Clinical trial NCT05174065
Conditions: Palmoplantar Pustulosis
Keywords: Palmoplantar Pustulosis PPP AMG 407 Apremilast Otezla
Sponsor: Amgen
Start date: 2022-03-08; Completion date: 2024-06-01
Enrollment: 176 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the efficacy of apremilast (AMG 407) twice daily (BID) compared with placebo in participants with Palmoplantar Pustulosis (PPP).

Detailed description:

Arms: arm 1: Apremilast will be administered to participants twice daily (BID) arm 2: Matching placebo will be administered to participants twice daily (BID) until week 16. After week 16, Apremilast will be administered to participants BID.
Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets intervention 2: Oral tablets

Protocol documents:
Prot_000.pdf: 
Product:  Apremilast 
Protocol Number:  20200195 
Date:  15 April 2022 
Page 1 of 99 
CONFIDENTIAL 
Title Page 
Protocol Title: 
A Phase 3, Multicenter, Randomized, 
Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of Apremilast 
(AMG 407) in Japanese Subjects with 
Palmoplantar Pustulosis (PPP) 
Short Protocol Title: 
Phase 3, Randomized Study of Apremilast in 
Japanese Subjects with Palmoplantar Pustulosis 
Protocol Number: 
20200195 
Investigational Product: 
Apremilast 
Trade Name: 
Otezla 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, United States 
Telephone Number: 
1-805-447-1000
Protocol 
Approver 
Name: 
 
Function: 
Vice President Global Development 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive, Thousand Oaks, CA 
91320, United States 
Telephone Number: 
Email Address: 
 
EudraCT Number: 
N/A 
NCT Number: 
N/A 
Protocol Version Date: 
Document Version 
Date 
Original 
29 June 2021 
Amendment 1 
30 July 2021 
Amendment 2 
30 March 2022 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  15 April 2022 
Page 2 of 99 
CONFIDENTIAL 
Superseding 
Amendment 2 
15 April 2022 
Data Elements Standards 
Version: 
8.0 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (International Council for Harmonisation 
[ICH] E6). 
NCT Number: NCT05174065
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  Apremilast 
Protocol Number:  20200195  
Date:  15 April 2022 
Page 3 of 99 
CONFIDENTIAL  
 
 
Confidentiality Notice 
 
 
This document contains confidential information of Amgen Inc. 
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 Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Japanese sites, +81-120-790-549; Amgen’s general number in 
the US, 1-805-447-1000. 


Product:  Apremilast 
Protocol Number:  20200195  
Date:  15 April 2022 
Page 4 of 99 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 3, Multicenter, Randomized, 
Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Apremilast 
(AMG 407) in Japanese Subjects with Palmoplantar Pustulosis (PPP), dated 15 April 
2022, and agree to abide by all provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
Date (DD Month YYYY) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 


Product:  Apremilast 
Protocol Number:  20200195  
Date:  15 April 2022 
Page 5 of 99 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ............................................................................................................ 5 
1. 
Protocol Summary .................................................................................................. 9 
1.1 
Synopsis ..................................................................................................... 9 
1.2 
Study Schema ........................................................................................... 15 
1.3 
Schedule of Activities  ............................................................................... 16 
2. 
Introduction ........................................................................................................... 20 
2.1 
Study Rationale ......................................................................................... 20 
2.2 
Background ............................................................................................... 21 
2.2.1 
Disease ..................................................................................... 21 
2.2.2 
Current Treatment Options ........................................................ 21 
2.2.3 
Amgen Investigational Product Background:  
Apremilast ................................................................................. 22 
2.3 
Benefit/Risk Assessment ........................................................................... 22 
3. 
Objectives and Endpoints/Estimands .................................................................... 24 
4. 
Study Design ........................................................................................................ 26 
4.1 
Overall Design .......................................................................................... 26 
4.2 
Patient Input into the Study Design ........................................................... 27 
4.3 
Justification for Dose ................................................................................. 27 
4.3.1 
Justification for Investigational Product Dose............................. 27 
4.4 
End of Study ............................................................................................. 28 
5. 
Study Population .................................................................................................. 29 
5.1 
Inclusion Criteria ....................................................................................... 29 
5.2 
Exclusion Criteria ...................................................................................... 30 
5.3 
Subject Enrollment .................................................................................... 32 
5.4 
Screen Failures ......................................................................................... 33 
6. 
Study Intervention ................................................................................................. 33 
6.1 
Study Interventions Administered .............................................................. 33 
6.1.1 
Investigational Products ............................................................ 33 
6.1.2 
Other Protocol-required Therapies ............................................ 35 
6.1.3 
Product Complaints ................................................................... 35 
6.1.4 
Excluded Treatments and/or Procedures During Study 
Period ....................................................................................... 35 
6.2 
Preparation/Handling/Storage/Accountability ............................................ 37 
6.3 
Measures to Minimize Bias:  Randomization and Blinding ......................... 37 
6.3.1 
Method of Treatment Assignment .............................................. 37 
6.3.2 
Blinding ..................................................................................... 38 
6.3.2.1 
Site Personnel Access to Unblinding 
Information .............................................................. 38 


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Protocol Number:  20200195  
Date:  15 April 2022 
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6.3.2.2 
Access to Unblinding Information by 
Amgen or Designees ............................................... 38 
6.4 
Treatment Compliance .............................................................................. 38 
6.5 
Treatment of Overdose ............................................................................. 39 
6.6 
Prior and Concomitant Treatment ............................................................. 39 
6.6.1 
Prior Treatment ......................................................................... 39 
6.6.2 
Concomitant Treatment ............................................................. 39 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal ................................................................................... 40 
7.1 
Discontinuation of Study Treatment........................................................... 40 
7.2 
Subject Discontinuation/Withdrawal From the Study ................................. 41 
7.2.1 
Reasons for Removal From Study ............................................. 41 
7.3 
Lost to Follow-up ....................................................................................... 41 
8. 
Study Assessments and Procedures .................................................................... 43 
8.1 
General Study Periods .............................................................................. 43 
8.1.1 
Screening, Enrollment, and/or Randomization ........................... 43 
8.1.2 
Treatment Period ....................................................................... 43 
8.1.3 
Safety Follow-up ........................................................................ 44 
8.1.4 
End of Study .............................................................................. 44 
8.2 
General Assessments ............................................................................... 44 
8.2.1 
Informed Consent ...................................................................... 44 
8.2.2 
Demographics ........................................................................... 44 
8.2.3 
Medical History .......................................................................... 44 
8.2.4 
Physical Examination ................................................................ 44 
8.2.5 
Physical Measurements ............................................................ 45 
8.2.6 
Substance Abuse History .......................................................... 45 
8.3 
Efficacy Assessments ............................................................................... 45 
8.3.1 
Subject and Physician-reported Outcomes/ Quality of 
Life Measurements .................................................................... 45 
8.3.1.1 
Palmoplantar Pustulosis Area and Severity 
Index (PPPASI) ....................................................... 45 
8.3.1.2 
Palmoplantar Pustulosis Severity Index 
(PPSI) ..................................................................... 45 
8.3.1.4 
Pruritis and Pain/Discomfort Assessment 
with Subject Visual Analogue Scale (VAS) 
for PPP Symptoms .................................................. 45 
8.3.1.5 
Dermatology Life Quality Index (DLQI) .................... 46 
8.4 
Safety Assessments .................................................................................. 46 
8.4.1 
Vital Signs ................................................................................. 46 
8.4.2 
Clinical Laboratory Assessments ............................................... 46 


Product:  Apremilast 
Protocol Number:  20200195  
Date:  15 April 2022 
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8.4.3 
Suicidal Risk Monitoring ............................................................ 47 
8.4.4 
Adverse Events and Serious Adverse Events ............................ 47 
8.4.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 47 
8.4.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 48 
8.4.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 48 
8.4.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 49 
8.4.4.5 
Safety Monitoring Plan ............................................ 50 
8.4.4.6 
Pregnancy and Lactation ......................................... 50 
8.5 
Pharmacokinetic Assessments .................................................................. 50 
8.6 
Biomarkers ................................................................................................ 51 
8.6.1 
Biomarker Discovery ................................................................. 51 
8.6.1.1 
Biomarker Development/Future Research ............... 51 
9. 
Statistical Considerations ...................................................................................... 51 
9.1 
Statistical Hypotheses ............................................................................... 51 
9.2 
Sample Size Determination ....................................................................... 51 
9.3 
Populations for Analysis ............................................................................ 52 
9.3.1 
Covariates ................................................................................. 52 
9.3.2 
Subgroups ................................................................................. 52 
9.4 
Statistical Analyses ................................................................................... 52 
9.4.1 
Planned Analyses ...................................................................... 52 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 52 
9.4.1.2 
Primary Analysis ..................................................... 53 
9.4.1.3 
Final Analysis .......................................................... 53 
9.4.2 
Methods of Analyses ................................................................. 53 
9.4.2.1 
General Considerations ........................................... 53 
9.4.2.2 
Efficacy Analyses .................................................... 54 
9.4.2.3 
Safety Analyses ...................................................... 56 
............ 57 
10. 
References ........................................................................................................... 58 
11. 
Appendices ........................................................................................................... 61 
11.1 
Appendix 1.  List of Abbreviations ............................................................. 62 
11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 64 
11.3 
Appendix 3.  Study Governance Considerations ....................................... 66 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 75 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 84 


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Protocol Number:  20200195  
Date:  15 April 2022 
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11.6 
Appendix 6.  Sample Storage and Destruction .......................................... 90 
11.7 
Appendix 7.  Protocol-specific Anticipated Serious Adverse 
Events ....................................................................................................... 91 
11.8 
Appendix 8.  Palmoplantar Pustulosis Area and Severity Index 
(PPPASI)................................................................................................... 92 
11.9 
Appendix 9.  Palmoplantar Pustulosis Severity Index (PPSI)..................... 93 
11.10 
11.11 
Appendix 11.  Visual Analogue Scale (VAS) —PPP Symptoms 
for Palms and Soles .................................................................................. 94 
11.12 
Appendix 12.  Dermatology Life Quality Index (DLQI) ............................... 96 
11.13 
 
List of Tables 
Table 1-1.  Schedule of Activities ................................................................................... 16 
Table 6-1.  Investigational Products ............................................................................... 34 
Table 6-2.  Excluded Treatments and/or Procedures During Study Period .................... 35 
Table 11-1.  Analyte Listing ........................................................................................... 65 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 15 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 81 
Figure 11-2.  Pregnancy and Lactation Notification Forms ............................................. 88 


Product:  Apremilast 
Protocol Number:  20200195  
Date:  15 April 2022 
Page 9 of 99 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Apremilast (AMG 407) in Japanese 
Subjects with Palmoplantar Pustulosis (PPP) 
Short Protocol Title:  Phase 3, Randomized Study of Apremilast in Japanese Subjects 
with Palmoplantar Pustulosis  
Study Phase:  3 
Indication:  Treatment of palmoplantar pustulosis 
Study Rationale 
The characteristic histopathological features of palmoplantar pustulosis (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 interleukin (IL)-17 as a promoter of neutrophil 
accumulation and activation (Yamamoto, 2009; Hagforsen et al, 2010).  Patients with 
PPP have both elevated serum tumor necrosis factor (TNF)-α, IL-17, IL-22, and IL8 
levels and elevated neutrophil and Th17 gene expression in the pustular skin (IL-8, 
IL-17A, IL-36G, IL-12A [p40], IL-17F, IL-22, IL-23B [p19], DEFB4A, and TNF-α) 
(Murakami, 2011).  Eccrine ducts, keratinocyte, and more inflammatory cell involvement 
is also suggested in PPP pathogenesis (Hagforsen et al, 2010; Murakami et al, 2014; 
Murakami et al, 2017).   
Although corticosteroids, active vitamin D3 ointments, and phototherapy (ultraviolet [UV] 
radiation therapy) are common PPP treatments, evidence showing their efficacy in 
moderate to severe PPP cases is quite limited, highlighting the need for optimal, 
convenient, and targeted therapeutic options for the disease (Kobayashi et al 2010).  By 
inhibiting phosphodiesterase-4 (PDE4), an enzyme prevalent in immune cells, 
apremilast is expected to inhibit the production of IL-17, IL-8, and several other 
inflammatory cytokines related to PPP pathogenesis.   
The efficacy of apremilast has also been reported in patients with synovitis, acne, 
pustulosis, hyperostosis osteitis (SAPHO) syndrome (Adamo, 2018).  One form of 
SAPHO syndrome, pustulotic arthro-osteitis (PAO), is a known complication of PPP, 
suggesting that apremilast may be an effective treatment in PPP patients with or without 
PAO (Sonozaki et al, 1981; Okubo, 2012; Okuno et al, 2018). 


Product:  Apremilast 
Protocol Number:  20200195  
Date:  15 April 2022 
Page 10 of 99 
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Apremilast studies, CC-10004-PSOR-005, CC-10004-PSOR-008 (hereafter referred to 
as ESTEEM-1), and CC-10004-PSOR-009 (hereafter referred to as ESTEEM-2), 
showed improvement of palmoplantar disease status in subjects with palmoplantar 
psoriasis, a closely related dermatological condition (Bissonnette et al, 2016).  Efficacy 
was also demonstrated in Study CC-10004-BCT-002 for oral ulcers in subjects with 
Bechet’s Disease (BD) in which IL-17 and neutrophils play important roles (Hatemi et al, 
2019).   
In a randomized, double-blind, placebo-controlled phase 2 study in Japan 
(Study CC-10004-PPP-001 [20200055]), apremilast showed efficacy in PPP treatment 
and safety and tolerability data was consistent with the known safety profile of 
apremilast.  The phase 3 study is intended to confirm the risk-benefit balance of 
apremilast in the treatment of PPP in Japanese patients.   
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the efficacy of 
apremilast 30 mg twice daily (BID) 
compared with placebo in subjects 
with PPP 
 
Achieving at least 50% reduction 
from baseline in Palmoplantar 
Pustulosis Area and Severity 
Index (PPPASI) total score 
(PPPASI-50) at week 16 
Secondary 
 
To evaluate the efficacy of 
apremilast 30 mg BID compared 
with placebo in subjects with PPP 
 
Change from baseline in PPPASI 
total score at week 16 
 
Change from baseline in 
Palmoplantar Pustulosis Severity 
Index (PPSI) total score at 
week 16 
 
Change from baseline in subject’s 
Visual Analogue Scale (VAS) 
assessment for PPP symptoms 
(pruritis and pain/discomfort) at 
week 16 
 
Change from Baseline in 
Dermatology Life Quality Index 
(DLQI) total score at week 16 
 
To evaluate the safety and 
tolerability of apremilast 30 mg 
BID compared with placebo in 
subjects with PPP 
 
Treatment-emergent adverse 
events, serious 
treatment-emergent adverse 


Product:  Apremilast 
Protocol Number:  20200195  
Date:  15 April 2022 
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CONFIDENTIAL  
 
 
events, and adverse events of 
interest 
 
Clinically significant changes in 
body weight, vital signs, and 
laboratory abnormalities 
 
 
Primary Estimand 
The primary efficacy endpoint is the achievement of PPPASI-50 at week 16 and the 
main estimand is the difference between apremilast 30 mg BID and placebo in the 
proportion of PPPASI-50 responders at week 16 based on the intent-to-treat (ITT) 
population including all randomized subjects, where subjects who discontinue 
investigational product (IP) due to lack of efficacy, adverse event, or use of 
protocol-prohibited medication are considered treatment failures.  
 
The target population of interest is Japanese subjects with PPP defined through 
the inclusion/exclusion criteria. 
 
The primary endpoint is the achievement of PPPASI-50 at week 16. 
 
Intercurrent events (IEs) are IP discontinuation due to lack of efficacy, adverse 
event, or protocol-prohibited medication use.  A subject will be considered a 
non-responder after any of the IEs. 
 
The summary measure is the difference in proportion of responders. 
Missing values of the data in which the treatment failures are considered as 
non-responders will be imputed using multiple imputation (MI) method.  
Secondary Estimand(s) 
The main estimand for the secondary efficacy endpoints is the difference in change from 
baseline at week 16 in PPPASI total score, PPSI total score, subject’s VAS assessment 
for PPP symptoms (pruritus and pain/discomfort), and DLQI total score based on the 
ITT population in which subjects who discontinue the IP due to lack of efficacy, adverse 
event, or use of protocol prohibited medication are considered as treatment failures. 
 
The target population of interest is Japanese subjects with PPP defined through the 
inclusion/exclusion criteria. 
 
The secondary endpoints are the change from baseline at week 16 in PPPASI total 
score, PPSI total score, subject’s VAS assessment for PPP symptoms (pruritus and 
pain/discomfort), and DLQI total score. 


Product:  Apremilast 
Protocol Number:  20200195  
Date:  15 April 2022 
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 
The IEs are IP discontinuation due to lack of efficacy, adverse event, or use of 
protocol prohibited medication.  The baseline value will be assigned to the data after 
any of the IEs through week 16 regardless of the observed data. 
 
The summary measure is the mean difference in change from baseline. 
The data where the baseline value is assigned for the treatment failures will be used for 
the analysis model based on the assumption of missing at random (MAR) 
(eg, mixed-effect model for repeated measures (MMRM).  
Overall Design 
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled study 
evaluating the efficacy and safety of apremilast 30 mg BID versus placebo in Japanese 
subjects with PPP.  During the double-blind placebo-controlled study period, subjects will 
be randomized 1:1 to apremilast 30 mg BID or placebo for 16 weeks.  During the active 
treatment period, all subjects will receive apremilast 30 mg BID from week 16 through 
week 52.  Following the last treatment dose, subjects will enter a 30-day observational 
safety follow-up period.  The total study duration per subject is approximately 
60 weeks.  Randomization will be stratified by a subject's rounded PPPASI total score 
(≤ 20 / 21-30/ ≥31) at baseline and baseline focal infection status (yes/no).  
Number of Subjects 
Approximately 170 subjects will be randomized in this study.  
Summary of Subject Eligibility Criteria 
Eligible Japanese subjects must be  18 years of age with PPP diagnosed at least 
24 weeks prior to screening, have a PPPASI total score  12, a PPPASI severity score 
 2 for pustules/vesicles on palms or soles at screening and baseline, and an 
inadequate response to topical treatment therapy.   
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
During the double-blind placebo-controlled period of the study, all IP will be provided in 
blister cards.  Apremilast will be provided as 10, 20, and 30 mg tablets in the titration 
cards.  Placebo will be provided by the Sponsor as identically appearing 10, 20, and 
30 mg tablets. 


