Clinical trial NCT03701763
Conditions: Psoriasis
Keywords: Pediatric 6 through 17 years Plaque Psoriasis Psoriasis CC-10004 Apremilast Otezla Children Adolescents SPROUT
Sponsor: Amgen
Start date: 2018-12-19; Completion date: 2023-03-27
Enrollment: 245 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study of the efficacy and safety of apremilast (CC-10004) in pediatric subjects with moderate to severe plaque psoriasis.

At least 230 pediatric subjects (ages 6 through 17 years) will be randomized 2:1 to receive either apremilast or placebo for the first 16 weeks and then all subjects will receive apremilast during the 36 week Extension Phase for a total of 52 weeks. Randomization to apremilast arm or placebo arm will be stratified by age group (6 to 11 years or 12 to 17 years). Subjects will receive apremilast treatment of either 20 mg twice daily (BID) or 30 mg BID, depending on weight. This Phase 3 study is being conducted to evaluate the safety and efficacy of apremilast in the treatment of pediatric subjects.

Detailed description:
Treatment will be assigned by weight with subjects 20 kg to \< 50 kg receiving apremilast 20 mg BID or placebo BID and subjects ≥ 50 kg receiving apremilast 30 mg BID or placebo BID. Total study duration is up to 71 weeks. Subjects completing all 52 weeks of the treatment and extension phase will be able to enter the Long-term study. Subjects not entering the Long-term study will return for 3 observational follow-up visits, 4, 8 and 14 weeks after last dose of study drug.

Arms: arm 1: Apremilast 20mg Twice Daily (BID) arm 2: Apremilast 30mg Twice Daily (BID) arm 3: Placebo tablet Twice Daily (BID)
Interventions: intervention 1: Apremilast (CC-10004) intervention 2: Placebo
Intervention descriptions: intervention 1: Apremilast (CC-10004) intervention 2: Placebo

Protocol documents:
Prot_002.pdf: 
Apremilast 
Protocol CC-10004-PPSO-003 
 
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TITLE PAGE 
A PHASE 3, MULTI-CENTER, RANDOMIZED, 
DOUBLE- BLIND, PLACEBO-CONTROLLED STUDY 
TO ASSESS THE EFFICACY AND SAFETY OF 
APREMILAST (CC-10004) IN PEDIATRIC SUBJECTS 
FROM 6 THROUGH 17 YEARS OF AGE WITH 
MODERATE TO SEVERE PLAQUE PSORIASIS 
 
PROTOCOL NUMBER: 
 
CC-10004-PPSO-003 
DATE FINAL: 
 
15 Aug 2018 
AMENDMENT 1 DATE FINAL: 
 
12 Apr 2019 
AMENDMENT 2 DATE FINAL: 
 
23 Sep 2019 
AMENDMENT 3 DATE FINAL: 
 
01 May 2020 
AMENDMENT 4 DATE FINAL: 
 
26 Aug 2021 
AMENDMENT 5 DATE FINAL: 
 
17 Dec 2021 
EudraCT NUMBER: 
 
2018-002918-12 
IND NUMBER: 
 
070270 
NCT NUMBER: 
 
NCT03701763 
SPONSOR NAME/ADDRESS: 
 
 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
 
CONFIDENTIAL NOTICE 
This document contains confidential information of Amgen. This document 
must not be disclosed to anyone other than the site study staff and members 
of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent.  The information in this document 
cannot be used for any purpose other than the evaluation or conduct of the 
clinical investigation without the prior written consent of Amgen. If you 
have any questions regarding how this document may be used or shared, 
call the Amgen Medical Information number: 1-800-77-AMGEN.  


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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION  
 
Contact Information: 
Name: 
, MD 
Title: Associate Director, Clinical Research & Development 
Address: One Amgen Center Drive, Thousand Oaks, CA 913200 
Phone: 
 
E-mail: 
 
 
Note: Only call Amgen Medical Information if you are not able to reach the Clinical 
Research Physician(s) or Medical Monitor or designee for emergency calls.  
Amgen Medical Information: +1-800-77-AMGEN (1-800-772-6436) 
 
 


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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
Signature of Site Principal Investigator 
 
dd mmm yyyy 
 
 
Printed Name of Site Principal Investigator 
Institution Name:_____________________________________________________ 
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Amgen representatives, the Declaration of Helsinki, International Council for 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies. 
 


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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
Signature of Coordinating Principal Investigator 
 
dd mmm yyyy 
 
 
Printed Name of Coordinating Principal Investigator 
Institution Name: ____________________________________________ 
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed. 


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PROTOCOL SUMMARY 
Study Title 
A Phase 3, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Assess the 
Efficacy and Safety of Apremilast (CC-10004) in Pediatric Subjects from 6 Through 17 Years of 
Age with Moderate to Severe Plaque Psoriasis 
Indication 
Psoriasis is a chronic, inflammatory skin disorder that is estimated to affect up to 2.5% of the 
world’s population (Christophers, 2001). The worldwide prevalence of psoriasis in children 
ranges from 0% to 1.37%. European populations have a higher prevalence than African and 
Asian populations (Michalek, 2017). The prevalence of psoriasis in children in the United States 
(US) from birth to age 18 years is 1%, with an incidence of 40.8 per 100,000 (Tollefson, 2010). 
The most common form of the disease in both adults and children is plaque-type psoriasis that is 
characterized by erythematous plaques with silvery-white scales (Fan, 2007; Mallbris, 2005; 
Morris, 2001; Lebwohl, 2003). The nails and scalp, less often, the mucous membranes may also 
be affected (Weinstein, 2003). 
Most pediatric patients present with mild, localized psoriasis that can be treated primarily with 
topical medications. Phototherapy is not recommended for fair-skinned or younger children, and 
psoralens with long-wave ultraviolet radiation (PUVA) is not recommended for use in pediatric 
psoriasis patients, due to the increased risk of malignancies (Ståhle, 2010). Due to this risk, 
phototherapy is usually reserved for older children and adolescents with extensive areas of 
involvement or refractory plaque disease (Shah, 2013; Marqueling, 2013). Systemic medications 
are utilized for more extensive or refractory disease; however, approved therapies for moderate 
to severe psoriasis in children are limited.  As of 2017, the only approved systemic medications 
in the US for pediatric patients with this indication are the injection-delivered anti-tumor 
necrosis factor (anti-TNF) biologic agents, etanercept (Enbrel) and the anti-p40 inhibitor 
ustekinumab (Stelara). In the EU, etanercept (Enbrel), adalimumab (Humira), and ustekinumab 
(Stelara) are approved for pediatric use. Fear of needles is common in both children and adults 
and can contribute to negative experiences with needle procedures and health care for patients, 
caregivers, and health professionals (McMurtry, 2016). Thus, there remains an unmet need for 
effective systemic therapies that offer oral convenient dosing and a favorable benefit/risk profile 
for the treatment of pediatric patients with moderate to severe plaque psoriasis. 
Apremilast is an oral selective phosphodiesterase type 4 (PDE4) inhibitor marketed worldwide 
under the trade name Otezla. Apremilast 30 mg twice per day (BID) received its first global 
marketing approval for the treatment of adult patients with moderate to severe plaque psoriasis in 
2014. Clinical data from multiple Phase 2 and Phase 3 trials have consistently demonstrated that 
apremilast is an effective oral therapy with an acceptable safety profile for psoriasis. The safety 
profile of apremilast in the post-marketing setting has remained consistent with that seen in the 
clinical development program. Thus, the benefit/risk profile of apremilast continues to be 
favorable in adult psoriasis patients.  
Moderate to severe plaque psoriasis also occurs in children and adolescents. Exploratory 
analyses from a recent Phase 2 study (CC-10004-PPSO-001) indicate that apremilast may be 
effective for the treatment of moderate to severe plaque psoriasis in the pediatric population as in 
adults. This Phase 3 study is being conducted to evaluate the safety and efficacy of apremilast 


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in the treatment of pediatric subjects, ages 6 through 17 years, with moderate to severe plaque 
psoriasis. 
Objectives 
Primary Objective 
 The primary objective of the study is to evaluate the clinical efficacy of apremilast 
compared with placebo in children and adolescents (ages 6 through 17 years) with 
moderate to severe plaque psoriasis. 
Secondary Objectives 
 To evaluate the safety and tolerability of apremilast compared with placebo, in children 
and adolescents (ages 6 through 17 years) with moderate to severe plaque psoriasis 
 To evaluate the effect of apremilast compared with placebo on health-related quality of 
life (HRQoL). 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study. 
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs). 
At least 230 pediatric subjects (ages from 6 through 17 years) will be randomized 2:1 to receive 
either apremilast or placebo for the first 16 weeks. Randomization to the apremilast arm or the 
placebo arm will be stratified by baseline age group (6 to 11 years or 12 to 17 years). A 
minimum of 75 subjects will be randomized in each age group. The sponsor may halt enrollment 
of one age group if that age group reaches 155 randomized subjects to allow the other group to 
randomize at least 75 subjects. Treatment will be assigned by weight with subjects 20 kg to 
< 50 kg receiving apremilast 20 mg BID or placebo BID and subjects ≥ 50 kg receiving 
apremilast 30 mg BID or placebo BID. After all subjects have completed Week 16 (Visit 7), or 
discontinued from the study, a Week 16 database lock will be performed; the primary data 
analysis will be conducted and a Week 16 clinical study report will be generated. Study 
investigators and subjects will remain blinded to initial treatment assignments until the final 
database lock at the conclusion of the study. The blind also should be maintained for persons 
responsible for the ongoing conduct of the study. Blinded persons may include but are not 
limited to: clinical research physician, clinical research scientist, clinical trial manager, study 
statistician, data manager, programmer, and clinical research associate. At the end of the study, 
after all subjects have either completed Week 52 (Visit 16) and entered the Long-term Study, or 
completed the Observational Follow-up Phase, or been discontinued from the Apremilast 
Extension Phase (Weeks 16 to 52) or the Observational Follow-up Phase, a final analysis will be 
performed and a final clinical study report will be generated.  
The study will consist of four phases: 
 Screening Phase – up to 35 days 
 Placebo-controlled Treatment Phase – Weeks 0 to 16 
 Subjects will be randomly assigned in a 2:1 ratio to weight-based apremilast or 
placebo.  Subjects 20 kg to < 50 kg will receive apremilast 20 mg BID or placebo 


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BID and subjects ≥ 50 kg will receive apremilast 30 mg BID or placebo BID. The 
primary endpoint will be the proportion of subjects with a Static Physician Global 
Assessment (sPGA) score of clear (0) or almost clear (1) with at least a 2-point 
reduction from baseline at Week 16. 
 From Week 8 through Week 16, any subject with a Psoriasis Area Severity Index 
(PASI) increase ≥ 50% from baseline will be eligible to commence treatment with 
moderate-to-high potency topical steroid preparations (early escape) and continue 
with randomized investigational product (IP). 
 Apremilast Extension Phase – Weeks 16 to 52 
Placebo subjects will be switched at Week 16 to receive apremilast 20 mg BID or 
30 mg BID, according to baseline weight. All other subjects will continue to 
receive either apremilast 20 mg BID or apremilast 30 mg BID based on their 
original dosing assignment.   
 Observational Follow-up Phase – 14 weeks 
All eligible subjects who complete the Apremilast Extension Phase may opt to enroll 
in a separate Long-term Study (for up to 4 years or until approval, whichever comes 
first). Subjects who choose not to participate in the Long-term Study, or discontinue 
the study early, should return for observational follow-up visits four, eight and 
fourteen weeks after the last dose of IP. 
Study Population 
Pediatric subjects, ages 6 through 17 years, weighing at least 20 kg, with moderate to severe 
plaque psoriasis defined by: 
 PASI score ≥ 12; and 
 Body surface area ≥ 10%; and 
 sPGA ≥ 3 (moderate to severe) 
Subjects must have diagnosis of chronic plaque psoriasis for at least 6 months prior to Screening. 
Length of Study 
The study will have a total duration of up to 71 weeks and will consist of four phases. 
 Screening Phase – up to 35 days (5 weeks) 
 Placebo-controlled Treatment Phase – Weeks 0 to 16 
 Apremilast Extension Phase – Weeks 16 to 52 
 Observational Follow-up Phase – 14 weeks (subjects continuing in the Long-term Study 
will not complete this phase) 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date. 


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Study Treatments 
Investigational product (IP) will be provided in blister cards throughout the Placebo-controlled 
Treatment Phase as well as the first month of the Apremilast Extension Phase. Apremilast blister 
cards provided by the sponsor, Amgen Inc., will contain 10, 20, and 30 mg tablets, depending on 
baseline weight. Placebo will be provided as identically appearing 10, 20, and 30 mg tablets. 
After completion of the Apremilast Extension Phase titration period, IP will be distributed in 
bottles containing 20 or 30 mg tablets for the remainder of the study. All IP will be taken orally 
twice daily, approximately 12 hours apart, without restriction of food or drink. To reduce 
potential gastrointestinal (GI) side effects, dose titration will be implemented during Week 0 of 
this study and at Week 16. 
During Week 0 (Days 1 to 7), subjects will be dispensed dose titration blister cards with 10, 20, 
and 30 mg apremilast tablets or identically appearing placebo tablets. The blister cards will 
contain all IP required for 4 weeks of treatment. Titration supplies or matching placebo will be 
dispensed over the first 3 days for the 20 mg BID treatment group, and over the first 5 days for 
the 30 mg BID treatment group (see Table 5: Treatment Schema for Dose Titration at Visit 2 
[Week 0]) which details the titration supplies from Day 1 to Day 3 or Day 1 to Day 5 in the 
Placebo-controlled Treatment Phase. IP will be dispensed as indicated below: 
 Weeks 0 to 16 (Placebo-controlled Treatment Phase): Apremilast 20 mg BID or 
apremilast 30 mg BID or placebo BID. 
 Week 0: subjects will be dose titrated as described above and in Table 5. 
 Weeks 16 to 52 (Apremilast Extension Phase): Apremilast 20 mg BID or 30 mg BID 
 Week 16: subjects will be dose titrated as described in Table 6. 
At Visit 2 (Week 0), subjects who meet entry criteria will be randomized using a permuted 
block, randomization in parallel 2:1 to receive either apremilast or placebo treatment, using a 
centralized Interactive Response Technology (IRT). Randomization to the apremilast arm or the 
placebo arm will be stratified by baseline age group (6 to 11 years or 12 to 17 years). Subjects 
with baseline weight between 20 kg to < 50 kg will receive apremilast 20 mg BID or placebo 
BID and subjects with baseline weight ≥ 50 kg will receive apremilast 30 mg BID or placebo 
BID.  
At Week 16, subjects who were originally randomized to placebo at Week 0 will be switched to 
receive apremilast treatment, where dose levels (either 20 mg BID or 30 mg BID) would have 
been determined at Week 0 using their baseline weight categories (20 kg to < 50 kg, or ≥ 50 kg). 
Subjects randomized to the apremilast arm at Week 0 will remain on their assigned dose levels 
(either 20 mg BID or 30 mg BID).  
During Weeks 16 to 52, study investigators and study subjects will remain blinded to the initial 
IP assignments. To maintain the blind, all subjects will receive dose titration cards at the 
Week 16 visit. Although only subjects initially randomized to placebo will be dose titrated 
during their first week of the Apremilast Extension Phase, all subjects entering the Apremilast 
Extension Phase will receive identically-appearing titration/treatment cards (see Table 6). 


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Overview of Key Efficacy Assessments 
Primary Efficacy Assessment 
 Static Physician Global Assessment (sPGA) 
Additional Efficacy Assessments 
 Psoriasis Area Severity Index (PASI) 
 Body Surface Area (BSA) 
 Scalp Physician Global Assessment (ScPGA) 
 Modified Static Physician Global Assessment – Genital (sPGA-G) 
Overview of Key Safety Assessments 
Safety Assessments will include: 
 Adverse events (AE) 
 Physical examinations 
 Vital signs 
 Pregnancy test for females of childbearing potential (FCBP) 
 Clinical laboratory tests 
 Stool Diary 
 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 Weight and height 
 Tanner staging 
 Psoriasis flare and rebound 
Overview of Quality of Life Assessments 
 Children’s Dermatology Life Quality Index (CDLQI) 
 Family Dermatology Life Quality Index (FDLQI) 
Patient Reported Outcome Assessment 
 Modified Whole Body Itch Numeric Rating Scale (NRS)  


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Statistical Methods 
At least 230 pediatric subjects (ages from 6 through 17) will be randomized to receive either 
apremilast or placebo (2:1) at Week 0. The sample size estimation is based on the results of the 
adult Phase 3 and 3b studies with apremilast (CC-10004-PSOR-008, PSOR-009 and PSOR-010) 
which demonstrated positive treatment effects between apremilast and placebo in the proportion 
of subjects achieving sPGA response and PASI-75 response at Week 16. 
With a total of 230 patients and a randomization ratio of 2:1, the study will have 90% power to 
detect a 15% difference (20% versus 5%) between the apremilast arm and the placebo arm for 
the proportion of subjects achieving sPGA response at Week 16, based on a Chi-square test at a 
two-sided significance level of 0.05. The study will also have more than 95% power to detect a 
20% difference (30% versus 10%) between apremilast and placebo for the proportion of subjects 
achieving PASI-75 response at Week 16.  
Analysis for efficacy endpoints will be mainly using the intent-to-treat (ITT) population, defined 
as all randomized subjects. Statistical comparisons will be made between the apremilast arm and 
the placebo arm. All statistical tests will be at the two-sided 0.05 significance level and the 
corresponding p-values and two-sided 95% confidence intervals (CIs) will be reported. 
To maintain an overall family-wise Type I error rate at the two-sided 0.05 significance level, a 
fixed-sequence testing procedure will be used to test the primary and the major secondary 
endpoints in a predefined order. The primary endpoint (sPGA response at Week 16) will be 
tested first at the two-sided 0.05 significance level. The comparison with respect to the major 
secondary endpoint (PASI-75 response at Week 16) will be conducted conditional on the test 
result of the primary endpoint, where statistical significance will be claimed only if the two-sided 
p-values for both endpoints are below 0.05.  
The primary endpoint, the proportion of subjects who achieve sPGA response at Week 16 for 
apremilast versus placebo will be compared using Cochran–Mantel–Haenszel (CMH) test 
adjusted by stratification factor at randomization. Subjects who terminate early due to lack of 
efficacy or add moderate-to-high potency topical steroid preparations (early escape) or other 
protocol prohibited medications prior to Week 16 will be assigned as non-responders. Missing 
values will be imputed using the multiple imputation (MI) method as the primary analysis. 
Sensitivity analyses will be performed using the last observation carried forward (LOCF) 
method, the non-responder imputation (NRI) method and the tipping point analyses. A sensitivity 
analysis using the PP population will also be performed. The major secondary endpoint and other 
binary secondary efficacy endpoints will be analyzed similarly as the primary endpoint. 
Subgroup analyses for the primary and the major secondary endpoints based upon demographics 
(age, gender, race, weight category, etc.) and baseline characteristics will be provided to 
determine the robustness of the treatment effect. 
The analysis for the continuous secondary endpoints will be performed using the analysis of 
covariance (ANCOVA) model. The ANCOVA model will use the change or percent change 
from baseline as the dependent variable and will include treatment group and stratification 
factors as independent variables and the baseline value as a covariate variable. The treatment 
comparison between apremilast and placebo will be conducted. Missing values will be imputed 
using the (MI) method.  


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The safety analysis will be performed using the safety population defined as all subjects who 
received at least one dose of IP. Safety will be assessed by clinical review of all relevant 
parameters including treatment-emergent adverse events (TEAEs), laboratory tests and vital 
signs. Data from safety assessments will be summarized descriptively for the Placebo-controlled 
Treatment Phase (Weeks 0 to 16) and the Apremilast Exposure Period when subjects receive 
apremilast treatment. Adverse events will be classified using the Medical Dictionary for 
Regulatory Activities (MedDRA) classification system. All TEAEs will be summarized by 
system organ class, preferred term, severity, and relationship to IP. TEAEs leading to death or to 
IP withdrawal and serious TEAEs will also be summarized and listed separately. 
 


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TABLE OF CONTENTS 
Title page .......................................................................................................................................... 1 
Protocol Summary ........................................................................................................................... 5 
1. 
Introduction ......................................................................................................................... 18 
1.1. 
Disease Background ................................................................................................ 18 
1.2. 
Compound Background .......................................................................................... 18 
1.3. 
Rationale ................................................................................................................. 18 
1.3.1. 
Study Rationale and Purpose ................................................................ 18 
1.3.2. 
Rationale for the Study Design .............................................................. 19 
1.3.3. 
Rationale for Dose, Schedule and Regimen Selection .......................... 20 
1.3.4. 
Rationale for Pharmacodynamics and Potential Predictive 
Biomarkers ............................................................................................ 21 
2. 
Study Objectives and endpoints .......................................................................................... 23 
3. 
Overall Study Design ............................................................................................................ 27 
3.1. 
Study Design............................................................................................................ 27 
3.2. 
Study Duration for Subjects .................................................................................... 29 
3.3. 
End of Trial .............................................................................................................. 29 
4. 
Study Population .................................................................................................................. 30 
4.1. 
Number of Subjects................................................................................................. 30 
4.2. 
Inclusion Criteria ..................................................................................................... 30 
4.3. 
Exclusion Criteria ..................................................................................................... 33 
5. 
Table of Events ..................................................................................................................... 35 
6. 
Procedures ........................................................................................................................... 38 
6.1. 
Screening Period ..................................................................................................... 39 
6.2. 
Treatment Period .................................................................................................... 40 
6.2.1. 
End of Treatment .................................................................................. 41 
6.3. 
Observational Follow-up Period ............................................................................. 42 
6.3.1. 
Observational Follow-up ....................................................................... 42 
6.4. 
Efficacy Assessments............................................................................................... 43 
6.5. 
Safety Assessments ................................................................................................. 44 
6.5.1. 
Adverse Events ...................................................................................... 44 
6.5.2. 
Contraception Education ...................................................................... 44 
6.5.3. 
Serum and Urine Pregnancy Tests for Females of Childbearing 
Potential ................................................................................................ 44 
6.5.4. 
Complete Physical Exam........................................................................ 45 
6.5.5. 
Abbreviated Physical Exam ................................................................... 45 


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6.5.6. 
Hepatitis B and C Testing....................................................................... 45 
6.5.7. 
Vital Signs, Height, Weight and Body Mass Index ................................. 45 
6.5.8. 
Clinical Laboratory Evaluations ............................................................. 45 
6.5.9. 
Hematology ........................................................................................... 46 
6.5.10. 
Serum Chemistry ................................................................................... 46 
6.5.11. 
Urinalysis ............................................................................................... 46 
6.5.12. 
Psychiatric Evaluation ........................................................................... 46 
6.5.13. 
Stool Diary ............................................................................................. 47 
6.5.14. 
Tanner Staging ....................................................................................... 47 
6.5.15. 
Worsening of Psoriasis and Rebound Assessments .............................. 47 
6.5.16. 
Unscheduled Visits ................................................................................ 47 
6.6. 
Pharmacokinetics .................................................................................................... 48 
6.7. 
Biomarkers, Pharmacodynamics, Pharmacogenomics ........................................... 48 
6.8. 
Subject Reported Outcomes or Health Related Quality of Life .............................. 49 
7. 
Description of Study Treatments ......................................................................................... 50 
7.1. 
Description of Investigational Product ................................................................... 50 
7.2. 
Treatment Administration and Schedule ................................................................ 50 
7.3. 
Overdose ................................................................................................................. 53 
7.4. 
Method of Treatment Assignment ......................................................................... 53 
7.5. 
Packaging and Labeling ........................................................................................... 53 
7.6. 
Investigational Product Accountability and Disposal .............................................. 54 
7.7. 
Investigational Product Compliance ....................................................................... 54 
8. 
Concomitant Medications and Procedures ......................................................................... 55 
8.1. 
Permitted Concomitant Medications and Procedures ........................................... 55 
8.2. 
Prohibited Concomitant Medications and Procedures ........................................... 55 
8.3. 
Required Concomitant Medications and Procedures ............................................. 56 
9. 
Statistical considerations ..................................................................................................... 57 
9.1. 
Overview ................................................................................................................. 57 
9.2. 
Study Population Definitions .................................................................................. 57 
9.3. 
Sample Size and Power Considerations .................................................................. 57 
9.4. 
Background and Demographic Characteristics ....................................................... 57 
9.5. 
Subject Disposition .................................................................................................. 58 
9.6. 
Efficacy Analysis ...................................................................................................... 58 
9.6.1. 
Efficacy Evaluation for the Placebo-controlled Treatment Phase 
(Weeks 0 to 16) ..................................................................................... 58 
9.6.1.1. 
Primary Efficacy Endpoint ................................................. 58 
9.6.1.2. 
Major Secondary Efficacy Endpoint .................................. 59 
9.6.1.3. 
Other Secondary Efficacy Endpoints ................................ 61 


