Clinical trial NCT04057937
Conditions: Palmoplantaris Pustulosis
Keywords: Palmoplantar Pustulosis CC-10004 Apremilast Only Japanese Efficacy Safety Phase 2
Sponsor: Amgen
Start date: 2019-10-16; Completion date: 2021-06-07
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate whether apremilast is better than placebo (inactive substance in the same form as the drug) for the treatment in Japanese subjects with PPP. This study also will evaluate the safety and tolerability of apremilast in Japanese subjects with PPP.CC-10004-PPP-001 is a multicenter, randomized, double-blind, placebo-controlled, parallel group, Phase 2 study of apremilast in Japanese subjects with PPP and inadequate response to treatment with topical steroid and/or topical vitamin D3 derivative preparations.

The placebo-controlled period will be 16 weeks and patients will receive apremilast or placebo. After the 16-week placebo-controlled period, all subjects will receive apremilast for 16 weeks. All subjects will have their final study visit 4 weeks after stopping apremilast treatment.

Detailed description:

Arms: arm 1: Participants received matched placebo as oral tablets twice daily (BID) for up to 16 weeks (Week 0 to Week 16). Participants who completed the placebo-controlled phase entered the active-treatment phase and received apremilast 30 mg as oral tablets BID for up to an additional 16 weeks (Week 16 to Week 32). arm 2: Participants received apremilast 30 mg as oral tablets BID for up to 16 weeks (Week 0 to Week 16). Participants who completed the placebo-controlled phase entered the active-treatment phase and received apremilast 30 mg as oral tablets BID for up to an additional 16 weeks (Week 16 to Week 32).
Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: Apremilast intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE 
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP 
STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF APREMILAST (CC-10004) IN JAPANESE SUBJECTS 
WITH PALMOPLANTAR PUSTULOSIS 
PROTOCOL NUMBER: 
CC-10004-PPP-001
ORIGINAL DATE FINAL: 
08 Apr 2019
AMENDMENT 2 DATE FINAL: 
20 Apr 2020 
EudraCT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
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: NCT04057937
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 Inc.  Clinical Research Physician/Medical Monitor 
Name:
 
Title:  Associate Dir, Global Development 
Address: One Amgen Center Drive. Thousand Oaks, CA 91320 
Phone: 
 
 E-mail: 
 
 
Note: Only call Amgen Medical Information, if you are not able to reach the Clinical 
Research Physician(s) or Medical Monitor or designee for emergency calls.  
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 Council for 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies. 
 


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PROTOCOL SUMMARY 
Study Title 
A Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of apremilast (CC-10004) in Japanese subjects with 
Palmoplantar pustulosis  
Indication 
Palmoplantar pustulosis (PPP) 
PPP is a chronic and intense inflammatory skin disease with pustules, erythema and scaling 
localized to the palms and soles. PPP is an inflammatory hyperkeratosis that appears most 
commonly in middle-aged men and women, particularly those who are smokers. 
The etiology of PPP remains unknown, and it is still controversial whether PPP and localized 
pustular psoriasis are distinct entities. However, typical PPP usually presents in patients who do 
not have a personal or family history of psoriasis. Furthermore, the absence of immunogenetic 
associations of PPP with psoriasis suggests that PPP may represent a separate and distinct entity.  
Objectives 
The primary objective of the study is to evaluate the efficacy of apremilast 30 mg twice daily 
(BID) compared with placebo in Japanese subjects with PPP.  
The secondary objective is to evaluate the safety and tolerability of apremilast 30 mg BID 
compared with placebo in Japanese subjects with PPP. 
The exploratory objectives are:  
Study Design 
CC-10004-PPP-001 is a multicenter, randomized, double-blind, placebo-controlled, parallel-
group, Phase 2 study of one dose of apremilast in Japanese subjects with PPP. 
Approximately 86 subjects will be randomized in a 1:1 ratio to one of the two treatment groups. 
Subject randomization for treatment assignments will be stratified according to a subject’s 
rounded Palmo-Plantar Pustulosis Area and Severity Index (PPPASI) score (≤20 / 21-30 / ≥31), 
and whether a subject has any focal infection (yes/no).  
The study includes 4 phases: 
1. Screening phase for up to 4 weeks (28 days) 
2. Sixteen weeks, double-blind, placebo-controlled phase (apremilast 30 mg BID and 
placebo) 
3. Sixteen weeks, active treatment phase (apremilast 30 mg BID) 
• Subjects randomized to apremilast continue apremilast treatment  


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• Subjects randomized to placebo treatment switch to apremilast treatment in a blind 
manner. 
4. Four weeks post-treatment observational follow-up phase at any time the subject 
completes or discontinues the trial 
During the treatment phase, all subjects will visit the clinical site every 2 weeks until Week 16 
and every 4 weeks from Week 16 to Week 32.  
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed and the primary data analysis will be conducted. However, 
unblinded data will only be made available to selected Sponsor and contract research 
organization (CRO) team members involved with analysis of the data. All other Sponsor, site, 
and CRO personnel directly involved with the conduct of the study, will remain blinded to 
treatment assignments until the final database lock at the conclusion of the study. 
The study will be conducted in compliance with ICH Good Clinical Practices (GCPs). 
Study Population 
Study population is adult Japanese subjects (≥ 20 years of age) with PPP and inadequate 
response to the treatment with topical steroid and/or topical vitamin D3 derivative preparations.  
Length of Study 
This study consists of 4 phases: screening period of up to 4 weeks, 16 weeks for double-blind, 
placebo-controlled phase, 16 weeks for active treatment phase and 4 weeks for follow-up. Total 
study duration per subject is approximately 40 weeks at maximum. 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date. 
Study Treatments 
All Investigational Product (IP) will be provided in blister cards throughout the entire study. 
Apremilast will be provided as 10, 20, or 30 mg tablets. Placebo will be provided as identically 
appearing 10, 20, or 30 mg tablets by the Sponsor.  
Apremilast will be taken orally twice daily, approximately 12 hours apart, without restriction of 
food or drink. To mitigate potential gastrointestinal (GI) side effects, dose titration will be 
implemented in the first week of this study and at Week 16 for subjects initially randomized to 
placebo when they switch to apremilast 30 mg BID treatment. 
Any dose modifications outside of the dose described above are not permitted in this study. 
Overview of Key Efficacy Assessments 
1. Primary Efficacy Assessments  
• PPPASI  
− The primary endpoint is the proportion of subjects who achieve ≥ 50% 
improvement in PPPASI total score from baseline (PPPASI-50) at Week 16. 


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2. Secondary/Exploratory Efficacy Assessments 
• PPPASI 
− Proportion of subjects who achieve a PPPASI-50 except for Week 16. 
− Proportion of subjects who achieve ≥ 75% improvement in PPPASI total score 
from baseline (PPPASI-75).  
− Area under the curve (AUC) of PPPASI total score 
− Percent change from baseline of PPPASI total score 
− Change from baseline of individual sub scores 
• Palmo-Plantar Pustulosis Severity Index (PPSI) 
− AUC of PPSI total score 
− Percent change from baseline of PPSI total score 
• Physician’s Global Assessment (PGA) score for palms and soles 
− Change from baseline of PGA score for palms and soles 
− Proportion of subjects who achieve a PGA score of cleared (0) or minimal (1) 
− Proportion of subjects who achieve a PGA score of cleared (0) or minimal (1) and 
have at least a 2-grade improvement 
• Modified PPPASI 
− Proportion of subjects who achieve a modified PPPASI-50. 
− Proportion of subjects who achieve a modified PPPASI-75. 
− AUC of modified PPPASI total score 
− Percent change from baseline of modified PPPASI total score 
− Change from baseline of individual sub scores 
• Subject’s Reported Outcome (SRO) 
− Subject’s Visual Analogue Scale (VAS) assessment for PPP symptoms 
− Subject’s assessment for each sign/finding of PPP (using PPSI scale) 
• Health-Related Quality of Life (HRQoL) questionnaires 
− Dermatology Life Quality Index (DLQI) 
− EuroQol 5 Dimension (EQ-5D) 
Overview of Key Safety Assessments 
Safety and tolerability assessments will include; 
1. Treatment-emergent adverse events (TEAEs) 


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• Frequency and incidence rate of any TEAEs by System Organ Class (SOC), Preferred 
Term (PT), severity, and relationship of adverse events (AEs) to IP. 
2. Clinically significant changes in body weight, vital signs, and/or laboratory findings  
• Frequency of clinically significant changes in body weight, vital signs, and/or 
laboratory findings. 
Statistical Methods 
Efficacy 
The primary analysis of the proportion of subjects who achieve a PPPASI-50 at Week 16 will be 
carried out using a chi-square test. A result will be expressed as number and percentages of 
subjects who achieve a PPPASI-50 and associated 90% confidence intervals (CIs) and p-values. 
The statistical test will be conducted at the α = 0.10 (two-sided) level. 
For the exploratory purpose, secondary and exploratory efficacy endpoints including but not 
limited to PPPASI, PPSI, PGA and SRO, will be tested without multiplicity adjustment, 
therefore p-values for those endpoints will be regarded as nominal. 
Safety 
All safety data will be listed and summarized by treatment group and/or study period as 
appropriate. All treatment-emergent AEs will be coded and tabulated by system organ class and 
preferred term. Incidence of treatment-emergent AEs, serious adverse events (SAEs), AEs 
leading to discontinuation, and AEs of special interest will be summarized and presented in 
descending order of frequency in the apremilast 30 mg BID group. Individual subject values will 
be listed and values outside of the standard reference range will be flagged. Shift tables and 
analyses of changes from baseline will be produced. The change from baseline for the vital signs 
including weight will be summarized. Incidence of abnormal vital signs parameters will be 
tabulated. 
Sample Size Justification 
A total of approximately 86 subjects will be randomized 1:1 ratio to receive apremilast 30 mg 
BID or placebo. The study has 80% power (based on a chi-square test at a 2-sided significance 
level of 0.10) to demonstrate the superiority of apremilast 30 mg BID over placebo with respect 
to the primary endpoint of PPPASI-50 at Week 16, assuming the PPPASI-50 rates of 45% 
(apremilast 30 mg BID) and 20% (placebo), respectively. PPPASI-50 rate of 20% at Week 16 in 
placebo is based on the placebo rate of 21% at Week 16 in guselkumab Phase 2 study. 
Considering at least 20% difference as a clinically meaningful difference, apremilast 30 mg BID 
PPPASI rate of 45% is expected in this study. 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL SUMMARY ...............................................................................................................5 
1. 
INTRODUCTION ......................................................................................................16 
1.1. 
Disease Background ...................................................................................................16 
1.1.1. 
Palmoplantar Pustulosis ..............................................................................................16 
1.1.2. 
Diagnosis of PPP ........................................................................................................16 
1.1.3. 
Evaluation of Complication ........................................................................................17 
1.1.4. 
Current Treatment Guidance ......................................................................................17 
1.2. 
Compound Background ..............................................................................................18 
1.3. 
Rationale .....................................................................................................................18 
1.3.1. 
Study Rationale and Purpose ......................................................................................18 
1.3.2. 
Rationale for the Study Design ...................................................................................19 
1.3.3. 
Rationale for Dose, Schedule and Regimen Selection ...............................................19 
1.3.4. 
Rationale for Choice of Comparator Compounds ......................................................20 
1.3.5. 
Rationale for Pharmacodynamics and Predictive Biomarkers ...................................20 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................21 
3. 
OVERALL STUDY DESIGN ....................................................................................25 
3.1. 
Study Design ...............................................................................................................25 
3.2. 
Study Duration for Subjects ........................................................................................27 
3.3. 
End of Trial .................................................................................................................27 
4. 
STUDY POPULATION .............................................................................................28 
4.1. 
Number of Subjects ....................................................................................................28 
4.2. 
Inclusion Criteria ........................................................................................................28 
4.3. 
Exclusion Criteria .......................................................................................................29 
5. 
TABLE OF EVENTS .................................................................................................33 
6. 
PROCEDURES ..........................................................................................................37 
6.1. 
Screening Period .........................................................................................................37 
6.2. 
Treatment Period (Placebo-controlled phase and Active treatment phase) ................39 
6.2.1. 
End of Treatment ........................................................................................................41 
6.3. 
Follow-up Period ........................................................................................................41 
6.3.1. 
Observational Follow-up Visit ...................................................................................42 


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6.4. 
Efficacy Assessment ...................................................................................................42 
6.4.1. 
PPPASI .......................................................................................................................42 
6.4.2. 
PPSI ............................................................................................................................43 
6.4.3. 
PGA for Palms and Soles ...........................................................................................43 
6.4.4. 
Modified PPPASI .......................................................................................................43 
6.5. 
Safety Assessment ......................................................................................................43 
6.5.1. 
Adverse Events ...........................................................................................................43 
6.5.2. 
Psychiatric Evaluation ................................................................................................43 
6.5.3. 
Serum and Urine Pregnancy Tests for Females of Childbearing Potential 
(FCBP) ........................................................................................................................44 
6.5.4. 
Contraception Education ............................................................................................44 
6.5.5. 
Severe Diarrhea, Nausea and Vomiting ......................................................................44 
6.5.6. 
Hepatitis B and C ........................................................................................................44 
6.5.7. 
Vital Signs, Height, and Weight .................................................................................44 
6.5.8. 
Complete Physical Examination .................................................................................45 
6.5.9. 
Limited Physical Examination ....................................................................................45 
6.5.10. 
Clinical Laboratory Evaluations .................................................................................45 
..........................................45 
..........................................46 
..........................................46 
..........................................46 
6.7. 
Subject Reported Outcomes .......................................................................................46 
6.7.1. 
Subject’s VAS Assessment for PPP Symptom ...........................................................46 
6.7.2. 
Subject’s Assessment for PPP Signs/Findings ...........................................................46 
6.7.3. 
Quality of Life/ Treatment Satisfaction ......................................................................46 
6.7.3.1. 
DLQI ...........................................................................................................................47 
6.7.3.2. 
EQ-5D .........................................................................................................................47 
7.
DESCRIPTION OF STUDY TREATMENTS ..........................................................48 
7.1. 
Description of Investigational Product(s) ...................................................................48 
7.2. 
Description of Placebo ................................................................................................49 
7.3. 
Treatment Administration and Schedule ....................................................................51 
7.3.1. 
Dose Modification/Interruptions ................................................................................51 
7.4. 
Overdose .....................................................................................................................51 


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7.5. 
Method of Treatment Assignment ..............................................................................51 
7.6. 
Packaging and Labeling ..............................................................................................52 
7.7. 
Investigational Product Accountability and Disposal .................................................52 
7.7.1. 
Investigational Product Accountability ......................................................................52 
7.7.2. 
Record of Administration ...........................................................................................52 
7.8. 
Investigational Product Compliance ...........................................................................52 
8. 
CONCOMITANT MEDICATIONS AND PROCEDURES ......................................54 
8.1. 
Permitted Concomitant Medications and Procedures .................................................54 
8.1.1. 
Double Blind, Placebo-controlled Phase (Week 0 to Week 16) .................................54 
8.1.2. 
Active Treatment Phase (from Week 16 to 32) ..........................................................54 
8.2. 
Prohibited Concomitant Medications and Procedures ................................................55 
8.2.1. 
Double-blind, Placebo-controlled Phase (Week 0 to Week 16) .................................55 
8.2.2. 
Active Treatment Phase (from Week 16 to 32) ..........................................................56 
8.2.3. 
Observational Follow-up ............................................................................................56 
8.3. 
Required Concomitant Medications and Procedures ..................................................56 
9. 
STATISTICAL CONSIDERATIONS .......................................................................57 
9.1. 
Overview .....................................................................................................................57 
9.2. 
Study Population Definitions ......................................................................................57 
9.3. 
Sample Size and Power Considerations .....................................................................57 
9.4. 
Background and Demographic Characteristics ..........................................................58 
9.5. 
Subject Disposition .....................................................................................................58 
9.6. 
Efficacy Analysis ........................................................................................................58 
9.6.1. 
Efficacy Evaluation for the Primary and Secondary Endpoints .................................58 
9.6.1.1. 
Primary Efficacy Endpoint - (Weeks 0 - 16) ..............................................................58 
9.6.1.2. 
Secondary Efficacy Endpoints - (Weeks 0 - 16) ........................................................58 
9.6.1.3. 
Primary and Secondary Endpoints - (Weeks 16 - 32) ................................................59 
9.6.1.4. 
Subgroup Analysis ......................................................................................................59 
9.6.2. 
Efficacy Evaluation for Exploratory Endpoints - (Weeks 0 - 16) ..............................59 
9.6.3. 
Efficacy Evaluations for Exploratory Endpoints (Weeks 16 - 32) .............................59 
9.7. 
Safety Analysis ...........................................................................................................59 
9.8. 
Interim Analysis ..........................................................................................................60 
9.9. 
Other Topics ...............................................................................................................60 
9.9.1. 
Concomitant Therapy .................................................................................................60 


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10. 
ADVERSE EVENTS..................................................................................................62 
10.1. 
Monitoring, Recording and Reporting of Adverse Events .........................................62 
10.2. 
Evaluation of Adverse Events ....................................................................................62 
10.2.1. 
Seriousness .................................................................................................................62 
10.2.2. 
Severity/Intensity ........................................................................................................64 
10.2.3. 
Causality .....................................................................................................................65 
10.2.4. 
Duration ......................................................................................................................65 
10.2.5. 
Action Taken ..............................................................................................................65 
10.2.6. 
Outcome ......................................................................................................................65 
10.3. 
Abnormal Laboratory Values .....................................................................................65 
10.4. 
Pregnancy ...................................................................................................................66 
10.4.1. 
Females of Childbearing Potential (FCBP) – Collection of Pregnancy 
Information .................................................................................................................66 
Collection of Lactation Information ..............................................................................................67 
10.5. 
Reporting of Serious Adverse Events .........................................................................68 
10.5.1. 
Safety Queries .............................................................................................................68 
10.6. 
Expedited Reporting of Adverse Events .....................................................................69 
11. 
DISCONTINUATIONS .............................................................................................70 
11.1. 
Treatment Discontinuation .........................................................................................70 
11.2. 
Study Discontinuation ................................................................................................70 
12. 
EMERGENCY PROCEDURES ................................................................................72 
12.1. 
Emergency Contact .....................................................................................................72 
12.2. 
Emergency Identification of Investigational Products ...............................................72 
13. 
REGULATORY CONSIDERATIONS......................................................................73 
13.1. 
Good Clinical Practice ................................................................................................73 
13.2. 
Investigator Responsibilities .......................................................................................73 
13.3. 
Subject Information and Informed Consent ...............................................................74 
13.4. 
Confidentiality ............................................................................................................74 
13.5. 
Protocol Amendments ................................................................................................74 
13.6. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval .....................................................................................................................74 
13.7. 
Ongoing Information for Institutional Review Board/ Ethics Committee .................75 


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13.8. 
Termination of the Study ............................................................................................75 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................76 
14.1. 
Data/Documents .........................................................................................................76 
14.2. 
Data Management .......................................................................................................76 
14.3. 
Record Retention ........................................................................................................76 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
15.1. 
Study Monitoring and Source Data Verification ........................................................78 
15.2. 
Audits and Inspections ................................................................................................78 
15.3. 
Product Quality Complaint .........................................................................................78 
16. 
PUBLICATIONS .......................................................................................................80 
17. 
REFERENCES ...........................................................................................................81 
18. 
APPENDICES ............................................................................................................85 
APPENDIX A. TABLE OF ABBREVIATIONS .......................................................................86 
APPENDIX B. PPPASI (PALMO-PLANTAR PUSTULOSIS AREA AND 
SEVERITY INDEX) ..................................................................................................91 
APPENDIX C. PALMO-PLANTAR PUSTULOSIS SEVERITY INDEX (PPSI) ....................92 
APPENDIX D. PHYSICIAN’S GLOBAL ASSESSMENT (PGA) FOR PALMS AND 
SOLES ........................................................................................................................93 
APPENDIX E. VISUAL ANALOGUE SCALES (VAS) - PPP SYMPTOMS FOR 
HANDS AND FEET ..................................................................................................94 
APPENDIX F. MODIFIED PPPASI ..........................................................................................95 
APPENDIX G. SUBJECT’S ASSESSMENT - PPP SIGNS/FINDINGS FOR HANDS 
AND FEET .................................................................................................................96 
APPENDIX H. DERMATOLOGY LIFE QUALITY INDEX (DLQI) ......................................97 
APPENDIX I. EUROQOL 5 DIMENSION (EQ-5D) ................................................................98 
APPENDIX J. SAMPLE SERIOUS ADVERSE EVENT REPORT FORM ...........................101 
APPENDIX K. PREGNANCY NOTIFICATION FORM .......................................................104 
APPENDIX L. LACTATION NOTIFICATION FORM .........................................................105 
 
 
 


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LIST OF TABLES 
Table 1: 
Study Objectives .........................................................................................................21 
Table 2: 
Study Efficacy Endpoints ...........................................................................................21 
Table 3: 
Study Safety Endpoint ................................................................................................24 
.....................................................................................24 
Table 5: 
Schedule of Events .....................................................................................................33 
Table 6: 
Treatment Schema for Dose Titration at Visit 2 (Week 0) .........................................50 
Table 7: 
Treatment Schema for Dose Titration at Visit 10 (Week 16) .....................................50 
Table 8: 
Abbreviations and Specialist Terms ...........................................................................86 
 


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


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1. 
INTRODUCTION 
1.1. 
Disease Background  
1.1.1. 
Palmoplantar Pustulosis 
Palmoplantar pustulosis (PPP) is a chronic and intensely inflammatory skin disease with 
pustules, erythema and scaling localized to the palms and soles. PPP is an inflammatory 
hyperkeratosis that appears most commonly in middle-aged men and women, particularly those 
who are smokers (Kobayashi, 2010). PPP was first reported by Andrews in 1934, which 
described 15 patients with recalcitrant pustular eruptions of the extremities in whom there was no 
evidence of psoriasis (Andrews, 1934). Andrews called this disease “Pustular Bacterid of the 
hands and feet” (Andrews, 1935). 
PPP is characterized by the mixture of blisters and pustules on the palms and soles. Pseudo-
vesicle with pimple and pustule are observed in the center of the blister. Pimples can be observed 
by dermoscopic examination, even if it is difficult to be observed by the naked eye. Symptoms 
first develop as erythema with pruritus followed by vesicle formation. The blister gradually 
enlarges to form a pustule with neutrophils. Then, it becomes crusted and scaly around the 
lesion, and it desquamates. After that, erythematous desquamation plaque is observed in addition 
to the blister and the pustule. In some cases, exanthem on the outside of the palm, sole and nail 
lesion is also observed (Tsuruta, 2016). 
The etiology of PPP remains unknown, and it is still controversial whether PPP and localized 
pustular psoriasis are distinct entities. However, typical PPP usually presents in patients who do 
not have a personal or family history of psoriasis. Furthermore, the absence of immunogenetic 
associations of PPP with psoriasis suggests that PPP may represent a separate and distinct entity 
(Murakami, 2010). Also, it was reclassified as an independent disease in 2007 by the 
International Psoriasis Council (Griffiths, 2007). 
The number of Japanese PPP patients was reported as 136,224 in 2010 and the national 
prevalence of PPP was reported as 0.12% (Kubota, 2015). 
1.1.2. 
Diagnosis of PPP 
The diagnosis criteria of PPP are proposed as follows (Hayama, 2017): 
• Sterile pustules located in palms and/or soles, 
• Change from blister to pustule via pustulo-vesicles with progression of disease, and 
• Repeat recurrence at the same skin lesion and shows the chronic course profile 
Tinea pedis, dyshidrosis, pustular psoriasis, palmoplantar exanthem with eosinophilic pustular 
folliculitis, and acrodermatitis continua suppurativa hallopeau are excluded. Only the blister 
(dyshidrosis) or the pustule (pustular psoriasis, exanthem with eosinophilic pustular folliculitis 
on palm and sole, and acrodermatitis continua suppurativa hallopeau) is also excluded from 
palmoplantar pustulosis. If a tinea is suspected on an interdigit and nail and trichophyton is 
observed by KOH direct microscopy, it is excluded from palmoplantar pustulosis, even if mixed 
with the blister and the pustule is observed. However, palmoplantar pustulosis is rarely 
complicated with tinea pedis. 


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1.1.3. 
Evaluation of Complication 
It is necessary to evaluate if patients have any focal infection such as tonsillitis, periodontal 
disease and sinusitis. Focal infection is the infected lesion localized somewhere in the body and 
the infection itself is asymptomatic and mild, or the symptoms are repeated only intermittently. 
Focal infection such as tonsillitis, sinusitis and dental lesion including periodontal disease are 
suggested as important players in PPP pathogenesis. (Kobayashi, 2016). 
Pustulotic arthro-osteitis (PAO) associated with PPP are observed in 10~20% of Japanese PPP 
patients and PAO is frequently observed in the sternum, clavicles, upper ribs, body axis 
(including but not limited to spine and sacroiliac joints) and peripheral joints (including but not 
limited to acromioclavicular joint and finger joint). Sternum arthritis is most commonly observed 
(Sonozaki, 1981; Yamamoto, 2013). Bone scintigraphy, computed tomography (CT) or magnetic 
resonance imaging (MRI) should be employed to confirm inflammation at the joint, bone and its 
extent, in order to evaluate complication of arthralgia (sternocostal joint) with pain in chest, neck 
and lower back. 
If necessary, a complication of thyroid disease, diabetes mellitus and Immunoglobulin A (IgA) 
nephropathy is evaluated. 
1.1.4. 
Current Treatment Guidance 
Topical treatments such as corticosteroids, active vitamin D3 ointments or phototherapy 
(ultraviolet [UV] radiation therapy) are listed as common treatments of PPP (Kobayashi, 2010; 
Okubo, 2016). Topical therapy is the basic treatment for exanthem on palm and sole. 
Combination therapy of topical steroid and topical active Vitamin D3 is applied for blisters and 
pustules. Monotherapy of topical active Vitamin D3 is applied for mild events after remission. 
However, the efficacy is limited because thicker stratum corneum of the palms and soles 
represents a barrier, and systemic treatments including phototherapy and some experimental 
therapies have shown limited efficacy in comparison with the results seen in chronic plaque-type 
psoriasis (Terui, 2018; Ohtsuki, 2018). 
In the case of patients with limited response to topical treatment, ultraviolet B (UVB) therapy 
(Narrowband UVB or Excimer) may be applied 1 to 3 times a week. 
As oral / systemic treatment, etretinate (orally [po]) and guselkumab (subcutaneous [sc]) are 
listed.  
Nonsteroidal anti-inflammatory drugs (NSAIDs), biotin, cyclosporine, bisphosphonate, 
methotrexate (MTX) or biologics are considered for the treatment for PAO. 
In case pathogenesis and complicating factors are clear, patients should be treated for focal 
infection. Tonsillectomy with hospitalization or dental treatment for infection will be applied for 
treatment of focal infection. 
Guselkumab was approved in 2018 for moderate to severe PPP patients as systemic therapy in 
Japan. However, guselkumab is a biologic which needs to be injected and can be used in limited 
Japanese hospitals. Therefore, high unmet medical needs for an effective, convenient (eg, oral), 
and well tolerated treatment for moderate to severe PPP still exist.  