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During the active treatment period, apremilast will be provided as 10, 20, and 30 mg 
tablets in titration cards and 30 mg will be provided in bottles containing 80 tablets after 
titration.  Apremilast will be taken orally BID without food or drink restrictions.  To 
mitigate potential gastrointestinal side effects, dose titration will be implemented in a 
blinded manner during the first week of the study and during week 16 for subjects initially 
randomized to placebo who are switching to apremilast 30 mg BID treatment. 
Dose modifications outside of the doses described above are not permitted in this study.  
Statistical Considerations 
Sample Size Considerations 
The sample size estimation is based on the results of the phase 2 study 
(CC-10004-PPP-001 [20200055]).  Assuming that a proportion of subjects achieve 
PPPASI-50 response of 40% and 65% at week 16 for the placebo group and the 
apremilast 30 mg BID group, respectively, a sample size of approximately 170 subjects 
in total (85 subjects per group) provides 90% power using a chi-square test with a 
2-sided alpha of 0.05.  A dropout rate of 5% is anticipated during the double-blind 
placebo-controlled period of the study. 
Planned Analyses 
The primary analysis will be performed after all subjects have completed the week 16 
visit (visit 8) or have been discontinued from the study.  An additional analysis will be 
conducted after all subjects have completed the week 24 visit (visit 10) or have been 
discontinued from the study.  At the end of the study, after all subjects have either 
completed the study or been discontinued, the final analysis will be performed.  The 
efficacy analyses will be performed on the ITT population. 
The primary endpoint is the achievement of PPPASI-50 at week 16.  Subjects who 
discontinued treatment prior to week 16 (due to lack of efficacy, an adverse event, or 
protocol deviation due to prohibited medication usage) will be considered as treatment 
failures and non-responders in the primary analysis.  Missing values of the data in which 
the treatment failures are considered as non-responders will be imputed using multiple 
imputation (MI). 
The treatment difference between the apremilast 30 mg BID group and the placebo 
group will be analyzed using the Cochran–Mantel–Haenszel (CMH) test, adjusting for 
the stratification factor at randomization.  The 2-sided p-value from the CMH test, the 
adjusted treatment difference in proportion using the weighted average of the treatment 


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CONFIDENTIAL  
 
 
differences across the strata, and the associated 2-sided 95% CI will be provided.  The 
statistical test will be 2-sided at the significance level of alpha  0.05. 
Secondary efficacy endpoints, such as the PPPASI total score change from baseline at 
week 16, will be analyzed using the mixed-effect model for repeated measures (MMRM) 
with treatment group, visit time, treatment-by-time interaction, and stratification factors 
as fixed effects, and the baseline value as a covariate. 
To control the overall Type I error rate at the 0.05 level (2-sided) for comparisons 
between the apremilast 30 mg BID group and the placebo group, a fixed-sequence 
testing procedure will be applied for efficacy endpoints.  Secondary efficacy endpoints 
will be statistically tested in the following order (change from baseline at week 16) if the 
primary analysis result is statistically significant:  
1. PPPASI total score 
2. PPSI total score 
3. Subject’s VAS assessment for PPP symptoms (pruritus) 
4. Subject’s VAS assessment for PPP symptoms (pain/discomfort) 
5. DLQI total score 
Further sequence will be prespecified in the statistical analysis plan (SAP) prior to the 
week 16 database lock. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
Null Hypothesis  
The treatment effect of apremilast 30 mg BID and placebo is equivalent. 
Alternative Hypothesis 
There is a difference in treatment effect between apremilast 30 mg BID and placebo.   
Sponsor Name:  Amgen Inc. 
 


Product:  Apremilast   
Protocol Number:  20200195 
Date:  15 April 2022 
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1.2 
Study Schema 
Figure 1-1.  Study Schema 
Safety follow-up 
period 30 days
Active treatment period 36 weeks
Double-blind, placebo-controlled 
period 16 weeks
Screening 
period up 
to 4 weeks
Ramdomization 1:1*
Apremilast 30 mg BID
Apremilast 30 mg BID
Apremilast 30 mg BID
Placebo BID 
Titration
Titration
*Stratified by subject’s rounded PPPASI total score (≤ 20/ 21-30/ ≥ 31) at baseline and focal infection status (yes/no) at baseline 
W-4
W0
W2
W4
W6
W8
W12
W16
W20
W24
W32
W44
W52
W56
Baseline
Primary endpoint: 
PPPASI-50
 
BID  twice daily; PPPASI  Palmoplantar Pustulosis Area and Severity Index; W  week 


Product:  Apremilast   
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1.3 
Schedule of Activities  
Table 1-1.  Schedule of Activities 
  
Screening 
Double-blind, placebo-controlled period 
Active treatment period 
Safety 
follow-upa 
Visit Number 
1 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ET 
14 
(Baseline) 
Week 
- 4 to 0 
0 
2 
4 
6 
8 
12 
16 
20 
24 
32 
44 
52 
30 Days after 
last dose 
Allowance (days) 
- 
+ 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 4 
± 4 
± 4 
± 4 
± 4 
 7 
GENERAL AND SAFETY ASSESSMENTS 
Informed consentc 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Complete medical 
historyd 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Disease historye 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Dental examinationf 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Status of smokingg 
X 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
Prior / concomitant 
medications and 
proceduresh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric evaluationi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 1 of 3 
Footnotes are defined on the last page of this table 
 


Product:  Apremilast   
Protocol Number:  20200195 
Date:  15 April 2022 
Page 17 of 99 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities 
  
Screening 
Double-blind, placebo-controlled period 
Active treatment period 
Safety 
follow-upa 
Visit Number 
1 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ET 
14 
 
 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
Week 
- 4 to 0 
0 
2 
4 
6 
8 
12 
16 
20 
24 
32 
44 
52 
30 Days after 
last dose 
Allowance (days) 
- 
+ 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 4 
± 4 
± 4 
± 4 
± 4 
 7 
GENERAL AND SAFETY ASSESSMENTS 
Pregnancy test and 
contraception 
education for females 
of childbearing 
potential j 
X 
X 
  
  
  
  
  
X 
  
  
  
  
X 
  
Vital signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height l 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
Complete physical 
examination m 
X 
  
  
  
  
  
  
 X 
  
  
  
  
X 
  
Limited physical 
examination n 
  
Xo 
X 
X 
X 
X 
X 
  
X 
X 
X 
X 
  
X 
LABORATORY ASSESSMENTS 
Hepatitis B and Cp 
X 
  
  
  
  
  
  
  
 
  
  
  
  
  
Clinical laboratory 
evaluations 
(Hematology/ 
Chemistry/Urinalysis)p 
X 
X 
  
  
  
X 
  
X 
 
X  
X  
  
X  
 X 
Urine Drug 
Screeningp 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
EFFICACY ASSESSMENTS 
PPPASIq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 2 of 3 
Footnotes are defined on the last page of this table. 


Product:  Apremilast   
Protocol Number:  20200195 
Date:  15 April 2022 
Page 18 of 99 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities 
  
Screening 
Double-blind, placebo-controlled period 
Active treatment period 
Safety 
follow-upa 
Visit Number 
1 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/ET 
14 
 
 
(Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
Week 
- 4 to 0 
0 
2 
4 
6 
8 
12 
16 
20 
24 
32 
44 
52 
30 Days after 
last dose 
Allowance (days) 
- 
+ 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 4 
± 4 
± 4 
± 4 
± 4 
 7 
EFFICACY ASSESSMENTS 
PPSI r 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SUBJECT REPORTED OUTCOMES / QUALITY OF LIFE 
Subject’s VAS 
assessment for PPP 
symptoms for palms 
and solest 
  
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
  
X 
X 
DLQI u 
  
X 
  
  
  
X 
  
X 
  
X 
X 
  
X 
  
PHARMACOKINETIC ASSESSMENTS 
BIOMARKER ASSESSMENTS 
STUDY TREATMENT 
Randomization (IRT)  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Dispense IP  
  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
  
  
Return and count IP 
tablets (IP 
accountability) 
  
  
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
Page 3 of 3 


Product:  Apremilast   
Protocol Number:  20200195 
Date:  15 April 2022 
Page 19 of 99 
CONFIDENTIAL  
 
 
BID = twice daily; ET = End of Treatment; IP = investigational product; PAO = pustulotic arthro-osteitis;
 PK = pharmacokinetic; PPP = Palmoplantar 
Pustulosis; PPPASI = Palmoplantar Pustulosis Area and Severity Index; PPSI = Palmoplantar Pustulosis Severity Index 
a. 
Subjects who discontinue treatment with IP or withdraw during the active or placebo-controlled treatment period will be asked to enter the 30-day safety follow-up period after the ET 
visit.  Once the study has ended, the investigator will report to Amgen any serious adverse event(s) suspected to be related to the investigational product that he becomes 
aware of.  Refer to Section 8.4.4 for additional details. 
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 starting within 5 years prior to screening must be taken. 
e. 
Disease history will capture the following information:  specific information regarding diagnosis, presence or absence of focal infection (eg, periapical pathosis, periodontitis, angina, 
and sinusitis), presence or absence of PAO, and presence or absence of PPP with nail.   
f. 
Dental examination must be conducted by a dentist during screening period, with data obtained if there is any or no dental focal infection (eg, chronic periapical periodontitis, chronic 
marginal periodontitis), 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 dental focal infections is preferred to study enrollment.  Focal infection status will 
be confirmed at baseline. 
g. 
Smoking history (years/ amount) and current status (yes/no and average number of packs/day). 
h. 
Inadequate response to any topical treatment should be confirmed. 
i. 
At any time when suicidal thoughts or suicide attempt is identified, evaluate the need for referral to psychiatrist and other actions, including discontinuations, as required in 
Section 8.4.3. 
j. 
See Section 11.5. 
k. 
See Section 8.4.1. 
l. 
See Section 8.2.5. 
m. 
See Section 8.2.4. 
n. 
A limited physical exam may be performed to evaluate an adverse event or for any reason at the discretion of the Investigator 
o. 
Presence of PAO and focal infection status will be assessed during the limited physical examination at baseline. 
q. 
See Section 11.8. 
r. 
See Section 11.9. 
 
t. 
Worst status between visit in which an assessment is scheduled and the previous visit should be recorded.  Indicated assessments should be performed for any tests, procedures, or 
consultations (PPPASI, PPSI, and
for palms and soles) for that visit.  See Section 11.11. 


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 20 of 99 
CONFIDENTIAL  
 
 
2. 
Introduction 
2.1 
Study Rationale 
The characteristic histopathological features of palmoplantar pustulosis (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 interleukin (IL)-17 as a promoter of neutrophil 
accumulation and activation (Yamamoto, 2009; Hagforsen et al, 2010).  Patients with 
PPP have both elevated serum tumor necrosis factor (TNF)-α, IL-17, IL-22, and IL8 
levels and elevated neutrophil and Th17 gene expression in the pustular skin (IL-8, 
IL-17A, IL-36G, IL-12A [p40], IL-17F, IL-22, IL-23B [p19], DEFB4A, and TNF-α) 
(Murakami, 2011).  Eccrine ducts, keratinocyte, and more inflammatory cell involvement 
is also suggested in PPP pathogenesis (Hagforsen et al, 2010; Murakami et al, 2014; 
Murakami et al, 2017).   
Although corticosteroids, active vitamin D3 ointments, and phototherapy (ultraviolet [UV] 
radiation therapy) are common PPP treatments, evidence showing their efficacy in 
moderate to severe PPP cases is quite limited, highlighting the need for optimal, 
convenient, and targeted therapeutic options for the disease (Kobayashi et al 2010).  By 
inhibiting phosphodiesterase-4 (PDE4), an enzyme prevalent in immune cells, 
apremilast is expected to inhibit the production of IL-17, IL-8, and several other 
inflammatory cytokines related to PPP pathogenesis.   
The efficacy of apremilast has also been reported in patients with synovitis, acne, 
pustulosis, hyperostosis osteitis (SAPHO) syndrome (Adamo, 2018).  One form of 
SAPHO syndrome, pustulotic arthro-osteitis (PAO), is a known complication of PPP, 
suggesting that apremilast may be an effective treatment in PPP patients with or without 
PAO (Sonozaki et al, 1981; Okubo, 2012; Okuno et al, 2018). 
Apremilast studies, CC-10004-PSOR-005, CC-10004-PSOR-008 (hereafter referred to 
as ESTEEM-1), and CC-10004-PSOR-009 (hereafter referred to as ESTEEM-2), 
showed improvement of palmoplantar disease status in subjects with palmoplantar 
psoriasis, a closely related dermatological condition (Bissonnette et al, 2016).  Efficacy 
was also demonstrated in Study CC-10004-BCT-002 for oral ulcers in subjects with 
Bechet’s Disease (BD) in which IL-17 and neutrophils play important roles (Hatemi et al, 
2019).   


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 21 of 99 
CONFIDENTIAL  
 
 
In a randomized, double-blind, placebo-controlled phase 2 study in Japan 
(Study CC-10004-PPP-001 [20200055]), apremilast showed efficacy in PPP treatment 
and safety and tolerability data was consistent with the known safety profile of 
apremilast.  The phase 3 study is intended to confirm the risk-benefit balance of 
apremilast in the treatment of PPP in Japanese patients.   
2.2 
Background 
2.2.1 
Disease 
Palmoplantar pustulosis is a chronic, inflammatory, and recurrent skin disease 
characterized by erythema, scaling, and pustule eruptions on the palm and sole 
(Misiak-Galazka et al, 2017; Misiak-Galazka et al, 2020; Murakami and Terui, 2020).  An 
inflammatory hyperkeratosis, PPP appears most commonly in middle-aged men and 
women, particularly those who are smokers (Kobayashi, 2010).  In 2010, the national 
prevalence of PPP was reported as 0.12% with 136 224 Japanese patients living with 
the disease (Kubota et al, 2015). 
Following the early appearance of erythema with pruritus, fluid-filled vesicles begin to 
form.  The blisters then gradually enlarge, becoming pustules enclosed by neutrophils 
that crust around the lesions before desquamating.  In some cases, exanthem on the 
exterior of palm, sole, and nail lesions are also observed (Tsuruta and Terui, 2016).  
The etiology of PPP remains unknown.  Palmoplantar pustulosis usually presents in 
patients without a personal or family history of pustular psoriasis (PsO).  There is still 
controversy surrounding whether PPP and localized PsO are distinct entities.  The 
absence of immunogenetic associations of PPP with PsO suggests that PPP may 
represent a separate entity (Murakami et al, 2010; Murakami and Terui, 2020).  
Palmoplantar pustulosis was also reclassified as an independent disease by the 
International Psoriasis Council in 2007 (Griffiths and Barker, 2007).       
2.2.2 
Current Treatment Options  
Topical treatments such as corticosteroids, active vitamin D3 ointments or phototherapy 
(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 


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 22 of 99 
CONFIDENTIAL  
 
 
comparison with the results seen in chronic plaque-type PsO (Terui et al, 2018; Ohtsuki 
et al, 2018). 
In patients with limited response to topical treatment, ultraviolet B (UVB) therapy 
(Narrowband UVB or Excimer), etretinate and guselkumab are often used.  Nonsteroidal 
anti-inflammatory drugs (NSAIDs), biotin, cyclosporine, bisphosphonate, methotrexate 
(MTX) or biologics are considered for the treatment of PAO.  In cases with clear 
pathogenesis and complicating factors, 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 is administered 
subcutaneously and can be used in limited Japanese hospitals.  Therefore, there is a 
high unmet medical need for an effective, convenient (eg, oral), and well tolerated 
treatment for moderate to severe PPP. 
2.2.3 
Amgen Investigational Product Background:  Apremilast 
Apremilast (AMG 407) is an oral, small-molecule PDE4 inhibitor that, through cyclic 
adenosine monophosphate elevation, intracellularly regulates a network of pro- and 
anti-inflammatory mediators, many of which have been implicated in PsO, psoriatic 
arthritis (PsA), inflammatory bowel disease, and PPP (Schett, 2010; Schafer, 2012).  Not 
only has apremilast reduced Th17 gene expression in the lesioned skin and peripheral 
blood of patients with PsO, the treatment has also directly inhibited IL-8 production, 
migration, and adherence to endothelium (Schafer, 2010; Schafer, 2012; Gottlieb, 2013; 
Schafer, 2015).  Clinical studies in North American, European, and Japanese subjects 
with PsO demonstrated that apremilast 30 mg BID similarly reduced peripheral IL-17 and 
IL-22 cytokine levels (Garcet, 2018).  
Apremilast is approved in 56 countries for the treatment of inflammatory conditions, 
including PsO, PsA, and oral ulcers associated with BD.   
A detailed description of the chemistry, pharmacology, efficacy, and safety of apremilast 
is provided in the Investigator’s Brochure/package insert. 
2.3 
Benefit/Risk Assessment 
Pivotal phase 3 studies demonstrated statistically significant and clinically meaningful 
improvement in the signs and symptoms of PsA, PsO, and BD in subjects given 
apremilast 30 mg BID.  The most commonly observed treatment-emergent adverse 


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 23 of 99 
CONFIDENTIAL  
 
 
events (reported in ≥ 5% of subjects) included diarrhea, nausea, headache, upper 
respiratory tract infections, and nasopharyngitis, most of which occurred within the first 
2 weeks of treatment and resolved within 4 weeks.  Most treatment-emergent adverse 
events were mild or moderate in severity and resolved during continued apremilast 
treatment.  The incidence of serious adverse events was low and comparable between 
apremilast and placebo treatment groups in placebo-controlled periods and was not 
driven by any single preferred term or specific individual organ toxicity.  The safety 
profile of apremilast is comparable across its approved indications of PsA, PsO, and BD. 
A phase 2 study (CC-10004-PPP-001 [20200055]) evaluated the risk and benefit of 
apremilast 30 mg BID in Japanese subjects with PPP.  The results from this phase 2 
study supported the efficacy of apremilast across multiple endpoints with safety and 
tolerability data consistent with the known safety profile of apremilast.  Based on these 
results this phase 3 confirmatory trial is being implemented. 
As of 20 March 2021, over 9000 subjects have received apremilast doses ranging from 
10 to 105 mg/day in various completed and ongoing clinical studies and more than 
736 035 unique patients worldwide have been treated with apremilast.  Frequently 
reported adverse events have included gastrointestinal disorders (diarrhea, nausea, 
vomiting, abdominal discomfort) and nervous system disorders (headache).  The 
benefit-risk balance of apremilast continues to remain favorable for approved indications.  
Amgen closely monitors the COVID-19 pandemic around the world.  As part of this 
effort, Amgen performs a rigorous assessment, considering the study design, patient 
safety, public health risk, benefit-risk assessment, as well as the burden on country 
healthcare systems.  Decisions are made on a study-by-study and country-by-country 
basis to minimize risk to patients and avoid undue burden on healthcare facilities.   
Patients who display symptoms consistent with COVID-19 infections or who have tested 
positive for COVID-19 should contact the investigator to ensure appropriate care as well 
as documentation and management of study activities. 
Amgen considers that it is important to continue the proposed development of apremilast 
in this study in order to advance potential therapy options for patients as rapidly as 
possible, while balancing this with appropriate measures to monitor and mitigate the 
potential impact of COVID-19. 
Subjects enrolled in this study are permitted to receive vaccinations for COVID-19. 


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 24 of 99 
CONFIDENTIAL  
 
 
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure and Prescribing Information for further 
data on apremilast. 
3. 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the efficacy of 
apremilast 30 mg twice daily (BID) 
compared with placebo in subjects 
with PPP 
 
Achieving at least 50% reduction 
from baseline in Palmoplantar 
Pustulosis Area and Severity 
Index (PPPASI) total score 
(PPPASI-50) at week 16 
Secondary 
 
To evaluate the efficacy of 
apremilast 30 mg BID compared 
with placebo in subjects with PPP 
 
Change from baseline in PPPASI 
total score at week 16 
 
Change from baseline in 
Palmoplantar Pustulosis Severity 
Index (PPSI) total score at 
week 16 
 
Change from baseline in subject’s 
Visual Analogue Scale (VAS) 
assessment for PPP symptoms 
(pruritis and pain/discomfort) at 
week 16 
 
Change from Baseline in 
Dermatology Life Quality Index 
(DLQI) total score at week 16 
 
To evaluate the safety and 
tolerability of apremilast 30 mg 
BID compared with placebo in 
subjects with PPP 
 
Treatment-emergent adverse 
events, serious 
treatment-emergent adverse 
events, and adverse events of 
interest 
 
Clinically significant changes in 
body weight, vital signs, and 
laboratory abnormalities 
 
Estimand for the Primary Endpoint 
The primary efficacy endpoint is the achievement of PPPASI-50 at week 16 and the 
main estimand is the difference between apremilast 30 mg BID and placebo in the 
proportion of PPPASI-50 responders at week 16 based on the intent-to-treat (ITT) 
population including all randomized subjects, where subjects who discontinue 


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 25 of 99 
CONFIDENTIAL  
 
 
investigational product (IP) due to lack of efficacy, adverse event, or use of 
protocol-prohibited medication are considered treatment failures.  
 