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9.6.1.4. 
Multiplicity Adjustment .................................................... 62 
9.6.1.5. 
Exploratory Endpoints ...................................................... 62 
9.6.1.6. 
Subgroup Analysis ............................................................. 62 
9.6.2. 
Efficacy Evaluation – Apremilast Extension Phase (Weeks 16 to 52) ... 62 
9.7. 
Safety Analysis ........................................................................................................ 63 
9.8. 
Interim Analysis ....................................................................................................... 63 
9.9. 
Other Topics ............................................................................................................ 64 
9.9.1. 
Data Monitoring Committee ................................................................. 64 
9.9.2. 
Scientific Steering Committee ............................................................... 64 
........................................ 64 
........................................ 64 
10. 
Adverse Events ..................................................................................................................... 65 
10.1. 
Monitoring, Recording and Reporting of Adverse Events ...................................... 65 
10.2. 
Evaluation of Adverse Events .................................................................................. 65 
10.2.1. 
Seriousness ............................................................................................ 66 
10.2.2. 
Severity/Intensity .................................................................................. 67 
10.2.3. 
Causality ................................................................................................ 68 
10.2.4. 
Duration ................................................................................................ 68 
10.2.5. 
Action Taken .......................................................................................... 68 
10.2.6. 
Outcome ................................................................................................ 68 
10.3. 
Abnormal Laboratory Values .................................................................................. 68 
10.4. 
Pregnancy ................................................................................................................ 69 
10.4.1. 
Females of Childbearing Potential – Collection of Pregnancy 
Information: .......................................................................................... 69 
10.4.2. 
Male Subjects With Partners Who Become Pregnant .......................... 70 
10.4.3. 
Collection of Lactation Information ...................................................... 70 
10.5. 
Reporting of Serious Adverse Events ...................................................................... 70 
10.5.1. 
Safety Queries ....................................................................................... 71 
10.6. 
Expedited Reporting of Adverse Events .................................................................. 71 
11. 
Discontinuations .................................................................................................................. 73 
11.1. 
Treatment Discontinuation ..................................................................................... 73 
11.2. 
Study Discontinuation ............................................................................................. 74 
12. 
Emergency Procedures ........................................................................................................ 75 
12.1. 
Emergency Contact ................................................................................................. 75 
12.2. 
Emergency Identification of Investigational Products ............................................ 75 
13. 
REgulatory Considerations ................................................................................................... 76 
13.1. 
Good Clinical Practice ............................................................................................. 76 
13.2. 
Investigator Responsibilities ................................................................................... 76 


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13.3. 
Subject Information and Informed Consent ........................................................... 77 
13.4. 
Confidentiality ......................................................................................................... 77 
13.5. 
Protocol Amendments ............................................................................................ 77 
13.6. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval .................................................................................................................. 77 
13.7. 
Ongoing Information for Institutional Review Board/ Ethics Committee .............. 78 
13.8. 
Termination of the Study ........................................................................................ 78 
14. 
Data handling and recordkeeping ........................................................................................ 79 
14.1. 
Data/Documents ..................................................................................................... 79 
14.2. 
Data Management .................................................................................................. 79 
14.3. 
Record Retention .................................................................................................... 79 
15. 
Quality Control and Quality Assurance ................................................................................ 81 
15.1. 
Study Monitoring and Source Data Verification ..................................................... 81 
15.2. 
Audits and Inspections ............................................................................................ 81 
15.3. 
Product Complaint .................................................................................................. 81 
16. 
Publications .......................................................................................................................... 83 
17. 
References ........................................................................................................................... 84 
18. 
Appendices ........................................................................................................................... 87 
Appendix A: 
Table of Abbreviations .......................................................................... 87 
Appendix B: 
Static Physician Global Assessment (sPGA) .......................................... 90 
Appendix C: 
Psoriasis Area Severity Index (PASI) ...................................................... 91 
Appendix D: 
Scalp Physician Global Assessment (ScPGA) ......................................... 93 
Appendix E: 
Modified Static Physician Global Assessment of Genitalia (sPGA-G) ... 94 
Appendix F: 
Columbia-Suicide Severity Rating Scale ................................................ 95 
Appendix G: 
Stool Diary ........................................................................................... 101 
Appendix H: 
Tanner Staging .................................................................................... 102 
Appendix I: 
Pharmacokinetic Sample Processing Instructions .............................. 103 
Appendix J: 
The Children’s Dermatology Life Quality Index (CDLQI) ..................... 105 
Appendix K: 
Family Dermatology Life Quality Index (FDLQI) .................................. 106 
Appendix L: 
Modified Whole Body Itch Numeric Rating Scale (NRS) ..................... 108 
Appendix M: 
Monthly Blister Card Configurations................................................... 109 
Appendix N: 
Sample Serious Adverse Event Report Form ...................................... 120 
Appendix O: 
Pregnancy Notification Form .............................................................. 123 
Appendix P: 
Lactation Notification Form ................................................................ 124 
 
 
 


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LIST OF TABLES 
Table 1: 
Study Objectives .................................................................................................. 23 
Table 2: 
Study Endpoints ................................................................................................... 24 
Table 3: 
Table of Events .................................................................................................... 35 
Table 4: 
Acceptable Time Windows for Pharmacokinetic Blood Sampling ....................... 48 
Table 5: 
Treatment Schema for Dose Titration at Visit 2 (Week 0) .................................. 51 
Table 6: 
Treatment Schema for Dose Titration at Visit 7 (Week 16) ................................ 52 
Table 7: 
Abbreviations and Specialist Terms ..................................................................... 87 
 


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LIST OF FIGURES 
Figure 1: 
Overall Study Design ............................................................................................ 29 
 


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1. 
INTRODUCTION  
1.1. 
Disease Background  
Psoriasis is a chronic, inflammatory skin disorder that is estimated to affect up to 2.5% of the 
world’s population (Christophers, 2001). The worldwide prevalence of psoriasis in children 
ranges from 0% to 1.37%. European populations have a higher prevalence than African and 
Asian populations (Michalek, 2017). The prevalence of psoriasis in children in the United States 
(US) from birth to age 18 years is 1%, with an incidence of 40.8 per 100,000 (Tollefson, 2010). 
The first manifestation of psoriasis may occur at any age, with approximately one-third of cases 
reporting onset during childhood (Ståhle, 2010; Silverberg, 2010). Regardless of the timing of 
disease onset, the most common form of the disease in both adults and children is plaque-type 
psoriasis, characterized by erythematous plaques with silvery-white scales (Bronckers, 2015; 
Silverberg, 2010; Fan, 2007; Mallbris, 2005; Morris, 2001; Lebwohl, 2003). The nails and, less 
often, the mucous membranes may also be affected (Weinstein, 2003). One-third of patients 
present with the first signs and symptoms of psoriasis by the age of 20 years. (Tollefson, 2010; 
Benoit, 2007; Raychaudhuri, 2001). 
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 cytokines, and 
increasing the production of anti-inflammatory mediators.  
In completed Phase 3 studies in subjects with moderate to severe plaque psoriasis and active 
psoriatic arthritis, treatment with apremilast was associated with statistically significant and 
clinically meaningful improvements in multiple efficacy measures. On the basis of these studies, 
apremilast (OTEZLA®) is approved in multiple countries worldwide for the treatment of patients 
with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic 
therapy, and the treatment of adult patients with active psoriatic arthritis.  
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 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 
The treatment options for pediatric patients with plaque psoriasis remain limited. While most 
pediatric patients present with mild, localized psoriasis that can be treated primarily with topical 
medications, these therapies may be limited by their short treatment durations, poor treatment 
compliance and significant adverse effects (Chan, 2009; Kragballe, 2013). Phototherapy is not 


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recommended for fair-skinned or younger children, and psoralens with long-wave ultraviolet 
radiation (PUVA) is not recommended for use in pediatric psoriasis patients, due to the increased 
risk of malignancies (Ståhle, 2010). Due to this risk, phototherapy is usually reserved for older 
children and adolescents with extensive areas of involvement or refractory plaque disease (Shah, 
2013; Marqueling, 2013).  
Systemic medications are utilized for more extensive or refractory disease; however, approved 
therapies for moderate to severe psoriasis in children is limited. Management of psoriasis in 
children can be challenging owing to a paucity of data and lack of standardized guidelines to the 
pediatric population (Vogel, 2012). As of 2017, the only approved systemic medications in the 
US for pediatric patients with this indication are the anti-TNF biologic agent etanercept (Enbrel), 
and the anti-p40 inhibitor ustekinumab (Stelara). In the European Union (EU), etanercept 
(Enbrel), adalimumab (Humira) and ustekinumab (Stelara) are approved for pediatric use. Fear 
of needles is common in both children and adults and can contribute to negative experiences with 
needle procedures and health care for patients, caregivers, and health professionals (McMurtry, 
2016). Thus, there remains an unmet need for effective systemic therapies that offer oral 
convenient dosing and a favorable benefit/risk profile for the treatment of pediatric patients with 
moderate to severe plaque psoriasis. 
The systemic therapies used in pediatric psoriasis are essentially the same as those used in 
adulthood, with dosage and strength reductions calculated based on age, weight, and available 
formulations (Silverberg, 2010). However, most of these therapies are used off-label as they are 
not approved for pediatric use (Ståhle, 2010). In clinical trials, biologic therapies, etanercept 
(Enbrel), adalimumab (Humira), and ustekinumab (Stelara) demonstrated similar efficacy in 
pediatric patients with psoriasis as with the adult patients (Dogra, 2018). 
Apremilast is an oral selective PDE4 inhibitor marketed worldwide under the trade name 
OTEZLA®.  Apremilast 30 mg twice per day (BID) received its first global marketing approval 
for the treatment of adult patients with moderate to severe plaque psoriasis in 2014. Clinical data 
from multiple Phase 2 and Phase 3 trials and in the post-marketing setting have consistently 
demonstrated that apremilast is an effective oral therapy with an acceptable safety profile in 
adults. Thus, the benefit/risk profile of apremilast continues to be favorable in adult psoriasis 
patients.  
Moderate to severe plaque psoriasis also occurs in pediatric patients. Exploratory analyses from 
a recent Phase 2 study (CC-10004-PPSO-001) indicate that apremilast may be effective for the 
treatment of moderate to severe plaque psoriasis in the pediatric population as in adults. This 
Phase 3 study (CC-10004-PPSO-003) is being conducted to evaluate the safety and efficacy of 
apremilast in the treatment of pediatric subjects, ages 6 through 17, with moderate to severe 
plaque psoriasis. 
1.3.2. 
Rationale for the Study Design 
This Phase 3, multi-center, randomized, double-blind, placebo-controlled study is designed to 
assess the efficacy and safety of apremilast in pediatric subjects aged 6 through 17 years of age 
with moderate to severe psoriasis. 
Study CC-10004-PPSO-003 will investigate the safety and efficacy of apremilast 20 mg BID and 
apremilast 30 mg BID, compared to placebo, in the treatment of subjects with moderate to severe 


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plaque psoriasis. The primary endpoint will be the proportion of subjects who achieve a static 
Physician Global Assessment (sPGA) of clear (0) or almost clear (1), with at least a 2-point 
reduction from baseline at Week 16, in the intent-to-treat population. The first secondary 
endpoint will be the proportion of subjects achieving a 75% improvement in the Psoriasis Area 
Severity Index (PASI-75) response from baseline at Week 16. Both sPGA and PASI-75 have 
been required key endpoints for efficacy in psoriasis trials in both adults and children with 
moderate to severe plaque psoriasis.   
The use of placebo for 16 weeks has been acceptable in clinical trials of pediatric subjects with 
moderate to severe plaque psoriasis (Paller, 2008). To retain subjects in the study until the 
primary endpoint at Week 16 is reached, an early escape option for subjects demonstrating a 
worsening of their psoriasis, measured as a ≥ 50% increase in PASI score from baseline will be 
permitted. These early escape subjects will be allowed to use moderate to high potency topical 
steroids but will be considered non-responders for the purposes of statistical analysis. The total 
treatment duration of the trial will be 52 weeks to assess the long-term effects of apremilast on 
safety and maintenance of efficacy. 
Eligible subjects will be randomized 2:1 to receive either apremilast (20 mg BID for subjects 
weighing 20 to 50 kg, and 30 mg BID for subjects weighing ≥ 50 kg) or placebo, to reduce 
exposure to placebo without greatly increasing the number of subjects exposed to investigational 
product, while maintaining the statistical power of the study. Randomization will be stratified by 
baseline age group to ensure balance between treatment arms with respect to baseline age. 
1.3.3. 
Rationale for Dose, Schedule and Regimen Selection  
Two Phase 2 dose finding studies have been conducted in adult subjects with moderate to severe 
plaque psoriasis. In study CC-10004-PSOR-005, a clear dose response was demonstrated with 
statistically significant improvement in the apremilast 20 mg BID and 30 mg BID, but not the 
apremilast 10 mg BID treatment groups, compared with placebo. Similar findings were observed 
in Study CC-10004-PSOR-011 which enrolled adult Japanese subjects with lower body weight 
and Body Mass Index (BMI) than the subjects enrolled in study CC-10004-PSOR-005. The 
safety and tolerability profiles of the apremilast 20 mg BID and 30 mg BID treatment groups 
were acceptable with no clinically significant safety signals observed in either dose group. In 
both of these studies, the apremilast 30 mg BID treatment group provided a superior benefit/risk 
profile compared to apremilast 20 mg BID. The apremilast 30 mg BID dose was evaluated in 
two large pivotal Phase 3 studies (studies CC-10004-PSOR-008 and CC-10004-PSOR-009), and 
was subsequently approved for use in adult patients with moderate to severe plaque psoriasis. 
Moderate to severe plaque psoriasis also occurs in children and adolescents ages 6 through 
17 years. The pharmacokinetic (PK) profiles of two effective adult dosages, apremilast 20 mg 
BID and apremilast 30 mg BID, are being evaluated in the ongoing pediatric Phase 2 study 
CC-10004-PPSO-001. The PK results from this study show that the apremilast exposure area 
under the plasma concentration-time curve (AUCtau) and peak observed plasma concentration of 
drug (Cmax) on Day 14 in adolescents (12 to 17 years) treated with 30 mg BID, and children (6 to 
11 years) treated with 20 mg BID appear to be comparable to the exposure observed in adult 
patients treated with 30 mg BID (Study CC-10004 PSOR-011). A population PK model was 
subsequently developed based on the data pooled from the pediatric study CC-10004-PPSO-001, 
and the adult studies CC-10004-PSOR-005 and CC-10004-PSOR-011. The model-based 


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simulations were conducted to determine the range of body weight in pediatric subjects taking 
apremilast 20 mg BID that could achieve similar exposure (AUCtau) to that in adult subjects 
taking the approved apremilast dose (30 mg BID). Two hundred clinical trials were simulated 
with each trial having pediatric subjects weighing between ≥ 20 kg and < 70 kg and adult 
reference population. The ratio of geometric mean (GM) of AUCtau for a given pediatric body 
weight group (body weight grouped by 5 kg increments) relative to the GM of AUCtau in adults 
was computed and the median of ratio and its 90% predictive interval were summarized. Based 
on modeling and simulation, the exposure of apremilast 20 mg BID in pediatric subjects 
weighing between ≥ 20 kg and < 50 kg is predicted to be similar to the exposure of apremilast 
30 mg BID in adults (median of ratio within 0.8 and 1.25). The pediatric subjects weighing 
≥ 50 kg are recommended to take the adult dose of 30 mg BID. 
Exploratory efficacy analysis indicates that both apremilast doses (20 mg BID and 30 mg BID) 
may be efficacious in the treatment of moderate to severe plaque psoriasis in pediatric subjects. 
The safety analyses showed a similar safety profile to that of adults but with higher incidence 
rates of adverse events, particularly of diarrhea, nausea and vomiting. These adverse events 
(AEs) were mostly mild to moderate, and of short duration with the majority of these AEs lasting 
< 3 days. It should be noted that dose titration, which has been shown to ameliorate 
gastrointestinal-related adverse events in the adult studies, was not implemented in 
CC-10004-PPSO-001.   
Based on these Phase 2 results, the Phase 3 study will evaluate the efficacy and safety of 
apremilast 20 mg BID for subjects < 50 kg and 30 mg BID for subjects ≥ 50 kg, compared to 
placebo, in the treatment of children and adolescent subjects with moderate to severe plaque 
psoriasis. As in the adult Phase 3 studies, dose titration will be implemented in order to mitigate 
potential gastrointestinal-related adverse events.  
1.3.4. 
Rationale for Pharmacodynamics and Potential Predictive Biomarkers  
Phosphodiesterase 4 (PDE4) is the predominant cyclic adenosine monophosphate (cAMP)-
selective phosphodiesterase that regulates intracellular cAMP levels and gene expression in cells 
of the immune system. PDE4 is highly overexpressed in the peripheral blood of a subset of 
psoriasis patients (Schafer, 2016). Apremilast has been found to reduce Th17 and Th22 cytokine 
expression in the lesional skin and peripheral blood of psoriasis patients (Gottlieb, 2013; 
Krueger, 2016). In adult patients with moderate to severe psoriasis, treatment with apremilast is 
associated with significant reductions in plasma levels of interleukin (IL)-17F, IL-17A, IL-22, 
and tumor necrosis factor-α (TNF-α) compared with placebo as early as Week 4; decreases in 
cytokine levels were sustained with continued treatment. Multivariate analyses demonstrated that 
while changes in IL-17F are the most important predictor of improvement in Psoriasis Area and 
Severity Index scores, apremilast exerts synergistic attenuating effects among a key group of 
cytokines involved in the pathology of psoriasis, and these effects correlate with improved skin 
symptoms. These in vitro and clinical data demonstrate that the beneficial effects of apremilast 
on known inflammatory mediators are associated with its clinical efficacy. Peripheral blood will 
be drawn to measure RNA expression at baseline and during the treatment period. Whole blood 
will be used for the analysis. The expression of specific RNAs, such as but not limited to 
PDE4A, PDE4B, PDE4C, PDE4D, IL17A, IL17F, IL22, and TNF-α, will be analyzed at baseline 
and during the placebo-controlled treatment period. These data will further define the mechanism 


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of action of apremilast in this patient population, and may inform on the subset of patients who 
are responding well to apremilast treatment. 
Psoriasis is driven in part by genetic factors, including HLA-Cw6, TNF-α, LCE3B/3C, IL12B, 
IL23A, IL23R, LCE, TNIP1, IFHIH1, and NFKBIA. Apremilast has been shown to inhibit the 
expression of some of these genes, including TNF-α, IL12B, and IL23A (Gottlieb, 2013). 
Therefore, clinical response to apremilast may be dependent upon the underlying genetic drivers 
in some psoriasis patients. Pharmacogenetic testing will be conducted using deoxyribonucleic 
acid (DNA) isolated from a buccal swab at Visit 2 (Baseline Visit; day of randomization). DNA 
will be examined for the presence of polymorphisms in the genes encoding the targets of 
apremilast (PDE4A, PDE4B, PDE4C, and PDE4D), and in genes associated with psoriasis, 
including but not limited to HLA-Cw6, TNF-α, LCE3B/3C, IL12B, IL23A, IL23R, LCE, TNIP1, 
IFHIH1, and NFKBIA. 
The microbial species present on the skin of psoriasis patients may play a role in the transition 
from healthy skin to psoriatic plaques (Langan 2017). The microbial composition of the patients’ 
skin will be examined to identify the predominant bacterial and fungal species present before and 
after apremilast treatment, to determine if the microbiome either predicts response to apremilast 
or changes upon apremilast therapy.  


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
Table 1: Study Objectives 
Primary Objective 
The primary objective of the study is to evaluate the clinical efficacy of apremilast compared 
with placebo in children and adolescents (ages 6 through 17 years) with moderate to severe 
plaque psoriasis. 
Secondary Objectives 
The secondary objectives are: 
 To evaluate the safety and tolerability of apremilast compared with placebo, in children 
and adolescents (ages 6 through 17 years) with moderate to severe plaque psoriasis 
 
To evaluate the effect of apremilast compared with placebo on health-related quality of 
life (HRQoL) 
Exploratory Objectives 
The exploratory objectives are: 
 To evaluate the effect of apremilast on plaque psoriasis 
 To evaluate the effect of apremilast on plaque psoriasis of the scalp 
 To evaluate the effect of apremilast on genital psoriasis  
 To evaluate the effect of apremilast on itch over the whole body caused by plaque 
psoriasis 
 To evaluate the effect of apremilast on HRQoL of family members 
 


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Table 2: Study Endpoints 
Endpoint 
Name 
Description 
Timeframe 
Primary  
Static PGA (sPGA) 
0/1 
Proportion of subjects with an sPGA score 
of clear (0) or almost clear (1) with at least a 
2-point reduction from baseline 
Week 16 
Major Secondary 
Endpoints 
PASI-75 
 
Proportion of subjects who achieve at least 
a 75% reduction in PASI (PASI-75) from 
baseline 
Week 16 
Other Secondary 
Endpoints 
PASI-50 
Proportion of subjects who achieve at least 
a 50% reduction in PASI (PASI-50) from 
baseline 
Week 16 
PASI 
Percent change from baseline in total PASI 
score 
Week 16 
BSA 
Percent change from baseline in affected 
BSA 
Week 16 
CDLQI (0/1) 
Proportion of subjects who achieve CDLQI 
(0/1) 
Week 16 
CDLQI 
Change from baseline in CDLQI score 
Week 16 
Exploratory 
PASI-50 
Proportion of subjects who achieve PASI-
50 
All visits 
PASI-75 
Proportion of subjects who achieve PASI-
75 
All visits 
PASI-90 
Proportion of subjects who achieve PASI-
90 
All visits 
PASI 
Percent change from baseline in total PASI 
score 
All visits 
sPGA (0/1) 
Proportion of subjects with sPGA of clear 
(0) or almost clear (1) with at least a 2-point 
reduction from baseline 
All visits 
BSA 
Percent change from baseline in affected 
BSA 
 Select visits 
ScPGA 
Proportion of subjects with scalp psoriasis 
with improvement of ScPGA of clear (0) or 
almost clear (1)  
 Select visits 
sPGA-G 
Proportion of subjects with genital psoriasis 
with improvement of sPGA-G of clear (0) 
or minimal (1)  
Select visits 
Modified Whole 
Body Itch NRS 
Proportion of subjects with ≥ 4-point 
reduction (improvement) from baseline in 
the whole body itch NRS score 
Select visits 


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Table 2: 
Study Endpoints (Continued) 
Endpoint 
Name 
Description 
Timeframe 
 
Modified Whole 
Body Itch NRS 
Change from baseline in the whole body 
itch NRS score 
Select visits 
CDLQI (0/1) 
Proportion of subjects who achieve CDLQI 
(0/1) 
Select visits 
CDLQI 
Change from baseline in CDLQI scores 
Select visits 
FDLQI (0/1) 
Proportion of subjects achieving FDLQI 
(0/1) 
Select visits 
FDLQI 
Change from baseline in FDLQI scores 
Select visits 
Safety 
Adverse events 
Type, frequency, 
severity, and 
relationship of AEs 
to IP 
Day 0 through end of Observational Follow 
Up 
Study duration 
(up through 
14-week 
follow-up) 
Diarrhea 
Stool Diary 
(frequency, 
duration and 
associated 
symptoms) 
Completed daily by 
subject/parent(s)/guardian(s) and reviewed 
at each visit by study investigator 
Study duration 
(up through 4-
week follow-
up) 
Depression, 
suicidal thoughts 
and behavior 
Columbia-Suicide 
Severity Rating 
Scale (C-SSRS) 
Questionnaire completed at Screening, 
Baseline, and visits thereafter as indicated in 
Table 3  
Study duration 
(up through 
Week 52) 
Growth and 
Development 
Tanner Staging of 
sexual development 
Assessment of sexual maturity 
Performed at 
beginning and 
end of study 
(Week 52 or 
ET) 
Body weight, 
height and BMI 
Height and body weight are measured and 
recorded at each visit 
Study duration 


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Table 2: 
Study Endpoints (Continued) 
Endpoint 
Name 
Description 
Timeframe 
Psoriasis Flare 
Psoriasis disease 
flare as defined in 
Section 6.5.15  
Proportion of subjects with sudden 
intensification of psoriasis (new generalized 
erythrodermic, inflammatory or pustular 
psoriasis) requiring medical intervention 
beyond allowable medications 
Study duration 
(while taking 
study 
medication) 
Psoriasis Rebound 
Rebound as defined 
in Section 6.5.15 
Severe and sudden worsening of disease 
(PASI ≥ 125% of baseline or new 
generalized, pustular, erythrodermic 
psoriasis) after treatment has been 
discontinued 
14-week 
follow-up 
period 
sPGA = static Physician Global Assessment; PASI = Psoriasis Area Severity Index; BSA = Body Surface Area; 
CDLQI = Children’s Dermatological Life Quality Index; ScPGA = Scalp Physician Global Assessment; sPGA-G = 
Scalp Physician Global Assessment-Genital; FDLQI = Family Dermatological Life Quality Index; NRS = Numeric 
Rating Scale; 
. 