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1.2. 
Compound Background  
Apremilast (CC-10004) is an oral small-molecule inhibitor of Phosphodiesterase 4 (PDE4) that 
works intracellularly to modulate a network of pro- and anti-inflammatory mediators. PDE4 is a 
cAMP specific PDE and the dominant PDE in inflammatory cells (dendric cells, monocytes, 
neutrophils, T-cells, natural killer (NK) cells, keratinocytes and synoviocytes). Inhibition of 
PDE4 elevates intracellular cAMP levels, which in turn downregulates the inflammatory 
response by modulating the expression of TNFα, IL23, IL17, and other inflammatory cytokines. 
Elevation of cAMP also increases anti-inflammatory cytokines. These pro- and anti-
inflammatory mediators have been implicated in psoriasis, psoriatic arthritis (PsA), 
Inflammatory Bowel Disease (IBD), and PPP (Schett, 2010; Schafer, 2012). Apremilast has been 
shown to reduce Th17 gene expression in lesioned skin and in the peripheral blood of psoriasis 
patients, and directly inhibits neutrophil responses in vitro such as IL8 production, migration, 
and adherence to the endothelium (Schafer, 2010; Schafer, 2012; Gottlieb, 2013; Schafer, 2015). 
In clinical studies for psoriasis, it is reported that apremilast 30 mg twice daily (BID) reduced 
peripheral Th17 and Th22 cytokine levels in subjects with psoriasis from North America/Europe 
and Japan in a similar manner (Garcet, 2018). 
Apremilast was approved in 53 countries for the treatment of psoriasis and PsA and is under 
clinical development for the treatment of Behcet's disease (BD) as of 29 Nov 2018. 
Please refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile of 
the Investigational Product (IP). 
1.3. 
Rationale 
1.3.1. 
Study Rationale and Purpose 
This is the first study of apremilast administered in Japanese subjects with PPP. In completed 
clinical studies (See Section 1.3.3), apremilast demonstrated acceptable safety and 
pharmacokinetics in several populations, such as Psoriasis, PsA and BD in a similar manner. 
As mentioned above, there remains an unmet medical need for an effective, convenient, and well 
tolerated treatment for moderate to severe PPP.  
The characteristic histopathological features of PPP exhibit intraepidermal infiltration of 
polymorphonuclear neutrophils forming pustules. Although the mechanisms of neutrophil 
chemotaxis towards the epidermis are unknown, there are several publications that support a role 
for IL17 as a promoter of neutrophil accumulation and activation (Yamamoto, 2009; Hagforsen, 
2010). PPP patients have elevated serum TNFα, IL17, IL22, and IL8, and elevated neutrophil 
and Th17 gene expression in the pustular skin (IL8, IL17A, IL36G, IL12A (p40), IL17F, IL22, 
IL23B (p19), DEFB4A, TNFα) (Murakami, 2011). Also, the involvement of eccrine ducts, 
keratinocytes and more inflammatory cells, such as lymphocytes T, dendritic cells, and 
Langerhans cells is suggested in PPP pathogenesis (Hagforsen, 2010; Murakami, 2014; 
Murakami, 2017). 
By inhibiting PDE4, apremilast is expected to inhibit production of several inflammatory 
cytokines related to pathogenesis of PPP such as IL17 and IL8, followed by inhibition of 
development of pustules. Given apremilast’s action in a wide spectrum of cytokines and its 


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efficacy reported in palmoplantar psoriasis (Bissonnette, 2018), apremilast may also be effective 
treatment in patients with PPP. 
Also, there are a few reports about the clinical efficacy of apremilast in PPP subjects (Haebich, 
2017; Eto, 2019) and additionally, on synovitis, acne, pustulosis, hyperostosis and osteitis 
(SAPHO) syndrome (Adamo, 2018). PAO which is known as a complication of PPP, is 
considered as a part of SAPHO syndrome (Sonozaki, 1981; Okubo, 2012; Okuno, 2018), 
therefore, it is suggested that apremilast may also be effective treatment in patients with PAO in 
PPP patients.  
As mentioned above, completed apremilast studies PSOR-005, ESTEEM-1 and ESTEEM-2 
showed an improvement of palmoplantar disease status in subjects with palmoplantar psoriasis 
(Bissonnette, 2016), even if it is not palmoplantar pustulosis. 
Moreover, efficacy is demonstrated in Study BCT-001 for oral ulcers in subjects with BD in 
which IL17 and neutrophils play important roles (Hatemi, 2015). 
1.3.2. 
Rationale for the Study Design 
This is the first study to evaluate directly the efficacy and safety of apremilast in Japanese PPP 
patients.  
In several completed studies for moderate to severe plaque psoriasis of apremilast, efficacy and 
safety of apremilast have been demonstrated (PSOR-005 [Papp, 2012], PSOR-008 [ESTEEM-1] 
[Papp, 2015], PSOR-009 [ESTEEM-2] [Paul, 2015], PSOR-011 [Ohtsuki, 2017]). The overall 
design of this study was selected based on these psoriasis clinical studies of apremilast. 
The clinical efficacy of apremilast was assessed by 16 weeks of observation in moderate to 
severe plaque psoriasis studies mentioned above. The time to maximal effect of apremilast in 
Japanese PPP patients is still unknown. However considering obtained observations in moderate 
to severe plaque psoriasis studies and the mode of action of apremilast, and furthermore a recent 
publication of guselkumab study in Japanese PPP patients (Terui, 2018; Terui, 2018), the 
primary endpoint evaluation is set at Week 16. Also, the use of placebo for the first 16 weeks 
would be medically acceptable for PPP considering patients will not be intolerably 
uncomfortable. Sixteen weeks without concomitant treatment has also been accepted in the study 
for systemic psoriasis. A total treatment duration of 32 weeks was selected in order to assess 
longer term effect of apremilast in the treatment of PPP. 
Experience in clinical studies for PPP is very limited. Palmo-Plantar Pustulosis Area and 
Severity Index (PPPASI) is reported as a relatively objective endpoint and recently used to 
evaluate the efficacy in several studies for PPP, palmoplantar psoriasis and such kinds of 
localized dermatological diseases (Bhushan, 2001; Guenther, 2007; Bissonnette, 2014; Reich, 
2016; Hayashi, 2017). Considering current published data of guselkumab in Japanese PPP 
subjects, PPPASI-50 (≥50% improvement in PPPASI total score from baseline) at Week 16 can 
be a primary endpoint to detect clinical meaningful efficacy compared with placebo because of 
poor response of PPP to current treatment and being refractory (Terui, 2018). 
1.3.3. 
Rationale for Dose, Schedule and Regimen Selection 
The efficacy and safety of apremilast 30 mg BID is demonstrated in several clinical studies of 
apremilast for psoriasis (CC-10004-PSOR-005 [Papp, 2012], PSOR-008 [ESTEEM-1] [Papp, 


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2015], PSOR-009 [ESTEEM-2] [Paul, 2015], PSOR-011 [Ohtsuki, 2017]), PsA (CC-10004-
PSA-002 [PALACE-1] [Kavanaugh, 2015], PSA-003 [PALACE-2] [Cutolo, 2016], PSA-004 
[PALACE-3] [Edwards, 2016]) and BD (CC-10004-BCT-001 [Hatemi, 2015], BCT-002 
[Hatemi, 2018], and the risk and benefit of apremilast 30 mg BID is also established. Details of 
each study are described in the IB. Based on these findings, apremilast 30 mg BID was selected 
as the investigated dose in this study. 
1.3.4. 
Rationale for Choice of Comparator Compounds 
A placebo control in the double blind, placebo-controlled phase will be used to establish the 
frequency and magnitude of changes in clinical response that may occur in the absence of active 
treatment. Randomization will be used to minimize bias in the assignment of subjects to 
treatment groups, to increase the likelihood that known and unknown subject attributes (eg, 
demographic and baseline characteristics) are evenly balanced across treatment groups, and to 
enhance the validity of statistical comparisons across treatment groups. 
1.3.5. 
Rationale for Pharmacodynamics and Predictive Biomarkers  
Although several pathogeneses of PPP such as concomitant tonsillitis, periodontitis or metal 
allergy have been proposed, the etiology of PPP remains unknown. 
Recently, pathophysiology of PPP at skin lesion (from vesicle formation to pustule development 
via pustulo-vesicle) is reported that shows serum IL17, IL22, TNFα, and IL8 are elevated in 
serum in PPP patients (Murakami, 2011) and IL-36 pathway and neutrophil gene expression 
(IL8, CXCL1, IL17A, IL36G, IL12A, IL17F, IL22, IL23B, DEFB4A, TNFα) in the pustular skin 
is also reported (Murakami, 2011; Liang, 2017).  
Evidence of an anti-neutrophil effect in lesioned skin from psoriasis patients was observed after 
apremilast 20 mg BID treatment for 12 weeks resulted in a 44% decrease in IL8 messenger RNA 
(mRNA) levels (N=15, p=0.018) (Gottlieb, 2013). 
Based on those results, the following hypotheses are expected. 
1. Apremilast will significantly reduce the serum IL17A protein level as part of suppressed 
Th17 response 
2. Apremilast will significantly reduce expression of IL8 mRNA as marker of neutrophils at 
the pustular skin 
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
Table 1: 
Study Objectives 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of apremilast 30 mg BID compared with 
placebo in Japanese subjects with PPP.  
Secondary Objective(s) 
The secondary objective is to evaluate the safety and tolerability of apremilast 30 mg BID compared with 
placebo in Japanese subjects with PPP. 
Exploratory Objective(s) 
The exploratory objectives are:  
 
Table 2: 
Study Efficacy Endpoints
Endpoint 
Name 
Description 
Timeframe 
Primary  
PPPASI: PPPASI-50 
See Appendix B about 
PPPASI total score. 
Proportion of subjects who 
achieve a PPPASI- 50 at 
Week 16. 
Week 16 
Secondary 
PPPASI: PPPASI-50 
Proportion of subjects who 
achieve a PPPASI- 50 at 
each visit.  
By visit in double blind, 
placebo-controlled phase 
(except for baseline and 
Week 16) 
PPPASI: PPPASI-75 
Proportion of subjects who 
achieve a PPPASI- 75 at 
each visit. 
By visit in double blind, 
placebo-controlled phase 
(except for baseline) 
PPPASI total score 
AUC. 
Week 0-16 
Percent change from 
baseline. 
By visit in double blind, 
placebo-controlled phase 
(except for baseline) 
PPSI total score 
See Appendix C about 
PPSI total score. 
AUC. 
Week 0-16 
Percent change from 
baseline. 
By visit in double blind, 
placebo-controlled phase 
(except for baseline) 


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Table 2: 
Study Efficacy Endpoints (Continued)
Endpoint 
Name 
Description 
Timeframe 
Secondary (cont.) 
PGA score for palms 
and soles:  
See Appendix D about 
PGA for palms and 
soles score 
Change from baseline. 
By visit in double blind, 
placebo-controlled phase 
(except for baseline) 
Proportion of subjects who 
achieve a PGA score of 
cleared (0) or minimal (1) 
By visit in double blind, 
placebo-controlled phase 
(except for baseline) 
Proportion of subjects who 
achieve a PGA score of 
cleared (0) or minimal (1) 
and have at least a 2-grade 
improvement 
By visit in double blind, 
placebo-controlled phase 
(except for baseline) 
SRO: Subject’s VAS 
assessment for PPP 
symptoms 
Details are shown in 
Appendix E. 
Change from baseline.  
By visit until Week 8 and 
Week 12, 16 in double 
blind, placebo-controlled 
phase (except for baseline) 
Exploratory 
 
PPPASI: Three sub 
scores (Erythema, 
Pustules/Vesicle, 
Desquamation/Scale) 
Change from baseline of 
individual sub scores. 
By visit in double blind, 
placebo-controlled phase, 
active treatment phase and 
follow-up (except for 
baseline) 
Modified PPPASI: 
modified PPPASI-50 
See Appendix F about 
modified PPPASI total 
score. 
Proportion of subjects who 
achieve a modified 
PPPASI-50.  
By visit in double blind, 
placebo-controlled phase, 
active treatment phase and 
follow-up (except for 
baseline) 
Modified PPPASI: 
modified PPPASI-75 
Proportion of subjects who 
achieve a modified 
PPPASI-75. 
By visit in double blind, 
placebo-controlled phase, 
active treatment phase and 
follow-up (except for 
baseline) 
Modified PPPASI 
total score 
Modified PPPASI: 
Two sub scores 
(Pustules, Vesicle) 
AUC. 
Week 0-16 
Percent change from 
baseline. 
By visit in double blind, 
placebo-controlled phase, 
active treatment phase and 
follow-up (except for 
baseline) 
 
Change from baseline of 
individual sub scores. 
By visit in double blind, 
placebo-controlled phase, 
active treatment phase and 
follow-up (except for 
baseline) 


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Table 2: 
Study Efficacy Endpoints (Continued)
Endpoint 
Name 
Description 
Timeframe 
Exploratory (cont.) 
SRO: Subject’s 
assessment for each 
sign/finding of PPP 
(Erythema, 
Pustules/Vesicle and 
Desquamation/Scale) 
PPSI scale is used for 
assessment. Details 
are shown in 
Appendix G. 
Change from baseline. 
By visit in double blind, 
placebo-controlled phase, 
Week 24 and 32 in active 
treatment phase and follow-
up (except for baseline) 
SRO: DLQI 
See Appendix H. 
Change from baseline. 
Week 8, 16, 24 and 32 
SRO: EQ-5D 
See Appendix I about 
EQ-5D 
Change from baseline of 
the utility index and VAS 
score. 
Week 8, 16, 24 and 32 
PPPASI: PPPASI-50 
Proportion of subjects who 
achieve a PPPASI- 50 at 
each visit.  
By visit in active treatment 
phase  
PPPASI: PPPASI-75 
Proportion of subjects who 
achieve a PPPASI- 75 at 
each visit. 
By visit in active treatment 
phase 
PPPASI total score 
Percent change from 
baseline. 
By visit in active treatment 
phase 
PPSI total score 
Percent change from 
baseline. 
By visit in active treatment 
phase 
PGA score for palms 
and soles 
Change from baseline. 
By visit in active treatment 
phase 
Proportion of subjects who 
achieve a PGA score of 
cleared (0) or minimal (1) 
By visit in active treatment 
phase 
Proportion of subjects who 
achieve a PGA score of 
cleared (0) or minimal (1) 
and have at least a 2-grade 
improvement 
By visit in active treatment 
phase 
Exploratory (cont.) 
SRO: Subject’s VAS 
assessment for PPP 
symptoms 
Change from baseline.  
Week 24 and 32 in active 
treatment phase 
AUC = Area under the curve; DLQI = Dermatology Life Quality Index; EQ-5D = EuroQol 5 Dimension; modified 
PPPASI-50 = defined as ≥50% improvement of modified PPPASI total score from baseline; modified PPPASI-75 = 
defined as ≥75% improvement of modified PPPASI total score from baseline; PGA = Physician’s Global 
Assessment; PPP = Palmoplantar pustulosis; PPPASI = Palmo-Plantar Pustulosis Area and Severity Index; PPPASI-


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50 = defined as ≥ 50% improvement in PPPASI total score from baseline; PPPASI-75 = defined as ≥ 75% 
improvement in PPPASI total score from baseline; PPSI = Palmo-Plantar Severity Index; SRO: Subject’s Reported 
Outcome; VAS = Visual Analogue Scale. 
 
Table 3: 
Study Safety Endpoint 
Endpoint 
Name 
Description 
Timeframe 
Safety 
TEAEs 
Frequency and 
incidence rate of any 
TEAE by SOC, PT, 
severity, and 
relationship of AEs to 
IP. 
During double blind, 
placebo-controlled 
phase and active 
treatment phase 
Clinically significant 
changes in body weight, 
vital signs, and/or 
laboratory findings 
Frequency of clinically 
significant changes in 
body weight, vital signs, 
and/or laboratory 
findings. 
During double blind, 
placebo-controlled 
phase and active 
treatment phase 
AE = Adverse event; IP = Investigational Product; PT = Preferred terms; SOC = System Organ Class; TEAE = 
Treatment-emergent adverse event. 
 
 


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3. 
OVERALL STUDY DESIGN 
3.1. 
Study Design 
CC-10004-PPP-001 is a multicenter, randomized, double-blind, placebo-controlled, parallel-
group, Phase 2 study of apremilast in Japanese subjects with PPP and inadequate response to 
treatment with topical steroid and/or topical vitamin D3 derivative preparations.  
The study design is shown in Figure 1. 
Figure 1: 
Overall Study Design 
Screening Phase:
up to 4-weeks
Randomized, double-blind, placebo controlled Phase: 16-weeks
Active Treatment Phase: 16-weeks 
Observational
Follow-up: 
4-Weeks
W-4
W0
W2
W4
W6
W8
W10
W12
W14
W16
W20
W24
W28
W32
W36
Primary 
Endpoint
Apremilast  30 mg BID
Placebo BID
Apremilast 30 mg BID
Randomization 1:1 to 
apremilast 30 mg BID 
or Placebo BID
At Week 16, placebo 
subjects switch to 
apremilast 30 mg BID
For all subjects 
who complete 
the study or 
discontinue the 
study early
Apremilast  30 mg BID
dose titration
at W0
dose titration
at W16
 
The study includes 4 phases: 
1. Screening phase for up to 4 weeks (28 days) 
2. Sixteen weeks, double-blind, placebo-controlled phase (apremilast 30 mg BID and 
Placebo) 
a. Subjects randomized to the apremilast 30 mg BID treatment group will receive 
apremilast 30 mg tablets orally twice daily for the first 16 weeks 
b. Subjects randomized to the placebo treatment group will receive placebo tablets 
(identical in appearance to apremilast 30 mg tablets) orally twice daily for the first 16 
weeks 
3. Sixteen weeks, active treatment phase (apremilast 30 mg BID) 
a. Subjects randomized to the apremilast 30 mg BID treatment group will continue to 
receive apremilast 30 mg tablets orally twice daily for the second 16 weeks 
b. Subjects randomized to the placebo treatment group will switch to apremilast 
treatment in a blind manner orally twice daily for the second 16 weeks 
4. Four weeks post-treatment observational follow-up phase at any time the subject 
completes or discontinues the trial 


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Subjects who meet eligibility criteria for the study will be randomized in a 1:1 ratio to one of the 
two treatment groups. Subject randomization for treatment assignments will be stratified 
according to a subject’s rounded PPPASI score (≤20 / 21-30 / ≥31) at randomization, and 
whether a subject has any focal infection at randomization (yes/no). 
Approximately 86 subjects who meet eligibility criteria for the study at Baseline visit (Week 0) 
will initiate IP treatments. To mitigate potential gastrointestinal (GI) side effects (primarily mild 
to moderate nausea and diarrhea), dose titration (using blister cards) will be implemented over a 
5-day period starting at the Baseline Visit (Week 0) for subjects randomized to apremilast 30 mg 
BID or Placebo. Subjects randomized to placebo will receive blister cards with dummy dose 
titration.  
The blind should be maintained for persons responsible for the ongoing conduct of the study 
until the final database lock at the conclusion of the study with some exceptions mentioned 
below. Blinded persons may include but are not limited to: Clinical Research Physician, Clinical 
Research Scientist, Clinical Trial Manager, Study Statistician, Data Manager, Programmers, 
Clinical Research Associates. 
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed, and the primary data analysis will be conducted. 
However, unblinded data will only be made available to selected Sponsor and contract research 
organization (CRO) team members involved with analysis of the data. All other Sponsor, site, 
and CRO personnel directly involved with the conduct of the study, will remain blinded to 
treatment assignments until the final database lock at the conclusion of the study.  
All subjects will be switched to (or continue with) apremilast 30 mg BID at Week 16 and will 
maintain this dosing through Week 32. 
Observational Follow-up evaluation will be performed 4 weeks after last dose of IP. Subjects 
who discontinue treatment with IP or withdraw during the Treatment Phase will be also asked to 
enter the 4-week Observational Follow-up Phase after Early Termination assessment. 
An interim Analysis is not planned. An independent committee (eg, steering committee, data 
monitoring committee, safety monitoring committee) is also not planned. At the end of the study, 
after all subjects have completed, or have been discontinued from the active treatment phase 
(Weeks 16 to 32) and the post-treatment observational follow-up phase, the final analysis will be 
performed, and a final clinical study report will be generated. 
The efficacy, safety, and pharmacodynamic assessments to be performed during the study are 
outlined in the Schedule of Assessments (Table 5). 
 are an optional 
measurement for a subset of subjects who agree to additional informed consent (IC) at limited 
clinical study sites.   
The study will be conducted in compliance with the ICH of Technical Requirements for 
Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable 
regulatory requirements. 


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3.2. 
Study Duration for Subjects 
This study consists of 4 phases: screening period of up to 4 weeks, 16 weeks for double blind, 
placebo-controlled phase, 16 weeks for active treatment phase and 4 weeks for follow-up. Total 
study duration per subject is approximately 40 weeks maximum. 
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 86 Japanese subjects with PPP will be randomized to the apremilast 30 mg BID 
group or the placebo group in a 1:1 ratio (43 subjects, respectively). 
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).  
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted.  
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements. 
4. Subject has a diagnosis of PPP with or without PAO (not requiring treatment by 
immunosuppressant) for at least 24 weeks before screening, regardless of presence or 
absence of concurrent extra-palmoplantar lesions. 
The diagnosis criteria are as follows: 
a. Sterile pustules located on palms and/or soles, 
b. Change from blister to pustule via pustulo-vesicles with progression of disease, and 
c. Repeat recurrence at the same skin lesion and shows the chronic course profile 
5. Subject has a total score of PPPASI: ≥ 12 at screening and baseline. 
6. Subject has moderate or severe pustules/vesicles on palms or soles (PPPASI severity 
score: ≥ 2) at screening and baseline. 
7. Subject has inadequate response to treatment with topical steroid and/or topical vitamin 
D3 derivative preparations prior to or at screening. Inadequate response to the treatment 
is defined as “repeated relapsing-remitting in the same lesion is observed in 6 months 
treatment period ". 
8. Subject meets the following laboratory criteria at screening: 
a. White blood cell count ≥ 3000/mm3 (≥ 3.0 x 109/L) and ≤ 14,000/mm3 (≤ 14 x 109/L)  
b. Platelet count ≥ 100,000/μL (≥ 100 x 109/L) 
c. Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L) 
d. Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase 
(SGOT), and alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase 
(SGPT) ≤ 2.0 x upper limit of normal (ULN). 
e. Total bilirubin ≤ 2.0 mg/dL  
f. Hemoglobin > 9 g/dL 
9. Subject agrees not to change his/her lifestyle habits (eg, exercise, diet, smoking) 
extremely. 


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10. Subject is in good health as judged by the Investigator, based on medical history, physical 
examination, clinical laboratory evaluation. 
11. A female of childbearing potential§(FCBP) must have a negative pregnancy test at 
Screening and Baseline. While on IP and for at least 28 days after taking the last dose of 
IP, FCBP who engage in activity in which conception is possible must use one of the 
approved contraceptive†options described below: 
• Option 1‡: Any one of the following highly effective methods: hormonal 
contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine 
device (IUD); tubal ligation; or partner’s vasectomy; 
OR 
• Option 2: Male or female condom PLUS, one additional barrier method: (a) 
diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive 
sponge with spermicide. 
4.3. 
Exclusion Criteria 
The presence of any of the following will exclude a subject from enrollment: 
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study. 
2. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study. 
3. Subject has any condition that confounds the ability to interpret data from the study. 
4. Subject has a diagnosis of plaque-type psoriasis. 
5. Subject has the presence of pustular psoriasis in any part of the body other than the palms 
and soles (excluding derived from PPP). 
6. Subject has obvious improvement during screening (≥ 5 PPPASI total score improvement 
during the screening). 
7. Subject has received any procedures for focal infection (eg, tonsillectomy and dental 
therapy) within 24 weeks of baseline. 
a. Example of dental therapy: treatment for periodontitis includes any endodontic 
treatment for periapical pathosis (chronic periapical periodontitis) (eg, infected root 
canal treatment, tooth extraction), and periodontal surgery for moderate to severe 
periodontitis (chronic marginal periodontitis). 
 
§ A FCBP is a sexually mature female who 1) has not undergone a hysterectomy (the surgical removal of the uterus) 
or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been postmenopausal for at least 24 
consecutive months (that is, has had menses at any time during the preceding 24 consecutive months). 
† The female subject’s chosen form of contraception must be effective by the time the female subject is randomized 
into the study (ex, hormonal contraception should be initiated at least 28 days before randomization). 
‡ Hormonal contraception (injection, implant, transdermal patch) are not approved in Japan. 


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8. Subject has periodontitis obviously requiring treatment at screening. 
a. Treatment for periodontitis includes any endodontic treatment for periapical pathosis 
(chronic periapical periodontitis) (eg, infected root canal treatment, tooth extraction), 
and periodontal surgery for moderate to severe periodontitis (chronic marginal 
periodontitis). 
9. Subject has chronic or recurrent tonsillitis or sinusitis requiring any continuous treatment 
for a month or more at screening. 
a. Subject who received a continuous treatment less than one month prior to screening is 
excluded if the subject is assumed to continue the treatment more than one month. 
Subject who has repeated and acute tonsillitis or sinusitis and receive any treatment 
for a month or more is also excluded. 
10. Subject has evidence of skin conditions of hands and feet that would interfere with 
evaluations of the effect of study medication. 
11. Subject with current or planned concurrent use of the following therapies that may have a 
possible effect on PPP during the course of the study: 
a. Topical therapy within 2 weeks prior to randomization, including, but not limited to, 
topical corticosteroids, topical retinoid or vitamin D3 analogue preparations, 
tacrolimus, antihistamine, antibiotics or traditional Chinese/Japanese herbal 
preparations. 
− Exceptions: An unmedicated skin moisturizer will be permitted as needed. 
Subjects should not use this treatment within 24 hours prior to clinic visit. 
b. Conventional systemic therapy within 4 weeks prior to randomization, including, but 
not limited to, corticosteroids, retinoids, antihistamine, antibiotics, JAK inhibitors, 
1,25-dihydroxy vitamin D3 and analogues, psoralens, sulfasalazine, hydroxyurea, 
dimethyl fumarate, biotin, colchicine or traditional Chinese/Japanese herbal 
preparations.  
− As for retinoids (etretinate), has received within 2 years prior to baseline for 
FCBP, 6 months prior to the baseline for males, and 4 weeks prior to baseline for 
non-FCBP. 
c. Granulocyte and monocyte adsorption apheresis (GMA) within 2 weeks prior to 
randomization. 
d. Phototherapy treatment within 4 weeks prior to randomization (ie, UVB, psoralen and 
ultraviolet A [PUVA]). 
e. Biologic therapy 
− TNFα or IL17 blockers such as adalimumab, brodalumab, certolizumab pegol, 
etanercept, golimumab, infliximab, ixekizumab, secukinumab (or biosimilars for 
each) within 12 weeks or 5 times of half-lives, whichever is longer duration, prior 
to randomization. 


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− Anti-IL12 or anti-IL23 monoclonal antibodies such as guselkumab, ustekinumab 
or tildrakizumab∗ and other biologics within 24 weeks or 5 times of half-lives, 
whichever is the longer duration, prior to randomization. 
12. Subject with current or planned concurrent use of the following therapies for PAO: 
− Systemic therapy within 4 weeks prior to randomization, including, but not 
limited to, bisphosphonates, immunosuppressants [eg, MTX, azathioprine, 
cyclosporine or 6-thioguanine, mercaptopurine, mycophenolate mofetil, 
tacrolimus]) and other biologics (eg, anti-IL1 antibody). 
Background stable doses of NSAIDs for treatment of PAO are permitted.  
13. Subject has received prolonged sun exposure or used tanning booths or other ultraviolet 
light sources within 4 weeks of baseline.  
− Subjects who cannot agree to avoid prolonged sun exposure or use tanning booths 
or other ultraviolet light sources during the study are also excluded. 
14. Subject has used strong cytochrome P450 3A4 (CYP3A4) enzyme inducers (eg, rifampin, 
phenobarbital, carbamazepine, phenytoin and St. John’s Wort) within 2 weeks or 5 times 
of half-lives, whichever is the longer duration, prior to randomization. 
15. Subject had prior treatment with apremilast. 
16. Subject has bacterial infections requiring treatment with oral or injectable antibiotics, or 
significant viral or fungal infections, within 4 weeks of signing the ICF. Any treatment 
for such infections must have been completed at least 4 weeks prior to randomization. 
17. Subject is positive for hepatitis B surface antigen (HBsAg) (indicative of chronic 
hepatitis B or recent acute hepatitis B) at screening.  
a. If negative for HBsAg and positive for anti-hepatitis B core antibody (HBcAb), 
hepatitis B virus deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) is 
necessary. Detectable hepatitis B virus DNA suggests acute hepatitis B. 
18. Subject is positive for Hepatitis C virus antibody (HCVAb) at screening:  
a. If pogative for HCVAb, hepatitis C virus ribonucleic acid (RNA) by PCR is 
necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C. 
19. Subject has active tuberculosis (TB) or a history of incompletely treated TB. 
20. Subject has a prior medical history of suicide attempt at any time in the subject's lifetime 
prior to signing the informed consent or randomization, or major psychiatric illness 
requiring hospitalization within the last 3 years prior to signing the informed consent. 
21. Subject has unstable cardiovascular disease, defined as a recent clinical deterioration (eg, 
unstable angina, rapid atrial fibrillation) in the last 12 weeks or a cardiac hospitalization 
within the last 12 weeks before screening. 
22. Subject has malignancy or history of malignancy, except for: 
a. Treated (ie, cured) basal cell or squamous cell in situ skin carcinomas. 
 