The target population of interest is Japanese subjects with PPP defined through 
the inclusion/exclusion criteria. 
 
The primary endpoint is the achievement of PPPASI-50 at week 16. 
 
Intercurrent events (IEs) are IP discontinuation due to lack of efficacy, adverse 
event, or protocol-prohibited medication use.  A subject will be considered a 
non-responder after any of the IEs. 
 
The summary measure is the difference in proportion of responders. 
 
Missing values of the data in which the treatment failures are considered as 
non-responders will be imputed using multiple imputation (MI) method.  
Estimand(s) for Secondary Endpoint(s) 
The main estimand for the secondary efficacy endpoints is the difference in change from 
baseline at week 16 in PPPASI total score, PPSI total score, subject’s VAS assessment 
for PPP symptoms (pruritus and pain/discomfort), and DLQI total score based on the 
ITT population in which subjects who discontinue the IP due to lack of efficacy, adverse 
event, or use of protocol prohibited medication are considered as treatment failures. 
 
The target population of interest is Japanese subjects with PPP defined through the 
inclusion/exclusion criteria. 
 
The secondary endpoints are the change from baseline at week 16 in PPPASI total 
score, PPSI total score, subject’s VAS assessment for PPP symptoms (pruritus and 
pain/discomfort), and DLQI total score. 
 
The IEs are IP discontinuation due to lack of efficacy, adverse event, or use of 
protocol prohibited medication.  The baseline value will be assigned to the data after 
any of the IEs through week 16 regardless of the observed data. 
 
The summary measure is the mean difference in change from baseline. 
The data where the baseline value is assigned for the treatment failures will be used for 
the analysis model based on the assumption of missing at random (MAR) (eg, 
mixed-effect model for repeated measures (MMRM).  


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 26 of 99 
CONFIDENTIAL  
 
 
 
Exploratory 
 
 
4. 
Study Design 
4.1 
Overall Design 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
Approximately 170 subjects will be enrolled in the study, with subjects being randomized 
in a 1:1 ratio to 1 of 2 treatment arms:  apremilast 30 mg BID or placebo.  Subject 


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 27 of 99 
CONFIDENTIAL  
 
 
randomization will be stratified by a subject’s rounded PPPASI total score 
( 20/ 21 - 30/ 31) at baseline and baseline focal infection status (yes/no).  
Randomized subjects will receive either apremilast 30 mg BID or placebo for 16 weeks, 
the duration of the double-blind placebo-controlled treatment period.  During the active 
treatment period (week 16 to week 52), all subjects will receive apremilast 30 mg BID.  
The dose titration procedure (in line with the label) will be implemented for all subjects 
over a 5-day period at week 0 (the beginning of the double-blind placebo-controlled 
treatment period) and at week 16 (the beginning of the active treatment period) to 
mitigate potential gastrointestinal side effects and to maintain blinding.  
After the final dose treatment, subjects will enter a 30-day safety follow-up period.  The 
total study duration per subject is approximately 60 weeks.  
The primary analysis will be performed after the last subject has completed the week 16 
visit (visit 8) or study discontinuation.  An additional analysis will be conducted after all 
subjects have completed the week 24 visit (visit 10) or have been discontinued from the 
study.  The final analysis will be conducted after all subjects have either completed or 
discontinued the study. 
Approximately 45 sites in Japan are planned to participate in the study.  Sites that do not 
enroll a subject within 6 months of site initiation may be closed.  
Participants in this clinical investigation shall be referred to as “subjects”.  For the 
sample size justification, see Section 9.2. 
4.2 
Patient Input into the Study Design 
Patient input was not obtained in the design of this study.  
4.3 
Justification for Dose 
4.3.1 
Justification for Investigational Product Dose 
In this study, apremilast 30 mg BID, after a 5-day dose titration, will be evaluated.  This 
dose was approved in Japan for PsA, PsO, and BD-associated oral ulcer treatment.  
Compared with placebo, apremilast 30 mg demonstrated significant efficacy and safety 
in clinical study subjects with PsO (CC-10004-PSOR-005 [Papp et al, 2012], ESTEEM-1 
[Papp et al, 2015], ESTEEM-2 [Paul et al, 2015], CC-10004-PSOR-011 [Ohtsuki et al, 
2017]), PsA (CC-10004-PSA-002 [PALACE-1] [Kavanaugh et al, 2015], 
CC-10004-PSA-003 [PALACE-2] [Cutolo et al, 2016], CC-10004-PSA-004 [PALACE-3] 
[Edwards et al, 2016]), BD (CC-10004-BCT-001 [Hatemi et al, 2015], 
CC-10004-BCT-002 [Hatemi et al, 2018].  A phase 2 PPP study (CC-10004-PPP-001 


Product:  Apremilast  
Protocol Number:  20200195  
Date:  15 April 2022 
Page 28 of 99 
CONFIDENTIAL  
 
 
[20200055]) evaluated the risk and benefit of apremilast 30 mg BID in Japanese 
subjects.  The results from this study supported the efficacy and safety of apremilast 
30 mg BID in Japanese subjects.  Apremilast can be administered whether in a fasting 
or fed state.  
Apremilast PK, safety, and tolerability has been evaluated in a phase 1 study (CP-018) 
in healthy Japanese, Chinese (living in the United States), and white (Western) subjects 
after a single-dose administration of apremilast 20 or 40 mg.  Results from this phase 1 
study demonstrated that dose‑normalized apremilast exposures in healthy Japanese 
and Chinese subjects were similar to dose‑normalized exposures in healthy white 
subjects, thus suggesting that apremilast PK is not expected to be different between 
Japanese and white subjects. 
In addition, apremilast population PK analyses in white subjects with PsO 
(CC-10004-PSOR-005) and Japanese subjects with PsO (CC-10004-PSOR-011) 
demonstrated that the steady-state (ss) exposures (AUCtau [ss] and Cmax [ss]) in 
Japanese subjects at doses of 20 mg BID and 30 mg BID were comparable to the 
values observed in non-Japanese (white subjects), demonstrating that ethnic factors do 
not significantly affect the PK of apremilast.  The PK of apremilast was similar in 
Japanese and non-Japanese subjects following the same dosing regimen in subjects 
with BD-associated oral ulcers (CC-10004-BCT-002).  
In summary, based on the available PK, efficacy, and safety data from several clinical 
studies in healthy Japanese and white subjects (CC-10004-CP-018), Japanese and 
non-Japanese subjects with moderate-to-severe PsO (CC-10004-PSOR-011, 
ESTEEM-1, and ESTEEM-2), BD (BCT-002), as well as Japanese subjects with PPP 
(PPP-001 [20200055]) suggests that exposures associated with a 30 mg BID dose of 
apremilast is expected to provide maximal efficacy in Japanese subjects with PPP, with 
a manageable safety profile. 
4.4 
End of Study 
An individual subject is considered to have completed the study if he/she has completed 
the last visit or the last scheduled procedure shown in the Schedule of Activities.  The 
total study duration for an individual subject is up to 60 weeks. 
The end of study date is defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit). 


Product:  Apremilast  
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5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Japanese subjects ≥ 18 years of age upon entry into initial screening 
103 
Palmoplantar pustulosis diagnosis with or without PAO for no less than 24 weeks 
before screening.  All 3 of the following diagnosis criteria must be fulfilled:   
 
Sterile pustules located on palms and/or soles,  
 
change from blister to pustule via pustule-vesicles with progression of 
disease, and 
 
repeat recurrence at the same skin location showing the chronic course 
profile (for at least 6 months).  
104 
PPPASI total score of 12 at screening  
105 
PPPASI total score of  12 at baseline 
106 
Moderate or severe pustules/vesicles on palms or soles (PPPASI severity score 
 2) at screening  
107 
Moderate or severe pustules/vesicles on palms or soles (PPPASI severity score 
 2) at baseline 
108 
Inadequate response (defined as repeated relapsing-remitting in the same 
location for a 24-week period) to topical treatments prior to or at screening. 
109 
Meet the following lab criteria at screening:  
 
White blood cell count ≥ 3000/mm3 (≥ 3.0 x 109 /L) and ≤ 14,000/mm3 
(≤ 14 x 109 /L),  
 
Platelet count ≥ 100,000/µL (≥ 100 x 109 /L), 
 
Serum creatine ≤ 1.5 mg/dL (≤ 132.6 µmol/L), 


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 
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), 
 
Total bilirubin ≤ 2.0 mg/dL, and 
 
Hemoglobin > 9 g/dL 
110 
Agree to avoid prolonged sun exposure and avoid the use of tanning booths or 
other ultraviolet light sources to the palms and/or soles during the study 
111 
Agree to not make extreme changes to lifestyle habits (eg, exercise, diet, and 
smoking) during the study 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Changes in disease severity during screening (PPPASI total score change ≥ 5 
improvement, from screening to baseline) 
202 
Periodontitis requiring treatment such as any endodontic treatment for periapical 
pathosis (chronic periapical periodontitis), infected root canal treatment, tooth 
extraction, and periodontal surgery for moderate to severe periodontitis (chronic 
marginal periodontitis) 
203 
Chronic or recurrent tonsillitis or sinusitis requiring any continuous treatment for 
≥ 4 weeks or repeated and acute tonsillitis or sinusitis requiring treatment for 
≥ 4 weeks; 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. 
204 
Has a diagnosis of plaque-type psoriasis at baseline 
205 
Has the presence of pustular psoriasis on any part of the body other than the 
palms and soles (excluding those derived from PPP) at baseline 
206 
Has evidence of skin conditions of hand and feet at baseline that would interfere 
with evaluations of the effect of Investigational Product 
Other Medical Conditions 
207 
Positive for hepatitis B virus surface antigen (HBsAg) or positive for anti-hepatitis 
B core antibody (HBcAb) and anti-HBeAg antibody (HBeAb) with Hepatitis B 
virus DNA detected (indicative of chronic or acute hepatitis B)  
208 
Positive for hepatitis C antibody (HCVAb) and hepatitis C virus RNA is detected 
209 
Has unstable cardiovascular disease, defined as a recent clinical deterioration 
(eg, unstable angina, atrial fibrillation) or a cardiac hospitalization within 
12 weeks prior to screening 
210 
Malignancy or history of malignancy, except for treated (eg, cured) basal cell or 
squamous cell in situ skin carcinomas or cervical intraepithelial neoplasia or 
carcinoma in situ of the cervix with no evidence of recurrence within 5 years prior 
to screening 


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211 
Has significant viral or fungal infections or bacterial infections requiring treatment 
with oral or injectable antibiotics within 4 weeks of baseline.  Any treatment for 
such infections must have been completed at least 4 weeks prior to baseline 
212 
Has active tuberculosis (TB) or a history of incompletely treated TB at baseline 
213 
Has a history of positive human immunodeficiency virus (HIV) or has congenital 
or acquired immunodeficiency (eg, common variable immunodeficiency disease) 
at baseline 
Prior/Concomitant Therapy 
214 
Subject’s current or planned use of excluded treatments.  For excluded 
treatments, see Section 6.1.4 
215 
Subject has received any procedures for focal infection (eg, tonsillectomy and 
dental therapy) within 24 weeks of baseline.  Examples of dental therapy:  
treatment for periodontitis include 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). 
Prior/Concurrent Clinical Study Experience 
216 
Currently receiving treatment in another investigational device or drug study, or 
less than 5 pharmacokinetic/pharmacodynamic half-lives of investigational study 
drug since ending treatment on another investigational device or drug study(ies).  
Other investigational procedures while participating in this study are excluded. 
Other Exclusions 
217 
Female subjects of childbearing potential unwilling to use protocol specified 
method of contraception see Appendix 5 (Section 11.5) during treatment and for 
an additional 30 days after the last dose of Investigational Product 
218 
Female subjects who are breastfeeding or who plan to breastfeed while on study 
through 30 days after the last dose of Investigational Product 
219 
Female subjects planning to become pregnant while on study through 30 days 
after the last dose of Investigational Product 
220 
Female subjects of childbearing potential with a positive pregnancy test 
assessed by a highly sensitive urine or serum pregnancy test 
221 
Had prior treatment with apremilast 
222 
Has scheduled surgery or other interventions that would interrupt the subject’s 
participation in the study 
223 
Has active alcohol abuse, substance abuse, and/or recreational illicit drug use or 
has a history of alcohol abuse, substance abuse, and/or recreational illicit drug 
use within 12 months prior to screening based on medical records, patient 
self-report, or positive urine drug test performed during screening 
224 
Has a history of allergy to any of the products or components to be administered 
during dosing  
225 
Has a prior medical history of suicide attempt at any time in the subject’s lifetime 
prior to signing of informed consent or randomization, or major psychiatric illness 


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requiring hospitalization within the last 3 years prior to signing of informed 
consent 
226 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge 
227 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion 
5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject or the subject’s legally authorized representative must personally sign and 
date the IRB/IEC informed consent before commencement of study-specific procedures. 
Each subject who enters into the screening period for the study (screening period begins 
after the subject signs and dates the informed consent form) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned by interactive response technology (IRT).  
This number will be used to identify the subject throughout the clinical study and must be 
used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria and has been randomized into the study.  The investigator is to 
document this decision and date, in the subject’s medical record and in/on the Subject 
Enrollment Case Report Form (CRF). 
The sponsor may monitor enrollment into the prespecified strata.  Enrollment into any 
particular stratum may be paused to ensure the adequate representation of other strata 
in the study population, in line with study objectives. 
Sites that do not enroll subjects within 6 months of site initiation may be closed. 


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5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened.  Refer to Section 8.1.1. 
6. 
Study Intervention 
Study intervention is defined as any investigational product(s), non-investigational 
product(s), placebo, combination product(s), or medical device(s) intended to be 
administered to a study subject according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
A summary of the dosing and administration of each treatment is shown in Table 6-1 
below. 
6.1 
Study Interventions Administered 
6.1.1 
Investigational Products 


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Table 6-1.  Investigational Products 
Amgen Investigational Product:a 
Apremilast 
Placebo 
Dosage Formulation 
film-coated tablet; 10, 20, and 30 mg tablets in blister 
cards for double-blind, placebo-controlled period; 
30 mg tablets provided in bottles for the active 
treatment period 
Placebo will be presented in identical packaging, and 
stored/packaged the same as apremilast 
Unit Dose Strength(s) 
 
30 mg 
Placebo 
Dosage Level(s) 
 
BID 
BID 
Route of Administration 
 
Oral 
Oral 
Accountability 
The amount dispensed, amount returned, date dispensed, date returned, and lot number of Investigational 
Product(s) is to be recorded on each subject's CRF(s). 
 
Dosing Instructions 
 
Dosing will occur as follows: 
Day 1 AM:  10 mg 
Day 2 AM:  10 mg 
Day 2 PM: 10 mg 
Day 3 AM:  10 mg 
Day 3 PM:  20 mg 
Day 4 AM:  20 mg 
Day 4 PM:  20 mg 
Day 5 AM:  20 mg 
Day 5 PM:  30 mg 
Day 6 and thereafter AM:  30 mg 
Day 6 and thereafter PM:  30 mg 
Dosage Preparation 
 
N/A 
BID = twice daily; N/A = not applicable 
a Apremilast will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures. 


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6.1.2 
Other Protocol-required Therapies 
There are no other protocol-required therapies. 
6.1.3 
Product Complaints 
A product complaint 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 it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors or partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging drug containers, delivery systems, labeling, and inserts. 
This includes any investigational/non-investigational product(s), device(s) or combination 
product(s) provisioned and/or repackaged/modified by Amgen:  
Any product complaint(s) associated with an investigational product(s), 
non-investigational products(s), devices(s), or combination product(s) supplied by 
Amgen are to be reported. 
 
6.1.4 
Excluded Treatments and/or Procedures During Study Period 
Table 6-2.  Excluded Treatments and/or Procedures During Study Period 
Prohibited Treatment 
Time Period for Exclusion 
Strong cytochrome P450 3A4 (CYP3A4) 
enzyme inducers (eg, rifampin, phenobarbital, 
carbamazepine, phenytoin and St. John’s Wort) 
2 weeks or 5 times the half-life, whichever 
duration is longer, prior to randomization 
and until the end of active treatment  
Granulocyte and monocyte adsorption 
apheresis 
2 weeks prior to randomization until the end 
of active treatment 
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).  
2 weeks prior to randomization and during 
double-blind, placebo-controlled period; 
allowed after week 16  
Note:  Only use of topical antibiotics for the 
treatment after skin biopsy is permitted.  
Unmedicated skin moisturizer (eg, Vaseline) 
will be permitted as needed. 
Conventional systemic therapies that could 
affect PPP or the efficacy evaluation (including, 
but not limited to corticosteroids, antihistamine, 
antibiotics, JAK inhibitors, 1,25-dihydroxy 
vitamin D3 and analogues, psoralens, 
sulfasalazine, hydroxyurea, dimethyl fumarate, 
biotin, or colchicine) 
4 weeks prior to randomization until end of 
active treatment 
 
Note:  Systemic antihistamines are allowed 
after week 16 
Systemic therapy for PAO including, but not 
limited to bisphosphonates, 
4 weeks prior to randomization and until 
end of active drug treatment period 


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immunosuppressants [eg, MTX, azathioprine, 
cyclosporine or 6-thioguanine, mercaptopurine, 
mycophenolate mofetil, tacrolimus]) and other 
biologics (eg, anti-IL1 antibody)  
 
Note:  Background stable doses of NSAIDs 
for treatment of PAO are permitted. 
Page 1 of 2 


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Table 6-2.  Excluded Treatments and/or Procedures During Study Period 
Prohibited Treatment 
Time Period of Exclusion 
Prolonged sun exposure or used tanning booths 
or other ultraviolet light sources 
4 weeks prior to randomization and until the 
end of active treatment period 
Biologic therapy such as: 
TNFα or IL17 blockers (eg, 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 and other biologics 
 
12 weeks or 5 times the half-life, whichever 
duration is longer, prior to randomization 
and until end of active treatment period. 
24 weeks OR 5 times the half-life, 
whichever duration is longer, prior to 
randomization and until end of active 
treatment period. 
Phototherapy (ultraviolet B radiation [UVB] or 
psoralen ultraviolet A radiation [UVA]) 
4 weeks prior to randomization; allowed 
after week 16 during drug treatment period  
The following focal infection treatments for PPP 
(but not limited to): 
 
Tonsillectomy for tonsils 
 
Endodontic treatment for periapical pathosis 
 
Periodontal surgery for moderate to severe 
periodontitis 
24 weeks prior to baseline until the end of 
active treatment period 
Note:  Dental therapy (non-invasive dental 
care [eg, scaling and root planning for 
periodontal disease]) is permitted 
throughout the study 
Systemic retinoids (eg, etretinate) 
2 years prior to randomization for females of 
childbearing potential, 4 weeks prior to 
randomization for females of 
non-childbearing potential, and 6 months 
prior to randomization for males until end of 
active treatment period. 
Page 2 of 2 
 
6.2 
Preparation/Handling/Storage/Accountability 
Guidance and information on drug accountability for the investigational product will be 
provided to the site. 
6.3 
Measures to Minimize Bias:  Randomization and Blinding 
6.3.1 
Method of Treatment Assignment 
Subjects will be randomized in 1:1 allocation ratio to apremilast or placebo in a 
double-blind manner after meeting all randomization requirements. 
Subject randomization for treatment assignments will be stratified according to a 
subject’s rounded PPPASI total score ( 20/21 to 30/ 31) at baseline and whether a 
subject has any focal infection at baseline (yes/no).  