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3. 
OVERALL STUDY DESIGN  
3.1. 
Study Design 
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study of the 
efficacy and safety of apremilast (CC-10004) in pediatric subjects with moderate to severe 
plaque psoriasis. 
At least 230 pediatric subjects (ages 6 through 17 years) will be randomized 2:1 to receive either 
apremilast or placebo for the first 16 weeks. Randomization to apremilast arm or placebo arm 
will be stratified by age group (6 to 11 years or 12 to 17 years). A minimum of 75 subjects will 
be randomized in each age group. The sponsor may halt enrollment of one age group if that age 
group reaches 155 randomized subjects to allow the other group to randomize at least 
75 subjects. The integrated response technology (IRT) system will monitor total enrollment of 
each age group so enrollment can be halted once a group reaches 155 randomized subjects. 
Treatment will be assigned by weight with subjects 20 kg to < 50 kg receiving apremilast 20 mg 
BID or placebo BID and subjects ≥ 50 kg receiving apremilast 30 mg BID or placebo BID. After 
all subjects have completed the Week 16 Visit (or discontinued from the study), a Week 16 
database lock will be performed; the primary data analysis will be conducted and a Week 16 
clinical study report will be generated. Study investigators and subjects will remain blinded to 
initial treatment assignments until the final database lock at the conclusion of the study. The 
blind also should be maintained for persons responsible for the ongoing conduct of the study. 
Blinded persons may include but are not limited to: clinical research physician, clinical research 
scientist, clinical trial manager, study statistician, data manager, programmer, clinical research 
associate. At the end of the study, after all subjects have either completed Visit 16 and entered 
the Long-term Study, or completed the Observational Follow-up Phase, or been discontinued 
from the Apremilast Extension Phase (Weeks 16 to 52) or the Observational Follow-up Phase, a 
final analysis will be performed and a final clinical study report will be generated. 
The study will consist of four phases: 
 Screening Phase – up to 35 days 
 Placebo-controlled Treatment Phase – Weeks 0 to 16 
- 
Subjects will be randomly assigned in a 2:1 ratio to apremilast or placebo.  
Subjects 20 kg to < 50 kg will receive apremilast 20 mg BID or placebo BID and 
subjects ≥ 50 kg will receive apremilast 30 mg BID or placebo BID. The primary 
endpoint will be the proportion of subjects with an sPGA score of clear (0) or 
almost clear (1) with at least a 2-point reduction from baseline at Week 16. 
- 
From Week 8 through Week 16, any subject with a PASI increase ≥ 50% from 
baseline will be eligible to commence treatment with moderate-to-high potency 
topical steroid preparations (early escape) and continue with randomized IP. 
 Apremilast Extension Phase – Weeks 16 to 52 
- 
Placebo subjects will be switched at Week 16 to receive apremilast 20 mg BID or 
30 mg BID, according to baseline weight. All other subjects will continue to 
receive either apremilast 20 mg BID or apremilast 30 mg BID based on their 
original dosing assignment. 


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 Observational Follow-up Phase – 14 weeks 
- 
All eligible subjects who complete the apremilast Extension Phase may opt to 
enroll in a separate Long-term Study (for up to 4 years or until approval, 
whichever comes first). Subjects who choose not to participate in the Long-term 
Study, or discontinue the study early, should return for observational follow-up 
visits four, eight, and fourteen weeks after the last dose of IP. 
An external, independent data monitoring committee (DMC) will review available safety and 
efficacy data approximately semi-annually or on an ad-hoc basis throughout the study. The DMC 
consists of 4 external independent members (3 independent clinical trialists and 1 independent 
biostatistician) with voting privileges. All members are selected by Amgen with consideration 
for their respective expertise in the subject matter and/or in their experience in convening or 
participating in a DMC. 
A Scientific Steering Committee (SSC) has also been formed in support of this study. The SSC 
provides input into the study protocol and is responsible for supporting the conduct of the trial, 
promoting effective enrollment and reviewing study data. The SSC is comprised of 5 clinicians 
that may or may not be participating in the study. The SSC will interact with Amgen and other 
parties on a periodic basis throughout the conduct of the trial with meetings based upon patient 
recruitment throughout the entire conduct of the trial.  
Treatment administration and schedule are discussed in Section 7.2. 
At this time, there are no consistent AEs or laboratory findings that would generally constitute a 
reliable stopping rule for this study. Subjects will be monitored for AEs, vital signs, and 
laboratory assessments at each study visit. All AEs, clinically significant changes in laboratory 
measures and clinically meaningful changes in vital signs will be recorded. Clinically 
meaningful changes that increase the risk to the subject, as assessed by the Investigator or 
Sponsor, may result in discontinuation of the subject from the study. Subjects who have psoriasis 
disease flare at any time during the period of the study and require additional psoriasis 
medication including systemic therapies such as methotrexate, systemic corticosteroids, or 
biologics, will be discontinued from the study and treated according to local treatment 
guidelines. 
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. 


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Figure 1: 
Overall Study Design 
 
3.2. 
Study Duration for Subjects  
The study will last for up to a total of 71 weeks which includes screening, treatment, and 
observational follow-up. 
Each subject will undergo a Screening period of up to 5 weeks, a 16-week Placebo-controlled 
Treatment Phase, and a 36-week Apremilast Extension Phase. All eligible subjects who complete 
the Apremilast Extension Phase may opt to enroll in a separate, up to 4-year Long-term Study. 
Subjects who choose not to participate in the Long-term Study, or discontinue the study early, 
should return for the three observational follow-up visits at four, eight, and fourteen weeks after 
the last dose of IP. 
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 efficacy and/or safety assessments, as prespecified in the protocol, whichever is the 
later date. 
 


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4. 
STUDY POPULATION 
4.1. 
Number of Subjects  
At least 230 pediatric subjects with moderate to severe plaque psoriasis will be randomized from 
investigator sites in North America, the EU, and rest of world. 
4.2. 
Inclusion Criteria 
Subject must satisfy the following criteria to be enrolled in the study: 
1. Males or female subjects 6 to 17 years of age, inclusive, at the time the informed consent 
form is signed by the legal guardian 
2. Subjects must have a weight of ≥ 20 kg 
3. Subjects must have an age and sex specific BMI value no lower in range than the 5th 
percentile on the Centers for Disease Control (CDC) growth chart for children and 
adolescents (CDC, 2000). 
4. Subject is able to swallow the study medication tablet 
5. Able to sign an age-appropriate assent with a legal guardian(s) who understand(s) and 
voluntarily sign(s) an informed consent prior to any study-related assessments/procedures 
being conducted. 
6. Be willing and able to adhere to the study visit schedule and other protocol requirements. 
7. Diagnosis of chronic plaque psoriasis for at least 6 months prior to Screening. 
8. Has moderate to severe plaque psoriasis at Screening and Baseline as defined by: 
 PASI score ≥ 12; and 
 Body surface area (BSA) ≥ 10%; and 
 sPGA ≥ 3 (moderate to severe) 
9. Disease inadequately controlled by or inappropriate for topical therapy for psoriasis 
10. Candidate for systemic therapy or phototherapy   
11. At Screening, laboratory values must be within the following ranges:  
 White blood cell (WBC) count 
Age (years) 
Males (x 103 /µL) 
Females (x 103 /µL) 
6-11 
3.5 – 13.5 
3.5 – 13.5 
12-18 
3.5 – 13.5 
3.5 – 13.5 
 Platelet count 
Age (years) 
Males (x 103 /µL) 
Females (x 103 /µL) 
6-11  
125 – 500 
125 – 500 
12-18  
125 – 500 
125 – 500 


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 Serum creatinine ≤ 1.2 x upper-limit of normal (ULN) for age and gender. Please 
see reference ranges of the central laboratory 
 Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase 
[SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic 
transaminase [SGPT]) ≤ 1.5 x ULN for age and gender. If initial test of ALT or 
AST is > 1.5 x ULN, one repeat test is allowed during Screening. Please see the 
reference ranges of the central laboratory 
 Total bilirubin ≤ 2 mg/dL (≤ 34 µmol/L). If initial test result is > 2 mg/dL, one 
repeat test is allowed during the Screening period 
 Hemoglobin (Hb) 
Age (years) 
Males (g/dL) 
Females (g/dL) 
6-11  
10.0 – 15.0 
10.0 – 15.0 
12-18  
11.0 – 16.5 
10.5 – 15.5 
12. All females of childbearing potential (FCBP) must either practice abstinence* from 
heterosexual contact or use one of the approved contraceptive options as described below 
while on apremilast and during any dose interruption, and for at least 28 days after 
administration of the last dose of apremilast. For the purpose of this study, a female 
subject is considered of childbearing potential if she is ≥ 12 years old or has reached 
menarche, whichever occurred first. 
At the time of study entry, and at any time during the study when a female subject of 
childbearing potential’s contraceptive measures or ability to become pregnant changes, 
the Investigator will educate the subject regarding abstinence or contraception options 
and the correct and consistent use of effective contraceptive methods in order to 
successfully prevent pregnancy. 
Females of childbearing potential must have a negative pregnancy test at Screening and 
Baseline. All 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 
(for example, birth control pills, intravaginal ring, transdermal patch, injection, implant); 
intrauterine device (IUD); tubal ligation; or partner’s vasectomy. 
OR 
Option 2: Male or female 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. 
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 


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+ If a female subject is a FCBP when entering the study, the 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). 
 
 


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4.3. 
Exclusion Criteria 
The presence of any of the following will exclude a subject from enrollment: 
1. Other than psoriasis, history of any clinically significant (as determined by the 
Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, 
hematologic, immunologic disease, or other major uncontrolled disease. 
2. Any condition, including the presence of laboratory abnormalities, or psychiatric illness, 
that would place the subject at unacceptable risk if he/she were to participate in the study 
3. Any condition that confounds the ability to interpret data from the study. 
4. Evidence of skin conditions, other than psoriasis, that would interfere with clinical 
assessments 
5. Pregnant or breastfeeding 
6. Guttate, erythrodermic, or pustular psoriasis at Screening and Baseline 
7. Psoriasis flare or rebound within 4 weeks prior to Screening 
8. Positive Hepatitis B surface antigen, or anti-hepatitis C antibody, at Screening 
9. History of positive human immunodeficiency virus infection (HIV), congenital and 
acquired immunodeficiencies (eg, common variable immunodeficiency, immunoglobulin 
A deficiency) 
10. Active tuberculosis (TB) or a history of incompletely treated TB 
11. History of recurrent significant infections 
12. Active infection or infection treated with antibiotic treatment within 2 weeks of first dose 
13. Any history of or active malignancy 
14. History of allergy/intolerance to any component of the investigational product, ie, 
apremilast, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, hypromellose 15cP, titanium dioxide, polydextrose food chemical 
color, talc, maltodextrin, medium chain triglycerides, iron oxide red, iron oxide yellow, 
and iron oxide black. 
15. Deficiencies in lactose metabolism, ie, galactose-1-phosphate uridylyltransferase, 
UDP-galactose 4-epimerase, galactokinase or Fanconi Bickel syndrome, including 
congenital lactase deficiencies, and glucose-galactose malabsorption. 
16. Prior history of suicide attempt at any time in the subject’s lifetime prior to Screening or 
randomization in the study, or major psychiatric illness requiring hospitalization within 
3 years prior to signing the assent and informed consent 
17. Answer “Yes” to any question on the Columbia-Suicide Severity Rating Scale during 
Screening or at Baseline 
18. Current or planned concurrent use of the following therapies that may have a possible 
effect on psoriasis 


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a. Topical therapy within 2 weeks prior to randomization (including but not limited 
to topical corticosteroids, topical retinoid or vitamin D analog preparations, 
tacrolimus, pimecrolimus, or anthralin/dithranol) 
Exceptions*: 
i. 
Low potency or weak corticosteroids (please refer to the 
Investigators’ Manual) will be allowed as background therapy for 
treatment of the face, axillae and groin in accordance with 
manufacturer’s suggested usage 
ii. 
Unmedicated skin moisturizer (eg, Eucerin®) will also be permitted 
for body lesions  
*Subjects should not use these topical treatments within 24 hours prior to the clinic visit. 
 
b. Conventional systemic therapy for psoriasis within 4 weeks prior to 
randomization (including but not limited to cyclosporine, corticosteroids, 
methotrexate, oral retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, 
sulfasalazine, azathioprine, and fumaric acid esters) 
c. Phototherapy treatment (ie, ultraviolet B [UVB], PUVA) within 4 weeks prior to 
randomization 
d. Biologic therapy: 
i. 
Etanercept (or biosimilar) treatment four weeks prior to randomization 
ii. 
Adalimumab (or biosimilar) treatment ten weeks prior to randomization 
iii. 
Other TNF or IL-17 blockers (such as infliximab, certolizumab pegol, 
secukinumab, ixekizumab, brodalumab, or their biosimilars) within 
12 weeks prior to randomization 
iv. 
Anti-IL-12 or anti-IL-23 treatment (such as ustekinumab, guselkumab, or 
tildrakizumab) within 24 weeks prior to randomization 
e. Use of any investigational drug within 4 weeks prior to randomization, or 
5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer) 
19. Prolonged sun exposure or use of tanning booths or other ultraviolet (UV) light sources 
20. Children in Care: a child who has been placed under the control or protection of an 
agency, organization, institution or entity by the courts, the government or a government 
body, acting in accordance with powers conferred on them by law or regulation 
21. Prior treatment with apremilast 
 


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5. 
TABLE OF EVENTS 
Table 3: 
Table of Events 
 
Screening Baselinea 
Placebo-controlled 
Treatment Phase 
Apremilast Extension Phase 
Observational 
Follow-upb 
UNSc 
ET 
Visit Number 
1 
2  
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
Week 
-35 to 0 
(Days) 
0 
(Day 1) 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
66 
 
 
Administrative/Demographics 
Informed consent/Assentd 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion / Exclusion criteria 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographic data 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical history 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Prior / concomitant medications 
and Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior psoriasis meds/therapies 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Safety Assessments 
Adverse events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Screeninge 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) Since 
Last Visitf 
- 
X 
X 
X 
X 
X 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
- 
- 
- 
X 
X 
Complete physical examination 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X 
Abbreviated physical 
examinationg 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
Clinical laboratory evaluations 
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
X 
X 
Psoriasis flare/rebound 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 3: 
Table of Events (Continued) 
 
Screening Baselinea 
Placebo-controlled 
Treatment Phase 
Apremilast Extension Phase 
Observational 
Follow-upb 
UNSc 
ET 
Visit Number 
1 
2  
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
Week 
 -35 to 0 
(Days) 
0 
(Day 1) 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
66 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Mass Index (BMI) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Hepatitis B and C tests 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Pregnancy test and contraception 
education (FCBP only)i 
X 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Stool Diary Collectionj 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
X 
Tanner Staging Assessmentk 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X 
Clinical Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
sPGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ScPGA 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
sPGA-G 
- 
X 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X 


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Table 3: 
Table of Events (Continued) 
 
Screening Baselinea 
Placebo-controlled 
Treatment Phase 
Apremilast Extension Phase 
Observational 
Follow-upb 
UNSc 
ET 
Visit Number 
1 
2  
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
Week 
-35 to 0 
(Days) 
0 
(Day 1) 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
66 
 
 
Patient Reported Outcome 
Modified Whole Body Itch NRS 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
- 
X 
Quality of Life Assessments 
CDLQI 
- 
X 
- 
X 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
X 
- 
- 
- 
- 
X 
FDLQI 
- 
X 
- 
X 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
X 
- 
- 
- 
- 
X 
Dosing 
IP Dispensation 
 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
- 
X 
- 
Oral Dose Apremilast/placebol 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
X 
- 
IP Drug Accountability 
- 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
X 
X 
Abbreviations: ET = early termination; FCBP = females of childbearing potential; BMI = body mass index; BSA = body surface area; FCBP = females of childbearing potential; 
 UNS = unscheduled visit; sPGA = Static Physician Global Assessment; CDLQI = Children’s Dermatology Life Quality Index; FDLQI = Family 
Dermatology Life Quality Index; ScPGA = Scalp Physician Global Assessment; PASI = psoriasis area severity index; sPGA-G = Static Physician Global Assessment – Genital; 
NRS = Numeric Rating Scale; 
; IP = investigational product; ET = early termination. 
a All baseline assessments must be completed prior to randomization and dispensing of IP. Week 0 is the beginning of the Placebo-controlled Treatment Phase 
b Subjects who choose not to participate in the Long-term Study, or discontinue the study early, should return for observational follow-up visits four, eight and fourteen weeks 
after the last dose of IP. Subjects who discontinue early should be encouraged to come back for an Early Termination Visit within 4 days of last intake of IP. 
c Refer to Section 6.5.16 for details. 
d Written informed consent from subject’s legal guardian and subject assent will be obtained by the Principal Investigator or designee prior to performing any study assessments.  
e Any subject, during Screening, that answers ‘Yes’ to any question on the Columbia-Suicide Severity Rating Scale, will be ineligible for study participation and should be 
referred immediately for a psychiatric evaluation 
f Any subject that answers ‘Yes’ to any question on the Columbia-Suicide Severity Rating Scale, at any time during the study (Baseline to completion or early withdrawal) will be 
immediately withdrawn from study treatment and must be referred immediately for a psychiatric evaluation. 
g An abbreviated physical examination may be performed at the discretion of the Investigator, if clinically needed. 
h Vital signs will be obtained after the subject has been in the supine position for at least 5 minutes.   
i Serum and urine pregnancy testing will be required for FCBP at Screening.  Urine pregnancy testing will be performed at Baseline and at each visit during the Placebo-controlled 
Treatment (except Visit 3) and Apremilast Extension Phases, the Week 56, 60, and 66 Follow-up Visits (if applicable), and the early termination (ET) visit (if applicable).  If a 
urine test is positive, a serum test will be done for confirmation. 
j Subjects and their parent/guardian will complete the Stool Diary every day, beginning after the first dose of apremilast, up to the 4-week post last dose follow-up visit (Visit 17). 
Subjects continuing into the Long-term Study will submit their last entries at Visit 16.  
k Tanner Staging assessment will be performed at Baseline and Visit 16 (Week 52) or the Early Termination visit for subjects that do not complete the study. 
l IP will be administered orally twice daily from Visit 2 to Visit 16 (Week 52). IP morning dose to be taken at the study site for Visits 4, 7, and 9. 


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6. 
PROCEDURES 
The following administrative/demographic procedures will be conducted as outlined in the 
Table of Events, Section 5. 
Informed Consent and Subject Assent 
Both an age-specific assent (by the study subject) and an informed consent form (ICF) by 
subject’s legal guardian must be signed before any study-related assessments are performed. This 
process must be repeated with new signatures if a subject fails Screening for any reason and 
chooses to return and rescreen for a second attempt to meet study entrance criteria. 
Inclusion/Exclusion Criteria 
Subjects must meet all inclusion criteria (Section 4.2) and must not have any of the conditions 
specified in the exclusion criteria (Section 4.3) to qualify for participation in the study. The 
subject’s source documents must support his/her qualifications for the study. Inclusion and 
exclusion criteria will be assessed at Screening and Baseline. 
Demographic Data 
The demographic data will include (but not be limited to) the subject’s month and year of birth 
(or as allowed by local regulations), age, gender, and race/ethnic origin. The demographic profile 
will be recorded in the source documents and electronic case report form (eCRF). 
Medical and Disease History  
Relevant medical history, as defined in the eCRF Completion Guidelines, should be recorded. 
Disease history should include history of plaque psoriasis. 
Prior/Concomitant Medications and Procedures  
All medications and therapies (including prescription and non-prescription systemic and topical 
medications, as well as herbal supplements) taken by the subject up to 30 days prior to Visit 1 
should be recorded, including the stop dates for medications prohibited in the study, at the time 
of consent. All medications and procedures being taken by or performed on the subject at any 
time during the study must be recorded. The stop dates and reasons for discontinuation of any 
medication or therapy discontinued at any time during the study should be recorded.  
All procedures performed up to 30 days prior to Visit 1 should be recorded. 
Additional instructions can be found in the eCRF Completion Guidelines. 
Refer to Section 8 for further details regarding permitted and prohibited concomitant medications 
and procedures. 
Oral Dose of Apremilast and Placebo 
Apremilast or placebo will be administered orally twice daily. Evening doses will be 
administered approximately 12 hours after the morning dose.   