* Not approved in Japan. 


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b. Treated (ie, cured) cervical intraepithelial neoplasia or carcinoma in situ of the cervix 
with no evidence of recurrence within 5 years of screening. 
23. Subject has a history of positive human immunodeficiency virus (HIV), or has congenital 
or acquired immunodeficiency (eg, common variable immunodeficiency disease). 
24. Subject has scheduled surgery or other interventions that would interrupt the subject's 
participation in the study. 
25. Subject is pregnant or breastfeeding. 
26. Subject has received investigational drug within 4 weeks prior to the randomization, or 5 
pharmacokinetic/pharmacodynamic half-lives, if known (whichever was longer). 
27. Subject has a history of allergy to any component of the apremilast.  
28. Subject has active substance abuse or has a history of substance abuse within 6 months 
prior to signing the informed consent. 
 


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5. 
TABLE OF EVENTS 
Table 5: 
Schedule of Events 
 
Screening 
Double-blind, placebo-controlled phase 
Active treatment phase  
Observational follow-up a 
Visit Number 
1 
2 b 
(Baseline) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14/E
T 
15 
Week 
-4 to 0 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
4 Weeks after last dose 
Day 
-28 to 0 
1 
15 
29 
43 
57 
71 
85 
99 
113 
141 
169 
197 
225 
- 
Allowance (days) 
- 
- 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±4 
±4 
±4 
±4 
±7 
STUDY ENTRY AND GENERAL ASSESSMENTS 
Informed consentc 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion / Exclusion criteria 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Complete medical history d 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Disease historye 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Dental examination f 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Status of smoking g 
X 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
X 
X 
- 
Prior / concomitant medications 
and procedures h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY AND LABORATORY ASSESSMENTS 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric evaluation i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test for FCBPj and 
Contraception education for 
FCBP j 
X 
X 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
Vital signs j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height j 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


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Table 5: 
Schedule of Events (Continued) 
 
Screening 
Double-blind, placebo-controlled phase 
Active treatment phase  
Observational follow-up a 
Visit Number 
1 
2 b 
(Baseline) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14/ET 
15 
Week 
-4 to 0 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
4 weeks after last dose 
Day 
-28 to 0 
1 
15 
29 
43 
57 
71 
85 
99 
113 
141 
169 
197 
225 
- 
Allowance (days) 
- 
- 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±4 
±4 
±4 
±4 
±7 
Weight j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical examination j 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
Limited physical examination k 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
- 
X 
Hepatitis B and C l 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Clinical laboratory evaluations 
(Hematology/Chemistry) m 
X 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
X 
- 
X 
X 
Clinical laboratory evaluations 
(Immunology/Inflammation) m 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
X 
- 
X 
X 
Clinical laboratory evaluations 
(Urinalysis) m 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
EFFICACY ASSESSMENT(S) 
PPPASI n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Modified PPPASI o 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PPSI p 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGA for palms and soles q 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SUBJECT REPORTED OUTCOMES / QUALITY OF LIFE 
Subject’s assessment for PPP 
signs/findings (using PPSI scale) r 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
X 
X 
Subject’s VAS assessment for PPP 
symptoms for hands and feet s 
- 
X 
X 
X 
X 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
DLQI t 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
X 
- 
X 
- 
EQ-5D t 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
X 
- 
X 
- 


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Table 5: 
Schedule of Events (Continued) 
 
Screening 
Double-blind, placebo-controlled phase 
Active treatment phase  
Observational follow-up a 
Visit Number 
1 
2 b 
(Baseline) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14/ET 
15 
Week 
-4 to 0 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
4 weeks after last dose 
Day 
-28 to 0 
1 
15 
29 
43 
57 
71 
85 
99 
113 
141 
169 
197 
225 
- 
Allowance (days) 
- 
- 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±4 
±4 
±4 
±4 
±7 
INVESTIGATIONAL PRODUCTS (IP) 
Randomization (IRT)  
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Dispense IP  
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
X 
- 
- 
Return and count IP tablets (IP 
accountability) 
- 
- 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
X 
X 
- 
Abbreviation: AE = Adverse event; DLQI = The Dermatology Life Quality Index; EQ-5D = Euro QOL 5 Dimension; ET = Early Termination; FCBP = Females of childbearing potential; IP = 
Investigational Product; IRT = Interactive Response Technology; PAO = Pustulotic arthro-osteitis; PGA = Physician’s Global Assessment; PPP = Palmoplantar pustulosis; PPPASI = Palmo-Plantar 
Pustulosis Area and Severity Index; PPSI = Palmo-Plantar Severity Index; QOL = Quality of Life; RNA = Ribonucleic Acid; VAS = Visual Analogue Scale. 
a Subjects who discontinue treatment with IP or withdraw during the treatment phase will be also asked to enter the 4-week observational follow-up phase after ET assessment. 
b Visit 2 is Day 1 (Week 0) and the baseline for all Efficacy Assessments. All assessments should be conducted prior to the first administration of IP. 
c Written informed consent will be obtained by the Principal Investigator or designee prior to performing any study assessments. 
d A complete medical history must be taken and must include a query about whether a subject has known active current or history of recurrent infections. 
e Disease history will capture the following information: specific information regarding diagnosis, presence or absence of focal infection, ie, periapical pathosis, periodontitis, 
angina and sinusitis, Presence or absence of regular dental examination and presence or absence of PAO. 
f Dental examination must be conducted by a dentist at Screening and obtain data if there is any dental focal infection (eg, chronic periapical periodontitis, chronic marginal 
periodontitis) or not, and to evaluate the necessity of treatment (any endodontic treatment for periapical pathosis [eg, infected root canal treatment, tooth extraction], and 
periodontal surgery for moderate to severe periodontitis). Investigators should evaluate whether a treatment for focal infection is preferred to study enrolment. 
g Including smoking history (years/amount) and current status (yes/no and average packs/day). 
h Inadequate response to PPP by the treatment with topical steroid and/or topical vitamin D3 derivative preparations should be confirmed. 
i At any time when suicidal thoughts or a suicide attempt is identified, evaluate the need for referral to a psychiatrist and other actions, including discontinuation, as required in 
Section 6.5.2.  
j See Section 6.5. 
k A limited physical exam may be performed to evaluate an AE, or for any reason, at the discretion of the Investigator. 


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l See Section 6.5.6  
m Each panel of clinical laboratory evaluations is described in Section 6.5.10. Unscheduled clinical laboratory e valuation is acceptable (eg, to follow AEs) 
n See Appendix B. 
o SeeAppendix F. 
p See Appendix C. 
q See Appendix D. 
r Worst status between the visit in which an assessment is scheduled and the previous visit should be recorded. Indicated assessments should be performed before any tests, 
procedures, or other consultations (PPPASI, modified PPPASI, PPSI, and PGA for palms and soles) for that visit. See Appendix G. 
s Worst status between the visit in which an assessment is scheduled and the previous visit should be recorded. PPP-related symptoms should be included in these assessments. 
Indicated assessments should be performed before any tests, procedures, or other consultations (PPPASI, modified PPPASI, PPSI, and PGA for palms and soles) for that visit. 
See Appendix E. 
t Indicated assessments should be performed before any tests, procedures, or other consultations (PPPASI, modified PPPASI, PPSI, and PGA for palms and soles) for that visit. 
See Appendix H, Appendix I, respectively. 
 


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6. 
PROCEDURES 
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 administrative/demographic procedures will be conducted as outlined in the Table 
of Events (Table 5). Waivers to the protocol will not be granted during the conduct of this trial, 
under any circumstances. 
Any questions regarding the protocol should be directed to the Amgen Medical Monitor or 
designee. 
Informed Consent 
An ICF must be signed by the subject before any study-related assessments are performed. 
Details of the informed consent process may be found in Section 13.3. 
Inclusion / Exclusion Criteria (Eligibility Criteria) 
Subjects must meet all inclusion criteria (Section 4.2) and must not have any of the conditions 
specified in the exclusion criteria (Section 4.3) to qualify for participation in the study. The 
subject’s source documents must support his/her qualifications for the study (eg, if a female 
subject does not require pregnancy testing and birth control because of a hysterectomy, the date 
of the hysterectomy must be included in the medical history). 
Medical and Disease History 
Relevant medical history should be recorded, including smoking and alcohol history, as well as 
previous relevant surgeries (please refer to the electronic Case Report Form (eCRF) Completion 
Guidelines for further details). Disease history includes history of PPP and PAO. 
Prior/Concomitant Medications and Therapies 
All medications and therapies being taken/used by the subject at the time of consent or at any 
time during the study should be recorded. Other key medications and therapies, such as previous 
treatment for TB or relevant diseases, should be recorded. Please refer to the eCRF Completion 
Guidelines for additional instructions. 
All medications and therapies for PPP used within the last 5 years prior to the randomization, 
including topicals, systemics, and all other therapies, should be recorded. The stop dates for all 
medications and therapies prohibited in the study should be recorded. Responses to prior PPP 
therapies should also be recorded. Please refer to the eCRF Completion Guidelines for additional 
instructions. 
6.1. 
Screening Period 
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 28 days of Baseline (Visit 2) unless noted otherwise 
below.  
Safety laboratory analyses will be performed by the central laboratory. Screening laboratory 
values must demonstrate subject eligibility, but exclusionary results may be re-tested one time 


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within the screening window, without AmgenMedical Monitor approval. Subjects who fail initial 
screening may re-screen one additional time for the study.  
The following assessments will be performed at screening as specified in the Table of Events 
(Table 5), after informed consent has been obtained: 
• Demographics (year of birth, sex, race, and ethnicity-if allowed by local regulations) 
• Complete medical history (all relevant medical conditions diagnosed/ occurring prior 
to screening should also be included) 
• Disease history (including specific information regarding diagnosis, date of diagnosis, 
negation of plaque-type psoriasis, and of presence of pustular psoriasis in any part of 
the body other than the palms and soles).  
The following information is also included: 
− Presence or absence of focal infection, ie, periapical pathosis, periodontitis, 
Angina and Sinusitis 
− Smoking History (years/amount) and Current Status (Yes/No and average 
packs/day) 
− Presence or absence of regular dental examination (eg, annually at least) 
− Presence or absence of PAO 
• Dental Examination and Evaluation of necessity of treatment for focal infection 
− To conduct medical examination by dentist at Screening and obtain data if there is 
any dental focal infection (eg, chronic periapical periodontitis, chronic marginal 
periodontitis) or not,  
− To evaluate the necessity of treatment (any endodontic treatment for periapical 
pathosis [eg, infected root canal treatment, tooth extraction], and periodontal 
surgery for moderate to severe periodontitis). 
− Investigators should evaluate whether a treatment for focal infection is preferred 
to enrolment in the study.  
• Prior/Concomitant Medications and Procedures 
− Inadequate response to PPP by treatment with topical steroid and/or topical 
vitamin D3 derivative preparations should be confirmed. 
− Prior and concomitant medications/procedures except for PPP and focal infection 
should be recorded including all procedures occurring ≤ 28 days prior to the 
baseline. 
− History of treatment for focal infection should be recorded within 24 weeks prior 
to the baseline. 
− All medications and therapies for PPP used within the last 5 years prior to the 
randomization, including topicals, systemics and all other therapies, should be 
recorded. 


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• AE/SAE assessment (begins when the subject signs the informed consent form) 
• Psychiatric evaluation 
• Serum Pregnancy test is required for all female subjects of childbearing potential.  
Serum beta human chorionic gonadotropin (β-hCG pregnancy test will be performed).  
• Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted.  
• Hepatitis B and C 
• Vital signs 
• Height and Weight  
• Complete physical examination  
• Clinical laboratory evaluations  
− Hematology/Chemistry  
− Urinalysis 
• PPPASI (see Section 6.4.1) 
− If obvious improvement during screening (≥ 5 PPPASI total score improvement) 
is observed at randomization, the initiation of study treatment is not permitted. 
− Efficacy assessments may be performed by the qualified physician who has 
completed the training for efficacy evaluation. 
• Examination for other Inclusion / Exclusion Criteria  
Randomization is performed via Interactive Response Technology (IRT). 
6.2. 
Treatment Period (Placebo-controlled phase and Active treatment 
phase) 
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment within 28 days of signing the informed consent form (ICF). For subsequent visits, an 
administrative window of ± 2 days until Visit 10 (Week 16) and ± 4 days for Visit 11 to 14 
(Week 20 to 32) are permitted respectively. If screening assessments are performed within 72 
hours of Baseline Visit, physical examinations and clinical laboratory evaluations, except for 
Immunology and Inflammation, need not be repeated at Baseline.   
Treatment will occur as described in Section 7.3.  
During the treatment period: 
• Subjects must complete all SROs prior to any other study procedure being performed.  
• Subjects should complete the questionnaires in the following order when applicable: 
1) Subject’s VAS assessment for PPP symptoms for hands and feet, 2) Subject’s 
assessment for PPP signs/findings, 3) DLQI, 4) EQ-5D. 


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• Efficacy assessments may be performed by the qualified physician who has 
completed the training for efficacy evaluation at any time during a study visit, but 
only after the subject has completed all SROs assessments, when required.  
• The physician performing efficacy assessments shall make independent observations 
at a given study visit and shall not review previous assessments or subject-derived 
data in advance of conducting the assessments.  
The following evaluations/assessments will be performed at the frequency specified in the Table 
of Events (Table 5).  
• Status of smoking  
• Concomitant medications and procedures evaluation 
• AE/SAE evaluation (continuously) 
• Psychiatric evaluation 
• Pregnancy test for FCBP 
− Urine dipstick pregnancy test will be performed at Baseline (within 72 hours prior 
to the first administration of IP)and Visit 10 (Week 16). An unscheduled urine 
pregnancy test should be conducted administered if the subject has missed a 
menstrual period. See Section 6.5.3.  
• Contraception education for FCBP  
• Vital signs  
• Weight  
• Complete or limited physical examination  
• Clinical laboratory evaluations  
− Hematology/Chemistry 
− Immunology/Inflammation  
• Efficacy assessment (see Section 6.4)  
− PPPASI, PPSI, PGA and modified PPPASI 
• Subject reported outcomes or quality of life questionnaires (see Section 6.7) 
− Subject’s VAS assessment for PPP symptom, Subject’s assessment for PPP 
signs/findings,  
− DLQI, EQ-5D 


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6.2.1. 
End of Treatment 
An end of treatment (EOT) evaluation will be performed on Visit 14 (Week 32) or for subjects 
who are withdrawn from treatment for any reason as soon as possible after the decision to 
permanently discontinue treatment has been made.  
For Visit 15 (4 Weeks After Last Dose), an administrative window of ± 7 days is permitted.  
The following evaluations will be performed as specified in the Table of Events (Table 5): 
• Status of smoking  
• Concomitant medications and procedures evaluation 
• AE/SAE evaluation (monitored through 28 days after the last dose of IP)  
• Psychiatric evaluation 
• Pregnancy test for FCBP 
− Urine dipstick pregnancy test will be performed. 
• Vital signs  
• Weight 
• Complete physical examination (source documented only) 
• Clinical laboratory evaluations  
− Hematology/Chemistry 
− Immunology/Inflammation 
• Efficacy assessment (see Section 6.4)  
− PPPASI, PPSI, PGA and modified PPPASI 
• Subject reported outcomes or quality of life questionnaires (see Section 6.7) 
− Subject’s VAS assessment for PPP symptom, Subject’s assessment for PPP 
signs/findings,  
− DLQI, EQ-5D 
6.3. 
Follow-up Period  
All subjects will be followed for 28 days after the last dose of IP for AE reporting, as well as any 
serious adverse events (SAEs) made known to the Investigator at any time thereafter, as 
described in Section 10.1.  


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6.3.1. 
Observational Follow-up Visit 
Observational Follow-up evaluation will be performed on 28 days after last dose of IP. An 
administrative window of ± 7 days is permitted. 
During the observational follow-up period; 
• Subjects must complete all SROs prior to any other study procedure being performed. 
• Efficacy assessments may be performed by the qualified physician who has 
completed the training for efficacy evaluation, but only after the subject has 
completed all SROs assessments. 
• The physician performing efficacy assessments shall make independent observations 
at a given study visit and shall not review previous assessments in advance of 
conducting the assessments. 
The following evaluations will be performed as specified in the Table of Events (Table 5): 
• Concomitant medications and procedures evaluation 
• AE/SAE evaluation (monitored through 28 days after the last dose of IP) 
• Psychiatric evaluation 
• Vital signs 
• Weight 
• Limited physical examination 
• Clinical laboratory evaluations  
− Hematology/Chemistry  
− Immunology/Inflammation 
• Efficacy assessment (see Section 6.4)  
− PPPASI, PPSI, PGA and modified PPPASI 
• Subject reported outcomes (see Section 6.7) 
− Subject’s VAS assessment for PPP symptom, Subject’s assessment for PPP 
signs/findings  
6.4. 
Efficacy Assessment 
6.4.1. 
PPPASI 
PPPASI is a disease-specific efficacy assessment tool by Investigators. See Appendix B. This is 
established to detect a change of disease status on palms or soles. The right/left palm and 
right/left sole are evaluated for 3 signs of the disease (erythema, pustules/vesicle and 
desquamation/scale) as sub-scores. 
PPPASI produces numeric scores that can range from 0 to 72. A higher score indicates more 
severe disease. 


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6.4.2. 
PPSI 
PPSI is a disease-specific efficacy assessment tools by Investigators. See Appendix C. This is 
established to detect a change of disease status on a specified palm or sole. Evaluated skin lesion 
is identified by either palms or soles, which has the most severe skin lesion at screening. 
PPSI produces numeric scores that can range from 0 to 12. A higher score indicates more severe 
disease.  
6.4.3. 
PGA for Palms and Soles 
PGA for palms and soles is a Physician’s Global Assessment localized to palms and soles, which 
is skin lesions of PPP. Physician’s Global Assessment is commonly used for assessment of the 
intervention. See Appendix D.  
PGA for palms and soles also produces numeric score that can range from 0 to 5. A higher score 
indicates more severe disease.  
6.4.4. 
Modified PPPASI 
Modified PPPASI is an exploratory disease-specific efficacy assessment by Investigators, which 
emphasizes on pustules and vesicles. The right/left palm and right/left sole are evaluated for 4 
signs of the disease (erythema, pustules, vesicle and desquamation/scale) as sub-scores. The 
development of vesicles followed by pustule in palm and sole is distinctive pathophysiology in 
PPP. See Appendix F.  
The range of modified PPPASI score is from 0 to 96. A higher score indicates more severe 
disease. 
6.5. 
Safety Assessment 
6.5.1. 
Adverse Events 
In addition to 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. 
6.5.2. 
Psychiatric Evaluation 
Treatment with apremilast is associated with an increase in adverse reactions of depression. 
Before using apremilast in subjects with a history of depression and/or suicidal thoughts or 
behavior, the Investigator should carefully weigh the risks and benefits of treatment with 
apremilast in such subjects. Subjects should be advised of the need to be alert for the emergence 
or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur 
to contact the Investigator.  
If a subject suffers from new or worsening psychiatric symptoms, or suicidal ideation or suicidal 
attempt is identified, it is recommended to discontinue the subject participation to the study (see 
Section 11). At any time when suicidal thoughts or a suicide attempt is identified, evaluate the 
need for referral to a psychiatrist and other actions, including discontinuation. The result of 
psychiatric evaluation should be recorded in eCRF. 


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6.5.3. 
Serum and Urine Pregnancy Tests for Females of Childbearing Potential 
(FCBP) 
A serum pregnancy test with a sensitivity of ≤ 25 mIU/mL will be required for FCBP subjects at 
screening. In addition, a urine pregnancy test will be performed at the site on all FCBP subjects 
at the Baseline Visit, Visit 10 (Week 16) and Last Treatment Visit (Visit 14 [Week 32]). An 
unscheduled urine pregnancy test should be performed if the FCBP subject has missed a 
menstrual period. If positive results are obtained from a urine pregnancy test, a serum pregnancy 
test should be performed to confirm, and if positive results are obtained from a serum pregnancy 
test, IP should be discontinued. The event must be reported (See Section 10.4.1). 
6.5.4. 
Contraception Education 
The risks to a fetus or to a nursing child from apremilast are not known at this time. Results of 
animal and in vitro studies can be found in the Investigator’s Brochure. 
All FCBPs must use one of the approved contraceptive options as described in Section 4.2 while 
on IP and for at least 28 days after administration of the last dose of the IP. The female subject’s 
chosen form of contraception must be effective by the time the female subject is randomized into 
the study (ex, hormonal contraception should be initiated at least 28 days before randomization). 
At screening and at baseline, and at any time during the study when a FCBP’s contraceptive 
measures or ability to become pregnant changes, the Investigator will educate the subject 
regarding contraception options and correct and consistent use of effective contraceptive 
methods in order to successfully prevent pregnancy. 
6.5.5. 
Severe Diarrhea, Nausea and Vomiting 
There have been post-marketing reports of severe diarrhea, nausea, and vomiting associated with 
the use of apremilast. Most events occurred within the first few weeks of treatment. In some 
cases, patients were hospitalized. Patients 65 years of age or older and patients taking 
medications that can lead to volume depletion or hypotension may be at a higher risk of 
complications. Subjects should be monitored for severe diarrhea, nausea and vomiting. If 
patients develop severe diarrhea, nausea, or vomiting, discontinuation of treatment may be 
necessary. 
6.5.6. 
Hepatitis B and C 
Hepatitis testing will include HBsAg, HBcAb and HCVAb. 
6.5.7. 
Vital Signs, Height, and Weight 
Vital signs, including pulse, temperature, and seated blood pressure, will be taken during the 
visits indicated in the Table of Events (Table 5). Weight will be measured and recorded at the 
Screening Visit and then as indicated in the Table of Events (Table 5); body mass index (BMI) 
will be calculated programmatically based on the height measured and recorded at Screening. In 
the event of unexplained and clinically significant weight loss, the subjects should be evaluated 
by the Investigator and discontinuation of treatment should be considered.  


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6.5.8. 
Complete Physical Examination 
A complete physical examination includes evaluations of skin, nasal cavities, eyes, ears, lymph 
nodes, and respiratory, cardiovascular, gastrointestinal, neurological, and musculoskeletal 
systems. The complete physical examination is done at screening, at Visit 10 (Week 16) and at 
Visit 14 (Week 32) or at Early Termination. 
6.5.9. 
Limited Physical Examination 
A limited physical exam may be performed to evaluate an AE, or for any reason, at the discretion 
of the Investigator. 
6.5.10. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed by a central laboratory and as indicated in 
Table 5.  
Clinical laboratory hematology panel includes complete blood count (CBC) (red blood cell 
[RBC] count, hemoglobin, hematocrit, white blood cell [WBC] count [absolute and differential], 
and platelet count). 
Clinical laboratory chemistry panel includes sodium, potassium, calcium, chloride, phosphorous, 
blood urea nitrogen (BUN), creatinine, glucose, hemoglobin A1c (HbA1c), albumin, total 
protein, alkaline phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum 
glutamic oxaloacetic transaminase (AST/SGOT), alanine aminotransferase (ALT/SGPT), uric 
acid, lactate dehydrogenase (LDH), magnesium, total cholesterol, high-density lipoprotein 
cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], LDL to HDL ratio, total 
cholesterol to HDL ratio, triglycerides. Fasting is not required. However, if significant elevation 
of serum lipid(s) is observed, a fasting retest should be requested to determine whether or not the 
elevation was caused by food. 
Clinical laboratory immunology/inflammation panel includes fibrinogen, high sensitivity C-
reactive protein (hs-CRP), MMP-3, quantitative assessment of serum immunoglobulins (IgA, 
immunoglobulin M [IgM], and immunoglobulin G [IgG]) will also be assessed at selected visits. 
Dipstick urinalysis includes specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
leukocyte esterase, nitrite, and urobilinogen) will be performed by the central laboratory; 
microscopic urinalysis (epithelial cells, casts, RBCs, and WBCs) will be performed in the event 
of a positive dipstick result. 


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6.7. 
Subject Reported Outcomes 
These assessments should be performed before any tests, procedures, or other consultations at 
the visit. 
6.7.1. 
Subject’s VAS Assessment for PPP Symptom 
VAS is a tool used to help a person rate the intensity of certain sensations and feelings, such as 
pain. Each score ranges from 0 to 100. 
Subject assesses a degree of pruritus and pain as symptoms on hands and feet caused by PPP. 
See Appendix E. Worst status by a subject’s impression between visits will be recorded. PPP-
related symptoms should be included in these assessments.  
6.7.2. 
Subject’s Assessment for PPP Signs/Findings 
A part of PPSI assessment is used as a questionnaire. Skin lesion for the evaluation is the same 
as a palm or sole identified by Investigator for evaluation of PPSI at screening. This means the 
evaluated skin lesion site is the same with PPSI evaluation. Three signs of the disease (erythema, 
pustules/vesicle and desquamation/scale) are assessed by the subject him/herself, similar to PPSI. 
A numeric score is produced for each sign/finding of PPP and the range is from 0 to 4 and the 
total score will be 0 to 12. 
A subject’s assessment for each sign/finding on hands or feet (erythema, pustules/vesicles and 
desquamation/scale) are an exploratory disease-specific efficacy assessment. See Appendix G. 
Worst status by a subject’s own assessment between visits will be recorded.  
6.7.3. 
Quality of Life/ Treatment Satisfaction 
These assessments should be performed before any tests, procedures, or other consultations at 
the visit. 


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6.7.3.1. 
DLQI 
DLQI is a skin disease-specific Quality of Life (QoL) questionnaire consisting of 10 items which 
assess the subject status over the last one week. See Appendix H. 
DLQI can be used to assess 6 different aspects that may affect quality of life: symptoms and 
feelings, daily activities, leisure, work or school performance, personal relationships, and 
treatment. The DLQI produces a numeric score that can range from 0 to 30. A higher score 
indicates more severe disease. 
6.7.3.2. 
EQ-5D 
EQ-5D-5L is also a general and comprehensive QoL questionnaires which assesses the subject 
status on the visit day. See Appendix I. 
The EQ-5D is a generic health status measure composed of a descriptive system which 
comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression, and a VAS asking individuals to rate their own health. A lower utility index 
and VAS score indicates more severe disease.  
 


