Clinical trial NCT03774875
Conditions: Psoriasis
Keywords: Apremilast CC-10004 Quality of life Safety Efficacy Psoriasis manifestations
Sponsor: Amgen
Start date: 2019-03-28; Completion date: 2021-11-03
Enrollment: 277 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to assess the impact of treatment with apremilast 30 mg twice daily for 16 weeks, compared to placebo, on health-related quality of life (QOL) in adults with manifestations of plaque psoriasis and impaired quality of life.

Detailed description:
Participants will be randomized 2 (apremilast):1 (placebo) in approximately 10 countries in Western Europe. Participants will be block-randomized to each of the manifestations of psoriasis (scalp psoriasis, nail psoriasis, palmoplantar psoriasis, genital psoriasis, and psoriasis in visible locations). Participants presenting with multiple manifestations will be allocated to the manifestation which is most severe, as determined by the participant. All manifestations will be assessed for efficacy at each study visit.

The study will consist of 4 phases:

* Screening Phase - up to 5 weeks (35 days)
* Double-blind Placebo-controlled Phase - Weeks 0 to 16 Participants will receive treatment with either apremilast or matched placebo.
* Apremilast Extension Phase - Weeks 16 through 52 All participants will be switched to (or continue with) apremilast at week 16 and will maintain this dosing through week 52.
* Post-treatment Observational Follow-up Phase 4-week post-treatment observational follow-up phase for all participants who complete the study on treatment or discontinue from the study treatment early.

Arms: arm 1: Participants will take apremilast 30 mg tablets orally twice a day for up to 52 weeks. arm 2: Participants will take placebo tablets orally twice a day for 16 weeks. After week 16, participants will be switched to receive apremilast 30 mg twice daily until Week 52.
Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: Apremilast 30 mg tablets taken orally twice a day. intervention 2: Placebo tablets taken orally twice a day

Protocol documents:
Prot_000.pdf: 
EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
1
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
TITLE PAGE
A PHASE 4, MULTI-CENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 
THE IMPACT OF APREMILAST (CC-10004) ON 
QUALITY OF LIFE, EFFICACY, AND SAFETY IN 
SUBJECTS WITH MANIFESTATIONS OF PLAQUE 
PSORIASIS AND IMPAIRED QUALITY OF LIFE
PROTOCOL NUMBER:
CC-10004-PSOR-020
DATE FINAL:
26 SEP 2018
Amendment 1:
17 JAN 2019
Amendment 2:
01 NOV 2019
Amendment 3:
01 MAY 2020
EudraCT NUMBER:
2018-002850-58
NCT Number:
NCT03774875
IND NUMBER:
070270
SPONSOR NAME / ADDRESS:
AMGEN, INC.
One Amgen Center Drive
Thousand Oaks, CA 91320
CONFIDENTIALITY NOTICE
This document contains confidential information of Amgen. This document 
must not be disclosed to anyone other than the site study staff and members of 
the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. The information in this document cannot 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Amgen. If you have 
questions regarding how this document may be used or shared, call the Amgen 
Medical Information number: 1- 800-77-AMGEN 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information
Name:  
 MD
Title:  Senior Director, Global Development
Address: Amgen Inc.
                One Amgen Center Drive
                Thousand Oaks, CA 91320
Phone:  
E-mail:  
 
Note: Only call Amgen Medical Information, if you are not able to reach the Clinical Research 
Physician(s) or Medical Monitor or designee for emergency calls.
Amgen Medical Information: +1-800-77-AMGEN (1-800-772-6436) 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
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Confidential and Proprietary
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, MD 
Vice President and Head of Immunology & Fibrosis Clinical Development 
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.
NOTE: Signed by Celgene based on Approval from Amgen Therapeutic Head 
 
  
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
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CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Amgen representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
5
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
6
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
PROTOCOL SUMMARY
Study Title
A phase 4, multi-center, randomized, double-blind, placebo-controlled study of the impact of 
apremilast (CC-10004) on quality of life, efficacy, and safety in subjects with manifestations of 
plaque psoriasis and impaired quality of life.
Indication
Psoriasis vulgaris is a chronic inflammatory immunologic disorder which manifests primarily in 
the skin. It is characterized by sharply demarcated areas of affected skin which appear thickened, 
red, and scaly. The scalp, elbows, knees, lower back, hands, and feet are commonly affected 
sites. About 80% of affected patients complain of pruritus (Gottlieb, 1998). The psoriatic 
appearance of the skin is initiated by an antigen presenting cell (APC) – T-cell interaction 
leading to the release of multiple inflammatory cytokines (Nestle, 2009). In time, this leads to an 
increased rate of epidermal proliferation with impaired differentiation of keratinocytes, resulting 
in a thickened epidermis covered by a thickened, parakeratotic stratum corneum. Dermal 
capillaries become tortuous and dilated, and there is infiltration of both epidermis and dermis 
with immunologically active cells (Lowes, 2007).
According to a European consensus statement on the definition of treatment goals for patients 
with plaque psoriasis, mild psoriasis is defined as body surface area (BSA) ≤ 10% and Psoriasis
Area Severity Index (PASI) ≤ 10 and Dermatology Life Quality Index (DLQI) ≤ 10. However, 
patients with mild psoriasis, as indicated by the somatic scores, BSA and PASI, may present with 
disease manifestations not adequately controlled by topical therapy alone which, in addition, may 
lead to a significantly impaired quality of life. These manifestations can include the following: 
involvement of visible areas, involvement of major parts of the scalp, involvement of genitals, 
involvement of palms and/or soles, onycholysis or onychodystrophy of at least two fingernails, 
pruritus leading to scratching, and presence of single recalcitrant plaques.  
The presence of any of the previously mentioned manifestations alters the classification of mild 
psoriasis to moderate to severe psoriasis in need of systemic therapy due to significantly 
impaired quality of life (Mrowietz, 2011).
Objectives
Primary Objective

To assess the impact of apremilast 30 mg twice daily (BID), compared to placebo, 
on Health-related Quality of Life (QOL) in subjects with manifestations of plaque 
psoriasis and impaired quality of life at Week 16
Secondary Objectives

To assess the efficacy and safety of apremilast 30 mg BID, compared to placebo 
in subjects with manifestations of plaque psoriasis and impaired quality of life at 
Week 16

To assess the long-term effects of apremilast 30 mg BID, with respect to quality 
of life, efficacy, and safety at Weeks 32 and 52
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
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CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Study Design
The study will be conducted in compliance with International Council for Harmonisation (ICH)
Good Clinical Practices (GCPs). This is a Phase 4, multi-center, randomized, placebo-controlled, 
double-blind study of the impact of apremilast on quality of life, efficacy, and safety in subjects 
with manifestations of plaque psoriasis and impaired quality of life.
Approximately 255 subjects will be randomized 2 (apremilast):1 (placebo) in approximately 6 to 
10 countries in Western Europe. Subjects will be block-randomized to each of the 5 
manifestations of plaque psoriasis. If subjects present with multiple manifestations, they will be 
allocated to the manifestation which is most severe, as determined by the subject. However, all 
manifestations will be assessed for efficacy at each study visit.  

After a 5-day titration with apremilast, subjects will receive apremilast 30 mg tablets 
or matching placebo orally twice daily (BID) for 16 weeks. Subjects randomized to 
the apremilast treatment group will receive apremilast 30 mg tablets orally twice daily 
for 52 weeks.

Subjects randomized to the placebo treatment group will receive placebo tablets 
(identical in appearance to the apremilast 30 mg tablets) orally twice daily for 16 
weeks. Beginning at Week 16 and after a 5-day titration with apremilast, subjects 
initially randomized to placebo will be switched to receive apremilast 30 mg BID for 
an additional 36 weeks (52 weeks total).
The study will consist of 4 phases:

Screening Phase – up to 5 weeks (35 days)

Double-blind Placebo-controlled Phase – Weeks 0 to 16
Subjects will receive treatment with either:

Apremilast 30 mg tablets orally BID, or

Matched placebo tablets orally BID

Apremilast Extension Phase – Weeks 16 through 52

All subjects will be switched to (or continue with) apremilast 30 mg BID at 
Week 16 (after a 5-day titration for subjects initially randomized to placebo). All 
subjects will maintain this dosing to Week 52.

Post-treatment Observational Follow-up Phase

4-week post-treatment observational follow-up for all subjects who complete the 
52-week study treatment or discontinue from the study treatment early
Study Population
Adult subjects ≥ 18 years of age with manifestations of plaque psoriasis and impaired quality of 
life.
Length of Study
The study is designed as a 52-week study, with a 4-week post-treatment observational follow-up. 
Visits will be scheduled at screening (no more than 5 weeks prior to randomization), Week 0 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
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Amgen, Inc.
Confidential and Proprietary
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CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
(baseline/randomization), Weeks 2, 4, 16, 20, 32, 44, and 52. A post-treatment observational 
follow-up will be conducted by telephone at Week 56 or 4 weeks after subject discontinues from 
the study treatment.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary, and/or exploratory analysis, as pre-specified in the protocol, 
whichever is the later date. 
Study Treatments
Subjects will be dispensed blister cards with 10, 20, and 30 mg apremilast tablets, or identically 
appearing placebo, for the dose titration, at the baseline visit (Week 0). The treatment schema for 
dose titration at Baseline is shown in Appendix P.
Starting at Week 16, all subjects will be switched to, or will continue with, apremilast. Subjects 
originally randomized to placebo at Week 0 will be switched to apremilast at Week 16. Dose 
titration blister cards will be used for subjects switching from placebo to apremilast; blister cards 
with dummy titration (dosing at 30 mg BID directly) will be used for subjects originally 
randomized to apremilast. Beginning with the Week 20 visit, all subjects will receive open label 
high-density polyethylene (HDPE) bottles of investigational product (IP) tablets. All subjects 
will maintain this dosing through Week 52.  
Apremilast tablets will be taken orally twice daily, approximately 12 hours apart, through the last 
treatment visit.
Overview of Key Efficacy Assessments
Primary Efficacy Endpoint
The primary endpoint will be the proportion of subjects who achieve a ≥ 4-point reduction from 
baseline in the DLQI in subjects receiving apremilast compared to placebo at Week 16.
Secondary Efficacy Endpoints

Dermatology Life Quality Index (DLQI) 

Itch Numeric Rating Scale (NRS)

Skin Discomfort/Pain Visual Analog Scale (VAS)

Body Surface Area (BSA)

Psoriasis Area and Severity Index (PASI)

Patient Benefit Index (PBI)

European Quality of Life 5-Dimension Questionnaire (EQ-5D)

The Work Productivity and Activity Impairment Questionnaire: Psoriasis (WPAI: 
PSO)
Overview of Key Safety Assessments
Safety assessments will include:

Adverse events (AE)
Approved 
 
 


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Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
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
Pregnancy tests for females of childbearing potential (FCBP)

Vital signs 

Body weight and waist circumference

Clinical laboratory tests
Statistical Methods
This study will randomize approximately 255 subjects to either apremilast 30 mg BID or placebo 
in a 2:1 ratio, respectively. 
Assuming a placebo DLQI Responder proportion of 0.50 at Week 16, a minimum total sample 
size of 210 subjects (140 allocated to apremilast 30 mg and 70 allocated to placebo) is needed to 
detect a 0.20 difference in the DLQI Responder proportions between apremilast and placebo with 
at least 0.807 power using a two-sided test at the 0.05 level of significance. This sample size 
calculation was determined using the commercial software EaST, Version 6.3. Allowing for an
18% discontinuation rate prior to Week 16, the sample size was revised from a total of 210 
subjects to a final sample size of 255.
The primary analysis for the primary endpoint at Week 16 will be the Cochran–Mantel–Haenszel 
(CMH) test adjusted for the stratification factor at randomization (ie, the 5 manifestation types). 
This form of the CMH test will use the sample sizes in each of the strata as weights when 
estimating the adjusted difference in the treatment proportions, constructing 95% Wald 
confidence intervals for the difference, and conducting a statistical test of no difference between 
the treatment proportions (ie, H0: πAPR – πPBO = 0 as the null hypothesis). 
All reasonable attempts will be made to prevent missing data from occurring in this study, 
especially at Week 16. However, in the case of missing data at Week 16 a multiple imputation 
(MI) method will be incorporated into the primary analysis. The aim of the multiple imputation 
approach is to incorporate a representative random sample in place of the missing data such that 
unbiased estimation and valid statistical inferences (ie, confidence intervals and hypothesis 
testing) can be made. 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
10
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................17
1.1.
Disease Background ...............................................................................................17
1.2.
Compound Background ..........................................................................................17
1.3.
Rationale ................................................................................................................18
1.3.1.
Study Rationale and Purpose ..................................................................................18
1.3.2.
Rationale for the Study Design ...............................................................................18
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................20
3.
OVERALL STUDY DESIGN ................................................................................23
3.1.
Study Design ..........................................................................................................23
3.2.
Study Duration for Subjects....................................................................................24
3.3.
End of Trial ............................................................................................................25
4.
STUDY POPULATION.........................................................................................26
4.1.
Number of Subjects ................................................................................................26
4.2.
Inclusion Criteria....................................................................................................26
4.3.
Exclusion Criteria...................................................................................................27
5.
TABLE OF EVENTS.............................................................................................29
6.
PROCEDURES......................................................................................................32
6.1.
Screening Period.....................................................................................................32
6.2.
Treatment Period ....................................................................................................33
6.2.1.
End of Treatment....................................................................................................34
6.3.
Follow-up Period....................................................................................................34
6.3.1.
Post-Treatment Observational Follow-up................................................................34
6.4.
Efficacy Assessments .............................................................................................34
6.4.1.
The Dermatology Life Quality Index (DLQI) .........................................................34
6.4.2.
Static Physicians Global Assessment (sPGA) of Visible Locations .........................35
6.4.3.
Scalp Physician Global Assessment (ScPGA).........................................................35
6.4.4.
Nail Assessments/Nail Psoriasis Severity Index (NAPSI) .......................................35
6.4.5.
Modified static Physicians Global Assessment of Genitalia (Modified 
sPGA-G) ................................................................................................................35
6.4.6.
Palmoplantar Psoriasis Physicians Global Assessment (PPPGA) ............................36
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
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Amgen, Inc.
Confidential and Proprietary
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CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
6.4.7.
Itch Numeric Rating Scale (NRS)...........................................................................36
6.4.8.
Skin Discomfort/Pain Visual Analog Scale (VAS)..................................................36
6.4.9.
Body Surface Area (BSA).......................................................................................36
6.4.10.
Psoriasis Area Severity Index (PASI)......................................................................36
6.4.11.
Patient Benefit Index (PBI).....................................................................................37
6.4.12.
The European Quality of Life 5-Dimension Questionnaire (EQ-5D).......................37
6.4.13.
The Work Productivity and Activity Impairment Questionnaire: Psoriasis 
(WPAI: PSO)..........................................................................................................37
.......................................................................................37
6.4.15.
Photography ...........................................................................................................37
6.5.
Safety Assessments.................................................................................................38
6.5.1.
Serum and Urine Pregnancy Tests for Females of Childbearing Potential ...............38
6.5.2.
Vital Signs, Weight and Waist Circumference ........................................................38
6.5.3.
Physical Examination .............................................................................................38
6.5.4.
Psychiatric Evaluation ............................................................................................39
6.5.5.
Severe Diarrhea, Nausea and Vomiting...................................................................39
6.5.6.
Clinical Laboratory Evaluations..............................................................................39
6.5.7.
Tuberculosis ...........................................................................................................39
6.5.8.
Adverse Events.......................................................................................................40
7.
DESCRIPTION OF STUDY TREATMENTS........................................................41
7.1.
Description of Investigational Product(s)................................................................41
7.2.
Treatment Administration and Schedule .................................................................41
7.3.
Method of Treatment Assignment...........................................................................41
7.4.
Packaging and Labeling..........................................................................................42
7.5.
Investigational Product Accountability and Disposal ..............................................42
7.6.
Investigational Product Compliance........................................................................42
7.7.
Overdose ................................................................................................................43
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................44
8.1.
Permitted Concomitant Medications and Procedures...............................................44
8.2.
Concomitant Medications Not Recommended ........................................................44
8.3.
Prohibited Concomitant Medications and Procedures..............................................44
8.4.
Required Concomitant Medications and Procedures................................................45
9.
STATISTICAL CONSIDERATIONS ....................................................................46
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
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Confidential and Proprietary
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CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
9.1.
Overview................................................................................................................46
9.2.
Study Population Definitions ..................................................................................46
9.3.
Sample Size and Power Considerations...................................................................46
9.4.
Background and Demographic Characteristics........................................................47
9.5.
Subject Disposition.................................................................................................47
9.6.
Efficacy Analysis....................................................................................................47
9.6.1.
Primary Endpoint....................................................................................................47
9.6.2.
Secondary and Exploratory Efficacy Endpoints ......................................................48
9.6.3.
Photography ...........................................................................................................48
....................................................................................48
9.6.5.
Multiplicity Adjustment..........................................................................................49
9.7.
Safety Analysis.......................................................................................................49
9.8.
Interim Analysis .....................................................................................................49
9.9.
Other Topics...........................................................................................................49
9.9.1.
Investigational Product Compliance (Tablets).........................................................49
9.9.2.
Concomitant Therapy .............................................................................................50
9.9.3.
Steering Committee ................................................................................................50
10.
ADVERSE EVENTS..............................................................................................51
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................51
10.2.
Evaluation of Adverse Events.................................................................................51
10.2.1.
Seriousness.............................................................................................................51
10.2.2.
Severity / Intensity..................................................................................................53
10.2.3.
Causality ................................................................................................................53
10.2.4.
Duration .................................................................................................................54
10.2.5.
Action Taken..........................................................................................................54
10.2.6.
Outcome.................................................................................................................54
10.3.
Abnormal Laboratory Values..................................................................................54
10.4.
Pregnancy...............................................................................................................55
10.4.1.
Females of Childbearing Potential – Collection of Pregnancy Information..............55
10.4.2.
Male Subject With Partners Who Become Pregnant................................................56
10.4.3.
Collection of Lactation Information........................................................................56
10.5.
Reporting of Serious Adverse Events......................................................................56
10.5.1.
Safety Queries ........................................................................................................57
Approved


EDMS Doc. Number: 24684941 - 22835610
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Confidential and Proprietary
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10.6.
Expedited Reporting of Adverse Events..................................................................57
11.
DISCONTINUATIONS .........................................................................................59
11.1.
Treatment Discontinuation......................................................................................59
11.2.
Study Discontinuation ............................................................................................59
12.
EMERGENCY PROCEDURES.............................................................................61
12.1.
Emergency Contact.................................................................................................61
12.2.
Emergency Identification of Investigational Products .............................................61
13.
REGULATORY CONSIDERATIONS...................................................................62
13.1.
Good Clinical Practice............................................................................................62
13.2.
Investigator Responsibilities ...................................................................................62
13.3.
Subject Information and Informed Consent.............................................................63
13.4.
Confidentiality........................................................................................................63
13.5.
Protocol Amendments.............................................................................................63
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................64
13.7.
Ongoing Information for Institutional Review Board/Ethics Committee .................64
13.8.
Termination of the Study ........................................................................................65
14.
DATA HANDLING AND RECORDKEEPING.....................................................66
14.1.
Data/Documents .....................................................................................................66
14.2.
Data Management...................................................................................................66
14.3.
Record Retention....................................................................................................66
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................68
15.1.
Study Monitoring and Source Data Verification......................................................68
15.2.
Audits and Inspections............................................................................................68
15.3.
Product Complaint..................................................................................................68
15.3.1.
How to Report a Product Complaint to Amgen .......................................................69
16.
PUBLICATIONS ...................................................................................................70
17.
REFERENCES.......................................................................................................71
18.
APPENDICES........................................................................................................72
Appendix A:
Table of Abbreviations ......................................................................................72
Appendix B:
The Dermatology Life Quality Index (DLQI).....................................................75
Appendix C:
Static Physicians Global Assessment (sPGA) Of Visible Locations....................77
Appendix D:
Scalp Physician Global Assessment (ScPGA)....................................................78
Approved 
 
 


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Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
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Appendix E:
Nail Psoriasis Severity Index (NAPSI)...............................................................79
Appendix F:
Modified Static Physicians Global Assessment of Genitalia (Modified 
sPGA-G) ................................................................................................................80
Appendix G:
Palmoplantar Psoriasis Physicians Global Assessment (PPPGA) .......................81
Appendix H:
Itch Numeric Rating Scale (NRS)......................................................................82
Appendix I:
Skin Discomfort/Pain Visual Analog Scale (VAS) ..............................................83
Appendix J:
Psoriasis Area Severity Index (PASI)..................................................................84
Appendix K:
Patient Needs Questionnaire (PNQ)...................................................................85
Appendix L:
Patient Benefit Questionnaire (PBQ)..................................................................86
Appendix M:
European Quality of Life 5-Dimension Questionnaire (EQ-5D) ........................87
Appendix N:
Work Productivity and Activity Impairment Questionnaire: Psoriasis 
(WPAI: PSO)..........................................................................................................90
Appendix O:
Waist Circumference Measurement & Body Mass Index ...................................91
Appendix P:
Treatment Schema for Dose Titration at Baseline...............................................92
Appendix Q:
Treatment Schema for Dose Titration at Week 16..............................................93
Appendix R:
Titration Blister Card.........................................................................................94
Appendix S:
Sample Serious Adverse Event Form..................................................................95
Appendix T:
Pregnancy Notification Form .............................................................................98
Appendix U:
Lactation Notification Form...............................................................................99
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
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CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................20
Table 2:
Study Endpoints .....................................................................................................20
Table 3:
Table of Events.......................................................................................................29
Table 4:
Abbreviations and Specialist Terms........................................................................72
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
16
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................24
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
17
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
1.
INTRODUCTION 
1.1.
Disease Background 
Psoriasis vulgaris is a chronic inflammatory immunologic disorder which manifests primarily in 
the skin. It is characterized by sharply demarcated areas of affected skin which appear thickened, 
red, and scaly. The scalp, elbows, knees, lower back, hands, and feet are commonly affected 
sites. About 80% of affected patients complain of pruritus (Gottlieb, 1998). The psoriatic 
appearance of the skin is initiated by an antigen presenting cell (APC) – T-cell interaction 
leading to the release of multiple inflammatory cytokines (Nestle, 2009). In time, this leads to an 
increased rate of epidermal proliferation with impaired differentiation of keratinocytes, resulting 
in a thickened epidermis covered by a thickened, parakeratotic stratum corneum. Dermal 
capillaries become tortuous and dilated, and there is infiltration of both epidermis and dermis 
with immunologically active cells (Lowes, 2007).
According to a European consensus statement on the definition of treatment goals for patients 
with plaque psoriasis, mild psoriasis is defined as body surface area (BSA) ≤ 10% and Psoriasis 
Area Severity Index (PASI) ≤ 10 and Dermatology Life Quality Index (DLQI) ≤ 10. However, 
patients with mild psoriasis, as indicated by the somatic scores, BSA and PASI, may present with 
disease manifestations not adequately controlled by topical therapy alone which, in addition, may 
lead to a significantly impaired quality of life. These manifestations can include the following: 
involvement of visible areas, involvement of major parts of the scalp, involvement of genitals, 
involvement of palms and/or soles, onycholysis or onychodystrophy of at least two fingernails, 
pruritus leading to scratching, and presence of single recalcitrant plaques. The presence of any of 
the previously mentioned manifestations may alter the classification of mild psoriasis to 
moderate to severe psoriasis in need of systemic therapy due to significantly impaired quality of 
life (Mrowietz, 2011).
1.2.
Compound Background
Apremilast (CC-10004) is a specific phosphodiesterase type 4 (PDE4) inhibitor under 
development for use in the treatment of inflammatory conditions. PDE4 is one of the major 
phosphodiesterases expressed in leukocytes. PDE4 inhibition by apremilast elevates cyclic 
adenosine monophosphate (cAMP) levels in immune cells, which in turn down-regulates the 
inflammatory response by reducing the expression of pro-inflammatory mediators such as tumor 
necrosis factor (TNF)-α, interleukin (IL)-23, IL-17, and other inflammatory cytokines, and 
increasing the production of anti-inflammatory mediators. 
In completed Phase 3 studies in subjects with moderate to severe plaque psoriasis and active 
psoriatic arthritis, treatment with apremilast was associated with statistically significant and 
clinically meaningful improvements in multiple efficacy measures. On the basis of these studies, 
apremilast (OTEZLA) is approved within Europe for the treatment of moderate to severe chronic 
plaque psoriasis in patients who failed to respond to or who have a contraindication to, or are 
intolerant to other systemic therapies including cyclosporine, methotrexate or psoralens and 
long-wave ultraviolet radiation (PUVA) and alone or in combination with disease-modifying 
antirheumatic drugs (DMARDs) for the treatment of active psoriatic arthritis in adult patients 
who have had an inadequate response or who have been intolerant to a prior DMARD.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
18
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Apremilast remains under further clinical development for the treatment of inflammatory/ 
autoimmune disorders including Behçet’s disease and ulcerative colitis. Further studies within 
the approved indications of plaque psoriasis and psoriatic arthritis are also ongoing.
Please refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP).
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
Psoriasis vulgaris is a chronic inflammatory immunologic disorder which manifests primarily in 
the skin. It is characterized by sharply demarcated areas of affected skin which appear thickened, 
red, and scaly. The scalp, elbows, knees, lower back, hands, and feet are commonly affected 
sites. About 80% of affected patients complain of pruritus (Gottlieb, 1998). The psoriatic 
appearance of the skin is initiated by an APC – T-cell interaction leading to the release of 
multiple inflammatory cytokines (Nestle, 2009). In time, this leads to an increased rate of 
epidermal proliferation with impaired differentiation of keratinocytes, resulting in a thickened 
epidermis covered by a thickened, parakeratotic stratum corneum. Dermal capillaries become 
tortuous and dilated, and there is infiltration of both epidermis and dermis with immunologically 
active cells (Lowes, 2007).
According to a European consensus statement on the definition of treatment goals for patients 
with plaque psoriasis, mild psoriasis is defined as BSA ≤ 10% and PASI ≤ 10 and DLQI ≤ 10. 
However, many patients may present with BSA ≤ 10% and PASI ≤ 10 but due to the presence of 
disease manifestations that are difficult to control with topical therapy alone, may have a 
significantly impaired quality of life (DLQI > 10). These manifestations can include the 
following: involvement of visible areas, involvement of major parts of the scalp, involvement of 
genitals, involvement of palms and/or soles, onycholysis or onychodystrophy of at least two, 
fingernails, pruritus leading to scratching, and presence of single recalcitrant plaques. The 
presence of any of the previously mentioned manifestations may alter the classification of mild 
psoriasis to moderate to severe psoriasis in need of systemic therapy due to significantly 
impaired quality of life (Mrowietz, 2011).
1.3.2.
Rationale for the Study Design
This is a Phase 4, multi-center, randomized, double-blind, placebo-controlled study to assess the 
impact of apremilast on health-related quality of life, efficacy, and safety in patients with 
manifestations of plaque psoriasis and impaired quality of life. The primary endpoint in this 
study is the proportion of subjects who achieve a ≥ 4-point change in the DLQI at Week 16 
compared to placebo. The study population will be very heterogeneous and consist of subjects 
with a variety of clinical manifestations of psoriasis, such as scalp, nail, palmoplantar, and 
genital psoriasis and lesions in visible locations. Common among patients with any of these 
manifestations is a high impairment in Quality of Life (QOL); therefore, assessing the proportion 
of subjects who achieve a minimal clinically important difference in the DLQI is clinically 
meaningful. Although the DLQI is the gold standard QOL assessment in psoriasis and other 
dermatologic diseases, as a patient-reported outcome, it is often associated with a high placebo 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
19
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
response rate. To understand the true impact of apremilast on QOL in patients with 
manifestations of psoriasis and impaired quality of life, a 16-week placebo-controlled period is 
necessary. After Week 16, subjects who were randomized to placebo will receive active 
treatment with apremilast through Week 52.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
20
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to assess the impact of apremilast 30 mg twice daily (BID), 
compared to placebo, on health-related quality of life (qol) in subjects with manifestations of plaque 
psoriasis and impaired quality of life at Week 16.
Secondary Objective(s)
The secondary objectives are:
•
To assess the efficacy and safety of apremilast 30 mg BID, compared to placebo in subjects with 
manifestations of plaque psoriasis and impaired quality of life at Week 16
•
To assess the long-term effects of apremilast 30 mg BID, with respect to quality of life, efficacy, and 
safety at Weeks 32 and 52
Exploratory Objective(s)
The exploratory objectives are:
•
To assess the efficacy of apremilast 30 mg BID, compared to placebo in subgroups of subjects with 
specific manifestations
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Dermatology Life Quality 
Index (DLQI)
Proportion of subjects who achieve 
a ≥ 4-point reduction from baseline 
Weeks 16
Secondary 
DLQI
Proportion of subjects who achieve 
a ≥ 4-point reduction from baseline
Weeks 32, 52
DLQI
Mean change from baseline
Weeks 16, 32, 52
Itch Numeric Rating Scale 
(NRS)
Mean change from baseline in Itch
NRS score
Weeks 16, 32, 52
Skin Discomfort/Pain Visual 
Analog Scale (VAS)
Mean change from baseline in skin 
discomfort/pain VAS 
Weeks 16, 32, 52
Body Surface Area (BSA)
Mean percent change in BSA 
affected by psoriasis 
Weeks 16, 32, 52
Patient Benefit Index (PBI)
Proportion of subjects who achieve 
PBI score of ≥ 1 
Weeks 16, 32, 52
Psoriasis Area Severity Index 
(PASI)
Proportion of subjects who achieve 
PASI < 3
Weeks 16, 32, 52
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
21
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
European Quality of Life 5-
Dimension (EQ-5D)
Mean percent change from 
baseline in EQ-5D score
Weeks 16, 52
Work Productivity and 
Activity Impairment 
Questionnaire: Psoriasis 
(WPAI: PSO)
Mean change in WPAI domain 
scores
Weeks 16, 52
Treatment-emergent Adverse 
events
Frequency and incidence rate of 
any TEAE by SOC, PT, severity, 
and relationship of adverse events 
(AEs) to investigational product 
(IP).
During double-
blinded treatment 
and throughout the 
duration of the 
apremilast treatment
Clinically significant changes 
in body weight, waist 
circumference, vital signs, 
and/or laboratory findings
Frequency of clinically 
significant changes in body 
weight, waist circumference, vital 
signs, and/or laboratory findings.
During double-
blinded treatment 
and throughout the 
duration of the 
apremilast treatment
Exploratory
Static Physician Global 
Assessment (sPGA) of 
Visible locations
Proportion of subjects who 
achieve sPGA score of 0 or 1 
(among subjects randomized with 
moderate to severe psoriasis in 
visible areas, defined as sPGA ≥ 
3, which include the dorsal hand, 
face, neck, or hairline)
Weeks 16, 32, 52
Scalp Physician Global 
Assessment (ScPGA)
Proportion of subjects who 
achieve ScPGA score of 0 or 1 
(among subjects randomized with 
moderate to severe scalp 
psoriasis, ScPGA ≥ 3)
Weeks 16, 32, 52
Nail Psoriasis Severity Index 
(NAPSI)
Proportion of subjects who 
achieve NAPSI score of 0 in the 
target fingernail (among subjects 
randomized with presence of nail 
psoriasis, defined as onycholysis 
and onychodystrophy in at least 2 
fingernails)
Weeks 16, 32, 52
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
22
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Modified Static Physician 
Global Assessment-Genitalia 
(sPGA-G)
Proportion of subjects who achieve 
modified sPGA-G score of 0 or 1 
(among subjects randomized with 
moderate to severe genital 
psoriasis, modified sPGA-G ≥ 3)
Weeks 16, 32, 52
Palmoplantar Psoriasis 
Physician Global Assessment 
(PPPGA)
Proportion of subjects who achieve 
PPPGA score of 0 or 1 (among 
subjects randomized with 
moderate to severe palmoplantar 
psoriasis, PPPGA ≥ 3)
Weeks 16, 32, 52
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
23
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 4, multi-center, randomized, placebo-controlled, double-blind study of the impact 
of apremilast on quality of life, efficacy, and safety in subjects with manifestations of plaque 
psoriasis and impaired quality of life.
Approximately 255 subjects will be randomized 2 (apremilast):1 (placebo) in approximately 6 to 
10 countries in Western Europe. Subjects will be block-randomized to each of the manifestations 
of psoriasis (scalp psoriasis, nail psoriasis, palmoplantar psoriasis, genital psoriasis, and psoriasis 
in visible locations). If subjects present with multiple manifestations, they will be allocated to the 
manifestation which is most severe, as determined by the subject. However, all manifestations 
will be assessed for efficacy at each study visit. 