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6.1. 
Screening Period 
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 35 days prior randomization. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances. 
The Columbia-Suicide Severity Rating Scale questionnaire will be administered at this visit by 
the investigator or authorized site staff.  
Safety laboratory analyses and all assessments will be performed by the central laboratory. 
Screening laboratory values must demonstrate subject eligibility, but exclusionary results may be 
re-tested one time within the Screening window, without Amgen Medical Monitor approval.  
Subjects who fail initial Screening may re-screen one additional time for the study. 
Efficacy assessments may be performed by the investigator or qualified designee at any time 
during the Screening Visit. However, when conducting the efficacy assessments, the investigator 
or qualified designee must complete these assessments in the following order: 1) sPGA; 2) BSA; 
3) PASI.  
The following assessments will be performed at Screening as specified in the Table of Events, 
Section 5, after informed consent has been obtained: 
 Demographics (initials, month and year of birth (or as allowed by local regulations), 
age, sex, race, and ethnicity-if allowed by local regulations) 
 Review of inclusion/exclusion criteria to confirm subject eligibility 
 Prior psoriasis therapies: includes topical, systemic, and phototherapies 
 Prior and current Concomitant medications and procedures evaluation 
 Medical history (all relevant medical conditions diagnosed/ occurring prior to 
Screening should be included) 
 Complete physical exam 
 Vital signs (including blood pressure, temperature, respiratory rate and pulse) 
 Columbia-Suicide Severity Rating Scale Screening questionnaire 
 Body weight, height and BMI 
 Efficacy assessments (sPGA, BSA, and PASI)  
 Hematology and chemistry panels as well as urinalysis 
 Hepatitis B and C screening 
 Serum and urine pregnancy tests are required for all female subjects of childbearing 
potential, as defined in Section 6.5.3. Counselling about pregnancy precautions and 
the potential risks of fetal exposure 
 Adverse event assessment (begins when the subject signs the informed consent form) 


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6.2. 
Treatment Period 
The subject will begin treatment upon confirmation of eligibility. For visits within the 
Placebo-controlled Treatment Phase, the Apremilast Extension Phase, and the Observational 
Follow-up Phase, an administrative window of ± 4 days is permitted.  
During the treatment period (Placebo-controlled Treatment and Apremilast Extension Phases), 
subjects must complete the whole body itch NRS and subject questionnaires prior to any other 
study procedure being performed and in the following order when applicable: 1) whole body itch 
NRS; 2) children’s dermatological life quality index (CDLQI) and family dermatological life 
quality index (FDLQI).  The subject’s caregiver/family member may complete the FDLQI when 
not assisting the subject. The same caregiver/family member that completes the first FDLQI 
questionnaire at the Baseline visit, should complete all subsequent FDLQI questionnaires at the 
required visits. 
The Columbia Suicide Severity Rating Scale questionnaire will also be administered at treatment 
visits as designated in Table 3 by the investigator or authorized site staff. 
During the treatment period, efficacy assessments may be performed by the investigator or 
qualified designee at any time during a study visit but only after the subject has completed the 
whole body itch NRS and health-related quality of life (HRQoL) assessments, when required. 
The investigator performing efficacy assessments shall make independent observations at a given 
study visit and shall not review assessments or subject-derived data in advance of conducting the 
assessments. When conducting the efficacy assessments, the investigator must complete these 
assessments in the following order when applicable: 1) sPGA; 2) BSA; 3) PASI; 4) scalp 
physician global assessment (ScPGA); 5) modified static physician global assessment-genital 
(sPGA-G).  
The following evaluations will be performed at the frequency specified in the Table of Events, 
Section 5. 
 Whole body itch NRS, CDLQI, and FDLQI – Patient reported outcomes and Health-
related quality of life (HRQoL)  
 Concomitant medications and procedures evaluation 
 Physical examination (abbreviated from Baseline to Visit 15 and complete exam at 
Visit 16) 
 Vital signs (including blood pressure, temperature, respiratory rate and pulse) 
 Body weight, height and BMI 
 Apremilast or placebo morning dose to be taken at study site for Visits 4, 7 and 9 
 Hematology and chemistry panels as well as urinalysis  


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 Columbia-Suicide Severity Rating Scale  
 Tanner Staging (Baseline and Visit 16) 
 Stool Diary review (completed at home and reviewed at study visits) 
 Adverse event evaluation (continuously) 
 Psoriasis flare/rebound assessment 
 Efficacy assessments (sPGA, PASI, BSA, ScPGA, sPGA-G)  
 Investigational product dispensation and accountability 
 Urine pregnancy test is required at Baseline for all female subjects of childbearing 
potential as defined in Section 6.5.3. Counselling about pregnancy precautions and 
the potential risks of fetal exposure. 
6.2.1. 
End of Treatment 
An Early Termination visit 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 Investigator should make every attempt possible to have the subject evaluated at the 
Early Termination Visit within 4 days of the last intake of IP. 
At the Early Termination Visit, subjects must complete the whole body itch NRS and subject 
questionnaires prior to any other study procedure being performed and in the following order 
when applicable: 1) Modified Whole body itch NRS; 2) CDLQI and FDLQI. The subject’s 
caregiver/family member may complete the FDLQI when not assisting the subject. The same 
caregiver/family member that completes the first FDLQI questionnaire at the Baseline visit, 
should complete all subsequent FDLQI questionnaires at the required visits. 
The Columbia Suicide Severity Rating Scale questionnaire will also be administered at this visit 
by the investigator or authorized site staff. 
During the end of treatment visit, efficacy assessments may be performed by the investigator or 
qualified designee at any time during the study visit. The investigator performing efficacy 
assessments shall make independent observations at this study visit and shall not review 
assessments or subject-derived data in advance of conducting the assessments. When conducting 
the efficacy assessments, the investigator must complete these assessments in the following order 
when applicable: 1) sPGA; 2) BSA; 3) PASI; 4) ScPGA; 5) sPGA-G. 
The following evaluations will be performed as specified in the Table of Events, Section 5: 
 Modified Whole body itch NRS, CDLQI, and FDLQI – Patient reported outcomes 
and Health-related quality of life (HRQoL)   
 Concomitant medications and procedures evaluation 
 Physical examination (complete) 
 Vital signs including height and weight 
 Body Mass Index (BMI) 
 Hematology and chemistry panels as well as urinalysis  


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 Columbia-Suicide Severity Rating Scale  
 Tanner Staging 
 Stool Diary collection (completed at home and reviewed at study visits) 
 Adverse eventevaluation (continuously) 
 Psoriasis flare/rebound assessment 
 Efficacy assessments (sPGA, PASI, BSA, ScPGA, sPGA-G)  
 Investigational product accountability 
 Urine pregnancy test required for all females of child bearing potential as defined in 
Section 6.5.3. Counselling about pregnancy precautions and the potential risks of fetal 
exposure. 
6.3. 
Observational Follow-up Period  
6.3.1. 
Observational Follow-up 
All subjects that complete Week 52 treatment and opt not to continue into the Long-term Study 
or discontinue treatment early, will be followed for 98 days (14 weeks) after the last dose of IP 
for AE reporting, as well as any serious adverse events (SAEs) made known to the Investigator 
at any time following the protocol-required reporting period or end of study-as described in 
Section 10.1. The follow up period consists of three visits, one 4 weeks after last dose of IP, one 
8 weeks after last dose of IP, and one 14 weeks after the last dose of IP.  
During the follow-up period, efficacy assessments may be performed by the investigator or 
qualified designee at any time during a study visit. 
The following evaluations will be performed at all three Observational Follow-up Visits as 
specified in the Table of Events, Section 5. 
 Concomitant medications and procedures evaluation 
 Physical examination (abbreviated) 
 Vital signs 
 Height and weight  
 Hematology panel (only at 4-week post-last dose follow-up visit) 
 Chemistry panel (only at 4-week post-last dose follow-up visit) 
 Urinalysis (only at 4-week post-last dose follow-up visit) 
 Stool Diary collection (only at 4-week post-last dose follow-up visit) 
 Adverse event evaluation (continuously) 
 Efficacy assessments (sPGA, PASI, BSA, ScPGA)  
 Urine pregnancy test required for all females of child bearing potential as defined in 
Section 6.5.3. 


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 Psoriasis flare/rebound assessments 
6.4. 
Efficacy Assessments  
The following assessments, when applicable, will be conducted as outlined in the Table of 
Events, Section 5: 
 Static Physician Global Assessment (sPGA) 
The sPGA is the assessment by the Investigator of the overall disease severity at the time 
of evaluation. The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), 
incorporating an assessment of the severity of the three primary signs of the disease: 
erythema, scaling and plaque elevation. When making the assessment of overall severity, 
the Investigator should factor in areas that have already been cleared (ie, have scores of 0 
and not just evaluate remaining lesions for severity, ie, the severity of each sign is 
averaged across all areas of involvement, including cleared lesions. 
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 details in 
Appendix B. 
 Psoriasis Area Severity Index (PASI) 
The PASI is a measure of psoriatic disease severity taking into account qualitative lesion 
characteristics (erythema, thickness, and scaling) and degree of skin surface area 
involvement on defined anatomical regions. The PASI is a validated instrument that has 
become standard in clinical trials for psoriasis. 
The PASI scores range from 0 to 72, with higher scores reflecting greater disease severity 
(Frederiksson, 1978). Erythema, thickness, and scaling are scored on a scale of 0 (none) 
to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower 
limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 
(no involvement) to 6 (90% to 100% involvement). The total qualitative score (sum of 
erythema, thickness, and scaling scores) is multiplied by the degree of involvement for 
each anatomic region and then multiplied by the degree of involvement for each anatomic 
region and then multiplied by a constant. These values for each anatomic region are 
summed to yield the PASI score. See details in Appendix C. 
 Body Surface Area (BSA) 
BSA is a measurement of involved skin. The overall BSA affected by psoriasis is 
estimated based on the palm area of the subject’s hand, which equates to approximately 
1% of total body surface area. 
 Scalp Physician Global Assessment (ScPGA) 
The ScPGA is the Investigator’s assessment of severity of psoriasis of the scalp, if 
present at baseline. 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. See details in Appendix D.  


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 Modified Static Physician Global Assessment of Genitalia (sPGA-G) 
The sPGA-G is the Investigator’s assessment of severity of psoriasis of the genitals, if 
present at baseline. See details in Appendix E. 
6.5. 
Safety Assessments 
6.5.1. 
Adverse Events 
Safety assessments will be performed as outlined in the Table of Events, Section 5. 
Details of AE reporting can be found in Section 10.  All AEs will be monitored and recorded 
from the time the subject signs the ICF until 98 days (14 weeks) after the last dose of 
investigational product for subjects that discontinue the study early or opt not to continue into the 
long-term study.  Any Serious adverse events (SAEs) made known to the Investigator at any time 
will be monitored, recorded and reported following the protocol-required reporting period or 
after the end of study. 
6.5.2. 
Contraception Education 
There are no adequate and well controlled studies of apremilast in pregnant women. 
All females of childbearing potential (FCBP) must practice abstinence or use one of the 
approved contraceptive options as described in Section 4.2 while on investigational product and 
for at least 28 days after administration of the last dose of the investigational product. If a female 
subject is considered a FCBP when entering the study, the chosen form of contraception must be 
effective by the time the female subject is randomized in to the study (for example, hormonal 
contraception should be initiated at least 28 days before randomization). 
When a female subject of childbearing potential’s contraceptive measures or ability to become 
pregnant changes at the time of study entry or at any time during the study, the Investigator will 
educate the subject regarding options, including abstinence, and the correct and consistent use of 
effective contraceptive methods in order to successfully prevent pregnancy. 
More information regarding the effects of apremilast on reproduction in animal and in vitro 
studies can be found in the Investigator’s Brochure. 
6.5.3. 
Serum and Urine Pregnancy Tests for Females of Childbearing Potential 
A serum pregnancy test with a sensitivity of ≤ 25 mI U/mL will be required for all FCBP at 
Screening and as confirmation of any positive urine test.  Urine pregnancy testing will be 
performed on all FCBP at Screening, Baseline, and at each visit, except Visit 3, during the 
Placebo-controlled and Apremilast Extension Phases as well as at the 4, 8 and 14 week post-last-
dose follow-up visits (Early Termination Visit as well if applicable). A urine pregnancy test kit 
will be provided by the central laboratory. Pregnancy testing should be performed if the FCBP 
has missed a menstrual period or the contraception method has changed.  
For the purposes of this study, a female subject is considered of childbearing potential if she is 
≥ 12 years old or has reached menarche, whichever occurred first. 


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6.5.4. 
Complete Physical Exam 
A complete physical examination includes evaluations of general appearance, skin, nasal 
cavities, eyes, ears, lymph nodes, and respiratory, cardiovascular, GI, neurological, and 
musculoskeletal systems will be performed at Screening and the Week 52 visit or any early 
termination visit. 
6.5.5. 
Abbreviated Physical Exam 
An abbreviated physical examination includes evaluation of the general appearance, respiratory, 
cardiovascular and GI systems may be performed at any visit after Screening at the discretion of 
the investigator, if clinically needed. 
6.5.6. 
Hepatitis B and C Testing 
Hepatitis testing will be performed at Screening and will include hepatitis B surface antigen and 
hepatitis C antibody. 
6.5.7. 
Vital Signs, Height, Weight and Body Mass Index 
Vital signs, including temperature, respiratory rate, pulse, and blood pressure, will be taken 
during the visits indicated in the Table of Events (Section 5).  Vital signs will be obtained after 
the subject has been in the supine position for at least 5 minutes. Height (using stadiometer) and 
weight and body mass index will be measured and recorded at Screening and then as indicated in 
the Table of Events (Section 5). 
Blood pressure will be obtained after the subject has been in the supine position for at least 
5 minutes. Since drinking hot or cold beverages (including water) has a significant impact on 
recorded oral body temperature, no beverages should be ingested within 15 minutes when using 
an oral thermometer. 
Investigators are to report any clinically significant abnormal findings as AEs. 
6.5.8. 
Clinical Laboratory Evaluations 
A central laboratory will be used for this study.  Clinical laboratory evaluations will be 
performed as indicated in the Table of Events (Section 5). The Principal Investigator (PI) or 
medically-qualified designee will review and assess all clinical laboratory data. The laboratory 
reports should be initialed and dated by the PI or medically-qualified designee, and the clinical or 
nonclinical significance of any abnormal laboratory results should be indicated. Abnormal 
laboratory results may be repeated to rule out laboratory errors. Any clinically significant 
abnormal laboratory result should be reported as an AE and should be followed to resolution 
(ie, stabilizes, returns to baseline or becomes clinically insignificant). 
Additional clinical safety laboratory evaluations should be performed if judged clinically 
appropriate by the Investigator or by a medically qualified designee, or if the ongoing review of 
the data suggests a more detailed assessment of clinical laboratory safety evaluations is 
warranted. 
The amount of blood taken from subjects at each visit and cumulatively over the course of the 
entire study is within the safety limits as described in a bulletin published by the World Health 


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Organization (WHO). (Howie, 2011). The volume of blood drawn will not exceed 11 mL at any 
visit. 
6.5.9. 
Hematology 
Hematology laboratory evaluations will include red blood cells (RBCs), hemoglobin, hematocrit, 
white blood cells (WBCs), absolute and differential and platelet count. Approximately 2 mL of 
blood will be taken to complete hematology evaluations at each visit as designated in Table 3. 
An additional 5 mL of blood will be collected at the Screening visit to screen for hepatitis.  
6.5.10. 
Serum Chemistry 
Serum chemistry laboratory evaluations will include sodium, potassium, chloride, carbon 
dioxide, calcium, blood urea nitrogen, creatinine, glucose, albumin, total protein, alkaline 
phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase (AST/SGOT), alanine aminotransferase/serum glutamate pyruvic transaminase 
(ALT/SGPT), gamma-glutamyl transpeptidase, lactate dehydrogenase, phosphate, and 
magnesium. Approximately 3.5 mL of blood will be taken to complete serum chemistry 
evaluations at each visit as designated in Table 3. 
6.5.11. 
Urinalysis 
Urinalysis will include specific gravity, pH, glucose, protein, ketones, and hemoglobin/blood. A 
microscopic examination (eg, casts, RBCs, and WBCs) will be performed in the event of a 
positive result. 
6.5.12. 
Psychiatric Evaluation 
Psoriasis has been associated with an increased risk of developing psychiatric disorders, 
including depression and anxiety in pediatric patients (Kimball, 2012). Apremilast prescriber 
information (eg, Summary of Product Characteristics, Package Insert) includes a warning 
regarding depression and suicidal thoughts. The investigators should advise subjects, their 
caregivers, and families of the need to be alert for the emergence or worsening of depression or 
other mood changes, and if such changes occur, to contact the investigator.  
All subjects will complete the Columbia-Suicide Severity Rating Scale (C-SSRS) (Appendix F) 
assessment. This questionnaire is suitable for assessment of suicidal ideation and behavior in 
clinical and research settings (Posner, 2011). Any subject, during Screening or at Baseline, that 
answers ‘Yes’ to any question on the C-SSRS, will be ineligible for study participation and 
should be referred immediately for a psychiatric evaluation. 
During the study (post Baseline), each subject will complete an additional C-SSRS questionnaire 
at each study visit up to Week 16 and then approximately every other visit thereafter. Any 
subject that answers ‘Yes’ to any question on the C-SSRS at any time during the study will be 
immediately withdrawn from study treatment and must be referred immediately for a psychiatric 
evaluation. The subject should return for the Observational Follow-up Visits at four, eight and 
fourteen weeks after Early Termination. 
A copy of the psychiatric evaluation report, if available, should be in the subject’s source 
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6.5.13. 
Stool Diary 
Diarrhea is the passage of three or more watery/liquid stools per day (WHO, 2017).  
Subjects and their parent/guardian will be supplied with diaries (either paper or electronic) that 
will be filled out daily to record and describe any diarrhea, including duration, frequency, and 
associated symptoms (Appendix G). Subjects and their parent/guardian will complete the Stool 
Diary every day beginning after the first dose of apremilast, up to the 4-week post last dose 
Observational Follow-up visit (Visit 17). The investigator will review diary entries with the 
subject and his/her caregiver at each study visit. 
6.5.14. 
Tanner Staging 
Assessments of sexual maturity (Tanner Staging) will be performed at Baseline and Week 52 
(Visit 16) or the Early Termination visit for subjects that do not complete the study. A 
description of each Tanner stage is provided in Appendix H (WHO, 2010). 
6.5.15. 
 Worsening of Psoriasis and Rebound Assessments 
Psoriasis flare is an AE (and will be recorded as an AE) and represents an atypical or unusual 
worsening of disease during treatment (Carey, 2006). It is defined as a sudden intensification of 
psoriasis requiring medical intervention or a diagnosis of new generalized erythrodermic, 
inflammatory, or pustular psoriasis. A more typical, gradual worsening of plaque psoriasis will 
not to be recorded as an AE. 
Rebound is an AE and is defined as a severe and sudden worsening of disease that occurs after 
treatment had been discontinued. This exacerbation is characterized by a PASI ≥ 125% of 
baseline or a new generalized pustular, erythrodermic, or more inflammatory psoriasis after 
stopping therapy (Gordon, 2005). 
6.5.16. 
Unscheduled Visits 
Unscheduled visits may be necessary during the course of the study to capture a subject’s status 
between regularly scheduled visits. Examples include, but are not limited to, a worsening of 
psoriasis symptoms, occurrence of an AE, or follow-up to a previously reported AE. 
The following assessments will be performed at these visits: 
 Assess vital signs (temperature, respiratory rate, pulse, and blood pressure) and weight 
 Record concomitant medications/procedures and AEs 
 Drug accountability and dispensation if needed 
 sPGA and PASI 
 Psoriasis flare/rebound 
 C-SSRS questionnaire 
The following assessments may also be performed at the discretion of the Investigator, if 
clinically needed: 
 Obtain blood sample and/or urine sample for any necessary laboratory test indicated in 
the Table of Events (Table 3) 


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 Perform abbreviated physical examination 
6.6. 
Pharmacokinetics 
All enrolled subjects who take at least one dose of apremilast should have one blood specimen 
drawn at four visits (Weeks 4, 8, 16, and 24) for measurement of apremilast in plasma. A small 
amount of blood (approximately 2 mL) will be drawn before the morning apremilast dose at 
Weeks 4, 16, and 24. The Week 8 blood specimen, also approximately 2 mL, will be drawn at 
least 30 minutes after the morning apremilast dose. The evaluable PK data from 
CC-10004-PPSO-003 will be pooled with those from CC-10004-PPSO-001 and the studies in 
adults with moderate-to-severe plaque-type psoriasis for the population PK analysis. 
The blood samples will be taken through an indwelling venous cannula by direct venipuncture at 
the following nominal times shown in Table 4. Concentrations of apremilast in plasma will be 
measured using a validated liquid chromatography tandem mass spectrometry assay.  
Table 4: 
Acceptable Time Windows for Pharmacokinetic Blood Sampling 
Scheduled PK Blood Draw Time 
Acceptable Time Window 
Pre-dose (Weeks 4, 16, and 24) 
Within 60 minutes prior to dosing 
Post-dose (Week 8) 
At least 30 minutes post-dose 
The date and time of the last evening dose (for pre-dose blood draw) on the day prior to the 
clinical visit and the current morning dose (for post-dose blood draw) on the day of visit will be 
recorded in the source documents and eCRF. Actual PK blood sample collection date and time 
will also be recorded in the source documents and eCRF. Explanations should be provided in the 
source documents and eCRF for missed or mishandled samples and for samples collected outside 
the acceptable time window as described in Table 4. Specific details regarding collection, 
handling, processing, storage, and shipment of PK samples can be found in Appendix I. 
6.7. 
Biomarkers, Pharmacodynamics, Pharmacogenomics  
 Pharmacodynamic Peripheral Blood RNA Gene Expression 
PDE4 is highly overexpressed in the peripheral blood of a subset of psoriasis patients (Schafer, 
2016). Furthermore, apremilast has been found to reduce Th17 and Th22 cytokine expression in 
the lesional skin and peripheral blood of psoriasis patients (Gottlieb, 2013; Krueger, 2016). By 
optional consent, peripheral blood (approximately 2.5 mL) will be drawn to measure RNA 
expression at baseline and during the treatment period. 
Whole blood will be used for the analysis. The expression of specific RNAs, such as but not 
limited to PDE4A, PDE4B, PDE4C, PDE4D, IL17A, IL17F, IL22, and TNF-α, will be analyzed 
at Baseline (Week 0) and during the Placebo-controlled Treatment Phase at Week 16. These data 
will further define the mechanism of action of apremilast in this patient population, and may 
inform on the subset of patients who are responding well to apremilast treatment. 
 Pharmacogenetic DNA Analysis 
By optional consent, a buccal swab will be collected at Visit 2 (Baseline Visit; day of 
randomization) for the purposes of analyzing the genetic polymorphisms that are associated with 


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clinical and pharmacodynamic interaction with apremilast. Deoxyribonucleic acid (DNA) will be 
examined for the presence of polymorphisms in the genes encoding the targets of apremilast 
(PDE4A, PDE4B, PDE4C, and PDE4D), and in genes associated with psoriasis, including but 
not limited to HLA-Cw6, TNF-α, LCE3B/3C, IL12B, IL23A, IL23R, LCE, TNIP1, IFHIH1, and 
NFKBIA. Subjects at selected sites will have the option to participate in the Pharmacogenetic 
Analysis sub-study and must sign a separate consent form specific to the Pharmacogenetic 
Analysis sub-study at Visit 1 (Screening Visit). Detailed instructions for sample preparation and 
handling will be contained in the separate laboratory manual prepared for the sites. 
 Skin Microbiome Analysis 
By optional consent, the microbial species (bacterial and fungal) present on the patients’ skin 
will be assessed by swabbing the affected and unaffected skin and subjected the swabbed 
material to 16S and ITS ribosomal RNA gene amplification and sequencing. Affected and 
unaffected skin will be analyzed at Baseline (Week 0) and during the Placebo-controlled 
Treatment Phase at Week 16. 
6.8. 
Subject Reported Outcomes or Health Related Quality of Life 
 Children’s Dermatology Life Quality Index (CDLQI) 
The CDLQI is designed to measure the impact of skin disease on children’s quality of 
life. It is a self-explanatory questionnaire that can be handed to the subject to fill out with 
the help of a parent or guardian, See details in Appendix J. 
 Family Dermatology Life Quality Index (FDLQI) 
This is a self-explanatory questionnaire designed for adults (more than 16 years of age), 
that must be handed to a subject’s caregiver/family member for completion. The FDLQI 
will assess the impact of skin disease experienced by a family member. See details in 
Appendix K. 
 Modified Whole Body Itch Numeric Rating Scale (NRS)  
The pruritus NRS whole body assessment is a tool designed to measure the amount of 
whole body itch due to psoriasis in the previous 24-hour period by circling a number on a 
scale from 0 to 10. See details in Appendix L. 
 


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7. 
DESCRIPTION OF STUDY TREATMENTS 
7.1. 
Description of Investigational Product 
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].  
Investigational product will be provided in blister cards and bottles, depending on the phase of 
the study. Apremilast will be provided as 10, 20, and 30 mg tablets. Placebo will be provided as 
identically appearing 10, 20, and 30 mg tablets. Investigational product will be taken orally twice 
daily, approximately 12 hours apart, without restriction of food or drink. To reduce potential 
gastrointestinal (GI) symptoms, dose titration will be implemented during Week 0 and Week 16 
of this study (see Table 5). 
7.2. 
Treatment Administration and Schedule 
At Visit 2 (Week 0), subjects who meet entry criteria will be randomized using a permuted block 
randomization in parallel 2:1 to receive either apremilast or placebo treatment, using a 
centralized IRT. Randomization to apremilast arm or placebo arm will be stratified by baseline 
age group (6 to 11 years or 12 to 17 years). Subjects with baseline weight between 20 kg to 
< 50 kg will receive apremilast 20 mg BID or placebo BID and subjects with baseline weight 
≥ 50 kg will receive apremilast 30 mg BID or placebo BID.   
During Week 0 visit, subjects will be dispensed dose titration blister cards with 10, 20, and 
30 mg apremilast tablets, depending on baseline weight, or identically appearing placebo tablets. 
The blister cards will contain all IP required for 4 weeks of treatment, and the titration supplies 
or matching placebo are in the 1st week (see Table 5 Treatment Schema for Dose Titration at 
Visit 2 [Week 0]). Investigational product will be administered as indicated below: 
 Weeks 0 to 16: Placebo-controlled Treatment Phase: Apremilast 20 mg BID, 
Apremilast 30 mg BID or placebo BID. 
 Week 0: subjects will be dose titrated as described in Table 5.  
 Weeks 16 to 52: Apremilast Extension Phase: Apremilast 20 mg BID and apremilast 
30 mg BID. 
 Week 16: subjects will be dose titrated as described in Table 6. 
 
 


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Table 5: 
Treatment Schema for Dose Titration at Visit 2 (Week 0) 
 
Week 0 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6-7 
 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Apremilast 30 
mg BID 
10 mg A 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg A 
20 mg P 
30 mg P 
10 mg P 
20 mg A 
30 mg P 
 
20 mg A 
30 mg P 
 
20 mg A 
30 mg P 
 
20 mg A 
30 mg P 
 
20 mg P 
30 mg A 
 
 
30 mg A 
 
 
30 mg A 
Placebo (30 mg) 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
10 mg P 
20 mg P 
30 mg P 
 
20 mg P 
30 mg P 
 
20 mg P 
30 mg P 
 
20 mg P 
30 mg P 
 
20 mg P 
30 mg P 
 
 
30 mg P 
 
 
30 mg P 
Apremilast 20 
mg BID 
 
10 mg A 
20 mg P 
 
10 mg P 
20 mg P 
 
10 mg A 
20 mg P 
 
10 mg A 
20 mg P 
 
10 mg A 
20 mg P 
 
10 mg P 
20 mg A 
 
 
20 mg A 
 
 
20 mg A 
 
 
20 mg A 
 
 
20 mg A 
 
 
20 mg A 
 
 
20 mg A 
Placebo (20 mg) 
 
10 mg P 
20 mg P 
 
10 mg P 
20 mg P 
 
10 mg P 
20 mg P 
 
10 mg P 
20 mg P 
 
10 mg P 
20 mg P 
 
10 mg P 
20 mg P 
 
 
20 mg P 
 
 
20 mg P 
 
 
20 mg P 
 
 
20 mg P 
 
 
20 mg P 
 
 
20 mg P 
A=Apremilast; BID= twice daily; P= Placebo. 
 