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7. 
DESCRIPTION OF STUDY TREATMENTS 
7.1. 
Description of Investigational Product(s) 
The chemical name of apremilast (CC-10004) is N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro -1H-isoindol-4-yl} acetamide. 
Apremilast will be supplied by the Sponsor and labeled appropriately as IP for this study. 
All IP will be provided in blister cards throughout the entire study. Apremilast will be provided 
as 10, 20, or 30 mg tablets. Placebo will be provided as identically appearing 10, 20, or 30 mg 
tablets. Apremilast, the IP, will be taken orally twice daily, approximately 12 hours apart, 
without restriction of food or drink. To mitigate potential GI side effects, dose titration will be 
implemented in the first week of this study (see Table 6). 
During Week 0 (Days 1-7), subjects will be dispensed dose titration blister cards with 10, 20, and 
30 mg apremilast tablets or identically appearing placebo tablets. The blister cards will contain 
all IP required for 4 weeks of treatment, with the first 7 days containing the titration supplies or 
matching placebo (see Table 6 Treatment Schema for Dose Titration at Visit 2 [Week 0] which 
details the titration supplies from Day 1 to Day 7). 
At Visit 2 (Week 0), subjects who meet eligibility criteria will be randomized using a permuted 
block randomization in parallel 1:1 to receive either apremilast 30 mg BID or placebo, using a 
centralized IRT. IP will be dispensed as indicated below. 
• Weeks 0 to 16: double-blind, placebo-controlled phase: apremilast 30 mg BID or 
placebo BID. 
− Week 0 to 1: subjects will be dose titrated as described above and detailed in 
Table 6. 
• Weeks 16 to 32: active treatment phase: apremilast 30 mg BID  
− Week 16 to 17: Subjects will be dose titrated as described below and detailed in 
Table 7  
Starting at Week 16, all subjects will receive apremilast. Subjects originally randomized to 
placebo at Week 0 will be switched to apremilast 30 mg BID at Week 16 and dose titration 
blister cards will be used. Dummy titration blister cards (dosing at 30 mg BID directly) will be 
used for subjects originally randomized to apremilast 30 mg BID. At all other visits during the 
active treatment phase, all subjects will receive apremilast 30 mg tablets which are to be taken 
twice daily. 
During Weeks 16 to 32, the IP will remain blinded, to prevent study personnel and subjects from 
knowing the IP assignment in the double blind, placebo-controlled Phase (Week 0 to 16) and to 
maintain the blind regarding the initial treatment assignment, all subjects will receive dose 
titration cards at Visit 10 (Week 16). Although only subjects initially randomized to placebo will 
be dose titrated during their first week of the active treatment phase, all subjects entering the 
active treatment phase will receive identically-appearing titration/treatment cards as shown in 
Table 7. 


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Please refer to local apremilast prescribing information for more details on available 
formulations, preparation, storage conditions, the approved indications, known precautions, 
warnings, and adverse reactions of apremilast (see current version of Prescribing Information). 
The apremilast dosing schedule and dose adjustments to be followed for this study are described 
in Section 7.3. 
Additional information may be included on the label as needed or applicable. Label(s) for IP will 
contain information as required per local health authority. 
7.2. 
Description of Placebo 
Placebo tablets will be provided as identically appearing apremilast 10, 20, or 30 mg tablets. 
 


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Table 6: 
Treatment Schema for Dose Titration at Visit 2 (Week 0) 
 
Week 0 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 -7 and 
thereafter 
 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Apremil
ast 30 
BID 
10 mg A 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg P 
30 mg A 
 
 
30 mg A 
 
 
30 mg A 
Placebo 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
 
 
30 mg P 
 
 
30 mg P 
A=Apremilast; BID= twice daily; P= Placebo. 
 
Table 7: 
Treatment Schema for Dose Titration at Visit 10 (Week 16) 
 
Week 16 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 -7 and 
thereafter 
 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Apremil
ast 30 
BID 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
10 mg P 
20 mg P 
30 mg A 
 
 
30 mg A 
 
 
30 mg A 
Placebo 
10 mg A 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
10 mg P 
20 mg P 
30 mg A 
 
 
30 mg A 
 
 
30 mg A 
A=Apremilast; BID= twice daily; P= Placebo. 
 


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7.3. 
Treatment Administration and Schedule 
IP will be taken orally twice daily, approximately 12 hours apart, without restriction of food or 
drink. To mitigate potential GI side effects, dose titration will be implemented in this study. 
During Week 0 (Days 1 to 7) and Week 16 (when placebo subjects are switched to receive 
apremilast 30 mg BID), subjects will be dispensed blister cards with 10, 20, and 30 mg 
apremilast tablets or identically appearing placebo for the dose titration.  
At all other visits where IP is dispensed, apremilast will be provided in blister cards as 10, 20, 
and 30 mg tablets or identically appearing placebo tablets. The treatment schema for dose 
titration at baseline (Week 0) and Week 16 is shown in Table 6 and Table 7, respectively. 
7.3.1. 
Dose Modification/Interruptions 
Any dose modifications outside of the dose described in Section 7.3 are not permitted in this 
study. 
Dose interruptions are not permitted except for safety reasons. The administration of apremilast 
can be resumed by Investigator’s judgement.  
7.4. 
Overdose 
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP(s) only. 
Therefore, for a drug to be subject to the overdose definition it must be both required and an 
investigational drug. In this study the only required and investigational drug is apremilast and the 
control arm drug (ie, placebo), hence overdose definition will apply to only apremilast (or 
matching placebo). 
Overdose for this protocol, on a per-dose basis, is defined as ingestion of 4 or more apremilast 
30  mg (or matching placebo) tablets in any 24-hour period whether by accident or intentionally. 
On a schedule or frequency basis, an overdose is defined as complete dosing more than 4 times 
during any 24-hour period. 
AEs associated with an overdose must be collected on the AE page of the eCRF for all 
overdosed subjects, but the overdose itself is not considered an AE. Other required or optional 
non-IPs intended for prophylaxis of certain side effects, etc., are excluded from this definition. 
Detailed information about overdose in this study, regardless of whether the overdose was 
accidental or intentional, should be reported on the drug exposure eCRF page. 
7.5. 
Method of Treatment Assignment 
At Visit 2, subjects who meet eligibility criteria will be randomized using a permuted block 
randomization in parallel with 1:1 ratio to receive either apremilast 30 mg BID or placebo, using 
a centralized IRT. Eligible subjects will be stratified according to a subject’s rounded PPPASI 
score (≤20 / 21-30 / ≥31) at randomization, and whether a subject has or not any focal infection 
at randomization (yes/no). Designated research personnel at the investigational sites will be 
assigned password protected, coded identification numbers, which give them authorization to 
enter the IRT to randomize subjects.  


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The system will present a menu of questions by which the research center personnel will identify 
the subject and confirm eligibility. When all questions have been answered, the IRT will assign a 
randomization identification number.  
Confirmation of the randomization will be sent to the investigational site, Amgen, and/or its 
representative. During the study visits, the pharmacy or authorized study personnel at the 
investigational site will dispense coded IP kits in accordance with the randomization 
identification number assigned by the IRT. 
7.6. 
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. 
7.7. 
Investigational Product Accountability and Disposal 
7.7.1. 
Investigational Product Accountability 
The Investigator(s) or designee(s) is responsible for accounting for all IP that is issued to and 
returned by the subject during the course of the study. 
The Investigator(s) or designee(s) is responsible for taking an inventory of each shipment of IP 
received, and comparing it with the accompanying IP accountability form. The Investigator(s) or 
designee(s) will verify the accuracy of the information on the form, sign and date it, retain a copy 
in the study file, and return a copy to Amgen. 
At the study site, all IP will be stored in a locked, safe area to prevent unauthorized access.  
The IP should be stored as directed on the package label. 
Amgen (or designee) will review with the Investigator and relevant site personnel the process for 
IP return, disposal, and/or destruction including responsibilities for the site versus Amgen(or 
designee). 
7.7.2. 
Record of Administration 
Accurate recording of all IP administration (including dispensing and dosing) will be made in the 
appropriate section of the subject’s eCRF and source documents. 
7.8. 
Investigational Product Compliance 
Study personnel will review the instructions printed on the package with the study subjects prior 
to dispensing the IP. IP will be dispensed as indicated in (Table 5). The subjects will be 
instructed to return the IP blister cards, including any unused IP, to the study site at each visit for 
pill counts and reconciliation. Subjects will be asked whether they have taken their IP as 
instructed at each study visit. Any problems with IP compliance will be reviewed with the 
subject. If a subject misses 4 or more consecutive days of dosing, Amgen should be contacted to 


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decide whether dosing should resume or whether the subject should be terminated from the 
Treatment phase of the study and enter into the Observational follow-up phase. 
Gross compliance problems (eg, missing 4 or more consecutive days of dosing or taking less 
than 75% of the doses between study visits) should be discussed with Amgen. Compliance is 
defined as taking between 75% and 120% of dispensed IP of the expected doses during a 
subject’s participation while in the treatment phases (double blind, placebo-controlled phase and 
active treatment phase) of the study. This definition of compliance is only for the purpose of 
study analysis, not study conduct. 
 


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8. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression.  
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigators Brochure and/or local package insert. 
8.1. 
Permitted Concomitant Medications and Procedures 
8.1.1. 
Double Blind, Placebo-controlled Phase (Week 0 to Week 16) 
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 nonprescription), treatments and therapies taken by the subject 
from screening throughout their entire participation in the study, including those initiated prior to 
the start of the study, must be recorded on the subject’s source document and on the appropriate 
page of the eCRF. The dose, unit, frequency, route, indication, and the date the medication 
started and stopped (if not ongoing) must be recorded.  
The following therapies will be permitted for the duration of the study. 
• Topical Therapy for PPP 
The only allowable concomitant treatments for PPP throughout the study are topical 
moisturizers (Vaseline). Subjects should not use moisturizers within 24 hours prior to 
the clinic visit. 
• Treatment for focal infection 
Noninvasive dental care (eg, scaling and root planing for periodontal disease) is 
allowed throughout the study. About one month for treatment for acute tonsillitis or 
sinusitis is also allowed throughout the study. If tooth abscess and/or tooth cavity is 
newly recognized after starting the study, the dental therapy for them is permitted.  
• Treatment for PAO 
The use of background stable doses of NSAIDs for PAO is allowed. 
• Treatment for complication of disease other than PPP 
Every effort should be made to keep subjects on stable concomitant medications.  
Topical use of corticosteroids to body area other than palms and soles, inhaled, otic, 
ocular, nasal or other routes of mucosal delivery of corticosteroids are allowed 
throughout the study. 
8.1.2. 
Active Treatment Phase (from Week 16 to 32) 
In addition to permitted concomitant medications and procedures (Section 8.1.1), subjects in the 
active treatment phase will have the option of adding topical therapies (including, but not limited 
to, topical corticosteroids, topical retinoids or vitamin D3 analogue preparations) and/or 


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phototherapy (excluding oral PUVA) to their treatment regimen. Dose modification is permitted 
for background doses of NSAIDs for PAO and concomitant medications for complication of 
disease other than PPP. 
8.2. 
Prohibited Concomitant Medications and Procedures 
8.2.1. 
Double-blind, Placebo-controlled Phase (Week 0 to Week 16) 
The following treatment cannot be employed for the duration of the double-blind, placebo-
controlled phase: 
• Topical therapy  
Topical therapies that could affect PPP or the efficacy evaluation (including, but not 
limited to, corticosteroids, retinoid, vitamin D3 derivatives, tacrolimus, antihistamine, 
antibiotics or traditional Chinese/Japanese herbal preparations). 
Note: only use of topical antibiotics for the treatment after skin biopsy is permitted. 
• Conventional systemic therapy 
Systemic therapies that could affect PPP or the efficacy evaluation (including, but not 
limited to corticosteroids, retinoids, antihistamine, antibiotics, JAK inhibitors, 1,25-
dihydroxy vitamin D3 and analogues, psoralens, sulfasalazine, hydroxyurea, dimethyl 
fumarate, biotin, colchicine or traditional Chinese/Japanese herbal preparations). 
• GMA 
• Phototherapy 
− UVB or PUVA 
• Biologic therapies: 
− TNFα or IL17 blockers such as adalimumab, brodalumab, certolizumab pegol, 
etanercept, golimumab, infliximab, ixekizumab, secukinumab (or biosimilars for 
each) 
− Anti-IL12 or anti-IL23 monoclonal antibodies such as guselkumab, ustekinumab 
or tildrakizumab∗ (or biosimilars for each) 
− Other biologics that could affect PPP or the efficacy evaluation 
• Treatment for focal infection 
Focal infection must be carefully assessed in all subjects, and if treatment for focal 
infection is obviously required, treatment for the focal infection (examples are shown 
in Section 4.3) should be completed prior to 24 weeks before baseline. 
Focal infection treatments for PPP below (but not limited to) except for dental 
therapy (see Section 8.1.1) at any time during the study.  
− Tonsillectomy for tonsillitis 
 
∗ Not approved in Japan. 


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− Endodontic treatment for periapical pathosis 
− Periodontal surgery for moderate to severe periodontitis 
• Systemic medications for PAO 
Systemic therapy, including, but not limited to, corticosteroids, bisphosphonates, 
immunosuppressants [eg, MTX, azathioprine, cyclosporine or 6-thioguanine, 
mercaptopurine, mycophenolate mofetil, tacrolimus]) and other biologics (eg, anti-
IL1 antibody). 
• Treatment for complication of disease other than PPP 
− Systemic corticosteroids 
− Disease-modifying agents such as MTX, sulfasalazine, or intramuscular (IM) gold 
are prohibited during the study.  
• Use of strong CYP3A4 enzyme inducers (eg, rifampicin, phenobarbital, 
carbamazepine, phenytoin and St. John’s Wort) 
− Coadministration of the strong CYP3A4 enzyme inducer, rifampicin, resulted in a 
reduction of systemic exposure of apremilast, which may result in a loss of 
efficacy of apremilast.  
• Use of any investigational drug or device 
• Prolonged sun exposure or use of tanning booths or other ultraviolet light sources are 
also not permitted. 
8.2.2. 
Active Treatment Phase (from Week 16 to 32) 
Use of medications and procedures except for those described in Section 8.1.2 are not permitted. 
8.2.3. 
Observational Follow-up 
There is no restriction of concomitant medication during the observational follow-up phase. 
8.3. 
Required Concomitant Medications and Procedures 
Not applicable. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Overview 
This is a 16-week placebo-controlled study, followed by a 16-week active treatment phase to 
evaluate the efficacy of apremilast (CC-10004) in Japanese subjects with PPP. 
The primary efficacy endpoint, PPPASI-50 at Week 16 will be assessed and the apremilast 
30 mg BID group will be compared to the placebo group. 
The primary analysis will be performed when all subjects complete Week 16. Additionally, an 
analysis will be performed after all subjects complete the active treatment phase of the study (16 
weeks of blinded treatment) and follow-up at Week 32 or discontinue early. 
A Statistical analysis plan (SAP), which includes detailed list of analyses, will be written based 
on this protocol. 
9.2. 
Study Population Definitions 
The safety population will include all randomized subjects who received at least one dose of IP. 
The analysis of safety data in this study will be based on the safety population and subjects will 
be included in the treatment to which they actually received. 
The intent-to-treat (ITT) population will be defined as all randomized subjects who received at 
least one dose of IP. Subjects will be included in the treatment group to which they are 
randomized. 
The per protocol (PP) population will include all subjects in the ITT population who have no 
protocol deviations that may substantially affect the efficacy results during the 16 weeks 
placebo-controlled treatment phase. The final determination of protocol deviation criteria to 
define the PP population will be made prior to the unblinding of the database and will be 
documented separately. 
9.3. 
Sample Size and Power Considerations 
A total of approximately 86 subjects will be randomized 1:1 ratio to receive apremilast 30 mg 
BID or placebo. The study has 80% power (based on a chi-square test at a 2-sided significance 
level of 0.10) to demonstrate the superiority of apremilast 30 mg BID over placebo with respect 
to the primary endpoint of PPPASI-50 at Week 16, assuming the PPPASI-50 rates of 45% 
(apremilast 30 mg BID) and 20% (placebo), respectively. PPPASI-50 rate of 20% at Week 16 in 
placebo is based on the placebo rate of 21% at Week 16 in guselkumab Phase 2 study (Terui, 
2018). Considering at least 20% difference as a clinically meaningful difference, apremilast 30 
mg BID PPPASI rate of 45% is expected in this study. The sample-size was estimated using SAS 
9.4 power procedure. 
For the skin biopsy RNA expression analysis, N=13 subjects per arm will provide 80% 
probability to observe the lower limit of the 90% confidence interval (CI) of a decrease of IL8 
mRNA expression from baseline to Week 16 in the apremilast treated arm is over -44% , based 
on the mean and standard deviation (SD) change observed in a 12 weeks apremilast psoriasis 
study CC-10004-PSOR-004 (Gottlieb, 2013). For the serum protein biomarker analysis, N=17 
subjects per arm will provide 80% probability to observe the lower limit of the 90%CI of an 


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absolute difference from baseline to Week 16 of IL17A levels in the apremilast arm is over 60%, 
based on the mean and SD change observed in the psoriasis study in Japan, CC-10004-PSOR-
011 (Garcet, 2018). 
9.4. 
Background and Demographic Characteristics 
Subjects’ age, weight, height and other continuous demographics and baseline characteristics 
will be summarized using descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum), while gender, race, and other categorical variables will be summarized with 
frequency tabulations. Medical history data will be summarized using frequency tabulations by 
system organ class and preferred term. 
9.5. 
Subject Disposition 
Subjects disposition (analysis population allocation, entered, completed, discontinued, along 
with primary reason for discontinuation) will be summarized using frequency and percent by 
phase. A summary of subjects randomized by site will be provided. Protocol deviations will be 
summarized using frequency tabulations. 
9.6. 
Efficacy Analysis 
9.6.1. 
Efficacy Evaluation for the Primary and Secondary Endpoints 
All efficacy analyses will be performed using the ITT population. In addition, an analysis using 
the PP population will be provided for the primary efficacy endpoint. The analyses using the ITT 
population will be considered as the primary analysis. 
9.6.1.1. 
Primary Efficacy Endpoint - (Weeks 0 - 16) 
The primary efficacy endpoint of the proportion of subjects receiving apremilast 30 mg BID or 
placebo who achieve a PPPASI-50 at Week 16 from baseline will be evaluated. 
The primary efficacy endpoint will be analyzed using a chi-square test. The testing will be 
conducted at the two-sided 0.10 significant level and the two-sided 90% CI for the treatment 
difference of the PPPASI-50 response rates will be provided. The two-sided 95% CI will also be 
provided for reference. The primary missing data handling approach for PPPASI-50 responder 
will be nonresponder imputation (NRI), by which a subject without sufficient data for the 
response determination will be considered a nonresponder. Sensitivity analysis using the PP 
population and/or the other missing data handling approach [eg, last observation carried forward 
(LOCF) method] will be performed and the Cochran-Mantel-Haenszel (CMH) test stratified by 
the randomization stratification factors [PPPASI total score range (≤ 20 score, 21-30 score, ≥ 31 
score) and focal infection status (Yes, No) at baseline] will be conducted to support the primary 
analysis. 
9.6.1.2. 
Secondary Efficacy Endpoints - (Weeks 0 - 16) 
Descriptive statistics will be presented for all secondary endpoints in Table 2. Specifically, for 
continuous endpoints, descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum) for baseline, Week 16 and Week 16 change from baseline will be provided. Binary 
endpoints will be summarized with frequency tabulations.  


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Treatment comparisons between the apremilast 30 mg BID and placebo will be performed for the 
secondary endpoints. Continuous efficacy endpoint will be analyzed using the analysis of 
covariance (ANCOVA) model adjusted for PPPASI total score range (≤ 20 score, 21-30 score, ≥ 
31 score) and focal infection status (yes, no) at baseline as factors, and the associated baseline 
value as covariate, while binary endpoints will be evaluated using the CMH test previously 
described for the primary endpoint. The primary missing data handling approach for continuous 
endpoint will be multiple imputation (MI). 
Secondary efficacy endpoints will be tested without multiplicity adjustment, therefore the p-
value for those endpoints will be regarded as nominal. For secondary efficacy endpoints, the 
two-sided 95% CI will be provided. 
9.6.1.3. 
Primary and Secondary Endpoints - (Weeks 16 - 32) 
The active treatment phase runs from Week 16 to Week 32. Descriptive statistics will be 
provided. Specifically, for continuous variables, descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum) for baseline, specified time points and changes 
from baseline will be provided. Categorical variables will be summarized with frequency 
tabulations.  
9.6.1.4. 
Subgroup Analysis 
Subgroup analyses for comparisons of the proportion of subjects who achieve PPPASI-50 at 
Week 16 between apremilast 30 mg BID and placebo, based upon baseline demographic, and 
baseline disease characteristics, will be provided to determine the robustness of the treatment 
effect. 
9.6.2. 
Efficacy Evaluation for Exploratory Endpoints - (Weeks 0 - 16) 
Descriptive statistics will be presented for exploratory endpoints. Specifically, for continuous 
variables, descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) 
for baseline, specified time points and change from baseline will be provided. Categorical 
variables will be summarized with frequency tabulations. 
The Kaplan-Meier procedure will be used to characterize the time to achieve at least PPPASI-50 
and PPPASI-75 during the double-blind placebo-controlled phase (Weeks 0-16).  
9.6.3. 
Efficacy Evaluations for Exploratory Endpoints (Weeks 16 - 32) 
The active treatment phase runs from Week 16 to Week 32. Descriptive statistics will be 
provided. Specifically, for continuous variables, descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum) for baseline, specified time points and changes 
from baseline will be provided. Categorical variables will be summarized with frequency 
tabulations. These data summaries will be presented according to the treatment sequence 
received, ie, apremilast 30 mg BID/30 mg BID, or placebo/apremilast 30 mg BID. 
9.7. 
Safety Analysis 
The safety analyses will be performed using the Safety population. Safety will be assessed by 
clinical review of all relevant parameters including TEAEs which are defined as any AEs that 


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begin or worsen on or after the first dose of IP through 28 days after the last dose of IP, 
laboratory tests, and vital signs; no inferential testing for statistical significance will be 
performed. Data from safety assessments will be summarized descriptively for the double-blind, 
placebo-controlled phase (Weeks 0 to 16) and the apremilast exposure period when subjects 
receive apremilast treatment. For safety analyses in the active treatment phase, baseline will be 
relative to the first dose date following randomization at Week 0. For safety analyses in 
apremilast exposure period, baseline will be relative to the first apremilast dose date at Week 0 
for subjects initially randomized to apremilast or Week 16 for subjects initially randomized to 
placebo and switched to apremilast in the active treatment phase (Weeks 16 to 32). 
AEs will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) 
classification system. All TEAEs will be summarized by system organ class, preferred term, 
severity, and relationship to IP. AEs leading to death or to discontinuation from treatment and 
SAEs will also be summarized and listed separately. 
Laboratory data will be summarized descriptively. In addition, shift tables showing the number 
of subjects with values low, normal, and high compared to the normal ranges of pretreatment 
versus posttreatment will be provided. Associated clinical laboratory parameters such as hepatic 
enzymes, renal function, and hematology values will be grouped and presented together. 
Individual subject values will be listed and values outside of the standard reference range will be 
flagged. Shift tables and analyses of changes from Baseline will be produced. To account for the 
different exposure to the IP, TEAEs or marked laboratory abnormalities will also be summarized 
using the exposure-adjusted incidence rate, in addition to the simple incidence rates. 
Vital sign measurements, including weight, will be summarized descriptively by visit. In 
addition, shift tables showing the number of subjects with values low, normal, and high based on 
the specified ranges pre-treatment versus post-treatment will be provided. 
The change from baseline for each of the vital signs including weight will be summarized. 
Incidence of abnormal vital signs parameters will be tabulated. 
The detailed safety analyses will be specified in the SAP. 
9.8. 
Interim Analysis 
No interim analysis is planned for this study. 
9.9. 
Other Topics 
9.9.1. 
Concomitant Therapy 
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations. The anatomical therapeutic chemical (ATC) coding scheme of the World Health 
Organization (WHO) will be used to group medications into relevant categories for these 
tabulations. Separate data summaries of background medications will be provided. 


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10. 
ADVERSE EVENTS 
10.1. 
Monitoring, Recording and Reporting of Adverse Events 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE. A diagnosis or syndrome should be recorded on 
the AE/SAE case report form (CRF) rather than the individual signs or symptoms of the 
diagnosis or syndrome.  
 
Abuse, withdrawal, sensitivity or toxicity to an IP should be reported as an AE.  Overdose, 
accidental or intentional, whether or not it is associated with an AE should be reported on the 
overdose CRF.  (See Section 7.4 for the definition of overdose.)  Any sequela of an accidental or 
intentional overdose of an IP should be reported as an AE on the AE CRF. If the sequela of an 
overdose is an SAE, then the sequela must be reported on the paper SAE report form and on the 
AE CRF. The overdose resulting in the SAE should be identified as the cause of the event on the 
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 SAEs made known to the 
Investigator at any time following the protocol-required reporting period or after end of study. 
All AEs (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 J) by facsimile/email of the paper SAE Form directly to Amgen Global 
PatientSafety.   
10.2. 
Evaluation of Adverse Events 
A qualified Investigator will evaluate all AEs as to:  
10.2.1. 
Seriousness  
An SAE is any AE occurring at any dose that: 
• Results in death; 


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


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


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10.2.3. 
Causality 
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected: 
a causal relationship of the AE to IP administration is unlikely 
or remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the 
observed event. 
Suspected: 
there is a reasonable possibility that the administration of IP 
caused the AE. ‘Reasonable possibility’ means there is evidence 
to suggest a causal relationship between the IP and the AE. 
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available. 
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by 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 or interruption 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 SAE. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE/SAE page/screen of the eCRF. 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 are immediately reportable events.   
10.4.1. 
Females of Childbearing Potential (FCBP) – Collection of Pregnancy 
Information 
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
FCBP regardless of disease state) occurring while the subject is on IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events. If positive results are 
obtained from a serum pregnancy test, IP is to be discontinued immediately and the subject 
instructed to return any unused portion of the IP to the Investigator. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Amgen Global Patient 
Safetyimmediately by email, phone or facsimile, or other appropriate method, using the 
Pregnancy Notification Form, or approved equivalent form in English language. (refer to 
Appendix K). 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 follow the female subject until completion of the pregnancy and must 
notify Amgen Global Patient Safetyimmediately about the outcome of the pregnancy (either 
normal or abnormal outcome). 
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Amgen Global PatientSafety via the paper Serious 


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Adverse Event Report Form in English language within 24 hours of the Investigator’s knowledge 
of the even. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in-utero exposure to the IP should also be reported to Amgen Global Patient Safety 
by facsimile, 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 L) and submitted by facsimile or email to Amgen Global Patient Safety witin 
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 # 25). 
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. 


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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 J). 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 
period or after end of study. SAEs occurring prior to treatment (after signing the ICF) will be 
collected/recorded/reported. 
Any follow-up datato the existing SAE should be resubmitted to Amgen Global Patient Safety in 
English language. 
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board (IRB)/Ethics Committee (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 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 J).     
 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 J). 
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 appropriated method. 


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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 
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, suspected unexpected serious adverse 
reactions [SUSARs]); 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• Other important safety information and periodic reports 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 Clgene/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 J), Pregnancy Notification  Form (refer to Appendix K) and/or 
the Lactation Notification Form (refer to Appendix L). 
 


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11. 
DISCONTINUATIONS 
11.1. 
Treatment Discontinuation 
The following events are considered sufficient reasons for discontinuing a subject from the IP(s): 
• AE 
• Lack of efficacy 
• Non-compliance with IP 
• Withdrawal by subject 
• Death 
• Lost to follow-up 
• Pregnancy (of FCBP) 
• Important protocol deviation 
• Physician’s decision 
• Study terminated by Sponsor 
• Other (to be specified on the CRF) 
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents. 
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor. However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion. 
11.2. 
Study Discontinuation 
The following events are considered sufficient reasons for discontinuing a subject from the 
study: 
• Screen failure 
• AE 
• Lack of efficacy 
• Non-compliance with IP 
• Withdrawal by subject 
• Death 
• Lost to follow-up 
• Pregnancy (of FCBP) 
• Important protocol deviation 


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• Physician’s decision 
• Study terminated by Sponsor 
• Other (to be specified on the CRF) 
The reason for study discontinuation should be recorded in the CRF and in the source 
documents. 
 


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


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13. 
REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Amgen, its authorized representative, and 
Investigator abide by GCP, as described in 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 ofAmgen 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 ICF and are 
screened for entry into the study. Subjects who fail screening must have the reason(s) recorded in 
the subject’s source documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of CRFs and queries. 
The information contained in the protocol and amendments (with the exception of the 
information provided by Amgen on public registry websites) is considered Amgen confidential 
information. Only information that is previously disclosed by Amgen on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement. Amgen protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Amgen. Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Amgen for review and approval, providing at least 5 
business days for review. 
At the time results of this study are made available to the public, Amgen will provide 
Investigators with a summary of the results that is written for the lay person.  The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject. 