After a 5-day titration with apremilast, subjects will receive apremilast 30 mg tablets 
or matching placebo orally twice daily (BID) for 16 weeks. Subjects randomized to 
the apremilast treatment group will receive apremilast 30 mg tablets orally twice daily 
for 52 weeks.

Subjects randomized to the placebo treatment group will receive placebo tablets 
(identical in appearance to the apremilast 30 mg tablets) orally twice daily for 16 
weeks. Beginning at Week 16 and after a 5-day titration with apremilast, subjects 
initially randomized to placebo will be switched to receive apremilast 30 mg BID for 
an additional 36 weeks (52 weeks total).
The study will consist of 4 phases:

Screening Phase – up to 5 weeks (35 days)

Double-blind Placebo-controlled Phase – Weeks 0 to 16
Subjects will receive treatment with either

apremilast 30 mg tablets orally BID, or

matched placebo tablets orally BID

Apremilast Extension Phase – Weeks 16 through 52

All subjects will be switched to (or continue with) apremilast 30 mg BID at 
Week 16 (after a 5-day titration for subjects initially randomized to placebo). All 
subjects will maintain this dosing through Week 52.

Post-treatment Observational Follow-up Phase

4-week post-treatment observational follow-up phase for all subjects who 
complete the study on treatment or discontinue from the study treatment early 
After all subjects complete the Week 16 Visit (or discontinue prematurely from the study), 
selected members of the Amgen study team and external partner who do not have direct 
interaction with subjects will be unblinded for the analysis of the Week 16 data. These persons 
may include but are not limited to the following: Therapeutic Area Head, Study lead, Medical 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
24
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Director and the Statistician. The results from these analyses may be published prior to the end 
of the study.
The blind should be maintained for persons responsible for the ongoing conduct of the study. 
Subjects, Investigators and persons responsible for the ongoing conduct of the study will 
continue to be blinded to the original treatment assignment until the end of the study. These 
persons are those individuals who have direct interaction with subjects and/or subject 
assessments, and may include but are not limited to the following: Clinical Trial Manager, Data 
Manager, Clinical Research Associates (Amgen and External Partners) and Site Monitors. 
The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
Figure 1:
Overall Study Design
BID = twice daily; BL = baseline; DLQI = Dermatology Life Quality Index.
3.2.
Study Duration for Subjects
The study is designed as a 1-year (52-week) study, with a 4-week Post-treatment Observational 
Follow-up Phase.
Visits will be scheduled at screening (no more than 5 weeks prior to randomization), Week 0 
(baseline/randomization), Weeks 2, 4, 16, 20, 32, 44, and 52. Subjects who discontinue before 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
25
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Week 52 will be asked to attend an Early Termination visit. A post-treatment observational 
follow-up will be conducted by phone at Week 56 for subjects who complete the 52-week study 
treatment, or 4 weeks after study treatment discontinuation.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary, and/or exploratory analysis, as pre-specified in the protocol, 
whichever is the later date.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
26
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 255 subjects will be enrolled in the study across approximately 6 to 10 countries 
in Western Europe.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. Subject has diagnosis of chronic plaque psoriasis for at least 6 months prior to baseline, 
that cannot be controlled by topical therapy.
5. Subject has a PASI score ranging from ≥3 to ≤ 10 at baseline.
6. Subject has a DLQI score > 10 at baseline.
7. Subject has presence of ≥ 1 clinical manifestations of plaque psoriasis, defined as at least 
one of the following: 
a.
Moderate to severe scalp psoriasis, defined as Scalp Physician Global Assessment 
(ScPGA) ≥ 3
b. Nail psoriasis, defined as onycholysis and onychodystrophy in at least 2 fingernails
c.
Moderate to severe genital plaque psoriasis, defined as modified static Physicians 
Global Assessment of Genitalia (sPGA-G) ≥3
d. Moderate to severe palmoplantar psoriasis, defined as Palmoplantar Psoriasis 
Physicians Global Assessment (PPPGA) ≥ 3
e.
Moderate to severe plaque psoriasis in visible locations (dorsal hand, face, neck, and 
hairline) with static Physicians Global Assessment (sPGA) ≥ 3
8. Subject must be in general good health (except for psoriasis) as judged by the 
Investigator, based on medical history, physical examination, and clinical laboratories. 
(NOTE: The definition of good health means a subject does not have uncontrolled 
significant co-morbid conditions.) 
9. Subject must have failed to respond to, or be contraindicated to, or intolerant to other 
systemic therapy including, but not limited to, cyclosporine, methotrexate, acitretin, 
psoralen and ultraviolet-A-light (PUVA), fumaric acid esters or biologic therapies.
10. Subjects (in Italy only) must be non-responder to, contraindicated to, or intolerant to 
other systemic therapy (including cyclosporine, methotrexate, or PUVA) AND also be 
contraindicated to, or intolerant to biologics.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
27
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
11. Females of childbearing potential (FCBP)† must have a negative pregnancy test at 
Screening and Baseline. While on investigational product and for at least 28 days after 
taking the last dose of investigational product, FCBP who engage in activity in which 
conception is possible must use one of the approved contraceptive§ options described 
below:
Option 1: Any one of the following highly effective methods: hormonal contraception 
(oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal 
ligation; or partner’s vasectomy;
OR
Option 2: Male or female condom (latex condom or nonlatex condom NOT made out of 
natural [animal] membrane [for example, polyurethane]) PLUS one additional barrier 
method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) 
contraceptive sponge with spermicide.
NOTE: Option 2 may not be acceptable as a highly effective contraception option in all
countries per local guidelines/regulations.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any condition, including other inflammatory diseases or dermatologic 
conditions, which confounds the ability to interpret data from the study, including other 
types of psoriasis (ie, erythrodermic, or guttate), other than plaque psoriasis or inverse 
psoriasis.
2. Subject has history of drug-induced psoriasis.
3. Subject has arthritis that requires disease-modifying antirheumatic drug (DMARD)
treatment.
4. Subject unable to avoid use of tanning booths for at least 4 weeks prior to baseline and 
during study.
5. Subject is currently enrolled in any other clinical trial involving an investigational 
product.
6. Other than psoriasis, subject has history of clinically significant or uncontrolled disease
(as determined by the Investigator), including the presence of laboratory abnormalities,
cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, 
immunologic disease, or other major disease, which places the subject at unacceptable 
risk if he/she were to participate in the study.
                                               
† A female of childbearing potential is defined as a sexually mature female who 1) has not undergone a 
hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) 
or 2) has not been postmenopausal for at least 24 consecutive months (that is, has had menses at any time during 
the preceding 24 consecutive months).
§ The female subject’s chosen form of contraception must be effective by the time the female subject is randomized 
into the study (for example, hormonal contraception should be initiated at least 28 days before randomization).
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen, Inc.
Confidential and Proprietary
28
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
7. Prior history of suicide attempt at any time in the subject’s lifetime prior to signing the 
informed consent, or major psychiatric illness requiring hospitalization within the last 3 
years prior to signing the informed consent.
8. Subjects with severe renal impairment, defined by eGFR (estimated glomerular filtration 
rate) or CLcr (creatinine clearance) less than 30 mL/min, are also categorized as having 
Stage 4 Chronic Kidney Disease (CKD), and are excluded from the study.
9. Malignancy or history of malignancy or myeloproliferative or lymphoproliferative 
disease within the past 3 years, except for treated (ie, cured) basal cell or squamous cell 
in situ skin carcinomas.
10. Bacterial infections requiring treatment with oral or injectable antibiotics, or significant 
viral or fungal infections, within 4 weeks of Screening. Any treatment for such infections 
must have been completed and the infection cured, at least 4 weeks prior to Screening 
and no new or recurrent infections prior to the Baseline Visit. 
11. Subject has received a live vaccine within 3 months of baseline or plans to do so during 
study.
12. Subject is a pregnant or breastfeeding (lactating) woman.
13. Subject has used topical therapy within 2 weeks of randomization (including, but not 
limited to, topical corticosteroids, retinoids or vitamin D analog preparations, tacrolimus, 
pimecrolimus, anthralin/dithranol, or moisturizers which contain urea or salicylic acid). 
Use of phototherapy within 4 weeks prior to randomization. Use of conventional 
systemic therapy or systemic corticosteroids within 4 weeks prior to randomization, 
except for conditions other than psoriasis or psoriatic arthritis. Use of biologic therapy 
within 5 pharmacokinetic half-lives.
14. Prior treatment with apremilast, or participation in a clinical study, involving apremilast.
15. Subject has any condition that confounds the ability to interpret data from the study.
16. Subject has history of allergy or hypersensitivity to any components of the IP (including 
placebo).
17. Subject has rare hereditary problem of galactose intolerance, lapp lactase deficiency or 
glucose-galactose malabsorption.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
29
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
5.
TABLE OF EVENTS
Table 3:
Table of Events
Screening
Placebo-Controlled Phasea
Apremilast Extension Phaseb
Post-Treatment 
Observational Follow-upd
Visit Number
1
Baseline
2
3
4
5
6
7
8
9/ETc
Week
-35 to 0
days
0
(Day 1)
2
(± 3 days)
4
(± 3 days)
16
(± 3 days)
20
(± 4 days)
32
(± 4 days)
44
(± 4 days)
52
(± 4 days)
56 weeks (or 4 weeks after 
study discontinuation)
Informed consente
X
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion 
criteria
X
X
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
Medical history
X
-
-
-
-
-
-
-
-
-
Prior / concomitant 
medications or therapies
X
X
X
X
X
X
X
X
X
-
Clinical and Laboratory Assessments
Adverse eventsf
X
X
X
X
X
X
X
X
X
X
Pregnancy test and 
contraception educationg
X
X
-
-
-
-
-
-
X
-
Vital signs
X
X
X
X
X
X
X
X
X
-
Height
X
-
-
-
-
-
-
-
-
-
Weight
X
X
X
X
X
X
X
X
X
-
Waist Circumference
X
X
X
X
X
X
X
-
X
-
Body Mass Index
X
-
-
-
-
-
-
-
-
-
Physical Examination
X
-
-
-
-
-
-
-
-
-
Clinical laboratory 
evaluations,h,i
X
X
-
-
X
-
X
-
X
-
 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
30
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Table 3:
Table of Events (Continued)
Screening
Placebo-Controlled Phasea
Apremilast Extension Phaseb
Post-Treatment 
Observational Follow-upd
Visit Number
1
Baseline 
2
3
4
5
6
7
8
9/ETc
Week
-35 to 0
days
0
(Day 1)
2
(± 3 days)
4
(± 3 days)
16
(± 3 days)
20
(± 4 days)
32
(± 4 days)
44 
(± 4 days)
52
(± 4 days)
56 (or 4 weeks after study 
discontinuation)
Health-related Quality of Life and Efficacy Assessmentsj
DLQI
X
X
X
X
X
X
X
-
X
-
sPGA of Visible 
Locationk
X
X
X
X
X
X
X
-
X
-
ScPGAk
X
X
X
X
X
X
X
-
X
-
Nail Assessmentl
X
X
X
X
X
X
X
-
X
-
NAPSIk
X
X
X
X
X
X
-
X
-
Modified sPGA-Gk
X
X
X
X
X
X
X
-
X
-
PPPGAk
X
X
X
X
X
X
X
-
X
-
Itch NRS
-
X
X
X
X
X
X
-
X
-
Skin Discomfort/Pain 
VAS
-
X
X
X
X
X
X
-
X
-
PASI
X
X
X
X
X
X
X
-
X
-
BSA
-
X
X
X
X
X
X
-
X
-
EQ-5D
-
X
-
-
X
-
-
-
X
-
PNQ
-
X
-
-
-
-
-
-
-
-
PBQ
-
-
-
X
X
-
X
-
X
-
WPAI: PSO
-
X
-
-
X
-
-
-
X
-
Photographym
-
X
-
-
X
-
X
-
X
-
 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
31
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Table 3:
Table of Events (Continued)
Screening
Placebo-Controlled Phasea
Apremilast Extension Phaseb
Post-Treatment 
Observational Follow-upd
Visit Number
1
Baseline 
2
3
4
5
6
7
8
9/ETc
Week
-35 to 0
days
0
(Day 1)
2
(± 3 days)
4
(± 3 days)
16
(± 3 days)
20
(± 4 days)
32
(± 4 days)
44 
(± 4 days)
52
(± 4 days)
56 (or 4 weeks after study 
discontinuation)
Dispense IP
-
X
-
X
X
X
X
X
-
-
Return and Count IP 
Tablets
-
-
-
X
X
X
X
X
X
-
Abbreviations:  BMI = body mass index; BSA = body surface area; 
 DLQI = Dermatology Life Quality Index; EQ-5D = European Quality of Life 5-
Dimension; FCBP = females of childbearing potential; IP = investigational product; NAPSI = Nail Psoriasis Severity Index; PASI = Psoriasis Area Severity Index; PBQ = Patient 
Benefit Questionnaire; PNQ = Patient Needs Questionnaire; PPPGA = Palmoplantar Psoriasis Physicians Global Assessment; NRS = Numeric Rating Scale; ScPGA = Scalp 
Physician Global Assessment; sPGA = static Physicians Global Assessment; sPGA-G = static Physicians Global Assessment of Genitalia; VAS = Visual Analog Scale; 
WPAI:PSO = Work Productivity and Activity Impairment Questionnaire: Psoriasis.
a Visits in the Placebo-controlled Phase to be performed ± 3 days.
b Visits in the Apremilast Extension Phase to be performed ± 4 days.
c Visit 9 will serve as the Early Termination Visit for any subject who prematurely discontinues from the study, prior to Week 52. All subjects who complete the study or 
discontinue the study early will be asked to enter the Four-week Post-treatment Observational Follow-up Phase.
d Post-treatment observational follow-up will be conducted by telephone.
e Written informed consent will be obtained by the Principal Investigator or designee prior to initiation of any study procedures, including washouts from prior medications.
f Adverse event review should include new or worsening psychiatric symptoms, suicidal ideation, suicidal attempt, severe diarrhea, nausea and vomiting, and unexplained and 
clinically significant weight loss. See Section 6.5.
g Females of childbearing potential (FCBPs) only. Serum pregnancy tests are performed at Screening, and Early Termination Visit/Last Treatment Visit. Urine pregnancy test kit 
will also be provided to the site and performed at baseline prior to randomization. The Investigator will educate all FCBP about the different options of contraceptive methods 
and their correct use at Screening and Baseline visits. The subject will be reeducated every time their contraceptive measures/methods or their ability to become pregnant 
changes. A pregnancy test(s) should be administered if the FCBP subject misses a menstrual period.
h Laboratory assessments will include routine/standard chemistry and hematology panel of tests. A lipid panel will be included in the standard chemistry panel. If screening
laboratory assessments are within 7 days of Baseline (Week 0), laboratory assessment does not need to be repeated at Baseline (Week 0). For females of childbearing potential 
urine pregnancy test will be performed at Baseline (Week 0) to confirm subject eligibility (negative results required for IP administration).  
j Subject assessments must be completed in the following order: DLQI, Itch NRS, Skin Discomfort/Pain VAS, EQ-5D, PNQ/PBQ, and WPAI: PSO, as scheduled in the Table of 
Events.
k All manifestations should be assessed in all subjects at all visits, so that improvement, worsening, or new onset of any of these manifestations can be assessed.
l Nail assessments will evaluate presence of nail psoriasis, defined as onycholysis and onychodystrophy.
m Photographs will be obtained from subjects who provide separate consent to be photographed and at select sites only.
 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
32
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
6.
PROCEDURES
The following procedures will be conducted as outlined in the Table of Events, Table 3.
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 5 weeks of randomization.  Subjects who do not meet 
eligibility criteria for the study may be re-screened once, after a minimum of 35 days from the 
date of their first screening.
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Safety laboratory analyses and all assessments will be performed (locally/centrally). Screening 
laboratory values must demonstrate subject eligibility, but may be repeated once within the 
screening window, if necessary.
The following will be performed at screening as specified in the Table of Events, after informed 
consent has been obtained:

Demographics (year of birth, sex, and race, if allowed by local regulations, will be 
collected). 

Complete medical history

Prior and concomitant medications

Physical examination, height, weight, waist circumference, body mass index (see 
Appendix O)

Vital signs (including blood pressure and heart rate)

Hematology panel including complete blood count (CBC) with differential, including red 
blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), RBC Morphology, mean 
corpuscular volume (MCV), white blood cell (WBC) count (with differential), and 
platelet count.

Chemistry panel including sodium, potassium, calcium, chloride, blood urea nitrogen 
(BUN), creatinine, creatinine clearance, glucose, albumin, total protein, alkaline 
phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum glutamic pyruvic 
transaminase (ALT/SGPT), gamma-glutamyl transferase (GGT), lactate dehydrogenase 
(LDH). A lipid panel will be included in the standard chemistry panel. 
 

Pregnancy test is required for all female subjects of childbearing potential. Serum beta 
human chorionic gonadotropin (β-hCG) pregnancy test will be performed at screening. 
Urine (or serum) pregnancy test will be performed to assess subject eligibility within 72 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
33
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
hours prior to the first administration of IP, if the initial serum pregnancy test did not 
already occur with 72 hours of dosing (negative results required for IP administration).

Contraception education will be performed by the Investigator at screening for all FCBP 
about the options for and correct use of contraceptive methods at the Screening and 
Baseline Visits and at any time when a FCBP’s contraceptive measures or ability to 
become pregnant changes.

A pregnancy test should be performed if the FCBP subject has missed a menstrual 
period or the contraception method has changed

Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted. 

Adverse event assessment begins when the subject signs the informed consent form

Health-related quality of life and efficacy assessments to determine study eligibility, 
including DLQI, sPGA of visible locations, ScPGA, NAPSI, modified sPGA-G, PPPGA,
and PASI
6.2.
Treatment Period
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment within 35 days (5 weeks) of signing the ICF. An administrative window of ± 3 day is 
permitted for Visits 3 and 4 and ± 4 days is permitted for Visits 5 through 9. 
The following procedures will be conducted as outlined in the Table of Events, Table 3. The 
evaluations should be performed prior to dosing on the visit day, unless otherwise specified.

Inclusion/Exclusion criteria (Baseline/Visit 2)

Concomitant medications and therapies evaluation

Vital signs

Weight, waist circumference

Adverse event evaluation (continuously and through 28 days after last dose of 
apremilast)

Clinical laboratory evaluations [If screening laboratory assessments are within 7 days 
of Baseline (Week 0), laboratory assessment does not need to be repeated at Baseline 
(Week 0)]

Efficacy assessment (see Section 6.4) [In addition to assessments specified in Table 3, 
investigator will follow country guidelines to monitor therapy outcomes according to 
clinical routine care and may assess efficacy or safety at any unscheduled visit and 
document in source documents.]