At Week 16, subjects who were originally randomized to placebo at Week 0 will be switched to receive apremilast treatment, where 
dose levels (either 20 mg BID or 30 mg BID) would have been determined at Week 0 using their baseline weight categories (20 kg to 
< 50 kg, or ≥ 50 kg). Subjects randomized to the apremilast arm at Week 0 will remain on their assigned apremilast dose levels (either 
20 mg BID or 30 mg BID). 
During Weeks 16 to 52, study investigators and study subjects will remain blinded to the initial IP assignments. To maintain the blind, 
all subjects will receive dose titration cards at the Week 16 visit. Although only subjects initially randomized to placebo will be dose 
titrated during their first week of the Apremilast Extension Phase, all subjects entering the Apremilast Extension Phase will receive 
identically-appearing titration/treatment cards. The treatment schema for dose titration at Week 16 is shown in the tables below. 
 


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


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Investigational product will be taken orally twice daily, approximately 12 hours apart, without 
restriction of food or drink. To reduce potential gastrointestinal (GI) symptoms, dose titration 
will be implemented in this study (Table 5 and Table 6). Apremilast dose titration will be 
provided in blister cards as 10, 20, and 30 mg tablets or identically appearing placebo tablets. 
Blister card configurations are pictured in Appendix M. The Apremilast Extension Phase begins 
with a titration period where IP will be supplied in blister cards. After completion of the 
Apremilast Extension Phase titration period, IP will be distributed in bottles containing 20 or 
30 mg tablets for the remainder of the study. 
7.3. 
Overdose 
Overdose, as defined for this protocol, applies to protocol-required dosing of the investigational 
products 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 (ie, placebo), hence overdose definition will apply to only 
apremilast (or matching placebo). Other required or optional non-IP intended for prophylaxis of 
certain side effects, etc, are excluded from this definition.  
Overdose for this protocol, on a per dose basis, is defined as ingestion of greater than 100 mg of 
apremilast (or matching placebo) tablets in any 24-hour period whether by accident or 
intentionally. On a schedule or frequency basis, an overdose is defined as dosing more than 
4 times during any 24-hour period. 
7.4. 
Method of Treatment Assignment 
At Visit 2 (Week 0), subjects who meet entry criteria will be randomized to receive either 
apremilast or placebo (2:1), using a centralized interactive response technology (IRT). 
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 IRT will assign a randomization identification number. 
Confirmation of the randomization will be sent to the investigational site, Amgen, and/or its 
representative. The confirmation reports should be maintained as source documents.  
During the study visits, the pharmacy or authorized study personnel at the investigational site 
will dispense coded IP kits in accordance with the randomization number assigned by the IRT. 
7.5. 
Packaging and Labeling 
The label(s) for IP may include, but may not be limited to, 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. 


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7.6. 
Investigational Product Accountability and Disposal  
The Investigator(s) or a qualified designee(s) is/are responsible for taking an inventory of each 
shipment of apremilast received, and comparing it with the accompanying apremilast 
accountability form. The Investigator(s) or designee(s), will verify the accuracy of the 
information on the form, sign and date it, retain a copy in the study file, and record the 
information in the IRT. 
At the study site, all apremilast will be stored in a secure, locked area to prevent unauthorized 
access.  Investigational product must be stored as directed on the label(s). 
The Investigator(s) or qualified designee(s) is responsible for the accountability of all apremilast 
issued to the site during the course of the study.  
Amgen (or designee) will review with the Investigator and relevant site personnel the process for 
apremilast return, disposal, and/or destruction including responsibilities for the site versus 
Amgen (or designee). 
7.7. 
Investigational Product Compliance 
All doses administered in the clinic will be administered under direct supervision of trained staff. 
The individual(s) responsible for dosing will check the subject’s mouth to ensure that the tablet 
has been swallowed whole (ie, not chewed or crushed). 
The study staff will maintain an ongoing record of the dispensing and administration of 
apremilast for each subject via an accountability record or equivalent document that will be 
verified by Amgen’s study monitor. 
For apremilast dispensed to the subject/guardian for outpatient administration, study personnel 
will review the instructions printed on the package with the study subject and/or legal guardian 
prior to dispensing apremilast in tablet form. Investigational product will be dispensed as noted 
in the Table of Events, Section 5. The subjects will be instructed to return the apremilast blister 
cards and bottles, including any unused medication, to the study site at each visit for tablet 
counts and reconciliation. Subjects will be asked whether they have taken their apremilast as 
instructed at each study visit. Any problems with apremilast compliance will be reviewed with 
the subject. If a subject misses four 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. 
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. Overall 
compliance with the study treatment regimen is defined as taking between 75% and 120% of the 
expected doses during a subject’s participation while in the treatment phases (Placebo-controlled 
Treatment Phase and Apremilast Extension Phase) of the study. 
Accurate recording of all apremilast administration (including dispensing and dosing) will be 
made in the appropriate section of the subject’s eCRF and source documents. 


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8. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression.  
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigators Brochure and/or local package insert. 
8.1. 
Permitted Concomitant Medications and Procedures 
Subjects may take any medication that is not restricted by the protocol, is not expected to 
interfere with the conduct of the study and will not affect study assessments. Chronic medication 
should be dosed on a stable regimen and continued through the 36-week Apremilast Extension 
Phase. 
All medications (prescription and non-prescription), treatments and therapies taken by the 
subject from Screening throughout the Placebo-controlled Treatment Phase and Apremilast 
Extension Phase and the 4-, 8-, and 14-week follow-up periods, including those initiated within 
30 days prior to the start of the study, must be recorded on the subject’s source document and on 
the appropriate page of the eCRF. The name of the medication/treatment, dose, unit, frequency, 
route, indication, the date the medication was started and the date the medication was stopped (if 
not ongoing) must be recorded. The recording of any permitted topical medications taken for 
psoriasis should also include the area of the body to which they are applied. 
The following topical therapy will be permitted*: 
 Low-potency or weak corticosteroids (such as hydrocortisone, desonide, alclometasone 
dipropionate) will be allowed as background therapy for treatment of the face, axillae, 
and groin in accordance with the manufacturers’ suggested usage during the course of the 
study. 
 An unmedicated skin moisturizer (eg, Eucerin®) will also be permitted for body lesions 
only 
* Subjects should not use these topical treatments within 24 hours of a study visit. 
From Week 8 through Week 16, subjects who meet the criteria for early escape (PASI increase 
≥ 50% from baseline) will be allowed to commence treatment with moderate-to-high potency 
topical steroid preparations and continue receiving IP. 
At Week 32, subjects who did not achieve a 50% improvement in psoriasis area severity index 
(PASI-50) from baseline, can add topical standard of care therapy and continue to receive 
apremilast.  
8.2. 
Prohibited Concomitant Medications and Procedures 
The following psoriasis medications cannot be administered while subjects are receiving study 
medication: 
 Topical therapy unless otherwise specified (including but not limited to topical 
corticosteroids, topical retinoid or vitamin D analog preparations, tacrolimus, 
pimecrolimus, or anthralin/dithranol. 


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 Systemic therapy including but not limited to cyclosporine, corticosteroids, methotrexate, 
oral retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, sulfasalazine, 
azathioprine, and fumaric acid esters  
 Phototherapy including UVB and PUVA 
 Biologic agents such as etanercept, infliximab, adalimumab, certolizumab pegol, 
guselkumab, tildrakizumab, ixekizumab, brodalumab, or ustekinumab  
 Use of tanning booths or other ultraviolet light sources 
 Use of an investigational drug 
Subjects who need to be treated with protocol-prohibited medication will be withdrawn from the 
study. 
8.3. 
Required Concomitant Medications and Procedures 
Not applicable. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Overview 
This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled study to assess the 
efficacy and safety of apremilast (CC-10004) in pediatric subjects from 6 through 17 years of 
age with moderate to severe plaque psoriasis. Integrated Response Technology (IRT) will be 
utilized to ensure a central randomization based on a parallel permuted block randomization 
scheme. Randomization to the apremilast arm or the placebo arm will be stratified by age group 
(6 to 11 years or 12 to 17 years), with a minimum of 75 subjects for each age group. Subjects 
randomized to apremilast will receive weight-based apremilast dose which will provide 
comparable exposure to the adult subjects treated with 30 mg BID. Therefore, the apremilast arm 
will include both 20 mg BID and 30 mg BID for the statistical analysis.  
9.2. 
Study Population Definitions 
The safety population will consist of all subjects who are randomized and received at least one 
dose of investigational product (IP). Subjects will be included in the treatment group 
corresponding to the IP they actually received. 
The intent-to-treat (ITT) population will consist of all subjects who are randomized regardless of 
whether or not the subject received IP. Subjects will be included in the treatment group to which 
they are randomized. 
The per protocol (PP) population will consist of all subjects included in the ITT population who 
receive at least one dose of IP, have both baseline and at least one post-treatment sPGA 
assessment, and have no important protocol deviations which may affect efficacy assessments in 
the Placebo-controlled Treatment Phase. 
9.3. 
Sample Size and Power Considerations 
At least 230 pediatric subjects (ages from 6 through 17 years) will be randomized to receive 
either apremilast or placebo (2:1) at Week 0. The sample size estimation is based on the results 
of the adult Phase 3 and 3b studies with apremilast (CC-10004-PSOR-008, 
CC-10004-PSOR-009 and CC-10004-PSOR-010) which demonstrated positive treatment effects 
between apremilast and placebo in the proportion of subjects achieving sPGA response and 
PASI-75 response at Week 16.  
With a total of 230 patients and a randomization ratio of 2:1, the study will have 90% power to 
detect a 15% difference (20% versus 5%) between apremilast arm and placebo arm for the 
proportion of subjects achieving sPGA response at Week 16, based on a Chi-square test at a 
two-sided significance level of 0.05. The study will also have more than 95% power to detect a 
20% difference (30% versus 10%) between apremilast and placebo for the proportion of subjects 
achieving PASI-75 response at Week 16. 
9.4. 
Background and Demographic Characteristics 
Subject’s age, height (as measured with stadiometer), weight, and baseline characteristics will be 
summarized using descriptive statistics, while sex, race and other categorical variables will be 
provided using frequency tabulations. Medical history data will be summarized using frequency 


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tabulations by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and 
preferred term. 
9.5. 
Subject Disposition 
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for the 
Placebo-controlled Treatment Phase (Weeks 0 to 16) and the Apremilast Extension Phase 
(Weeks 16 to 52). A summary of subjects enrolled by site will be provided. Protocol deviations 
and important protocol deviations will be summarized using frequency tabulations. 
9.6. 
Efficacy Analysis 
9.6.1. 
Efficacy Evaluation for the Placebo-controlled Treatment Phase (Weeks 0 to 16) 
Statistical comparisons will be made between apremilast arm and placebo arm. All statistical 
tests will be at the two-sided 0.05 significance level and the corresponding p-values will be 
reported. Data summaries will be provided for the two randomized treatment arms (apremilast 
and placebo). 
9.6.1.1. 
Primary Efficacy Endpoint 
The primary endpoint is the proportions of subjects achieving sPGA response at Week 16 
(defined as sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from 
baseline at Week 16). The estimand of primary interest is defined in terms of the following four 
attributes: 
A. The population is defined through appropriate inclusion/exclusion criteria to reflect the 
targeted patient population for approval (eg, ITT Population); 
B. The variable is the proportion of subjects who achieve sPGA response at Week 16. 
Subjects who terminate early due to lack of efficacy or add moderate-to-high potency topical 
steroid preparations (early escape) or other protocol prohibited medications prior to Week 16 
will be assigned as non-responders.  
C. Potential intercurrent events are captured through the variable definition (B). 
D. The summary measure is the difference in response proportions. 
Missing values at Week 16 for this estimand will be imputed using the multiple imputation (MI) 
method (SAS Institute Inc, 2011) based on similar subjects who remained in the study as the 
primary method. With this missing data handling approach, the estimand answers a clinically 
relevant question that compares the number of subjects who achieve the defined response criteria 
at Week 16 in the ITT population.  
The primary endpoint will be analyzed using the CMH (Cochran–Mantel–Haenszel) test 
adjusting for the stratification factor at randomization. The two-sided p-values from the CMH 
test, the adjusted treatment difference in proportion using the weighted average of the treatment 
differences across the strata with the CMH weights, along with the associated two-sided 95% CIs 
using a normal approximation to the weighted average will be provided. 


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Sensitivity analysis will be conducted to account for missing data using the last observation 
carried forward (LOCF) method, the non-responder imputation (NRI) method and the tipping 
point analyses. A sensitivity analysis using the PP population will also be performed.  
For the multiple imputation method, the SAS procedure MI will be used to impute missing sPGA 
scores at the scheduled analysis visits in the Placebo-controlled Treatment Phase (Weeks 0 to 16) 
to create M=25 complete data sets. The sPGA assessment data will not be included in multiple 
imputation steps from subjects who terminate early due to lack of efficacy or add moderate-to-
high potency topical steroid preparations (early escape) or other protocol prohibited medications 
prior to Week 16. The missing data patterns will be checked at the scheduled analysis visits, ie, 
Baseline (Week 0), and Weeks 2, 4, 8, 12 and 16. If there are non-monotone missing patterns, 
two separate imputation procedures will be used to complete the imputation process.  
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used with a single 
chain to impute missing scores by treatment and stratification factor to create M=25 imputed data 
sets with monotone missing patterns.  In case there are convergence issues, a simple model will 
be used to impute the missing scores by treatment, with further simplification by dropping both 
treatment and stratification factor in imputation model if necessary. The seed will be set to 
17813721. The imputed scores will be rounded to the nearest integer. The minimum and the 
maximum values for imputation will be 0 and 4, which correspond to the lowest and the highest 
sPGA scores.  
In the second step, the predictive mean matching method will be used to impute the remaining 
missing scores for the 25 data sets with monotone missing patterns. The imputation procedure 
will use monotone statement to create one complete data set for each of the monotone data set 
from the first step, and the variables will include treatment arm, stratification factor, and sPGA 
scores at scheduled analysis visits from Baseline to Week 16. The seed will be set to 55218163.  
After the completion of imputation, sPGA response at Week 16 will be derived based on both 
observed and imputed scores. Data from subjects who terminate early due to lack of efficacy or 
add moderate-to-high potency topical steroid preparations (early escape) or other protocol 
prohibited medications prior to Week 16 as non-responders will be added to the 25 imputed data 
sets. The same CMH method will be used to analyze the 25 complete data sets and the SAS 
procedure MIANALYZE will be used to combine the results for the statistical inferences. This 
study is a multicenter study and planned to have more than 100 study sites to enroll at least 
230 subjects. A single site may not have a sufficient number of subjects to allow a meaningful 
within-site analysis; therefore, study sites will be pooled for the analysis. The primary endpoint 
will be further analyzed adjusting for the stratification factor and the pooled site and examining 
whether the treatment differences are consistent with those from the primary analysis. In 
addition, the consistency of the treatment effect across individual study sites (or pooled sites) 
will also be assessed by performing a subgroup-type analysis with individual study sites (or 
pooled sites) treated as subgroups. Listings of response rates will be provided by individual study 
site and by pooled site. The treatment difference for each of the individual study sites (or pooled 
sites) will be reviewed to evaluate the effect among the individual study sites (or pooled sites). 
9.6.1.2. 
Major Secondary Efficacy Endpoint 
The major secondary efficacy endpoint is the proportions of subjects who achieving PASI-75 
response at Week 16 (defined as at least a 75% reduction in total PASI score from baseline at 


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Week 16), which will be analyzed using the same approaches as the primary endpoint. The 
estimand of primary interest is defined in terms of the following four attributes: 
A. The population is defined through appropriate inclusion/exclusion criteria to reflect the 
targeted patient population for approval (eg, ITT Population); 
B. The variable is the proportion of subjects who achieving PASI-75 response at Week 16. 
Subjects who terminate early due to lack of efficacy or add moderate-to-high potency topical 
steroid preparations (early escape) or other protocol prohibited medications prior to Week 16 
will be assigned as non-responders.  
C. Potential intercurrent events are captured through the variable definition (B).  
D. The summary measure is the difference in response proportions. 
Missing values at Week 16 will be imputed using the multiple imputation (MI) method (SAS 
Institute Inc, 2011) based on similar subjects who remained in the study. With this missing data 
handling approach, the estimand answers a clinically relevant question that compares the number 
of subjects who achieve the defined response criteria at Week 16 in the ITT population 
The primary analysis for this estimand will use CMH (Cochran–Mantel–Haenszel) test adjusting 
for the stratification factor at randomization. The two-sided p-values from the CMH test, the 
adjusted treatment difference in proportion using the weighted average of the treatment 
differences across the strata with the CMH weights, along with the associated two-sided 95% CIs 
using a normal approximation to the weighted average will be provided. 
Sensitivity analysis will be conducted to account for missing data using the last observation 
carried forward (LOCF) method, the NRI method, and tipping point analyses. A sensitivity 
analysis using the PP population will also be performed.  
For using the multiple imputation method, the SAS procedure MI will be used to impute missing 
total PASI scores at the scheduled analysis visits in the Placebo-controlled Treatment Phase 
(Weeks 0-16) to create M=25 complete data sets. The PASI assessment data will not be included 
in multiple imputation steps from subjects who terminate early due to lack of efficacy or who 
added moderate-to-high potency topical steroid preparations (early escape) or other protocol 
prohibited medications prior to Week 16. The missing data patterns will be checked at the 
scheduled analysis visits, ie, Baseline (Week 0), and Weeks 2, 4, 8, 12 and 16. If there are 
non-monotone missing patterns, two separate imputation procedures will be used to complete the 
imputation process.  
In the first step, the 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. In case 
there are convergence issues, a simple model will be used to impute the missing scores by 
treatment, with further simplification by dropping both treatment and stratification factor in 
imputation model if necessary. The minimum and the maximum values for imputation will be 0 
and 72, which correspond to the lowest and the highest total PASI scores. The seed will be set to 
17813721 and a single chain will be used to produce imputations. The imputed scores will be 
rounded to numbers with one digit.  
In the second step, the predictive mean matching method will be used to impute the remaining 
missing scores for the 25 data sets with monotone missing patterns. The imputation procedure 
will use monotone statement to create one complete data set for each of the monotone data set 


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from the first step, and the variables will include treatment arm, stratification factor, and total 
PASI scores at scheduled analysis visits from baseline to Week 16. The seed will be set to 
55218163.  
After the completion of imputation, PASI-75 response at Week 16 will be derived based on both 
observed and imputed scores. Data from subjects who early terminate early due to lack of 
efficacy or add moderate-to-high potency topical steroid preparations (early escape) or other 
protocol prohibited medications prior to Week 16 as non-responders will be added to the 25 
imputed data sets. The same CMH method will be used to analyze the 25 complete data sets and 
the SAS procedure MIANALYZE will be used to combine the results for the statistical 
inferences. 
The major secondary endpoint will also be further analyzed adjusting for the stratification factor 
and the pooled site and examining whether the treatment differences are consistent with those 
from the primary analysis. In addition, the consistency of the treatment effect across individual 
study sites (or pooled sites) will also be assessed by performing a subgroup-type analysis with 
individual study sites (or pooled sites) treated as subgroups. Listings of response rates will be 
provided by individual study site and by pooled site. The treatment difference for each of the 
individual study sites (or pooled sites) will be reviewed to evaluate the effect among the 
individual study sites (or pooled sites). 
9.6.1.3. 
Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints will be analyzed similarly as the primary and the 
secondary endpoints. The main analysis will be based on the ITT population with missing values 
imputed using multiple imputation methods. The 2-sided p-values and 2-sided 95% CIs will be 
reported for treatment difference between apremilast and placebo arms.  
The binary endpoint (PASI-50, CDLQI [0/1] response) will be analyzed similarly as the primary 
endpoint. The treatment difference between apremilast arm and placebo arm will be compared 
using CMH (Cochran–Mantel–Haenszel) test adjusting for the stratification factor at 
randomization. The 2-sided p-values from the CMH test, the adjusted treatment difference in 
proportion using the weighted average of the treatment differences across the strata with the 
CMH weights, along with the associated 2-sided 95% CIs using a normal approximation to the 
weighted average will be provided. Subjects who terminate early due to lack of efficacy or add 
moderate-to-high potency topical steroid preparations (early escape) or other protocol prohibited 
medications prior to Week 16 will be considered non-responders. Missing values will be imputed 
using the similar MI method as the primary and major secondary endpoints, with sensitivity 
analysis using the LOCF method and NRI method. 
The continuous endpoint (ie, PASI percent change, BSA percent change, and CDLQI change 
from baseline at Week 16) will be analyzed based on the ITT population using the analysis of 
covariance (ANCOVA) model. The ANCOVA model will use the change from baseline as the 
dependent variable and will include treatment group and stratification factor as independent 
variables and 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. Missing values at Week 16 will be imputed 
using the MI method, with sensitivity analysis using the LOCF method. The primary analysis 


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will estimate treatment effect without additional psoriasis medications, ie, data from assessments 
after adding those medications will be removed before using MI method for subjects who add 
moderate-to-high potency topical steroid preparations (early escape) or other protocol prohibited 
medications prior to Week 16. A sensitivity analysis will be performed with all available data 
using MI method regardless whether subjects add moderate-to-high potency topical steroid 
preparations (early escape) or any protocol prohibited medications prior to Week 16. 
9.6.1.4. 
Multiplicity Adjustment 
The primary and the major 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 (sPGA response at 
Week 16), if the 2-sided p-value from the comparison between apremilast arm and placebo arm 
is below 0.05, the outcome will be considered statistically significant and apremilast will be 
declared effective. For the major secondary endpoint, statistical significance will be claimed only 
if its 2-sided p-value is below 0.05 and tests for the primary endpoint is significant at the 2-sided 
0.05 level. The proposed test sequence for the primary and secondary efficacy endpoints is listed 
as the following: 
 Proportions of subjects who achieve sPGA response at Week 16 (defined as sPGA 
score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline at 
Week 16) 
 Proportion of subjects who achieve PASI-75 response at Week 16 (defined as at least 
a 75% reduction in total PASI score from baseline at Week 16) 
For the other secondary efficacy endpoints, multiplicity adjustment will not be applied and 
statistical significance will not be claimed. 
9.6.1.5. 
Exploratory Endpoints 
Descriptive summary statistics or proportion of subjects achieving specified criteria will be 
summarized by treatment group. When appropriate, exploratory endpoints at Week 16 will also 
be analyzed using CMH or ANCOVA methods similar to the primary and secondary endpoints. 
9.6.1.6. 
Subgroup Analysis 
Subgroup analyses for sPGA and PASI-75 responses at Week 16 based upon baseline 
demographic (age, gender, race, etc.) or baseline disease characteristics will be provided to 
determine the robustness of the treatment effect. These two endpoints will also be evaluated in 
patients using or not using low potency topical corticosteroids in the phase as two subgroups. 
9.6.2. 
Efficacy Evaluation – Apremilast Extension Phase (Weeks 16 to 52) 
Efficacy endpoints for time points in the Apremilast Extension Phase (Weeks 16 to 52) will be 
summarized for subjects who continue apremilast treatment or who switch to apremilast from 
placebo according to the treatment arms assigned at randomization. For all subjects, changes in 
measurements will be calculated relative to measurements obtained at Baseline (Week 0). 
Descriptive summary statistics or proportion of subjects achieving specified criteria will be 
summarized by treatment group. For continuous variables, descriptive statistics for baseline and 


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changes or percent changes from baseline will be provided. Categorical variables will be 
summarized with frequency tabulations. Two-sided 95% CIs will be provided for changes or 
percent changes and response rates. 
9.7. 
Safety Analysis 
The safety analyses will be performed using the safety population as defined in Section 9.2. 
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 Treatment Phase (Weeks 0 to 16) and the Apremilast 
Exposure Period when subjects receive apremilast treatment. For safety analyses in the 
Placebo-controlled Treatment Phase, baseline will be relative to the first dose date following 
randomization at Week 0. For safety analyses in Apremilast Exposure Period, baseline will be 
relative to the first apremilast dose date at Week 0 for subjects initially randomized to apremilast 
or Week 16 for subjects initially randomized to placebo and switched to apremilast in the 
Apremilast Extension Phase. 
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. Adverse events will be tabulated for the Placebo-controlled 
Treatment Phase (Weeks 0 to 16) and the Apremilast Exposure Phase in the study. All TEAEs 
will be summarized by system organ class, preferred term, severity, and relationship to IP. 
Adverse events leading to death or to IP withdrawal and serious AEs will also be summarized 
and listed separately.  
Data from other safety assessments will be summarized descriptively. Shift tables for laboratory 
parameters showing the number of subjects with values low, normal, and high compared with the 
normal reference ranges pre-treatment versus post-treatment will be provided.  
To account for the different exposure to the investigational product, adverse events or marked 
laboratory abnormalities will also be summarized using the exposure adjusted incident rate, in 
addition to the simple incidence rates. 
By-subject listings will be provided for all relevant safety data. 
9.8. 
Interim Analysis 
No interim analysis will be conducted. 
After all subjects have completed Week 16 (Visit 7), or discontinued from the study, a Week 16 
database lock will be performed; the primary data analysis will be conducted and a Week 16 
Clinical Study Report will be generated. Study investigators and subjects will remain blinded to 
treatment assignments until the final database lock at the conclusion of the study. At the end of 
the study, after all subjects have either completed the Observational Follow-up Phase or have 
been discontinued from the Apremilast Extension Phase (Weeks 16 to 52) or the Observational 
Follow-up Phase, the final analysis will be performed and a final Clinical Study Report will be 
generated.  