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The randomization will be performed by and the randomization number will be provided 
by IRT.  
The randomization date is to be documented in the subject’s medical record and on the 
Subject Enrollment CRF. 
6.3.2 
Blinding 
This is a double-blind study.  Unblinding information consists of subject treatment 
assignments, including contents of investigational product boxes (eg, manufacturing lot 
number), and potentially unblinding data (PUBD) which has the potential to indicate 
treatment assignment for an individual subject.  Unblinding information will be blinded to 
all subjects, site personnel, and Amgen as described below (Section 6.3.2.1 and 
Section 6.3.2.2). 
The following assessments will be considered unblinding information: 
 
Apremilast pharmacokinetic assessments (Section 8.5) 
 
Apremilast biomarker assessments (Section 8.6) 
6.3.2.1 
Site Personnel Access to Unblinding Information 
A subject’s treatment assignment is to only be unblinded by the investigator when 
knowledge of the treatment is essential for the further management of the subject on this 
study or may potentially impact the safety of the subject.  Unblinding at the study site for 
any other reason will be considered a protocol deviation.  It is encouraged that the 
Amgen Trial Manager be notified before the blind is broken unless the investigator 
believes that identification of the study treatment is required for a medical emergency.  If 
this is not possible, the Amgen Trial Manager must be notified within 24 hours after 
breaking the blind.  The date and reason that the blind was broken must be recorded in 
the source documentation. 
Unblinding information will not be accessible by investigative sites or subjects prior to the 
completion of the final analysis except for an emergency unblinding. 
6.3.2.2 
Access to Unblinding Information by Amgen or Designees 
Preidentified members of the clinical study team will be unblinded in order to conduct the 
primary analysis (Section 9.4.1.2).  Other members of the clinical study team will not 
have access to unblinding information until the completion of the final analysis. 
6.4 
Treatment Compliance 
When subjects self-administer apremilast at home, compliance with the treatment will be 
assessed at scheduled visits and documented in the source documents and CRF. 


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6.5 
Treatment of Overdose 
For this study, any dose 4 times greater than the treatment-specified dose within a 
24-hour time will be considered an overdose. 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the Amgen medical monitor immediately. 
2. Evaluate adverse events associated with overdose and document them in the 
CRF.  
3. Action will be taken for overdose associated adverse events if requested by the 
investigator or the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the 
overdose in the CRF. 
6.6 
Prior and Concomitant Treatment 
6.6.1 
Prior Treatment 
Prior therapies that were being taken/used for PPP (eg, topicals, systemics, 
phototherapy, etc.) within the last 5 years prior to randomization, will be collected.  For 
prior therapies that were being taken for PPP, collect therapy name, dose, unit, 
frequency, route, start date and stop date, and reason for discontinuation.  Prior focal 
infection and PAO therapies will be collected within the last 6 months (24 weeks) 
prior to randomization.  For prior therapies that were being taken for focal 
infection and PAO, collect therapy name, indication, dose, unit, frequency, route, 
start date, and stop date.  All other prior therapies that were being taken/used from 
4 weeks prior to screening through the first dose of IP, will be collected.  For all other 
prior therapies, collect therapy name, indication, dose, unit, frequency, route, start 
date, and stop date. 
6.6.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.4. 
Concomitant therapies are to be collected from day 1 through the 30-day post-treatment 
safety follow-up.  For all other concomitant therapies, collect therapy name, indication, 
dose, unit, frequency, route, start date, and stop date.  


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7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in Section 7. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally authorized representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies and/or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 1-1) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
and must document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product and/or other protocol-required therapies and/or 
procedures should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
decision by Sponsor 
 
lost to follow-up 
 
death 
 
adverse event 
 
subject request 
 
lack of efficacy 
 
protocol deviation 
 
pregnancy 


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7.2 
Subject Discontinuation/Withdrawal From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study and must document the 
subject’s decision to withdraw in the subject’s medical records.  Subjects who are 
withdrawn or removed from treatment or the study will not be replaced.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Table 1-1) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor 
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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 
For subjects who are lost to follow-up, the investigator should search publicly 
available records where permitted to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as 
possible. 
If the subject has missed more than 1 visit, and the actions above have been taken to 
contact the subject, then the subject will be considered lost to follow up. 


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8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 1-1).  
If an enrolled subject is subsequently determined to be ineligible for the study, this must 
be discussed with the sponsor immediately upon occurrence or awareness to determine 
if the subject is to continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment, and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject in the IRT and screen 
the subject in order to assess eligibility for participation.  The screening window is up to 
4 weeks. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 1 time.  
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 4-week 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 
after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1-1).  On-study visits may be 
completed as specified in the Schedule of Activities.  The date of the first dose of 
apremilast is defined as day 1.  All subsequent doses and study visits will be scheduled 


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based on the day 1 date.  Apremilast is to be administered during each visit that it is 
required. 
8.1.3 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, a safety 
follow-up visit will be performed approximately 30 days ( 7 days) after the end of the 
last dose of apremilast. 
8.1.4 
End of Study 
A subject is considered to have completed the study if he/she has completed all periods 
of the study including the last scheduled procedure / last follow up shown in the 
Schedule of Activities (Table 1-1). 
8.2 
General Assessments  
8.2.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
8.2.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarkers variability 
and pharmacokinetics of the protocol-required therapies. 
8.2.3 
Medical History 
The Investigator or designee will collect a complete medical history that started within 
5 years prior to enrollment through screening.  Medical history will include information on 
the subject's concurrent medical conditions.  Record all findings on the medical history 
CRF.  In addition to the medical history above, PPP history must date back to the 
original diagnosis.  The current severity will be collected for each condition that has not 
resolved. 
8.2.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 


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8.2.5 
Physical Measurements 
Height [in centimeters] should be measured without shoes.  Weight [in kilograms] should 
be measured without shoes.  Body Mass Index should be calculated using the following 
formula:  BMI (kg/m2) = weight (kg)/[height (cm)/100] 2. 
8.2.6 
Substance Abuse History  
Obtain a detailed history of prior and/or concurrent use of tobacco. 
8.3 
Efficacy Assessments 
8.3.1 
Subject and Physician-reported Outcomes/ Quality of Life 
Measurements 
8.3.1.1 
Palmoplantar Pustulosis Area and Severity Index (PPPASI) 
PPPASI is a disease-specific efficacy assessment tool used by Investigators established 
to detect a change of disease status on palms or soles (Section 11.8).  As sub-scores 
right/left palm and right/left sole are evaluated for 3 signs of the disease (erythema, 
pustules/vesicle and desquamation/scale). 
PPPASI produces numeric scores that can range from 0 to 72.  A higher score indicates 
more severe disease. 
8.3.1.2 
Palmoplantar Pustulosis Severity Index (PPSI) 
PPSI is a disease-specific efficacy assessment tools by Investigators (Section 11.9).  
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 baseline. 
PPSI produces numeric scores that can range from 0 to 12.  A higher score indicates 
more severe disease.  
8.3.1.4 
Pruritis and Pain/Discomfort Assessment with Subject Visual 
Analogue Scale (VAS) for PPP Symptoms 
Subjects will use VAS (with scores ranging from 0 to 100, with 100 being most severe) to 
assess the degree of PPP pain/discomfort and pruritus on the hands and feet 
(Section 11.11).   


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8.3.1.5 
Dermatology Life Quality Index (DLQI) 
DLQI is a skin disease-specific Quality of Life (QoL) questionnaire comprised of 10 items 
assessing the subject’s status over the previous week (Section 11.12).  DLQI can be 
used to assess 6 different aspects that may affect QoL:  symptoms and feelings, daily 
activities, leisure, work, or school performance, personal relationships, and treatment.  A 
numeric score ranging from 0 to 30 is produced with higher scores indicating increased 
disease severity. 
8.4 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 1-1). 
8.4.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  If abnormalities are found and they are 
considered to be an adverse event, record on the event CRF.  
8.4.2 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-1) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Events CRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a clinically significant change from the subject’s baseline values.  In general, 
abnormal laboratory findings without clinical significance (based on the investigator's 
judgment) are not to be recorded as adverse events.  However, laboratory value 


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changes that require treatment or adjustment in current therapy are considered adverse 
events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 1-1).  
8.4.3 
Suicidal Risk Monitoring 
Apremilast treatment is associated with increased depression adverse reactions.  Prior 
to apremilast use in subjects with a history of depression and/or suicidal thought or 
behavior, the Investigator should carefully weigh apremilast treatment risks and benefits.  
Evaluation of suicidal ideation and treatment-emergent suicidal ideation, new or 
worsening psychiatric symptoms will be assessed at scheduled visits during the study.  
Subjects should be advised to be alert for the emergence and/or worsening of 
depression, suicidal thoughts, or mood changes.  Should any changes occur, the 
Investigator should be contacted.  
If a subject suffers from new and/or worsening psychiatric symptoms, suicidal ideation, 
or attempt suicide, subject treatment discontinuation is recommended.  Any time suicidal 
thoughts or suicide attempts are identified, the need for psychiatrist referral and any 
other pertinent actions (including treatment discontinuation) should be evaluated.  
Psychiatric evaluation results should be recorded in the CRF.  
8.4.4 
Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of adverse events, and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 11.4. 
8.4.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.4.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Amgen Standard 
Grading Scale and is described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the end of study are reported using the Events CRF. 


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8.4.4.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 ( 7) days after the last day of the dosing interval of investigational 
product(s)/end of study/safety follow-up visit, whichever occurs later are reported using 
the Events CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s awareness of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 
8.4.4.1.3 
Serious Adverse Events After the Protocol Required Reporting 
Period 
There is no requirement to monitor study subjects for serious adverse events after 
the protocol-required reporting period (as defined in Section 8.4.4.1.2) or after end of 
study.  However, these serious adverse events should be reported to Amgen 
(regardless of causality) if the investigator becomes aware of them.  The investigator 
will report serious adverse events to Amgen within 24 hours following the investigator’s 
awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
If further safety related data is needed to fulfill any regulatory reporting requirements for 
a reportable event, then additional information may need to be collected from the 
subject’s records after the subject ends the study. 
8.4.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to inquire introduce bias when detecting adverse events and/or 
serious adverse events.  Open-ended and non-leading verbal questioning of the subject 
is the preferred method to about adverse event occurrence. 
8.4.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 


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otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Events CRF. 
8.4.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
For studies in which the treatment assignment is blinded, to comply with worldwide 
reporting regulations for serious adverse events, the treatment assignment of subjects 
who develop serious, unexpected, and related adverse events may be unblinded by 
Amgen before submission to regulatory authorities.  Aggregate analyses may also be 
unblinded by the Safety Assessment Team, as appropriate.  Investigators will receive 
notification of related serious adverse events reports sent to regulatory authorities in 
accordance with local requirements. 


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8.4.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.4.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects will be collected after the 
start of study treatment and until 30 days. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 11.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at screening and 
baseline for females of childbearing potential. 
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 11-2).  Refer to Section 11.5 for contraceptive requirements.  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.5 
Pharmacokinetic Assessments 
Subjects randomized to apremilast will have pharmacokinetic samples assessed.  Drug 
concentration values will unblind the individual treatment assignment and will not be 
reported to investigative sites or accessible by blinded study team personnel until the 
completion of the final analysis. 


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8.6 
Biomarkers 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
8.6.1 
Biomarker Discovery 
Samples will also be collected for biomarker analysis, eg, to evaluate potential 
biomarkers that may correlate with treatment response. 
8.6.1.1 
Biomarker Development/Future Research 
Biomarker Development refers to using samples collected for Biomarker Discovery for 
future research after the study ends. 
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity.   
Amgen or another third party may attempt to develop test(s) designed to identify 
subjects most likely to respond positively or negatively to apremilast to investigate and 
further understand PPP. 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
Null Hypothesis 
The treatment effect of apremilast 30 mg BID and placebo is equivalent. 
Alternative Hypothesis  
There is a difference in treatment effect between apremilast 30 mg BID and placebo.   
9.2 
Sample Size Determination 
The primary endpoint is the achievement of PPPASI-50 response at week 16.  The 
sample size estimation is based on the results of the phase 2 (CC-10004-PPP-001 
[20200055]) study.  Assuming a proportion of subjects achieving PPPASI-50 response at 
week 16 of 40% and 65% for the placebo group and the apremilast 30 mg BID group, 


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respectively, a sample size of approximately 170 subjects in total (85 subjects per group) 
provides 90% power using a chi-square test with a 2-sided alpha of 0.05.  A dropout rate 
of 5% during double-blind placebo-controlled treatment period is anticipated. 
9.3 
Populations for Analysis 
The following populations are defined: 
Population 
Description 
Intent-to-treat (ITT)  
The ITT population will include all randomized subjects.   
Subjects will be included in the treatment group to which they are 
randomized.  
Safety 
The safety population will include all randomized subjects who 
received at least 1 dose of IP. 
Subjects will be included in the treatment group corresponding to 
the IP they received. 
Pharmacokinetic 
The PK analysis population will include all randomized subjects 
who received at least 1 dose of apremilast and have an evaluable 
PK concentration. 
 
9.3.1 
Covariates 
Baseline value will be the covariate in the analysis model (eg, Mixed-effect Model for 
Repeated Measures [MMRM]) to derive within-group means and standard errors (SEs), 
treatment differences (from placebo) in means and SEs, and 95% CI. 
9.3.2 
Subgroups 
Subgroup analyses based upon baseline demographic and baseline disease 
characteristics including the stratification factors at randomization will be provided to 
determine the robustness of the treatment effect.  Details of the subgroup analyses will 
be specified in the statistical analysis plan (SAP). 
9.4 
Statistical Analyses 
The SAP will be developed and finalized before the week 16 database lock for the 
primary analysis.  Below is a summary of the timing and methods for the planned 
statistical analyses. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis will be conducted prior to the primary analysis.  After all subjects 
have either completed week 24 (visit 10) or discontinued the study, an additional 
supplemental analysis will be conducted. 


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9.4.1.2 
Primary Analysis 
The primary analysis will be performed after all subjects have either completed week 16 
or discontinued the study. 
9.4.1.3 
Final Analysis 
Final analysis will be conducted based on all study data collected after all subjects have 
either completed or discontinued the study. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Efficacy analyses will be performed on the ITT population by randomized treatment 
group and safety analyses will be performed on the safety population by actual treatment 
group, unless otherwise specified. 
Subject disposition, demographics, baseline characteristics, and exposure to IP will be 
summarized. 
Summary statistics for continuous variables including the number of subjects (n), mean, 
SD, median, the 25th (Q1) and 75th (Q3) percentiles, minimum, and maximum.  All mean 
and median values will be formatted to 1 more decimal place than the measured value.  
Standard deviation values will be formatted to 2 more decimal places than the measured 
value.  Minimum and maximum values will be presented to the same number of decimal 
places as the measured value.  Frequency summary for categorical variables includes 
number of percentages.  All percentages will be rounded to 1 decimal place.  Number 
and percentage values will be presented as xx (xx.x%). 


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9.4.2.2 
Efficacy Analyses 
 
Endpoint/ 
Estimand 
Statistical Analysis Methods 
Primary 
The primary efficacy endpoint is the achievement of PPPASI-50 at 
week 16 and the main estimand is the difference between apremilast 
30 mg BID and placebo in proportion of PPPASI-50 responders at 
week 16 based on the ITT population in which subjects who 
discontinue IP due to lack of efficacy, adverse event, or use of protocol 
prohibited medication are considered as treatment failures.  
 
The target population of interest is Japanese subjects with PPP 
defined through the inclusion/exclusion criteria. 
 
The primary endpoint is the achievement of PPPASI-50 at 
week 16. 
 
The IEs are IP discontinuation due to lack of efficacy, adverse 
event, or protocol-prohibited medication use.  A subject will be 
considered as a non-responder after any of the IEs. 
 
The summary measure is the difference in proportion of the 
responders. 
Missing values of the data in which the treatment failures are 
considered as non-responders will be imputed using multiple 
imputation (MI) method based on similar subjects who remained in the 
study. 
The treatment difference between apremilast 30 mg BID and placebo 
will be analyzed using the Cochran–Mantel–Haenszel (CMH) test 
adjusting for the stratification factor at randomization.  The testing will 
be conducted at the 2-sided 0.05 significance level and the adjusted 
treatment difference of the proportion of subjects achieving 
PPPASI-50 response, using the weighted average of the treatment 
differences across the strata, along with the associated 2-sided 
95 % CIs will be provided. 
Secondary 
The main estimand for the secondary efficacy endpoints is the 
difference in change from baseline at week 16 in PPPASI total score, 
PPSI total score, subject’s VAS assessment for PPP symptoms 
(pruritus and pain/discomfort), and DLQI total score based on the ITT 


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population in which subjects who discontinue the IP due to lack of 
efficacy, adverse event, or use of protocol prohibited medication are 
considered as treatment failures. 
 
The target population of interest is Japanese subjects with PPP 
defined through the inclusion/exclusion criteria. 
 
The secondary endpoints are the change from baseline at week 16 
in PPPASI total score, PPSI total score, subject’s VAS assessment 
for PPP symptoms (pruritus and pain/discomfort), and DLQI total 
score. 
 
The IEs are IP discontinuation due to lack of efficacy, adverse 
event, or use of protocol prohibited medication.  The baseline 
value will be assigned to the data after any of the IEs through 
week 16 regardless of the observed data. 
 
The summary measure is the mean difference in change from 
baseline. 
For the continuous efficacy secondary endpoints including change 
from baseline at week 16 in PPPASI total score, PPSI total score, 
subject’s VAS assessment for PPP symptoms (pruritus and 
pain/discomfort), and DLQI total score, the MMRM with treatment 
group, visit time, treatment-by-time interaction, and stratification 
factors as fixed effects, and the baseline value as a covariate will be 
applied.  The data where the baseline value is assigned for the 
treatment failures will be used for the MMRM analyses based on the 
assumption of MAR.  The least square (LS) means and standard 
errors (SEs) within-group and treatment differences (from placebo) in 
LS means, and SEs along with 95%CI and p-values will be derived 
from the MMRM. 
To control the overall Type I error rate at the 0.05 level (2-sided) for 
comparisons between the apremilast 30 mg BID group and the 
placebo group, a fixed-sequence testing procedure will be applied for 
efficacy endpoints.  Secondary efficacy endpoints will be statistically 
tested in the order following order (change from baseline at week 16) if 
the primary analysis result is statistically significant: 
1. PPPASI total score 
2. PPSI total score 
3. Subject’s VAS assessment for PPP symptoms (pruritus) 


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4. Subject’s VAS assessment for PPP symptoms 
(pain/discomfort) 
5. DLQI total score 
Further sequence will be prespecified in the SAP prior to the week 16 
database lock.  
Exploratory 
Will be described in the SAP finalized before the database lock for the 
primary endpoint. 
Additional estimand(s) providing additional treatment efficacy insight will be included in 
the SAP.  
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to discontinuation from investigational product or other 
protocol-required therapies, and treatment-emergent adverse events will also be 
provided.  Subject incidence of device-related events, if applicable, will be tabulated by 
system organ class and preferred term. 
9.4.2.3.2 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics over time.  
Shift tables of these safety laboratory parameters between baseline and worst on-study 
value will be provided. 
9.4.2.3.3 
Vital Signs 
The analyses of vital signs will include summary statistics over time.  Shifts in vital sign 
values of these safety vital sign parameters between baseline and worst on-study value 
will be provided. 
9.4.2.3.4 
Physical Measurements 
The analyses of physical measurements will include summary statistics over time. 
9.4.2.3.5 
Exposure to Investigational Product 
Exposure to and compliance with investigational product will be summarized using 
descriptive statistics. 


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9.4.2.3.6 
Exposure to Prior/Concomitant Medications and Procedures 
Number and proportion of subjects receiving prior/concomitant medications and 
procedures will be summarized by preferred term or category for each treatment group 
as coded by the World Health Organization Drug dictionary. 