Dispense IP

Return and count IP tablets

Urine (or serum) pregnancy test (prior to dosing on Day 1)
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
34
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
6.2.1.
End of Treatment
An end of treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made. The end of treatment (Visit 9) assessments will also be performed for 
subjects who complete the study.
The following evaluations will be performed as specified in the Table of Events:

Weight, waist circumference

Vital signs

Concomitant medications and therapies evaluation

Adverse event evaluation (through 28 days past last dose of apremilast)

Clinical laboratory evaluations

Serum pregnancy test for females of childbearing potential (β-subunit of human chorionic 
gonadotropin [Serum β-hCG])

Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted

Return and count IP tablets

Efficacy assessment
6.3.
Follow-up Period
6.3.1.
Post-Treatment Observational Follow-up
All subjects will be followed for 28 days after the last dose of apremilast for AE reporting , as 
well as all SAEs made known to the Investigator at any time following the protocol-required 
reporting period or after end of study, as described in Section 10.1. A 4-week post-treatment 
observational follow-up will be conducted by telephone at Week 56 for subjects who complete 
the 52-week study treatment or 4 weeks after study treatment discontinuation.
6.4.
Efficacy Assessments
The following assessments will be conducted as outlined in the Table of Events, Table 3.
6.4.1.
The Dermatology Life Quality Index (DLQI)
The DLQI (Finlay, 1994) will be assessed by the subject upon arrival at the site
before any other procedures or assessments are performed. The DLQI was developed 
as a simple, compact, and practical questionnaire for use in a dermatology clinical 
setting to assess limitations related to the impact of skin disease (Finlay, 1994). The 
instrument contains 10 items pertaining to the subject’s skin. With the exception of 
Item Number 7, the subject responds on a four-point scale, ranging from “Very 
Much” to “Not at All.” Item Number 7 is a multi-part item, the first part of which 
ascertains whether the subject’s skin prevented them from working or studying (Yes 
or No), and if “No,” then the subject is asked how much of a problem the skin has 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
35
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
been at work or study over the past week, with response alternatives being “A lot,” 
“A little,” or “Not at all.”  
The DLQI total score has a possible range from 0 to 30, with 30 corresponding to the 
worst quality of life, and 0 corresponding to the best score. The developers suggest 
that the DLQI can be grouped into six subscales: symptoms and feelings, daily 
activities, leisure, work/school, personal relationships, and treatment. Scores for four 
of the subscales (symptoms and feelings, daily activities, leisure, and personal 
relationships) range from 0 to 6; scores for two of the subscales (work/school and 
treatment) range from 0 to 3. Higher scores correspond to poorer quality of life. See 
Appendix B.
6.4.2.
Static Physicians Global Assessment (sPGA) of Visible Locations
The sPGA is the assessment by the Investigator of the overall disease severity at the 
time of evaluation.  The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), 
incorporating an assessment of the severity of the three primary signs of the disease: 
erythema, scaling and plaque elevation.  In this study, sPGA is used to evaluate 
psoriasis only in visible locations, defined as dorsal hand, face, neck and hairline. 
When making the assessment of overall severity, the investigator should factor in 
areas that have already been cleared (ie, have scores of 0) and not just evaluate 
remaining lesions for severity, ie, the severity of each sign is averaged across all areas 
of involvement, including cleared lesions. In the event of different severities across 
disease signs, the sign that is the predominant feature of the disease should be used to 
help determine the sPGA score. See Appendix C for grading criteria.
6.4.3.
Scalp Physician Global Assessment (ScPGA)
The ScPGA will assess scalp involvement. See Appendix D for grading criteria. The 
5-point ScPGA scale ranges from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), to 
4 (severe).
6.4.4.
Nail Assessments/Nail Psoriasis Severity Index (NAPSI)
The number of fingers with psoriasis nail involvement, defined as onycholysis and 
onychodystrophy, will be counted.
The NAPSI will assess one target thumb nail or fingernail representing the worst nail 
psoriasis involvement at Baseline. See Appendix E for grading criteria.
6.4.5.
Modified static Physicians Global Assessment of Genitalia (Modified sPGA-G)
The modified sPGA-G is the assessment by the Investigator of the overall disease 
severity at the time of evaluation of the genital regions. The assessment area includes 
the vulvar region in women, from the clitoral prepuce to the perineum, and the penis, 
scrotum, and perineum in men. It does not include the pubis, inguinal folds, peri-anal 
region, or gluteal cleft; however, in this study, the assessment will be modified to also 
include the peri-anal region and gluteal cleft. As with the sPGA, it is a 5-point scale, 
ranging from 0 (clear) to 4 (severe). Note that not all three individual features will 
always be present on evaluation. Thus, while the total represents a combination of the 
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
36
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
three features, it should be primarily determined by the degree of erythema, as that is 
the dominant feature in the majority of cases of genital psoriasis (Merola, 2017). 
Appendix F.
6.4.6.
Palmoplantar Psoriasis Physicians Global Assessment (PPPGA)
The PPPGA is the assessment by the Investigator of the overall disease severity at the 
time of evaluation of palms and soles (Leonardi, 2007). The scale ranges from 
ranging from 0 (clear) to 4 (severe). See Appendix G.
6.4.7.
Itch Numeric Rating Scale (NRS)
The Itch NRS is a single-item patient-reported outcome that asks subjects to assess 
the worst severity of itch over the past 24 hours. Subjects indicate itch severity by 
circling the number that best describes the worst level of itching due to psoriasis in 
the past 24 hours on an 11-point scale anchored at 0, representing ‘no itching’ and 10, 
representing ‘worst itch imaginable’ (Naegeli, 2015). See Appendix H.
6.4.8.
Skin Discomfort/Pain Visual Analog Scale (VAS)
The subject will be asked to place a vertical stroke on a 100 mm VAS on which the 
left-hand boundary represents no skin discomfort/pain, and the right-hand boundary 
represents skin discomfort/pain as severe as can be imagined. The distance from the 
mark to the left-hand boundary will be recorded. See Appendix I.
6.4.9.
Body Surface Area (BSA)
Body surface area is a measurement of involved skin. The overall BSA affected by 
psoriasis is estimated based on the palm area of the subject’s hand (entire palmar 
surface or “handprint”), which equates to approximately 1% of total BSA.
6.4.10.
Psoriasis Area Severity Index (PASI)
The PASI will be determined for all subjects throughout the study. The PASI 
calculation is described in Appendix J.
The PASI is a measure of psoriatic disease severity taking into account qualitative 
lesion characteristics (erythema, thickness, and scaling) and degree of skin surface 
area involvement on defined anatomical regions. The PASI is a validated instrument 
that has become standard in clinical trials for psoriasis.
The PASI scores range from 0 to 72, with higher scores reflecting greater disease 
severity (Fredriksson, 1978). Erythema, thickness, and scaling are scored on a scale 
of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper 
limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is 
scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The total 
qualitative score (sum of erythema, thickness, and scaling scores) is multiplied by the 
degree of involvement for each anatomic region and then multiplied by a constant. 
These values for each anatomic region are summed to yield the PASI score.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
37
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
6.4.11.
Patient Benefit Index (PBI)
The PBI is a validated patient-reported instrument to assess patient-relevant benefits 
of psoriasis treatment (Feuerhahn, 2012). Prior to starting therapy, subjects are asked 
to assess their treatment expectations by completing the Patient Needs Questionnaire 
(PNQ) (See Appendix K). After a period of treatment, subjects are then asked to 
assess the benefits of treatment by completing the Patient Benefit Questionnaire 
(PBQ) (See Appendix L). The Patient Benefit Index represents the subject benefits 
realized as a function of most important subject needs. The PBI score ranges from 0 
(no benefit) to 4 (maximum benefit).
6.4.12.
The European Quality of Life 5-Dimension Questionnaire (EQ-5D)
EQ-5D (The EuroQol Group, 1990) measures the subject’s general health state as a 
vertical VAS and 5 quality of life domains as multiple-choice questions: mobility, 
self-care, main activity (work, study, housework, family/leisure activities), 
pain/discomfort, and anxiety/depression, the combination of which generates 243
possible health states. See Appendix M.
6.4.13.
The Work Productivity and Activity Impairment Questionnaire: Psoriasis 
(WPAI: PSO)
The WPAI: PSO questionnaire is a validated, 6-item self-administered instrument 
used to assess the impact of disease on work productivity in psoriasis due to general 
health or a specified health problem (Reilly, 2012; Appendix N).
6.4.15.
Photography
Photographs will be collected only at selected sites, in subjects who consent, and will 
be considered as supportive evidence of efficacy. Descriptive summary of 
photography will be addressed in the statistical analysis plan (SAP) and included in 
the clinical study report.  
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
38
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Photographs will be taken of all effected manifestations of plaque psoriasis at Weeks 
0, 16, 32, and 52.  Appropriate protective mechanisms shall be implemented to ensure 
that the photographs do not contain any subject-specific identifiers (such as tattoos, 
scars, etc) when shared with the Sponsor.
The procedure for taking the photographs and processing and shipping photographs 
will be described in a separate procedure manual distributed to investigational sites 
performing photographic assessments.
Photographic assessments are an optional part of this study. Subjects enrolled at the 
selected photography sites will be asked to sign a separate consent form specific to 
photography at Visit 1 (Screening Visit), prior to being photographed.
6.5.
Safety Assessments
In addition to safety monitoring conducted by Investigators and individual study personnel, AEs, 
serious adverse events (SAEs), discontinuations and laboratory findings will be reviewed by the 
study team. The review follows the Council for International Organizations for Medical 
Sciences, Working Group VI (CIOMS VI) recommendations. 
The study will be conducted in compliance with the ICH of Technical Requirements for 
Registration of Pharmaceuticals for Human Use/GCP and applicable regulatory requirements.
The following assessments will be conducted as outlined in Table 3, Table of Events.
6.5.1.
Serum and Urine Pregnancy Tests for Females of Childbearing Potential 
A serum pregnancy test with a sensitivity of ≤ 15 mIU/mL will be required for FCBP subjects at 
Screening and the Week 52 Visit (or at the Early Termination Visit for subjects who prematurely 
discontinue from the study). Urine pregnancy test will be performed on all FCBP subjects at the 
Baseline Visit, prior to randomization. A urine pregnancy test kit will be provided by the central 
laboratory. Pregnancy tests should be performed if the FCBP subject has missed a menstrual 
period or the contraception method has changed.
6.5.2.
Vital Signs, Weight and Waist Circumference
Vital signs, including pulse, and seated blood pressure, will be taken during the visits indicated 
in Table 3, Table of Events. Weight and waist circumference will  be measured and recorded at 
the Screening Visit and then as indicated in Table 3, Table of Events; Body mass index (BMI) 
will be calculated programmatically based on the Height measured and recorded at Screening. In
the event of unexplained and clinically significant weight loss, the patients should be evaluated 
by the investigator and discontinuation of treatment should be considered (see Section 11).
6.5.3.
Physical Examination
A physical examination includes evaluations of skin, nasal cavities, eyes, ears, lymph nodes, and 
respiratory, cardiovascular, gastrointestinal, neurological, and musculoskeletal systems. A 
physical examination is done at Screening as indicated in Table 3, Table of Events. Additional 
physical examinations may be performed during the course of study as deemed necessary per 
investigator’s judgment and recorded in source documents.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
39
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
6.5.4.
Psychiatric Evaluation
Treatment with apremilast is associated with an increase in adverse reactions of depression. 
Before using apremilast in subjects with a history of depression and/or suicidal thoughts or 
behavior, the Investigator should carefully weigh the risks and benefits of treatment with 
apremilast in such patients. Subjects should be advised of the need to be alert for the emergence 
or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur 
to contact the Investigator. 
If a patient suffers from new or worsening psychiatric symptoms, or suicidal ideation is 
identified, it is recommended to discontinue the subject participation to the study. Subjects who 
are identified by the Investigator as having attempted suicide must be immediately withdrawn 
from the study (see Section 11). 
6.5.5.
Severe Diarrhea, Nausea and Vomiting
There have been post-marketing reports of severe diarrhea, nausea, and vomiting associated with 
the use of apremilast. Most events occurred within the first few weeks of treatment.  In some 
cases, patients were hospitalized. Patients 65 years of age or older and patients taking 
medications that can lead to volume depletion or hypotension may be at a higher risk of 
complications. Subjects should be monitored for severe diarrhea, nausea and vomiting. If 
patients develop severe diarrhoea, nausea, or vomiting, discontinuation of treatment may be 
necessary (see Section 11).
6.5.6.
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed as indicated in Table 3, Table of Events. These 
include complete blood count (red blood cell [RBC] count, hemoglobin, hematocrit, white blood 
cell [WBC] count and differential, absolute WBC counts, platelet count) and serum chemistries
including sodium, potassium, calcium, chloride, blood urea nitrogen (BUN), creatinine, 
creatinine clearance, glucose, albumin, total protein, alkaline phosphatase, bilirubin (total and 
direct), aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), 
alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT), gamma-glutamyl 
transferase (GGT), lactate dehydrogenase (LDH). A lipid panel will be included in the standard 
chemistry panel. 
 
6.5.7.
Tuberculosis
After an extensive clinical development program, there is no current evidence that apremilast has 
the potential to activate latent TB. Therefore, no TB testing will be done in this protocol. 
Investigators can test for TB if clinically indicated, using the site’s local or country-specific 
guidelines. If the subject has active or latent TB, he/she should be treated according to local 
guidelines. Subjects who require TB treatment at any time during the study must be 
discontinued.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
40
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
6.5.8.
Adverse Events
All subjects will be monitored for adverse events (AEs) during the study. Assessments may 
include monitoring of any or all of the following parameters: the subject’s clinical symptoms, 
laboratory, radiological, or surgical findings; physical examination findings; psychiatric 
evaluation; or other appropriate tests and procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent to 
28 days after the last dose of IP. Adverse events and serious adverse events (SAEs) will be 
recorded on the AE page of the electronic case report form (eCRF), the paper SAE reporting 
form (SAEs) and in the subject’s source documents. All SAEs must be reported to Amgen 
Global Patient Safety within 24 hours of the Investigator’s knowledge of the event by recording 
on the CRF and using the paper Serious Adverse Event Report Form by facsimile/email of the 
paper SAER Form directly to Amgen Global Patient Safety.
Details of AE reporting can be found in Section 10.1 of the protocol.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
41
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
The chemical name of apremilast (CC-10004) is acetamide, N-[2-[(1S)-1-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl].
Apremilast will be provided by Amgen as 10, 20, or 30 mg tablets in blister cards for dose 
titration purposes. Apremilast will also be provided as 30 mg tablets in high-density polyethylene 
(HDPE) bottles (approximately 80 tablets) with child-resistant caps.
Identically-appearing placebo tablets will also be provided by Amgen in blister cards.
7.2.
Treatment Administration and Schedule
Subjects will be dispensed blister cards with 10, 20, and 30 mg apremilast tablets, or identically 
appearing placebo, for the dose titration, at the baseline visit (Week 0) and Week 16.
Starting at Week 16, all subjects will be switched to, or will continue with, apremilast. Subjects 
originally randomized to placebo at Week 0 will be switched to apremilast at Week 16. At all 
visits (Week 0 to Week 16), titration / treatment will be dispensed in blister cards with apremilast 
or placebo tablets and will be identically appearing.  Beginning with the Week 20 visit, all 
subjects will receive open label HDPE bottles of IP tablets.  All subjects will maintain this 
dosing through Week 52.
Apremilast or placebo tablets will be taken orally twice daily, approximately 12 hours apart, 
through the last treatment visit.
The titration blister card configurations are pictured in Appendix R. The treatment schema for 
dose titration at Baseline is shown in Appendix P, and at Week 16 is shown in Appendix Q.
Dose modifications are not permissible in this study.
7.3.
Method of Treatment Assignment
After the informed consent is signed, subjects will be assigned a subject identification number 
using a centralized interactive response technology (IRT). At the Baseline Visit, a centralized 
schema will be applied to assign subjects who meet the eligibility criteria in a 2:1 ratio to receive 
either apremilast 30 mg tablets orally BID or identically-appearing placebo tablets using the IRT. 
Subjects will be block-randomized to each of the manifestations of plaque psoriasis specified in 
the protocol. If subjects present with multiple manifestations, they will be allocated to the 
manifestation which is most severe, as determined by the subject at the screening and baseline 
visits. However, all manifestations will be assessed for efficacy at each study visit. 
Designated research personnel at the investigational sites will be assigned password protected, 
coded identification numbers, which gives them authorization to enter the IRT to randomize 
subjects.  The system will present a menu of questions by which the research center personnel 
will identify the subject and confirm subject eligibility. When all questions have been answered 
and the subject deemed eligible, the IRT will assign a randomization identification number.  
Confirmation of the randomization will be sent to the investigational site, Amgen, and/or its 
representative. The confirmation reports should be maintained as source documents.  During the 
Approved 
 
 


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study visits, the pharmacy or authorized study personnel at the investigational site will dispense 
coded IP kits in accordance with the randomization number assigned by the IRT.
7.4.
Packaging and Labeling
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
All IP tablets, including apremilast and identically-appearing placebo, will be supplied by 
Amgen. Investigational product for dose titration at Baseline and to Week 20 will be supplied in 
blister cards. Investigational product tablets at Week 20 and through Week 52 will be supplied in 
open label HDPE bottles with child-resistant caps.
7.5.
Investigational Product Accountability and Disposal 
The Investigator, or designee, is responsible for taking an inventory of each shipment of oral IP 
received, and comparing it with the accompanying IP shipping order/packing list. 
The Investigator, or designee, will verify the accuracy of the information on the form, sign and 
date it, retain a copy in the study file, and record the information in the IRT..
Investigational product will be stored per the storage conditions identified on the IP label. At the 
study site, all IP will be stored in a locked, safe area to prevent unauthorized access.
Amgen (or designee) will review with the Investigator and relevant site personnel the process for 
IP return, disposal, and/or destruction including responsibilities for the site versus Amgen (or 
designee). 
7.6.
Investigational Product Compliance
Study personnel will review the instructions printed on the package with the study subjects prior 
to dispensing the IP in tablet form (both blister cards and bottles). Investigational product will be 
dispensed as noted in the Table of Events, Table 3. The subjects will be instructed to return the 
IP containers, including any unused medication, to the study site at each visit for tablet counts 
and reconciliation. At each study visit, subjects will be asked whether they have taken their IP as 
instructed. Any problems with IP compliance will be reviewed with the subject. If a subject 
misses 4 or more consecutive days of dosing, Amgen should be contacted to decide whether 
dosing should resume or whether the subject should be terminated from the Treatment Phase of 
the study, and enter into the Posttreatment Observational Follow-up Phase.
Gross compliance problems (eg, missing 4 or more consecutive days of dosing or taking less 
than 75% of the doses between study visits) should be discussed with Amgen. Compliance is 
defined as taking between 75% and 120% of dispensed IP.
Approved 
 
 


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7.7.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the investigational 
product(s) (IPs) only. Therefore, for a drug to be subject to the overdose definition it must be 
both required and an investigational drug. In this study the only required and investigational 
drug is apremilast and the control arm drug (ie, placebo), hence overdose definition will apply to 
only apremilast (or matching placebo). Other required or optional non-study drugs intended for 
prophylaxis of certain side effects, etc, are excluded from this definition.
Overdose for this protocol, on a per dose basis, is defined as ingestion of 4 or more 30 mg 
apremilast (or matching placebo) tablets in any 24-hour period, whether by accident or 
intentionally. On a schedule or frequency basis, an overdose is defined as dosing more than 4 
times during any 24-hour period. 
Adverse Events associated with an overdose must be collected on the Adverse Events page of the 
eCRF (see Section 10.1) for all overdosed subjects, but the overdose itself is not considered an 
AE.
Approved 
 
 


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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
8.1.
Permitted Concomitant Medications and Procedures
Subjects may take any medication that is not restricted by the protocol and would not be 
expected to interfere with the conduct of the study or affect assessments. Chronic medication 
should be dosed on a stable regimen.
All medications (prescription and non-prescription), treatments, and therapies taken by the 
subject from signing the informed consent throughout their entire participation in the study, 
including those initiated prior to signing the informed consent and continued through the start of 
the study, must be recorded on the subject’s source document and on the appropriate page of the 
eCRF. The dose, unit, frequency, route, indication, the date the medication was started, and the 
date the medication was stopped (if not ongoing) must be recorded.
During the study, the initiation of new concomitant medications or a change of existing 
concomitant medications may potentially indicate the presence of a new adverse event or the 
worsening of an existing condition. If appropriate, such events should be recorded in the eCRF.
The following topical therapies will be permitted throughout the study:

Unmedicated skin moisturizers will be permitted for body lesions only.

Permitted skin moisturizers may not contain urea or salicylic acid.
8.2.
Concomitant Medications Not Recommended
Co-administration of the strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, 
resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy 
of apremilast. Therefore, the use of strong CYP3A4 enzyme inducers (eg, rifampicin, 
phenobarbital, carbamazepine, phenytoin and St. John’s Wort) with apremilast is not 
recommended during the study.
8.3.
Prohibited Concomitant Medications and Procedures
The following psoriasis medications cannot be administered for the duration of the study.

Topical therapy

Topical therapy, unless otherwise specified in Section 8.1 (including, but not 
limited to topical corticosteroids, retinoids or Vitamin D analog preparations,
tacrolimus, pimecrolimus, coal tar, anthralin/dithranol, or urea- and salicylic acid-
containing moisturizers)

Conventional systemic therapy

Conventional systemic therapy including but not limited to cyclosporine, 
methotrexate, retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, 
sulfasalazine, azathioprine, fumaric acid esters, and corticosteroids

Biologic agents, including:
Approved 
 
 


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
Adalimumab, etanercept, infliximab, or certolizumab pegol, ustekinumab, 
secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab

Phototherapy

Ultraviolet light B (UVB) or psoralens and long-wave ultraviolet radiation 
(PUVA)

Use of any investigational drug or device

Use of tanning booths, which may confound the ability to interpret data from the 
study.
8.4.
Required Concomitant Medications and Procedures
Not applicable.
Approved 
 
 


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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
The objective of this study is to evaluate the health-related quality of life, efficacy, and safety of 
apremilast compared to placebo, for 16 weeks, and evaluate the long-term effects of apremilast 
on quality of life, efficacy, and safety for up to 52 weeks in subjects with manifestations of 
plaque psoriasis and impaired quality of life.
9.2.
Study Population Definitions
Four analysis populations will be defined for this study. These populations include the safety 
population, the intent to treat (ITT) population, the per protocol (PP) population, and the 
apremilast exposure population. 

The Safety population will consist of all subjects who are randomized and receive at 
least one dose of investigational product (IP). This set of subjects will be included in 
the treatment group corresponding to the IP they actually receive. This will be the 
population for all safety analyses on data from the Placebo-controlled Phase.

The ITT population will consist of all subjects who are randomized. This will be the 
primary population for the primary endpoint and all other quality of life and efficacy 
analyses. Baseline summaries will also be based on the ITT population.

The PP population will consist of all subjects who are in the ITT population, 
complete the Placebo-controlled Phase, and have no major protocol violations. The 
PP population will only be used to supplement the primary endpoint ITT analysis. 

The apremilast (APR) exposure population will consist of only those subjects who 
receive at least one dose of apremilast treatment. The APR exposure population will 
only be used for the purposes of safety reporting including all safety data during 
apremilast treatment.
9.3.
Sample Size and Power Considerations
Using an exploratory analysis on a subset of subjects meeting the following criteria: 1) ScPGA ≥ 
3 at baseline or 2) NAPSI ≥ 1 at baseline or PPPGA ≥ 3 at baseline and DLQI ≥ 10 at baseline in 
the PSOR-008 and PSOR-009 Phase 3 studies, it was estimated that the proportion of subjects 
who achieved a ≥ 4-point reduction from baseline in DLQI was 0.50 (97 responders out of 193 
subjects) and 0.83 (337 responders out of 406 subjects) for placebo and apremilast 30 mg,
respectively. 
Assuming a placebo DLQI Responder proportion of 0.50 at Week 16, a minimum total sample 
size of 210 subjects (140 allocated to apremilast 30 mg and 70 allocated to placebo) is needed to 
detect a 0.20 difference in the DLQI Responder proportions between apremilast and placebo with 
at least 0.807 power using a two-sided test at the 0.05 level of significance. This sample size 
calculation is based on an unpooled variance, and was determined using the commercial software 
EaST, Version 6.3. Allowing for a 18% discontinuation rate prior to Week 16, the sample size 
was revised from a total of 210 subjects to a final sample size of 255. If there are no 
discontinuations prior to Week 16, then the power with a sample size of 255 subjects would 
Approved 
 
 


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Amgen Inc.
Confidential and Proprietary
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CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
increase to 0.872. Hence when addressing missing data due to discontinuations with multiple 
imputations, we would expect the power to be in between the bounds of 0.807 (based on 210 
subjects) and 0.872 (based on 255 subjects), as the analysis that incorporates multiple imputation 
under a missing at random assumption will always be more efficient compared to the observed 
analysis when the missing data is actually missing completely at random.
9.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while sex, race, and other categorical variables will be provided using frequency 
tabulations. The disease characteristics at baseline will also be summarized using appropriate 
descriptive statistics. These descriptive statistics will be summarized by the randomized 
treatment group using the ITT population.
9.5.
Subject Disposition
The distribution of enrollment by site will be provided. Subject disposition (analysis population 
allocation, entered, completed, discontinued, along with primary reason for discontinuation) will 
be summarized using frequency and percent for the Placebo-controlled Phase (Weeks 0 to 16) 
and the apremilast Extension Phase (Weeks 16 to 52). Protocol deviations will be summarized 
using frequency tabulations.  
9.6.
Efficacy Analysis
Statistical comparisons will be made between apremilast and placebo at Week 16. The statistical 
test on the primary endpoint will be at a 2-sided 0.05 significance level with treatment effect 
estimates and the corresponding 95% confidence intervals (CIs) being reported. Any p-values 
reported other than for the primary endpoint analysis will be considered as summary statistics. 
Descriptive statistic summaries for the observed data will also be provided by visit and 
randomized treatment group. 
9.6.1.
Primary Endpoint
The primary endpoint is the proportion of subjects achieving a ≥4 point reduction from baseline 
in DLQI at Week 16. It will be analyzed using the ITT population. However, a supplemental 
analysis will be performed using the PP population.
The primary analysis for the primary endpoint at Week 16 will be the Cochran–Mantel–Haenszel 
(CMH) test adjusted for the stratification factor at randomization (ie, the 5 difficult to treat 
manifestation types). This form of the CMH test will use the sample sizes in each of the strata as 
weights when estimating the adjusted difference in the treatment proportions, constructing 95% 
Wald confidence intervals for the difference, and conducting a statistical test of no difference 
between the treatment proportions (ie, H0: πAPR – πPBO = 0 as the null hypothesis). 
All reasonable attempts will be made to prevent missing data from occurring in this study, 
especially through Week 16. However, in the case of missing data at Week 16 a multiple 
imputation (MI) method will be incorporated into the primary analysis. Imputations will be made 
on the continuous-like scale of the total DLQI score, and then dichotomized according to the 
primary endpoint definition prior to performing the CMH analysis. The aim of the multiple 
Approved 
 
 


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imputation approach is to incorporate a representative random sample in place of the missing 
data such that unbiased estimation and valid statistical inferences (ie, confidence intervals and 
hypothesis testing) can be made. 
Details with respect to the construction of the CMH test statistic, multiple imputation procedure 
and the terminal analysis method for combining the multiple imputation results, as well as all 
supportive sensitivity and subgroup analyses involving the stratums for the primary endpoint will 
be specified in the SAP.  
9.6.2.
Secondary and Exploratory Efficacy Endpoints
For continuous endpoints at Week 16, an analysis of covariance (ANCOVA) model with 
treatment and randomization strata as fixed effects and corresponding baseline value as a 
continuous covariate will be employed. Missing data will be addressed using multiple 
imputation. The adjusted means and standard errors will be reported for each of the treatment 
group using the ANCOVA model, as well as the estimated treatment effect (ie, difference in the 
adjusted treatment means, their standard errors, and 95% confidence intervals). In addition, 
descriptive statistics will be provided based upon the observed data which will not address 
missing data. Details regarding the methods of estimation to be performed at Weeks 32 and 52 
will be provided in the statistical analysis plan (SAP).  
For discrete endpoints, the CMH estimation method stratified by the randomization strata for 
assessing the difference in proportion between the treatment groups will be conducted. The 
weights in the CMH estimation method will be same as those used in the primary endpoint 
analysis. The adjusted difference in the proportions between the treatment groups, their standard 
errors, and corresponding 95% confidence intervals will be reported. Missing data will be 
addressed through multiple imputation similar to that of the primary endpoint analysis. In 
addition, descriptive statistics involving the sample size, the number of responders, and 
proportion of responders will be summarized by treatment group. Details regarding the methods 
of estimation to be performed at Weeks 32 and 52 will be provided in the SAP.
9.6.3.
Photography
Photographs will be collected only at selected sites in subjects who consent and will be 
considered as supportive evidence of efficacy. Descriptive summary of photography will be 
addressed in the SAP and included in the clinical study report.  
Photographs will be taken of all effected manifestations of plaque psoriasis at Weeks 0, 16, 32, 
and 52.
Subjects must sign a separate consent form specific to Photography at Visit 1 (Screening Visit).
Approved 
 
 


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9.6.5.
Multiplicity Adjustment
There will be no multiplicity adjustment. Only the primary endpoint analysis will be used to 
declare a statistical significance.
9.7.
Safety Analysis
The safety analyses will be performed using the safety population as defined in Section 9.2, 
defined as all subjects who are randomized and receive at least one dose of investigational 
product. Safety will be assessed by clinical review of all relevant parameters including treatment-
emergent adverse events (TEAEs), laboratory tests, and vital signs; no inferential testing for 
statistical significance will be performed. Data from safety assessments will be summarized 
descriptively for the Placebo-controlled Phase (Weeks 0 to 16) and the Apremilast Exposure 
Period when subjects receive apremilast treatment. For safety analyses in the Placebo-controlled 
Phase, baseline will be relative to the first dose date following randomization at Week 0. For 
safety analyses in Apremilast Exposure Period, baseline will be relative to the first apremilast 
dose date at Week 0 for subjects initially randomized to apremilast or Week 16 for subjects 
initially randomized to placebo and switched to apremilast in the Apremilast Extension Phase 
(Weeks 16-52).
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. Adverse events will be tabulated by study phase (Double-blind 
Placebo-controlled Phase or apremilast Exposure Phase). All treatment-emergent adverse events 
(AEs) will be summarized by system organ class, preferred term, severity, and relationship to IP. 
Adverse events leading to death or to discontinuation from treatment and serious AEs will also 
be summarized and listed separately. 
Laboratory data will be summarized using shift tables showing the number of subjects with low, 
normal, and high values based on the normal ranges, pretreatment versus post-treatment. 
Vital sign measurements, including weight, will be summarized by visit descriptively (count, 
mean, median, standard deviation, and range). In addition, shift tables showing the number of 
subjects with values below, within and above the normal reference ranges pretreatment versus 
post-treatment will be provided. 
The changes and percent changes in body weight will be summarized by visit. In addition, the 
changes by baseline body mass index (BMI; (< 18.5, 18.5 to < 25, 25 to < 30, 30 to < 35, 35 to 
< 40, ≥40 kg/m2) will be explored.
9.8.
Interim Analysis
No interim analysis is planned for this study.
9.9.
Other Topics
9.9.1.
Investigational Product Compliance (Tablets)
Investigational product record information will be summarized. Overall compliance will be 
estimated by the proportion of subjects who take between 75% and 120% of the intended 
quantity of IP.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
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Amgen Inc.
Confidential and Proprietary
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CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
9.9.2.
Concomitant Therapy
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations. The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health 
Organization (WHO) will be used to group medications into relevant categories for these 
tabulations. Separate data summaries of background medications will be provided.
9.9.3.
Steering Committee
The conduct of this trial will be overseen by a steering committee (SC), presided over by the 
coordinating Principal Investigator. The SC will serve in an advisory capacity to the Sponsor. 
Operational details for the SC will be detailed in a separate SC charter.
Approved 
 
 


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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE. A diagnosis or syndrome should be recorded on 
the AE/SAE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome.
Abuse, withdrawal, sensitivity, or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF. (See Section 7.7 for definition of overdose.)  Any sequela of an 
accidental or intentional overdose of an investigational product should be reported as an AE on 
the AE eCRF. If the sequela of an overdose is a serious adverse event (SAE), then the sequela 
must be reported on the paper SAE report form and on the AE eCRF. The overdose resulting in 
the SAE should be identified as the cause of the event on the paper SAE report form and eCRF, 
but should not be reported as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for apremilast overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study. Assessments may include monitoring of 
any or all of the following parameters: the subject’s clinical symptoms; laboratory, pathological, 
radiological, or surgical findings; physical examination findings; or findings from other tests 
and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP as well all SAEs made known to the Investigator at any 
time following the protocol-required reporting period or after end of study. All adverse events 
(serious/non-serious) will be recorded on the eCRF, the paper SAE report form (for SAEs) and in 
the subject’s source documents.  All SAEs must be reported to Amgen Global Patient Safety
within 24 hours of the Investigator’s knowledge of the event by recording on the eCRF 
submitting the SAE information using the paper Serious Adverse Event Report Form by 
facsimile/email directly to Amgen Global Patient Safety.
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:

Results in death;
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
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately 
life-threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

A standard procedure for protocol therapy administration. However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling). However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.

Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

A procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF. Hospitalization or prolonged 
hospitalization for a complication from such a procedure remains a reportable SAE.

An elective treatment of, or an elective procedure for, a pre-existing condition 
unrelated to the studied indication, that has not worsened from baseline. 

Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the paper SAE Report 
Form must be completed. All SAEs must be reported to Amgen Global Patient  Safety within 24 
hours of the investigator’s knowledge of the event by submitting the SAE information using the 
Approved 
 
 


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paper Serious Adverse Event Report Form by facsimile/email directly to Amgen Global Patient 
Safety.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity / Intensity
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event 
according to the following grading scale:
Mild

Asymptomatic or mild symptoms; clinical or diagnostic observations only

Intervention not indicated

Activities of Daily Living (ADLs) minimally or not affected

No or minimal intervention/therapy may be required 
Moderate 

Symptom(s) cause moderate discomfort

Local or noninvasive intervention indicated

More than minimal interference with ADLs but able to carry out daily social and 
functional activities.

Drug therapy may be required
Severe (could be non-serious or serious)

Symptoms causing severe discomfort/pain

Symptoms requiring medical/surgical attention/intervention

Interference with AEs including inability to perform daily social and functional 
activities (eg, absenteeism and/or bed rest)

Drug therapy is required
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate, 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious”, which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality 
The Investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Approved 
 
 


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Not Suspected:
A causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the observed 
event.
Suspected:
There is a reasonable possibility that the administration of IP caused the 
adverse event. ‘Reasonable possibility’ means there is evidence to 
suggest a causal relationship between the IP and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary, or additional IP 
that has not been manufactured or provided by Amgen, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, or interruption, or dose reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/interruption of IP dose, or any other therapeutic 
intervention; or

is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.  
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
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If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF. If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.
10.4.1.
Females of Childbearing Potential – Collection of Pregnancy Information
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 28 days of the subject’s last dose of IP, are considered immediately reportable 
events. Investigational product is to be discontinued immediately. A female subject with 
suspected pregnancy may resume IP after a confirmed negative pregnancy test and consultation 
with the sponsor. The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to Amgen Global Patient Safety , or designee, immediately by email, , facsimile, or 
other appropriate method, using the Pregnancy Notification Form or approved equivalent form 
(refer to Appendix T). The Pregnancy Notification Form must be submitted to Amgen Global 
Patient Safety within 24 hours of learning of a subject’s pregnancy. (Note:  Sites are not required 
to provide any information on the Pregnancy Notification Form that violates the country or 
regions local privacy laws). 
After obtaining the female subject’s signed consent for release of pregnancy and infant health 
information, the investigator will collect pregnancy and infant health information and complete 
the pregnancy questionnaire for any female subject who becomes pregnant while taking IP 
through 28 days of the subject’s last dose of IP. This information will be forwarded to Amgen 
Global Patient Safety. Generally, infant follow-up will be conducted 12 months after the birth of 
the child (if applicable).
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
The Investigator will monitor the progress of the pregnancy of a female subject, and must notify 
Amgen Global Patient Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome).
If the outcome of the pregnancy was abnormal (eg, spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Amgen Global Patient Safety by 
facsimile, email or other appropriate method, within 24 hours of the investigator’s knowledge of 
the event using the paper SAE Report Form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in-utero exposure to the IP should also be reported as an SAE to Amgen Global 
Approved 
 
 


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


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(from the time the subject signs informed consent until 28 days after the last dose of IP) and all  
SAEs made known to the Investigator at any time following the protocol-required reporting 
period or after end of study. . Serious adverse events occurring prior to treatment (after signing 
the ICF) are to be collected/recorded/reported.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Amgen and the IRB/EC.
Serious Adverse Event Reporting transmitted via paper Serious Adverse Event Report 
Form:

Facsimile transmission of the Serious Adverse Event Report Form is the preferred 
method to transmit this information. If facsimile is unavailable, the email method to 
transmit this information is acceptable (refer to Appendix S).

In rare circumstances and in the absence of facsimile equipment, this form may be sent 
via email, or notification by telephone is acceptable with a copy of the Serious Adverse 
Event Report Form in English language sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated 
reporting timeframes.  

Once the study has ended, serious adverse events (regardless of causality) should be 
reported to Amgen Global Patient Safety if the investigator becomes aware of them and 
may use the paper Serious Adverse Event Report Form (refer to Appendix S).
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated/generated from Amgen Global Patient Safety 
to the site via Amgen’s safety query paper process or other appropriate method.  
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Amgen Global Patient Safety will determine the 
expectedness of events suspected of being related to apremilast based on the Investigator’s 
Brochure. For countries within the European Economic Area (EEA), Amgen or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements. 
Amgen or its authorized representative shall notify the Investigator of the following information: 

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR).

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Approved 
 
 


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Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Amgen and the IRB/EC. (See Section 14.3 for record retention 
information).
Amgen Global Patient Safety Contact Information (fax/email):
For Amgen Global Patient Safety contact information, please refer to your site’s paper Serious 
Adverse Event Report Form, paper Pregnancy Notification Form and/or paper Lactation 
Notification Form (Appendix S, Appendix T, Appendix U).
Approved 
 
 


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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):

Adverse event

Lack of efficacy 

Non-compliance with investigational products 

Withdrawal by subject

Death

Lost to follow-up

Protocol deviation

Pregnancy

Physician decision

Study terminated by sponsor

Other (to be specified on the eCRF)
Subjects have the right to withdraw from the study at any time and for any reason. The reason for 
discontinuation should be recorded in the eCRF and in the source documents.
When a subject is discontinued from treatment, the Investigator should make every attempt 
possible to have the subject evaluated at the Early Termination Visit within 4 days of the last 
intake of investigational product.
The decision to discontinue a subject can be taken at any time and remains the responsibility of 
the treating physician, which will not be delayed or refused by the sponsor. However, prior to 
discontinuing a subject, the Investigator may contact the Medical Monitor or designee and 
forward appropriate supporting documents for review and discussion, without identifying the 
subject.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure

Adverse event

Withdrawal by subject

Death

Lost to follow-up
Approved 
 
 


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
Protocol deviation

Pregnancy

Physician decision

Study terminated by Sponsor

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
Approved 
 
 


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


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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Amgen, its authorized representative, and 
Investigator abide by Good Clinical Practice (GCP), as described in International Council for
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations. Amgen staff or an authorized representative will evaluate and approve all 
Investigators, who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Amgen information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an ICF and are 
screened for entry into the study. Subjects who fail screening must have the reason(s) recorded in 
the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries, and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Amgen on public registry websites) is considered Amgen confidential 
information. Only information that is previously disclosed by Amgen on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement. Amgen protocol, amendment, and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Amgen. Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Amgen for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Amgen will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
Approved 
 
 


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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study-related procedures.  In addition to the main consent for the research study, the 
subjects will be given the opportunity to consent to two optional sub-studies, ie, the 
 and, at selected sites only, photography. 
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents, 
including the date. The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject. In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised. Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF. The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.  
Subjects have the right to withdraw from the study and sub-studies at any time and for any 
reason.  Subject information already obtained as part of the study and sub-studies will be retained 
for analysis subject to applicable law. The Investigator shall ensure that all appropriate processes 
regarding research ethics and subject consent have been followed in accordance with applicable 
law and will notify Amgen in the event that any subject whose data is stored at or otherwise 
processed by Amgen withdraws consent. 
The subject data shall be key-coded (the direct identifiers will have been removed or replaced 
with a subject code) prior to being transferred to the Sponsor or third parties.  In particular, 
appropriate protective mechanisms shall be implemented to ensure that photographs from the 
sub-study do not contain any subject identifiers (for example, scars, tattoos, etc) when shared 
with the Sponsor.  
13.4.
Confidentiality
Amgen affirms the subject’s right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Amgen requires 
the Investigator to permit Amgen’s representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Amgen Clinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/EC for written approval. 
Written approval must be obtained before implementation of the amended version occurs. The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title, and amendment number(s) that is applicable. Amendments that are 
Approved 
 
 


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administrative in nature do not require IRB/EC approval, but will be submitted to the IRB/EC for 
information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by Amgen or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Amgen or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Amgen and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
Approved 
 
 


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Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
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13.8.
Termination of the Study
Amgen reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Amgen has the right to discontinue a single site at any time during 
the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
Approved 
 
 


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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed, and 
retained. Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Amgen standard 
operating procedures (SOPs). These data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The Investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer. Essential documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, Amgen, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 
Approved 
 
 


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
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Amgen if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period. 
The Investigator must obtain approval in writing from Amgen prior to destruction of any records. 
If the Investigator is unable to meet this obligation, the Investigator must ask Amgen for 
permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents.
Approved 
 
 


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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Amgen or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Amgen ensures that appropriate monitoring procedures are performed before, during, and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigator meeting. Prior to enrolling subjects into the study, a 
Amgen representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator. Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, 
investigational product storage area, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Amgen representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation. Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff. Any necessary 
corrections will be made directly to the eCRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified. Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Quality, Compliance & Audit, Learning & 
Performance unit exists within Amgen. Representatives of this unit will conduct audits of clinical 
research activities in accordance with Amgen SOPs to evaluate compliance with Good Clinical 
Practice guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs, and applicable supporting records of study subject participation for
audits and inspections by IRB/IECs, regulatory authorities (eg, Food and Drug Administration 
[FDA], European Medicines Agency [EMA], Health Canada) and company authorized 
representatives. The Investigator should make every effort to be available for the audits and/or 
inspections. If the Investigator is contacted by any regulatory authority regarding an inspection, 
he/she should contact Amgen immediately.
15.3.
Product Complaint
A product complaint (PC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product or device after they are released for distribution to 
market or clinic by either Amgen or by distributors, and partners with whom Amgen 
manufactures the material.  This includes any drugs, devices, or combination products 
provisioned and/or repackaged/modified by Amgen.  Drugs or devices include investigational 
Approved 
 
 


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product.  Any product complaints associated with an investigational product, or non-
investigational products or devices supplied by Amgen are to be reported according to the 
instructions provided in the Investigational Product Instruction Manual or equivalent. 
If you become aware of a suspected PC, you are obligated to report the issue within 24 hours of 
discovery or notification of the concern or irregularity.  Amgen requires notification of any 
concern or irregularity at any stage of the study.
15.3.1.
How to Report a Product Complaint to Amgen  
Complete Amgen’s paper Clinical Product Complaint Intake Form and email the form to the 
following Amgen email address: 
Clinical-Complaint-Intake@amgen.com
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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Amgen on public registry websites, is considered 
Amgen confidential information and is not to be used in any publications. Amgen protocol-
related information proposed for use in a publication must be submitted to Amgen for review and 
approval, and should not be utilized in a publication without express written approval from 
Amgen, or as described in the Clinical Trial Agreement.
Amgen will ensure Amgen-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance. This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes. Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for authorship, will be in alignment with ICMJE authorship criteria and be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, and contribution to abstract, presentation, 
and/or publication development.
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17.
REFERENCES
EuroQol Group. EuroQol - a new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199–208.
Feuerhahn J, Blome C, Radtke M, Augustin M. Validation of the patient benefit index for the 
assessment of patient-relevant benefit in the treatment of psoriasis. Arch Dermatol Res.
2012;304(6):433–41.
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for 
routine clinical use. Clin Exp Dermatol. 1994;19(3):210–6.
Fredriksson T, Pettersson U. Severe psoriasis - oral therapy with a new retinoid. Dermatologica.
1978;157(4):238–44.
Gottlieb AB. Psoriasis – Enhanced epidermal differentiation and reduced cell-mediated 
inflammation are unexpected outcomes. Dis Manag Clin Outcome. 1998;1(6):195–202.
Leonardi C, Sobell J, Sofen H, Krell J. Phase IV study to evaluate the safety and efficacy of 
efalizumab for treatment of hand and foot plaque psoriasis. Poster presented at: 65th Annual 
Meeting of the American Academy of Dermatology; 2007 Feb 2-6; Washington, DC.
Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 
2007;445(7130):866–73.
Merola JF, Bleakman AP, Gottlieb AB, Menter A, Naegeli AN, Bissonnette R, et al. The Static 
Physician's Global Assessment of Genitalia: a clinical outcome measure for the severity of 
genital psoriasis. J Drugs Dermatol. 2017;16(8):793–9.
Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE, Nast A, et al. Definition of treatment 
goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res.
2011;303(1):1–10.
Naegeli AN, Flood E, Tucker J, Devlen J, Edson-Heredia E. The Worst Itch Numeric Rating 
Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis. Int J Dermatol.
2015;54(6):715–22.
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496–509.
NHLBI Obesity Education Initiative. The practical guide: identification, evaluation, and 
treatment of overweight and obesity in adults. [cited 2018 Apr 04].  Available from:  
http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf. 
Reilly Associates. Work Productivity and Activity Impairment Questionnaire: Psoriasis 
(WPAI:PSO).  2012. [cited 2018 May 01].  Available from:
http://www.reillyassociates.net/WPAI_References3.html. Accessed May 01,.
Rich P, Scher RK. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. 
J Am Acad Dermatol. 2003;49(2):206–12.
Walsh JA, McFadden M, Woodcock J, Clegg DO, Helliwell P, Dommasch E, et al. Product of 
the Physician Global Assessment and body surface area: a simple static measure of psoriasis 
severity in a longitudinal cohort. J Am Acad Dermatol. 2013;69(6):931–7.
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18.
APPENDICES
Appendix A:
Table of Abbreviations
Table 4:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADL
Activities of daily living
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of covariance
APC
Antigen presenting cell
APR
Apremilast
AST
Aspartate aminotransferase (SGOT)
ATC
Anatomical Therapeutic Chemical
β-hCG
Beta human chorionic gonadotropin
BID
Twice daily
BMI
Body mass index
BSA
Body surface area
BUN
Blood urea nitrogen
cAMP
Cyclic adenosine monophosphate
CBC
Complete blood count
CI
Confidence interval
CIN
Cervical intraepithelial neoplasia
CMH
Cochran–Mantel–Haenszel
CRO
Contract Research Organization
CLcr
Creatinine clearance 
CRF
Case report form
DLQI
Dermatology Life Quality Index
DMARD
Disease-modifying antirheumatic drug
EC
Ethics Committee
eCRF
Electronic case report form
EEA
European Economic Area
eGFR
Estimated glomerular filtration rate
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Table 4:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
EMA
European Medicines Agency
EOT
End of treatment
EQ-5D
European Quality of Life 5-Dimension Questionnaire
FCBP
Females of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEE
Generalized estimating equations
GGT
Gamma-Glutamyl Transferase
HDPE
High-density polyethylene
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IL
Interleukin
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive response technology
ITT
Intent to treat
IUD
Intrauterine device
LDH
Lactate Dehydrogenase
MCH
Mean Corpuscular Hemoglobin 
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MG
Milligrams
MI
Multiple imputation
MMRM
Mixed-Effect Model Repeated Measure
Modified sPGA-G
Modified Static Physicians Global Assessment of Genitalia
NAPSI
Nail Psoriasis Severity Index
NRS
Numeric Rating Scale
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Table 4:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
PASI
Psoriasis Area Severity Index
PBI
Patient Benefit Index
PBQ
Patient Benefit Questionnaire
PDE
Phosphodiesterase
PDE4
Phosphodiesterase type 4
PNQ
Patient Needs Questionnaire
PP
Per protocol
PPPGA
Palmoplantar Psoriasis Physicians Global Assessment
PC
Product Complaint
PUVA
Psoralens and long-wave ultraviolet radiation
QOL
Quality of life
RBC
Red blood cell 
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Steering committee
ScPGA
Scalp Physician Global Assessment
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
sPGA
static Physicians Global Assessment
sPGA-G
static Physicians Global Assessment of Genitalia
SUSAR
Suspected unexpected serious adverse reaction
TNF
Tumor necrosis factor
UVB
Ultraviolet light B
VAS
Visual Analog Scale
WBC
White blood cell 
WHO
World Health Organization
WPAI: PSO
Work Productivity and Activity Impairment Questionnaire: Psoriasis 
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Appendix B:
The Dermatology Life Quality Index (DLQI)
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE 
LAST WEEK. Please check one box for each question.
1. 
Over the last week, how itchy, sore, painful or stinging has 
your skin been? 
_ Very much _ A lot 
_ A little _ Not at all 
2. 
Over the last week, how embarrassed or self conscious have 
you been because of your skin? 
_ Very much _ A lot 
_ A little _ Not at all 
3. 
Over the last week, how much has your skin interfered with 
you going shopping or looking after your home or garden? 
_ Very much _ A lot 
_ A little _ Not at all 
_ Not relevant 
4. 
Over the last week, how much has your skin influenced the 
clothes you wear? 
_ Very much _ A lot 
_ A little _ Not at all 
_ Not relevant 
5. 
Over the last week, how much has your skin affected any 
social or leisure activities? 
_ Very much _ A lot 
_ A little _ Not at all 
_ Not relevant 
6. 
Over the last week, how much has your skin made it difficult 
for you to do any sport? 
_ Very much _ A lot 
_ A little _ Not at all 
_ Not relevant 
7. 
Over the last week, has your skin prevented you from working 
or studying? 
_ Yes _ No 
_ Not relevant 
If “No”, over the last week how much has your skin been a 
problem at work or studying? 
_ A lot _ A little 
_ Not at all 
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Appendix B:
The Dermatology Life Quality Index (DLQI) (Continued)
Please check one box for each question.
8. 
Over the last week, how much has your skin created problems 
with your partner or any of your close friends or relatives? 
_ Very much _ A lot 
_ A little _ Not at all
_ Not relevant
9. 
Over the last week, how much has your skin caused any 
sexual difficulties?
_ Very much _ A lot 
_ A little _ Not at all
_ Not relevant
10. 
Over the last week, how much of a problem has the 
treatment for your skin been, for example, by making your 
home messy, or by taking up time?
_ Very much _ A lot 
_ A little _ Not at all
_ Not relevant
Source: Finlay, 1994.
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Appendix C:
Static Physicians Global Assessment (sPGA) Of Visible 
Locations
The sPGA is the assessment by the Investigator of the overall disease severity at the time of 
evaluation.  In this study, sPGA is used to evaluate psoriasis only in visible locations, defined as 
dorsal hand, face, neck and hairline.
Score
Category
Description
0
Clear
Plaque elevation = 0 (no elevation over normal skin)
Scaling = 0 (no evidence of scaling)
Erythema = 0 (except for residual hyperpigmentation/ 
hypopigmentation)
1
Almost Clear
Plaque elevation = ± (possible but difficult to ascertain whether 
there is a slight elevation above normal skin)
Scaling = ± (surface dryness with some desquamation)
Erythema = ± (faint, diffuse pink or slight red coloration)
2
Mild
Plaque elevation = slight (slight but definite elevation, typically 
edges are indistinct or sloped)
Scaling = fine (fine scale partially or mostly covering lesions)
Erythema = mild (light red coloration)
3
Moderate
Plaque elevation = marked (marked definite elevation with rough 
or sloped edges)
Scaling = coarser (coarser scale covering most or all of the 
lesions)
Erythema = moderate (definite red coloration)
4
Severe
Plaque elevation = marked (marked elevation typically with hard 
or sharp edges)
Scaling = coarser (coarse, non tenacious scale predominates 
covering most or all of the lesions)
Erythema = severe (very bright red coloration)
Source: Walsh, 2013.
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Appendix D:
Scalp Physician Global Assessment (ScPGA)
Score
Category
Category Description
0
Clear
Scalp Plaque Elevation = 0 (no elevation over normal skin)
Scalp Scaling = 0 (no evidence of scaling)
Scalp Erythema = 0 (except for residual 
hyperpigmentation/hypopigmentation)
1
Almost 
Clear
Scalp Plaque Elevation = ± (possible but difficult to ascertain 
whether there is a slight elevation above normal skin)
Scalp Scaling = ± (surface dryness with some desquamation)
Scalp Erythema = ± (faint, diffuse pink or slight red coloration)
2
Mild
Scalp Plaque Elevation = slight (slight but definite elevation, 
typically edges are indistinct or sloped)
Scalp Scaling = fine (fine scale partially or mostly covering lesions)
Scalp Erythema = mild (light red coloration)
3
Moderate
Scalp Plaque Elevation = marked (marked definite elevation with 
rough or sloped edges)
Scalp Scaling = coarser (coarser scale covering most or all of the 
lesions)
Scalp Erythema = moderate (definite red coloration)
4
Severe
Scalp Plaque Elevation = marked (marked elevation typically with 
hard or sharp edges)
Scalp Scaling = coarser (coarse, non tenacious scale predominates 
covering most or all of the lesions)
Scalp Erythema = severe (very bright red coloration)
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Appendix E:
Nail Psoriasis Severity Index (NAPSI)
The target thumb or finger nail which represents the worst nail 
psoriasis is graded for nail matrix psoriasis and nail bed psoriasis. 
The sum of these two scores is the total score for that nail.
Evaluation 1: Nail matrix. In each quadrant of 
the nail, nail matrix psoriasis is evaluated by 
presence of any of the nail matrix features 
(pitting, leukonychia red spots in the lunula, 
crumbling):
Score for nail matrix psoriasis  _____________
0 = none
1 = present in 1/4 nail
2 = present in 2/4 nail
3 = present in 3/4 nail
4 = present in 4/4 nail
Evaluation 2: Nail bed. Nail bed psoriasis is 
evaluated by the presence of any of the nail bed 
features (onycholysis, splinter hemorrhages, 
subungual hyperkeratosis, “oil drop” (salmon 
patch dyschroma): 
Score for nail bed psoriasis  _____________
0 = none
1 = present in 1/4 nail
2 = present in 2/4 nail
3 = present in 3/4 nail
4 = present in 4/4 nail
TOTAL FOR NAIL___________  (0-8)
Source: Rich, 2003.
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Appendix F: Modified Static Physicians Global Assessment of Genitalia 
(Modified sPGA-G)
The Modified Static Physician Global Assessment of Genitalia
Score1
Category
Category Description2
0
Clear
Erythema: no erythema (except for residual 
hyperpigmentation/ hypopigmentation)
Plaque elevation: no elevation
Scaling: no scale
1
Almost Clear
Erythema: faint, light pink erythema
Plaque elevation: elevation is very slight and difficult to 
confirm
Scaling: some fine, white surface dryness
2
Mild
Erythema: mild, pink erythema
Plaque elevation: slight elevation with sloped edges
Scaling: fine scale on some or most lesions
3
Moderate
Erythema: moderate, red erythema
Plaque elevation: moderate elevation with definite edges 
that are either sloped or rough 
Scaling: coarse scale on most lesions
4
Severe
Erythema: severe, bright or deep red erythema 
Plaque elevation: substantial elevation, hard and sharp 
edges
Scaling: coarse, non-adherent scale on most to all lesions
Adapted from source: Merola, 2017.
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Appendix G: Palmoplantar Psoriasis Physicians Global Assessment (PPPGA)
Source: Leonardi, 2007.
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Appendix H:
Itch Numeric Rating Scale (NRS)
Please rate the itching severity due to your psoriasis by circling the number that best describes 
your worst level of itching in the past 24 hours.
0        1        2        3        4        5        6        7        8        9        10
0 = No itching
     10 = Worst itch imaginable
Source:  Naegeli, 2015.
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Appendix I:
Skin Discomfort/Pain Visual Analog Scale (VAS)
On average, how much skin discomfort/pain have you had because of your condition in the past 
week?
Please note: VAS above is not drawn to scale and is for illustrative purposes only.
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Appendix J:
Psoriasis Area Severity Index (PASI) 
* Round all calculations to 1 decimal place.
Source: Fredriksson, 1978.
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Appendix K:
Patient Needs Questionnaire (PNQ)
With the help of the following questions, we’d like to know how important the below mentioned 
goals are to you personally in the current treatment of your skin disease.
For each of the following statements, please mark how important this treatment goal is to you.  
If a statement does not apply to you, e.g. because you do not have pain, please mark “does not 
apply to me”. 
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Appendix L:
Patient Benefit Questionnaire (PBQ)
At the start of the treatment, you indicated in a questionnaire how important various goals were 
in the treatment of your skin disease.
Please mark each of the following statements according to the extent that these treatment goals 
were achieved, thereby indicating if the treatment has benefitted you. If a statement did not 
apply to you, e.g. because you had no pain, please mark “did not apply to me”.
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Appendix M: European Quality of Life 5-Dimension Questionnaire (EQ-5D)
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Appendix M: European Quality of Life 5-Dimension Questionnaire (EQ-5D) 
(Continued)
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Appendix M: European Quality of Life 5-Dimension Questionnaire (EQ-5D) 
(Continued)
Source: The EuroQol Group, 1990.
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Appendix N: Work Productivity and Activity Impairment Questionnaire: 
Psoriasis (WPAI: PSO)
Source:  Reilly, 2012.
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Appendix O:
Waist Circumference Measurement & Body Mass Index
Measuring Tape Position for Waist (Abdominal) Circumference
How to Measure Waist Circumference
1. Place a tape measure around subject’s waist above the tip 
of hipbone.
2. Ask the subject to exhale.
3. Measure the waist after exhaling.
How to Measure Body Mass Index (BMI)
Body Mass Index (BMI) is a person's weight in kilograms divided by the square of 
height in meters. To estimate BMI, multiply the individual’s weight (in pounds) by 
703, then divide by the height (in inches) squared. This approximates BMI in 
kilograms per meter squared (kg/m2).
BMI calculator can be found at: 
https://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/english_bmi_calculator/bmi_calcul
ator.html 
Source: NHLBI Obesity Education Initiative.
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Appendix P:
Treatment Schema for Dose Titration at Baseline
Dose
Day 1
Day 2
Day 3
Day 4
Day 5
Group
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Placebo 
(dummy 
titration)
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
placebo
30 mg
apremilast 
(titration)
10 mg 
apremilast 
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilast 
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilast 
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilast
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
apremilast 
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
apremilast 
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
apremilast 
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
apremilast 
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
apremilast
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Appendix Q:
Treatment Schema for Dose Titration at Week 16
Dose
Day 1
Day 2
Day 3
Day 4
Day 5
Group
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Placebo to
30 mg
apremilast 
(titration)
10 mg 
apremilast 
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilast 
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilast 
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
apremilast
+ 20 mg 
placebo
+ 30 mg 
placebo
10 mg 
placebo
+ 20 mg 
apremilast 
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
apremilast 
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
apremilast 
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
apremilast 
+ 30 mg 
placebo
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
apremilast
30 mg
apremilast
(dummy 
titration) 
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo
+ 20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
apremilast
10 mg 
placebo + 
20 mg 
placebo
+ 30 mg 
apremilast
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
94
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Appendix R:
Titration Blister Card
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
95
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Appendix S:
Sample Serious Adverse Event Form
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
96
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Appendix S:
Sample Serious Adverse Event Form (Continued)
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
97
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Appendix S:
Sample Serious Adverse Event Form (Continued)
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
98
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Appendix T:
Pregnancy Notification Form
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Apremilast
Protocol CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
99
CC-10004-PSOR-020 Amendment 3 FINAL: 01 May 2020
Appendix U:
Lactation Notification Form
Approved 
 
 


EDMS Doc. Number: 24684941 - 22835610
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  Vice President and Head of Immunology & Fibrosis Clinical Develo
Date: Tuesday, 05 May 2020, 08:23 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
Approved 
 
 


EDMS Doc. Number: 24684941 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
1
CC-10004-PSOR-020 Amendment # 3 Final:  01 May 2020
TITLE PAGE
– SUMMARY OF CHANGES –
A PHASE 4, MULTI-CENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY OF THE IMPACT 
OF APREMILAST (CC-10004) ON QUALITY OF LIFE, 
EFFICACY, AND SAFETY IN SUBJECTS WITH 
MANIFESTATIONS OF PLAQUE PSORIASIS AND IMPAIRED 
QUALITY OF LIFE
AMENDMENT NO. 3
INVESTIGATIONAL PRODUCT (IP):
Apremilast
PROTOCOL NUMBER:
CC-10004-PSOR-020
ORIGINAL DATE:
26 SEP 2018
AMENDMENT No. 1 DATE:
17 JAN 2019
AMENDMENT No. 2 DATE:
01 NOV 2019
AMENDMENT No. 3 DATE:
01 MAY 2020
EudraCT NUMBER:
2018-002850-58
IND NUMBER: 
070270
NTC NUMBER:
NCT03774875
Contact Information: 
Name:
, MD
Title:
Senior Director, Global Development
Address: 
Amgen Inc,
Amgen Center Dr, Thousand Oaks, CA 91320
USA
Phone:
E-mail:
Note: Only call Amgen Medical Information, if you are not able to reach the Clinical Research 
Physician(s) or Medical Monitor or designee for emergency calls.
CONFIDENTIALITY NOTICE
This document contains confidential information of Amgen. This document must not be disclosed to 
anyone other than the site study staff and members of the institutional review board/independent ethics 
committee/institutional scientific review board or equivalent. The information in this document cannot 
be used for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Amgen. If you have questions regarding how this document may be used or 
shared, call the Amgen Medical Information number: 1- 800-77-AMGEN
Amgen Medical Information: 1- 800-77-AMGEN (1-800-772-6436)


EDMS Doc. Number: 24684941 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
2
CC-10004-PSOR-020 Amendment # 3 Final:  01 May 2020
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, Vice President and Head of Immunology &Fibrosis Clinical 
Development
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.
NOTE: Signed by Celgene based on Approval from Amgen Therapeutic Head 
 


EDMS Doc. Number: 24684941 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Amgen Inc.
Confidential and Proprietary
3
CC-10004-PSOR-020 Amendment # 3 Final:  01 May 2020
JUSTIFICATION FOR AMENDMENT
The purpose of this amendment is to update the change in Sponsor, as well as key contact and 
emergency information, and to update safety reporting and product complaints to align with 
Amgen processes.
Significant changes included in this amendment are summarized below:

All references to “Celgene Corporation” were removed and replaced with “Amgen Inc” 
and “Celgene” changed to “Amgen” throughout the protocol. 