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9.9. 
Other Topics 
9.9.1. 
Data Monitoring Committee  
Monitoring will also be performed by an independent, external Data Monitoring Committee 
(DMC) that will assess safety as outlined in the DMC charter (available upon request). The DMC 
is comprised of three independent external clinical trialists and one independent external 
biostatistician for whom there is no identified conflict of interest. The DMC will meet as outlined 
in the DMC charter. The DMC scope, conduct, processes, and accountabilities are prespecified 
in its charter. Recommendations of the DMC based on the overall benefit/risk evaluation may 
include proceeding with the study per protocol, proceeding with the study with modification, or 
study suspension. 
9.9.2. 
Scientific Steering Committee 
Guidance in protocol development and interpretation of data analysis will be provided by a 
Scientific Steering Committee (SSC).  The SSC will serve in an advisory capacity to the 
Sponsor.  Details for the SSC are pre-specified in a SSC charter. 


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10. 
ADVERSE EVENTS 
10.1. 
Monitoring, Recording and Reporting of Adverse Events 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a 
pre-existing condition) should be considered an AE. A diagnosis or syndrome should be recorded 
on the AE/SAE page of the case report form (CRF) rather than the individual signs or symptoms 
of the diagnosis or syndrome.  
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE.  Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 7.2 for the definition of overdose.) Any sequela of 
an accidental or intentional overdose of an investigational product should be reported as an AE 
on the AE/SAE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on the AE/SAE CRF and the paper SAE report form. The overdose resulting in the SAE 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’s legal guardian signs 
informed consent until 98 days (14 weeks) after the last dose of IP for those subjects that early 
terminate or choose not to enroll in the Long-term Study. All SAEs made known to the 
Investigator at any time following the protocol-required reporting period or after end of study 
will also be reported for these subjects. Subjects entering the Long-term Study will not complete 
the 14-week follow up period and therefore will report any AE or SAE occurring after Visit 16 in 
the Long-term Study CRF. AEs and SAEs for either study will be recorded on the AE/SAE page 
of the CRF, the paper SAE report form and in the subject’s source documents associated with 
that particular study.   
All SAEs must be reported to Amgen Global Patient Safety within 24 hours of the Investigator’s 
knowledge of the event using the paper Serious Adverse Event Report Form by facsimile/email 
of the paper SAER Form directly to Amgen Global Patient Safety.    
10.2. 
Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to:  


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10.2.1. 
Seriousness  
An SAE is any AE occurring at any dose that: 
 Results in death; 
 Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE); 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
 Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions); 
 Is a congenital anomaly/birth defect; 
 Constitutes an important medical event. 
Important medical events are defined as those occurrences that may not be immediately 
life-threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
Events not considered to be SAEs are hospitalizations for: 
 a standard procedure for protocol therapy administration. However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE.  
 routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
 the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE. 
 a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE. 
 hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
 a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE. 
 an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline.  
 emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 


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


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10.2.3. 
Causality 
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected: 
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event. 
Suspected: 
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event. 
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available. 
If an event is assessed as suspected of being related to a comparator, ancillary or additional 
non-IP that has not been manufactured or provided by Amgen, please provide the name of the 
manufacturer when reporting the event. 
10.2.4. 
Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event. 
10.2.5. 
Action Taken 
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation or interruption of IP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event.  
10.2.6. 
Outcome 
The Investigator will report the outcome of the event for both AEs and SAEs. 
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE). 
10.3. 
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
 results in discontinuation from the study; 
 requires treatment, modification/ interruption of IP dose, or any other therapeutic 
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 is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE/SAE page/screen of the eCRF. If the abnormality was 
not a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the 
AE. If possible, the laboratory abnormality should be recorded as a medical term and not simply 
as an abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets). 
10.4. 
Pregnancy 
All pregnancies or suspected pregnancies are immediately reportable events.   
10.4.1. 
Females of Childbearing Potential – Collection of Pregnancy Information: 
Pregnancies and suspected pregnancies (including elevated β-subunit of chorionic gonadotropin 
[βhCG] or positive pregnancy test in a female subject of childbearing potential regardless of 
disease state) occurring while the subject is on IP, or within 28 days of the subject’s last dose of 
IP, are considered immediately reportable events. Investigational product is to be discontinued 
immediately and the subject instructed to return any unused portion of the IP to the Investigator. 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Amgen 
Global Patient Safety immediately by facsimile, email or other appropriate method, using the 
Pregnancy Notification Form or approved equivalent form (refer to Appendix O). 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 follow the female subject until completion of the pregnancy and must 
notify Amgen Global Patient Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome).  
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Amgen Global Patient  Safety using the paper Serious 
Adverse Event Report Form within 24 hours of the Investigator’s knowledge of the event. 


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All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to in utero exposure to the IP should also be reported to Amgen Global Patient Safety by 
facsimile, email, or other appropriate method, within 24 hours of the Investigator’s knowledge of 
the event using the paper SAE Report Form.  
10.4.2. 
Male Subjects With Partners Who Become Pregnant  
In the event a male subject fathers a child during treatment, and for an additional 28 days after 
discontinuing IP, the information will be recorded on the Pregnancy Notification Form (refer to 
Appendix O). 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 P) 
and submitted by facsimile or email to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  
 Study treatment will be discontinued if female subject breastfeeds during the study. 
 With the female subjects signed consent for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while taking 
IP through 28 days after discontinuing IP.        
10.5. 
Reporting of Serious Adverse Events 
Any AE that meets any criterion for an SAE requires the completion of the AE/SAE page/screen 
of the eCRF and the completion of the paper Serious Adverse Event Report Form (refer to 
Appendix N).  All SAEs must be reported to Amgen Global Patient Safety by facsimile or email 
via the paper Serious Adverse Event Report form within 24 hours of the Investigator’s 


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knowledge of the event.  This instruction pertains to initial SAE reports as well as any follow-up 
reports. 
The Investigator is required to ensure that the data on these forms is accurate and consistent. This 
requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the legal guardian signs informed consent and subject signs assent until 28 days 
after the last dose of IP) or any SAE made known to the Investigator at any time following the 
protocol-required reporting period or after end of study. Serious adverse events occurring prior to 
treatment (after signing the ICF/assent) will be collected/recorded/reported. 
Any follow-up data to the existing SAE should be resubmitted to Amgen Global Patient Safety.   
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
source documents and all correspondence with the IRB/EC. 
Serious Adverse Event Reporting transmitted via paper Serious Adverse Event Report Form:  
 Facsimile transmission of the Serious Adverse Event Report Form is the preferred 
method to transmit this information. If facsimile is unavailable, the email method to 
transmit this information is acceptable (refer to Appendix N).     
 In rare circumstances and in the absence of facsimile equipment, this form may be sent 
via email, or notification by telephone is acceptable with a copy of the Serious Adverse 
Event Report Form in English language sent by overnight mail or courier service.      
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated 
reporting timeframes.   
 Once the study has ended, serious adverse events (regardless of causality) should be 
reported to Amgen Global Patient Safety if the investigator becomes aware of them and 
may use the paper Serious Adverse Event Report Form (refer to Appendix N).     
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based on 
relationship to investigational product. 
If further safety related data is needed to fulfill any regulatory reporting requirements for a 
reportable event, then additional information may need to be collected from the subject's records 
after the subject ends the study.   
10.5.1. 
Safety Queries 
Queries pertaining to SAEs will be communicated from Amgen Global Patient Safety to the site 
via Amgen’s safety query paper process,or other appropriate method.   
10.6. 
Expedited Reporting of Adverse Events 
For the purpose of regulatory reporting, Amgen Global Patient Safety will determine the 
expectedness of events suspected of being related to apremilast based on the Investigator 
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In the US, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32. 
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. 
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 N, Appendix O, Appendix P). 
 


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11. 
DISCONTINUATIONS 
11.1. 
Treatment Discontinuation 
Subjects who have psoriasis disease flare during the apremilast treatment periods and require 
systemic conventional therapies, biologics, phototherapy, or prohibited topical therapies (defined 
in Section 8.1) will be discontinued from the study and properly treated according to local 
treatment guidelines. In the case of psoriasis disease flare during the apremilast treatment 
periods, the reason for discontinuation will be lack of efficacy. Subjects will not be withdrawn 
from the study if the disease flare and the need for treatment occur during the follow-up periods. 
Every attempt will be made to collect all or specific final data on a discontinued subject. Any 
subject whose calculated BMI falls below the 5th percentile on the CDC growth chart (CDC, 
2000) at any visit will be discontinued from the study.  
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s): 
 Adverse Event  
 Lack of efficacy 
 Withdrawal by subject 
 Death 
 Lost to follow-up 
 Non-compliance with IP 
 Protocol deviation 
 Pregnancy 
 Physician decision 
 Study terminated by Sponsor 
 Other (to be specified on the CRF) 
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents. 
When a subject is discontinued from treatment, the Investigator should make every attempt 
possible to have the subject evaluated at the Early Termination Visit within 4 days of the last 
intake of IP. 
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion. 


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11.2. 
Study Discontinuation 
The following events are considered sufficient reasons for discontinuing a subject from the 
study: 
 Screen failure 
 Adverse event  
 Withdrawal by subject 
 Death 
 Lost to follow-up 
 Protocol deviation 
 Pregnancy 
 Physician decision 
 Study terminated by Sponsor 
 Other (to be specified on the CRF) 
The reason for study discontinuation should be recorded in the CRF and in the source 
documents. 
 


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


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


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13.3. 
Subject Information and Informed Consent 
Both an age-specific assent (by the study subject) and an informed consent form (ICF; by 
subject’s legal guardian) must be signed before any study-related assessments are performed. 
Documentation that the subject assent and legal guardian informed consent occurred prior to the 
study subject’s entry into the study and of the assent/informed consent process should be 
recorded in the study subject’s source documents including the date. The original assent and 
informed consent documents signed and dated by the study subject (assent), subject’s legal 
guardian (ICF), and by the person facilitating the process (assent and ICF), 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’s legal guardian. In addition, if a protocol is amended and it impacts 
on the content of the assent and informed consent, the two documents must be revised. Study 
subjects participating in the study, and their legal guardians, must repeat the assenting/consenting 
process with the revised assent/consent documents when the amended protocol is implemented. 
The revised documents signed and dated by the study subject, subject’s legal guardian, and by 
the person facilitating the process, must be maintained in the Investigator’s study files and a copy 
given to the study subject’s legal guardian. 
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 
signed ICF and assent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. 
13.5. 
Protocol Amendments 
Any amendment to this protocol must be approved by the Amgen Clinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/EC for written approval. 
Written approval must be obtained before implementation of the amended version occurs. The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes. 
13.6. 
Institutional Review Board/Independent Ethics Committee Review 
and Approval 
Before the start of the study, the study protocol, legal guardian ICF, subject assents, 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. 


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


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14. 
DATA HANDLING AND RECORDKEEPING  
14.1. 
Data/Documents 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or compact disc, read only memory device (CD-
ROMs). 
14.2. 
Data Management 
Data will be collected via CRF and entered into the clinical database per Amgen standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all 
changes made to the data. 
14.3. 
Record Retention 
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following: 
 Signed legal guardian ICFs and assents for all subjects; 
 Subject identification code list, screening log (if applicable), and enrollment log; 
 Record of all communications between the Investigator and the IRB/EC; 
 Composition of the IRB/EC; 
 Record of all communications between the Investigator, Amgen, and their authorized 
representative(s); 
 List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures; 
 Copies of CRFs (if paper) and of documentation of corrections for all subjects; 
 IP accountability records; 
 Record of any body fluids or tissue samples retained; 
 All other source documents (subject records, hospital records, laboratory records, 
etc.);  


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


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
All aspects of the study will be carefully monitored by Amgen or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs. 
15.1. 
Study Monitoring and Source Data Verification 
Amgen ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting. Prior to enrolling subjects into the study, an 
Amgen representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator. Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Amgen representative in accordance with the 
Study Monitoring Plan. 
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation. Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff. Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified. Additional 
monitoring activities may be outlined in a study-specific monitoring plan. 
15.2. 
Audits and Inspections 
In addition to the routine monitoring procedures, a Quality, Compliance & Audit, Learning & 
Performance unit exists within Amgen. Representatives of this unit will conduct audits of clinical 
research activities in accordance with Amgen SOPs to evaluate compliance with Good Clinical 
Practice guidelines and regulations. 
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, 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 


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product. Any product complaints associated with an investigational products, or 
non-investigational products or devices supplied by Amgen are to be reported according to the 
instructions provided in the Investigational Product Instruction Manual or equivalent.  
If you become aware of a suspected PC, you are obligated to report the issue within 24 hours of 
discovery or notification of the concern or irregularity. Amgen requires notification of any 
concern or irregularity at any stage of the study. 
How to Report a 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. 
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Dogra S, Mahajan R. Biologics in Pediatric Psoriasis – efficacy and safety. Expert Opin Drug 
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patients from China. J Eur Acad Dermatol Venereol. 2007 Jul;21(6):762–65.  
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Gottlieb AB, Matheson RT, Menter A, Leonardi CL, Day RM, Hu C, et al. Efficacy, tolerability, 
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Krueger JG, Ohtsuki M, Garcet S, Correa da Rosa J, Gonzalez J, Li X, Chen R, et al. Apremilast 
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Langan EA, Griffiths CEM, Solbach W, Knobloch JK, Zillikens D, Thaçi D. The role of the 
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Silverberg NB. Update on pediatric psoriasis, part 1: clinical features and demographics. Cutis. 
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and its clinical management: a European expert group consensus. J Dtsch Dermatol Ges. 2010 
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18. 
APPENDICES 
Appendix A: Table of Abbreviations 
Table 7: 
Abbreviations and Specialist Terms 
Abbreviation or 
Specialist Term 
Explanation 
ADL 
Activity of daily life 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of Covariance (model) 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
AUCss 
Area under the curve steady state 
AUCtau 
Area under the curve dosing interval 
β-hCG 
β-subunit of human chorionic gonadotropin 
BID 
Twice Daily 
BMI 
Body Mass Index 
BSA 
Body surface area 
cAMP 
Cyclic adenosine monophosphate 
CBC 
Complete blood count 
CDC 
Centers for Disease Control 
CDLQI 
Children’s Dermatological Life Quality Index 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
Cmax 
Peak observed plasma concentration of drug 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DLQI 
Dermatology Life Quality Index 
DCR 
Disease control rate 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 


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Table 7: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EU 
European Union 
EOT 
End of treatment 
FCBP 
Female of Childbearing Potential 
FDA 
Food and Drug Administration 
FDLQI 
Family Dermatological Life Quality Index 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GM 
Geometric Mean 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
Integrated Response Technology 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
LS 
Least Square  
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
NRI 
Non-responder Imputation 
NRS 
Numeric Rating Scale 
PASI 
Psoriasis Area Severity Index 
PASI-50 
50% reduction in Psoriasis Area Severity Index 


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Table 7: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
PASI-75 
75% reduction in Psoriasis Area Severity Index 
PCQ 
Product Complaint 
PDE4 
Phosphodiesterase type 4 
PD 
Pharmacodynamic 
PG 
Pharmacogenomic 
PK 
Pharmacokinetics 
PP 
Per protocol 
RBC 
Red blood cell count 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Steering committee 
SGOT 
Serum glutamic oxaloacetic transaminase  
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
sPGA 
Static Physician Global Assessment 
sPGA-G 
Static Physician Global Assessment-Genitalia 
SSC 
Scientific Steering Committee 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TEAE 
Treatment-emergent Adverse Event 
TNF 
Tumor necrosis factor 
TNF-α 
Tumor necrosis factor-α 
ULN 
Upper limit of normal 
US 
United States (of America) 
UVB 
Ultraviolet B 
WBC 
White blood cell count 
WHO 
World Health Organization 
 


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


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Appendix C: Psoriasis Area Severity Index (PASI) 
 
Psoriasis Area and Severity Index (PASI) 
* Round all calculations to 1 decimal place 
STEP A.   Please write in the appropriate number for rows 1 - 3 using the scale below: 
  
    0 = None    1 = Slight    2 = Moderate    3 = Severe    4 = Very Severe 
  
  
HEAD 
TRUNK 
UPPER 
LIMBS 
LOWER 
LIMBS 
1. Erythema 
2. Thickness 
3. Scaling 
4. TOTAL Each Column 
  
  
STEP B.  Enter the number of hands the psoriasis covers on each body area 
  
  
HEAD 
TRUNK 
UPPER 
LIMBS 
LOWER 
LIMBS 
5. Number of Hands 
6. Area (% of total BSA) 
10 
30 
20 
40 
  
 
 
 
  
STEP C. Calculate % of involvement:  
  
7. % of each region involved  [(Row 5 ÷ Row 6) x 100*] 
8. TOTAL BSA (sum of # of hands from row 5) 
  
  
  
STEP D. Select Degree of Involvement using value in Row 7: 
  
          0  = No involvement 
  
          1  = <10% 
  
          2  = 10 < 30% 
  
          3 = 30 < 50% 
  


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          4 = 50 < 70% 
  
          5 = 70 < 90% 
  
          6 = 90 < 100% 
  
9.  Degree of Involvement (0-6) of each region 
  
  
STEP E.  Calculate PASI (Row 4 x Row 6 x Row 9) ÷ 100* 
  
10. PASI for each body region 
11. TOTAL PASI (sum of Row 10 subscores) 
  
  
  
 
 


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Appendix D: Scalp Physician Global Assessment (ScPGA) 
 
Score 
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: Modified Static Physician Global Assessment of Genitalia 
(sPGA-G) 
 
Score 
Category 
Description 
 
0 
 
Clear 
Erythema: no erythema (except for residual 
hyperpigmentation/hypopigmentation) 
Plaque Elevation: no elevation 
Scaling = no scale 
 
1 
 
Almost clear 
Erythema: faint, light pink erythema 
Plaque Elevation: elevation is very slight and difficult to confirm 
Scaling = some fine, white surface dryness 
 
2 
 
Mild 
Erythema: mild, pink erythema 
Plaque Elevation: slight elevation with sloped edges 
Scaling = fine scale on some or most lesions 
 
3 
 
Moderate 
Erythema: moderate, red erythema 
Plaque Elevation: moderate elevation with definite edges that are either 
sloped or rough 
Scaling = course scale on most lesions 
 
4 
 
Severe 
Erythema: severe, bright red or deep red erythema 
Plaque Elevation: substantial elevation, hard or sharp edges 
Scaling = course, non-adherent scale on most to all lesions 
Adapted from source: Merola, 2017. 
 


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Appendix F: Columbia-Suicide Severity Rating Scale  
(C-SSRS) Children’s Baseline/Screening 
 
 
 


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Columbia-Suicide Severity Rating Scale (C-SSRS)  
Children’s Since Last Visit: 
 
 
 


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Appendix G: Stool Diary 
 
DAILY STOOL DIARY  
 
1. Did you have 3 or more liquid or watery stools today? 
 No  
 Yes 
 
 
2. Please indicate if you experienced any of these symptoms with your liquid or watery 
stools today 
 Nausea 
 Vomiting 
 Abdominal cramps  
 Abdominal pain 
 Fever  
 Bloating 
 Other: _______________________________________ 
 
Date: ______________________________________ 
 
Signature of person completing form 
Subject or parent/guardian: ______________________________  
 
 


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Appendix H: Tanner Staging 
 
Female 
Stage 
Breast growth 
Pubic hair growth 
Other changes 
I 
Pre-adolescent 
None 
Pre-adolescent 
II 
Breast budding (thelarche); 
areolar hyperplasia with small 
amount of breast tissue 
Long downy pubic hair near 
the labia, often appearing 
with breast budding or 
several weeks or months 
later 
Peak growth velocity often 
occurs soon after stage II 
III 
Further enlargement of breast 
tissue and areola, with no 
separation of their contours 
Increase in amount and 
pigmentation of hair 
Menarche occurs in 2% of 
girls late in stage III 
IV 
Separation of contours; 
areola and nipple form 
secondary mound above 
breasts tissue 
Adult in type but not in 
distribution 
Menarche occurs in most 
girls in stage IV, 1–3 years 
after thelarche 
V 
Large breast with single 
contour 
Adult in distribution 
Menarche occurs in 10% of 
girls in stage V. 
 
Male 
Stage 
Testes 
growth 
Penis growth 
Pubic hair 
growth 
Other changes 
I 
Pre-
adolescent 
testes 
(≤2.5 cm) 
Pre-adolescent 
None 
Pre-adolescent 
II 
Enlargement 
of testes; 
pigmentation 
of scrotal sac 
Minimal or no 
enlargement 
Long downy hair, 
often appearing 
several months 
after testicular 
growth; variable 
pattern noted with 
pubarche 
Not applicable 
III 
Further 
enlargement 
Significant 
enlargement, 
especially in diameter 
Increase in 
amount; curling 
Not applicable 
IV 
Further 
enlargement 
Further enlargement, 
especially in diameter 
Adult in type but 
not in distribution 
Development of axillary hair and 
some facial hair 
V 
Adult in size 
Adult in size 
Adult in 
distribution 
(medial aspects of 
thighs; linea alba) 
Body hair continues to grow and 
muscles continue to increase in 
size for several months to years; 
20% of boys reach peak growth 
velocity during this period 
 
 


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Appendix I: 
Pharmacokinetic Sample Processing Instructions 
PK Blood and Plasma Sample Labeling 
Labels will contain, at minimum, the following information: 
 Protocol No.: CC-10004-PPSO-003 
 Subject ID number 
 Nominal Time Point: eg, Week 4, Pre-dose or Week 8, Post-dose 
 Sample Type: Plasma (primary), or Plasma (back-up)  
All blood and plasma collection tubes and storage vials should be labeled and chilled on wet ice 
prior to sample collection and processing. 
PK Blood Sample Collection for Apremilast 
 Fill an ice bucket with a sufficient amount of wet ice to pre-chill all collection tubes 
before blood draw. 
 Collect approximately 2 mL of whole blood into a pre-chilled lithium heparin tube. 
Blood can be collected via direct vein puncture or indwelling catheter. 
 Accurately record the time of blood collection. 
 Gently invert the tube 3 to 5 times and immediately immerse it into ice to prevent 
possible compound degradation. 
PK Blood Sample Processing to Obtain Plasma 
 Within 30 minutes of collection, the blood sample must be centrifuged at 1,500 g 
(about 3,000 rpm) for 10 minutes at 4°C to obtain plasma.   
 Immediately record the time of sample entry into and out of the centrifuge. 
 Transfer approximately 0.5 mL of plasma into each of the two pre-labeled, pre-
chilled, citric acid-containing polypropylene storage tubes (one primary and one 
back-up). 
 Gently invert the tube 3 to 5 times. 
Note: Amgen will provide these tubes. 
 Keep storage tubes on ice before they are ready to be transferred into a freezer. 
 Within 60 minutes of blood collection, transfer plasma samples in storage vials into 
a –70oC freezer, where they will remain stored until shipping. 
 Immediately record the time of sample entry into the freezer.  
PK Sample Shipment 
 All PK sample label information on the storage tubes have to check against 
requisition form and then the samples must be shipped frozen and on dry ice to QPS. 
 QPS must be contacted via email PRIOR TO shipping, and confirmation of receipt 
from QPS must be documented at the site. 