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Apremilast Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
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Hagforsen E, Hedstrand H, Nyberg F, Michaëlsson G.  Novel findings of Langerhans 
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Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al.  Longterm (52-week) results of a 
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nouhousyou, chiryou senryaku souron].  Rinsho derma [Hifuka no Rinshou].  
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Kubota K, Kamijima Y, Sato T, Ooba N, Koide D, Iizuka H, et al.  Epidemiology of 
psoriasis and palmoplantar pustulosis:  a nationwide study using the Japanese national 
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Murakami M, Ohtake T, Horibe Y, Ishida-Yamamoto A, Morhenn VB, Gallo RL, et al.  
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pustulosis.  J Invest Dermatol.  2010;130(8):2010-2016. 
Murakami M, Kaneko T, Nakatsuji T, Kameda K, Okazaki H, Dai X, et al.  Vesicular 
LL-37 contributes to inflammation of lesional skin of palmoplantar pustulosis.  PLoS One.  
2014;9(10):e110677. 
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. 
Misiak-Galazka M, Wolska H, Rudnicka L.  What do we know about palmoplantar 
pustulosis?  J Eur Acad Dermatol Venereol.  2017;31:38-44. 
Misiak-Galazka M, Zozula J, Rudnicka L.  Palmoplantar Pustulosis:  Recent Advances in 
Etiopathogenesis and Emerging Treatments.  Am J Clin Dermatol.  2020;21:355-370. 
Murakami M, Terui T.  Palmoplantar pustulosis:  Current understanding of disease 
definition and pathomechanism.  J Dermatol Sci.  2020;98:13-19. 
Papp K, Cather JC, Rosoph L, Sofen H, Langley RG, Matheson RT, et al.  Efficacy of 
apremilast in the treatment of moderate to severe psoriasis:  a randomised controlled 
trial.  Lancet.  2012;380(9843):738-746. 
Papp K, Reich K, Leonardi CL, et al.  Apremilast, an oral phosphodiesterase 4 (PDE4) 
inhibitor, in patients with moderate to severe plaque psoriasis:  results of a phase III, 
randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of 
Apremilast in Psoriasis [ESTEEM] 1).  J Am Acad Dermatol.  2015;73(1):37-49. 
Paul C, Cather J, Gooderham M, et al.  Efficacy and safety of apremilast, an oral 
phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 
52 weeks:  a phase III, randomized controlled trial (ESTEEM 2).  Br J Dermatol.  
2015;173(6):1387-1399. 
Ohtsuki M, Okubu Y, Komine M, et al.  Apremilast, an oral phosphodiesterase 4 inhibitor, 
in the treatment of Japanese patients with moderate to severe plaque 
psoriasis:  efficacy, safety and tolerability results from a phase 2b randomized controlled 
trial.  J Dermatol.  2017;44(8):873-884. 
Ohtsuki M, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H.  Guselkumab, an 
anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe 
plaque-type psoriasis in Japanese patients:  efficacy and safety results from a phase 3, 
randomized, double-blind, placebo-controlled study.  J Dermatol.  
2018;45(9):1053-1062.  
Okubo Y.  Notable complications during the clinical course:  2)  Clinical feature and 
diagnosis of pustular arthritis and sternal arthritis (SAPHO syndrome) [Keikacyuu 
cyuuisubeki gappeisyou:  2.  Nouhouseikansetsuen, kyousa kansetsuen (SAPHO 
shoukougun) no rinshou to shindan].  Visual Dermatol.  2012;11(10):1030-1031. 
Okubo Y.  Therapy for palmoplantar pustulosis [Syouseki nouhousyou no chiryouhou].  
PPP Frontier.  2016;1:18-22. 


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Okuno H, Watanuki M, Kuwahara Y, Sekiguchi A, Mori Y, Hitachi S, et al.  Clinical 
features and radiological findings of 67 patients with SAPHO syndrome.  Mod 
Rheumatol.  2018;28(4):703-708. 
Rabin R, de Charro F.  ED-5D:  a measure of health status from the EuroQoL 
group.  Ann Med.  2001;33(5):337-343. 
Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, et al.  Apremilast, a 
cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and 
in a model of psoriasis.  Br J Pharmacol.  2010;159(4):842-855. 
Schafer PH.  Apremilast mechanism of action and application to psoriasis and psoriatic 
arthritis.  Biochem Pharmacol.  2012;83(12):1583-1590. 
Schafer PH, Chen P, Fang L, Wang A, Chopra R.  The pharmacodynamic impact of 
apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory 
biomarkers in patients with psoriatic arthritis:  Substudy results from a phase III, 
randomized, placebo-controlled trial (PALACE 1).  J Immunol Res.  2015; Article ID 
906349. 
Schett G, Sloan VS, Stevens RM, Schafer P.  Apremilast:  A novel PDE4 inhibitor in the 
treatment of autoimmune and inflammatory diseases.  Ther Adv Musculoskel Dis.  
2010;2(5):271-278. 
Sobell JM, Foley P, Toth D, Mrowietz U, Girolomont G, Goncalves J, et al.  Effects of 
apremilast on pruritus and skin discomfort/pain correlate with improvements in Quality of 
Life in patients with moderate to severe plaque psoriasis.  Acta Derm Venereol.  
2016;96(4):514-520. 
Sonozaki H, Mitsui H, Miyanaga Y, Okitsu K, Igarashi M, Hayashi Y, et al.  Clinical 
features of 53 cases with pustulotic arthro-osteitis.  Ann Rheum Dis.  
1981;40(6):547-553. 
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. 
Terui T, Zheng R, Morishima H, Goto R, Kimura T.  Interim results of phase 3 study 
demonstrating efficacy for guselkumab in subjects with palmoplantar pustulosis.  EADV 
2018. 12 Sep 2018, Abstract #P0422.  
Tsuruta D, Terui T.  Today’s clinical support, palmoplantar pustulosis [Kyou no rinsyou 
support, syouseki nouhousyou].  Elsevier Japan [updated 13 May 2016].  Available from:  
https://clinicalsup.jp/contentlist/1466.html. 
Yamamoto T.  Extra-palmoplantar lesions associated with palmoplantar pustulosis.  
J Eur Acad Dermatol Venereol.  2009;23(11):1227-1232.  


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11. 
Appendices 


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11.1 
Appendix 1.  List of Abbreviations 
 
Abbreviation 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUCtau 
area under plasma concentration-time curve for a dosing interval 
BD 
Bechet’s disease 
BID 
twice daily 
BMI 
Body Mass Index 
BUN 
blood urea nitrogen 
Cmax 
maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report forms 
CYP3A4 
cytochrome P450 3A4 
DLQI 
Dermatology Life Quality Index 
EMR 
electronic medical record 
ET 
end of treatment 
GCP 
good clinical practice 
HBcAB 
hepatitis B core antibody 
HCVAb 
hepatitis C antibody 
Hep 
hepatitis 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation 
IE 
intercurrent event 
IEC 
international ethics committee 
IL 
interleukin 
IP 
investigational product 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LS 
least square 
MAR 
missing at random 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MI 
multiple imputation 


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Abbreviation 
Explanation 
MMRM 
mixed-effect model for repeated measures 
MTX 
methotrexate 
N/A 
not applicable 
NSAIDS 
nonsteroidal anti-inflammatory drugs 
PAO 
pustulotic arthro-osteitis 
PDE4 
phosphodiesterase-4 
PK 
pharmacokinetic 
PPP 
palmoplantar pustulosis 
PPPASI 
Palmoplantar Pustulosis Area and Severity Index 
PPSI 
Palmoplantar Pustulosis Severity Index 
PsA 
psoriatic arthritis 
PsO 
psoriasis 
QoL 
quality of life 
QTL 
quality tolerance limit 
RBC 
red blood cell count 
rSDR/V 
remote Source Data Review and Verification 
SAP 
statistical analysis plan 
SAPHO 
synovitis, acne, pustulosis, hyperostosis osteitis syndrome 
SE 
standard error 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
ss 
steady-state 
TB 
tuberculosis 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
UV 
ultraviolet 
UVA 
ultraviolet A 
UVB 
ultraviolet B 
VAS 
Visual Analogue Scale 
WBC 
white blood cell count 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by central and local laboratory.  
Additional analyte test results may be reported by the local or central laboratory, in 
accordance with standard laboratory procedures (eg, components of a hematology 
panel). 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 


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Table 11-1.  Analyte Listing 
Central Laboratory:  
Chemistry 
Central Laboratory:  
Urinalysis 
Central Laboratory:  
Hematology 
Other Lab Analytes 
Sodium 
Potassium 
Chloride 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
Cholesterol 
HDL 
LDL 
Triglycerides 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
RBC 
Nucleated RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC 
Differential 
• Bands/stabs 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
• Myeloblasts 
• Neutrophils 
• Promyelocytes 
• Myelocytes 
• Metamyelocytes 
• Atypical lymphocytes 
Central Laboratory 
Hep B surface 
antigen 
Hep B core 
antibody 
Hep B envelope 
antigen 
Hep B envelope 
antibody 
Hep B DNA 
Hep C antibody 
Hep C RNA 
Serum pregnancyb 
 
Local Laboratory 
Urine drug 
screening  
HIVa 
Urine pregnancyb 
 
 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; HDL = high density lipoprotein; Hep = hepatitis; HIV = human immunodeficiency 
virus; LDH = lactate dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin 
time; RBC = red blood cell count; RDW = Red cell distribution width; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT - serum glutamic-pyruvic transaminase; WBC = white blood cell count 
a HIV assessment is recommended 
b Female of child-bearing potential only. 
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
Fasting is not required. 
 


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11.3 
Appendix 3.  Study Governance Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all protocol amendments and changes 
to the informed consent document that Amgen distributes to the site.  The investigator 
must send a copy of the approval letter from the IRB/IEC and amended protocol 
Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
During the course of the study, if new information becomes available that alters the 
benefit-risk of the study or the study drug, Amgen will follow applicable regulations to 
notify investigators, the IRB/IEC, and regulatory authorities, as appropriate. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 


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Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at their site.  Updates to the sample informed 
consent form are to be communicated formally in writing from the Amgen Trial Manager 
to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or their delegated representative will explain to the subject, or their 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have their primary care physician informed of 
the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of their 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 


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subject or a legally authorized representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 7. 
If important new information becomes available that may be relevant to the 
subject’s consent during their participation in the study, subjects will be 
re-consented.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
Subjects who are rescreened are required to sign a new informed consent form. 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period.  A separate 
signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
The subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 


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Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study. 
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to their study-related records, including personal 
information. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the Sponsor’s systems.  The 
Sponsor uses access-controlled systems to house, review and analyze subject data.  
These systems are backed-up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The Sponsor 
has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 
required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the Sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 


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Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, or the acquisition, analysis, or interpretation of data for the work; (2) drafting the 
work or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 


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adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Quality tolerance limit parameters (QTLs) will be predefined in the QTL definitions table 
to identify possible systematic issues that can impact participant safety and/or reliability 
of the study results.  These predefined parameters will be monitored during the study.  
Important deviations from the QTL threshold limits for these parameters and remedial 
actions taken will be summarized in the clinical study report. 


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Retention of study documents will be governed by the Clinical Trial Agreement. 
Case Report Forms (CRF) must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the IRT 
system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment or certain 
demographic information, such as gender, race, and ethnicity). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 


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Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Remote Source Data Review and Verification 
If permitted by national and/or local regulations, remote Source Data Review and 
Verification (rSDR/V) can be implemented.  The clinical monitor should be provided with 
a secure, read-only access to the Electronic Medical Record (EMR) system, including all 
modules relevant for review.  This access should be restricted to the records of only 
those patients who participate in the trial and who did not object to remote access to 
their medical records.  A list of the monitors to whom remote access has been granted 
should be maintained.  In order to prevent unauthorized access, access rights should be 
revoked once rSDR/V tasks have been completed for the trial.  The EMR system should 
have an audit trail and be able to log information on who accessed data and when.  
Remote access to the EMR should only be possible using a two-factor authentication. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by a separate protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 


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whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment. 
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Note:  Treatment-emergent adverse events will be defined in the Statistical 
Analysis Plan (SAP). 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the investigator (ie, 
not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as 
an adverse event/serious adverse event unless it is an intentional overdose taken 
with possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as adverse event or serious adverse event if they fulfill the definition of 
an adverse event or serious adverse event.  Also, “lack of efficacy” or “failure of 
expected pharmacological action” also constitutes an adverse event or serious 
adverse event. 
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 


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Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a preexisting condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 


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the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
 


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Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event Case Report Form (CRF). 
 
The investigator must assign the following mandatory adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
 
Dates of onset and resolution (if resolved); 
 
Did the event start prior to first dose of investigational product 
 
Assessment of seriousness; 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to apremilast, other protocol-required therapies 
and/or study-mandated activity and/or procedures; 
 
Action taken; and 
 
Outcome of event. 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor/responsible contact research organization (CRO) in 
lieu of completion of the Events CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on: 
The Amgen Standard Grading Scale as show below: 
Grade 
Definition 


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MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVEREa 
Incapacitating with inability to work or do usual activity 
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of a serious adverse event, NOT when it is rated as severe. 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product(s) protocol-required therapies, and/or study-mandated activity and/or 
procedure(s) and each occurrence of each adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in their assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change their opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 


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Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide [Amgen] with a copy of any postmortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Events 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system. 
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using a paper-based Serious Adverse Event 
Contingency Report Form (also referred to as the electronic Serious Adverse 
Event (eSAE) Contingency Report Form) (see Figure 11-1) within 24 hours of the 
investigator’s awareness of the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line 
to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC system has been taken off-line, then the site can report this information on 
the paper-based Serious Adverse Event Contingency Report Form (see 
Figure  11-1). 
 
Once the study has ended, serious adverse event(s) should be reported to 
Amgen (regardless of causality) if the investigator becomes aware of a serious 
adverse event.  The investigator should use the paper-based Serious Adverse 
Event Contingency Report Form to report the event. 
 
 
 


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form 
  
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for females of childbearing potential are 
outlined in Section 5.2.  Contraceptive use and methods should be consistent with local 
regulations for subjects participating in clinical studies. 
Female subjects of childbearing potential puberty should be advised of the pregnancy 
prevention requirements and the potential risk to the fetus if they become pregnant 
during treatment and for 30 days after the last dose of protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include documented 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  Females with 
documented permanent infertility due to an alternate medical cause (eg, Mullerian 
agenesis, androgen insensitivity, gonadal dysgenesis), can be considered not of 
childbearing potential. 
Note:  Bilateral tubal ligation/occlusion is not considered a permanent sterilization 
method. 
Note:  Documentation from the following sources is acceptable to provide confirmation of 
each sterilization method:  1) review of subject’s medical records; 2) subject’s medical 
examination; or 3) subject’s medical history interview. 
A postmenopausal female is defined as: 
 
A woman of ≥ 55 years with no menses for 12 months without an alternative medical 
cause OR 
 
A woman age < 55 years with no menses for at least 12 months and with a 
follicle-stimulating hormone (FSH) level within the definition of “postmenopausal 
range” for the laboratory involved.  In the absence of 12 months of amenorrhea, 
confirmation with more than 1 FSH measurement is required. 


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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 30 days. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form must be submitted to Amgen Global Patient Safety within 24 hours of the 
site’s awareness 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 protocol-required therapies through 30 days of the 
study drug.  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 pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an adverse event or serious adverse event.  Abnormal 
pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal death, congenital 
anomalies) will be reported as an adverse event or serious adverse event.  Note that 
an elective termination with no information on a fetal congenital malformation or 
maternal complication is generally not considered an adverse event, but still must be 
reported to Amgen as a pregnancy exposure case. 
 
Any serious adverse event occurring as a result of a poststudy pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 


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investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment while pregnant (see Section 7.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
30 days after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-2) must be 
submitted to Amgen Global Patient Safety within 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. 


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Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 30 days. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
awareness of the event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 217. 
 
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 protocol-required therapies 30 days after discontinuing protocol-required 
therapies. 


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Figure 11-2.  Pregnancy and Lactation Notification Forms 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Activities (Table 1-1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of biomarker discovery or biomarker development are not 
placed in the subject’s medical record and are not to be made available to the subject, 
members of the family, the personal physician, or other third parties, except as specified 
in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 


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longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
11.7 
Appendix 7.  Protocol-specific Anticipated Serious Adverse Events 
Anticipated serious adverse events are events that are anticipated to occur in the study 
population at some frequency independent of investigational product exposure and do 
not need to be reported individually as an United States Food and Drug Administration 
(FDA) Investigational New Drug (IND) safety report by the sponsor.  Identification and 
reporting of anticipated serious adverse events is the responsibility of the sponsor; the 
investigator is responsible for reporting adverse events and serious adverse events as 
described in Section 8.4.4 and Appendix 11.4. 
Anticipated Serious Adverse Events for Study 20200195 
MedDRA Preferred Terma 
Diarrhea 
Abdominal Pain 
a Exact Preferred Term according to MedDRA Version 24.0 


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11.8 
Appendix 8.  Palmoplantar Pustulosis Area and Severity Index 
(PPPASI) 
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)  
E = erythema; P = pustules/vesicle; D = desquamation/scale 
References:  Bhushan, 2001. 
 
 
 


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11.9 
Appendix 9.  Palmoplantar 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 baseline.  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 = pustules/vesicle and D = desquamation/scale 
The total score ranges from 0 to 12. 
Modified from:  Terui, 2018. 
 


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11.11 
Appendix 11.  Visual Analogue Scale (VAS) —PPP Symptoms for 
Palms and Soles 
Subject’s assessment for pruritus of palms and soles:   
At its worst, how much itch (on palms and soles) have you had because of your 
condition between the last visit and this visit? 
 
 
 
Subject’s assessment for pain of palms and soles: 
At its worst, how much skin discomfort/pain (on hands and feet) have you had 
because of your condition between the last visit and this visit? 
 
0 
100 
Please use a vertical stroke 
No itch  
at all 
Worst itch 
imaginable 


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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 pain  
at all 
Worst possible 
pain 


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11.12 
Appendix 12.  Dermatology Life Quality Index (DLQI) 
 


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Product:  Apremilast 
Protocol Number:  20200195 
Date:  15 April 2022 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Superseding Amendment 2 
Protocol Title:  A Phase 3, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Efficacy and Safety of Apremilast 
(AMG 407) in Japanese Subjects with Palmoplantar Pustulosis (PPP) 
 
Amgen Protocol Number 20200195 
 
Amendment Date: 
15 April 2022 
 
Rationale: 
This protocol is being amended to make changes including, but not limited to, the 
following: 
 
Update the age of inclusion to  18 years of age to follow the updated Japan Civil 
Code. 
 
 
Change “observational follow-up period” to “safety follow-up period” throughout the 
protocol to align with current Amgen standard language. 
 
Update the protocol to correct “IL-17” to “Th17” in Section 2.2.3 Amgen 
Investigational Product Background:  Apremilast. 
 
Update the protocol to clarify that “pain” is intended to capture “pain/discomfort.” 
 
Update the safety follow-up (SFU) period to 30 ( 7) days throughout the protocol to 
align with Amgen requirements. 
 
Update Section 6.5 Treatment of Overdose to clarify that any dose of apremilast 
greater than 4 times the treatment-specified dose within 24 hours will be considered 
an overdose to align with the overdose definition in the apremilast program. 
 
Update Section 6.6.1 Prior Treatment to change “procedures” to “therapies” to 
ensure both procedures and medications are captured.  Added the collection of 
pustulotic arthro-osteitis (PAO) therapies within the last 6 months (24 weeks) prior to 
randomization.  Updated “baseline” to “randomization” for consistency throughout the 
protocol and clarified prior treatment collection within the section. 
 
 
Update Appendix 2:  Clinical Laboratory Tests (Section 11.2) to include neutrophils. 
 