Cover Pages were updated with Amgen contact information

Section 6 Procedures was updated to align with Amgen Global Drug Safety processes

Section 10 Monitoring and Reporting of Adverse Events was updated to align with 
Amgen Global Drug Safety processes. 

Section 10.4 Pregnancy was modified according to the Amgen Global Drug Safety 
process:
o
Collection of Pregnancy Information and Infant Health Information
o
Collection of information: Male Subjects with Partners Who Become Pregnant 
o
Collection of Lactation Information

Section 10.5 Reporting of Serious Adverse Events was updated to include instructions for 
paper reporting of SAEs 

Section 12.1 Emergency Contact was updated with Amgen emergency contact 
information.

Section 15.3 Product Complaint Section was modified according to the Amgen product 
complaint reporting process
The amendment also includes addition of forms, minor clarifications and corrections to 
align with Amgen processes:

Section 7.5 Investigational Product Accountability

Section 15.2 Audits and Inspections

Section 16 Publications

Appendix S Sample Serious Adverse Event Form was added

Appendix T Pregnancy Notification Form was added 

Appendix U Lactation Notification Form was added 


EDMS Doc. Number: 24238115 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Celgene International II SARL
Confidential and Proprietary
1
CC-10004-PSOR-020 Amendment 2 Final: 01 Nov 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 2
A PHASE 4, MULTI-CENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY OF THE IMPACT 
OF APREMILAST (CC-10004) ON QUALITY OF LIFE, 
EFFICACY, AND SAFETY IN SUBJECTS WITH 
MANIFESTATIONS OF PLAQUE PSORIASIS AND IMPAIRED 
QUALITY OF LIFE
INVESTIGATIONAL PRODUCT (IP):
Apremilast (CC-10004)
PROTOCOL NUMBER:
CC-10004-PSOR-020
ORIGINAL DATE:
26-SEP-2018
AMENDMENT No. 1 DATE:
17-JAN-2019
AMENDMENT No. 2 DATE:
01 NOV 2019
EudraCT NUMBER:
2018-002850-58
IND NUMBER: 
070270
Contact Information: 
Name:
, MD
Title:
Senior Medical Director, Global Medical Affairs, Dermatology
Address: 
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


EDMS Doc. Number: 24238115 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Celgene International II SARL
Confidential and Proprietary
2
CC-10004-PSOR-020 Amendment 2 Final: 01 Nov 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, PhD, Vice President, Medical Affairs Inflammation and Immunology, 
Rheumatology and Dermatology
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.


EDMS Doc. Number: 24238115 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Celgene International II SARL
Confidential and Proprietary
3
CC-10004-PSOR-020 Amendment 2 Final: 01 Nov 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
- Randomization to each of the 5 manifestations of plaque psoriasis
The primary purpose of this protocol amendment is to remove the requirement for equal block-
randomization to each of the 5 manifestations of plaque psoriasis. The basis for this change 
stems from the different enrollment rates in the 5 manifestation groups with a corresponding risk 
of missing the sample size required for the primary endpoint. This change does not impact the 
study endpoints. 
Revised sections: Protocol Summary, 3.1 Study Design, 4.3 Exclusion Criteria, 7.3 Method of 
Treatment Assignment.
- Updated modalities for reporting of serious adverse events (SAEs) and pregnancy
Reporting modalities were updated to reflect the use of an electronic case report form (eCRF)-
based system for reporting of SAEs and clarified expectations for pregnancy reporting.  
Revised sections: 6.5.8 Adverse Events, 10.4.1 Females of Childbearing Potential, 10.5 
Reporting of Serious Adverse Events (with 10.5.1 deleted) and 10.6 Expedited Reporting of 
Adverse Events
The Amendment also includes several other minor clarifications and corrections:
−
Medical Monitor and Celgene Therapeutic Area Head information was updated.
−
In Section 2, Table 2 Safety endpoints were combined with Secondary endpoints; 
Exploratory endpoint on
 
−
In Section 4.3, Exclusion Criteria # 3 clarified to refer specifically to arthritis requiring 
disease-modifying antirheumatic drug.
−
In Section 5, Table 3, Screening visit window: clarified to be -35 to 0 days.
−
In Section 6.5.4, Psychiatric Evaluation, language aligned with Risk Benefit Assessment 
and Investigator Brochure for patients with identified attempted suicide.
−
Where appropriate, references to CRF have been revised to eCRF.


EDMS Doc. Number: 23372629 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Celgene International II SARL
Confidential and Proprietary
1
CC-10004-PSOR-020 Amendment 1 Final:  17 Jan 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO 1. 
A PHASE 4, MULTI-CENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY OF THE IMPACT 
OF APREMILAST (CC-10004) ON QUALITY OF LIFE,
EFFICACY, AND SAFETY IN SUBJECTS WITH 
MANIFESTATIONS OF PLAQUE PSORIASIS AND IMPAIRED 
QUALITY OF LIFE
INVESTIGATIONAL PRODUCT (IP):
Apremilast (CC-10004)
PROTOCOL NUMBER:
CC-10004-PSOR-020
ORIGINAL DATE:
26 SEP 2018
AMENDMENT No. 1 DATE:
17 JAN 2019
EudraCT NUMBER:
2018-002850-58
IND NUMBER: 
070270
Contact Information: 
Name:
, MD
Title:
Medical Director 
Address: 
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by you, your 
staff, and ethics committee/institutional review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, may not be disclosed to another party 
unless such disclosure is required by law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them.


EDMS Doc. Number: 23372629 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Celgene International II SARL
Confidential and Proprietary
2
CC-10004-PSOR-020 Amendment 1 Final:  17 Jan 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, MD, Corporate Vice President, Global Medical Affairs 
Inflammation and Immunology
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.


EDMS Doc. Number: 23372629 - 23306134
Apremilast
Summary of Changes CC-10004-PSOR-020
Celgene International II SARL
Confidential and Proprietary
3
CC-10004-PSOR-020 Amendment 1 Final:  17 Jan 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

In the Protocol Summary; Overview of Key Safety Assessments, Physical examinations 
was changed to Body weight and waist circumference as body weight and waist 
circumference is done throughout the study and Physical examination is done at 
Screening.

In Section 2, Table 1; removed text, “data from the exploratory objectives may not be 
included in the clinical study report”, as the clinical study report will include data from 
exploratory analyses.

In Section 2, Table 2; added Safety Endpoints, based on Health Authority 
recommendations. 

In Section 4.2; clarified Inclusion Criteria 4, 9 and 11, to align to approved label 
indication for psoriasis and address Health Authority recommendations.

In Section 4.3; deleted Exclusion Criteria 1, clarified Exclusion Criteria 6 and added 
Exclusion Criteria 7, 8, 16 and 17 to align to approved label and address Health Authority 
recommendations. Exclusion Criteria # 18 was added to address exclusions for 
completion of randomization blocks for the disease manifestations noted in Inclusion 
Criteria #7.   

Modified Section 5 Table of Events to include additional Vital signs and body weight 
measures, based on Health Authority recommendations.

Modified Section 6.1, to clarify demography data collection and clinical laboratory 
evaluation, based on Health Authority recommendations.   

Provided clarification in Section 6.2 for Efficacy assessment, as investigators may asses 
efficacy and safety at any unscheduled visit, following country guidelines.

Modified Sections 6.4.14 and 6.4.15 to clarify that data from 
 
 and photography will be included in the clinical study report.

Added Section 6.5 specifying safety assessments and address Health Authority 
recommendations.

Modified Section 8.1 to clarify data collection of permitted concomitant medication. 

Added Section 8.2, “Concomitant Medications Not Recommended”, based on Health 
Authority recommendations.  

Modified Sections 9.6.3 and 9.6.4 to include data from exploratory objectives in study 
report, based on Health Authority recommendations. 

Provided clarification in Section 9.7 Safety Analysis, based on Health Authority 
recommendations.

Modified Sections 10.1 and 10.5 to clarify AE and SAE reporting will be done 
electronically through database.

Clarified Section 11.1, Treatment Discontinuation, based on Health Authority 
recommendations.

SAP_001.pdf: 
Amgen Proprietary - Confidential
Apremilast 
Statistical Analysis Plan. Protocol CC-10004-PSOR-020 
Amgen INC. 
Confidential and Proprietary 
1 
STATISTICAL ANALYSIS PLAN 
A PHASE 4, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED 
STUDY 
OF 
THE 
IMPACT 
OF 
APREMILAST (CC-10004) ON QUALITY OF LIFE, EFFICACY, AND 
SAFETY IN SUBJECTS WITH MANIFESTATIONS OF PLAQUE 
PSORIASIS AND IMPAIRED QUALITY OF LIFE 
STUDY DRUG: 
Apremilast (CC-10004) 
PROTOCOL NUMBER: 
CC-10004-PSOR-020
DATE FINAL: 
10Feb2021 
Prepared by: 
AMGEN, INC 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
CONFIDENTIAL 
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them. 
NCT Number: NCT03774875
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Amgen Proprietary - Confidential 
 
Apremilast 
 
 
Statistical Analysis Plan. Protocol CC-10004-PSOR-020 
Amgen INC.  
Confidential and Proprietary 
2 
 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................6 
1. 
LIST OF ABBREVIATIONS ....................................................................................8 
2. 
INTRODUCTION ....................................................................................................11 
3. 
STUDY OBJECTIVES ............................................................................................12 
3.1. 
Primary Objective .......................................................................................................12 
3.2. 
Secondary Objectives .................................................................................................12 
3.3. 
Exploratory Objectives ...............................................................................................12 
4. 
INVESTIGATIONAL PLAN ..................................................................................13 
4.1. 
Overall Study Design and Plan ...................................................................................13 
4.2. 
Study Endpoints ..........................................................................................................14 
4.2.1. 
Primary Efficacy Endpoint(s) .....................................................................................14 
4.2.2. 
Secondary Efficacy Endpoint(s) .................................................................................14 
4.2.3. 
Exploratory Efficacy Endpoint(s) ...............................................................................15 
4.2.4. 
Safety Endpoints .........................................................................................................15 
4.2.5. 
Derivations of Efficacy Endpoints..............................................................................15 
4.3. 
Stratification, Randomization, and Blinding ..............................................................19 
4.4. 
Sample Size Determination ........................................................................................20 
5. 
GENERAL STATISTICAL CONSIDERATIONS ...............................................21 
5.1. 
Reporting Conventions ...............................................................................................21 
5.2. 
Analysis Phases or Periods .........................................................................................21 
5.2.1. 
Placebo-controlled Phase – Weeks 0 to16 ..................................................................21 
5.2.2. 
Apremilast Extension Phase – Weeks 16 to 52 ..........................................................22 
5.2.3. 
Apremilast Exposure Period .......................................................................................22 
5.2.4. 
Follow-up Phase .........................................................................................................22 
5.3. 
Analysis Populations ..................................................................................................23 
5.3.1. 
Intent-to-Treat Population ..........................................................................................23 
5.3.2. 
Per-Protocol Population ..............................................................................................23 
5.3.3. 
Safety Population ........................................................................................................23 
5.3.4. 
Apremilast Exposure Population ................................................................................23 
5.4. 
Definition of baseline .................................................................................................24 


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Statistical Analysis Plan. Protocol CC-10004-PSOR-020 
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3 
 
5.5. 
Time Points .................................................................................................................24 
6. 
SUBJECT DISPOSITION .......................................................................................26 
7. 
PROTOCOL DEVIATIONS ...................................................................................27 
8. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................28 
8.1. 
Demographics .............................................................................................................28 
8.2. 
Baseline Disease Characteristics ................................................................................28 
8.3. 
Medical History ..........................................................................................................29 
8.4. 
Prior Psoriasis Therapy ...............................................................................................29 
8.5. 
Prior and Concomitant Procedures .............................................................................30 
8.5.1. 
Prior Procedures..........................................................................................................30 
8.5.2. 
Concomitant Procedures .............................................................................................30 
8.5.3. 
Prior Medications........................................................................................................30 
8.5.4. 
Concomitant Medications ...........................................................................................31 
8.6. 
Study Treatment Duration ..........................................................................................31 
8.7. 
Treatment Compliance................................................................................................32 
9. 
EFFICACY ANALYSIS ..........................................................................................33 
9.1. 
General Approaches to Efficacy Analysis ..................................................................33 
9.2. 
Multiplicity .................................................................................................................34 
9.3. 
Analysis of Primary Efficacy Endpoint ......................................................................34 
9.4. 
Analyses of Secondary Efficacy Endpoints ................................................................36 
9.4.1. 
Secondary Efficacy Endpoints in the Placebo-controlled Phase ................................36 
9.4.2. 
Secondary Efficacy Endpoints in the Apremilast Extension Phase............................38 
9.5. 
Subgroup Analysis ......................................................................................................38 
9.6. 
Analyses of Exploratory Efficacy Endpoints .............................................................39 
............................39 
9.6.2. 
Manifestation specific clinical endpoints at Week 16, Week 32, and Week 
52 ................................................................................................................................39 
9.7. 
Assessing Study Center Effect and Treatment-by-Center Interaction ........................40 
10. 
SAFETY ANALYSIS ...............................................................................................41 
10.1. 
Adverse Events ...........................................................................................................42 
10.1.1. 
Overall Summary of TEAEs .......................................................................................42 
10.1.2. 
All TEAEs ..................................................................................................................42 


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Amgen INC.  
Confidential and Proprietary 
4 
 
10.1.3. 
TEAEs by Maximum Severity....................................................................................43 
10.1.4. 
Deaths .........................................................................................................................43 
10.2. 
Clinical Laboratory Evaluations .................................................................................43 
10.3. 
Vital Sign, Weight, and Waist Circumference Measurements ...................................44 
11. 
QUALITY OF LIFE ANALYSIS............................................................................45 
12. 
INTERIM ANALYSIS .............................................................................................46 
13. 
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL .............................................................................................................47 
14. 
REFERENCES ...........................................................................................................48 
15. 
APPENDICES ............................................................................................................49 
15.1. 
Handling of Dates .......................................................................................................49 
15.1.1. 
Calculation Using Dates .............................................................................................49 
15.2. 
Date Imputation Guideline .........................................................................................49 
15.2.1. 
Adverse Events ...........................................................................................................50 
15.2.2. 
Prior/Concomitant Medications/Procedures ...............................................................52 
15.2.3. 
Medical History ..........................................................................................................52 
15.2.4. 
Treatment Duration .....................................................................................................52 
15.3. 
Tablets Intended to be Taken for Treatment Compliance Calculation .......................52 
15.4. 
Laboratory Marked Abnormalities Criteria ................................................................53 
 
 
 


Amgen Proprietary - Confidential 
 
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Statistical Analysis Plan. Protocol CC-10004-PSOR-020 
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Confidential and Proprietary 
5 
 
LIST OF TABLES 
Table 1 
Abbreviations and Specialist Terms .............................................................................8 
Table 2  
Table for Visit Mapping for by Time Point Analysis .................................................24 
Table 3 
Adjustment and Mapping of Study Weeks for Placebo Subjects who are 
Treated with Apremilast 30 mg BID after Week 16 in Summary of Safety 
Data over Time ...........................................................................................................25 
Table 4 
Definitions of time intervals used to summarize exposure to study 
Medication ..................................................................................................................31 
Table 5 
Primary Method for Analysis on the Secondary Efficacy Endpoints at Week 
16 ................................................................................................................................36 
Table 6 
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially ......................................................................50 
Table 7 
Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Placebo Initially ...........................................................................51 
Table 8 
Laboratory Marked Abnormalities Criteria ................................................................53 
 


Amgen Proprietary - Confidential 
 
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Statistical Analysis Plan. Protocol CC-10004-PSOR-020 
Amgen INC.  
Confidential and Proprietary 
6 
 
SIGNATURE PAGE 
STATISTICAL ANALYSIS PLAN (SAP) AND SAP AMENDMENT APPROVAL SIGNATURE PAGE  
 
SAP TITLE 
(Statistical Analysis Plan for a Phase 4, Multi-Center, Randomized, Double-Blind, 
Placebo-Controlled Study of the Impact of Apremilast (CC-10004) on Quality of 
Life, Efficacy, and Safety in Subjects with Manifestations of Plaque Psoriasis and 
Impaired Quality of Life) 
SAP VERSION, DATE 
Version 1.0 10Feb2021 
SAP AUTHOR 
  
{See 
appended 
electronic 
signature page} 
Printed Name and Title 
Signature and Date 
PROTOCOL TITLE 
(A Phase 4, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study 
of the Impact of Apremilast (CC-10004) on Quality of Life, Efficacy, and Safety in 
Subjects with Manifestations of Plaque Psoriasis and Impaired Quality of Life) 
INVESTIGATIONAL 
PRODUCT 
(Apremilast (CC-10004)) 
PROTOCOL NUMBER 
(CC-10004-PSOR 020) 
PROTOCOL 
VERSION, 
DATE 
Amd 3.0, 1-MAY-2020 
SIGNATURE 
STATEMENT 
By my signature, I indicate I have reviewed this SAP and find its contents to be 
acceptable. 
Statistical Therapeutic Area Head 
 
 
 
 
Signature 
{See appended electronic signature page} 
 
 
 
 
 
 
Printed Name 
 
Date 
 
 
 
Lead Clinical Research Physician / Clinical Research Physician 
 
 
 
 
Signature 
{See appended electronic signature page} 
 
 
 
 
Printed Name 
 
Date 
 
 
 
Lead Product Safety Physician 
 


Amgen Proprietary - Confidential 
 
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Statistical Analysis Plan. Protocol CC-10004-PSOR-020 
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Signature 
{See appended electronic signature page} 
 
 
 
 
Printed Name 
 
Date 
 
 
 
 


Amgen Proprietary - Confidential 
 
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Statistical Analysis Plan. Protocol CC-10004-PSOR-020 
Amgen INC.  
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8 
 
1. 
LIST OF ABBREVIATIONS 
Table 1 
Abbreviations and Specialist Terms 
ALT 
Alanine aminotransferase (SGPT) 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase (SGOT) 
ATC 
Anatomical Therapeutic Chemical  
BID 
Twice Daily 
BSA 
Body Surface Area 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CRO 
Contract Research Organization  
CTCAE 
Common Terminology Criteria for Adverse Events 
DAO 
Data as Observed 
DMC 
Data Monitoring Committee 
DLQI 
Dermatology Life Quality Index 
EAIR 
Exposure-Adjusted Incidence Rate 
EQ-5D 
European Quality of Life 5-Dimension Questionnaire 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
ICH 
International Council for Harmonization 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
LDH 
Lactic dehydrogenase 
LOCF 
Last Observation Carried Forward 


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MedDRA 
Medical Dictionary for Regulatory Affairs 
MCMC 
Markov Chain Monte Carlo  
MI 
Multiple Imputation 
NA 
Not applicable 
NAPSI 
Nail Psoriasis Severity Index 
NRI 
Non-responder Imputation 
NRS 
Numeric Rating Scale 
PASI 
Psoriasis Area and Severity Index 
PBI 
Patient Benefit Index  
PP 
Per-Protocol 
PPPGA 
Palmoplantar Psoriasis Physician Global Assessment  
PBI 
Patient Benefit Index 
PNQ 
Patient Needs Questionnaire 
PBQ 
Patient Benefit Questionnaire 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
STDEV 
Standard deviation 
SE 
Standard error  
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
ScPGA 
Scalp Physician Global Assessment 
SOC 
system organ class  
sPGA 
Static Physician Global Assessment 
sPGA-G 
Static Physician Global Assessment-Genitalia  
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual Analog Scale 


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WHO DD 
World Health Organization Drug Dictionary  
WPAI: PSO 
Work Productivity and Activity Impairment Questionnaire: Psoriasis 
 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the analyses and data presentations for Amgen’s 
protocol CC-10004-PSOR 020 “A Phase 4, Multi-Center, Randomized, Double-blind, Placebo-
Controlled Study of the Impact of Apremilast (CC-10004) on Quality of Life, Efficacy, and Safety 
in Subjects with Manifestations of Plaque Psoriasis and Impaired Quality of Life” version 1.0, 
which was issued on 12Oct2020.  It contains definitions of analysis populations, derived variables 
and statistical methods for the analysis of Quality of Life, efficacy and safety. 
No interim analysis is planned.  There will be a Week 16 data transfer on all the data collected 
after all subjects have completed the Week 16 Visit (or discontinued from the study) for 
publication purpose; unblinded data will only be made available to selected Sponsor and Contract 
Research Organization (CRO) team members involved with publication preparations.  All other 
Sponsor, site, and CRO personnel directly involved with the conduct of the study, will remain 
blinded to treatment assignments until the final database lock at the final study completion.  After 
all subjects have completed the Observational Follow-up Phase following the Week 
52/discontinuation visit, the final data base will be locked and transferred for all analyses planned 
in the SAP to generate the Clinical Study Report (CSR) of the study. Only one CSR will be 
generated including the analyses for both the primary Week 16 timepoint and the other timepoints 
from the open label extension phase.   
Throughout this SAP, the treatment groups will be referred to as Apremilast 30 mg BID arm and 
placebo arm according to the original treatment assignment or treatment received during the 
Placebo-controlled Phase. The purpose of the SAP is to ensure the credibility of the study findings 
by pre-specifying the statistical approaches to the analysis of study data prior to the access to 
unblinded data. This SAP will be finalized and signed prior to Week 16 data transfer.  All statistical 
analyses detailed in this SAP will be conducted using SAS® Version 9.4 or higher.  
 


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3. 
STUDY OBJECTIVES 
3.1. 
Primary Objective 
The primary objective is to assess the impact of Apremilast, compared to placebo, on Health-
related Quality of Life (QOL) in subjects with manifestations of plaque psoriasis and impaired 
quality of life at Week 16 
3.2. 
Secondary Objectives 
The secondary objectives are: 
• 
To assess the efficacy and safety of Apremilast compared to placebo in patients with 
manifestations of plaque psoriasis and impaired quality of life at Week 16 
• 
To assess the long-term effects of Apremilast with respect to quality of life, efficacy, and 
safety at Weeks 32 and 52 
3.3. 
Exploratory Objectives 
The exploratory objectives are: 
• 
To assess the efficacy of Apremilast compared to placebo in subgroups of patients with 
specific manifestations 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a phase 4, multicenter, randomized, double-blind, placebo-controlled study of the impact 
of Apremilast on quality of life, efficacy, and safety in subjects with manifestations of plaque 
psoriasis and impaired quality of life.  Approximately 276 subjects in 6-10 countries in Western 
Europe meeting inclusion criteria will be randomized in 2:1 ratio to receive Apremilast 30 mg BID 
or placebo, and to each of the stratification factors of manifestations of psoriasis (scalp psoriasis, 
nail psoriasis, palmoplantar psoriasis, genital psoriasis, and psoriasis in visible locations). For 
patients with multiple manifestations, they will be allocated to the manifestation which is most 
severe, as determined by the patients.  
• Subjects randomized to the Apremilast treatment group will receive a 5-day titration 
with Apremilast followed by Apremilast 30 mg BID orally for 16 weeks. The subjects 
will continue with Apremilast 30 mg BID until Week 52 (i.e., a total of 52-week 
treatment with Apremilast). There is a dummy 5-day titration at Week 16 to maintain 
the blind to the original treatment assignment at randomization.  
• Subjects randomized to the placebo treatment group will start with a dummy 5-day 
titration and receive placebo tablets (identical in appearance to the Apremilast 30 mg 
tablets) orally twice daily for 16 weeks. Beginning at Week 16 and after a 5-day 
titration with Apremilast, subjects will receive Apremilast 30 mg BID until Week 52 
(i.e., a total of 36-week treatment with Apremilast). 
The study consists 4 phases:    
• Screening Phase – up to 5 weeks (35 days) 
• Double-blind Placebo-controlled Phase – Weeks 0 through 16 
Subjects will receive treatment with either 
− Apremilast 30 mg tablets orally BID, or 
− matched placebo tablets orally BID 
• Apremilast Extension Phase – Weeks 16 through 52 
− All subjects will be switched to (or continue with) Apremilast 30 mg BID at 
Week 16 (after a 5-day titration for subjects initially randomized to placebo). All 
subjects will maintain this dosing through Week 52. 
• Post-treatment Observational Follow-up Phase 
− 4-week post-treatment observational follow-up phase for all subjects who complete 
the study on treatment or discontinue from the study treatment early.  
 