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13.3. 
Subject Information and Informed Consent 
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures. 
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date. The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject. In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised. Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF. The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject. 
13.4. 
Confidentiality 
Amgen affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Amgen requires 
the Investigator to permit Amgen's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. 
13.5. 
Protocol Amendments 
Any amendment to this protocol must be approved by the Amgen Clinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/EC for written approval. 
Written approval must be obtained before implementation of the amended version occurs. The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/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 
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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 AEs as soon as possible;  
• Periodic reports on the progress of the study; 
• Deviations from the protocol or anything that may involve added risk to subjects. 
13.8. 
Termination of the Study 
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 IP are complete, accurate, filed and retained. Examples of source 
documents include: hospital records; clinic and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiche; x-ray film and reports; and records kept at the pharmacy, and the laboratories, as 
well as copies of CRFs or Compact disc read-only memory (CD-ROM). 
14.2. 
Data Management 
Data will be collected via CRF and entered into the clinical database per Amgen standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all 
changes made to the data. 
14.3. 
Record Retention 
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following: 
• Signed ICFs for all subjects; 
• Subject identification code list, screening log (if applicable), and enrollment log; 
• Record of all communications between the Investigator and the IRB/EC; 
• Composition of the IRB/EC; 
• Record of all communications between the Investigator, Amgen/Celgene, and their 
authorized representative(s); 
• List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures; 
• Copies of CRFs (if paper) and of documentation of corrections for all subjects; 
• IP accountability records; 
• Record of any body fluids or tissue samples retained; 
• All other source documents (subject records, hospital records, laboratory records, 
etc.);  


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• 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, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator. Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, IP 
storage area, CRFs, subject’s source documents, and all other study documentation will be 
inspected/reviewed by the Amgen representative in accordance with the Study Monitoring Plan. 
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation. Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff. Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified. Additional 
monitoring activities may be outlined in a study-specific monitoring plan. 
15.2. 
Audits and Inspections 
In addition to the routine monitoring procedures, a Quality, Compliance & Audit, Learning & 
Performance unit exists within Amgen. Representatives of this unit will conduct audits of clinical 
research activities in accordance with Amgen SOPs to evaluate compliance with Good Clinical 
Practice guidelines and regulations. 
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, Food and Drug Administration 
[FDA], European Medicines Agency [EMA], Pharmaceuticals and Medical Devices Agency 
[PMDA], Health Canada) and company authorized representatives. The Investigator should 
make every effort to be available for the audits and/or inspections. If the Investigator is contacted 
by any regulatory authority regarding an inspection, he/she should contact Celgene immediately. 
15.3. 
Product Quality Complaint 
 
A product complaint (PC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product or device after they are released for distribution to 
market or clinic by either Amgen or by distributors, and partners with whom Amgen 
manufactures the material.  This includes any drugs, devices, or combination products 
provisioned and/or repackaged/modified by Amgen.  Drugs or devices include investigational 


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product.  Any product complaints associated with an investigational products, 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: 
 
Complete Amgen’s paper Clinical Product Complaint Intake Form and email the form to the  
Following Amgen email address: 
Clinical-Complaint-Intake@amgen.com 
 


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16. 
PUBLICATIONS 
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Amgen on public registry websites, is considered 
Amgen confidential information and is not to be used in any publications. Amgen protocol-
related information proposed for use in a publication must be submitted to Amgen for review and 
approval and should not be utilized in a publication without express written approval from 
Amgen, or as described in the Clinical Trial Agreement. 
Amgen will ensure Amgen-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 2 and Phase 3 clinical studies, and any other study results of significant 
medical importance. This also includes results relating to investigational medicines whose 
development programs have been discontinued. 
Study results may also be presented at one or more medical congresses and may be used for 
scientific exchange and teaching purposes. Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations. 
Eligibility for external authorship, as well as selection of first 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, participation in study steering committee (when applicable) and contribution to 
abstract, presentation and/or publication development. 
 


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17. 
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Adamo S, Nilsson J, Krebs A, Steiner U, Cozzio A, French LE, et al. Successful treatment of 
SAPHO syndrome with apremilast. Br J Dermatol. 2018;179(4):959-962. 
Andrews GC, Birkman FW, Kelly RJ. Recalcitrant Pustular Eruptions of the Palms and Soles. 
Arch Dermatol Syphil. 1934;29(4):548-563. 
Andrews GC, Machacek GF. Pustular Bacterids of the Hands and Feet. Arch Derm Syphilol. 
1935;32(6):837-847. 
Bhushan M, Burden AD, McElhone K, James R, Vanhoutte FP, Griffiths CE. Oral liarozole in 
the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled 
study. Br J Dermatol. 2001;145(4):546-553. 
Bissonnette R, Nigen S, Langrey RG, Lynde CW, Tan J, Fuentes-Duculan J, et al. Increased 
expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) 
pustular psoriasis or PP pustulosis; results from a randomised controlled trial. J Eur Acad 
Dermatol Venereol. 2014;28(10):1298-1305. 
Bissonnette R, Pariser DM, Wasel NR, Goncalves J, Day RM, Chen R, et al. Apremilast, an oral 
phosphodiesterase-4 inhibitor, in the treatment of palmoplantar psoriasis: Results of a pooled 
analysis from phase II PSOR-005 and phase III Efficacy and Safety Trial Evaluating the Effects 
of Apremilast in Psoriasis (ESTEEM) clinical trials in patients with moderate to severe psoriasis. 
J Am Acad Dermatol. 2016;75(1):99-105. 
Bissonnette R, Haydey R, Rosoph LA, Lynde CW, Bukharo M, Fowler JF, et al. Apremilast for 
the treatment of moderate-to-severe palmoplantar psoriasis: results from a double-blind, placebo-
controlled, randomized study. J Eur Acad Dermatol Venereol. 2018;32(3):403-410. 
Cutolo M, Myerson GE, Fleischmann R, Lioté F, Díaz-González F, Van den Bosch F, et al. A 
Phase III, Randomized, Controlled Trial of Apremilast in Patients with Psoriatic Arthritis: 
Results of the PALACE 2 Trial. J Rheumatol. 2016;43(9):1724-34. 
Edwards CJ, Blanco FJ, Crowley J, Birbara CA, Jaworski J, Aelion J, et al. Apremilast, an oral 
phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a 
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Murakami M, Hagforsen E, Morhenn V, Ishida-Yamamoto A, Iizuka H. Patients with 
Palmoplantar Pustulosis have Increased IL-17 and IL-22 levels both in the lesion and serum. Exp 
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Murakami M, Kameda K, Tsumoto H, Tsuda T, Masuda K, Uysunomiya R, et al. TLN-58, an 
Additional hCAP18 processing form, found in the lesion vesicle of palmoplantar pustulosis in 
the skin. J Invest Dermatol. 2017;137(2):322-331. 
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18. 
APPENDICES 


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APPENDIX A. TABLE OF ABBREVIATIONS 
Table 8: 
Abbreviations and Specialist Terms 
Abbreviation or 
Specialist Term 
Explanation 
ADL 
Activity of daily life 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase (SGOT) 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
β-hCG 
β-subunit of human chorionic gonadotropin 
BID 
Twice daily 
BD 
Behcet's disease 
BMI 
Body Mass Index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
cAMP 
Adenosine 3’, 5’-cyclic monophosphate 
CBC 
Complete blood count 
CD-ROM 
Compact disc read-only memory 
CI 
Confidence Interval 
CIOMS 
The Council for International Organizations for Medical Sciences 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CXCL 
Chemokine (C-X-C motif) ligand 
CYP 
Cytochrome P450 
DEFB 
Defensin beta  
DLQI 
Dermatology Life Quality Index 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
eCRF 
Electronic case report form 


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Table 8: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
EDC 
Electronic data capture 
EOT 
End of treatment 
EMA 
European Medicines Agency 
ET 
Early Termination 
EQ-5D 
EuroQol 5 Dimension 
EudraCT 
European Clinical Trials Database 
FCBP 
Female of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMA 
Granulocyte and monocyte adsorption apheresis 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Anti-hepatitis B core antibody 
HCVAb 
Anti-hepatitis C virus antibody 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-related Quality of Life 
hs-CRP 
high sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IBD 
Inflammatory Bowel Disease 
IC 
Informed consent 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IFNG 
Interferon gamma 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL 
Interleukin 
IM 
Intramuscular 


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Table 8: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
ITT 
Intent-to-treat 
JAK 
Janus kinase 
KOH 
Potassium hydroxide 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
modified PPPASI-50 
Defined as ≥50% improvement of modified PPPASI total score from baseline. 
modified PPPASI-75 
Defined as ≥75% improvement of modified PPPASI total score from baseline. 
MRI 
Magnetic resonance imaging 
mRNA 
messenger RNA 
MTX 
Methotrexate 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
NK 
Natural killer 
NRI 
Nonresponder imputation 
PAO 
Pustulotic arthro-osteitis 
PCR 
Polymerase chain reaction 
PDE4 
Phosphodiesterase 4 
PGA 
Physician’s Global Assessment 
PIN 
Personal identification number 
PMDA 
Pharmaceuticals and Medical Devices Agency 
po 
orally 
PP 
Per protocol 
PPP 
Palmoplantar pustulosis 


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Table 8: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
PPPASI 
Palmo-Plantar Pustulosis Area and Severity Index 
PPPASI-50 
Defined as ≥ 50% improvement in PPPASI total score from baseline. 
PPPASI-75 
Defined as ≥ 75% improvement in PPPASI total score from baseline.  
PPSI 
Palmo-Plantar Severity Index 
PC 
Product Complaint 
QoL 
Quality of Life 
PsA 
Psoriatic arthritis 
PT 
Preferred term 
PUVA 
Psoralen and ultraviolet A 
RBC 
Red blood cell count 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAPHO 
Synovitis, acne, pustulosis, hyperostosis and osteitis 
sc 
subcutaneous 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase  
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SRO 
Subject’s Reported Outcome 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
UV 
Ultraviolet 
UVB 
Ultraviolet B 
VAS 
Visual Analogue Scale 


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Table 8: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
WBC 
White blood cell count 
WHO 
World Health Organization 
 


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APPENDIX B. PPPASI (PALMO-PLANTAR PUSTULOSIS AREA AND 
SEVERITY INDEX) 
The PPPASI is a system used for assessing and grading the severity and area of palmoplantar 
pustulosis lesions and their response to therapy. The PPPASI produces a numeric score that can 
range from 0 to 72. The severity of the disease is calculated as follows. 
In the PPPASI system, the palms and soles are divided into 4 regions: the right palm, left palm, 
right sole, and left sole, which account for 20%, 20%, 30%, and 30% of the total body surface 
area (BSA) of the palms and soles, respectively. Each of these areas is assessed separately for 
erythema, pustules and desquamation, which are each rated on a scale of 0 to 4. 
The scoring system for the signs of the disease (erythema, pustules/vesicle and desquamation 
/scale) is: 
0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = very severe. 
The scale for estimating the area of involvement for pustular lesions is outlined below. 
0 = no involvement 
1 = 1% to 9% involvement 
2 = 10% to 29% involvement 
3 = 30% to 49% involvement 
4 = 50% to 69% involvement 
5 = 70% to 89% involvement 
6 = 90% to 100% involvement 
 
The PPPASI formula is: 
PPPASI = (E + P + D) Area×0.2 (right palm) + (E + P + D) Area×0.2 (left palm) + (E + P + 
D) Area×0.3 (right sole) + (E + P + D) Area×0.3 (left sole)  
Where E = erythema, P = pustular/vesicle and D = desquamation/scale 
 
References: Bhushan, 2001. 
 


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APPENDIX C. PALMO-PLANTAR PUSTULOSIS SEVERITY INDEX 
(PPSI) 
The PPSI is a system used for assessing and grading the severity of palmoplantar pustulosis 
lesions and their response to therapy. The PPSI produces a numeric score that can range from 0 
to 12. 
In the PPSI system, evaluation skin lesion sites are identified by either palms or soles, which has 
the most severe skin lesion at screening. Any identified skin lesion site will be assessed at all 
subsequent visits. 
Evaluation of skin lesion site are assessed separately for erythema, pustules/vesicle and 
desquamation/scale, which are each rated on a scale of 0 to 4. 
 
The severity of the disease is calculated as follows. 
The scoring system for the signs of the disease (erythema, pustules/vesicle and 
desquamation/scale) is: 
0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = very severe. 
 
The PPSI formula is: 
PPSI total score= (E + P + D) 
Where E = erythema, P = pustular/vesicle and D = desquamation/scale 
The total score ranges from 0 to 12 
 
Modified from: Terui, 2018. 
 


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APPENDIX D. PHYSICIAN’S GLOBAL ASSESSMENT (PGA) FOR 
PALMS AND SOLES 
The PGA for palms and soles is used to determine the subject’s palmoplantar pustulosis lesions 
(palms and soles) at a given time point. 
 
<PGA for palms and soles > 
Lesions on palms and soles will be graded based on the scales below. 
0 = Clear 
1 = Almost clear 
2 = Mild 
3 = Moderate 
4 = Severe 
5 = Very severe 
The total score ranges from 0 to 5 
 
Modified from: Farhi, 2008; Terui, 2018. 
 


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APPENDIX E. VISUAL ANALOGUE SCALES (VAS) - PPP SYMPTOMS 
FOR HANDS AND FEET 
 
Subject’s assessment for Pruritus of hands and feet 
At its worst, how much itch (on hands and feet) have you had because of your condition 
during the last visit and this visit? 
 
 
 
Subject’s assessment for Pain of hands and feet 
At its worst, how much skin discomfort/pain (on hands and feet) have you had because of 
your condition during the last visit and this visit? 
 
 
Please note: VAS above is not drawn to scale and is for illustrative purposes only. 
 
Reference: Sobell, 2016. 
 
0 
100 
Please use a vertical stroke 
No itch  
at all 
Worst itch 
imaginable 
0 
100 
Please use a vertical stroke 
No pain  
at all 
Worst possible 
pain 


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APPENDIX F. MODIFIED PPPASI 
Based on characteristics that the development of vesicles followed by pustules on the palms and 
soles is distinctive pathophysiology in PPP, emphasizing vesicles and pustules on the palms and 
soles can be expected as a more sensitive assessment of PPP symptoms and that such a 
modification is considered to have a possibility to become a more appropriate assessment tool of 
PPP. Therefore, modified PPPASI is assessed as an exploratory investigation of a more 
appropriate endpoint for PPP. 
The modified PPPASI is an exploratory system used for assessing and grading the severity and 
area of palmoplantar pustulosis lesions and their response to therapy. The modified PPPASI 
produces a numeric score that can range from 0 to 96. The severity of the disease is calculated as 
follows. 
In the modified PPPASI system, the palms and soles are divided into 4 regions as well as normal 
PPPASI: the right palm, left palm, right sole, and left sole, which account for 20%, 20%, 30%, 
and 30% of the total body BSA of the palms and soles, respectively. Each of these areas is 
assessed separately for erythema, pustules, vesicles and desquamation, which are each rated on a 
scale of 0 to 4. 
 
The scoring system for the signs of the disease (erythema, pustules, vesicle and desquamation 
/scale) is: 
0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = very severe. 
 
The scale for estimating the area of involvement for pustular lesions is outlined below. 
0 = no involvement 
1 = 1% to 9% involvement 
2 = 10% to 29% involvement 
3 = 30% to 49% involvement 
4 = 50% to 69% involvement 
5 = 70% to 89% involvement 
6 = 90% to 100% involvement 
 
The modified PPPASI formula is: 
PPPASI = (E + P + V+ D) Area×0.2 (right palm) + (E + P + V + D) Area×0.2 (left palm) + 
(E + P + V + D) Area×0.3 (right sole) + (E + P + V + D) Area×0.3 (left sole) 
Where E = erythema, P = pustular, V = vesicle and D = desquamation/scale 
 
Reference: Modified from PPPASI scoring system for the signs of the disease (Appendix B). 


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APPENDIX G. SUBJECT’S ASSESSMENT - PPP SIGNS/FINDINGS FOR 
HANDS AND FEET 
 
This assessment will be performed using the PPSI scoring system (Appendix C). A subject will 
evaluate skin lesion sites which are identified by either palms or soles, which has the most severe 
skin lesion assessed by an Investigator at screening. Any identified skin lesion site will be 
assessed at all subsequent visits by a subject. 
Evaluation of skin lesion sites are assessed separately for erythema, pustules/vesicle and 
desquamation/scale, which are each rated on a scale of 0 to 4. 
 
Subject’s assessment for Erythema 
 
At its worst, how much abnormal redness of the skin on hands and feet have you had because 
of your condition during the last visit and this visit? 
0 = none, 1 = minimal, 2 = moderate, 3 = severe, and 4 = very severe. 
 
Subject’s assessment for Pustules/Vesicle 
At its worst, how many blisters and/or inflamed bumps that are filled with pus on your hands 
and feet have you had because of your condition during the last visit and this visit? 
0 = none, 1 = minimal, 2 = moderate, 3 = severe, and 4 = very severe. 
 
Subject’s assessment for Desquamation/Scale 
At its worst, how much peeling or shedding of skin and/or scabs on your hands and feet have 
you had because of your condition during the last visit and this visit? 
0 = none, 1 = minimal, 2 =moderate, 3 = severe, and 4 = very severe. 
 
The total score will be calculated by: 
PPSI total score= (E + P + D) 
Where E = erythema, P = pustular/vesicle and D = desquamation/scale 
The total score ranges from 0 to 12 
 
 
Reference: Modified from PPSI scoring system for the signs of the disease (Appendix C). 
 


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APPENDIX H. DERMATOLOGY LIFE QUALITY INDEX (DLQI) 
 
Finlay, 1994. 
 


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APPENDIX I. EUROQOL 5 DIMENSION (EQ-5D) 
 


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Source: The EuroQol Group, 1990. 
 
 


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APPENDIX J. SAMPLE SERIOUS ADVERSE EVENT REPORT FORM  
 


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APPENDIX K. PREGNANCY NOTIFICATION FORM  
 


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APPENDIX L. LACTATION NOTIFICATION FORM  
 
 


EDMS Doc. Number: 24644925 - 23981458
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: Monday, 20 April 2020, 12:05 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================


Signature Page for VV-TMF-13369539 v1.0
Signature Page for VV-TMF-13369539 v1.0
Reason for signing: Approved
Name:
Role: Records Manager
Date of signature: 08-Dec-2020 16:15:51 GMT+0000


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
1
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 1
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP 
STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF APREMILAST (CC-10004) IN JAPANESE SUBJECTS
WITH PALMOPLANTAR PUSTULOSIS
INVESTIGATIONAL PRODUCT (IP):
Apremilast (CC-10004)
PROTOCOL NUMBER:
CC-10004-PPP-001
ORIGINAL DATE:
08 Apr 2019
AMENDMENT No. 1 DATE:
02 Sep 2019
EudraCT NUMBER:
Not Applicable
IND NUMBER: 
Not Applicable
Contact Information: 
Name:
Title:
Dir, Clinical Research & Dev
Address: 
JP Tower, 2-7-2 Marunouchi, Chiyoda-ku, Tokyo 100-
7010, 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.


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
2
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
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 summary of changes and find its 
content to be acceptable.


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1. Description adjustment on Protocol Summary (See Underlined Part)
2. Description adjustment on Section 1. Introduction (See Underlined Part)
Palmoplantar Pustulosis
<original>
PPP is characterized by the mixture of blisters and pustules on the palms and soles. 
Pseudovesicle with pimple is observed in the center of the blister…
<revised>
PPP is characterized by the mixture of blisters and pustules on the palms and soles. 
Pseudovesicle with pimple and pustule are observed in the center of the blister…
Rationale: It is revised to correct the description. Pimple and pustules are typical characteristics 
of palmoplantar pustulosis (PPP).
Evaluation of Complication
<original>
It is necessary to evaluate if patients have any focal infection such as tonsillitis, periodontal 
disease, carious tooth and sinusitis. Focal infection is the infected lesion localized somewhere in 
the body and the infection itself is asymptomatic and mild, or the symptoms are repeated only 
intermittently. 


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
4
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
<revised>
It is necessary to evaluate if patients have any focal infection such as tonsillitis, periodontal 
disease and sinusitis. Focal infection is the infected lesion localized somewhere in the body and 
the infection itself is asymptomatic and mild, or the symptoms are repeated only intermittently. 
Rationale: Based on comments from Key Opinion Leaders (KOLs), ‘carious tooth’ is not 
included in Focal Infection.
Rationale for the Study Design
<original>
…Sixteen weeks without concomitant treatment for PPP has also been accepted in the study for 
systemic psoriasis.
<revised>
…Sixteen weeks without concomitant treatment has also been accepted in the study for systemic 
psoriasis.
Rationale: It is revised to correct an inconsistency within this sentence. 
3. Description adjustment on Section 2. Study Objectives and Endpoints (See 
Underlined Part)
Table 3: Study Safety Endpoint
<original>
Name: Clinically significant changes in body weight, waist circumference, vital signs, and/or 
laboratory findings
Description: Frequency of clinically significant changes in body weight, waist circumference,
vital signs, and/or laboratory findings.
<revised>
Name: Clinically significant changes in body weight, vital signs, and/or laboratory findings
Description: Frequency of clinically significant changes in body weight, vital signs, and/or 
laboratory findings.
Rationale: Those are typos, because waist circumference will not be measured in this protocol.


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
5
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
4. Description adjustment on Section 3. Overall Study Design (See Underlined Part)
Figure 1: Overall Study Design
<original>
Screening Phase:
up to 4-weeks
Randomized, double-blind, placebo controlled Phase: 16-weeks
Active Treatment Phase: 16-weeks 
Observational
Follow-up: 
4-Weeks
W-4
W0
W2
W4
W6
W8
W10
W12
W14
W16
W20
W24
W28
W32
W36
Primary 
Endpoint
Apremilast  30 mg BID
Placebo BID
Apremilast 30 mg BID
Randomization 1:1 to 
apremilast 30 mg BID 
or Placebo BID
At Week 16, placebo 
subjects switch to 
apremilast 30 mg BID
For all subjects 
who complete 
the study or 
discontinue the 
study early
Apremilast  30 mg BID
<revised>
Screening Phase:
up to 4-weeks
Randomized, double-blind, placebo controlled Phase: 16-weeks
Active Treatment Phase: 16-weeks 
Observational
Follow-up: 
4-Weeks
W-4
W0
W2
W4
W6
W8
W10
W12
W14
W16
W20
W24
W28
W32
W36
Primary 
Endpoint
Apremilast  30 mg BID
Placebo BID
Apremilast 30 mg BID
Randomization 1:1 to 
apremilast 30 mg BID 
or Placebo BID
At Week 16, placebo 
subjects switch to 
apremilast 30 mg BID
For all subjects 
who complete 
the study or 
discontinue the 
study early
Apremilast  30 mg BID
dose titration
at W0
dose titration
at W16
Rationale: It is added that “dose titration” at Week 0 and Week 16 for apremilast and placebo 
groups, respectively, to make it clear.
3.1 Study Design
<original>
Subjects who meet eligibility criteria for the study will be randomized in a 1:1 ratio to one of the 
two treatment groups. Subject randomization for treatment assignments will be stratified 
according to a subject’s PPPASI score (≤20 / 21-30 / ≥31) at randomization, and whether a 
subject has any focal infection at randomization (yes/no).
<revised>


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
6
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
Subjects who meet eligibility criteria for the study will be randomized in a 1:1 ratio to one of the 
two treatment groups. Subject randomization for treatment assignments will be stratified 
according to a subject’s rounded PPPASI score (≤20 / 21-30 / ≥31) at randomization, and 
whether a subject has any focal infection at randomization (yes/no).
Rationale: It is added to clarify the description for score handling.
5. Description adjustment on Section 4. Study Population (See Underlined Part)
4.2. Inclusion Criteria, Inclusion Criterion # 4
<original>
Subject has a diagnosis of PPP with or without PAO (not requiring treatment by 
immunosuppressant, concurrent extra-palmoplantar lesions) for at least 24 weeks before 
screening.
<revised>
Subject has a diagnosis of PPP with or without PAO (not requiring treatment by 
immunosuppressant) for at least 24 weeks before screening, regardless of presence or absence of 
concurrent extra-palmoplantar lesions.
Rationale: Because the sentence is confusing and unclear, the sentence is revised. 
4.2. Inclusion Criteria, Inclusion Criterion # 11
<original>

Option 2: Male or female condom (latex condom or non-latex condom NOT made out 
of natural [animal] membrane [ex, polyurethane]); PLUS, one additional barrier 
method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) 
contraceptive sponge with spermicide.
<revised>

Option 2: Male or female condom PLUS, one additional barrier method: (a) 
diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive 
sponge with spermicide.
Rationale: Because the material of condom is deleted in the current Apremilast safety language.
4.3. Exclusion Criteria, Exclusion Criterion # 11
<original>
a.
Topical therapy within 2 weeks prior to randomization, including, but not limited to, topical 
corticosteroids, topical retinoid or vitamin D analogue preparations, tacrolimus, or traditional 
Chinese/Japanese herbal preparations.


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
7
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
b. Conventional systemic therapy within 4 weeks prior to randomization, including, but not 
limited to, corticosteroids, retinoids, antibiotics, JAK inhibitors, 1,25-dihydroxy vitamin D3 and 
analogues, psoralens, sulfasalazine, hydroxyurea, fumaric acid derivatives, biotin, colchicine or 
traditional Chinese/Japanese herbal preparations).
<revised>
a.
Topical therapy within 2 weeks prior to randomization, including, but not limited to, topical 
corticosteroids, topical retinoid or vitamin D3 analogue preparations, tacrolimus, antihistamine, 
antibiotics or traditional Chinese/Japanese herbal preparations.
b. Conventional systemic therapy within 4 weeks prior to randomization, including, but not 
limited to, corticosteroids, retinoids, antihistamine, antibiotics, JAK inhibitors, 1,25-dihydroxy 
vitamin D3 and analogues, psoralens, sulfasalazine, hydroxyurea, dimethyl fumarate, biotin, 
colchicine or traditional Chinese/Japanese herbal preparations.
Rationale: It is revised to correct the description. The expression is unified as vitamin D3. 
Use of antihistamine as topical/conventional therapies is also excluded that could affect the 
efficacy evaluation. Fumaric acid derivatives is specified as dimethyl fumarate (Fumaric acid 
salts are excluded). 
6. Description adjustment on Section 5. Table of Events (See Underlined Part)
Table 5: Table of Events
<original>
SUBJECT REPORTED OUTCOMES / QUALITY OF LIFE/ HEALTH ECONOMICS 
RESEARCH
<revised>
SUBJECT REPORTED OUTCOMES / QUALITY OF LIFE
Rationale: Because ‘Health Economics Research’ is not included in this protocol, it is deleted.
<original>
BIOMARKER (Optional)
<revised>
BIOMARKER
Rationale: It is revised because a part of biomarkers is optional but not all.


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
8
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
Table 5: Footnote
<original>
d A complete medical history must be taken and must include a query to rule out whether a 
subject has known active current or history of recurrent infections.
<revised>
d A complete medical history must be taken and must include a query about whether a subject 
has known active current or history of recurrent infections.
Rationale: It is revised to correct the description. 
7. Description adjustment on Section 6. Procedures (See Underlined Part)
Prior/Concomitant Medications and Therapies
<original>
All medications and therapies for PPP, including topicals (used within the last 5 years prior to
the randomization), systemics, and all medications and therapies for PAO, should be recorded.
<revised>
All medications and therapies for PPP used within the last 5 years prior to the randomization, 
including topicals, systemics, and all other therapies, should be recorded.
Rationale: It is revised to keep consistency with other sentences within this protocol. All 
medications for only PPP within the last 5 years prior to the randomization are recorded.
6.1. Screening Period
<original>

Prior/Concomitant Medications and Procedures

Prior and concomitant medications/procedures except for PPP, PAO and focal 
infection should be recorded including all procedures occurring ≤ 28 days prior to 
the baseline.