Update reconsent language in Appendix 3:  Study Governance Considerations, 
Informed Consent Process (Section 11.3) to state that subjects will be reconsented if 
important new information becomes available that may be relevant to the subject’s 
consent during their participation in the study. 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Update adverse event and serious adverse event reporting language throughout 
protocol to align with current Amgen protocol template. 
 
Update sample pregnancy and lactation notification forms. 
 
Make typographical, formatting, and editorial changes throughout the protocol. 


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Protocol Number:  20200195 
Date:  30 March 2022 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Phase 3, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Efficacy and Safety of Apremilast 
(AMG 407) in Japanese Subjects with Palmoplantar Pustulosis (PPP) 
 
Amgen Protocol Number 20200195 
 
Amendment Date: 
30 March 2022 
 
Rationale: 
This protocol is being amended to make changes including, but not limited to, the 
following: 
 
Update the age of inclusion to  18 years of age to follow the updated Japan Civil 
Code. 
 
 
Change “observational follow-up period” to “safety follow-up period” throughout the 
protocol to align with current Amgen standard language. 
 
Update the protocol to correct “IL-17” to “Th17” in Section 2.2.3 Amgen 
Investigational Product Background:  Apremilast. 
 
Update the protocol to clarify that “pain” is intended to capture “pain/discomfort.” 
 
Update the safety follow-up (SFU) period to 30 ( 7) days throughout the protocol to 
align with Amgen requirements. 
 
Update Section 6.5 Treatment of Overdose to clarify that any dose of apremilast 
greater than 4 times the treatment-specified dose within 24 hours will be considered 
an overdose to align with the overdose definition in the apremilast program. 
 
Update Section 6.6.1 Prior Treatment to change “procedures” to “therapies” to 
ensure both procedures and medications are captured.  Added the collection of 
pustulotic arthro-osteitis (PAO) therapies within the last 6 months (24 weeks) prior to 
randomization.  Updated “baseline” to “randomization” for consistency throughout the 
protocol and clarified prior treatment collection within the section. 
 
 
Update Appendix 2:  Clinical Laboratory Tests (Section 11.2) to include neutrophils. 
 
Update reconsent language in Appendix 3:  Study Governance Considerations, 
Informed Consent Process (Section 11.3) to state that subjects will be reconsented if 
important new information becomes available that may be relevant to the subject’s 
consent during their participation in the study. 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  30 March 2022 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Update adverse event and serious adverse event reporting language throughout 
protocol to align with current Amgen protocol template. 
 
Make typographical, formatting, and editorial changes throughout the protocol. 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  30 July 2021 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 1 
Protocol Title:  A Phase 3, Multicenter, Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Efficacy and Safety of Apremilast (AMG 407) in 
Japanese Subjects with Palmoplantar Pustulosis (PPP) 
 
Amgen Protocol Number 20200195 
 
Amendment Date: 
30 July 2021 
 
Rationale: 
The purpose for this amendment is to reflect changes requested by the Japan 
Pharmaceuticals and Medical Devices Agency.  The following changes were made to 
the protocol, dated 29 June 2021: 
 
An analysis at week 24 was added to fulfill the requirement for at least 6 months of 
efficacy and safety data for all patients being evaluated (Sections 4.1, 9.4, 9.4.1.1, 
and 9.4.2.2) 
 
This amendment also includes the following minor updates: 
o Change the order of exclusion criteria (Section 5.2) 
o Clarification to subject enrollment and randomization (Section 5.3) 
o Change the information collected from screen failures (Section 5.4) 
o Clarification of timeframe prior treatments are collected (Section 6.6.1) 
o Clarifications on the biomarkers (Sections 8.6.1.1 and Appendix 6) 
o Correct the list of abbreviations (Appendix 1) 
o Modify the laboratory analyte listing (Table 11-1) 
 
Grammatical and typographical changes were made throughout the protocol. 
 
 

SAP_001.pdf: 
Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 1 of 46 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
A Phase 3, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Efficacy 
and Safety of Apremilast (AMG 407) in Japanese 
Subjects with Palmoplantar Pustulosis (PPP) 
Short Protocol Title: 
Phase 3, Randomized Study of Apremilast in 
Japanese Subjects with Palmoplantar Pustulosis 
Protocol Number: 
20200195 
NCT Number: 
N/A 
Authors: 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, United States  
SAP Date: 
Document Version 
Date 
Original (v1.0) 
Amendment (v2.0) 
03 August 2023 
25 September 2023 
NCT Number: NCT05174065
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 2 of 46 
CONFIDENTIAL 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
03AUG2023 
Amendment (v2.0) 
25SEP2023 
Changes 
1. Revise the table for exploratory
endpoints in section 2.1. And list all
the added exploratory endpoints in
section 10.
Rationale: to keep all the added
exploratory endpoints in Section
10.
2.
Rationale: to be consistent with
protocol defined subgroups.
3. Reword the baseline definition for
the apremilast exposure period in
section 5.3.3.
Rational: to improve clarity.
4.
5. Reword the language about the
listing for COVID-19 related PD in
section 9.3.
Rationale: to improve clarity.
6. Reword the analysis description for
the primary endpoint in section
9.5.1, including table 9-1.
Rationale: to improve clarity and
consistency.
7. Remove the rounding in the first
step of MI in section 9.5.1
Rationale: rounding was included
as an error.
8. Update the analysis description for
the exploratory endpoints in
section 9.5.3, including table 9-3.
Rationale: to improve clarity and
consistency.


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 3 of 46 
CONFIDENTIAL  
 
 
9. Reword the AE categories in 
section 9.6.2. 
Rationale: to improve clarity. 
10. Reword the description in section 
9.6.4 and 9.6.5. 
Rationale: to improve clarity. 
11. Add vital signs, physical 
measurement and laboratory test to 
the analysis window in Appendix B. 
Rationale: to improve clarity. 
12. Typo, redundancies and 
inconsistencies are addressed 
across the document. 
 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 4 of 46 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Introduction ........................................................................................................... 10 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 10 
2.1 
Objectives and Endpoints/Estimands ........................................................ 10 
2.2 
Hypotheses and/or Estimations ................................................................. 13 
3. 
Study Overview .................................................................................................... 14 
3.1 
Study Design ............................................................................................. 14 
3.2 
Sample Size .............................................................................................. 14 
4. 
Covariates and Subgroups ................................................................................... 14 
4.1 
Planned Covariates ................................................................................... 14 
4.2 
Subgroups ................................................................................................. 15 
5. 
Definitions ............................................................................................................. 15 
5.1 
Safety Related Definitions ......................................................................... 15 
5.1.1 
Treatment-emergent Adverse Events (TEAEs) .......................... 15 
5.1.2 
Treatment-related Adverse Events (TRAEs) .............................. 15 
5.2 
Study Dates/Timelines .............................................................................. 16 
5.2.1 
Enrollment Date ......................................................................... 16 
5.2.2 
End of IP Admin Date ................................................................ 16 
5.2.3 
Last IP Dose Date ..................................................................... 16 
5.2.4 
Randomization Date .................................................................. 16 
5.2.5 
Study Day .................................................................................. 16 
5.2.6 
Study End Date ......................................................................... 16 
5.2.7 
Subject-level End of Study (EOS) Date ..................................... 16 
5.2.8 
Treatment duration .................................................................... 16 
5.3 
Baseline Related Definitions ..................................................................... 17 
5.3.1 
Change from baseline ............................................................... 17 
5.3.2 
Percent Change from Baseline .................................................. 17 
5.3.3 
Study Baseline .......................................................................... 17 
5.4 
Study Endpoints ........................................................................................ 17 
5.4.1 
Palmoplantar Pustulosis Area and Severity Index 
(PPPASI) ................................................................................... 17 
5.4.2 
Palmoplantar Pustulosis Severity Index (PPSI) ......................... 18 
5.4.4 
Pruritis and Pain Assessment with Subject Visual 
Analogue Scale (VAS) for PPP Symptoms ................................ 19 
5.4.5 
Dermatology Life Quality Index (DLQI) ...................................... 19 
5.5 
Analysis Phases ........................................................................................ 20 


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Protocol Number:  20200195 
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CONFIDENTIAL  
 
 
6. 
Populations for Analysis........................................................................................ 21 
6.1 
Intent-to-treat Population ........................................................................... 21 
6.2 
Safety Analysis Population ........................................................................ 21 
6.3 
Study-specific Analysis Sets...................................................................... 21 
7. 
Planned Analyses ................................................................................................. 21 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 21 
7.2 
Primary Analysis ....................................................................................... 21 
7.3 
Supplemental Analysis .............................................................................. 21 
7.4 
Final Analysis ............................................................................................ 22 
8. 
Data Screening and Acceptance ........................................................................... 22 
8.1 
General Principles ..................................................................................... 22 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 22 
8.3 
Handling of Missing and Incomplete Data ................................................. 22 
8.3.1 
Missing Baseline ....................................................................... 22 
8.3.2 
Missing Post-Baseline Evaluation .............................................. 22 
8.3.3 
Missing and Incomplete Dates ................................................... 23 
8.4 
Detection of Bias ....................................................................................... 23 
8.5 
Outliers ..................................................................................................... 23 
8.6 
Distributional Characteristics ..................................................................... 24 
8.7 
Validation of Statistical Analyses ............................................................... 24 
9. 
Statistical Methods of Analysis.............................................................................. 24 
9.1 
General Considerations ............................................................................. 24 
9.2 
Subject Accountability ............................................................................... 25 
9.3 
Important Protocol Deviations ................................................................... 25 
9.4 
Demographic and Baseline Characteristics ............................................... 25 
9.4.1 
Demographics ........................................................................... 26 
9.4.2 
Baseline Disease Characteristics .............................................. 26 
9.4.3 
Medical History .......................................................................... 27 
9.4.4 
Prior and Concomitant Procedures ............................................ 27 
9.4.5 
Prior and Concomitant Medications ........................................... 27 
9.5 
Efficacy Analyses ...................................................................................... 29 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 29 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 31 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 32 
9.6 
Safety Analyses ........................................................................................ 34 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 34 
9.6.2 
Adverse Events ......................................................................... 34 
9.6.3 
Laboratory Test Results ............................................................ 37 
9.6.4 
Vital Signs ................................................................................. 37 
9.6.5 
Physical Measurements ............................................................ 38 
9.6.6 
Exposure to Investigational Product .......................................... 38 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
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CONFIDENTIAL  
 
 
9.6.7 
Exposure to Prior/Concomitant Medication and 
Procedures ................................................................................ 38 
9.7 
Other Analyses ......................................................................................... 39 
9.7.1 
Analyses of Pharmacokinetic Endpoints .................................... 39 
9.7.2 
Analyses of Biomarker Endpoints .............................................. 39 
10. 
Changes From Protocol-specified Analyses.......................................................... 39 
11. 
Literature Citations / References ........................................................................... 41 
12. 
Prioritization of Analyses....................................................................................... 41 
13. 
Data Not Covered by This Plan............................................................................. 41 
14. 
Appendices ........................................................................................................... 42 
Appendix A.  Criteria for Marked Changes in Laboratory Values ........................... 42 
Appendix B.  Analytical Windows .......................................................................... 43 
Appendix C.  Handling of Dates, Incomplete Dates and Missing Dates ................. 45 
 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 7 of 46 
CONFIDENTIAL  
 
 
List of Tables 
Table 9-1.  Primary Efficacy Endpoint Summary Table .................................................. 30 
Table 9-2.  Secondary Efficacy Endpoint Summary Table ............................................. 32 
Table 9-3.  Exploratory Efficacy Endpoint Summary Table ............................................ 33 
Table 10-1. Additional Exploratory Efficacy Endpoint Summary Table ........................... 40 
List of Figures 
No table of figures entries found. 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 8 of 46 
CONFIDENTIAL  
 
 
List of Abbreviations 
 
Abbreviation 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
BMI 
body mass index 
BSA 
body surface area 
CMH 
Cochran-Mantel-Haenszel 
COA 
clinical outcome assessment 
CRF 
case report forms 
CSR 
clinical study report 
DARS 
data acquisition requirements specifications 
DLQI 
dermatology life quality index 
DMARD 
disease modifying anti-rheumatic drug 
DMP 
data management plan 
EOS 
end of study 
ET 
early termination 
GSO-DM 
global study operations-data management 
IE 
intercurrent event 
IL 
interleukin 
IP 
investigational product 
IPD 
Important protocol deviation 
IRT 
interactive response technology 
ITT 
intent-to-treat 
MAR 
missing at random 
MI 
multiple imputation 
MMRM 
mixed-effect model for repeated measures 
N/A 
not applicable 
NRI 
non-responder imputation 
NSAID 
non-steroidal anti-inflammatory drugs 
PAO 
pustulotic arthro-osteitis 
PDE4 
phosphodiesterase-4 
PK 
pharmacokinetic 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 9 of 46 
CONFIDENTIAL  
 
 
Abbreviation 
Explanation 
PPP 
palmoplantar pustulosis 
PPPASI 
palmoplantar pustulosis area and severity index 
PPSI 
Palmoplantar Pustulosis Severity Index 
PRO 
Patient-report Outcome 
Q 
Quantile 
QoL 
Quality of Life 
SAP 
statistical analysis plan 
SAPHO 
synovitis, acne, pustulosis, hyperostosis osteitis syndrome 
SD 
standard deviation 
SE 
standard error 
TEAE 
treatment-emergent adverse event 
TFLSD 
table, figure, and listing shell document 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 10 of 46 
CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for the phase 3 study 20200195 of 
Apremilast in Japanese subjects with palmoplantar pustulosis (PPP) dated 30 March 
2022.  The scope of this plan includes the primary analysis (Week 16), supplemental 
analysis (Week 24), and the final analysis that are planned and will be executed by the 
Amgen Global Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the efficacy of 
apremilast 30 mg twice daily (BID) 
compared with placebo in 
subjects with PPP 
 
Achieving at least 50% reduction 
from baseline in Palmoplantar 
Pustulosis Area and Severity 
Index (PPPASI) total score 
(PPPASI-50) at week 16 
Secondary 
 
To evaluate the efficacy of 
apremilast 30 mg BID compared 
with placebo in subjects with PPP 
 
Change from baseline in PPPASI 
total score at week 16 
 
Change from baseline in 
Palmoplantar Pustulosis Severity 
Index (PPSI) total score at 
week 16 
 
Change from baseline in subject’s 
Visual Analogue Scale (VAS) 
assessment for PPP symptoms 
(pruritus and pain/discomfort) at 
week 16 
 
Change from Baseline in 
Dermatology Life Quality Index 
(DLQI) total score at week 16 
 
To evaluate the safety and 
tolerability of apremilast 30 mg 
BID compared with placebo in 
subjects with PPP 
 
Treatment-emergent adverse 
events (TEAEs), serious TEAEs, 
and TEAEs of interest 
 
Clinically significant changes in 
body weight, vital signs, and 
laboratory abnormalities 
 


Product:  Apremilast 
Protocol Number:  20200195 
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CONFIDENTIAL  
 
 
Primary Estimand 
The main estimand of primary interest for the primary efficacy endpoint (i.e., 
achievement of PPPASI-50 response defined as at least 50% reduction from baseline in 
PPPASI total score, at week 16) is defined in terms of the following attributes: 
 
The target population of interest is Japanese subjects with PPP defined through the 
inclusion/exclusion criteria. 
 
The primary endpoint is the achievement of PPPASI-50 response at week 16. 
 
Intercurrent events (IEs) are investigational product (IP) discontinuation due to lack 
of efficacy, adverse event, or protocol-prohibited medication use. A subject will be 
considered a treatment failure after any of the IEs. 
 
The summary measure is the difference between apremilast 30 mg BID group and 
placebo group in proportion of responders based on the intent-to-treat (ITT) 
population including all randomized subjects. 
A missing value after any of the IEs will be imputed as non-responders, otherwise, will 
be imputed with a multiple imputation (MI) method. A non-missing value after any of the 
IEs will also be imputed as non-responders. 
Secondary Estimand(s) 
The estimands for the secondary efficacy endpoints (i.e., change from baseline at week 
16 in PPPASI total score, PPSI total score, subject’s VAS assessment for PPP 
symptoms [pruritus and pain/discomfort], and DLQI total score) are defined in terms of 
the following attributes: 
 
The target population of interest is Japanese subjects with PPP defined through the 
inclusion/exclusion criteria. 
 
The secondary endpoints are the change from baseline at week 16 in PPPASI total 
score, PPSI total score, subject’s VAS assessment for PPP symptoms (pruritus and 
pain/discomfort), and DLQI total score. 
 
The IEs are IP discontinuation due to lack of efficacy, adverse event, or use of 
protocol prohibited medication. A subject will be considered a treatment failure after 
any of the IEs. 
 
The summary measure is the mean difference in change from baseline between 
apremilast 30 mg BID group and placebo group based on the ITT population. 


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Date:  25 September 2023 
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CONFIDENTIAL  
 
 
A missing value after any of the IEs will be imputed using baseline value. Other missing 
values will not be imputed. A non-missing value after any of the IEs will also be imputed 
using baseline value. 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
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CONFIDENTIAL  
 
 
 
Exploratory 
2.2 
Hypotheses and/or Estimations 
Null Hypothesis 
The treatment effect of apremilast 30 mg BID and placebo is equivalent. 
Alternative Hypothesis  
There is a difference in treatment effect between apremilast 30 mg BID and placebo. 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
Page 14 of 46 
CONFIDENTIAL  
 
 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled study 
evaluating the efficacy and safety of apremilast 30 mg BID versus placebo in Japanese 
subjects with PPP. 
Approximately 170 subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups: 
apremilast 30 mg BID or placebo. Subject randomization will be stratified by a subject’s 
rounded PPPASI total score (≤20/ 21-30/ ≥31) and focal infection status (yes/no) at 
baseline.  
Randomized subjects will receive either apremilast 30 mg BID or placebo for 16 weeks, 
the duration of the double-blind placebo-controlled treatment period. During the active 
treatment period (week 16 to week 52), all subjects will receive apremilast 30 mg BID. 
After the final dose treatment, subjects will enter a 30-day safety observational follow-up 
period. The total study duration including 4 weeks screening per subject is approximately 
60 weeks.  
The primary analysis will be performed after all subjects have either completed the week 
16 visit (visit 8) or have discontinued the study. A supplemental analysis will be 
conducted after all subjects have either completed the week 24 visit (visit 10) or have 
discontinued the study. The final analysis will be conducted after all subjects have either 
completed the week 56 visit (visit 14) or discontinued the study.  
3.2 
Sample Size 
The primary endpoint is the achievement of PPPASI-50 response at week 16. The 
sample size estimation is based on the results of the phase 2 study (CC-10004-PPP-001 
[20200055]).  Assuming a proportion of subjects achieving PPPASI-50 response at week 
16 of 40% and 65% for the placebo group and the apremilast 30mg BID group, 
respectively, a sample size of approximately 170 subjects in total (85 subjects per group) 
provides 90% power using a chi-square test with a 2-sided alpha of 0.05. A dropout rate 
of 5% during double-blind placebo-controlled treatment period is anticipated. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
For the secondary endpoints to be analyzed with MMRM model (i.e., change from 
baseline at week 16 in PPPASI total score, PPSI total score, subject’s VAS for PPP 


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CONFIDENTIAL  
 
 
symptoms [pruritus and pain/discomfort], DLQI total score), the corresponding baseline 
value of the endpoint will be included as a covariate in the model. 
4.2 
Subgroups 
The primary endpoint (PPPASI-50 response at week 16) and the selected key 
secondary endpoints such as change from baseline at week 16 in PPPASI total score 
and PPSI total score will be examined in the following subgroups to investigate the 
consistency of treatment effects. For each subgroup, a category with an insufficient 
number of subjects may be pooled. 
 