 


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Figure 1: 
Overall Study Design 
 
The study will be conducted in compliance with the International Council for Harmonization (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
 
4.2. 
Study Endpoints 
4.2.1. 
Primary Efficacy Endpoint(s) 
The primary endpoint is achieving a ≥ 4-point reduction from baseline in the Dermatology Life 
Quality Index (DLQI) at Week 16. 
4.2.2. 
Secondary Efficacy Endpoint(s) 
The secondary endpoints are  
• Achieving a ≥ 4-point reduction from baseline at weeks 32 and 52 
• Change from baseline in DLQI at weeks 16, 32, and 52  
• Change from baseline in Itch Numeric Rating Scale (NRS) at weeks 16, 32, and 52 
• Change from baseline in Skin Discomfort/Pain Visual Analog Scale (VAS) at weeks 16, 
32, and 52 
• Percent change from baseline in Body Surface Area (BSA) at weeks 16, 32, and 52 
• Achieving Psoriasis Area and Severity Index (PASI) score <3 at weeks 16, 32, and 52 
• Achieving Patient Benefit Index (PBI) score ≥1 at weeks 16, 32, and 52 
• Percent change from baseline in European Quality of Life 5-Dimension Questionnaire (EQ-
5D) at weeks 16 and 52 


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• Change from baseline in Work Productivity and Activity Impairment Questionnaire: 
Psoriasis (WPAI: PSO) at weeks 16 and 52 
4.2.3. 
Exploratory Efficacy Endpoint(s) 
The Exploratory efficacy endpoints are: 
•
• Achieving Static physician global assessment (sPGA) score of 0 or 1 at Weeks 16, 32, and 
52 among the subjects randomized to the strata with moderate to severe psoriasis in visible 
areas, defined as sPGA≥3 at baseline, which include the dorsal hand, face, neck, or hairline. 
• Achieving ScPGA score of 0 or 1 at weeks 16, 32, and 52 among the subjects randomized 
to the strata with moderate to severe scalp psoriasis (ScPGA ≥3 at baseline). 
• Achieving Nail Psoriasis Severity Index (NAPSI) score of 0 in the target fingernail at weeks 
16, 32, and 52 among the subjects randomized to the strata with presence of nail psoriasis, 
defined as onycholysis and onychodystrophy in at least 2 fingernails at baseline. 
• Achieving Static Physician Global Assessment-Genitalia (sPGA-G) score of 0 or 1 at weeks 
16, 32, and 52 among the subjects randomized to the strata with moderate to severe genital 
psoriasis (sPGA-G ≥3 at baseline). 
• Achieving Palmoplantar Psoriasis Physician Global Assessment (PPPGA) score of 0 or 1 at 
weeks 16, 32, and 52 among the subjects randomized to the strata with moderate to severe 
palmoplantar psoriasis (PPPGA ≥3 at baseline). 
4.2.4. 
Safety Endpoints 
Safety endpoints will include: 
• Adverse events (AE) 
• Pregnancy tests for females of child bearing potential (FCBP) 
• Vital signs  
• Clinical laboratory tests 
• Body weight and waist circumference  
4.2.5. 
Derivations of Efficacy Endpoints 
The derivation of each efficacy endpoint is described below in separate sections.  Baseline 
definition for all efficacy endpoints is given in Section 5.4. Change from baseline is calculated as 
on-treatment value minus the baseline value. Percent change from baseline is defined as 100* 
Change from baseline/Baseline value (%). Handling of time points is described in Section 5.5. 
4.2.5.1. 
Dermatology Life Quality Index (DLQI) 
The DLQI (Finlay, 1994) was developed as a simple, compact, and practical questionnaire for use 
in a dermatology clinical setting to assess limitations related to the impact of skin disease.  The 
instrument contains 10 items dealing with the subject’s skin. With the exception of Item Number 


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7, the subject responds on a four-point scale, ranging from “Very Much” (score 3) to “Not at All” 
or “Not relevant” (score 0). Item Number 7 is a multi-part item, the first part of which ascertains 
whether the subject’s skin prevented them from working or studying (Yes or No, scores 3 or 0 
respectively), and if “No,” then the subject is asked how much of a problem the skin has been at 
work or study over the past week, with response alternatives being “A lot,” “A little,” or “Not at 
all” (scores 2, 1, or 0 respectively). The DLQI total score is derived by summing all item scores, 
which has a possible range of 0 to 30, with 30 corresponding to the worst quality of life, and 0 
corresponding to the best.  
If one of the 10 items are left unanswered, it is scored 0 and the scores are summed and expressed 
as usual out of a maximum of 30. If two or more of the ten items are left unanswered, DLQI total 
score will be left missing. When using sub-scales, if the answer to one item in a sub-scale is missing, 
the score is set to missing for that sub-scale. 
4.2.5.2. 
Itch Numeric Rating Scale (NRS) Assessment   
The Itch NRS is a single-item patient-reported outcome that asks subjects to assess the worst 
severity of itch over the past 24 hours and select a number on a scale of 0 to 10, where “0” 
represents no itching, and “10” represents the worst itch imaginable (Naegeli, 2015). The number 
selected by the subject will be recorded in the database. 
4.2.5.3. 
Skin Discomfort/Pain Visual Analog Scale (VAS) 
The subject will be asked to place a vertical stroke on a 100 mm VAS on which the left-hand 
boundary represents no skin discomfort/pain, and the right-hand boundary represents skin 
discomfort/pain as severe as can be imagined. The number corresponding to the stroke will be 
recorded in the database. 
4.2.5.4. 
Body Surface Area (BSA) 
Body surface area is a measurement of involved skin. The overall BSA affected by psoriasis is 
estimated based on the palm area of the subject’s hand (entire palmar surface or “handprint”), 
which equates to approximately 1% of total BSA.  
4.2.5.5. 
Patient Benefit Index (PBI) 
The PBI is a validated patient-reported instrument to assess patient-relevant benefits of psoriasis 
treatment and represents the subject benefits realized as a function of most important subject needs 
(Feuerhahn, 2012). PBI consist of 2 questionnaires: 
• Patient Needs Questionnaire (PNQ): Prior to starting therapy, subjects are asked to assess 
their treatment expectations by completing the PNQ. Individual importance of treatment 
objectives is collected by marking the importance of a total of 25 treatment goal statements. 
The score ranges from 0 (no important at all) to 4 (very important) for each treatment 
objective will be recorded in the database.  
• Patient Benefit Questionnaire (PBQ): After a period of treatment, subjects are then asked 
to assess the benefits of treatment by completing the PBQ with the same 25 treatment goal 
statements. The score ranges from 0 (not at all) to 4 (very) will be recorded in the database. 


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A global score is calculated for each subject at a given visit by weighing the achievement values 
of the treatment objectives by their importance to the individual patient using the following 
Algorithm. Using this algorithm, the importance of each treatment goal is divided by the sum of 
all importance values of the respective patient and is multiplied with the goal attainment values. 
The resulting products are added up: 
𝑃𝐵𝐼= ∑
𝑃𝑁𝑄𝑖
∑
𝑃𝑁𝑄𝑖
𝑘
𝑖=1
𝑃𝐵𝑄𝑖
𝑘
𝑖=1
  
𝑖= 𝑡ℎ𝑒 𝑖𝑡ℎ 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑔𝑜𝑎𝑙 𝑠𝑡𝑎𝑡𝑒𝑚𝑒𝑛𝑡  
𝑘= 𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡ℎ𝑒  𝑎𝑝𝑝𝑙𝑖𝑐𝑎𝑏𝑙𝑒 𝑝𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑖𝑡𝑒𝑚𝑠 (𝑃𝑁𝑄) 𝑎𝑛𝑑 𝑏𝑒𝑛𝑒𝑓𝑖𝑡 𝑖𝑡𝑒𝑚𝑠 (𝑃𝐵𝑄)  
 
For score calculation, both “does/did not apply” and “question unanswered” will be treated as 
missing values. The global score will be calculated using only the items pairs (i.e., importance 
item and benefit items) for which the patient has given a response other than “does/did not apply” 
in both PNQ and PBQ. For example, importance items for which the corresponding benefit item 
has been rated as “did not apply” (or vice versa) will not be included in the denominator within 
the algorithm. 
4.2.5.6. 
Psoriasis Area and Severity Index (PASI)  
The PASI is a measure of psoriatic disease severity taking into account qualitative lesion 
characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on 
defined anatomical regions. The PASI is a validated instrument that has become standard in 
clinical trials for psoriasis. 
Psoriasis Area Severity Index scores range from 0 to 72, with higher scores reflecting greater 
disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very 
severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of 
involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 
(90% to 100% involvement).  The total qualitative score (sum of erythema, thickness, and scaling 
scores) is multiplied by the degree of involvement for each anatomic region and then multiplied 
by a constant.  These values for each anatomic region are summed to yield the PASI score. The 
PASI score will be set to missing if any severity score or degree of involvement is missing. PASI 
scores will be presented with one digit after the decimal point. 
4.2.5.7. 
The European Quality of Life 5-Dimension Questionnaire (EQ-5D) 
EQ-5D-3L (The EuroQol Group, 1990) measures the subject’s general health state as a vertical 
VAS and 5 quality of life domains as multiple-choice questions: mobility, self-care, main activity 
(work, study, housework, family/leisure activities), pain/discomfort, and anxiety/depression. The 
EQ-5D VAS scores range from 0 to 100, where score 0 indicates the worst imaginable health states 
and score 100 indicates the best imaginable health state. Using the 5-domain scores, EQ-5D index 
values using the UK scoring algorithm will be derived, where a higher score indicates a better 
health state.  


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4.2.5.8. 
The Work Productivity and Activity Impairment Questionnaire: Psoriasis 
(WPAI: PSO) 
The WPAI: PSO questionnaire is a validated, 6-item self-administered instrument used to assess 
the impact of disease on work productivity in psoriasis due to specified health problem during the 
last 7 days. The 6 questions are: Q1 = currently employed; Q2 = hours missed due to problems 
associated with psoriasis; Q3 = hours missed other reasons; Q4 = hours actually worked; Q5 = 
degree health affected productivity while working (using a 0 to 10 Visual Analogue Scale (VAS)); 
Q6 = degree health affected productivity in regular unpaid activities (VAS) [Reilly, 2012] The 
sum of work time missed and work impairment while working yielded the overall work 
impairment measure. Four types of scores were calculated as following. All scores were expressed 
as percentages, with higher scores indicating greater impairment.  
1) percent work time missed due to health = Q2/(Q2 + Q4) for those who were currently employed;  
2) percent impairment while working due to health = Q5/10 for those who were currently employed 
and actually worked in the past seven days;  
3) percent overall work impairment due to health Q2/(Q2 + Q4) + ((1 - Q2/(Q2 + Q4)) × (Q5/10)) 
for those who were currently employed. For those who missed work and did not actually work in 
the past seven days, the percent overall work impairment due to health will be equal to the percent 
work time missed due to health; 
4) percent activity impairment due to health Q6/10 for all respondents.  
4.2.5.9. 
Static Physician Global Assessment (sPGA) of visible locations 
The sPGA is the assessment by the Investigator of the overall disease severity at the time of 
evaluation.  In this study, sPGA is used to evaluate psoriasis only in visible locations, defined as 
dorsal hand, face, neck and hairlines. 
The sPGA is a 5-point scale ranging from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), to 4 
(severe), incorporating an assessment of the severity of the three primary signs of the disease: 
erythema, scaling and plaque elevation.  When making the assessment of overall severity, the 
Investigator should factor in areas that have already been cleared (i.e., have scores of 0) and not 
just evaluate remaining lesions for severity, i.e., the severity of each sign is averaged across all 
areas of visible locations, including cleared lesions.   
4.2.5.10. Scalp Physician Global Assessment (ScPGA) 
The ScPGA is a measurement of overall scalp involvement. The ScPGA is a 5-point scale that 
assesses three dimensions (Plaque Elevation, Scaling, and Erythema) on a scale of 0 (clear), 1 
(almost clear), 2 (mild), 3 (moderate), to 4 (severe). 
4.2.5.11. Nail Psoriasis Severity Index (NAPSI) Assessment  
The number of fingers with psoriasis nail involvement, defined as onycholysis and 
onychodystrophy, will be counted. 


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The NAPSI (Rich, 2003) will assess one target thumb nail or fingernail representing the worst nail 
psoriasis involvement at Baseline. The total NAPSI score ranging from 0 to 8 (most severe) will 
be recorded in the database.   
4.2.5.12. Modified Static Physician Global Assessment-Genitalia (sPGA-G) 
The modified sPGA-G is the assessment by the Investigator of the overall disease severity at the 
time of evaluation of the genital regions. As with the sPGA, it is a 5-point scale, ranging from 0 
(clear) to 4 (severe). 
4.2.5.13. Palmoplantar Psoriasis Physician Global Assessment (PPPGA) 
The PPPGA is the assessment by the Investigator of the overall disease severity at the time of 
evaluation of palms and soles (Leonardi, 2007). The scale ranges from 0 (clear) to 4 (severe). 
4.3. 
Stratification, Randomization, and Blinding 
Randomization is carried out using an Interactive Voice Response System (IVRS). Treatment 
assignment is following a 2:1 ratio between Apremilast 30 mg BID arm and placebo arm. 
Randomization method is based on permutated-block randomization. Subjects were targeted to be 
randomized within each of the 5 manifestations of plaque psoriasis (i.e., scalp psoriasis, nail 
psoriasis, palmoplantar psoriasis, genital psoriasis, and psoriasis in visible locations). If subjects 
present with multiple manifestations, they will be allocated to the manifestation which is most 
severe, as determined by the subject.  
Data analysis and reporting will be performed for publication after all subjects have completed the 
double-blind placebo-controlled phase at Week 16/Visit 5 or have discontinued early. A copy of 
the 16-week data extraction will be transferred for analysis after medical/scientific review has been 
completed, protocol violations/deviations have been identified, and the data have been declared 
cleaned. Selected members of the study team and external partner who do not have direct 
interaction with subjects are unblinded for the analysis of the Week 16 data. These persons may 
include but are not limited to the following: Therapeutic Area Head, Study lead, Medical Director 
and the Statistician. The results from these analyses may be published prior to the end of the study. 
Subjects, Investigators and persons responsible for the ongoing conduct of the study will continue 
to be blinded to the original treatment assignment until the 52-week database lock at end of the 
study. These persons are those individuals who have direct interaction with subjects and/or subject 
assessments and may include but are not limited to the following: Clinical Trial Manager, Data 
Manager, Clinical Research Associates and Site Monitors.  
For the purpose of the data analyses supporting the CSR after all subjects have completed the post-
treatment observational follow-up or have discontinued early, the 52-week database will be locked 
after medical/scientific review has been performed, protocol violations/deviations have been 
identified, and the data have been declared final and complete. 


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4.4. 
Sample Size Determination 
For the primary endpoint, i.e., the response rate (π) defined as the proportion of subjects achieving 
a ≥ 4-point reduction from baseline in DLQI at Week 16, the superiority of Apremilast 30 mg BID 
versus placebo will be tested. The hypotheses on superiority are defined as:  
H0: πAPR – πPBO = 0 
versus 
H1: πAPR – πPBO > 0 
Using an exploratory analysis on a subset of subjects meeting the following criteria: a) ScPGA ≥ 
3 or b) NAPSI ≥ 1 or c) PPPGA ≥ 3 at baseline and DLQI ≥ 10 at baseline in the PSOR-008 and 
PSOR-009 Phase 3 studies, it was estimated that the proportion of subjects who achieved a ≥ 4-
point reduction from baseline in DLQI was 0.50 (97 responders out of 193 subjects) and 0.83 (337 
responders out of 406 subjects) for placebo and Apremilast 30 mg BID, respectively.  
Assuming a placebo DLQI responder proportion of 0.50 at Week 16, a minimum total sample size 
of 210 subjects (140 allocated to Apremilast 30 mg and 70 allocated to placebo) is needed to detect 
a 0.20 difference in the DLQI responder rate between Apremilast and placebo with at least 0.807 
power using a two-sided test at the 0.05 level of significance. This sample size calculation is based 
on an unpooled variance, and determined using the commercial software EaST, Version 6.3. 
Allowing for an 24% discontinuation rate prior to Week 16, the sample size of 276 subjects should 
be sufficient. 


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5. 
GENERAL STATISTICAL CONSIDERATIONS 
5.1. 
Reporting Conventions 
• The statistical test on the primary endpoint is at a 2-sided 0.05 significance level, any p-values 
reported for other endpoints are considered as summary statistics; 
• P-values are rounded to 4 decimal places. P-values that round to 0.0000 are presented as 
‘<0.0001’ and p-values that round to 1.000 are presented as ‘>0.9999’;  
• Confidence intervals (CIs) are presented as 2-sided 95% CIs; 
• Summary statistics consist of the number and percentage of subjects in each category for 
discrete variables, and the sample size, mean, median, Standard Deviation (STDEV), 
minimum, and maximum for continuous variables; 
• All mean and median values are formatted to one more decimal place than the measured value, 
standard deviation values are formatted to two more decimal places than the measured value, 
minimum and maximum values are presented to the same number of decimal places as the 
measured value, and the 95% CI are formatted to two more decimal places than the measured 
value; 
• All percentages are rounded to one decimal place. The number and percentage of responses 
are presented in the form XX (XX.X), where the percentage is in the parentheses, and the 95% 
CI are presented to two decimal places. Exact 100% that is not rounded from a percent 
>99.50% is presented in the format xx (100); 
• All listings are sorted for presentation in order of treatment arm, study center, subject, and date 
of procedure or event; 
• All analysis and summary tables have the analysis population sample size (i.e., number of 
subjects); 
• All laboratory data will be reported using standard international (SI) units. 
5.2. 
Analysis Phases or Periods 
Data summary and analysis will be provided for the following analysis phases/periods. 
5.2.1. 
Placebo-controlled Phase – Weeks 0 to16  
The Placebo-controlled phase is per protocol specification. All the efficacy and safety analyses for 
the primary time point at Week 16 are based on placebo-controlled phase, including data collected 
from Day 1 for the core baseline (defined in Section 5.4). The end date is defined as following: 
 
(1) One day prior to the first dose date of Apremilast dispensed at Week 16/Visit 5 for patients 
who are entering the Apremilast Extension Phase;  
(2) the day of the discontinuation visit if the subject discontinued prior to or at Week 16/Visit 
5;   


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(3) the last known study day if the subject is lost to follow-up prior to Week 16/Visit 5. 
All by-treatment tabulations based on the data from Placebo-controlled Phase are grouped by 
Apremilast 30 mg BID vs. placebo. 
5.2.2. 
Apremilast Extension Phase – Weeks 16 to 52  
The Apremilast Extension Phase is per protocol specification. Quality of life and efficacy 
endpoints, patient disposition, protocol deviation/violation, and study treatment compliance are 
summarized based on data from this study phase.  
The Apremilast Extension Phase starts on the day that the first dose of treatment is dispensed for 
the phase at Week 16/visit 5 and the end date is defined as the following:  
(1) the day of Week 52/Visit 9 for patients who complete the study on treatment;  
(2) the day of the discontinuation visit if the subject discontinued prior to or at Week 52/Visit 
      9;  
(3) the last known study day if the subject is lost to follow-up prior to Week 52/Visit 9. 
All by-treatment tabulations are grouped by Apremilast 30 mg BID arm vs. placebo arm, i.e., the 
original treatment during the placebo-controlled phase. 
5.2.3. 
Apremilast Exposure Period 
In addition to the above defined phases, Apremilast Exposure Period will be used for safety 
analyses. This period starts on the date of either:  
(1) the first dose of IP following randomization (Week 0/Visit 2) for subjects who are treated 
with Apremilast 30 mg BID first;  
(2) the first dose of IP from the IP dispensed at Week16/Visit 5 for subjects who were 
originally treated with placebo and are treated with Apremilast 30 mg BID at Week 16. 
This period stops on either:  
(1) data cut-off date;  
(2) the day of the treatment discontinuation if the subject discontinued prior to or at Week 
52/Visit 9;  
(3) the last known study day if the subject is lost to follow-up prior to Week 52/Visit 9;  
(4) Week 52/Visit 9 visit date. 
Study treatment duration will also be summarized for the Apremilast Exposure Period. The outputs 
based on the Apremilast exposure period only have one Apremilast 30 mg BID arm. 
5.2.4. 
Follow-up Phase 
 
 


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For all subjects who complete the study or discontinue the study early, the Four-week 
Observational Follow-up Phase starts at the completion or discontinuation visit and stops at the 
follow-up visit or the last assessment date. 
Concomitant medications are summarized based on the follow-up phase including data collected 
after the last dose of the study treatment up to the 28 days post-treatment for subjects who entered 
the observational follow-up phase. 
5.3. 
Analysis Populations 
5.3.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population includes all subjects who are randomized. Subjects will be 
included in the treatment arm to which they are randomized. 
This is the primary population for the primary endpoint and all other quality of life and efficacy 
analyses. Baseline summaries and treatment compliance summaries are also based on the ITT 
population. 
5.3.2. 
Per-Protocol Population 
The per-protocol (PP) population includes all subjects who are in the ITT population, who receive 
at least one dose of IP, have both baseline and at least one post-treatment DLQI evaluation, and 
have no major protocol deviations which may affect analyses in the Placebo-controlled Phase. The 
PP population is only used to supplement the primary endpoint ITT analysis.  
5.3.3. 
Safety Population 
The safety population includes all subjects who are randomized and receive at least one dose of 
study drug. If a subject receives study drug other than the subject’s randomized treatment 
assignment, then the subject is assigned to the treatment arm reflecting the treatment that the 
subject actually received during the study. All safety endpoints, study treatment duration, and 
concomitant medication summaries for the placebo-controlled phases are based on the safety 
population.  
5.3.4. 
Apremilast Exposure Population 
The Apremilast exposure population consists of only those subjects who receive at least one dose 
of Apremilast treatment, i.e., all subjects in the Apremilast 30 mg BID arm from the safety 
population and the subset of subjects in the placebo arm from the safety set who also enter the 
Apremilast Extension Phase with at least one treatment of Apremilast. The Apremilast Exposure 
population are only used for the safety endpoints. 
  


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5.4. 
Definition of baseline  
Core baseline (Week 0) is used for all efficacy analyses, safety analyses for the placebo-
controlled period, and summary of baseline disease characteristics.  
For efficacy analysis and summary of baseline disease characteristics data, baseline is defined as 
the last value measured prior to or at the randomization visit. 
For safety summaries, baseline is defined as the last value measured on or before the day of the 
first dose of double-blind treatment.  
Apremilast treatment baseline is used for the summaries of safety analyses for the Apremilast 
Exposure Period. It is defined as the last value measured on or before the day of the first 
Apremilast dose.  
5.5. 
Time Points 
Time points in all analyses are based on the visits/study weeks using the following visit mapping 
algorithm, which may or may not be the same as the visits/study weeks as recorded in the 
database. 
Post baseline time points in all analyses will be captured based on analysis visit window (range 
of study days) around the target day for each analysis visit, based on the actual day of evaluation 
relative to a reference date. Appropriate dates will be used to calculate the study day, e.g., date of 
measurement or date of specimen collection will first be used, and then the date of visits/study 
weeks as recorded in the database will be used. If there are multiple measurements within a time 
point based on the study day, then the non-missing value from the closest measurement to the 
planned study day will be used for that visit. If the value at a scheduled visit is missing and there 
is no value available within the time window based on the study day, the value at the study week 
will be missing. 
Table 2:  
Table for Visit Mapping for by Time Point Analysis 
Analysis Visit 
Target Day 
Visit Window 
  Baseline 
1 
≤ 1 
Placebo-controlled Phase (for all endpoints) 
  Week 2 
15 
2 – 21 
  Week 4 
29 
22 – 70 
  Week 16 
113 
71 – End of Placebo-controlled 
Phase 
 
 
 
Apremilast Extension Phase (for efficacy endpoints) 
  Week 20 
141 
Start of Apremilast Extension 
Phase – 182 
  Week 32 
225 
183 – 294 
  Week 52 
365 
295 – End of Apremilast 
Extension Phase 
 
 
 
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  Week 20 
141 
Start of Apremilast Extension 
Phase – 182 
  Week 32 
225 
183 – 266 
  Week 44 
309 
267 –337 
  Week 52 
365 
338 – End of Apremilast 
Extension Phase 
 
Note: Target day and visit window are relative to the date of Visit 2/Week 0 (Day 1) for randomization. 
Definitions for baseline and start or end of the phases are specified in Section 5.25.2 and 5.4 for both 
efficacy and safety analysis.  
Time points in the analyses or summaries of efficacy data over time include the scheduled study 
weeks per protocol, the end of a study phase, and the observational follow-up visit. Appropriate 
dates (e.g., date of measurement or date of specimen collection) will first be used to ensure only 
data (including data from scheduled, unscheduled, container visits, discontinuation, and 
observational follow-up visits) measured or collected within the specific analysis phase (as 
defined in Section 5.2) being analyzed or summarized are included, and then the visits/study 
weeks as recorded in the database will be used to assign one value (possibly missing) to each 
time point at the subject level. It is possible that multiple assessment values will fall into the 
same visit window. The following rule may be used to select the unique value for that analysis 
visit:  
1. Among all assessments in the same visit window for the analysis visit, select the value 
with the assessment date closest to the target day of the analysis visit; 
2. If the relative days from 2 assessments are equally close to, but on different sides of the 
target day, then the latter assessment will be used for that analysis visit; 
3. If multiple assessments are available on the same relative day, then the highest value of 
these assessments will be used for that relative day. 
The time points for summaries of safety data (laboratory parameters, vital signs and weight) are 
based on study week/visit for the placebo-controlled phase. For the Apremilast Exposure Period, 
the scheduled study weeks for placebo subjects who are treated with Apremilast 30 mg BID at 
Week 16 will be mapped to reflect the study weeks relative to the first dose of Apremilast (see 
table below). 
Table 3: 
Adjustment and Mapping of Study Weeks for Placebo Subjects who are 
Treated with Apremilast 30 mg BID after Week 16 in Summary of Safety 
Data over Time 
Original Visit 
Re-Mapped Visit for subjects initially 
randomized to placebo 
Week 16  
Baseline 
Week 20  
Week 4 
Week 32  
Week 16 
Week 44 
Week 28 
Week 52 
Week 36 


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6. 
SUBJECT DISPOSITION 
The number and percentage of screened subjects randomized (as recorded in the IVRS database) 
and not randomized will be summarized. The failed inclusion/exclusion criteria of subjects who 
were screened and not randomized will be included in the summary. The percentages will be based 
on the number of subjects screened. For patients who were rescreened, the last screening status 
will be considered for the summary. 
Randomized subjects included in the ITT population, PP population, safety population, and 
Apremilast Exposure population will be summarized by treatment arm.  
The numbers and percentages of randomized subjects who entered, completed, and discontinued 
from the following protocol phases will also be summarized by treatment arm.  All the percentages 
will be based on the number of subjects randomized. 
• Placebo-controlled Phase – Weeks 0 to16: The summary on the numbers and percentages 
of the following subjects will be provided.  
o Subjects who completed the phase and entered the Apremilast Extension Phase 
(Weeks 16 to 52) 
o Subjects who completed the phase and did not enter the Apremilast Extension 
Phase (Weeks 16 to 52) as well as the reason 
o Subjects who discontinued early from the phase as well as the reason  
• Apremilast Extension Phase – Weeks 16 to 52: The number and percentage of subjects 
who entered the phase, had at least one dose of Apremilast in the phase, completed the 
phase, and discontinued early will be provided. The primary reason for discontinuation 
from the treatment in this phase will also be summarized.  
• Observational Follow-up Phase (4 weeks): Summary will be provided on the number and 
percentage of subjects who entered the phase, if not, the primary reason for not entering 
the phase, subjects who completed the phase, and if discontinued, the primary reason for 
not fulfilling follow-up visit 4 weeks after the completion or discontinuation of the study 
treatment.  
The number and percentage of subjects randomized by study site and treatment arm will be 
tabulated. The percentages will be calculated based on the number of randomized subjects. 
Listings will be provided for randomized subjects in analysis populations, for the reason of 
treatment or phase discontinuation, and for subjects excluded from the PP population along with 
the reason. 
 


