE – DSTART.
Depending on the study day definition, DSTART can be Day 1 for core baseline or the 
Day 1 for Apremilast treatment baseline. Negative study days are reflective of 
observations obtained before the corresponding baseline.  Note: Partial dates for the 
first study drug are not imputed in general. All effort should be made to avoid 
incomplete study drug start dates.
x
Age (in years) at the time of informed consent is collected.

When age in years is not available, age in days is calculated as (informed 
consent date – July 15 on the year of birth) + 1. Then age in years will be 
transformed to years by dividing age in days by 365.25 days, then truncating

If year of birth is also missing, set age missing 
x
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7
x
Intervals that are presented in months will be transformed from days to months by using 
(without truncation) the following conversion formula:
MONTHS = DAYS /30.4167
13.2.
Date Imputation Guideline
13.2.1.
Adverse Events
Partially missing AE start dates will be imputed in the ADaM dataset for AEs, but partially missing 
AE end dates will not be imputed. If the AE end date is complete with no missing year, month, or 
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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.
Let an AE start date be represented as “DEvent/MEvent/YEvent”, and the date of the first dose of 
apremilast as “DAPR/MAPR/YAPR”. The following table gives the imputation rules for partially 
missing AE start at Week 0/Visit 2.
Table 3:
Imputation Rules for Partially Missing AE Start Dates
Scenario
Condition
Imputation Rule
Partially missing date includes year only (both month and day are missing)
1
YEvent < YAPR
12/31/YEvent
2
Otherwise, i.e., YAPR ≤ YEvent
Max (date of first dose of apremilast, 
1/1/YEvent)
Partially missing date includes both year and month (only day is missing)
1
YEvent < YAPR, or (YEvent = YAPR and MEvent <
MAPR)
Last date of MEvent/YEvent
2
Otherwise, i.e., YAPR < YEvent, or (YAPR =
YEvent and MAPR ≤ MEvent)
Max (date of first dose of apremilast, 
1/MEvent/YEvent)
13.2.2.
Prior/Concomitant Medications/Procedures
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset for prior/concomitant 
medications/procedures. For prior/concomitant medications, if the stop date is complete with no 
missing year, month, or day, and the partially missing start date imputed by the rule below is after 
the stop date, then the start date will be imputed by the stop date.
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date.
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date.
13.2.3.
Medical History
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history (for the purposes of calculating durations of 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.
13.2.4.
Treatment Duration
Partially or completely missing last dose dates will be imputed in the ADaM dataset for treatment 
duration. 
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When partially missing last dose date is available, set last dose date to the maximum of [the earliest 
possible date given the non-missing field(s) of last dose date, the minimum of (the latest possible 
date given the non-missing field(s) of last dose date, last known date in database, first non-missing 
Early Termination (ET) visit date)].
When last dose date is completely missing, set last dose date to the minimum of (last known date 
in database, first non-missing Early Termination (ET) visit date).  
Last known date in database is defined as maximum of (last visit date, lab, vital signs, ECG 
assessment date, AE start or end dates, concomitant medications start or end dates, concomitant 
procedure date, last dose date from 'Disposition- Treatment' page, treatment exposure start or end 
dates where doses were completely or partially taken, death date).
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