Age (< 40, ≥ 40 to < 65, ≥ 65 years) 
 
Sex (male, female) 
 
BMI category (< 25, ≥ 25 to < 30, ≥ 30 kg/m2) 
 
Tobacco Use (current/former, never) 
 
Duration of PPP (< 2, ≥ 2 to < 6, ≥ 6 to < 10, ≥ 10 years) 
 
PPPASI total score range at baseline (clinical data) (≤ 20, ≥ 21 to ≤ 30, ≥ 31) 
 
Presence of focal infection at baseline (clinical data) (Yes, No) 
 
Presence of pustulotic arthro-osteitis (PAO) at baseline (Yes, No) 
 
Presence of nail lesion at baseline (Yes, No) 
 
Prior use of biologic disease modifying anti-rheumatic drugs (DMARDs) for PPP 
(Yes, No) 
 
History of focal infection including periodontitis, tonsilitis and sinusitis (Yes, No) 
 
5. 
Definitions 
5.1 
Safety Related Definitions 
5.1.1 
Treatment-emergent Adverse Events (TEAEs)  
Any AEs that begin or worsen on or after the first dose of IP through 30 days after the 
last dose of IP or study treatment discontinuation date, whichever is later. 
5.1.2 
Treatment-related Adverse Events (TRAEs)  
A treatment-related AE is any treatment-emergent AE with the relationship flag on the 
Events eCRF indicating there is a reasonable possibility that the event may have been 


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CONFIDENTIAL  
 
 
caused by investigational medicinal product. In the unlikely event that the relationship is 
missing, the treatment-emergent event will be considered treatment-related and 
documented in a footnote of the treatment-related summary. 
5.2 
Study Dates/Timelines 
5.2.1 
Enrollment Date  
Enrollment date is defined as the randomization date. 
5.2.2 
End of IP Admin Date 
End of IP Admin for each subject is defined as the date the decision was made to end IP 
as recorded on the End of IP CRF page. 
5.2.3 
Last IP Dose Date 
Last IP Dose Date for each subject is defined as the latest date IP is administered. 
5.2.4 
Randomization Date 
Randomization date is defined as the date subject was allocated to a treatment group. 
5.2.5 
Study Day 
The number of days from Study Day 1, inclusive, given by the following formula: 
 
Study Day = (Date of interest – Date of Study Day 1) + 1, if date of interest is on/after 
Study Day 1. 
 
Study Day = (Date of interest – Date of Study Day 1), if date of interest is before 
Study Day 1. 
Study Day 1 is defined as the first day of IP administration after randomization. If a 
subject is randomized but never dosed, then set Study Day 1 to randomization date. 
5.2.6 
Study End Date 
The Study End Date is defined as the last End of Study (EOS) date of all enrolled 
subjects. 
5.2.7 
Subject-level End of Study (EOS) Date 
End of study for each subject is defined as the date the subject last completed a 
protocol-specified measurement.  
5.2.8 
Treatment duration 
Last IP Dose Date minus Study Day 1 plus 1. 


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CONFIDENTIAL  
 
 
5.3 
Baseline Related Definitions 
5.3.1 
Change from baseline 
The arithmetic difference between a post-baseline value and baseline for a given time 
point: Change from baseline = (post-baseline value – baseline value).  
5.3.2 
Percent Change from Baseline 
The percent change from baseline for a given variable at a given time point is defined 
as: 100 x [(value at given time point – baseline value) / baseline value]. Subjects with a 
zero value at baseline will be excluded from the summary of percent change from 
baseline. 
5.3.3 
Study Baseline 
Study baseline is defined as the last non-missing value measured on or before Study 
Day 1. 
For efficacy analyses and summary of baseline disease characteristics, baseline is 
defined as the last value measured on or before Study Day 1. For the summaries of 
laboratory parameters and vital signs parameters in the apremilast exposure period, 
baseline is defined as the last value measured on or before Study Day 1 for subjects 
initially randomized to apremilast for the placebo-controlled period, 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. 
5.4 
Study Endpoints 
5.4.1 
Palmoplantar Pustulosis Area and Severity Index (PPPASI) 
PPPASI is a disease-specific efficacy assessment tool used by investigators established 
to detect a change of disease status on palms or soles. 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. 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: 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 as below. 


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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] 
PPPASI produces numeric total scores that can range from 0 to 72. A higher score 
indicates more severe disease. 
The PPPASI sub-score is defined as the PPPASI total score including only one sub-
domain of interest. For example, the PPPASI sub-score for erythema 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] 
PPPASI-50, PPPASI-75, and PPPASI-90 are defined as ≥ 50%, ≥ 75%, and ≥ 90% 
improvement (reduction) in PPPASI total score from baseline, respectively. 
5.4.2 
Palmoplantar Pustulosis Severity Index (PPSI) 
PPSI is a disease-specific efficacy assessment tools by investigators. This is established 
to detect a change of disease status on a specified palm or sole. Evaluated skin lesion is 
identified by either right or left palm or sole, which has the most severe skin lesion at 
baseline and the identified skin lesion site will be assessed at all subsequent visits. 
Evaluation of skin lesion site are assessed separately for erythema (E), pustules/vesicle 
(P) and desquamation/scale (D), which are each rated on a scale of 0 to 4: 0 = none, 1 = 
slight, 2 = moderate, 3 = severe, and 4 = very severe. 
The severity of the disease is calculated with the PPSI total score formula as below. 
 
PPSI total score= (E + P + D) 
PPSI sub-score (Erythema) = E. 
The total score ranges from 0 to 12. A higher score indicates more severe disease. 
PPSI-50 and PPSI-75 are defined as ≥ 50% and ≥ 75% improvement (reduction) in PPSI 
total score from baseline, respectively. 


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5.4.4 
Pruritis and Pain Assessment with Subject Visual Analogue Scale 
(VAS) for PPP Symptoms 
Subjects will use VAS (with scores ranging from 0 to 100, with 100 being most severe) to 
assess the degree of PPP pain/discomfort and pruritus on the hands and feet. 
5.4.5 
Dermatology Life Quality Index (DLQI) 
DLQI is a skin disease-specific Quality of Life (QoL) questionnaire comprised of 10 items 
assessing the subject’s status over the previous week. DLQI can be used to assess 6 
different aspects that may affect QoL: symptoms and feelings, daily activities, leisure, 
work, or school performance, personal relationships, and treatment. Each item is scored 
on a 4-point Likert scale: 0 = not at all/not relevant; 1 = a little; 2 = a lot; and 3 = very 
much. 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 [3], No, or Not relevant 
[0]), and if “No,” then the subject is asked how much of a problem the status has been at 
work or study over the past week, with response alternatives being “a lot (2),” “a little 
(1),” or “not at all (0)”. The DLQI total score is derived by summing all item scores, which 
has a possible range of 0 to 30 with higher scores indicating increased disease severity 
and correspond to poorer quality of life. 
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. 
DLQI response (score of 0 or 1) is defined as subject’s DLQI total score achieving 
0 or 1. 


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5.5 
Analysis Phases 
 
Placebo-controlled Phase/Period – Weeks 0 to16 
This period starts on the day of randomization (Week 0/Visit 2), and stops on below: 
(1) the day of Week 16/Visit 8 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 8  
(3) the last known study day if the subject is lost to follow-up prior to or at Week 16/Visit 
8 
 
Active Treatment Phase/Period – Weeks 16 to 52 
This period starts on one day after the day of the dose of apremilast distributed at Week 
16/Visit 8, and stops on either below. 
(1) the day of Week 52/Visit 13 
(2) the day of the discontinuation if the subject discontinued prior to or at Week 52/Visit 
13 
(3) the last known study day if the subject lost to follow-up prior to or at Week 52/Visit 13 
during the phase 
For safety analysis, the period starts on the day of the first dose of apremilast in the 
period. 
 
Safety Follow-up Phase/Period 
Subjects who complete or discontinue the study treatment, will be followed up for 30 
days after the end of treatment visit. 
For adverse event analysis, data from the first 30 days after the last dose of IP will be 
included in the precedent treatment phase and data after the 30 days will be presented 
separately. 
 
Apremilast exposure period 
This period starts on the date of either: 
- the first dose of IP following randomization (Week 0/Visit 2) for subject who are treated 
with apremilast from Week 0 


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- the first dose of IP from the IP dispensed at Week 16/Visit 8 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.  
6. 
Populations for Analysis 
6.1 
Intent-to-treat Population 
The intent-to-treat (ITT) population will include all randomized subjects. Subjects will be 
included in the treatment group to which they are randomized. Efficacy analyses will be 
performed based on the ITT population, unless otherwise specified. 
6.2 
Safety Analysis Population 
The safety analysis population will include all randomized subjects who received at least 
1 dose of IP. The analysis of safety data will be based on the safety population. Subjects 
will be included in the treatment group corresponding to the IP they actually received 
(apremilast or placebo). Subjects who inadvertently received more than 1 type or dose of 
IP in the placebo-controlled period will be analyzed according to their actual treatment 
received, where subjects who received ≥ 1 dose of apremilast will be analyzed in the 
apremilast treatment group regardless of the randomized treatment. Safety analyses for 
the apremilast-exposure period will be based on the apremilast subjects as treated 
population, which includes all subjects who actually receive the apremilast 30 mg BID at 
the randomization or switched to the apremilast 30 mg BID at the week 16 visit.  
6.3 
Study-specific Analysis Sets 
 Not applicable. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis will be conducted prior to the primary analysis.  
7.2 
Primary Analysis 
The primary analysis will be performed after all subjects have either completed week 16 
or discontinued the study. 
7.3 
Supplemental Analysis 
After all subjects have either completed week 24 (visit 10) or discontinued the study, a 
supplemental analysis will be conducted. Statistical comparisons of treatment 


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differences will not be performed for this supplemental analysis. All analyses for 
placebo-controlled period in PA will not be repeated. 
7.4 
Final Analysis 
Final analysis will be conducted based on all study data collected after all subjects have 
either completed or discontinued the study. In FA, the descriptive analyses at SA will be 
updated using the data from the final database lock. All analyses for placebo-controlled 
period in PA will not be repeated. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses including data from RAVE database, 
Clinical Outcome Assessment (COA), Patient-reported Outcome (PRO), and laboratory 
data (outside of RAVE database). The database will be subjected to edit checks outlined 
in the Data Management Plan (DMP). Additional details will be provided in DMP and 
Data Acquisition Requirements Specifications (DARS). 
8.3 
Handling of Missing and Incomplete Data 
Subjects may have missing specific data points for a variety of reasons. In general, data 
may be missing due to a subject’s early withdrawal from study, a missed visit, or inability 
to evaluate an endpoint at a particular point in time. The general procedures outlined 
below describe what will be done when a data point is missing. 
8.3.1 
Missing Baseline 
Missing at baseline evaluations will not be imputed.  
8.3.2 
Missing Post-Baseline Evaluation 
In the primary endpoint analysis of PPPASI-50 response at week 16, the PPPASI-50 
values will be imputed as non-responder for visits on and after a subject experiencing 
any of the IEs. The missing PPPASI-50 values due to other reasons will be imputed 
using MI method. 
For the secondary endpoints (i.e., the change from baseline at week 16 in PPPASI total 
score, PPSI total score, subject’s VAS assessment for PPP symptoms [pruritus and 
pain/discomfort], and DLQI total score), the corresponding endpoints’ baseline value will 


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be assigned to the data on and after any of the IEs regardless of the observed data and 
no imputation will be applied to the missing data (PPPASI total score) due to other 
reasons. Similar approach will be applied to the other endpoints of responses and 
continuous variables, unless otherwise specified. 
For safety data, missing post-baseline measurements/assessments will not be imputed. 
8.3.3 
Missing and Incomplete Dates 
For any listings, missing or incomplete dates will be listed as is. 
The handling of incomplete and partial dates for safety, medical history and 
concomitant/prior medication/procedures will be described in Appendix C.  
8.4 
Detection of Bias 
This study has been designed to minimize potential bias using randomization of subjects 
into treatment groups and the use of blinding. Other factors that may bias the results of 
the study include: 
 
major protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints 
 
subject level unblinding before the final database lock and formal unblinding 
 
IP dosing non-compliance 
 
reasons for early withdrawal from treatment or from study 
Important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints, and would significantly affect subject’s right, safety or wellbeing will 
be tabulated by treatment group in the Clinical Study Report (CSR). Any unblinding of 
individual subjects prior to formal unblinding of the study will be documented in the CSR. 
8.5 
Outliers 
Descriptive summaries will be examined to identify unexpected values. 
Outliers that are not due to data entry will be included in the analysis. If it is deemed 
necessary after the team reviews the output from the planned analyses after database 
snapshot, a post-hoc sensitivity analysis excluding subjects with outliers may be 
performed. 


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8.6 
Distributional Characteristics 
For categorical endpoints, descriptive summary will be provided. For continuous 
endpoints, normality will be assumed given the large sample size where central limit 
theorem applies. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures. 
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs. 
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
higher. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
The ITT principle will be used in statistical analyses for efficacy endpoints. For the 
placebo-controlled period (Weeks 0-16), efficacy evaluations will be conducted using the 
ITT population defined as all randomized subjects. Statistical comparisons for placebo-
controlled period in Primary Analysis (PA) will be made between the two treatment 
groups (placebo and apremilast 30 mg BID). For the active treatment period (Weeks 16-
52), analysis for differences between the two groups will not be performed although 
summaries of each group will be provided.  
Descriptive statistics will be presented for appropriate endpoints at specified time points. 
Specifically, summary statistics for continuous variables will include the number of 
subjects (n), mean, SD, median, the 25th (Q1) and 75th (Q3) percentiles, minimum, and 
maximum. For efficacy variables, standard errors (SEs) for estimates will be included, 
unless otherwise specified. Frequency summary for categorical variables includes 
counts and percentages. 
Statistical inferences will be provided for analyses of primary, secondary and the 
exploratory efficacy endpoints. Unless specified otherwise, all statistical tests are 2-sided 
with a significance level of 0.05; no statistical inference and imputation will be conducted 
for analyses of safety endpoints. 


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9.2 
Subject Accountability 
Frequency summary of subjects randomized, screened but not randomized among all 
screened subjects will be provided. The frequency of subjects who failed each 
inclusion/exclusion criteria will be included in the summary. 
The number and percentage of subjects included in the ITT and safety analysis 
population will be summarized. 
Subject disposition will be provided for placebo-controlled period and active treatment 
period based on ITT population respectively. Summary of safety follow-up period and 
study completion will be included in each disposition summary. The summaries include 
the number and percentage of subjects who entered the period, who completed the 
period, who completed IP, who ended IP and study with the reason. Subjects who ended 
IP are considered to enter the safety follow-up period unless the subjects ended the 
study on the same day. 
Key study dates for the first subject screened and enrolled (randomized), last subject 
enrolled (randomized), data cut-off (last subject’s week 16 and 24 visit), last subject end 
of IP, last subject end of study will be presented. 
The number and percentage of subjects randomized will be tabulated by study site. 
Listings of subject accountability will be provided. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study. 
These definitions of IPD categories, subcategory codes, and descriptions will be used 
during the course of the study. 
The number and percentage of subjects with at least one IPD will be summarized by 
each category in a table. The number of subjects reporting IPD and PD related to 
COVID-19 will be separately summarized. A by-subject listing of IPD will be provided. A 
COVID-19 related PD listing will also be provided. 
9.4 
Demographic and Baseline Characteristics 
Summaries for the demographics, baseline characteristics, medical history, prior 
medication/procedure will be presented for the ITT population by treatment group and 
overall. Concomitant procedures/medications will be summarized based on the safety 
population. 


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Individual subject listings will be provided to support the summary tables. 
9.4.1 
 Demographics 
Summary statistics will be provided for the following continuous variables: 
 
Age 
 
Weight 
 
Height 
 
BMI (Weight [kg]/Height [m2]) 
Number and percentage of subjects will be provided for the following categorical 
variables: 
 
Age (< 40, ≥ 40 to < 65, ≥ 65 years) 
 
Sex (male, female) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islanders, White, Other). If multiple races have been 
reported for a subject, the subject will be categorized as multiple-race, as well as by 
combination of races. 
 
BMI category (< 25, ≥ 25 to < 30, ≥ 30 kg/m2) 
9.4.2 
Baseline Disease Characteristics 
Summary statistics will be provided for the following continuous variables: 
 
Duration of PPP in years 
 
PPPASI total score 
 
PPSI total score 
 
VAS for PPP symptoms (pruritus and pain/discomfort) 
 
DLQI total score 
 
 
Number and percentage of subjects will be provided for the following categorical 
variables: 


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 
Tobacco Use (Current/Past User, Non-User) 
 
Duration of PPP (< 2, ≥ 2 to < 6, ≥ 6 to < 10, ≥ 10 years) 
 
PPPASI total score rounded range (clinical and IRT data) (≤ 20, ≥ 21 to ≤ 30, ≥ 31) 
 
 
Presence of focal infection (clinical and IRT data) (Yes, No) 
 
Presence of pustulotic arthro-osteitis (PAO) (Yes, No) 
 
Presence of nail lesion (Yes, No) 
 
Prior use of biologic DMARDs for PPP (Yes, No) 
 
History of focal infection including periodontitis, tonsilitis and sinusitis (Yes, No) 
9.4.3 
Medical History 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.0 or higher. A frequency summary (counts and percentage of 
subjects) of medical history will be presented by system organ class (SOC) and 
preferred term (PT). A similar table summarizing currently active medical histories that 
were not resolved/recovered by randomization will be provided. Medical history 
summaries of focal infection and PAO will be provided. Individual subject listings of 
medical history will be provided. 
9.4.4 
Prior and Concomitant Procedures 
Prior procedures are defined as those started before Study Day 1 (whether or not ended 
before Study Day 1). Concomitant procedures are defined as procedures that were 
either initiated before Study Day 1 and continued during the study treatment, or initiated 
on/after the date of Study Day 1 and on/before the date of treatment discontinuation. 
Procedures 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 procedures. 
Frequency summaries of prior and concomitant procedures will be provided by verbatim 
term, and location. 
A subject listing of prior and concomitant procedures will be provided. 
9.4.5 
Prior and Concomitant Medications 
Prior and concomitant medications are defined similarly as prior and concomitant 
procedures, respectively. 


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Number and proportion of subjects receiving prior/concomitant medications will be 
summarized by preferred term or category for each treatment group as coded by the 
World Health Organization Drug dictionary. The prior and concomitant medications for 
PPP, focal infection and PAO will be summarized separately. 
A subject listing of prior and concomitant medications will be provided. 


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9.5 
Efficacy Analyses 
The efficacy analyses will be performed based on the ITT population. 
To control the overall type I error at the level of 0.05 (2-sided), a fixed-sequence testing 
procedure will be applied. The secondary efficacy endpoints will be tested with the listed 
order in Section 9.5.2 if the primary endpoint achieves statistical significance. 
Sensitivity analyses will be performed for the primary estimand. 
Subject data listings of efficacy data will be provided. 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
The primary efficacy endpoint is the achievement of PPPASI-50 response at week 16. 
The proportion of subjects achieving PPPASI-50 response in apremilast 30 mg BID 
group and placebo group will be compared using Cochran-Mantel-Haenszel (CMH) test 
adjusting for the stratification factors for randomization [PPPASI total score range (≤20 / 
21-30 / ≥31) at baseline and subject’s focal infection status (yes/no) at baseline]. The 
testing will be conducted at the 2-sided 0.05 significance level. Subjects who discontinue 
IP prior to week 16 due to lack of efficacy, adverse event, or use of protocol prohibited 
medication will be considered as treatment failures as the result of the IE and the 
PPPASI-50 values for visits on and after the IE will be imputed as non-responders. The 
missing data (PPPASI total score) due to other reasons will be imputed using MI 
method. 
The two-sided p-values from the CMH test, the adjusted treatment difference in 
proportion using the weighted average of the treatment differences across the 
strata with the CMH weights, along with the associated two-sided 95% CIs using a 
normal approximation to the weighted average will be provided. Similarly, 
unadjusted treatment differences in proportions will also be provided. 
Sensitivity analyses for the primary endpoint will be conducted using the non-responder 
imputation (NRI) method for any missing data due to other reasons (not IE). 
Additionally, to assess sensitivity to departures from the missing data assumption 
(MAR), the tipping point analysis will be performed. Another sensitivity analysis for the 
primary endpoint will be performed based on data-derived stratification factors.  
For MI method, the SAS procedure MI will be used to impute missing PPPASI scores at 
the scheduled analysis visits in the Placebo-controlled Phase (Week 0-16) to create 
M=50 complete datasets. The missing data patterns will be checked at the scheduled 


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analysis visits, i.e., Baseline (week 0), week, 2, 4, 6, 8, 12, and 16. If there are non-
monotone missing patterns, two separate imputation procedures will be used to 
complete the imputation process.  
 