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7. 
PROTOCOL DEVIATIONS 
The protocol deviations and important protocol deviations were identified and assessed by clinical 
research physician or designee following company standard operational procedure. The protocol 
deviations and important protocol deviations will be summarized by treatment arm for the ITT 
population for the Placebo-controlled Phase and for the Apremilast Extension Phase.  
A by-subject listing of subjects with protocol deviations and important protocol deviations in the 
ITT population will be provided. The important protocol deviations that lead to the exclusion of 
the subjects from the PP population will be flagged. 


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8. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
The demographics, baseline characteristics, medical history, and Prior Psoriasis Medications will 
be summarized for the ITT population by treatment and overall. Individual subject listings will be 
provided to support the summary tables. 
8.1. 
Demographics 
Summary statistics will be provided for the following continuous variables: 
• Age (years) 
• Weight (kg) 
• Height (cm) 
• Baseline Body Mass Index (BMI; kg/m2), BMI will be calculated as: BMI (kg/m2) = 
Weight (kg)/ Height (m2) 
• Waist circumference (cm) 
Number and percentage will be provided for the following categorical variables: 
• Age category (< 65, ≥ 65 years)  
• Sex (Male, Female) 
• Race  
• Country  
• Alcohol intake (Current use, Former use, or Never use) 
• Tobacco use (Never Smoked, Past Smoker, Current Smoker) 
• Baseline BMI category (<18.5, 18.5 to < 25, 25 to < 30, ≥ 30 kg/m2) 
8.2. 
Baseline Disease Characteristics 
Baseline clinical characteristics will be summarized descriptively by treatment arm, which will 
include the following: 
• Duration of plaque psoriasis (from date of diagnosis to the date of informed consent; year, 
presented one digit after the decimal point) 
• Duration of plaque psoriasis categories (< 10, 10 to < 20, ≥ 20 years) 
• The primary manifestations for stratifications: scalp psoriasis, nail psoriasis, palmoplantar 
psoriasis, genital psoriasis, and psoriasis in visible locations 
• Baseline DLQI total score  
• Baseline DLQI score categories (>10 to 20, >20) 


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• Baseline sPGA score of visible locations: 0 (clear), 1 (almost clear), 2 (mild), 3 (Moderate), 
4 (Severe) 
• Baseline ScPGA score: 0 (clear), 1 (almost clear), 2 (mild), 3 (Moderate), 4 (Severe) 
• Number of affected nails: 0, 1, ≥2 
• Baseline NAPSI score for the target nail  
• Baseline sPGA-G score: 0 (clear), 1 (almost clear), 2 (mild), 3 (Moderate), 4 (Severe) 
• Baseline PPPGA score: 0 (clear), 1 (almost clear), 2 (mild), 3 (Moderate), 4 (Severe) 
• Baseline pruritus NRS score 
• Baseline skin discomfort/Pain VAS score 
• Baseline PASI score 
• Baseline PASI score categories (3 to 5, >5 to 10) 
• Baseline BSA (%) 
• Baseline BSA (%) category (≤3, >3 to 5, >5 to 10, >10) 
• Baseline EQ-5D vas and EQ-5D index value 
• Baseline WPAI: PSO: percentage of work missed due to Psoriasis and overall work 
impairment for those who were currently employed; percentage of work impairment and 
percentage of daily activity impairment due to Psoriasis among all subjects 
• Baseline PNQ: the importance of each of the 25 treatment goals will be summarized with 
count (%) by missing, does not apply to me, not at all, somewhat, moderately, quite and 
very.  
8.3. 
Medical History 
A summary of relevant medical history and concomitant diseases will be presented by system 
organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory 
Affairs (MedDRA) version 23.1 or higher, using frequency distributions (counts and percentages).   
8.4. 
Prior Psoriasis Therapy 
 Prior Psoriasis therapy are summarized descriptively by treatment arm for the following: 
• Number of prior conventional systemic therapies 
• Number of failed prior conventional systemic therapies for subjects who had prior 
conventional systemic therapies   
• Number of prior systemic therapies 
• Number of failed prior systemic therapies for subjects who had prior systemic therapies   
 


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• Number of prior biologic therapies  
• Number of failed prior biologic therapies for subjects who had prior biologic therapies  
• Number of prior topical therapies  
• Number of failed prior topical therapies for subjects who had prior topical therapies  
• Number of prior photo therapies  
• Number of failed prior photo therapies for subjects who had prior photo therapies  
8.5. 
Prior and Concomitant Procedures 
Prior and concomitant procedures will be coded using the MedDRA Version 22.1 or higher. 
8.5.1. 
Prior Procedures 
Prior procedures are defined as those started before the start of the study treatment (whether or not 
ended before the start of the study treatment) at the time of randomization. 
A frequency tabulation of the number of subjects with each previous procedure will be given for 
the ITT population by treatment arm, system organ class (SOC), and preferred term (PT).  
8.5.2. 
Concomitant Procedures 
Concomitant procedures that started during each of the following three study phase/period are 
summarized by SOC and PT: (1) Placebo-controlled Phase (Weeks 0 to16) using safety population 
by treatment, (2) Apremilast Exposure Period using Apremilast Exposure Population and (3) 
Observational Follow-up Phase for subjects who entered this phase. 
The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health Organization 
Drug Dictionary (WHO DD version DDE B3 March 2019 or higher) is used to group the prior and 
concomitant medications into the WHO therapeutic drug class (ATC2 level) and generic drug 
name.  
8.5.3. 
Prior Medications 
Only prior medications that are not discontinued at or before the time of consent are collected. 
Prior medications are defined as medications that were started before the start of the study 
treatment at the time of randomization and ended before the start of the study treatment. 
Medications initiated prior to the start of study treatment and continued after the start of study 
treatment are counted as both prior and concomitant medications.  
The number (%) of subjects receiving at least one prior medication are summarized for the ITT 
population by treatment arm, ATC2 level, and standardized medication name.  
Note that the prior psoriasis medications are summarized along with other baseline characteristics 
and not included in the prior medication summary. 


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8.5.4. 
Concomitant Medications 
Concomitant mediations are defined as non-study medications started during a study phase/period 
of interest or started before the study phase/period of interest but ended or remain ongoing during 
this study phase/period.  
The number (%) of subjects receiving at least one concomitant medication, the number (%) of 
subjects receiving at least one medication within a relevant category, and each concomitant 
medication are summarized for (1) Placebo-controlled Phase (Weeks 0 to 16) using safety 
population by treatment, (2) Apremilast Exposure Period using Apremilast Exposure Population, 
and (3) Observational Follow-up Phase for subjects who entered this phase. 
8.6. 
Study Treatment Duration 
Study treatment duration in weeks is calculated as (the date of the last dose of study treatment – 
the date of the first dose of study treatment + 1) / 7 and rounded to one decimal place for each 
subject for a given analysis phase/period. 
Study treatment duration will be summarized based on the safety population for the Placebo-
Controlled Phase (Weeks 0 to 16) by treatment and based on the Apremilast Exposure Population 
for the Apremilast Exposure period.  
Summary statistics for treatment duration as well as a frequency summary of treatment duration 
categories specified in Table 4 will be provided. 
Table 4 
Definitions of time intervals used to summarize exposure to study Medication 
Duration category 
Duration in terms of days 
Placebo-Controlled Phase  
   <4 weeks 
   <28 days 
   >= 4 to < 8 weeks                      >= 28 to < 56 days                                       
   >= 8 to < 12 weeks                    >= 56 to < 84 days                                      
   >= 12 to < 16 weeks                  >= 84 to < 112 days                                       
   >= 16 weeks 
   >= 112 days 
Apremilast Exposure period 
   >= 4 weeks                                >=28 days 
   >= 8 weeks                                >=56 days 
   >= 12 weeks                              >=84 days 
   >= 16 weeks                              >=112 days 
   >= 20 weeks                              >=140 days 
   >= 24 weeks                              >=168 days 
   >= 28 weeks                              >=196 days 
   >= 32 weeks                              >=224 days 
   >= 36 weeks                              >=252 days 
   >= 40 weeks                              >=280 days 
   >= 44 weeks                              >=308 days 
   >= 48 weeks                              >=336 days 
   >= 52 weeks                              >=364 days 


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The treatment duration is from the first non-zero dose and the last non-zero dose of the study treatment 
recorded on the study drug exposure form for the corresponding study phase/period.  
A subject data listing of study drug records including the reasons for missed dose will be provided. 
8.7. 
Treatment Compliance 
Summaries on the compliance rate are provided based on the ITT population for the Placebo-
Controlled Phase (Weeks 0 to 16) and the Apremilast Extension Phase (Weeks 16-52) for subjects 
who entered the Apremilast Extension Phase by treatment.  
The treatment compliance (in %) for each subject will be computed as 100 times the total number 
of tablets taken (the total number of tablets dispensed minus the total number of tablets returned) 
over the analysis phase of interest divided by the intended total number of tablets that should have 
been taken over the same phase. The algorithm on how the intended total number of tablets is 
calculated is provided in Appendix 15.3.  
Of note, compliance rate will not be calculated for subjects (if exist) who have only the dispense 
record at Week 0/Visit 2 and no other drug accountability records. 
Both the summary statistics for compliance rate (%) and a frequency summary with the following 
categories: <75%, 75% to 120%, and >120% are provided. A subject data listing of drug 
accountability records is also provided.  
 
 


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9. 
EFFICACY ANALYSIS 
9.1. 
General Approaches to Efficacy Analysis  
All efficacy evaluations will be conducted using the ITT population. Supplemental analysis of the 
primary efficacy endpoint using the PP population will be conducted.  
The summary and analyses of the primary and secondary endpoints evaluated at or prior to Week 
16 will be performed by treatment (placebo vs. apremilast 30 mg BID). Statistical comparisons 
will be made between apremilast 30 mg BID and placebo; the null hypothesis is that the effects 
of the two treatments (i.e., placebo vs. apremilast 30 mg BID) have no difference. 
Descriptive statistics (n, mean, stdev, median, Q1, Q3, min, max) will be presented for 
appropriate endpoints at specified time points. Specifically, for continuous variables, descriptive 
statistics for baseline and change (or percentage change) from baseline will be provided.  
Categorical variables will be summarized with frequency tabulations at baseline or by time point; 
shift tables will be provided when appropriate. 
For the primary and the secondary efficacy endpoints during the Double-blind Placebo-controlled 
Phase, the following analysis will be performed: 
• For binary endpoints, missing data from the original continuous-like score will be 
handled by multiple imputation (MI) as the primary approach. The response variable will 
then be derived based on the continuous score. Statistical outputs from each of the 
imputed complete data sets will be combined in making statistical inferences. For the 
combined inference, the response rates for each treatment arm and differences for 
treatment comparison were the averages from the 25 imputed data sets. The response rate 
and its 95% confidence interval (CI) will be calculated by treatment. The difference of 
the response rate (Apremilast 30 mg BID - placebo) and its 95% CI as well as the p-value 
will be produced using the Cochran-Mantel-Haenszel (CMH) test and adjusting for the 
stratification factor at randomization (i.e., the manifestations of scalp psoriasis, nail 
psoriasis, palmoplantar psoriasis, genital psoriasis, or psoriasis in visible locations). SAS 
PROC FREQ with the COMMONRISKDIFF (TEST=MH) option will be used for the 
analysis.  
• For continuous endpoints, the primary approach for handling missing data will be the 
multiple imputation (MI) method. Data will be analyzed using the analysis of covariance 
(ANCOVA) model with baseline values, treatment group and stratification factors (i.e., the 
manifestations of scalp psoriasis, nail psoriasis, palmoplantar psoriasis, genital psoriasis, 
or psoriasis in visible locations) as independent variables. SAS Proc Mixed will be used 
for the analysis. The least square mean (LS mean) with 95% CI for each treatment and 
difference of LS mean (Apremilast 30 mg BID - placebo) with 95% CI as well as the p-
value will be provided.  
Efficacy results will be considered statistically significant after consideration of the strategy for 
controlling the Type I error rate that is described in Section Error! Reference source not found.. A
ll statistical tests will be two-sided and be conducted at the 0.05 significance level, and p-values 
will be reported. For the efficacy endpoints evaluated after Week 16, only the treatment effect 


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estimates and the corresponding 95% confidence intervals (CIs) within each treatment arm will be 
provided to show the long-term treatment profile. No between group comparison will be 
conducted. Time plots on response rate or mean change (percent change) from baseline by 
treatment over the Placebo-controlled Phase and the Apremilast Extension Phase will be provided 
to show the maintenance of the treatment effect over time. 
Data listings for quality of life assessments and efficacy assessments over the Placebo-controlled 
Phase and the Apremilast Extension Phase will be provided. An analysis phase flag will be 
included in each listing to indicate the phase that a record belongs to. 
9.2. 
Multiplicity 
The primary and some secondary efficacy endpoints will be hierarchically ranked for testing in 
order to control the overall type I error rate in claiming statistical significance at the 2-sided 0.05 
significance level.  Specifically, for the primary efficacy endpoint (DLQI response at Week 16), 
if the 2-sided p-value from the comparison between Apremilast 30 mg BID and placebo is below 
0.05, the outcome will be considered statistically significant and Apremilast 30 mg BID will be 
declared effective. For any secondary endpoint, statistical significance will be claimed only if its 
2-sided p-value is below 0.05 and tests for the primary endpoint and all previous secondary 
endpoints are significant at the 2-sided 0.05 level. The proposed test sequence for the primary 
and some secondary efficacy endpoints is listed as the following: 
• Achieving DLQI response at Week 16 (defined as ≥ 4-point reduction in DLQI from 
baseline at Week 16) from baseline in DLQI at Week 16 
• Change from baseline in DLQI at Week 16 
• Percent change in Body Surface Area (BSA) affected by psoriasis at Week 16 
• Change from baseline in Pruritus Numeric Rating Scale (NRS) score at Week 16 
• Change from baseline in skin discomfort/pain Visual Analog Scale (VAS) at Week 16 
• Achieving Psoriasis Area Severity Index (PASI) < 3 at Week 16 
• Achieving Patient Benefit Index (PBI) global score of ≥ 1 at Week 16 
• Percent change from baseline in European Quality of Life 5-Dimension (EQ-5D) score at 
Week 16 
• Change in Work Productivity and Activity Impairment Questionnaire: Psoriasis (WPAI: 
PSO) domain scores at Week 16 
9.3. 
Analysis of Primary Efficacy Endpoint 
The primary endpoint is subjects achieving DLQI response at Week 16 (defined as ≥ 4-point 
reduction in DLQI from baseline at Week 16).  The primary endpoint will be analyzed using the 
ITT population. A supplemental analysis will be performed using the PP population.  
The treatment difference in proportions of DLQI response between Apremilast 30 mg BID and 
placebo will be compared using CMH test adjusted for the stratification factor at randomization 


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(i.e., the 5 difficult to treat manifestation types). This form of the CMH test will use the sample 
sizes in each of the strata as weights when estimating the adjusted difference in the treatment 
proportions, constructing 95% Wald confidence intervals for the difference, and conducting a 
statistical test of no difference between the treatment proportions (i.e., H0: πAPR – πPBO = 0 as the 
null hypothesis). The difference of the response rate (Apremilast 30 mg BID - placebo) and its 95% 
CI as well as the p-value will be produced using the Cochran-Mantel-Haenszel (CMH) test and 
adjusting for the stratification factor at randomization (i.e., the manifestations of scalp psoriasis, 
nail psoriasis, palmoplantar psoriasis, genital psoriasis, or psoriasis in visible locations). SAS 
PROC FREQ with the COMMONRISKDIFF (TEST=MH) option will be used for the analysis. 
All reasonable attempts will be made to prevent missing data from occurring in the study. 
However, in the case of missing data at Week 16, a multiple imputation (MI) method (SAS Institute 
Inc. 2008) will be incorporated as the primary analysis.   such that unbiased estimation and valid 
statistical inferences (i.e., confidence intervals and hypothesis testing) can be made.  
The SAS procedure MI will be used to impute missing DLQI scores at the scheduled assessments 
in the Placebo-controlled Phase (Weeks 0 to16) to create M=25 complete data sets. The missing 
data patterns will be checked by treatment and stratification factor at the core baseline (Week 0), 
Week 2, Week 4, and Week 16. If there are non-monotone missing patterns, two separate 
imputation procedures will be used to complete the imputation process.  
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used to impute missing 
scores by treatment and stratification factor to create M=25 imputed data sets with monotone 
missing patterns. The minimum and the maximum values for imputation will be 0 and 30, which 
correspond to the lowest and the highest DLQI scores. The seed will be set to 804529, the imputed 
values will be rounded to integers and a single chain will be used to produce imputations. In case 
there are convergence issues, the imputation will be done by treatment only. If the convergence 
issue remains, then the imputation will be done on data pooled from both treatment arms. 
In the second step, the predictive mean matching method will be used to impute the remaining 
missing values for the 25 data sets with monotone missing patterns. The MONOTONE REGPMM 
statement will be used with seed 447159. The missing values at each visit will be imputed based 
on treatment, stratification factor, and DLQI scores at the core baseline and previous visits. In 
presence of convergence issue, a simplified regression model without stratification factor will be 
used. The number of closest observations to be used in the selection will be K=5.  
After the completion of imputation made on the continuous-like scale of the total DLQI score, the 
primary endpoint will then be derived by dichotomizing the DLQI score prior to performing the 
CMH analysis described above. The same CMH method will be used to analyse the 25 complete 
data sets and the SAS procedure MIANALYZE will be used to combine the results for the 
statistical inferences. 
In addition to the primary analysis using MI method and the supplemental analysis in PP 
population, the following supportive analyses using CMH method for the primary endpoint will 
be performed for: (1) ITT population treating missing values using the last observation carried 


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forward (LOCF) method, (2) ITT population treating missing values using the non-responder 
imputation (NRI) method.  
In order to assess the impact of Covid-19 on the DLQI data collection, a sensitivity analysis will 
be conducted by excluding the data collected via paper version of the DLQI questionnaire. 
Similar analysis planned for Week 16 will be repeated for DLQI response at Week 2 and Week 4. 
9.4. 
Analyses of Secondary Efficacy Endpoints 
The analyses on secondary efficacy endpoints are discussed according to the analysis phase in the 
following two sections.  
9.4.1. 
Secondary Efficacy Endpoints in the Placebo-controlled Phase  
All analyses will be conducted using ITT population including data from the Placebo-controlled 
Phase (Week 0 to Week 16).  Table 5 is the summary on how the secondary efficacy endpoints at 
Week 16 will be analyzed. 
Table 5 
Analysis on the Secondary Efficacy Endpoints at Week 16  
Summary Measure of Endpoint 
Primary Analysis 
Supportive Analysis 
Mean change from baseline in 
DLQI at Week 16 
ANCOVA 
model 
adjusted 
by 
baseline DLQI score, treatment, 
stratification factor on data with MI 
ANCOVA model adjusted by 
baseline DLQI score, treatment, 
stratification factor on data with 
LOCF 
Mean percent change in Body 
Surface Area (BSA) affected by 
psoriasis at Week 16 
ANCOVA model adjusted by BSA 
score, treatment, stratification factor 
on data with MI 
ANCOVA model adjusted by BSA 
score, 
treatment, 
stratification 
factor on data with LOCF 
Mean change from baseline in 
Pruritus Numeric Rating Scale 
(NRS) score at Week 16 
ANCOVA 
model 
adjusted 
by 
baseline NRS score, treatment, 
stratification factor on data with MI 
ANCOVA model adjusted by 
baseline NRS score, treatment, 
stratification factor on data with 
LOCF 
Mean change from baseline in 
skin 
discomfort/pain 
Visual 
Analog Scale (VAS) at Week 16 
ANCOVA 
model 
adjusted 
by 
baseline VAS score, treatment, 
stratification factor on data with MI 
ANCOVA model adjusted by 
baseline VAS score, treatment, 
stratification factor on data with 
LOCF 
Proportion 
of 
subjects 
who 
achieve Psoriasis Area Severity 
Index (PASI) < 3 at Week 16 
CMH 
test 
adjusting 
for 
the 
stratification factor on data with MI 
CMH 
test 
adjusting 
for 
the 
stratification factor on data with 
LOCF and data with NRI 
Proportion 
of 
subjects 
who 
achieve Patient Benefit Index 
(PBI) global score of ≥ 1 at Week 
16 
CMH 
test 
adjusting 
for 
the 
stratification factor on data with MI 
CMH 
test 
adjusting 
for 
the 
stratification factor on data with 
LOCF and data with NRI 
Mean 
percent 
change 
from 
baseline in European Quality of 
ANCOVA 
model 
adjusted 
by 
baseline EQ-5D score*, treatment, 
ANCOVA model adjusted by 
baseline EQ-5D score*, treatment, 


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For each continuous-like efficacy assessments, the SAS procedure MI will be used to impute 
missing values for each scheduled visit in the Placebo-controlled Phase (Weeks 0 to16). There are 
exceptions for the EQ-5D assessment and WPAI: PSO assessment, which are only assessed at 
Week 16/discontinuation visit in the Placebo-controlled Phase. For these two endpoints, no 
missing data imputation will be conducted and the analyses will be conducted on assessments 
collected at the scheduled Week 16 visit as well as on assessments collected at end of phase 
(section 5.5).   
For MI, the missing data patterns will be checked by treatment and stratification factor at Baseline 
(Week 0), and Weeks 2 (if applicable), 4, and 16. If there are non-monotone missing patterns, two 
separate imputation procedures will be used to complete the imputation process. In case of 
convergence issue, same strategy as for the primary endpoint will be followed.  
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used to impute missing 
data by baseline value, treatment and stratification factor to create M=25 imputed data sets with 
monotone missing patterns. The minimum and the maximum values for imputation will set 
depending on the rage of the corresponding score of interest. The seed will be set to 804529, the 
imputed values will be rounded to integers and a single chain will be used to produce imputations. 
This step will be skipped if the data missing pattern is monotone. 
In the second step, the predictive mean matching method will be used to impute the remaining 
missing values for the 25 data sets with monotone missing patterns. The MONOTONE REGPMM 
statement will be used with seed 447159. The missing values at each visit will be imputed based 
on treatment, stratification factor, and the score of interest at baseline and previous visits. The 
number of closest observations to be used in the selection will be K=5 for DLQI, skin 
discomfort/pain VAS, BSA, as well as PASI and K=2 for PBI.  
The binary endpoints at Week 16 will be analysed similarly as the primary endpoint. Missing data 
from the original continuous-like score will be handled by multiple imputation (MI) as the primary 
approach. The response variable will then be derived based on the continuous score. Statistical 
outputs from each of the imputed complete data sets will be combined in making statistical 
inferences. For the combined inference, the response rates for each treatment arm and differences 
Life 5-Dimension (EQ-5D) score* 
at Week 16 
stratification factor on data collected 
on scheduled Week 16 visit 
stratification factor on end of phase 
assessment  
Mean 
change 
in 
Work 
Productivity 
and 
Activity 
Impairment 
Questionnaire: 
Psoriasis (WPAI: PSO) domain 
scores** at Week 16 
ANCOVA 
model 
adjusted 
by 
baseline Psoriasis WPAI score**, 
treatment, stratification factor on 
data collected on scheduled Week 16 
visit 
ANCOVA model adjusted by 
baseline Psoriasis WPAI score**, 
treatment, stratification factor on 
end of phase assessment 
*two variables will be evaluated individually: EQ-5D VAS and EQ-5D index value 
**four variables will be evaluated individually: percentage work missed, work impairment, overall 
work impairment, and activity impairment 
 


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for treatment comparison were the averages from the 25 imputed data sets. The difference of the 
response rate (Apremilast 30 mg BID - placebo) and its 95% CI as well as the p-value will be 
produced using the Cochran-Mantel-Haenszel (CMH) test and adjusting for the stratification factor 
at randomization. SAS PROC FREQ with the COMMONRISKDIFF (TEST=MH) option will be 
used for the analysis.  Same analyses will also be conducted for other scheduled assessment visits 
(e.g., at Week 2 and Week 4) during the Placebo-controlled Phase. In addition to the MI method, 
supportive analyses using CMH method for the binary endpoints will be performed on data with 
LOCF and data with NRI. Same analyses will be repeated for assessments scheduled at time points 
before Week16.  
For continuous endpoints, missing data will be imputed by MI as the primary approach. Change 
(or percent change) from baseline in each score at Week 16 will be analyzed using the same 
analysis of covariance (ANCOVA) model to analyze the 25 complete datasets and the SAS 
procedure MIANALYZE will be used to combine the results for the statistical inferences. The 
ANCOVA model will use the change (or percent change) from baseline as the dependent variable 
and will include treatment group and stratification factor as independent variables as well as the 
baseline value as a covariate variable. Within-group least-squares (LS) mean changes from 
baseline at Week 16, the associated standard errors (SEs) and 2-sided 95% CIs, treatment 
differences in LS mean changes from baseline, and the associated 2-sided 95% CIs and p-values, 
will be derived from the ANCOVA model based on each of the 25 complete datasets. Same 
analyses will also be conducted for other scheduled assessment visits (i.e., at Week 2 and Week 4) 
during the Placebo-controlled Phase. In addition to the MI method, supportive analyses using 
ANCOVA model for the continuous endpoints will be performed on data with LOCF. The same 
analyses will be repeated for assessments scheduled at time points before Week16. Summary 
statistics will also be provided by treatment and time point based on Data as Observed (DAO) for 
each continuous variable. 
9.4.2. 
Secondary Efficacy Endpoints in the Apremilast Extension Phase 
The analyses will be conducted using the ITT population for subjects who entered the Apremilast 
Extension Phase. For binary endpoints, frequency tables will be provided by time point based on 
data with NRI. For continuous endpoints, summary statistics will be provided by time point 
(including end of phase assessment) on DAO.  
9.5. 
Subgroup Analysis 
The consistency of the treatment effect on DLQI response at Week 16 will be assessed across the 
following subgroups: 
• The randomization stratum based on the primary manifestation of plaque psoriasis: 
scalp psoriasis, nail psoriasis, palmoplantar psoriasis, genital psoriasis, and psoriasis in 
visible locations  
• Sex (Male, Female) 
• Race (White, Others) 


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• Age category (< 65, ≥ 65 years)  
• Baseline BMI category (< 25, 25 to < 30, ≥ 30 kg/m2)  
• Prior conventional systemic therapies (Yes/No) 
• Prior biologic therapies (Yes/No) 
Analysis will be based on ITT population and missing values will be imputed using MI method. 
The number (%) of subjects with improvement (≥ 4-point reduction) in DLQI and the between 
group difference will be summarized for each subgroup category. The adjusted treatment 
difference in proportion using the weighted average of the treatment differences across the strata 
(i.e., the 5 difficult to treat manifestation types) with the CMH weights, along with the associated 
2-sided 95% CIs using a normal approximation to the weighted average will be provided within 
each subgroup. For subgroups based on primary manifestation, the adjusted estimates mentioned 
above are not applicable; unadjusted treatment differences in proportions and the associated 2-
sided 95% CI using a normal approximation will be provided. Similarly, for other classification 
variables, if no subject falls into a stratum of the primary manifestation strata in a treatment group, 
unadjusted treatment differences in proportions and the associated 2-sided 95% CI using a normal 
approximation will be provided. Forest plot on rate difference and 95% CI by subgroups will be 
provided.  
9.6. 
Analyses of Exploratory Efficacy Endpoints 
For exploratory efficacy endpoints, descriptive summary statistics or proportion of subjects 
achieving pre-specified criteria will be summarized by treatment arm by time points. 
9.6.2. 
 Manifestation specific clinical endpoints at Week 16, Week 32, and Week 52 
The following is the list of manifestation specific endpoints according to the pre-specified 
treatment improvement criteria.  
• Achieving Static Physician Global Assessment (sPGA) score of 0 or 1 (among subjects 
randomized to the strata with moderate to severe psoriasis in visible areas, defined as sPGA 
≥ 3 at baseline, which include the dorsal hand, face, neck, or hairline) at Weeks 16, 32, 52 
• Achieving Scalp Physician Global Assessment (ScPGA) score of 0 or 1 (among subjects 
randomized to the strata with moderate to severe scalp psoriasis, ScPGA ≥ 3 at baseline) 
at Weeks 16, 32, 52 


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• Achieving Nail Psoriasis Severity Index (NAPSI) score of 0 in the target fingernail (among 
subjects randomized to the strata with presence of nail psoriasis, defined as onycholysis 
and onychodystrophy in at least 2 fingernails at baseline) at Weeks 16, 32, 52 
• Achieving Static Physician Global Assessment-Genitalia (sPGA-G) score of 0 or 1 (among 
subjects randomized to the strata with moderate to severe genital psoriasis, sPGA-G ≥ 3 at 
baseline) at Weeks 16, 32, 52 
• Achieving Palmoplantar Psoriasis Physician Global Assessment (PPPGA) score of 0 or 1 
(among subjects randomized to the strata with moderate to severe palmoplantar psoriasis, 
PPPGA ≥ 3 at baseline) at Weeks 16, 32, 52 
The number and percentage of subjects with improvement among the subgroup of subjects 
demonstrating the corresponding manifestation at baseline by time point (including all visits with 
scheduled assessments and end of phase assessment) will be summarized based on data with NRI 
(including end of phase assessment). Shift tables for each of the manifestation assessment shift 
from baseline to post-baseline visits and end of phase assessment in all subjects will be provided 
based on DAO.  The new onset on subject without such manifestations at baseline will also be 
assessed using shift tables.  
Similar to the analysis mentioned above, all the manifestation specific endpoints will also be 
summarized based on subjects who met each specific condition regardless of whether they were 
stratified to the specific manifestation group. 
9.7. 
Assessing Study Center Effect and Treatment-by-Center Interaction  
This study is a multicenter study and has approximately 75 study sites from 6 Europe countries. 
Given the small sample size, no sufficient number of subjects will be available to allow a 
meaningful within-site analysis of treatment difference in proportions of DLQI response stratified 
by the manifestations at baseline. Thus the assessment on study center effect won’t be conducted 
for this study. 