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
9
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019

History of treatment for focal infection should be recorded within 24 weeks prior 
to the baseline.

All medications and procedures for PPP used within the last 5 years prior to the 
randomization, including topicals, systemics including biologics, and all 
medications and therapies for PAO, should be recorded.
<revised>

Prior/Concomitant Medications and Procedures

Prior and concomitant medications/procedures except for PPP and focal infection
should be recorded including all procedures occurring ≤ 28 days prior to the 
baseline.

History of treatment for focal infection should be recorded within 24 weeks prior 
to the baseline.

All medications and therapies for PPP used within the last 5 years prior to the 
randomization, including topicals, systemics and all other therapies, should be 
recorded.
Rationale: It is revised to keep consistency within this protocol. Prior and concomitant 
medications for pustulotic arthro-osteitis (PAO) is recorded within ≤ 28 days prior to the baseline
and prior and concomitant medications for Focal Infection is recorded within 24 weeks prior to 
the baseline. Medications for only PPP are recorded within the last 5 years prior to the 
randomization.
Also, it is revised to unify the word with other sentences in this protocol. 
6.5.3. Serum and Urine Pregnancy Tests for Females of Childbearing Potential (FCBP)
<original>
A serum pregnancy test with a sensitivity of ≤ 25 mIU/mL will be required for FCBP subjects at 
screening. In addition, a urine pregnancy test will be performed at the site on all FCBP subjects 
at the Baseline Visit, Visit 10 (Week 16) or Last Treatment Visit (Visit 14 [Week 32]). An 
unscheduled urine pregnancy test should be performed if the FCBP subject has missed a 
menstrual period. If positive results are obtained from a urine pregnancy test, a serum pregnancy 
test should be performed to confirm, and if positive results are obtained from a serum pregnancy 
test, the event must be reported and IP should be discontinued (See Section 10.4.1).
<revised>
A serum pregnancy test with a sensitivity of ≤ 25 mIU/mL will be required for FCBP subjects at 
screening. In addition, a urine pregnancy test will be performed at the site on all FCBP subjects 
at the Baseline Visit, Visit 10 (Week 16) and Last Treatment Visit (Visit 14 [Week 32]). An 
unscheduled urine pregnancy test should be performed if the FCBP subject has missed a 
menstrual period. If positive results are obtained from a urine pregnancy test, a serum pregnancy 
test should be performed to confirm, and if positive results are obtained from a serum pregnancy 
test, IP should be discontinued. The event must be reported (See Section 10.4.1).


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
10
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
Rationale: It is revised to correct the description. 
Rationale: Those are added to meet International Council for Harmonisation (ICH)-E18 
requirement. Most of those contents are transcribed from the study informed consent form (ICF).
8. Description adjustment on Section 8. Concomitant Medications and Procedures (See 
Underlined Part)
8.1.1. Double Blind, Placebo-Controlled Phase (Week 0 to Week 16)
<original>
…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 PPP should also include the area of the body to which they are 
applied and the frequency of application.
<revised>
…The dose, unit, frequency, route, indication, and the date the medication started and stopped (if 
not ongoing) must be recorded.
Rationale: It is revised to correct the description. Permitted topical medications are also recorded 
as same as other medications.
<original>
The following therapies will be permitted duration of the study.

Topical Therapy for PPP


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
11
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
The only allowable concomitant treatments for PPP throughout the study are topical 
moisturizers including horny softener. Subjects should not use moisturizers within 24 
hours prior to the clinic visit.
<revised>
The following therapies will be permitted for the duration of the study.

Topical Therapy for PPP
The only allowable concomitant treatments for PPP throughout the study are topical 
moisturizers (Vaseline). Subjects should not use moisturizers within 24 hours prior to 
the clinic visit.
Rationale: Because only Vaseline can be used as topical moisturizers.
8.1.2. Active Treatment Phase (from Week 16 to 32)
<original>
In addition to permitted concomitant medications and procedures (Section 8.1.1), subjects in the
active treatment phase will have the option of adding topical therapies (including, but not limited 
to, topical corticosteroids, topical retinoids or vitamin D analogue preparations) and/or 
phototherapy (excluding oral PUVA) to their treatment regimen.
<revised>
In addition to permitted concomitant medications and procedures (Section 8.1.1), subjects in the
active treatment phase will have the option of adding topical therapies (including, but not limited 
to, topical corticosteroids, topical retinoids or vitamin D3 analogue preparations) and/or 
phototherapy (excluding oral PUVA) to their treatment regimen. Dose modification is permitted 
for background doses of NSAIDs for PAO and concomitant medications for complication of 
disease other than PPP.
Rationale: It is revised to correct the description. The expression is unified as vitamin D3. 
Dose modification of concomitant background medication is permitted during active treatment 
phase.
8.2.1 Double Blind, Placebo-Controlled Phase (Week 0 to Week 16)
<original>
The following psoriasis treatment cannot be employed for the duration of the study:
<revised>
The following treatment cannot be employed for the duration of the double-blind, placebo-
controlled phase:
Rationale: ‘Psoriasis’ is deleted because of typo. Also, it is revised to correct the description.


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
12
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
<original>

Topical therapy
Topical therapies that could affect PPP or the efficacy evaluation (including, but not 
limited to, corticosteroids, vitamin D3 derivatives, tacrolimus, and antibiotics).

Conventional systemic therapy
Systemic therapies that could affect PPP or the efficacy evaluation (including, but not 
limited to corticosteroids, retinoids, antibiotics, JAK inhibitors, 1,25-dihydroxy 
vitamin D3 and analogues, psoralens, sulfasalazine, hydroxyurea, fumaric acid 
derivatives, biotin, colchicine or traditional Chinese/Japanese herbal preparations).

Breastfeeding
<revised>

Topical therapy
Topical therapies that could affect PPP or the efficacy evaluation (including, but not 
limited to, corticosteroids, retinoid, vitamin D3 derivatives, tacrolimus, antihistamine, 
antibiotics or traditional Chinese/Japanese herbal preparations).
Note: only use of topical antibiotics for the treatment after skin biopsy is permitted.

Conventional systemic therapy
Systemic therapies that could affect PPP or the efficacy evaluation (including, but not
limited to corticosteroids, retinoids, antibiotics, antihistamine, JAK inhibitors, 1,25-
dihydroxy vitamin D3 and analogues, psoralens, sulfasalazine, hydroxyurea, dimethyl 
fumarate, biotin, colchicine or traditional Chinese/Japanese herbal preparations.
Rationale: Antihistamine is also prohibited as topical/conventional therapies that could affect the 
efficacy evaluation. Fumaric acid derivatives is specified as dimethyl fumarate (Fumaric acid 
salts are excluded). 
The note is added considering a site-specific procedure of skin biopsy. Some sites are 
recommending using topical antibiotics after skin biopsy.
Breastfeeding is also deleted because that is not a concomitant procedure. Subject is pregnant or 
breastfeeding will be excluded by exclusion criterion #25.
8.2.3. Observational Follow-Up
<original>
No description.
<revised>
There is no restriction of concomitant medication during the observational follow-up phase.
Rationale: It is revised to clarify the description. 


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
13
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
9. Description adjustment on Section 9. Statistical Considerations (See Underlined 
Part)
9.7. Safety Analysis
<original>
Laboratory data will be summarized descriptively. In addition, shift tables showing the number 
of subjects with values low, normal, and high compared to the normal ranges of pretreatment 
versus posttreatment will be provided. Associated clinical laboratory parameters such as hepatic 
enzymes, renal function, and hematology values will be grouped and presented together. 
Individual subject values will be listed and values outside of the standard reference range will be 
flagged. Shift tables and analyses of changes from Baseline will be produced. Associated clinical 
laboratory parameters such as hepatic enzymes, renal function, and hematology values will be 
grouped and presented together. Individual subject values will be listed and values outside of the 
standard reference range will be flagged. Shift tables and analyses of changes from Baseline will 
be produced. To account for the different exposure to the IP, TEAEs or marked laboratory 
abnormalities will also be summarized using the exposure-adjusted incidence rate, in addition to 
the simple incidence rates.
<revised>
Laboratory data will be summarized descriptively. In addition, shift tables showing the number 
of subjects with values low, normal, and high compared to the normal ranges of pretreatment 
versus posttreatment will be provided. Associated clinical laboratory parameters such as hepatic 
enzymes, renal function, and hematology values will be grouped and presented together. 
Individual subject values will be listed and values outside of the standard reference range will be 
flagged. Shift tables and analyses of changes from Baseline will be produced. To account for the 
different exposure to the IP, TEAEs or marked laboratory abnormalities will also be summarized 
using the exposure-adjusted incidence rate, in addition to the simple incidence rates.
Rationale: Duplicate sentence is removed.
10. Description adjustment on Section 10. Adverse Events (See Underlined Part)
10.4.1. Females of Childbearing Potential (FCBP)
<original>
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
FCBP regardless of disease state) occurring while the subject is on IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events. IP is to be discontinued 
immediately and the subject instructed to return any unused portion of the IP to the Investigator. 
<revised>
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
FCBP regardless of disease state) occurring while the subject is on IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events. If positive results are 
obtained from a serum pregnancy test, IP is to be discontinued immediately and the subject 
instructed to return any unused portion of the IP to the Investigator. …


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
14
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
Rationale: It is revised to correct the description. 
11. Description adjustment on Appendix C. PALMO-PLANTAR PUSTULOSIS
SEVERITY INDEX (PPSI) (See Underlined Part)
<original>
The scoring system for the signs of the disease (erythema, pustules/vesicle and 
desquamation/scale) is:
0 = none, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe.
References: Terui, 2018.
<revised>
The scoring system for the signs of the disease (erythema, pustules/vesicle and 
desquamation/scale) is:
0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = very severe.
Modified from: Terui, 2018.
Rationale: Expression of the scoring system for the signs of the disease is adjusted with the 
Primary Endpoint (Palmo-Plantar Pustulosis Area and Severity Index [PPPASI]). 
12. Description adjustment on Appendix E. VISUAL ANALOGUE SCALES (VAS) -
PPP SYMPTOMS FOR HANDS AND FEET (See Underlined Part)
Subject’s assessment for Pruritus of hands and feet
<original>
On average, how much itch (on hands and feet) have you had because of your condition during 
the last visit and this visit?
<revised>
At its worst, how much itch (on hands and feet) have you had because of your condition during 
the last visit and this visit?
Rationale: It is revised to keep consistency within this protocol. Worst score during visits is 
captured. 
Subject’s assessment for Pain of hands and feet
<original>
On average, how much skin discomfort/pain (on hands and feet) have you had because of your 
condition during the last visit and this visit?


EDMS Doc. Number: 23981183 - 23981458
Apremilast (CC-10004) 
Summary of Changes CC-10004-PPP-001
Celgene Corporation
Confidential and Proprietary
15
CC-10004-PPP-001 Amendment 1 Final: 02 Sep 2019
<revised>
At its worst, how much skin discomfort/pain (on hands and feet) have you had because of your 
condition during the last visit and this visit?
Rationale: It is revised to keep consistency within this protocol. Worst score during visits is 
captured. 
Other minor editorial changes were made throughout the document.  (ex. changing "Sibject" to 
"Subject" in the Exclusion Criteria #9(a)). All editorial changes are captured in the document 
below. 

SAP_001.pdf: 
CC-10004 (Apremilast)
Statistical Analysis Plan. Protocol CC-10004-PPP-001
Confidential and Proprietary 
1 
STATISTICAL ANALYSIS PLAN 
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF APREMILAST 
(CC-10004) IN JAPANESE SUBJECTS WITH PALMOPLANTAR 
PUSTULOSIS 
STUDY DRUG: 
Apremilast (CC-10004) 
PROTOCOL NUMBER: 
CC-10004-PPP-001
DATE FINAL: 
4Feb2021 
Prepared by: 
Amgen K.K. 
Midtown Tower, 9-7-1 Akasaka Minato-ku 
Tokyo 107-6239 Japan 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to another party unless such 
disclosure is required by law or regulations.  Persons to whom the information is disclosed must 
be informed that the information is confidential and may not be further disclosed by them. 
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: NCT04057937
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
2 
 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................6 
1. 
LIST OF ABBREVIATIONS.......................................................................................7 
2. 
INTRODUCTION ........................................................................................................9 
3. 
STUDY OBJECTIVES ..............................................................................................10 
3.1. 
Primary Objective .......................................................................................................10 
3.2. 
Secondary Objective ...................................................................................................10 
3.3. 
Exploratory Objectives ...............................................................................................10 
4. 
INVESTIGATIONAL PLAN .....................................................................................11 
4.1. 
Overall Study Design and Plan ...................................................................................11 
4.2. 
Study Endpoints ..........................................................................................................12 
4.2.1. 
Primary Efficacy Endpoint(s) .....................................................................................12 
4.2.2. 
Secondary Efficacy Endpoint(s) .................................................................................12 
4.2.3. 
Exploratory Efficacy Endpoint(s) ...............................................................................12 
4.2.4. 
Derivation of Efficacy Endpoints ...............................................................................14 
4.2.5. 
Safety Endpoints .........................................................................................................18 
4.3. 
Stratification, Randomization, and Blinding ..............................................................18 
4.4. 
Sample Size Determination ........................................................................................18 
5. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................20 
5.1. 
Reporting Conventions ...............................................................................................20 
5.2. 
Study Phases and Analysis Periods ............................................................................20 
5.2.1. 
Analysis Periods .........................................................................................................20 
5.3. 
Baseline Definitions ....................................................................................................21 
5.4. 
Time points .................................................................................................................22 
5.5. 
Analysis Populations ..................................................................................................22 
6. 
SUBJECT DISPOSITION ..........................................................................................24 
7. 
PROTOCOL DEVIATION AND IMPORTANT PROTOCOL DEVIATION .........25 
8. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................26 
8.1. 
Demographics .............................................................................................................26 
8.2. 
Baseline Characteristics ..............................................................................................26 
8.3. 
Medical History ..........................................................................................................27 
8.4. 
Prior and Concomitant Medications/Procedures ........................................................27 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
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8.4.1. 
Prior and Concomitant Medications ...........................................................................27 
8.4.2. 
Prior and Concomitant Procedures .............................................................................27 
9. 
STUDY TREATMENTS AND EXTENT OF EXPOSURE......................................28 
9.1. 
Treatment Duration .....................................................................................................28 
9.2. 
Treatment Compliance ................................................................................................28 
10. 
EFFICACY ANALYSIS ............................................................................................29 
10.1. 
Multiplicity .................................................................................................................29 
10.2. 
Analysis of Primary Efficacy Endpoint ......................................................................29 
10.3. 
Analyses of Secondary and Exploratory Efficacy Endpoints .....................................29 
10.3.1. 
Binary Variables .........................................................................................................29 
10.3.2. 
Continuous Variables ..................................................................................................30 
10.3.3. 
Categorical Variables ..................................................................................................32 
10.4. 
Subgroup Analysis ......................................................................................................32 
11. 
SAFETY ANALYSIS ................................................................................................33 
11.1. 
Adverse Events ...........................................................................................................33 
11.2. 
Adverse Events of Special Interest .............................................................................35 
11.3. 
Clinical Laboratory Evaluations .................................................................................35 
11.4. 
Vital Sign Measurements ............................................................................................36 
11.5. 
Physical Examination .................................................................................................36 
12. 
ANALYSIS FOR COVID-19 IMPACT .....................................................................37 
.............................................................................38 
.............................................................................38 
13.2. 
Definition of Baseline .................................................................................................38 
13.3. 
Baseline Demographic and Disease Background Characteristics ..............................38 
........................................................38 
14. 
INTERIM ANALYSIS ...............................................................................................40 
15. 
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL ...............................................................................................................41 
16. 
REFERENCES ...........................................................................................................42 
17. 
APPENDICES ............................................................................................................43 
17.1. 
Handling of Dates .......................................................................................................43 
17.1.1. 
Calculation Using Dates .............................................................................................43 
17.2. 
Date Imputation Guideline .........................................................................................44 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
4 
 
17.2.1. 
Adverse Events ...........................................................................................................44 
17.2.2. 
Prior/Concomitant Medications/Procedures ...............................................................46 
17.2.3. 
Medical History ..........................................................................................................47 
17.2.4. 
Treatment Duration .....................................................................................................47 
17.3. 
Laboratory Marked Abnormalities Criteria ................................................................48 
 
 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
5 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms .............................................................................7 
Table 2: 
Secondary Efficacy Endpoints ....................................................................................12 
Table 3: 
Exploratory Efficacy Endpoints .................................................................................13 
Table 4  
Table for Visit Mapping for by Time Point Analysis .................................................22 
Table 5: 
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially ......................................................................44 
Table 6: 
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Placebo Initially ...........................................................................45 
Table 7: 
Laboratory Marked Abnormalities Criteria ................................................................48 
 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
7 
 
1. 
LIST OF ABBREVIATIONS 
Table 1: 
Abbreviations and Specialist Terms 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DBL 
Database Lock 
DLQI 
Dermatology Life Quality Index 
DMARD 
Disease-modifying Antirheumatic Drug 
EAIR 
Exposure-adjusted Incidence Rate 
eCRF 
electronic Case Report Form 
EQ-5D 
EuroQol 5 Dimension 
GI 
Gastrointestinal 
IL 
Interleukin 
IL 
Interleukin 
IP 
Investigational Product 
IPD 
Important Protocol Deviation 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat 
LOCF 
Last Observation Carried Forward 
LS 
Least-squares 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
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MI 
Multiple Imputation 
MMRM 
Mixed-effect Model for Repeated Measures 
NRI 
Non-responder Imputation 
NSAIDs 
Non-steroidal Anti-inflammatory Drugs 
PAO 
Pustulotic Arthro-osteitis 
PD 
Protocol Deviation 
PGA 
Physician’s Global Assessment 
PP 
Per Protocol 
PPP 
Palmoplantar pustulosis 
PPPASI 
Palmoplantar Pustular Area and Severity Index 
PPSI 
Palmoplantar Severity Index 
PT 
Preferred Term 
Q 
Quantile 
QoL 
Quality of Life 
RNA 
Ribonucleic Acid 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International 
SMQ 
Standardised MedDRA Querie 
SOC 
System Organ Class 
SRO 
Subject’s Reported Outcome 
TEAE 
Treatment-emergent Adverse Event 
TNF 
Tumor Necrosis Factor 
VAS 
Visual Analogue Scale 
WHO DD 
World Health Organization Drug Dictionary 
 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
9 
 
2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the analyses and data presentations for Amgen’s 
protocol CC-10004-PPP-001 “A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) 
in Japanese Subjects with Palmoplantar Pustulosis”. It contains definitions of analysis 
populations, derived variables and statistical methods for the analysis of efficacy and safety. 
After all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database restriction will be performed for the primary data analysis. No interim analysis is 
planned prior to this primary data analysis. At the end of the study, after all subjects have 
completed, or have been discontinued from the active treatment phase (Weeks 16 to 32) and the 
post-treatment observational follow-up phase, the final analysis will be performed, and a final 
clinical study report (CSR) will be generated. 
The purpose of the SAP is to ensure the credibility of the study findings by pre-specifying the 
statistical approaches to the analysis of study data prior to the database restriction and any data 
analysis for unblinding. This SAP will be finalized and signed prior to unblinding of the Week 
16 database. All statistical analyses detailed in this SAP will be conducted using SAS® Version 
9.2 or higher. 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
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3. 
STUDY OBJECTIVES 
3.1. 
Primary Objective 
The primary objective is to evaluate the efficacy of apremilast 30 mg twice daily (BID) 
compared with placebo in Japanese subjects with palmoplantar pustulosis (PPP). 
3.2. 
Secondary Objective 
The secondary objective is to evaluate the safety and tolerability of apremilast 30 mg BID 
compared with placebo in Japanese subjects with PPP. 
3.3. 
Exploratory Objectives 
The exploratory objectives are: 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
11 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2 
study of apremilast in Japanese subjects with PPP and inadequate response to treatment with 
topical steroid and/or topical vitamin D3 derivative preparations. 
This study consists of a screening phase for up to 4 weeks, a 16-week placebo-controlled phase, 
a 16-week active treatment phase, and a 4-week post-treatment observational follow-up phase at 
any time the subject completes or discontinues the treatment. To mitigate potential 
gastrointestinal (GI) side effects (primarily mild to moderate nausea and diarrhea), dose titration 
(using blister cards) will be implemented over a 5-day period starting at the baseline visit (Week 
0) for subjects randomized to apremilast 30 mg BID or Placebo. Subjects randomized to placebo 
will receive blister cards with dummy dose titration. All subjects will be switched to (or continue 
with) apremilast 30 mg BID at Week 16 and will maintain this dosing through Week 32. 
Subjects who discontinue treatment with investigational product (IP: apremilast 30 mg BID or 
Placebo) or withdraw during the treatment phase will be also asked to enter the 4-week 
observational follow-up phase after early termination assessment. 
Approximately 86 subjects who meet eligibility criteria for the study will be randomized in a 1:1 
ratio to one of the two treatment groups. Subject randomization for treatment assignments will be 
stratified according to a rounded subject’s palmoplantar pustular area and severity index 
(PPPASI) score (≤20 / 21-30 / ≥31) at randomization, and whether a subject has any focal 
infection (yes/no) at randomization. 
The study schematic is presented below. 
Figure 1: 
Overall Study Design 
Screening Phase:
up to 4-weeks
Randomized, double-blind, placebo controlled Phase: 16-weeks
Active Treatment Phase: 16-weeks 
Observational
Follow-up: 
4-Weeks
W-4
W0
W2
W4
W6
W8
W10
W12
W14
W16
W20
W24
W28
W32
W36
Primary 
Endpoint
Apremilast  30 mg BID
Placebo BID
Apremilast 30 mg BID
Randomization 1:1 to 
apremilast 30 mg BID 
or Placebo BID
At Week 16, placebo 
subjects switch to 
apremilast 30 mg BID
For all subjects 
who complete 
the study or 
discontinue the 
study early
Apremilast  30 mg BID
dose titration
at W0
dose titration
at W16
 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
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4.2. 
Study Endpoints 
4.2.1. 
Primary Efficacy Endpoint(s) 
The primary efficacy endpoint is PPPASI-50 at Week 16: achieving a PPPASI-50 response 
defined as ≥ 50% improvement in PPPASI total score from baseline at Week 16 
4.2.2. 
Secondary Efficacy Endpoint(s) 
The secondary endpoints include below. 
Table 2: 
Secondary Efficacy Endpoints 
Assessment 
Description 
Timeframe 
PPPASI: PPPASI-50 
Achieving a PPPASI-50 response 
By visit in double blind, placebo-
controlled phase 
PPPASI: PPPASI-75 
Achieving a PPPASI-75 response 
By visit in double blind, placebo-
controlled phase 
PPPASI total score 
AUC 
Week 0-16 
Percent change from baseline. 
By visit in double blind, placebo-
controlled phase 
PPSI total score 
AUC 
Week 0-16 
Percent change from baseline 
By visit in double blind, placebo-
controlled phase 
PGA score for palms 
and soles 
Change from baseline 
By visit in double blind, placebo-
controlled phase 
Achieving a PGA score of cleared 
(0) or minimal (1) 
By visit in double blind, placebo-
controlled phase 
Achieving a PGA score of cleared 
(0) or minimal (1) with at least a 
2-grade improvement 
By visit in double blind, placebo-
controlled phase 
SRO: Subject’s VAS 
assessment for PPP 
symptoms 
Change from baseline 
By visit in double blind, placebo-
controlled phase (except for baseline) 
AUC = Area under the curve; PGA = Physician’s Global Assessment; PPP = Palmoplantar Pustulosis; 
PPPASI = Palmoplantar Pustular Psoriasis Area Severity Index; PPPASI-50 = defined as ≥ 50% 
improvement in PPPASI total score from baseline; PPPASI-75 = defined as ≥ 75% improvement in 
PPPASI total score from baseline; PPSI = Palmoplantar Severity Index; SRO: Subject’s Reported 
Outcome; VAS = Visual Analogue Scale. 
4.2.3. 
Exploratory Efficacy Endpoint(s) 
The exploratory endpoints include below. 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
13 
 