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used to 
impute missing scores by treatment and stratification factor to create M=50 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 
to 17813722, a single chain will be used to produce imputations. In case there are 
convergence issues, a simple model will be used to impute the missing scores by 
treatment, with further simplification by dropping both treatment and stratification 
factor in imputation model if necessary. 
 
In the second step, the predictive mean matching method will be used to impute the 
remaining missing values for the 50 data sets with monotone missing patterns. The 
MONOTONE REGPMM statement will be used with seed 55218164. The missing 
values at each visit will be imputed based on treatment, stratification factor 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 50 complete data sets and the SAS procedure MIANALYZE will be used to 
combine the results for the statistical inferences. 
Table 9-1.  Primary Efficacy Endpoint Summary Table 
Endpoint/Estimand 
Primary Summary and Analysis Method  
Sensitivity Analysis 
Achieving PPPASI-
50 response at week 
16 
The treatment failures will be considered as 
non-responders on and after the IE and the 
missing value (PPPASI total score) due to 
other reasons will be imputed using MI 
method. 
The two-sided p-values from the CMH test, 
the adjusted treatment difference in 
proportion using the weighted average of 
the treatment differences across the strata 
with the CMH weights, along with the 
associated two-sided 95% CIs using a 
normal approximation to the weighted 
average will be provided. Similarly, 
unadjusted treatment differences in 
proportions will also be provided. 
- 
Tipping point 
analysis to 
assess 
sensitivity to 
departures from 
the missing data 
assumption 
(MAR) 
- 
NRI for any 
missing data 
- 
Adjusting for 
the data-
derived 
stratification 
factors instead 
of the factor 
from IRT 


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9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
For the secondary endpoints including change from baseline at week 16 in PPPASI total 
score, PPSI total score, subject’s VAS assessment for PPP symptoms (pruritus and 
pain/discomfort), and DLQI total score, the MMRM with treatment group, visit time, 
treatment-by-time interaction, and stratification factors as fixed effect, and the baseline 
value as a covariate will be applied. An unstructured covariance matrix will be used to 
model the correlation among repeated measurements. For the treatment failures as the 
result of an IE (IP discontinuation prior to week 16 due to lack of efficacy, adverse event, 
or use of protocol prohibited medication), the corresponding endpoints’ baseline value 
will be assigned to the data on and after the IE up to week 16, regardless of the 
observed data. The missing data due to other reasons will not be imputed considering 
MMRM application based on the assumption of MAR. The least square (LS) means and 
SEs along with 95%CI within-group and treatment differences (from placebo) in LS 
means and SEs along with 95%CI and two-sided p-values will be derived from the 
MMRM. 
The secondary endpoints will be statistically tested in the following order if the primary 
analysis result achieve a statistically significant difference. The statistical testing will be 
performed in the sequence until one of the analyses has failed to show the statistically 
significant difference at a significance level of 0.05 (two-sided).  
1. Change from baseline in PPPASI total score at week 16 
2. Change from baseline in PPSI total score at week 16 
3. Change from baseline in Subject’s VAS assessment for PPP symptom (pruritus) 
at week 16 
4. Change from baseline in Subject’s VAS assessment for PPP symptom 
(pain/discomfort) at week 16 
5. Change from baseline in DLQI total score at week 16 


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Table 9-2.  Secondary Efficacy Endpoint Summary Table 
Endpoint/Estimand 
Summary and Analysis Method  
- 
Change from baseline in 
PPPASI total score at week 
16 
- 
Change from baseline in 
PPSI total score at week 16 
- 
Change from baseline in 
Subject’s VAS assessment 
for PPP symptom (pruritus) 
at week 16 
- 
Change from baseline in 
Subject’s VAS assessment 
for PPP symptom 
(pain/discomfort) at week 16 
- 
Change from baseline in 
DLQI total score at week 16 
- 
LS mean (SE) along with 95%CI within-group derived 
from the MMRM 
- 
LS mean difference from placebo (SE) along with 
95%CI and p-value (two-sided) based on the MMRM 
For the treatment failures, the corresponding endpoints’ 
baseline value will be assigned to the data on and after 
the IE up to week 16, regardless of the observed data. 
The missing data due to other reasons will not be imputed 
considering the MMRM application based on the 
assumption of MAR. 
Sensitivity analysis will not be performed for the secondary efficacy endpoints. 
 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 


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Table 9-3.  Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Summary and Analysis Method  


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Endpoint 
Summary and Analysis Method  
  
9.6 
Safety Analyses 
Safety analyses will be performed using the safety analysis population unless otherwise 
specified. Summaries of the safety analyses for the placebo-controlled period 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). The purpose of safety summary for the apremilast-
exposure period is to provide safety data under apremilast 30 mg BID. 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
There is no primary safety endpoint. As a secondary endpoint, the safety and tolerability 
of apremilast 30 mg BID will be compared to placebo. No inferential testing for statistical 
significance will be performed for safety analyses. 
Unless otherwise specified, the analyses of AEs and marked abnormalities (laboratory 
parameters and vital signs) for both the placebo-controlled period and apremilast-
exposure period will be summarized by subject incidence rate. For safety summaries of 
apremilast-exposure period, the exposure-adjusted incidence rate will be presented to 
account for the difference exposure to the IP. 
9.6.2 
Adverse Events 
Adverse events will be analyzed in terms of treatment-emergent adverse events 
(TEAEs) defined as any AEs that begin or worsen on or after the first dose of IP through 
30 days after the last dose of IP or study treatment discontinuation date, whichever is 
later.  The Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 or higher 
will be used to code all events categorized as adverse events to a system organ class 
and a preferred term.  
An overview of the following AE categories will be provided. 


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AE Categories: 
 
TEAE 
 
Drug-related TEAE 
 
Severe TEAE 
 
Serious TEAE 
 
Serious Drug-related TEAE 
 
TEAE Leading to Drug Interruption 
 
TEAE Leading to Drug Withdrawal 
 
TEAE Leading to Death 
Summary of the above AE categories for the subgroups in Section 4.2 will be provided. 
Tables summarizing the incidence of TEAEs by SOC and/or PT will be generated for 
each of the followings: 
 
All TEAEs 
 
Drug-related TEAE 
 
TEAEs by maximum severity 
 
Serious TEAE  
 
Serious Drug-related TEAE 
 
TEAE Leading to Drug Interruption 
 
TEAE Leading to Drug Withdrawal 
 
TEAE Leading to Death 
 
First onset and new event of TEAE by exposure interval 
 
Placebo controlled period (weeks): ≤ 1, > 1 to ≤ 2, > 2 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 
12, > 12 to ≤ 16, > 16 
 
Apremilast-exposure period (weeks): ≤ 1, > 1 to ≤ 2, > 2 to ≤ 4, > 4 to ≤ 8, > 8 to 
≤ 12, > 12 to ≤ 16, > 16 to ≤ 28, > 28 to ≤ 40, > 40 to ≤ 52, > 52 
 
TEAE for the subgroups in Section 4.2 


Product:  Apremilast 
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Tables summarizing the incidence of TEAEs by PT will be generated for each of the 
followings: 
 
TEAEs by NSAIDs status 
 
Most frequent TEAEs (subject incidence ≥ 5% in any group or another cut-off if 
justified) 
 
Most frequent TEAEs by maximum severity (subject incidence ≥ 5% in any group or 
another cut-off if justified) 
 
Most frequent TEAE for the subgroups in Section 4.2 (subject incidence ≥ 5% in any 
group or another cut-off if justified) 
 
First onset of most frequent TEAE by exposure interval (subject incidence ≥ 5% in 
any group or another cut-off if justified) 
 
Placebo controlled period (weeks): ≤ 1, > 1 to ≤ 2, > 2 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 
12, > 12 to ≤ 16, > 16 
 
Apremilast-exposure period (weeks): ≤ 1, > 1 to ≤ 2, > 2 to ≤ 4, > 4 to ≤ 8, > 8 to 
≤ 12, > 12 to ≤ 16, > 16 to ≤ 28, > 28 to ≤ 40, > 40 to ≤ 52, > 52 
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 exposure time 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. 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. For the summary of the first onset of TEAE by 
exposure interval, only the first onset of specific TEAE is considered for each subject. 
Following TEAEs of interest will be summarized according to their categories and PT by 
severity (mild, moderate, severe), relationship, action taken with IP, fatality, and 
seriousness. 


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 
Depression: MedDRA narrow scope SMQ of Depression (excluding suicide and 
self-injury) 
 
Serious infection: MedDRA primary SOC of Infections and infestations and the 
events assessed as serious 
 
Risk of Triggering Suicide: MedDRA narrow scope sub-SMQ of Suicide/self-
injury 
 
Serious Diarrhea, Nausea, and Vomiting: definition can be found in TFLSD. 
 
Malignancies: definition can be found in TFLSD. 
 
Vasculitis and Vasculopathy: MedDRA narrow scope SMQ of Vasculitis. 
 
Serious Hypersensitivity: MedDRA narrow scope SMQ of Hypersensitivity. 
 
Weight Change (Weight decrease): definition can be found in TFLSD. 
Subject listings of AEs including non-treatment-emergent AEs will be provided.  
9.6.3 
Laboratory Test Results 
Summary statistics of observed values and changes from baseline in the selected 
laboratory parameters will be provided over time. Frequency summary of shifts from 
baseline to the worst post-baseline value in terms of normal/abnormal will be provided. 
The selected laboratory parameters with abnormalities criteria are available in the 
Appendix A. For the purposes of the summary, 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 will be listed and values outside of the 
normal reference range will be flagged. 
9.6.4 
Vital Signs 
The analyses of vital signs including summary statistics of observed values and 
changes from baseline over time will be provided. Frequency summaries of shifts from 
baseline to the worst post-baseline value in terms of normal/abnormal(low/high) will be 
provided for heart rate and blood pressure. Normal ranges are defined as: 60-90 mmHg 
for diastolic blood pressure, 90-140 mmHg for systolic blood pressure, and 60-100 
beats/minute for heart rate. 
A subject data listing of all vital signs will be provided. 


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9.6.5 
Physical Measurements 
The observed values and change from baseline for weight and BMI will be 
summarized. 
A subject data listing of physical measurements will be provided. 
9.6.6 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to IP by treatment group. 
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. Summary statistics for treatment duration (in weeks), as well 
as a frequency summary of treatment duration categories (placebo-controlled period: < 
4, ≥ 4 to < 8, ≥ 8 to < 12, ≥ 12 to < 16, ≥ 16, active treatment period: ≥ 16 to < 20, ≥ 20 to 
< 24, ≥ 24 to < 32, ≥ 32 to < 44, ≥ 44 to < 52, ≥ 52 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 
8), to the last apremilast administered date of subjects who discontinue before the study 
completion or who complete the study at week 52 (visit 13). 
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 actually taken (sum of dose per administration) over the period divided by the 
intended total number of tablets that should have been taken over the same period. It is 
assumed that a subject takes 2 tablets per day from the first through the last IP 
administered date.  
A subject data listing of IP administration will be provided. 
9.6.7 
Exposure to Prior/Concomitant Medication and Procedures 
Prior medications and procedures 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 and procedures 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 and procedures 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 and procedures. 


Product:  Apremilast 
Protocol Number:  20200195 
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Number and proportion of subjects receiving prior/concomitant medications and 
procedures will be summarized by preferred term or category for each treatment group 
as coded by the World Health Organization Drug dictionary. The prior and concomitant 
medications for PPP, focal infection and PAO will be summarized.  
A subject listing of prior and concomitant medications and procedures will be provided. 
9.7 
Other Analyses 
PK and Biomarker analyses are planned separately. 
9.7.1 
Analyses of Pharmacokinetic Endpoints 
Detailed descriptions of PK analysis will be documented separately.  
9.7.2 
Analyses of Biomarker Endpoints 
Detailed descriptions of biomarker analysis will be documented separately, and the 
result will be separately reported. 
10. 
Changes From Protocol-specified Analyses 
Added additional exploratory endpoints: 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
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Table 10-1. Additional Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Summary and Analysis Method  


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Protocol Number:  20200195 
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11. 
Literature Citations / References 
van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-5L 
to EQ-5D-3L value sets. Value in Health 2012 Jul-Aug;15(5):708-15 
12. 
Prioritization of Analyses 
Not applicable 
13. 
Data Not Covered by This Plan 
A detailed description of PK and biomarker analysis will be documented separately. 


Product:  Apremilast 
Protocol Number:  20200195 
Date:  25 September 2023 
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14. 
Appendices 
Appendix A.  Criteria for Marked Changes in Laboratory Values 
 
Category 
Analyte 
Abnormality Criteria 
Chemistry 
Sodium 
>150, <130 mmol/L 
Potassium 
>5.5, <3.0 mmol/L 
Albumin 
<25 g/L 
Calcium 
>3.0, <1.8 mmol/L 
Magnesium 
> 1.2 mmol/L 
Phosphorus 
>1.60, <0.64 mmol/L 
Glucose 
>13.9, <2.8 mmol/L 
BUN or Urea *Blood Urea Nitrogen 
> 24 mmol/L 
Creatinine 
>1.5×ULN umol/L 
Uric acid 
> 480 umol/L 
Total bilirubin 
>1.8×ULN umol/L 
ALP *Alkaline Phosphatase 
>400 U/L 
LDH *Lactate Dehydrogenase 
> 2xULN U/L 
AST (SGOT) *Aspartate 
Aminotransferase 
>3.0×ULN U/L 
ALT (SGPT) *Alanine Aminotransferase 
>3.0×ULN U/L 
Cholesterol 
> 7.8 mmol/L 
Triglycerides 
> 3.4 mmol/L 
Hematology 
Hemoglobin 
>150, <110 g/L 
Platelets 
>600, <75 10^9/L 
WBC *Leukocytes 
< 2.0 10^9/L 
Lymphocytes 
<0.8 10^9/L 
Neutrophils, Segmented 
< 1.5 10^9/L 
 
 


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Protocol Number:  20200195 
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Appendix B.  Analytical Windows 
Per protocol, visits are to be performed within 2 days of the protocol-specified study day 
for placebo-controlled period, and within 4 days for the active treatment period. To allow 
for variations in scheduling, the following visit windows will be applied to selected 
efficacy evaluations to assign a most appropriate nominal visit for analysis. If more than 
one assigned visit falls within the same defined window, the closest visit to the target day 
(ie, scheduled visit week × 7 + 1) will be considered for analysis. If two assessment 
dates are the same distance from the target day, then the latest visit will be considered 
for analysis. 
Analysis window for PPPASI, PPSI, 
 Vital Signs and Physical Measurement 
Visit Week 
Target Day 
Window Definition 
Week 0 (Visit 2: Baseline)  
1  
Last Evaluation prior to or on Study Day 1 
Placebo-controlled Period  
Week 2 (Visit 3)  
15  
Study Day 2 – 22  
Week 4 (Visit 4)  
29  
Study Day 23 – 36  
Week 6 (Visit 5)  
43  
Study Day 37 – 50  
Week 8 (Visit 6)  
57  
Study Day 51 – 71  
Week 12 (Visit 7)  
85  
Study Day 72 – 99 
Week 16 (Visit 8)  
113  
Study Day 100 – End of the Period  
Active Treatment Period 
Week 20 (Visit 9)  
141  
One day after the first apremilast dosing 
day on Visit 8* – 155 
Week 24 (Visit 10)  
169  
Study Day 156 – 197  
Week 32 (Visit 11)  
225  
Study Day 198 – 267 
Week 44 (Visit 12)  
309 
Study Day 268 – 337 
Week 52 (Visit 13)  
365 
Study Day 338 – End of the Period 
 
Analysis window for Subject’s VAS assessment for PPP symptom for palms and 
soles 
Visit Week 
Target Day 
Window Definition 
Week 0 (Visit 2: Baseline)  
1  
Last Evaluation prior to or on Study Day 
1  
Placebo-controlled Period 
Week 2 (Visit 3)  
15  
Study Day 2 – 22 
Week 4 (Visit 4)  
29  
Study Day 23 – 36  
Week 6 (Visit 5)  
43  
Study Day 37 – 50  
Week 8 (Visit 6)  
57  
Study Day 51 – 71  
Week 12 (Visit 7)  
85  
Study Day 72 – 99 
Week 16 (Visit 8)  
113  
Study Day 100 – End of the Period  
Active Treatment Period 


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Visit Week 
Target Day 
Window Definition 
Week 24 (Visit 10)  
169  
One day after the first apremilast dosing 
day on Visit 8 – 197 
Week 32 (Visit 11)  
225  
Study Day 198 – 295 
Week 52 (Visit 13)  
365 
Study Day 296 – End of the Period 
 
Analysis window for DLQI, 
 and Laboratory Test 
Visit Week 
Target Day 
Window Definition 
Week 0 (Visit 2: Baseline)  
1  
Last Evaluation prior to or on Study Day 1  
Placebo-controlled Period  
Week 8 (Visit 6)  
57  
Study Day 2 – 85  
Week 16 (Visit 8)  
113  
Study Day 86 – End of the Period  
Active Treatment Period 
Week 24 (Visit 10)  
169  
One day after the first apremilast dosing day 
on Visit 8 – 197 
Week 32 (Visit 11)  
225  
Study Day 198 – 225 
Week 52 (Visit 13)  
365 
Study Day 226 – End of the Period 
Active treatment period start point for adverse event data shall be the first apremilast 
dosing day on Visit 8.  


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Appendix C.  Handling of Dates, Incomplete Dates and Missing Dates 
Imputation Rules for Partial or Missing Start Dates 
The reference date for the following rules is the date of first dose of apremilast. 
 
 
 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
 
3 
1 
 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1=Impute the date of first dose; 2=Impute the first of the month; 3=Impute January 1 of the year; 4=Impute 
January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set to the 
first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date.  
Imputation Rules for Partial or Missing Death Dates 
If death year and month are available but day is missing: 
 
If yyyymm for the date last known to be alive equals yyyymm for death date, set 
death date to the day after the date last known to be alive. 
 
If yyyymm for the date last known to be alive is less than the yyyymm for death date, 
set death date to the first day of the death month. 
 
If yyyymm for the date last known to be alive is greater than yyyymm for death date, 
assume date last known to be alive is in error, set death date to the first day of the 
death month. 
 If month and day are missing and year of death is known: 


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 
If yyyy for the date last known to be alive equals yyyy for death date, set death date 
to the day after last known to be alive date. 
 
If yyyy for the date last known to be alive is less than yyyy for death date, set death 
date to the first day of the death year. 
 
If yyyy for the date last known to be alive is greater than yyyy for death date, assume 
date last known to be alive is in error, set death date to the first day of the death 
year. 
 If a death date is totally missing: 
 
Set death date to the day after the date last known to be alive. If the date last known 
to be alive is a partial date, set it to the first day of the month last known to be alive 
or first day of the year last known to be alive if month is also missing.