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10. 
SAFETY ANALYSIS 
Safety will be assessed via descriptive statistics and point estimates on observed data.  
All safety analyses described in this section will be performed for both the Placebo-controlled 
Phase and the Apremilast Exposure Period. The safety analyses for the Placebo-controlled Phase 
will be based on the safety population and presented by treatment arm (placebo, and Apremilast 
30 mg BID). The safety analyses for the Apremilast Exposure Period will be based on the 
Apremilast Exposure Population and presented by Apremilast dose group (i.e., Apremilast 30 mg 
BID) irrespective of the start time of Apremilast exposure (at Week 0 or 16).  In addition, selected 
summaries on AEs for the Observational Follow-up Phase will be listed. 
For the analyses of AEs and laboratory marked abnormalities, both subject incidence and 
exposure-adjusted incidence rate (EAIR) per 100 subject-years for the Placebo-controlled Phase 
(Weeks 0 to16) and for the Apremilast Exposure Period will be provided. The point estimates of 
subject incidence and EAIR are distinguished as following: 
• Subject incidence: is defined as the number of subjects with the specific event divided by 
the number of subjects included in the analysis (i.e., percentage [%] used in a frequency 
summary). Subjects with multiple occurrences of the specific event in the specific analysis 
period will be counted only once in the numerator. 
• Exposure-adjusted incidence rate (EAIR) per 100 subject-years: The EAIR per 100 subject-
years is defined as 100 times the number of subjects with the specific event divided by the 
total exposure time (in years) among subjects included in the analysis. Subjects with 
multiple occurrences of the specific event in the specific analysis period will be counted 
only once in the numerator. The exposure time for a subject without the specific event is 
the treatment duration (i.e., last dose date-first dose date+1), whereas the exposure time for 
a subject with the specific event is the treatment duration up to the start date (inclusive) of 
the first occurrence of the specific event. The total exposure time in years is calculated by 
dividing the sum of exposure time in days over all subjects included in the analysis by 
365.25. The EAIR per 100 subject-years is interpreted as the expected number of subjects 
with at least one occurrence of the specific event per 100 subject-years of exposure to the 
IP. 
Descriptive statistics will be provided for vital signs, weight, waist circumference, laboratory 
values (continuous measurements) by treatment and visit, including the end of phase/period visits. 
The baseline value, value at the time point, and change from baseline (also percent change from 
baseline if applicable) will be summarized for subjects who have values at baseline and at the time 
point. 
Shift tables, that is, tables summarizing the baseline categories (normal, abnormal) versus the 
category at the end of the respective periods or versus the worst post-baseline category, include 
subjects who have values at baseline and at least one post-baseline value. Similarly, in frequency 
summaries of shifts from baseline at scheduled study weeks per protocol, only subjects who have 
values at baseline and at the corresponding time point will be included. 
 


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10.1. 
Adverse Events 
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs) which 
are defined as any AEs that begin or worsen on or after the start of study drug through 28 days 
after the last dose of study drug or the end of study phase/period date, whichever is earlier All AEs 
will be coded using the Medical Dictionary for Regulatory Affairs® (MedDRA) dictionary Version 
22.1 or higher.  
Unless otherwise specified, all TEAEs will be summarized by SOC and PT, with SOCs presented 
in the standard international order and PTs within SOCs will be presented in descending order of 
subject incidence of the 30mg BID and, if applicable, the placebo arms.  
All TEAEs will be summarized by age category (< 65, ≥ 65 years), sex, and race. 
10.1.1. 
Overall Summary of TEAEs 
An overall summary of the following TEAE categories will be provided for the Placebo-controlled 
Phase (Weeks 0 to16) and for the Apremilast Exposure Period: 
• Any TEAE 
• Any drug-related TEAE 
• Any severe TEAE 
• Any serious TEAE 
• Any serious drug-related TEAE 
• Any TEAE leading to drug interruption 
• Any TEAE leading to drug withdrawal 
• Any TEAE leading to death 
10.1.2. 
All TEAEs 
The incidence and EAIR will be summarized for all TEAEs by SOC and PT as well as by PT only 
(in descending order of subject incidence) for the Placebo-controlled Phase (Weeks 0 to16) and 
the Apremilast Exposure Period.  
The incidence and EAIR of TEAEs by SOC and PT will also be provided for each of the following: 
• Common TEAE with subject incidence ≥ 5% (or another cut-off if justified) in any 
treatment group 
• Drug-related TEAEs  
• Serious TEAEs  
• Serious drug-related TEAEs  
• TEAEs leading to drug interruption  
• TEAEs leading to drug withdrawal 


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Serious TEAEs and TEAEs leading to drug withdrawal will also be summarized by age category 
(< 65, ≥ 65 years), sex, and race. 
Listings for all AEs, drug-related AEs, serious AEs, AEs leading to drug interruption and AEs 
leading to drug withdrawal during the Placebo-controlled Phase and the Apremilast Extension 
Phase will be presented with a flag indicating the Phase when the AE started. 
A listing for non-treatment-emergent AEs will also be provided for safety population. 
10.1.3. 
TEAEs by Maximum Severity 
All TEAEs will be summarized with incidence and EAIR by SOC/PT as well as by maximum 
severity (mild, moderate, severe, and, if needed, missing). If subject reports multiple occurrences 
of a specific event within a specific analysis phase or period, the subject will be counted only once 
by the maximum severity. If the severity is missing for one or more of the occurrences, the 
maximum severity of the remaining occurrences will be used. If the severity is missing for all the 
occurrences, the subject will be counted only once in the “missing” category of severity. 
10.1.4. 
Deaths 
A subject data listing of all AEs leading to death will be provided. 
10.2. 
Clinical Laboratory Evaluations 
The endpoints for clinical laboratory evaluations include: 
- 
Laboratory marked abnormalities (see section 15.4) 
- 
Observed value and change from baseline over time in the following laboratory 
parameters 
▪ 
Hematology panel including complete blood count (CBC) with differential, including 
red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC), RBC Morphology, 
mean corpuscular volume (MCV), white blood cell (WBC) count (with differential), 
and platelet count. 
▪ 
Chemistry panel including sodium, potassium, calcium, chloride, blood urea nitrogen 
(BUN), creatinine, creatinine clearance, glucose, albumin, total protein, alkaline 
phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum glutamic 
pyruvic transaminase (ALT/SGPT), gamma-glutamyl transferase (GGT), lactate 
dehydrogenase (LDH).  A lipid panel will be included in the standard chemistry 
panel. 
- 
Shifts from baseline to post-baseline time points and to the worst post-baseline value in 
terms of normal/abnormal (low or high) in the above hematology and serum chemistry 
parameters. Normal range will be used to determine the categories of High, Low, and 
Normal for lab tests.  
Summary statistics (N, Mean, STDEV, Median, Minimum, and Maximum) of observed values and 
changes from baseline in laboratory parameters will be provided over time by scheduled visit and 


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for the end of Phase/Period assessment. Frequency summaries (shift tables) of shifts from baseline 
to post-baseline time points and to the worst post-baseline value during the given study 
phase/period in terms of normal/abnormal will be provided. 
Laboratory marked abnormalities will be summarized; subject incidence and EAIR for each 
abnormality will be calculated based on subjects with a baseline value and at least one post-
baseline value for criteria requiring baseline or subjects with at least one post-baseline value for 
criteria not requiring baseline. A subject data listing of laboratory marked abnormalities during the 
Placebo-controlled Phase and the Apremilast Exposure Phase will be presented.  
Laboratory marked abnormalities will also be summarized for subjects with normal values at 
baseline and for subjects with abnormal values at baseline separately. For the purposes of these 
summaries, subjects with abnormal (normal) values at baseline are defined as those whose baseline 
value is low (not low) for criteria concerning low values and those whose baseline value is high 
(not high) for criteria concerning high values; both low and high are relative to the laboratory 
normal range. 
A subject data listing of all laboratory data, including Pregnancy test, with abnormal flags and 
study phase/period flags will be provided. 
10.3. 
Vital Sign, Weight, and Waist Circumference Measurements  
The endpoints for vital sign parameters, weight, and waist circumference include: 
• Observed value and change from baseline over time in vital sign parameters including 
temperature, pulse, and blood pressure 
• Shifts from baseline to post-baseline time points and to the worst post-baseline value in 
terms of normal/abnormal in pulse and blood pressure (normal ranges are defined as: 60-
100 beats/minute for pulse, 90-140 mmHg for systolic blood pressure, and 60-90 mmHg 
for diastolic blood pressure) 
• Observed value, change and percent change from baseline over time in weight and waist 
circumference 
Summary statistics (N, Mean, STDEV, Median, Minimum, and Maximum) of observed values, 
changes from baseline, and percent change from baseline (applicable for weight and waist 
circumference) will be provided over time. Frequency summaries (shift tables) of shifts from 
baseline to post-baseline time points and to the worst post-baseline value in terms of 
normal/abnormal will be provided for pulse and blood pressure. 
Frequency summaries of percent change in weight from baseline to the end of the study 
phase/period will be provided by baseline BMI category (<18.5, 18.5 to < 25, 25 to < 30, ≥30  
kg/m2) and by baseline weight category (< 70, ≥ 70 to < 85, ≥85 to < 100, and ≥100 kg). The 
categories of weight change (kg) and percent change (%) are < -20, ≥-20 to < -10, ≥-10 to < -5, ≥-
5 to < 0, 0, > 0 to ≤ 5, > 5 to ≤ 10, > 10 to ≤ 20, and > 20.  
A subject data listing of all vital sign parameters, weight, and waist circumference data with 
abnormal flags where applicable and study phase/period flags will be provided. 


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11. 
QUALITY OF LIFE ANALYSIS 
The Quality of life endpoints, including DLQI (the primary endpoint), EQ-5D (secondary endpoint 
and WPSI:PSO (secondary endpoint) have been addressed in section 9. 
 


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12. 
INTERIM ANALYSIS 
No interim analysis will be conducted. No DMC is planned for this study either.  
For publication purpose, analyses on the data up to the primary timepoint of Week 16 are planned 
based on a Week 16 data transfer after all subjects have completed the Week 16 Visit (or 
discontinued from the study). However, unblinded data will only be made available to selected 
Sponsor and Contract Research Organization (CRO) team members involved with Week 16 data 
analysis and publication preparations.  All other Sponsor, site, and CRO personnel directly 
involved with the conduct of the study, will remain blinded to treatment assignments until the final 
database lock at the final study completion.  After all subjects have completed the Observational 
Follow-up Phase following the Week 52/discontinuation visit in the Apremilast Extension Phase 
(Weeks 16 to 52), the final database will be locked and transferred for all analyses planned in this 
SAP, based on which, a Clinical Study Report will be generated. 


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13. 
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL 
In order to control the overall type I error rate, the multiplicity adjustment is made to the primary 
endpoint and some secondary endpoints by following the hierarchical rank for testing in Section 
9.2. This is deviated from Section of 9.6.5 in the protocol, where no multiplicity adjustment is 
planned. 
Per-protocol (PP) population includes all subjects who are in the ITT population, who receive at 
least one dose of IP, have both baseline and at least one post-treatment DLQI evaluation, and 
have no major protocol deviations which may affect analyses in the Placebo-controlled Phase. 
This definition is deviated from Section 5.3.2 in the protocol. 


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14. 
REFERENCES 
 
SAS Institute Inc. 2008. SAS/STAT® 9.2 User’s Guide. Cary, NC: SAS Institute Inc. 
Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI): a simple practical measure for 
routine clinical use.   Clin Exp Dermatol.  1994;19:210-6. 
Feuerhahn J, Blome C, Radtke M, Augustin M. Validation of the patient benefit index for the 
assessment of patient-relevant benefit in the treatment of psoriasis. Arch Dermatol Res. 
2012;304(6):433–41. 
EuroQol Group. EuroQol - a new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199–208. 
Reilly Associates. Work Productivity and Activity Impairment Questionnaire: Psoriasis 
(WPAI:PSO).  2012. [cited 2018 May 01].  Available from:  
http://www.reillyassociates.net/WPAI_References3.html. Accessed May 01. 
Leonardi C, Sobell J, Sofen H, Krell J. Phase IV study to evaluate the safety and efficacy of 
efalizumab for treatment of hand and foot plaque psoriasis. Poster presented at: 65th Annual 
Meeting of the American Academy of Dermatology; 2007 Feb 2-6; Washington, DC. 
Naegeli, AN, Flood, E, Tucker J, Devlen J, Edson-Heredia E.  The Worst Itch Numeric Rating 
Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis.  Int J Dermatol 
2015; 54:715-22. 
Rich P, Scher RK. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis.  
J Am Acad Dermatol. 2003;49(2):206–12. 
Carey W, Glazer S, Gottlieb AB, Lebwohl M, Leonardi C, Menter A, et al.   Relapse, rebound and 
psoriasis adverse events: An advisory group report.  J Am Acad Dermatol.  2006;54: S171-81. 
Mehrotra, DV, and Railkar, R. Minimum risk weights for comparing treatments in stratified 
binomial trials. Statist. Med., 2000; 19: 811–825. 
 


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15. 
APPENDICES  
15.1. 
Handling of Dates  
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS).    
15.1.1. 
Calculation Using Dates 
Calculations using dates (e.g., subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions:  
• Study days after the start day of study drug will be calculated as the difference between the 
date of interest and the first date of dosing of study drug plus 1 day. The generalized calculation 
algorithm for relative day is the following:  
o If TARGET DATE >= DSTART then STUDY DAY = (TARGET DATE – 
DSTART) + 1;  
o Else use STUDY DAY = TARGET DATE – DSTART. 
Depending on the study day definition, DSTART can be Day 1 for core baseline or the 
Day 1 for Apremilast treatment baseline. Negative study days are reflective of 
observations obtained before the corresponding baseline.  Note: Partial dates for the 
first study drug are not imputed in general. All effort should be made to avoid 
incomplete study drug start dates.  
• Age (in years) at the time of informed consent is collected. 
− When age in years is not available, age in days is calculated as (informed consent 
date – July 15 on the year of birth) + 1. Then age in years will be transformed to 
years by dividing age in days by 365.25 days, then truncating 
− If year of birth is also missing, set age missing  
• Intervals that are presented in weeks will be transformed from days to weeks by using (without 
truncation) the following conversion formula: 
WEEKS = DAYS /7 
• Intervals that are presented in months will be transformed from days to months by using 
(without truncation) the following conversion formula: 
MONTHS = DAYS /30.4167 
15.2. 
Date Imputation Guideline 
 


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15.2.1. 
Adverse Events 
Partially missing AE start dates will be imputed in the ADaM dataset for AEs, but partially missing 
AE end dates will not be imputed. If the AE end date is complete with no missing year, month, or 
day, and the partially missing start date imputed by the rules below is after the AE end date, then 
the start date will be imputed by the AE end date. 
Subjects who were treated with Apremilast at Week 0/Visit 2 
The principle of the imputation rules for subjects who were treated with Apremilast initially is to 
treat the AE as treatment-emergent, i.e., occurring on or after the date of the first dose of 
Apremilast, if possible. 
Let an AE start date be represented as “DEvent/MEvent/YEvent”, and the date of the first dose of 
Apremilast as “DAPR/MAPR/YAPR”. The following table gives the imputation rules for partially 
missing AE start dates for subjects who were treated with Apremilast initially at Week 0/Visit 2. 
Table 6 
Imputation Rules for Partially Missing AE Start Dates for Subjects Who Were 
Treated with Apremilast Initially 
Scenario 
Condition 
Imputation Rule 
Partially missing date includes year only (both month and day are missing) 
1 
YEvent < YAPR 
12/31/YEvent 
2 
Otherwise, i.e., YAPR ≤ YEvent 
Max (date of first dose of Apremilast, 
1/1/YEvent) 
Partially missing date includes both year and month (only day is missing) 
1 
YEvent < YAPR, or (YEvent = YAPR and MEvent < 
MAPR) 
Last date of MEvent/YEvent 
2 
Otherwise, i.e., YAPR < YEvent, or (YAPR = 
YEvent and MAPR ≤ MEvent)  
Max (date of first dose of Apremilast, 
1/MEvent/YEvent) 
Subjects who were treated with placebo at Week 0/Visit 2 
The principle of the imputation rules for subjects who were treated with placebo initially and 
started Apremilast treatment at Week 16 is to consider the AE starting on or after the date of the 
first dose of Apremilast, if possible; if the partially missing start date suggests that it is prior to the 
date of the first dose of Apremilast, the AE will be considered starting on or after the date of the 
first dose of placebo, if possible. 
The following are 4 scenarios considered in the imputation rules: 
1. The partially missing AE start date suggests the date is prior to the date of the first dose of 
placebo: impute it by the latest possible date (determined by the non-missing field of the 
date); 


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2. The partially missing AE start date suggests the date is after the date of the first dose of 
Apremilast following Week 16: impute it by the earliest possible date (determined by the 
non-missing field of the date); 
3. The partially missing AE start date is in the same year (if both month and day are missing), 
or the same year/month (if only day is missing) of the first dose of Apremilast following 
Week 16: impute it by the date of the first dose of Apremilast; 
4. The partially missing AE start date suggests the date is no earlier than the date of the first 
dose of placebo but prior to the date of the first dose of Apremilast following Week 16: 
impute it by the date of the first dose of placebo, or the earliest possible date (determined 
by the non-missing field of the date), whichever occurs later. 
Let an AE start date be represented as “DEvent/MEvent/YEvent”, the date of the first dose of placebo as 
“DPBO/MPBO/YPBO”, and the date of the first dose of Apremilast following Week 16 as 
“DAPR/MAPR/YAPR”. The following table gives the imputation rules for partially missing AE start 
dates. 
Table 7 
Imputation Rules for Partially Missing AE Start Dates for Subjects Who Were 
Treated with Placebo Initially 
Scenario 
Condition 
Imputation Rule 
Partially missing date includes year only (both month and day are missing) 
1 
YEvent < YPBO 
12/31/YEvent 
2 
YEvent > YAPR 
1/1/YEvent 
3 
YEvent = YAPR 
Date of first dose of Apremilast following 
Week 16 
4 
Otherwise, i.e., YPBO ≤ YEvent< YAPR 
Max (date of first dose of PBO, 1/1/YEvent) 
Partially missing date includes both year and month (only day is missing) 
1 
YEvent < YPBO, or (YEvent = YPBO and MEvent < 
MPBO) 
Last date of MEvent/YEvent 
2 
YEvent > YAPR, or (YEvent = YAPR and MEvent > 
MAPR) 
1/MEvent/YEvent 
3 
YEvent = YAPR and MEvent = MAPR 
Date of first dose of Apremilast following 
Week 16 
4 
Otherwise, i.e., YPBO < YEvent < YAPR, or  
(YPBO = YEvent < YAPR and MPBO ≤ MEvent), or  
(YPBO = YEvent = YAPR and MPBO ≤ MEvent < 
MAPR), or (YPBO < YEvent = YAPR and MEvent < 
MAPR) 
Max (date of first dose of placebo, 
1/MEvent/YEvent) 


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15.2.2. 
Prior/Concomitant Medications/Procedures 
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset for prior/concomitant 
medications/procedures. For prior/concomitant medications, if the stop date is complete with no 
missing year, month, or day, and the partially missing start date imputed by the rule below is after 
the stop date, then the start date will be imputed by the stop date. 
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date. 
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date. 
15.2.3. 
Medical History 
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history (for the purposes of calculating durations of PsA and psoriasis). The 16th of the month will 
be used to impute a partially missing start date that has only the day missing, and July 1st will be 
used to impute a partially missing start date that has both the month and day missing. 
15.2.4. 
Treatment Duration 
Partially or completely missing last dose dates will be imputed in the ADaM dataset for 
treatment duration.  
When partially missing last dose date is available, set last dose date to the maximum of [the 
earliest possible date given the non-missing field(s) of last dose date, the minimum of (the latest 
possible date given the non-missing field(s) of last dose date, last known date in database, first 
non-missing Early Termination (ET) visit date)] 
When last dose date is completely missing, set last dose date to the minimum of (last known date 
in database, first non-missing Early Termination (ET) visit date) 
Last known date in database is defined as maximum of the observed dates (i.e., last visit date, 
lab, vital signs, AE start or end dates, concomitant medications start or end dates, concomitant 
procedure date, last dose date from 'Disposition- Treatment' page, treatment exposure start or end 
dates where doses were completely or partially taken, death date). 
 
15.3. 
Tablets Intended to be Taken for Treatment Compliance Calculation 
During the Placebo-controlled Phase (Weeks 0 to 16), blister cards with 33 rows of tablets 
(i.e., a maximum 33-day supply) will be supplied. A subject takes the first 5 rows of tablets (6 
tablets per row/day) on each complete blister card before taking the remaining rows (2 tablets 
per row/day), and completes the first 28 rows, skips rows 29-33 (5-day extra supply) and starts 
a new blister card. It is also assumed that a subject takes the full day’s tablets from a new 
blister card on a study drug dispense date.  


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The intended total number of tablets is calculated as follows. First order the first dose date, the 
second dispense date, the third dispense date, etc., and the last dose date. The first and last 
dose dates are defined in the same way as those defined for treatment duration calculations. 
The intended number of tablets between any 2 consecutive dates is calculated as 
2 × n + 4× int[(n + 27) / 28] + 4 × int[(n + 26) / 28] + 4 × int[(n + 25) / 28] + 4× int[(n + 24) / 28] + 
4 × int[(n + 23) / 28] 
where n denotes the number of days between the 2 consecutive dates (ie, the second date 
minus the first date for all pairs of consecutive dates, and the second date minus the first date 
plus 1 for the last pair), and “int” denotes the integer part of the result. Then the intended total 
number of tablets is the sum of all intended numbers of tablets as calculated above from the 
first dose date through the last dose date. 
During the Apremilast Extension Phase (Weeks 16 to 52), blister card with 33 rows of tablets 
will be supplied at Week 16 visit and open label bottles will be supplied at Week 20 through Week 
52.  
The intended number of tablets is calculated as follows. First order the first dose date, the 
second dispense date, the third dispense date, etc., and the last dose date. The first and last 
dose dates are for the treatments during the Apremilast Extension Phase. The intended number 
of tablets between any 2 consecutive dates is calculated as: 
• 2 × n + 4× int[(n + 27) / 28] + 4 × int[(n + 26) / 28] + 4 × int[(n + 25) / 28] + 4× int[(n + 24) 
/ 28] + 4 × int[(n + 23) / 28] for records on drugs in blister cards 
• 2 × n for records on drugs in open label bottles.  
Then the intended total number of tablets is the sum of all intended numbers of tablets as 
calculated above from the first dose date through the last dose date. 
15.4. 
Laboratory Marked Abnormalities Criteria 
Table 8 
Laboratory Marked Abnormalities Criteria 
Category / Analyte  
SI Units  
Criteria  
Chemistry 
 
 
Alanine Aminotransferase (SGPT)  
U/L  
> 3*ULN  
Albumin  
Kg/m3  
< 25  
Alkaline Phosphatase  
U/L  
> 400  
Aspartate Aminotransferase (SGOT)  
U/L  
> 3*ULN  
Total Bilirubin  
μmol/L  
> 1.8*ULN  
Blood Urea Nitrogen  
mmol/L  
> 15  
Calcium  
mmol/L  
 < 1.8  
> 3.0  
Creatinine  
μmol/L  
> 1.7*ULN  
Glucose  
mmol/L  
< 2.8  


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Category / Analyte  
SI Units  
Criteria  
> 13.9  
Hemoglobin A1C  
%  
> 9  
Lactate Dehydrogenase  
U/L  
> 3*ULN  
Magnesium  
mmol/L  
>1.2  
Phosphate  
mmol/L  
< 0.64  
>1.60  
Potassium  
mmol/L  
3.0  
5.5  
Sodium  
mmol/L  
< 130  
> 150  
Triglycerides  
mmol/L  
> 3.4  
Urate  
umol/L  
Male: > 590; Female: > 480  
Hematology 
 
 
Hemoglobin  
g/L  
Female < 8.5, Male < 10.5  
Female > 17, Male > 18.5  
Leukocytes  
10^9/L  
< 1.5  
Lymphocytes  
10^9/L  
< 0.8  
Neutrophils  
10^9/L  
< 1.0  
Platelets  
10^9/L  
< 75  
> 600  
Total cholesterol 
mmol/L  
> 7.8