Table 3: 
Exploratory Efficacy Endpoints 
Assessment 
Description 
Timeframe 
PPPASI: Three sub scores 
(Erythema, Pustules/Vesicle, 
Desquamation/Scale) 
Change from baseline of 
individual sub scores 
By visit in double blind, placebo-
controlled phase, active treatment 
phase and follow-up 
Modified PPPASI: modified 
PPPASI-50 
Achieving a modified PPPASI-50 
response 
By visit in double blind, placebo-
controlled phase, active treatment 
phase and follow-up 
Modified PPPASI: modified 
PPPASI-75 
Achieving a modified PPPASI-75 
response 
By visit in double blind, placebo-
controlled phase, active treatment 
phase and follow-up 
Modified PPPASI total 
score 
Modified PPPASI: Two sub 
scores (Pustules, Vesicle) 
AUC 
Week 0-16 
Percent change from baseline 
By visit in double blind, placebo-
controlled phase, active treatment 
phase and follow-up 
Change from baseline of 
individual sub scores 
By visit in double blind, placebo-
controlled phase, active treatment 
phase and follow-up 
SRO: Subject’s assessment 
for each sign/finding of PPP 
(Erythema, Pustules/Vesicle 
and Desquamation/Scale) 
(PPSI scale is used for 
assessment) 
Change from baseline 
By visit in double blind, placebo-
controlled phase, active treatment 
phase and follow-up 
SRO: DLQI 
Change from baseline 
Week 8, 16, 24 and 32 
SRO: EQ-5D 
Change from baseline of the 
utility index and VAS score 
Week 8, 16, 24 and 32 
PPPASI: PPPASI-50 
Achieving a PPPASI-50 response 
By visit in active treatment phase  
PPPASI: PPPASI-75 
Achieving a PPPASI-75 response 
By visit in active treatment phase 
PPPASI total score 
Percent change from baseline 
By visit in active treatment phase 
PPSI total score 
Percent change from baseline 
By visit in active treatment phase 
PGA score for palms and 
soles 
Change from baseline 
By visit in active treatment phase 
Achieving a PGA score of 
cleared (0) or minimal (1) 
By visit in active treatment phase 
Achieving a PGA score of 
cleared (0) or minimal (1) with at 
least a 2-grade improvement 
By visit in active treatment phase 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
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Assessment 
Description 
Timeframe 
SRO: Subject’s VAS 
assessment for PPP 
symptoms 
Change from baseline 
By visit in active treatment phase 
AUC = Area under the curve; DLQI = Dermatology Life Quality Index; EQ-5D = EuroQol 5 
Dimension; modified PPPASI-50 = defined as ≥50% improvement of modified PPPASI total score 
from baseline; modified PPPASI-75 = defined as ≥75% improvement of modified PPPASI total score 
from baseline; PGA = Physician’s Global Assessment; PPP = Palmoplantar Pustulosis; PPPASI = 
Palmoplantar Pustular Psoriasis Area Severity Index; PPPASI-50 = defined as ≥ 50% improvement in 
PPPASI total score from baseline; PPPASI-75 = defined as ≥ 75% improvement in PPPASI total score 
from baseline; PPSI = Palmoplantar Severity Index; SRO: Subject’s Reported Outcome; VAS = Visual 
Analogue Scale. 
Additional exploratory endpoints include below. 
y 
Time to response for PPPASI-50 and PPPASI-75 
4.2.4. 
Derivation of Efficacy Endpoints 
The definition and derivation of efficacy endpoints are described below and in the appendices of 
the protocol. Change from baseline is calculated as post-baseline visit value - the baseline value. 
Percent change from baseline is defined as 100*change from baseline/baseline value (%). 
Baseline definition for all efficacy endpoints is given in Section 5.3. Handling of time points is 
described in Section 5.4. 
4.2.4.1. 
PPPASI 
The PPPASI is a disease-specific efficacy assessment tool used by investigators for assessing 
and grading the severity and area of palmoplantar pustulosis lesions and their response to 
therapy. PPPASI is established to detect a change of disease status on palms or soles. The 
right/left palm and right/left sole are evaluated for 3 signs of the disease (erythema, 
pustules/vesicle and desquamation/scale) as sub-scores. PPPASI produces numeric scores that 
can range from 0 to 72 and a higher score indicates more severe disease. 
In the PPPASI system, the palms and soles are divided into 4 regions: the right palm, left palm, 
right sole, and left sole, which account for 20%, 20%, 30%, and 30% of the total body surface 
area (BSA) of the palms and soles, respectively. Each of these areas is assessed separately for 
erythema, pustules and desquamation, which are each rated on a scale of 0 to 4. 
The scoring system for the signs of the disease (E = erythema, P = pustules/vesicle and D = 
desquamation/scale) is: 0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = very severe. 
The scale for estimating the area of involvement for pustular lesions is outlined below. 
0 = no involvement, 1 = 1% to 9% involvement, 2 = 10% to 29% involvement, 3 = 30% to 49% 
involvement, 4 = 50% to 69% involvement, 5 = 70% to 89% involvement, and 6 = 90% to 100% 
involvement 
The PPPASI total score formula is: 
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PPPASI total score = (E + P + D)×Area×0.2 (right palm) + (E + P + D)×Area×0.2 (left palm) + 
(E + P + D)×Area×0.3 (right sole) + (E + P + D)×Area×0.3 (left sole) 
4.2.4.1.1. PPPASI-50, 75 
PPPASI-50 and PPPASI-75 are defined as ≥ 50% and ≥ 75% improvement in PPPASI total score 
from baseline, respectively. 
4.2.4.1.2. AUC for PPPASI total score 
The AUC for PPPASI total score from baseline through a timepoint is the sum of the AUCs in 
each time interval specified by the dates of the visits. The individual AUC for any given time 
interval is calculated based on the linear trapezoidal method, which uses linear interpolation 
between data points to calculate the AUC. The AUCwk16 which is AUC from baseline (Visit 
2/Day 1) through Week 16 (Visit 10/Day 113) is given by 
AUC୵୩ଵ଺=
113
(ݐଵ଴−ݐଶ) × ෍1
2
ଵ଴ିଵ
௜ୀଶ
(ܵ௜+ ܵ௜ାଵ)(ݐ௜ାଵ−ݐ௜) 
where Si = PPPASI total score for ith visit and ti = PPPASI assessment dates of ith visit. When 
Week 16 does not exactly coincide with the target Day 113, the AUC through Week 16 will be 
adjusted for the actual study duration by diving the total AUC by total study duration (in days) 
and multiplying this quantity by 113 days. 
4.2.4.1.3. PPPASI sub-scores (Erythema, Pustules/Vesicle, Desquamation/Scale) 
The PPPASI sub-score is defined the PPPASI total score including only one sub-domain (E = 
erythema, P = pustules/vesicle or D = desquamation /scale). For example, score of erythema as 
PPPASI sub-score will be calculated as below. 
PPPASI sub-score (Erythema) = (E)×Area×0.2 (right palm) + (E)×Area×0.2 (left palm) + 
(E)×Area×0.3 (right sole) + (E)×Area×0.3 (left sole)  
4.2.4.2. 
Modified PPPASI 
Modified PPPASI is an exploratory disease-specific efficacy assessment by investigators, which 
emphasizes on pustules and vesicles. The right/left palm and right/left sole are evaluated for 4 
signs of the disease (E = erythema, P = pustules, V = vesicle and D = desquamation/scale) as 
sub-scores. The development of vesicles followed by pustule in palm and sole is distinctive 
pathophysiology in PPP. Modified PPPASI is modified from PPPASI by distinguishing between 
pustules and vesicle. The range of modified PPPASI score is from 0 to 96. A higher score 
indicates more severe disease. 
The modified PPPASI formula is: 
Modified PPPASI total score = (E + P + V+ D)×Area×0.2 (right palm) + (E + P + V + 
D)×Area×0.2 (left palm) + (E + P + V + D)×Area×0.3 (right sole) + (E + P + V + D)×Area×0.3 
(left sole) 
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4.2.4.2.1. Modified PPPASI-50, 75 
Modified PPPASI-50 and Modified PPPASI-75 are defined as ≥ 50% and ≥ 75% improvement in 
Modified PPPASI total score from baseline, respectively. 
4.2.4.2.2. AUC for modified PPPASI total score 
The AUC for modified PPPASI total score is similarly defined as the AUC for PPPASI (Section 
4.2.4.1.2). 
4.2.4.2.3. Modified PPPASI sub-scores (Pustules, Vesicle) 
The modified PPPASI sub-score is similarly defined as the PPPASI sub-scores (Section 
4.2.4.1.3). The modified PPPASI sub-score for erythema and desquamation/scale are same as the 
PPPASI sub-score for erythema and desquamation/scale, respectively. 
4.2.4.3. 
PPSI 
PPSI is a disease-specific efficacy assessment tool used by investigators for assessing and 
grading the severity of palmoplantar pustulosis lesions and their response to therapy. In the PPSI 
system, evaluation skin lesion sites are identified by either palms or soles, which has the most 
severe skin lesion at screening. Any identified skin lesion site will be assessed at all subsequent 
visits. Evaluation of skin lesion sites are assessed separately for erythema, pustules/vesicle and 
desquamation/scale, which are each rated on a scale of 0 to 4. The PPSI produces a numeric 
score that can range from 0 to 12. A higher score indicates more severe disease. 
The severity of the disease is calculated as follows. 
The scoring system for the signs of the disease (E: erythema, P: pustules/vesicle:  and D: 
desquamation/scale) is: 0 = none, 1 = slight, 2 = moderate, 3 = severe, and 4 = very severe. 
The total score will be calculated by: PPSI total score= (E + P + D) 
4.2.4.3.1. AUC for PPSI total score 
The AUC for PPSI total score is similarly defined as the AUC for PPPASI (Section 4.2.4.1.2). 
4.2.4.4. 
Subject’s assessment for each sign/finding of PPP (Erythema, Pustules/Vesicle 
and Desquamation/Scale of PPSI scale) 
A subject’s assessment for each sign/finding on hands or feet (erythema, pustules/vesicles and 
desquamation/scale) are an exploratory disease-specific efficacy assessment. Worst status by a 
subject’s own assessment between visits will be recorded. A part of PPSI assessment is used as a 
questionnaire. A subject will evaluate skin lesion sites which has the most severe skin lesion 
assessed by an investigator for evaluation of PPSI at screening. Any identified skin lesion site 
will be assessed at all subsequent visits. 
A numeric score is produced for each sign/finding of PPP and the range is from 0 to 4 (0 = none, 
1 = minimal, 2 =moderate, 3 = severe, and 4 = very severe) and the total score will be 0 to 12. 
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4.2.4.5. 
PGA for palms and soles 
PGA for palms and soles is a physician’s global assessment localized to palms and soles, which 
is skin lesions of PPP. Physician’s global assessment is commonly used for assessment of the 
intervention. PGA for palms and soles also produces numeric score that can range from 0 to 5. A 
higher score indicates more severe disease. 
Lesions on palms and soles will be graded based on the scales: 0 = Clear, 1 = Almost clear, 2 = 
Mild, 3 = Moderate, 4 = Severe, 5 = Very severe 
4.2.4.6. 
Subject’s VAS Assessment for PPP Symptom 
VAS is a tool used to help a person to rate the intensity of certain sensations and feelings, such as 
pain. Each score ranges from 0 to 100. The left-hand boundary (0) represents no itch/pain and the 
right-hand boundary (100) represents itch/pain as severe as can be imagined. Subject assesses a 
degree of pruritus and pain as symptoms on hands and feet caused by PPP. Worst status by a 
subject’s impression between visits will be recorded. PPP-related symptoms should be included 
in these assessments. 
4.2.4.7. 
DLQI 
The DLQI is a Quality of Life (QoL) 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 status over the last one week. 
With the exception of the 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). The 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, score 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” (score 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 indicate more 
severe disease and correspond to poorer quality of life. 
4.2.4.8. 
EQ-5D 
EQ-5D is a general and comprehensive QoL questionnaires which assesses the subject status on 
the visit day. The EQ-5D is a generic health status measure composed of a descriptive system 
which comprises the 5 dimensions (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression) each of which has 5 levels: no problems, slight problems, moderate 
problems, severe problems and unable, and a VAS asking individuals to rate their own health on 
a vertical, visual analog scale where the endpoints are labeled ‘Best imaginable health state’ 
(score of 100) and ‘Worst imaginable health state’ (score of 0). EQ-5D health states will be 
converted into a single index value by applying country specific value set (Ikeda, 2015). 
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4.2.5. 
Safety Endpoints 
Safety endpoints will include: 
y 
Treatment-emergent adverse event (TEAE): type, frequency and incidence rate, severity, and 
relationship of TEAEs to IP 
y 
Clinically significant changes in body weight, vital signs, and/or laboratory findings 
4.3. 
Stratification, Randomization, and Blinding 
At Visit 2 (Week 0 [Day 1]), subjects who meet eligibility criteria will be randomized using a 
permuted block randomization in parallel with 1:1 ratio to receive either apremilast 30 mg BID 
or placebo, using a centralized Interactive Response Technology (IRT). Eligible subjects will be 
stratified according to a subject’s rounded PPPASI score (≤20 / 21-30 / ≥31) at randomization 
and whether a subject has or not any focal infection (yes/no) at randomization. 
This study will be conducted as a double-blind study for the placebo-controlled treatment phase. 
During the active treatment phase, the IP will remain blinded, to prevent study personnel and 
subjects from knowing the IP assignment in the placebo-controlled phase. After 16 weeks of 
treatment, all subjects originally randomized to the placebo arm at the baseline visit will be 
switched to receive apremilast 30 mg BID. 
The primary data analysis will be conducted after all subjects have completed the Week 16 visit 
(or discontinued from the study). However, unblinded data will only be made available to 
selected sponsor and contract research organization (CRO) team members involved with analysis 
of the data. Prior to the primary data analysis, the selected sponsor and CRO team members will 
be required to give their consent to declare not to disclose any subject-level data to maintain the 
data integrity of this study. All other sponsor, site, and CRO personnel directly involved with the 
conduct of the study, will remain blinded to treatment assignments until the final database lock at 
the end of the study. 
4.4. 
Sample Size Determination 
A total of approximately 86 subjects will be randomized 1:1 ratio to receive apremilast 30 mg 
BID or placebo. The study has 80% power (based on a chi-square test at a 2-sided significance 
level of 0.10) to demonstrate the superiority of apremilast 30 mg BID over placebo with respect 
to the primary endpoint of PPPASI-50 at Week 16, assuming the PPPASI-50 rates of 45% 
(apremilast 30 mg BID) and 20% (placebo), respectively. The PPPASI-50 rate of 20% at Week 
16 in placebo is based on the PPPASI-50 placebo rate of 21% at Week 16 in guselkumab Phase 2 
study (Terui, 2018). Considering at least 20% difference as a clinically meaningful difference, 
apremilast 30 mg BID PPPASI rate of 45% is expected in this study. The sample-size was 
estimated using SAS 9.4 power procedure. 
For the skin biopsy RNA expression analysis, N=13 subjects per arm will provide 80% 
probability to observe the lower limit of the 90% confidence interval (CI) of a decrease of IL8 
mRNA expression from baseline to Week 16 in the apremilast treated arm is over -44%, based 
on the mean and standard deviation (SD) change observed in a 12 weeks apremilast psoriasis 
study CC-10004-PSOR-004 (Gottlieb, 2013). For the serum protein biomarker analysis, N=17 
subjects per arm will provide 80% probability to observe the lower limit of the 90% CI of an 
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absolute difference of decrease from baseline to Week 16 of IL17A levels in the apremilast arm 
is over 60%, based on the mean and SD change observed in the psoriasis study in Japan, CC-
10004-PSOR-011 (Garcet, 2018). 
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5. 
GENERAL STATISTICAL CONSIDERATIONS 
5.1. 
Reporting Conventions 
Summary statistics for continuous variables include sample size (n), mean, standard deviation 
(SD), median, minimum, and maximum, also the 25th (Q1) and 75th (Q3) percentiles may be 
included in summary statistics. All mean, median and percentile values will be formatted to one 
more decimal place than the measured value and SD values will be formatted to two more 
decimal places than the measured value, if applicable. Minimum and maximum values will be 
presented to the same number of decimal places as the measured value. Frequency summary for 
categorical variables includes number and percentage. All percentages will be rounded to one 
decimal place. Number and percentage values will be presented as xx (xx.x%). All analysis and 
summary tables will have the population sample size for each treatment group in the column 
heading, if applicable. All p-values (2 sided) will be presented with 4 decimal places. All 
laboratory data will be reported using standard international (SI) units. 
5.2. 
Study Phases and Analysis Periods 
The study includes 4 phases: 
1. Screening phase for up to 4 weeks (28 days) 
2. Sixteen weeks, double-blind, placebo-controlled phase (apremilast 30 mg BID and 
placebo) 
3. Sixteen weeks, active treatment phase (apremilast 30 mg BID) 
x Subjects randomized to apremilast continue apremilast treatment  
x Subjects randomized to placebo treatment switch to apremilast treatment in a blind 
manner 
4. Four weeks post-treatment observational follow-up phase at any time the subject 
completes or discontinues the treatment 
5.2.1. 
Analysis Periods 
Per protocol specification, data summary and analysis will be provided for the following periods, 
if appropriate. 
y 
Placebo-controlled Phase/Period 
This period starts on the day of randomization (Week 0/Visit 2), and stops on below, whichever 
is later:  
(1) the day of Week 16/Visit 10 if the subject continued study treatment to the active treatment 
phase 
(2) the day of the discontinuation if the subject discontinued study treatment prior to or at Week 
16/Visit 10 
(3) the last known study day if the subject is lost to follow-up prior to Week 16/Visit 10 
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The two treatment arms are apremilast 30 mg BID or Placebo. 
y 
Active Treatment Phase/Period 
This period starts on one day after the day of the first dose of apremilast at Week 16/Visit 10, 
and stops on either below. 
(1) the day of Week 32/Visit 14 
(2) the day of the discontinuation if the subject discontinued prior to or at Week 32/Visit 14 
(3) the last known study day if the subject lost to follow-up prior to Week 32/Visit 14 during the 
phase 
The two treatment arms are 30 mg BID/30 mg BID, and Placebo/30 mg BID. 
For safety analysis, the period starts on the day of the first dose of apremilast in the period. 
y 
Observational Follow-up Phase/Period 
Subjects who complete or discontinue the study treatment, will be followed up for 28 days after 
last dose of IP. 
For adverse event analysis, data from the first 28 days after the last dose of IP will be included in 
the precedent treatment phase and data after the 28 days will be presented separately. 
y 
Apremilast-exposure Period 
This period starts on the date of either:  
(1) the first dose of IP following randomization (Week 0/Visit 2) for subject who are treated 
with apremilast from Week 0 
(2) the first dose of IP from the IP dispensed at Week16/Visit 10 for subjects who were 
originally treated with placebo and are switched to apremilast at Week 16 
This period stops on either: (1) data restriction date; or (2) the end of the study. 
During the apremilast-exposure period, data are presented by treatment sequence, i.e., 
Placebo/30 mg BID, 30 mg BID as Initiated, and a total column of 30 mg BID as Treated. 
5.3. 
Baseline Definitions 
Baseline is defined as the last value measured on or before the day of the first IP. 
For efficacy analyses and summary of baseline disease characteristics, baseline is defined as the 
last value measured on or before the day of the first dose of IP. For the summaries of laboratory 
parameters, and vital signs parameters, baseline is defined as the last value measured on or 
before the day of the first dose of IP in the summaries for the placebo-controlled phase, and 
defined as the last value measured on or before the day of the first apremilast dose for subjects 
initially randomized to placebo and switched to apremilast in the summaries for the apremilast 
exposure period. 
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5.4. 
Time points 
Time points in all analyses are based on the remapped visits/study weeks using the following 
visit mapping algorithm, which may 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 as below, rather than the recorded visit. 
The only exception is that the data with a recorded visit being a follow-up visit will be assigned 
to the analysis visit corresponding to the follow-up visit. 
Table 4  
Table for Visit Mapping for by Time Point Analysis 
Analysis Visit 
Target Day 
Analysis Window 
Week 0 (Visit 2: Baseline) 
1 
≤ 1 
Placebo-controlled Period 
Week 2 (Visit 3) 
15 
2 – 21 
Week 4 (Visit 4) 
29 
22 – 35 
Week 6 (Visit 5) 
43 
36 – 49 
Week 8 (Visit 6) 
57 
50 – 63 
Week 10 (Visit 7) 
71 
64 – 77 
Week 12 (Visit 8) 
85 
78 – 91 
Week 14 (Visit 9) 
99 
92 – 105 
Week 16 (Visit 10) 
113 
106 – End of the Period 
Active Treatment Period 
Week 20 (Visit 11) 
141 
One day after the first apremilast dosing day 
on Visit 10* – 154 
Week 24 (Visit 12) 
169 
155 – 182 
Week 28 (Visit 13) 
197 
183 – 210 
Week 32 (Visit 14) 
225 
211 – End of the Period 
* The first apremilast dosing day on Visit 10 shall be used for adverse event data 
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: 
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; 
1. 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; 
2. If multiple assessments are available on the same relative day, then the highest (worst) 
value of these assessments will be used for that relative day. 
5.5. 
Analysis Populations 
Analysis populations except for biomarker are defined as follows: 
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y 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will be defined as all randomized subjects who received 
at least one dose of IP. Subjects will be included in the treatment group to which they are 
randomized. 
y 
Safety Population 
The safety population will include all randomized subjects who received at least one dose of 
IP. The analysis of safety data in this study will be based on the safety population and 
subjects will be included in the treatment to which they actually received. Safety analyses 
for the apremilast-exposure period will be based on the apremilast subjects as treated 
population, which will include all subjects who actually receive the apremilast 30 mg BID at 
the randomization visit or switched (at the Week 16 visit) to the apremilast 30 BID. Subjects 
will be included in the treatment sequence they actually received. 
y 
Per-Protocol Population 
The per protocol (PP) population will include all subjects in the ITT population who have no 
important protocol deviations that may substantially affect the efficacy results during the 16 
weeks placebo-controlled treatment phase. The final determination of protocol deviation 
criteria to define the PP population will be made prior to the unblinding of the database and 
will be documented separately. 
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6. 
SUBJECT DISPOSITION 
Subject disposition will be provided. The number of subjects screened, the number and 
percentage of subjects randomized and not randomized among all subjects screened will be 
summarized. The failed inclusion/exclusion criteria of subjects who were screened and not 
randomized will be included in the summary. 
The number and percentage of subjects included in the ITT, PP, and safety analysis population 
and apremilast subjects as treated among all subjects randomized will be summarized. 
The number of subjects who entered, and the number and percentage of subjects who completed, 
and discontinued of each phase will be summarized according to reasons of discontinuation. 
Reasons for discontinuation will be summarized with the following categories in the eCRF: 
y 
Adverse Event 
y 
Lack of Efficacy 
y 
Lost to Follow-up 
y 
Pregnancy 
y 
Death 
y 
Protocol Deviation 
y 
Study Terminated by Sponsor 
y 
Withdrawal by Subject 
A listing of subject eligibility/analysis population and a listing of subjects who discontinue the 
study early and reasons for discontinuation will be provided. 
The number and percentage of subjects by site for ITT population will be tabulated. 
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7. 
PROTOCOL DEVIATION AND IMPORTANT PROTOCOL 
DEVIATION 
The protocol deviations (PD) and important protocol deviations (IPD) will be identified and 
assessed by clinical research physician or designee. A list of PD and IPD for all subjects for 
Week 16 analysis will be defined prior to the Week 16 database restriction and unblinding (i.e., 
prior to the unblinding of double-blind placebo-controlled phase data). The list of PD and IPD 
for all subjects for final analysis will be finalized prior to the final DBL. This list of PD and IPD 
for Week 16 analysis will also identify which subjects are to be excluded from the PP 
population. 
Summary tables showing the number and percentage of subjects with at least one PD and IPD 
and by each category of PD and IPD will be provided for the ITT population and subjects who 
entered active treatment phase. A by-subject listing of subjects with PD/IPD will be provided. 
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8. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
The demographics and baseline characteristics will be summarized for the ITT population. 
Individual subject listings will be provided to support the summary tables. 
8.1. 
Demographics 
Summary statistics will be provided for the following continuous variables: 
y 
Age (years) 
y 
Weight (kg) 
y 
Height (cm) 
y 
Baseline Body Mass Index (BMI; kg/m2) 
BMI will be programmatically calculated as BMI (kg/m2) = Weight (kg)/ Height (m2) based 
on the last weight measurement taken prior to the first dose of IP and the height 
measurement taken at screening. 
Number and percentage will be provided for the following categorical variables: 
y 
Age category (< 40, ≥ 40 to < 65, ≥ 65 to < 75, ≥ 75) 
y 
Sex (Male, Female) 
y 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
y 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Collected or Unknown) 
y 
Weight category (< 50, ≥ 50 to < 60, ≥ 60 to < 70, ≥ 70 to < 85, ≥ 85) 
y 
BMI category (< 18.5, ≥ 18.5 to < 25, ≥ 25 to < 30, ≥ 30) 
y 
Tobacco Use (Current User, Past User, Non-User) 
y 
Alcohol Use (Current User, Past User, Non-User) 
8.2. 
Baseline Characteristics 
Baseline clinical characteristics indicated below will be summarized descriptively: 
y 
Duration of Palmoplantar Pustulosis (PPP) (time [in years] from first diagnosis to the 
informed consent date) 
y 
Duration of PPP category (< 2, ≥ 2 to < 6, ≥ 6 to < 10, ≥ 10 years) 
y 
PPPASI score range based on IRT and clinical data (≤ 20, ≥ 21 to ≤ 30, ≥ 31) 
y 
Presence of focal infection based on IRT and clinical data (Yes/Presence, No/Absence) 
y 
History of focal infection including periapical pathosis, periodontitis, tonsillitis, and sinusitis 
(Yes, No) 
y 
Presence of pustulotic arthro-osteitis (PAO) (Presence, Absence, Unknown) 
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y 
Regular dental examination status (Presence, Absence) 
8.3. 
Medical History 
A summary of medical history will be presented by MedDRA version 21.1 or higher system 
organ class (SOC) and preferred term (PT). A similar summary will be generated for the 
currently active abnormalities only, by SOC and PT. 
8.4. 
Prior and Concomitant Medications/Procedures 
Prior medications/procedures will be summarized for the ITT population. Concomitant 
medications/procedures will be summarized for the safety population, apremilast subjects as 
treated, and subjects who entered the observational follow-up phase.  
8.4.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications that were started before the start of the study 
treatment and either ended before the start of the study treatment or continued after study 
treatment. Concomitant medications are defined as medications that were either initiated before 
the first dose of IP and continued during the study treatment, or initiated on/after the date of the 
first dose of IP and on/before the date of treatment discontinuation. Medications initiated prior to 
the start of study treatment and were continued after the start of study treatment will be counted 
as both prior and concomitant medications. 
The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health Organization 
Drug Dictionary (WHO DD version MAR 2019 or higher) will be used to group prior and 
concomitant medications into relevant categories. 
A frequency tabulation of the number of subjects with the different types of prior and 
concomitant medications will be presented. Similar summaries will be provided for the prior and 
concomitant medications for palmoplantar pustulosis. A subject data listing of prior and 
concomitant medications will be provided. 
8.4.2. 
Prior and Concomitant Procedures 
Prior procedures are defined as those started before the first dose of IP (whether or not ended 
before the first dose of IP). Concomitant procedures are defined similarly as concomitant 
medications. The MedDRA will be used for coding. Frequency summaries of prior and 
concomitant procedures will be provided. A subject data listing of prior and concomitant 
procedures will be provided. 
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9. 
STUDY TREATMENTS AND EXTENT OF EXPOSURE 
Study treatment and extent of exposure summaries will be provided on the safety population and 
apremilast subjects as treated. Descriptive statistics will be provided for treatment duration and 
compliance. A subject data listing of drug administration and accountability records will be 
provided. 
9.1. 
Treatment Duration 
Treatment duration will be descriptively summarized. Treatment duration (in weeks) is 
calculated as (the date of the last dose of IP – the date of the first dose of IP + 1) / 7. Imputation 
rule for partially or completely missing last dose date is specified in Section 17.2.4. Summary 
statistics for treatment duration (in weeks), as well as a frequency summary of treatment duration 
categories (placebo-controlled phase: < 4, ≥ 4 to < 8, ≥ 8 to < 12, ≥ 12 to < 16, ≥ 16, active 
treatment phase: ≥ 16 to < 20, ≥ 20 to < 24, ≥ 24 to < 28, ≥ 28 to < 32, ≥ 32 weeks) will be 
provided. 
Treatment duration for apremilast-exposure period is calculated from the date of the first 
apremilast administered, which is the date of the first administration of apremilast on/after the 
randomization at Week 0/Visit 2 or switched to apremilast at Week 16/Visit 10, to the last 
apremilast administered date for subjects who discontinue in the first 32 weeks or who complete 
the study at Week 32/Visit 14. Imputation rule for partially or completely missing last dose date 
is specified in Section 17.2.4. 
9.2. 
Treatment Compliance  
For treatment compliance, descriptive statistics will be provided. The treatment compliance (%) 
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 minus the number of 
tablets lost) over the period divided by the intended total number of tablets that should have been 
taken over the same period. 
It is assumed that from the first through the last IP administered date, a subject takes the first 5 
rows of tablets (6 tablets per row/day) on each complete blister card before taking the remaining 
rows (2 tablets per row/day), and completes the first 28 rows, skips rows 29-33 (5-day extra 
supply) and starts a new blister card, in case the subject visit at the planned date. It is also 
assumed that a subject takes the full day’s tablets from a new blister card on a study drug 
dispense date. 
The intended total number of tablets is calculated as 
ܶℎ݁ ݅݊ݐ݁݊݀݁݀ ݐ݋ݐ݈ܽ ݊ݑܾ݉݁ݎ ݋݂ ݐܾ݈ܽ݁ݐݏ= ൜
6 × ݊
(ݓℎ݁݊ ݊< 6)
30 + 2 × (݊−5)
(ݓℎ݁݊ ݊≥6) 
where n denotes the number of days between the returned date and dispensed date (ie, the date of 
return minus the date of dispense). 
Summary statistics for compliance rate (%) will be provided. A frequency summary of 
compliance rate will also be presented with the following categories: < 75%, ≥ 75% to ≤ 100%, 
> 100% to ≤ 120% and > 120%. 
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10. 
EFFICACY ANALYSIS 
The efficacy analyses will be based on the ITT population, and analyses of the primary efficacy 
endpoint will also be provided using the PP population. Statistical comparisons between 
apremilast 30 mg BID and placebo will be made for the primary endpoint. No inferential testing 
for statistical significance will be performed for the other endpoints. The statistical test will be 
two-sided at the significance level of α = 0.10, and the corresponding p-values and two-sided 
confidence intervals (CIs) for point estimates will be presented. A subject data listing of efficacy 
data will be provided. 
10.1. 
Multiplicity 
Planned statistical test will be conducted for the primary efficacy endpoint. Secondary efficacy 
endpoints will be tested without multiplicity adjustment, therefore, other than the primary 
efficacy endpoint, nominal 2-sided p-value will be computed as a measure of the strength of the 
association between the endpoint and the treatment effect rather than formal tests of hypotheses. 
10.2. 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint which is achieving a PPPASI-50 response at Week 16 will be 
analyzed using a chi-square test at the two-sided 0.10 significant level. The two-sided 90% CI 
for the treatment difference of the PPPASI-50 response rate will be provided. The two-sided 
95% CI will also be provided for reference. Missing values at Week 16 will be imputed using 
non-responder imputation (NRI) as the primary method, by which a subject without sufficient 
data for the response determination will be considered a non-responder. Last observation carried 
forward (LOCF) method imputing the last post-baseline observation to missing data at the time 
point under consideration will be applied as sensitivity analysis. In addition to the primary 
analysis using the ITT population, an analysis using the PP population will be provided. 
To support the primary analysis, sensitivity analysis using the Cochran-Mantel-Haenszel (CMH) 
test stratified by the randomization stratification factors [PPPASI total score range (≤ 20, 21-30, 
≥ 31) and focal infection status (Yes, No)] will be conducted. The two-sided p-values (nominal) 
from the CMH test, the adjusted treatment difference in proportion using the weighted average of 
the treatment differences across the strata with the CMH weights, along with the associated two-
sided 95% CIs using a normal approximation to the weighted average will be provided. 
10.3. 
Analyses of Secondary and Exploratory Efficacy Endpoints 
The secondary efficacy endpoints will be tested without multiplicity adjustment, therefore, both 
secondary and exploratory endpoints analyses are described in this section.  
10.3.1. 
Binary Variables 
The binary variables for secondary and exploratory endpoints include: 
Subjects achieving a 
y 
PPPASI-50 response 
y 
PPPASI-75 response 
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y 
PGA score of cleared (0) or minimal (1) 
y 
PGA score of cleared (0) or minimal (1) with at least a 2-grade improvement 
y 
Modified PPPASI-50 response 
y 
Modified PPPASI-75 response 
For these binary endpoints, proportion at each visit will be displayed along with 95% CIs. The 
treatment difference between apremilast 30 mg BID and placebo will be compared using 
difference in proportions and CMH test adjusting for the stratification factor. The two-sided p-
values (nominal) from the CMH test, the adjusted treatment difference in proportion using the 
weighted average of the treatment differences across the strata with the CMH weights, along 
with the associated two-sided 95% CIs using a normal approximation to the weighted average 
will be provided. The two-sided 95% CI based on the Clopper-Pearson method will be provided 
for un-adjusted difference. Missing values will be imputed using NRI. For the exploratory 
purpose, LOCF will be applied to the data of the placebo-controlled phase. 
10.3.2. 
Continuous Variables 
The continuous variables for secondary and exploratory endpoints in placebo-controlled phase 
include the following: 
y 
AUC for PPPASI total score from baseline through Week 16 
y 
PPPASI total score change from baseline at Week 16 
y 
AUC for PPSI total score from baseline through Week 16 
y 
PPSI total score change from baseline at Week 16 
y 
AUC for modified PPPASI total score from baseline through Week 16 
y 
Modified PPPASI total score change from baseline at Week 16 
y 
Subject’s assessment for PPP sign/finding (PPSI total score) at Week 16 
The analysis of covariance (ANCOVA) model with treatment and stratification factor as the 
fixed effects, the associated baseline value as the covariate and multiple imputation (MI) method 
to impute the missing data will be applied. Within-group least-squares (LS) means, the 
associated standard error (SE), and treatment differences in LS means, the associated SE, and 
associated 2-sided 95% CIs and 2-sided p-values (nominal) will be derived from the model. 
Missing value of at Week 16 will be imputed using the MI method (SAS Institude Inc. 2015) 
except for AUC. The SAS procedure MI will be used to impute missing scores to create M=100 
complete data sets. The missing data patterns will be checked by treatment at baseline, and Week 
2, 4, 6, 8, 10, 12, 14, and 16. If there are non-monotone missing patterns, following two separate 
imputation procedures will be used to complete the imputation process. 
1. In the first step, the Markov Chain Monte Carlo (MCMC) method will be used to impute 
missing scores by treatment to create M=100 imputed data sets with monotone missing 
patterns. The minimum and maximum values for imputation will correspond to the lowest 
and the highest scores. The seed will be set at random, a single chain will be used to produce 
imputations. In case there are convergence issues, a simple model will be used to impute the 
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missing scores by treatment, with further simplification by dropping both treatment and 
stratification factor in imputation model if necessary. 
2. In the second step, the predictive mean matching method will be used to impute the 
remaining missing values for the 100 data sets with monotone missing patterns. The 
MONOTONE REGPMM statement will be used with a random seed. The missing values at 
each visit will be imputed based on treatment and previous visits. The number of closest 
observations to be used in the selection will be K=2. 
After the completion of imputation, the same analysis method/model will be used to analyze 
the 100 complete data sets and the SAS procedure MIANALYZE will be used to combine 
the results for the statistical inferences. 
Following continuous variables for secondary and exploratory endpoints will be summarized by 
time point. Change and percent change from baseline will be provided. The mixed-effect model 
for repeated measures (MMRM) will be applied for the endpoints; PPPASI and modified 
PPPASI, PPSI, and subject's VAS assessment for PPP symptoms. The MMRM model will use 
the change from baseline as the response variable and include treatment group, visit time, 
treatment-by-time interaction, and stratification factor as fixed effects, and the baseline value as 
a covariate. An unstructured covariance matrix will be used to model the correlation among 
repeated measurements. Within-group LS means and the associated SEs and 2-sided 95% CIs, 
treatment differences in LS means and the associated 2-sided 95% CIs and 2-sided p-values 
(nominal) will be derived from the MMRM model. 
y 
PPPASI total score 
y 
Individual PPPASI sub-score (Erythema, Pustules/Vesicle, Desquamation/Scale) change and 
percent change from baseline at each visit 
y 
PPSI total score 
y 
Subject’s VAS assessment for PPP symptoms 
y 
Modified PPPASI total score 
y 
Modified PPPASI sub-score (Pustules, Vesicle)  
y 
Subject’s assessment for PPP sign/finding (PPSI total score)  
y 
DLQI 
y 
EQ-5D index value 
y 
EQ-5D VAS 
Analyses of time to PPPASI response during the placebo-controlled phase will use Kaplan-Meier 
method to estimate the median response time and its 2-sided 95% CIs. The stratified log-rank test 
will be used for calculating 2-sided p-values (nominal) for treatment comparison. The hazard 
ratio and 2-sided 95% CIs will be estimated using a stratified Cox model. For the time to 
PPPASI response, the baseline score will be included as covariate in the Cox model. The 
treatment comparison will only be conducted if appropriate. Kaplan-Meier curves for time to 
event endpoints will be provided. 
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10.3.3. 
Categorical Variables 
A shift table from baseline to applicable analysis visits will be provided for the categorical 
variables including PPSI score, PGA score for palms and soles, and subject’s assessment for PPP 
Sign/Finding using PPSI score. 
10.4. 
Subgroup Analysis 
Subgroup analyses for comparisons of subjects achieving PPPASI-50 at Week 16 between 
apremilast 30 mg BID and placebo, based upon following classification variables will be 
provided to determine whether the treatment effect is consistent across various subgroups. The 
categorical groups of each subgroup may be pooled based on the number of observations 
available. 
y 
Age category (< 40, ≥ 40 to < 65, ≥ 65 to < 75, ≥ 75) 
y 
Sex (Male, Female) 
y 
BMI category (< 25, ≥ 25 to < 30, ≥ 30) 
y 
Tobacco Use (Current/Past User, Non-User) 
y 
Duration of PPP category (< 2, ≥ 2 to < 6, ≥ 6 to < 10, ≥ 10 years) 
y 
PPPASI score range at randomization from clinical data (≤ 20, ≥ 21 to ≤ 30, ≥ 31) 
y 
Presence of focal infection at randomization from clinical data (Yes, No) 
y 
History of focal infection (Yes, No) 
y 
Presence of pustulotic arthro-osteitis (PAO) (Yes, No) 
y 
Prior Disease-modifying antirheumatic drugs (DMARDs) (Yes, No) 
The consistency of the treatment effect will be assessed in the context of the primary efficacy 
analysis model with terms for treatment, stratum, and the covariate. Treatment effects and 
nominal 95% confidence intervals by category for the classification variables listed above will be 
provided. Formal statistical testing of these interactions will not be performed. 
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11. 
SAFETY ANALYSIS 
Safety analyses will be performed using the safety population. The safety analyses for the 
placebo-controlled phase will be based on the safety population and presented by treatment 
group, and the safety analyses for the apremilast-exposure period will be based on the apremilast 
subjects as treated population and presented by treatment group (Placebo/30 mg BID, 30 mg BID 
as initiated and 30 mg BID as treated). 
For safety analyses in the placebo-controlled phase, baseline will be relative to the first dose date 
following randomization at Week 0. For safety analyses in apremilast-exposure period, baseline 
will be relative to the first apremilast dose date at Week 0 for subjects initially randomized to 
apremilast or Week 16 for subjects initially randomized to placebo and switched to apremilast in 
the active treatment phase (Weeks 16 to 32). 
Unless otherwise specified, the analyses of AEs and marked abnormalities (laboratory 
parameters and vital signs) for both the placebo-controlled phase and apremilast-exposure period 
will include the subject incidence rate. To account for the different exposure to the IP, the 
exposure-adjusted incidence rate will also be presented. 
࣭ 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 phase or analysis period will be counted only once in the numerator. If a subject 
experiences multiple AEs under the same preferred term (system organ class), then the 
subject will be counted only once for that preferred term (system organ class). 
࣭ 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 phase or 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 IP. 
For safety analysis, no inferential testing for statistical significance will be performed. 
Individual subject listings will be provided for all safety data obtained. 
As necessity requires, additional safety information may be provided. 
11.1. 
Adverse Events 
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs) which 
are defined as any AEs that begin or worsen on or after the first dose of IP through 28 days after 
the last dose of IP or study treatment discontinuation date, whichever is later. All AEs will be 
classified using the Medical Dictionary for Regulatory Activities (MedDRA) classification 
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system version 21.1 or higher. Unless otherwise specified, AEs will be summarized by system 
organ class (SOC) and preferred term (PT), with SOCs presented in the standard international 
order and PTs within SOCs will be presented in descending order of subject incidence. 
A treatment-related TEAE is defined as TEAE which was suspected to be related to the study 
drugs. 
AEs and marked abnormalities will be summarized by subject incidence and EAIR for the 
placebo-controlled phase (Weeks 0 to16) and for the Apremilast-exposure period. In addition, 
selected summaries for the active treatment phase (Weeks 16 to 32) and the observational 
follow-up phase (4 weeks) will be presented. 
An overall summary of the following AE categories will be provided. 
y 
TEAE 
y 
TEAE related to study drug 
y 
Severe TEAE 
y 
Serious TEAE 
y 
Serious TEAE Related to Study Drug 
y 
TEAE leading to dose reduction 
y 
TEAE leading to drug interruption 
y 
TEAE leading to drug withdrawal 
y 
TEAE leading to death 
In addition, for apremilast-exposure period overall summary of TEAEs will also be provided. 
Tables summarizing the incidence of TEAEs by SOP and/or PT will be generated for each of the 
following: 
y 
All TEAEs 
y 
Most frequent TEAEs (subject incidence ≥ 5% or another cut-off if justified) 
y 
Treatment-related TEAEs 
y 
TEAEs by maximum severity 
y 
Serious TEAEs and treatment-related serious TEAEs 
y 
TEAE leading to dose reduction 
y 
TEAE leading to drug interruption 
y 
TEAE leading to drug withdrawal 
y 
TEAE leading to death 
y 
First onset and new events of TEAE by exposure interval 
- 
placebo controlled phase (weeks): ≤ 1, > 1 to ≤ 2, > 2 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12, > 
12 to ≤ 16, > 16 
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- 
apremilast-exposure period (weeks): ≤ 1, > 1 to ≤ 2, > 2 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12, > 
12 to ≤ 16, > 16 to ≤ 24, > 24 to ≤ 32, > 32 
y 
TEAE for the subgroups in Section 10.4 
For the summary of the new events of TEAE by exposure interval, each subject is counted once 
for either subject incidence or EAIR for each applicable specific TEAE in each exposure interval 
where an event started. The denominator of a subject incidence is the number of subjects with 
treatment duration exceeding the lower bound of the particular exposure interval, while the 
denominator of an EAIR is the sum of the exposure time during the exposure interval (up to the 
first event start date for subjects with at least one event starting in the interval) among the same 
number of subjects as in the denominator of the corresponding subject incidence. For the 
summary of the first onset of TEAE by exposure interval, only the first onset of specific TEAE is 
considered for each subject. 
Listings for the corresponding summary tables will be presented separately. A listing including 
non-treatment-emergent AEs will be provided.  
11.2. 
Adverse Events of Special Interest 
The following TEAEs of special interest will be summarized: 
y 
Depression: MedDRA narrow scope sub-SMQ of Depression (excluding suicide and self-
injury) 
y 
Serious infection: MedDRA primary PTs from the SOC of Infections and infestations. Only 
the events that were assessed as serious 
y 
Risk of Triggering Suicide: MedDRA narrow scope SMQ of Suicide/self-injury 
The following summaries will be provided for TEAEs included in the above-mentioned AEs of 
interest: 
y 
All TEAEs;  
y 
Severe TEAEs;  
y 
Serious TEAEs;  
y 
TEAEs leading to treatment discontinuation; 
y 
TEAEs leading to dose reduction/interruption; 
y 
TEAEs leading to death. 
11.3. 
Clinical Laboratory Evaluations 
The endpoints for clinical laboratory evaluations include: 
y 
Laboratory marked abnormalities 
y 
Observed value and change from baseline over time in the following selected laboratory 
parameters 
¾ Hematology: platelets, hemoglobin, leukocytes, neutrophils, segmented, lymphocytes 
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¾ Serum chemistry: hemoglobin A1C, magnesium, sodium, potassium, total bilirubin, 
glucose, lactate dehydrogenase, calcium, albumin, creatinine, alanine aminotransferase, 
alkaline phosphatase, aspartate aminotransferase, blood urea nitrogen, urate, phosphate, 
triglycerides, cholesterol 
y 
Shifts from baseline to post-baseline time points and to the worst post-baseline value in 
terms of normal/abnormal (low and/or high) in the above hematology and serum chemistry 
parameters 
Summary statistics of observed values and changes from baseline in laboratory parameters will 
be provided over time. Frequency summaries (shift tables) of shifts from baseline to post-
baseline time points and to the worst post-baseline value in terms of normal/abnormal will be 
provided. 
Laboratory marked abnormalities will be summarized; subject incidence and EAIR for each 
abnormality will be calculated based on subjects with a baseline value and at least one post-
baseline value. Laboratory marked abnormalities will also be summarized for subjects with 
normal values at baseline and for subjects with abnormal values at baseline separately. For the 
purposes of these summaries, subjects with abnormal (normal) values at baseline are defined as 
those whose baseline value is low (not low) for criteria concerning low values and those whose 
baseline value is high (not high) for criteria concerning high values; both low and high are 
relative to the laboratory normal range. 
Individual subject data of all laboratory data including urinalysis will be listed and values outside 
of the standard reference range will be flagged.  
11.4. 
Vital Sign Measurements 
Vital sign measurements, including weight, will be summarized descriptively by visit. In 
addition, shift tables summarizing the baseline categories (normal, abnormal) versus the category 
at the end of the respective periods or versus the worst post-baseline category and including 
subjects who have values at baseline and at least one post-baseline value will be provided. 
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. The change 
from baseline for each of the vital signs including weight will be summarized. A subject data 
listing of all vital signs and weight data will be provided. 
11.5. 
Physical Examination 
A subject data listing of general physical examination will be provided. 
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12. 
ANALYSIS FOR COVID-19 IMPACT 
The following summary and listing to assess impact of Coronavirus Disease 2019 (COVID-19) 
will be provided. 
࣭ Summary tables showing the number and percentage of subjects with at least one PD and 
IPD related to COVID-19 and by each category of PD and IPD 
࣭ A listing of PD and IPD related to COVID-19 
࣭ A listing of treatment-emergent AE related to COVID-19 
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13.2. 
Definition of Baseline 
Baseline is defined as the value from a sample collected from that subject at the Week 0 
randomization visit, prior to dosing of apremilast or placebo. 
13.3. 
Baseline Demographic and Disease Background Characteristics 
Subject disposition will be provided. Demographic and baseline characteristics will be 
summarized descriptively by treatment group (placebo and apremilast 30 mg BID) for the 
 
, based on the subjects’ randomization assignments. No formal 
statistical tests will be performed to assess the comparability of the treatment groups at baseline. 
Descriptive statistics will be provided for the following demographic variables at baseline: age, 
age category, sex, race, ethnicity, weight and weight category, height, body mass index (BMI), 
BMI category, and alcohol and tobacco use. 
Descriptive statistics will be provided for the following disease background variables at baseline: 
duration and duration category of PPP; PPPASI total score, PPSI total score, PGA score for 
palms and soles; prior use of immunosuppressants, colchicines, oral corticosteroids, topical 
corticosteroids, biologics, non-steroidal anti-inflammatory drugs (NSAIDs), and other 
analgesics/anesthetics. 
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14. 
INTERIM ANALYSIS 
No interim analysis is planned prior to the analysis of the primary efficacy endpoint at Week 16. 
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15. 
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL 
No changes to the statistical analyses section of the protocol are made in this SAP. 
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16. 
REFERENCES 
Terui T, Kobayashi S, Okubo Y, Murakami M, Hirose K, Kubo H. Efficacy and safety of 
guselkumab, an anti-interleukin 23 monoclonal antibody, for palmoplantar pustulosis: A 
randomized clinical trial. JAMA Dermatol. 2018;154(3):309-316. 
Garcet S, Nograles K, Rosa JC, Schafer PH, Kruger JG. Synergistic cytokine effects as 
apremilast response predictors in patients with psoriasis. J Allergy Clin Immunol. 
2018:142(3);1010-1013. 
Gottlieb AB, Matheson RT, Menter A, Leonardi CL, Day RM, Hu C, et al. Efficacy, tolerability, 
and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. 
J Drugs Dermatol 2013;12(8):888-897. 
Ikeda S, Shiroiwa T, Igarashi A, Noto S, Fukuda T, Saito S, Shimozuma K. Developing a 
Japanese version of the EQ-5D-5L value set. J. Natl. Inst. Public Health 2015; 64(1): 47-55. 
SAS Institute Inc. 2015. SAS/STAT® 14.1 User’s Guide. Cary, NC: SAS Institute Inc. 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
43 
 
17. 
APPENDICES  
17.1. 
Handling of Dates  
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. datetime format in SAS).  Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates. 
x Procedure Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, etc. 
They should be present whenever data for a protocol-specified procedure are present 
and should only be missing when a procedure are marked as NOT DONE in the 
database. Procedure dates will not be imputed. 
x Log Dates are dates recorded in CRF data logs.  Specifically, they are the start and 
end dates for adverse events and concomitant medications/procedures.  They should 
not be missing unless an event or medication is marked as ongoing in the database. 
Otherwise, incomplete log dates will be imputed according to the rules in Section 
17.2 (eg, for duration or cycle assignment, etc). However, in listings, log dates will be 
shown as recorded without imputation. 
x Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc. They should not be 
missing if the milestone occurs for a subject. They will not be imputed. 
x Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, response etc. In most cases they are derived either from a milestone (eg, 
the survival date is derived from the death date), a procedure date (eg, the progression 
date is derived from the date of the tumor scan that was used to determine 
progression) or an assessment date. They may be subject to endpoint-specific 
censoring rules if the outcome did not occur, but are not otherwise subject to 
imputation. 
x Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules.  
Dates recorded in comment fields will not be imputed or reported in any specific format. 
17.1.1. 
Calculation Using Dates 
Calculations using dates (eg, subject’s age or relative day after the first dose of IP) 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; 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
44 
 
o Else use STUDY DAY = TARGET DATE – DSTART. 
Note that Study Day 1 is the first day of treatment of study drug. Negative study days 
are reflective of observations obtained during the baseline/screening period. 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 (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1.  In 
practice, age will be transformed to years by dividing the difference by 365.25 days, 
then truncating. 
 Preference is for using calculated age from clinical database. When not available, 
calculated age from CRF or IVRS may be used 
 Partial birth date: impute missing day as 15th of the month; impute missing month 
as July; set missing age for missing year 
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 
 
17.2. 
Date Imputation Guideline 
17.2.1. 
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 in the same dataset. If the AE end date is complete 
with no missing year, month, or day, and the partially missing start date imputed by the rules 
below is after the AE end date, then the start date will be imputed by the AE end date. 
Subjects who were treated with apremilast at Week 0/Visit 2 
The principle of the imputation rules for subjects who were treated with apremilast initially is to 
treat the AE as treatment-emergent, ie, occurring on or after the date of the first dose of IP, if 
possible. 
Let an AE start date be represented as “DEvent/MEvent/YEvent”, and the date of the first dose of IP as 
“DIP/MIP/YIP”. The following table gives the imputation rules for partially missing AE start dates 
for subjects who were treated with apremilast initially. 
Table 5: 
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially 
Scenario 
Condition 
Imputation Rule 
Partially missing date includes year only (both month and day are missing) 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
45 
 
Scenario 
Condition 
Imputation Rule 
1 
YEvent < YIP 
12/31/YEvent 
2 
Otherwise, ie, YIP ≤ YEvent 
Max (date of first dose of IP, 1/1/YEvent) 
Partially missing date includes both year and month (only day is missing) 
1 
YEvent < YIP, or (YEvent = YIP and MEvent < MIP) 
Last date of MEvent/YEvent 
2 
Otherwise, ie, YIP < YEvent, or (YIP = YEvent and 
MIP ≤ MEvent)  
Max (date of first dose of IP, 1/MEvent/YEvent) 
Subjects who were treated with placebo at Week 0/Visit 2 
The principle of the imputation rules for subjects who were treated with placebo initially and 
started apremilast treatment at Week 16 is to consider the AE starting on or after the date of the 
first dose of apremilast, if possible; if the partially missing start date suggests that it is prior to 
the date of the first dose of apremilast, the AE will be considered starting on or after the date of 
the first dose of IP, if possible. 
The following are 4 scenarios considered in the imputation rules: 
1. The partially missing AE start date suggests the date is prior to the date of the first dose 
of IP: impute it by the latest possible date (determined by the non-missing field of the 
date); 
2. The partially missing AE start date suggests the date is after the date of the first dose of 
apremilast following Week 16: impute it by the earliest possible date (determined by the 
non-missing filed of the date); 
3. The partially missing AE start date is in the same year (if both month and day are 
missing), or the same year/month (if only day is missing) of the first dose of apremilast 
following Week 16: impute it by the date of the first dose of apremilast; 
4. The partially missing AE start date suggests the date is no earlier than the date of the first 
dose of IP but prior to the date of the first dose of apremilast following Week 16: impute 
it by the date of the first dose of IP, or the earliest possible date (determined by the non-
missing field of the date), whichever occurs later. 
Let an AE start date be represented as “DEvent/MEvent/YEvent”, the date of the first dose of IP as 
“DIP/MIP/YIP”, and the date of the first dose of apremilast following Week 16 as 
“DAPR/MAPR/YAPR”. The following table gives the imputation rules for partially missing AE start 
dates. 
Table 6: 
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Placebo Initially 
Scenario 
Condition 
Imputation Rule 
Partially missing date includes year only (both month and day are missing) 
1 
YEvent < YIP 
12/31/YEvent 
2 
YEvent > YAPR 
1/1/YEvent 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
46 
 
Scenario 
Condition 
Imputation Rule 
3 
YEvent = YAPR 
Date of first dose of apremilast following 
the early escape 
4 
Otherwise, ie, YIP ≤ YEvent< YAPR 
Max (date of first dose of IP, 1/1/YEvent) 
Partially missing date includes both year and month (only day is missing) 
1 
YEvent < YIP, or (YEvent = YIP and MEvent < MIP ) 
Last date of MEvent/YEvent 
2 
YEvent > YAPR, or (YEvent = YAPR and MEvent > 
MAPR) 
1/MEvent/YEvent 
3 
YEvent = YAPR and MEvent = MAPR 
Date of first dose of apremilast following 
the early escape 
4 
Otherwise, ie, YIP < YEvent < YAPR, or  
(YIP = YEvent < YAPR and MIP ≤ MEvent), or  
(YIP = YEvent = YAPR and MIP ≤ MEvent < MAPR), 
or (YIP < YEvent = YAPR and MEvent < MAPR) 
Max (date of first dose of IP, 1/MEvent/YEvent) 
17.2.2. 
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.  
࣭ Incomplete Start Date: 
Missing day and month 
If the year is  
࣭ the same as the year of the first dosing date, then the day and month of the first dosing 
date will be assigned to the missing fields. 
࣭ prior to the year of first dosing date, then December 31 will be assigned to the missing 
fields. 
࣭ after the year of first dosing, then January 1 will be assigned to the missing fields. 
Missing day only 
࣭ If the month and year are the same as the year and month of first dosing date, then the 
first dosing date will be assigned to the missing day. 
࣭ If either the year of the partial date is before the year of the first dosing date, or the year 
of the partial date and the first dosing date are the same but the month of partial date is 
before the month of the first dosing date, then the last day of the month will be assigned 
to the missing day. 
࣭ If either the year of the partial date is after the year of the first dosing date, or the years 
of the partial date and the first dosing date are the same but the month of partial date is 
after the month of the first dosing date, then the first day of the month will be assigned to 
the missing day. 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
47 
 
࣭ If the stop date is not missing, and the imputed start date is after the stop date, the start 
date will be imputed by the stop date. 
Missing day, month, and year 
࣭ No imputation is needed. 
࣭ Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed 
stop date will be equal to the start date. 
Missing day and month 
࣭ If the  year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 
࣭ If the year of the incomplete stop date is prior to the year of the last dosing date or prior 
to the year of the first dosing date, then December 31 will be assigned to the missing 
fields. 
࣭ If the year of the incomplete stop date is prior to the year of the last dosing date but is 
the same as the year of the first dosing date, then the first dosing date will be assigned to 
the missing date. 
࣭ If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1st will be assigned to the missing fields. 
Missing day only 
࣭ If the month and year of the incomplete stop date are the same as the month and year of 
the last dosing date, then the day of the last dosing date will be assigned to the missing 
day. 
࣭ If either the year of the partial date is not equal to the year of the last dosing date or the 
year of the partial date and the last dosing date are the same but the month of partial date 
is not equal to the month of the last dosing date, then that last day of the month will be 
assigned to the missing day. 
17.2.3. 
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 Palmoplantar Pustulosis). The 16th of the 
month will be used to impute a partially missing start date that has only the day missing, and July 
1st will be used to impute a partially missing start date that has both the month and day missing. 
If the above imputation inappropriately results in a diagnosis date on or after the informed 
consent date, then the incomplete date will be assigned to the day prior to the informed consent 
date. 
17.2.4. 
Treatment Duration 
Partially or completely missing last dose dates will be imputed in the ADaM dataset for 
treatment duration. 
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CC-10004 (Apremilast) 
 
 
Statistical Analysis Plan. Protocol CC-10004-PPP-001 
 
Confidential and Proprietary 
48 
 
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 discontinuation 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 discontinuation 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). 
17.3. 
Laboratory Marked Abnormalities Criteria 
Table 7: 
Laboratory Marked Abnormalities Criteria 
Category 
Analyte 
Units  
 Criteria  
Chemistry 
Hemoglobin A1C 
% 
> 6.5 
Magnesium 
mmol/L 
> 1.2 
Sodium 
mmol/L 
>150, <130 
Potassium 
mmol/L 
>5.5, <3.0 
Total Bilirubin 
umol/L 
>1.8×ULN 
Glucose 
mmol/L 
>13.9, <2.8 
Lactate Dehydrogenase 
U/L 
> 2xULN 
Calcium 
mmol/L 
>3.0, <1.8 
Albumin 
g/L 
<25 
Creatinine 
umol/L 
>1.5×ULN 
Alanine Aminotransferase 
U/L 
>3.0×ULN 
Alkaline Phosphatase 
U/L 
>400 
Aspartate Aminotransferase 
U/L 
>3.0×ULN 
Blood Urea Nitrogen 
mmol/L 
> 24 
Urate 
umol/L 
> 480 
Phosphate 
mmol/L 
>1.60, <0.64 
Triglycerides 
mmol/L 
> 3.4 
Cholesterol 
mmol/L 
> 7.8 
Hematology 
Platelets 
10^9/L 
>600, <75 
Hemoglobin 
g/L 
>150, <110 
Leukocytes 
10^9/L 
< 2.0 
Neutrophils, Segmented 
10^9/L 
< 1.5 
Lymphocytes 
10^9/L 
<0.8 
 
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