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Attn:  
 
QPS  
Three Innovation Way; Suite 240  
Newark, Delaware 19711  
Office: 
  
Facsimile:
  
Email: 
  
PK Sample Collection Documents to Accompany Shipment(s) 
A copy of the completed shipment manifest must accompany the shipment, an electronic copy of 
the shipping manifest (EXCEL format preferred), and must list the following information at 
minimum: 
 Sponsor name: Amgen Inc. 
 Amgen Study Number: CC-10004-PPSO-003 
 Subject ID Numbers 
 Collection Date: eg, 10 Oct 2018 
 Nominal collection time point for plasma samples: eg, Week 4, Pre-dose 
Sample type (eg, primary plasma or back-up plasma) 
 
 


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Appendix J: 
The Children’s Dermatology Life Quality Index (CDLQI) 
 
 


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Appendix K: Family Dermatology Life Quality Index (FDLQI) 
 
 
 


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Appendix L: Modified Whole Body Itch Numeric Rating Scale (NRS) 
 
Instruction: Please think about your whole body when answering the 
question below. 
 
 
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 
 
 
 
 
Naegeli, 2015. 
 
 


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Appendix M: Monthly Blister Card Configurations 
 


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Appendix N: Sample Serious Adverse Event Report Form 
 
 


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Appendix O: Pregnancy Notification Form 
 
 
 
 


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Appendix P: 
Lactation Notification Form 
 
 
 


Product:  Apremilast 
Protocol Number:  CC-10004-PPSO-003 (20200056) 
Date:  17 December 2021 
Page 1 of 1 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 5 
Protocol Title:  A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF 
APREMILAST (CC-10004) IN PEDIATRIC SUBJECTS FROM 6 THROUGH 17 YEARS OF 
AGE WITH MODERATE TO SEVERE PLAQUE PSORIASIS 
Sponsor Number:  CC-10004-PPSO-003 (Apremilast 20200056) 
EudraCT Number:  2018-002918-12 
NCT Number:  NCT03701763 
Amendment Date: 
17 December 2021 
 
Rationale: 
The purpose of this protocol amendment is to revert the study sample size from at least 180 
randomized subjects to the original protocol goal of at least 230 randomized subjects.  This 
change has been made based on the enrollment progress for the study and advice from the 
United States Food and Drug Administration. 
The following modifications were made to the protocol: 
 
Updated sample size in the Synopsis, Section 3.1 Study Design, Section 4.1 Number of 
Subjects, Section 9.3 Sample Size and Power Considerations, and Section 9.6.1.1 Primary 
Efficacy Endpoint; and, 
 
Updated the power calculations based on the change in sample size in the Synopsis and 
Section 9.3 Sample Size and Power Considerations. 


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– SUMMARY OF CHANGES – 
AMENDMENT NO. 04 
A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE- 
BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF APREMILAST (CC-10004) IN 
PEDIATRIC SUBJECTS FROM 6 THROUGH 17 YEARS OF 
AGE WITH MODERATE TO SEVERE PLAQUE PSORIASIS 
 
INVESTIGATIONAL PRODUCT 
(IP): 
 
CC-10004 (apremilast) 
PROTOCOL NUMBER: 
 
CC-10004-PPSO-003 
ORIGINAL DATE: 
 
15 Aug 2018 
AMENDMENT No. 01 DATE: 
 
12 Apr 2019  
AMENDMENT No. 02 DATE: 
 
23 Sep 2019 
AMENDMENT No. 03 DATE: 
 
01 May 2020 
AMENDMENT No. 04 DATE: 
 
26 Aug 2021 
EudraCT NUMBER: 
 
2018-002918-12 
IND NUMBER:  
 
070270  
NCT NUMBER: 
 
NCT03701763 
 
Contact Information:  
 
 
Name: 
, MD 
 
Title: 
Associate Director, Clinical Research & Development 
 
Address:  
One Amgen Center Drive, Thousand Oaks, CA 91320 
 
Phone: 
 
 
E-mail: 
 
Note: Only call Amgen Medical Information if you are not able to reach the Clinical 
Research Physician(s) or Medical Monitor or designee for emergency calls. 
 
 
Amgen Medical Information:  1- 800-77-AMGEN (1-800-772-6436) 


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CONFIDENTIAL NOTICE 
This document contains confidential information of Amgen. This document must 
not be disclosed to anyone other than the site study staff and members of the 
institutional review board/independent ethics committee/institutional scientific 
review board or equivalent.  The information in this document cannot be used for 
any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen. If you have any questions regarding 
how this document may be used or shared, call the Amgen Medical Information 
number: 1-800-77-AMGEN. 


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JUSTIFICATION FOR AMENDMENT 
 
The purpose of this amendment is to reduce the study sample size from at least 230 subjects to at 
least 180 subjects.  This sample size retains adequate power for the primary and key secondary 
endpoints while making the overall study more efficient.  
The following changes were made to the protocol, dated 26 Aug 2021: 
 Updated sample size in the Synopsis, Section 3.1 Study Design, Section 4.1 Number of 
Subjects, Section 9.3 Sample Size and Power Considerations, and Section 9.6.1.1 Primary 
Efficacy Endpoint 
 Updated the power calculations based on the change in sample size in the Synopsis and 
Section 9.3 Sample Size and Power Calculations 
 Added language in Section 10.5 Reporting of Serious Adverse Events to comply with an 
Amgen template update 
 Deleted Celgene Therapeutic Area Head Signature Page to conform to the Amgen template 
 Grammatical and typographical changes were made throughout the protocol. 


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TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 03
A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF APREMILAST (CC-10004) IN 
PEDIATRIC SUBJECTS FROM 6 THROUGH 17 YEARS OF 
AGE WITH MODERATE TO SEVERE PLAQUE PSORIASIS
INVESTIGATIONAL PRODUCT (IP):
CC-10004 (apremilast)
PROTOCOL NUMBER:
CC-10004-PPSO-003
ORIGINAL DATE:
15 Aug 2018
AMENDMENT No. 01 DATE:
12 Apr 2019
AMENDMENT No. 02 DATE:
23 Sep 2019
AMENDMENT N0. 03 DATE:
01 May 2020
EudraCT NUMBER:
2018-002918-12
IND NUMBER: 
070270
NCT NUMBER:
NCT03701763
Contact Information: 
Name:
, MD
Title:
Associate Director, Clinical Research & Development
Address: 
One Amgen Center Dr. 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)


EDMS Doc. Number: 24685445 - 23672561
Apremilast
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CC-10004-PPSO-003 Amendment 3 Final:  1 May 2020
CONFIDENTIAL NOTICE
This document contains confidential information of Amgen. This document must 
not be disclosed to anyone other than the site study staff and members of the 
institutional review board/independent ethics committee/institutional scientific 
review board or equivalent.  The information in this document cannot be used for 
any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen. If you have any questions regarding 
how this document may be used or shared, call the Amgen Medical Information 
number: 1-800-77-AMGEN.


EDMS Doc. Number: 24685445 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Amgen Inc.
Confidential and Proprietary
3
CC-10004-PPSO-003 Amendment 3 Final:  1 May 2020
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, MD – VP and Head of Immunology & Fibrosis Clinical 
Development
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.
NOTE: Signed by Celgene based on approval from Amgen Therapeutic Head, 
 


EDMS Doc. Number: 24685445 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Amgen Inc.
Confidential and Proprietary
4
CC-10004-PPSO-003 Amendment 3 Final:  1 May 2020
1.
JUSTIFICATION FOR AMENDMENT
The purpose of this amendment is to update the change in Sponsor, as well as key contact and 
emergency information, and to update safety reporting and product complaints to align with 
Amgen processes.
Significant changes included in this amendment are summarized below:

All references to “Celgene Corporation” were removed and replaced with “Amgen Inc.” 
and “Celgene” changed to “Amgen” throughout the protocol. 

Cover Pages were updated with Amgen contact information

Section 6 Procedures was updated to align with Amgen Global Drug Safety processes

Section 10.1 Monitoring and Reporting of Adverse Events was updated to align with 
Amgen Global Drug Safety processes. 

Section 10.4 Pregnancy was modified according to the Amgen Global Drug Safety 
process:
o
Collection of Pregnancy Information and Infant Health Information
o
Collection of information: Male Subjects with Partners Who Become Pregnant 
o
Collection of Lactation Information

Section 10.5 Reporting of Serious Adverse Events was updated to include instructions for 
paper reporting of SAEs 

Section 12.1 Emergency Contact was updated with Amgen emergency contact 
information.

Section 15.3 Product Complaint section was modified according to the Amgen product 
complaint reporting process
The amendment also includes addition of forms, minor clarifications and corrections to 
align with Amgen processes:

Section 7.6 Investigational Product Accountability and Disposal

Section 15.2 Audits and Inspections

Section 16 Publications

Appendix N Sample Serious Adverse Event Form was added

Appendix O Pregnancy Notification Form was added 

Appendix P Lactation Notification Form was added


EDMS Doc. Number: 24089481 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Celgene Corporation
Confidential and Proprietary
1
CC-10004-PPSO-003 Amendment 2 Final: 23 Sep 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 2
A PHASE 3, MULTI-CENTER, RANDOMIZED, 
DOUBLE- BLIND, PLACEBO-CONTROLLED STUDY 
TO ASSESS THE EFFICACY AND SAFETY OF 
APREMILAST (CC-10004) IN PEDIATRIC SUBJECTS 
FROM 6 THROUGH 17 YEARS OF AGE WITH 
MODERATE TO SEVERE PLAQUE PSORIASIS
INVESTIGATIONAL PRODUCT (IP):
CC-10004 (apremilast)
PROTOCOL NUMBER:
CC-10004-PPSO-003
ORIGINAL DATE:
15 Aug 2018
AMENDMENT No. 1 DATE:
12 Apr 2019
AMENDMENT No. 2 DATE
23 Sep 2019
EudraCT NUMBER:
2018-002918-12
IND NUMBER: 
070270
Contact Information: 
Name:
, MD
Title:
Associate Director, Clinical Research & Development
Address: 
86 Morris Avenue, Summit, NJ 07901
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


EDMS Doc. Number: 24089481 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Celgene Corporation
Confidential and Proprietary
2
CC-10004-PPSO-003 Amendment 2 Final: 23 Sep 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.


EDMS Doc. Number: 24089481 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PPSO-003 Amendment 2 Final: 23 Sep 2019
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 2 has been written to implement changes to the study for all participating 
sites. The intent of the amendment is to include descriptions of the redesigned packaging of 
investigational product (IP) as well as a statement that IP will be supplied during the Apremilast 
Extension Phase in a blister pack for the first month and then in bottles for the rest of the study.
Significant changes included in this amendment are summarized below:
1. Removed previous depictions of IP blister card packaging and replaced them with 
depictions of the redesigned versions.
The blister cards were redesigned to address the fact that extra pills included in the old design 
were superfluous and not needed to ensure protection of the blind.
Revised section: Appendix M
2. Added text that informs of switch from blister card supplied IP to bottles during the 
Apremilast Extension Phase and provided an updated text description of the redesigned 
blister cards.
Revised sections: Protocol Summary; Section 7 Description of Study Treatments
3. Revised platelet ranges for subject eligibility.
It was learned during the study that the upper limit of the allowable platelet range was 
unnecessarily too low and could be raised safely to more closely align with what is typically seen 
in this disease population.
Revised section: Section 4.2 Inclusion Criteria, Inclusion Criterion number 11
4. Removed pregnancies of partners of male subjects as an event that must be reported.
Safety has updated the standard safety language to remove pregnancies of male subjects as an 
event that must be reported and followed.
Revised section: Section 10.4 Pregnancy 


EDMS Doc. Number: 23672889 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Celgene Corporation
Confidential and Proprietary
1
CC-10004-PPSO-003 Amendment 1 Final: 12 Apr 2019
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 1
A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF APREMILAST (CC-10004) IN 
PEDIATRIC SUBJECTS FROM 6 THROUGH 17 YEARS OF 
AGE WITH MODERATE TO SEVERE PLAQUE PSORIASIS
INVESTIGATIONAL PRODUCT (IP):
CC-10004 (apremilast)
PROTOCOL NUMBER:
CC-10004-PPSO-003
ORIGINAL DATE:
15 Aug 2018
AMENDMENT No. 1 DATE:
12 Apr 2019
EudraCT NUMBER:
2018-002918-12
IND NUMBER: 
070270
Contact Information: 
Name:
, MD
Title:
Associate Director, Clinical Research & Development
Address:
86 Morris Avenue, Summit, NJ 07901
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


EDMS Doc. Number: 23672889 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Celgene Corporation
Confidential and Proprietary
2
CC-10004-PPSO-003 Amendment 1 Final: 12 Apr 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
, MD – Vice President Clinical Research and Development
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable.


EDMS Doc. Number: 23672889 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PPSO-003 Amendment 1 Final: 12 Apr 2019
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 1 has been written to implement changes to the study for all participating 
sites. The intent of the amendment is to improve protocol clarity as well as address changes in 
response to requests from the Federal Institute for Drugs and Medical Devices (Bundesinstitut 
für Arzneimittel und Medizinprodukte [BfArM]).
Significant changes included in this amendment are summarized below:
1. Added a new inclusion criterion for baseline minimum allowable body mass index 
(BMI) 
The amendment adds a new Inclusion Criterion which provides a specific minimum for 
subject BMI in order to ensure that no underweight subjects are enrolled. The Otezla®
Summary of Product Characteristics (SmPC) mentions “underweight” under special 
warnings and precautions for use; this new inclusion criterion will exclude underweight 
subjects from the study.
Revised Section: Section 4.2 Inclusion Criterion #3
2. Added a specific BMI parameter as a reason for mandatory subject withdrawal.
Loss of weight is a known adverse reaction with apremilast therapy. If any subject, while on 
treatment, experiences weight loss and their BMI falls below the defined threshold, the 
subject will be terminated from the study.
Revised Section: Section 11.1 Treatment Discontinuation
3. Revised hemoglobin ranges for subject eligibility
This was an update made to the allowable upper ranges of entrance hemoglobin values in 
response to feedback from an active study investigator. The higher limits of the hemoglobin 
ranges were considered to be too low, which would make enrollment of study subjects 
unnecessarily challenging. The inclusion hemoglobin ranges were reviewed by the Celgene 
safety physician (executive director) and new ranges were approved which are wider but still 
well within established normal ranges for this patient population.
Age (years)
Males (g/dL)
Females (g/dL)
6-11 
10.0 – 13.515.0
10.0 – 13.515.0
12-18 
11.0 – 1416.5
10.5 – 14.015.5
Revised Section: Section 4.2 Inclusion Criterion #11
4. Added a NOTE under contraception Option 2 for females of childbearing potential 
(FCBP) 
The double-barrier methods listed in contraception Option 2 are not considered highly 
effective methods of contraception in all European Union (EU) countries which follow the 
“Recommendations related to contraception and pregnancy testing in clinical trials” of the 
Clinical Trial Facilitation Group (CTFG). In these cases, only Option 1 should be utilized as 
an acceptable contraception method for females of childbearing potential (FCBP) subjects. 
To make this clear in the protocol, a note was added below Option 2 which states:


EDMS Doc. Number: 23672889 - 23672561
Apremilast
Summary of Changes CC-10004-PPSO-003
Celgene Corporation
Confidential and Proprietary
4
CC-10004-PPSO-003 Amendment 1 Final: 12 Apr 2019
NOTE: Option 2 may not be acceptable as a highly effective contraception option in all 
countries per local guidelines/regulations.
Revised Section: Section 4.2 Inclusion Criterion #12
The amendment also includes other minor clarifications:

Added a sentence to Section 13.2 Investigator Responsibilities in response to a BfArM 
comment, which confirmed selection of qualified investigators.

Added a reference for the BMI chart to be used for determination of subject inclusion and 
possible study discontinuation  to the list of References in Section 17: 
Centers for Disease Control (CDC) National Center for Health Statistics Clinical 
Growth Charts, Modified 2000: 
https://www.cdc.gov/growthcharts/clinical_charts.htm

The reference to a Study Manual was removed from Section 6

A clarification was added to the Table 3 footnotes, indicating that a urine pregnancy test 
would not be performed at Visit 3

Added an attribution to Appendix E

Added a reference to Section 17 in connection with the attribution added to Appendix E:
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.

Added completion of the C-SSRS questionnaire to the Unscheduled Visit column in 
Section 5, Table 3 and Section 6.5.16.

Added Centers for Disease Control (CDC) to the list of abbreviations (Appendix A)

Added some text to Section 6.2 to clarify that efficacy assessments performed during the 
Treatment Period should be completed only after the subject has completed the whole 
body itch Numeric Rating Scale (NRS) and the health-related quality of life assessments

Deleted text from Section 6.3.1 that referenced completion of the whole body itch NRS 
and the health-related quality of life assessments at the observational follow-up visits 
since these are not actually completed at these visits

SAP_003.pdf: 
Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 1 of 66 
CONFIDENTIAL  
 
 
 
Statistical Analysis Plan 
Protocol Title: 
A PHASE 3, MULTI-CENTER, RANDOMIZED, 
DOUBLE- BLIND, PLACEBO-CONTROLLED 
STUDY TO ASSESS THE EFFICACY AND 
SAFETY OF APREMILAST (CC-10004) IN 
PEDIATRIC SUBJECTS FROM 6 THROUGH 17 
YEARS OF AGE WITH MODERATE TO SEVERE 
PLAQUE PSORIASIS 
Short Protocol Title: 
Not Applicable 
Protocol Number: 
20200056 (CC-10004-PPSO-003) 
NCT Number: 
NCT03701763 
Authors: 
, 
, 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, Thousand Oaks, CA 
91320, United States 
SAP Date: 
Document Version 
Date 
Original (v2.0) 
20 December 2021 
 
 
 
 
 
 
 
 


Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 2 of 66 
CONFIDENTIAL  
 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Celgene Version 0.2 
21Aug2018 
Original 
Amgen Version 1.0 
31Aug2021 
Sample size reduction to at least 180 
subjects to reach committed timelines 
with regulatory authorities while keeping 
sufficient power. 
Amgen Version 2.0 
20Dec2021 
Sample size was reverted from at least 
180 randomized subjects to the original 
protocol goal of at least 230 randomized 
subjects based on enrollment progress 
for the study and advice from the United 
States Food and Drug Administration. 
The other updates are presented in the 
following page of Summary of Changes. 
 
 
 
 


Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 3 of 66 
CONFIDENTIAL  
 
 
 
Summary of Changes  
 
1. Updated the document to align with the Amgen template for statistical analysis 
plans and adjusted the section numbers accordingly. 
2. Reworded the Hypotheses as follows: 
“The primary hypothesis for this study is: Apremilast is superior to placebo in subjects 
with moderate to severe psoriasis as measured by proportion of subjects with a sPGA 
score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline at 
Week 16. 
The major secondary hypothesis for this study is: Apremilast is superior to placebo in 
subjects with moderate to severe psoriasis as measured by proportion of subjects 
achieving at least a 75% reduction in PASI (PASI-75) from baseline at Week 16.” 
Versus the original text: 
“The null hypothesis is that the effects of the two treatment arms (i.e., placebo vs. 
apremilast) have no difference” in Page 27.  
Affected section: Section 2.2 
3. Added “Data Screening and Acceptance” details following the Amgen smart 
template. 
Affected section: Section 8.1, 8.2, 8.4, 8.6, 8.7 
4. Added “Withdrawal by parent/guardian” and “Discontinued reason due to COVID-
19 related control measures” in the categories of disposition. 
Affected section: Section 9.4 
5. Updated the MedDRA version and WHO DD version from 20.0 and March 2018 to 
24.0 or higher and March 2020 or later, respectively. 
Affected section: Section 9.5.3, 9.5.4, 9.5.5, 9.8.1, 9.8.7, 9.8.8 
6. Added Analyses of COVID-19 impacted data: “Analyses will be performed to 
assess the impact of COVID-19 on the amount of data collected for the study.” 
Affected section: Section 9.9.1 
 
 


Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 4 of 66 
CONFIDENTIAL  
 
 
 
Table of Contents 
1. 
Introduction ........................................................................................................... 11 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 11 
2.1 
Objectives and Endpoints/Estimands ........................................................ 11 
2.2 
Hypotheses and/or Estimations ................................................................. 13 
3. 
Study Overview .................................................................................................... 14 
3.1 
Study Design ............................................................................................. 14 
3.2 
Sample Size .............................................................................................. 15 
3.3 
Adaptive Design ........................................................................................ 16 
4. 
Covariates and Subgroups ................................................................................... 16 
4.1 
Planned Covariates ................................................................................... 16 
4.2 
Subgroups ................................................................................................. 16 
5. 
Definitions ............................................................................................................. 17 
5.1 
Baseline Definitions ................................................................................... 17 
5.2 
Time Points ............................................................................................... 18 
5.3 
Derivation of Efficacy Endpoints ................................................................ 18 
5.3.1 
Static Physician Global Assessment (sPGA) ............................. 18 
5.3.2 
Psoriasis Area and Severity Index (PASI) .................................. 18 
5.3.3 
Body Surface Area (BSA) .......................................................... 19 
5.3.4 
Scalp Physician Global Assessment (ScPGA) ........................... 19 
5.3.5 
Modified Static Physician Global Assessment of 
Genitalia (sPGA-G) ................................................................... 19 
5.3.6 
Modified Whole Body Itch Numeric Rating Scale 
(NRS) Assessment .................................................................... 20 
5.3.7 
Children’s Dermatology Life Quality Index (CDLQI) ................... 20 
5.3.8 
Family Dermatology Life Quality Index (FDLQI) ......................... 21 
5.4 
Derivation of Safety Endpoints .................................................................. 21 
5.4.1 
Treatment-emergent Adverse Event .......................................... 21 
5.4.2 
Treatment-emergent Adverse Events Leading to Drug 
Withdrawal, Leading to Drug Interruption, and Leading 
to Death, and Drug-related Treatment-emergent 
Adverse Events ......................................................................... 22 
5.4.3 
Stool Diary for Diarrhea ............................................................. 22 
5.4.4 
Psychiatric Evaluation ............................................................... 22 
5.4.5 
Psoriasis Flare and Psoriasis Rebound ..................................... 22 
5.4.6 
Body Weight, Height and Body Mass Index (BMI) ..................... 23 
5.4.7 
Vital Signs ................................................................................. 24 
5.4.8 
Clinical Laboratory Evaluations ................................................. 24 
6. 
Analysis Sets ........................................................................................................ 24 
6.1 
Intent-to-treat Population ........................................................................... 24 
6.2 
Safety Analysis Set ................................................................................... 24 


Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 5 of 66 
CONFIDENTIAL  
 
 
 
6.2.1 
Placebo-controlled Phases (Weeks 0 to16) ............................... 24 
6.2.2 
Apremilast Extension Phase (Weeks 16 to 52) .......................... 24 
6.2.3 
Apremilast-exposure Period ...................................................... 25 
6.3 
Per Protocol Set(s) .................................................................................... 25 
6.4 
Health-related Quality-of-Life or Health Economics Analyses 
Set(s) ........................................................................................................ 25 
....................... 25 
6.6 
Interim Analyses Set(s) ............................................................................. 25 
6.7 
Study-specific Analysis Sets...................................................................... 25 
7. 
Planned Analyses ................................................................................................. 25 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 25 
7.2 
Primary Analysis ....................................................................................... 26 
7.3 
Final Analysis ............................................................................................ 26 
7.4 
Analysis Phases or Periods ....................................................................... 26 
7.4.1 
Analysis Phases ........................................................................ 26 
7.4.2 
Apremilast-exposure Period for Safety Analysis ........................ 27 
8. 
Data Screening and Acceptance ........................................................................... 27 
8.1 
General Principles ..................................................................................... 27 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 27 
8.3 
Handling of Missing and Incomplete Data ................................................. 28 
8.4 
Detection of Bias ....................................................................................... 28 
8.5 
Outliers ..................................................................................................... 28 
8.6 
Distributional Characteristics ..................................................................... 29 
8.7 
Validation of Statistical Analyses ............................................................... 29 
9. 
Statistical Methods of Analysis.............................................................................. 29 
9.1 
General Considerations ............................................................................. 29 
9.2 
Subject Accountability ............................................................................... 30 
9.3 
Important Protocol Deviations ................................................................... 30 
9.3.1 
Treatment Compliance .............................................................. 31 
9.3.1.1 
Placebo-controlled Phase (Weeks 0 to 16) .............. 31 
9.3.1.2 
Apremilast Extension Phase (Weeks 16 to 
52) ........................................................................... 31 
9.3.1.3 
Apremilast-exposure Period .................................... 31 
9.4 
Subject Disposition .................................................................................... 31 
9.5 
Demographic and Baseline Characteristics ............................................... 33 
9.5.1 
Demographics ........................................................................... 33 
9.5.2 
Baseline disease characteristics ................................................ 34 
9.5.3 
Medical History .......................................................................... 35 
9.5.4 
Concomitant Procedures ........................................................... 35 
9.5.5 
Prior and Concomitant Medications ........................................... 35 


Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 6 of 66 
CONFIDENTIAL  
 
 
 
9.6 
Treatment Duration ................................................................................... 36 
9.6.1 
Placebo-controlled Phase (Weeks 0 to 16) ................................ 36 
9.6.2 
Apremilast Extension Phase (Weeks 16 to 52) .......................... 36 
9.6.3 
Apremilast-exposure Period ...................................................... 37 
9.7 
Efficacy Analyses ...................................................................................... 37 
9.7.1 
Multiplicity Adjustment ............................................................... 37 
9.7.2 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 37 
9.7.3 
Analyses of Major Secondary Efficacy Endpoint(s) .................... 39 
9.7.4 
Analyses of Other Secondary Efficacy Endpoint(s) .................... 41 
9.7.4.1 
Binary Variables ...................................................... 41 
9.7.4.2 
Continuous Variables .............................................. 42 
9.7.5 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 42 
9.7.5.1 
Study Phases .......................................................... 43 
9.7.5.2 
sPGA, PASI and BSA .............................................. 44 
9.7.5.3 
ScPGA and Modified sPGA-G ................................. 44 
9.7.5.4 
CDLQI and FDLQI ................................................... 44 
9.7.5.5 
Modified Whole Body Itch Numeric Rating 
Scale (NRS) ............................................................ 45 
9.7.6 
Assessing Study Site Effect ....................................................... 45 
9.8 
Safety Analyses ........................................................................................ 46 
9.8.1 
Adverse Events ......................................................................... 47 
9.8.1.1 
Overall Summary of TEAEs ..................................... 48 
9.8.1.2 
All TEAEs ................................................................ 48 
9.8.1.3 
Common TEAEs ..................................................... 49 
9.8.1.4 
Drug-related TEAEs ................................................ 49 
9.8.1.5 
TEAEs by Maximum Severity .................................. 49 
9.8.1.6 
Serious TEAEs ........................................................ 49 
9.8.1.7 
TEAEs Leading to Drug Interruption and 
TEAEs Leading to Drug Withdrawal ........................ 49 
9.8.1.8 
Deaths..................................................................... 50 
9.8.1.9 
Onset and duration .................................................. 50 
9.8.2 
Laboratory Test Results ............................................................ 50 
9.8.3 
Vital Signs ................................................................................. 50 
9.8.4 
Physical Measurements ............................................................ 51 
9.8.5 
Electrocardiogram ..................................................................... 51 
9.8.6 
Antibody Formation ................................................................... 51 
9.8.7 
Exposure to Concomitant Medication ........................................ 51 
9.8.8 
Exposure to Concomitant Procedures ....................................... 51 
9.8.9 
Stool Diary for Diarrhea ............................................................. 51 
9.8.10 
Psychiatric Evaluation ............................................................... 52 
9.8.11 
Tanner Staging of Sexual Development .................................... 52 
9.8.12 
Psoriasis Flare and Rebound .................................................... 52 
9.8.13 
Weight, Height and BMI ............................................................. 52 


Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 7 of 66 
CONFIDENTIAL  
 
 
 
9.9 
Other Analyses ......................................................................................... 52 
9.9.1 
Analyses of COVID-19 impacted data ....................................... 52 
....................... 53 
....................... 53 
10. 
Changes From Protocol-specified Analyses.......................................................... 53 
11. 
Literature Citations / References ........................................................................... 53 
12. 
Prioritization of Analyses....................................................................................... 54 
13. 
Data Not Covered by This Plan............................................................................. 54 
14. 
Appendices ........................................................................................................... 55 
Appendix A. Criteria for Marked Abnormalities Value ................................ 56 
Appendix B. Analytical Windows ............................................................... 58 
Appendix C. Partially Missing Date Imputation .......................................... 60 
Adverse Events ......................................................................... 60 
Prior/Concomitant Medications/Procedures ............................... 63 
Medical History .......................................................................... 64 
Treatment Duration ................................................................... 65 
Appendix D. Reporting conventions .......................................................... 66 
 
List of Table 
Table 1. Table for Visit Mapping for by Time Point Analysis .......................................... 58 
Table 2. Adjustment of Study Weeks for Placebo Subjects Who Are Treated 
with Apremilast 20 or 30 mg BID after Week 16 in Summary of 
Safety Data over Time ............................................................................ 59 
Table 3. Imputation Rules for Partially Missing AE Start Dates for Subjects 
Who Were Treated with Apremilast Initially ............................................. 60 
Table 4. Imputation Rules for Partially Missing AE Start Dates for Subjects 
Who Were Treated with Placebo Initially ................................................. 61 
 
List of Figures 
Figure 1: Study Design .................................................................................................. 15 
 
 
List of Appendices 
Appendix A. Criteria for Marked Abnormalities Value .................................................... 56 
Appendix B. Analytical Windows.................................................................................... 58 


Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 8 of 66 
CONFIDENTIAL  
 
 
 
Appendix C. Partially Missing Date Imputation .............................................................. 60 
Appendix D. Reporting conventions ............................................................................... 66 
  
 
 
 


Product:  AMG 407 
Protocol Number:  20200056 
Date:  20 December 2021 
Page 9 of 66 
CONFIDENTIAL  
 
 
 
List of Abbreviations 
 
Abbreviation 
Explanation 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance (model) 
ATC 
Anatomical-Therapeutic-Chemical 
BID 
Twice Daily 
BMI 
Body Mass Index 
BSA 
Body Surface Area (%) Affected by Psoriasis 
CDC 
Centers for Disease Control and Prevention 
CDLQI 
Children’s Dermatological Life Quality Index 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CRF or eCRF 
(electronic) Case Report Form 
CRO 
Contract Research Organization  
CRP 
Clinical Research Physician 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
FCBP 
Female of Childbearing Potential 
FDLQI 
Family Dermatological Life Quality Index 
HRQoL 
Health-Related Quality of Life 
IP 
Investigational Product 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
LS Mean 
Least Square Mean 
MCID 
Minimal Clinically Important Difference  
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
NRI 
Non-responder Imputation  


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NRS 
Numeric Rating Scale 
PASI 
Psoriasis Area Severity Index 
PBO 
Placebo 
PD 
Pharmacodynamic 
PG 
Pharmacogenetic 
PK 
Pharmacokinetic 
PP 
Per-Protocol (population) 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
ScPGA 
Scalp Physician Global Assessment 
SD or STDEV 
Standard Deviation 
SE 
Standard Error  
SI 
Standard International (unit) 
sPGA 
Static Physician Global Assessment 
sPGA-G 
Static Physician Global Assessment of Genitalia 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
USA 
United States of America 
WHODD 
World Health Organization Drug Dictionary 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for apremilast (CC-10004, AMG 
407) Study CC-10004-PPSO-003 (20200056), dated 17 Dec. 2021. The scope of this 
plan includes the primary analysis and the final analysis that are planned and will be 
executed by the Amgen Global Biostatistical Science department unless otherwise 
specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the clinical efficacy of 
apremilast compared with placebo in 
children and adolescents (ages 6 
through 17 years) with moderate to 
severe plaque psoriasis 
 
sPGA 0/1: Proportion of subjects with 
an sPGA score of clear (0) or almost 
clear (1) with at least a 2-point 
reduction from baseline at Week 16 
Secondary 
 
To evaluate the safety and tolerability 
of apremilast compared with placebo, 
in children and adolescents (ages 6 
through 17 years) with moderate to 
severe plaque psoriasis 
 
To evaluate the effect of apremilast 
compared with placebo on health-
related quality of life (HRQoL) 
 
PASI-75: Proportion of subjects who 
achieve at least a 75% reduction in 
PASI (PASI-75) from baseline at 
Week 16 
 
PASI-50: Proportion of subjects who 
achieve at least a 50% reduction in 
PASI (PASI-50) from baseline at 
Week 16 
 
PASI: Percent change from baseline 
in total PASI score at Week 16 
 
BSA: Percent change from baseline in 
affected BSA at Week 16 
 
CDLQI (0/1): Proportion of subjects 
who achieve CDLQI (0/1) at Week 16 
 
CDLQI: Change from baseline in 
CDLQI score at Week 16 
 
Adverse events: Type, frequency, 
severity, and relationship of AEs to IP 
for study duration (up through 14-
week follow-up) 
 
Diarrhea: Stool Diary (frequency, 
duration and associated symptoms) 


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for Study duration (up through 4-week 
follow-up)   
 
Depression, suicidal thoughts and 
behavior: Columbia-Suicide Severity 
Rating Scale (C-SSRS) questionnaire 
completed at screening and each visit 
thereafter for study duration (up 
through Week 52) 
 
Growth and Development:  
- 
Tanner Staging of sexual 
development performed at 
beginning and end of study (Week 
52 or ET) 
- 
Body weight, height and BMI for 
study duration 
 
Psoriasis Flare for study duration 
(while taking study medication) 
 
Psoriasis Rebound in 14-week follow-
up period 
 
 
 
Exploratory 
 
To evaluate the effect of apremilast 
on plaque psoriasis 
 
To evaluate the effect of apremilast 
on plaque psoriasis of the scalp 
 
To evaluate the effect of apremilast 
on genital psoriasis 
 
To evaluate the effect of apremilast 
on itch over the whole body caused 
by plaque psoriasis 
 
To evaluate the effect of apremilast 
on HRQoL of family members 
 
PASI-50: Proportion of subjects who 
achieve PASI-50 at all visits 
 
PASI-75: Proportion of subjects who 
achieve PASI-75 at all visits 
 
PASI-90: Proportion of subjects who 
achieve PASI-90 at all visits 
 
PASI: Percent change from baseline 
in total PASI score at all visits 
 
sPGA (0/1): Proportion of subjects 
with sPGA of clear (0) or almost clear 
(1) with at least a 2-point reduction 
from baseline at all visits 
 
BSA: Percent change from baseline in 
affected BSA at all visits 
 
ScPGA: Proportion of subjects with 
scalp psoriasis with improvement of 
ScPGA of clear (0) or almost clear (1) 
at select visits 
 
Modified sPGA-G: Proportion of 
subjects with genital psoriasis with 


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improvement of sPGA-G of clear (0) 
or almost clear  (1) at select visits 
 
Modified Whole Body Itch NRS: 
Proportion of subjects with ≥ 4-point 
reduction (improvement) from 
Baseline in the whole body itch NRS 
score at select visits 
 
Modified Whole Body Itch NRS: 
Change from Baseline in the whole 
body itch NRS score at select visits 
 
CDLQI (0/1): Proportion of subjects 
who achieve CDLQI (0/1) at select 
visits 
 
CDLQI: Change from baseline in 
CDLQI score at select visits  
 
FDLQI (0/1): Proportion of subjects 
achieving FDLQI (0/1) at select visits 
 
FDLQI: Change from baseline in 
FDLQI score at select visits 
 
2.2 
Hypotheses and/or Estimations 
The primary hypothesis for this study is: Apremilast is superior to placebo in subjects 
with moderate to severe psoriasis as measured by proportion of subjects with a sPGA 
score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline at 
Week 16. 
The major secondary hypothesis for this study is: Apremilast is superior to placebo in 
subjects with moderate to severe psoriasis as measured by proportion of subjects 
achieving at least a 75% reduction in PASI (PASI-75) from baseline at Week 16. 
 


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3. 
Study Overview 
3.1 
Study Design 
This is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study of the 
efficacy and safety of apremilast (CC-10004) in pediatric subjects with moderate to 
severe plaque psoriasis. 
At least 230 pediatric subjects (ages 6 through 17 years) will be randomized 2:1 to 
receive either apremilast or placebo for the first 16 weeks. Randomization to apremilast 
arm or placebo arm will be stratified by age group (6-11 yrs or 12-17 yrs). A minimum of 
75 subjects will be randomized in each age group. Treatment will be assigned by 
baseline weight with subjects 20 kg to < 50 kg receiving apremilast 20 mg BID or 
placebo BID and subjects ≥ 50 kg receiving apremilast 30 mg BID or placebo BID. After 
all subjects have completed Week 16 (Visit 7), or discontinued from the study, a Week 
16 database lock will be performed; the primary data analysis will be conducted and a 
Week 16 clinical study report will be generated. Study investigators and subjects will 
remain blinded to initial treatment assignments until the final database lock at the 
conclusion of the study. The blind also should be maintained for persons responsible for 
the ongoing conduct of the study. Blinded persons may include but are not limited to: 
clinical research physician, clinical research scientist, clinical trial manager, study 
statistician, data manager, statistical programmer, and clinical research associate. At the 
end of the study, after all subjects have either completed Week 52 (Visit 16) and entered 
the Long-term Study, or completed the Observational Follow-up Phase, a final analysis 
will be performed and a final clinical study report will be generated. 
Subjects must have a diagnosis of chronic, stable plaque psoriasis at least 6 months 
prior to screening and which is considered inadequately controlled by or inappropriate 
for topical therapy to qualify for this study. In addition, the subjects must have a 
Psoriasis Area Severity Index (PASI) score ≥ 12, body surface area (BSA) involvement ≥ 
10% and static Physician Global Assessment (sPGA) ≥ 3 (moderate to severe) at 
screening and baseline (Week 0). 
The study will consist of four phases: 
• 
Screening Phase – up to 35 days 
• 
Double-blind, Placebo-controlled Phase – Weeks 0-16 
- 
Subjects will be randomly assigned in a 2:1 ratio to weight-based 
apremilast or placebo.   


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- 
From Week 8 through Week 16, any subject with a PASI increase ≥ 50% 
from baseline will be eligible to commence treatment with moderate-to-
high potency topical steroid preparations (early escape) and continue with 
randomized IP. 
• 
Apremilast Extension Phase – Weeks 16-52 
- 
Placebo subjects will be switched at Week 16 to receive apremilast 20 mg 
BID or 30 mg BID, according to baseline weight. All other subjects will 
continue to receive either apremilast 20 mg BID or apremilast 30 mg BID 
based on their original dosing assignment. 
• 
Observational Follow-up Phase – 14 weeks 
- 
All eligible subjects who complete the Apremilast Extension Phase may 
opt to enroll in a separate Long-term Study (for up to 4 years or until 
approval, whichever comes first). Subjects who choose not to participate 
in the Long-term Study, or discontinue the study early, should return for 
observational follow-up visits four, eight, and fourteen weeks after the last 
dose of study drug. 
Figure 1: Study Design 
 
3.2 
Sample Size 
At least 230 pediatric subjects (ages from 6 through 17 years) will be randomized to 
receive either apremilast or placebo (2:1) at Week 0. The sample size estimation is 
based on the results of the adult Phase 3 and 3b studies with apremilast (CC-10004-
PSOR-008, PSOR-009 and PSOR-010) which demonstrated positive treatment effects 


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between apremilast and placebo in the proportion of subjects achieving sPGA response 
and PASI-75 response at Week 16.  
With a total of 230 patients and a randomization ratio of 2:1, the study will have 90% 
power to detect a 15% difference (20% versus 5%) between the apremilast arm and the 
placebo arm for the proportion of subjects achieving sPGA response at Week 16, based 
on a Chi-square test at a two-sided significance level of 0.05. The study will also have 
more than 95% power to detect a 20% difference (30% versus 10%) between apremilast 
and placebo for the proportion of subjects achieving PASI-75 response at Week 16. 
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The study will be stratified by age group (6 to 11 years or 12 to 17 years). Of the 
analyses, the CMH test for the binary endpoints and the ANCOVA model for the 
continuous endpoints will be adjusted for the baseline value. 
4.2 
Subgroups 
Subgroup analysis will be carried out for sPGA and PASI-75 responses at Week 16 in 
the Placebo-controlled Phase based upon baseline demographics and disease 
characteristics. These two endpoints will also be evaluated in patients using or not using 
low potency topical corticosteroids in the phase as two subgroups. Summary and 
analysis will be based on ITT population and missing values will be imputed using MI 
method. Treatment difference of response rates will be reported with two-sided 95% CI.  
The following subgroup variables will be used: 
· 
Sex (Male, Female)  
· 
Race (White, Non-white) 
· 
Age category (6-11 years, 12-17 years) 
· 
Baseline weight category (≥ 20 kg to < 50 kg, ≥ 50 kg) 
· 
Age and baseline weight category 
- 
6-11 years and ≥ 20 kg to < 50 kg 
- 
6-11 years and ≥ 50 kg 
- 
12-17 years and ≥ 20 kg to < 50 kg 


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- 
12-17 years and ≥ 50 kg 
· 
Baseline BMI category (Underweight, Healthy Weight, Overweight, Obesity) 
· 
Geographical region (USA, Canada, Europe, Rest of the World) 
· 
Duration of plaque psoriasis categories 
· 
Baseline sPGA score 3 (moderate), 4 (severe) 
· 
Baseline PASI score categories 
· 
Baseline BSA (%) categories 
· 
Baseline CDLQI total score categories 
· 
Baseline whole body itch NRS categories 
· 
Baseline ScPGA categories 
· 
Baseline sPGA-G categories 
· 
Prior phototherapies (Used or Never used) 
· 
Prior conventional systemic therapies (Used or Never used) 
· 
Prior biologic therapies (Used or Never used) 
· 
Prior systemic therapies (Used or Never used) 
5. 
Definitions 
5.1 
Baseline Definitions 
For efficacy analysis and summary of baseline disease characteristics data, baseline is 
defined as the last value measured prior to or at the randomization date. 
For safety analyses in the Placebo-controlled Phase, baseline will be relative to the first 
dose date following randomization at Week 0. It is the last value measured prior to or on 
the day of the first dose of IP.  
For safety analyses in Apremilast Exposure Period, baseline will be relative to the first 
apremilast dose date at Week 0 for subjects initially randomized to apremilast or Week 
16 for subjects initially randomized to placebo and switched to apremilast in the 
Extension Phase. It is the last value measured prior to or at the first apremilast dose 
date. 


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5.2 
Time Points 
Time points in all analyses are based on the remapped visits/study weeks using the 
following visit mapping algorithm, which may or may not be the same as the visits/study 
weeks as recorded in the database. 
Data collected in the placebo-controlled phase and apremilast extension phase will be 
summarized based on the weeks specified in protocol; the observational Follow-up 
Phase will be summarized separately using the three follow-up visits, i.e., 4-Week 
Follow-up, 8-Week Follow-up, 14-Week Follow-up. 
The details are specified in Appendix B. 
5.3 
Derivation of Efficacy Endpoints 
The derivation of efficacy endpoints is described below in separate sections. Baseline 
definition for all efficacy endpoints is given in Section 5.1. Change from baseline is 
calculated as post-baseline visit value minus the baseline value. Percent change from 
baseline is defined as 100* Change from baseline/Baseline value (%). Handling of time 
points is described in Section 5.2. 
5.3.1 
Static Physician Global Assessment (sPGA) 
The sPGA is the assessment of whole body psoriasis by the investigator of the overall 
disease severity at the time of evaluation. The sPGA is a 5-point scale ranging from 
clear (0), almost clear (1), mild (2), moderate (3), to severe (4), incorporating an 
assessment of the severity of the three primary signs of the disease: erythema, scaling 
and plaque elevation.   
The sPGA response at a post-baseline visit is defined as achieving sPGA score of clear 
(0) or almost clear (1) with at least a 2-point reduction from baseline. 
5.3.2 
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. PASI scores range from 0 to 72, with higher 
scores reflecting greater disease severity. Erythema, thickness, and scaling are scored 
on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, 
upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions 
is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement).  The total 
qualitative score (sum of erythema, thickness, and scaling scores) is multiplied by the 
degree of involvement for each anatomic region and then multiplied by a constant.  


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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. For post-baseline 
visits, PASI score change and percent change from baseline will be derived. PASI score 
percent change will be rounded to integers. 
For post-baseline visit, a subject is classified as having achieved PASI-75 (PASI-75 
response) if the PASI score is reduced by at least 75% from baseline, which is 
equivalent to a percent change from baseline ranging from −100% to −75%.  PASI-50 
and PASI-90 are similarly defined as PASI score reduction from baseline by at least 50% 
or 90%, respectively. 
5.3.3 
Body Surface Area (BSA) 
BSA is a measurement of involved skin over the whole body.  The overall BSA affected 
by psoriasis is estimated based on the palm area of the subject’s hand.  The surface 
area of the whole body is made up of approximately 100 palms or “handprints” (each 
entire palmar surface or “handprint” equates to approximately 1% of total body surface 
area). 
BSA scores will be presented with one digit after the decimal point. For post-baseline 
visits, BSA score change and percent change from baseline will be derived. BSA score 
percent change will be rounded to integers.   
5.3.4 
Scalp Physician Global Assessment (ScPGA) 
The ScPGA is the Investigator’s assessment of severity of psoriasis of the scalp, if 
present at Baseline. The ScPGA is a 5-point scale ranging from clear (0), almost clear 
(1), mild (2), moderate (3), to severe (4).  
The ScPGA response at a post-baseline visit is defined as achieving ScPGA score of 
clear (0) or almost clear (1). 
5.3.5 
Modified Static Physician Global Assessment of Genitalia (sPGA-G) 
The modified sPGA-G is the Investigator’s assessment of severity of psoriasis of the 
genitals, if present at Baseline. It is a 5-point scale ranging from clear (0), almost clear 
(1), mild (2), moderate (3), to severe (4).  
The modified sPGA-G response at a post-baseline visit is defined as achieving sPGA-G 
score of clear (0) or almost clear (1). 


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5.3.6 
Modified Whole Body Itch Numeric Rating Scale (NRS) Assessment 
The modified whole body itch NRS assessment is a tool designed to measure the 
amount of whole body itch due to psoriasis by circling a number on a scale from 0 to 10. 
Subjects will be asked to assess their worst level whole body itch in 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.  
For a post baseline visit, the whole body itch NRS response is defined as ≥ 4 points 
reduction (improvement) from baseline in the NRS score. Change from baseline in the 
NRS score will also be derived. 
5.3.7 
Children’s Dermatology Life Quality Index (CDLQI) 
The Children’s Dermatology Life Quality Index questionnaire is designed for use in 
children, i.e. patients from age 4 to age 16. It is self-explanatory and can be simply 
handed to the patient who is asked to fill it in with the help of the child’s parent or 
guardian. The instrument contains 10 questions, which have scores ranging from Very 
much (3), Prevented school (3) for Question 7, Quite a lot (2), Only a little (1), to Not at 
all (0).  
The CDLQI is calculated by summing the score of each question resulting in a maximum 
of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. If 
one of the 10 items is left unanswered, it is scored 0 and the total scores are summed 
and expressed as usual out of a maximum of 30. If two or more of the ten items are left 
unanswered, the total score will be left missing. If both parts of question 7 are completed 
the higher of the two scores should be counted. The severity banding for CDLQI total 
scores are: 
• 
0-1 = no effect on child’s life  
• 
2-6 = small effect  
• 
7-12 = moderate effect  
• 
13-18 = very large effect  
• 
19-30 = extremely large effect 
For CDLQI total score, change form baseline will be derived, where change = visit value 
− baseline value. For a post-baseline visit, CDLQI (0/1) response is defined as achieving 
CDLQI total scores 0 or 1.   


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5.3.8 
Family Dermatology Life Quality Index (FDLQI) 
The Family Dermatology Life Quality Index is a questionnaire designed for adult (more 
than 16 years of age) family members or partners of patients with any skin disease. The 
FDLQI total score is calculated by summing the score of each question resulting in a 
maximum of 30 and a minimum of 0. The higher the score, the more quality of life is 
impaired.  
If one question is left unanswered then it is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. If two or more questions are left 
unanswered then the questionnaire is not scored. 
For FDLQI total score, change from baseline will be derived, where change = visit value 
− baseline value. For a post-baseline visit, FDLQI (0/1) response is defined as achieving 
FDLQI total scores 0 or 1. 
5.4 
Derivation of Safety Endpoints 
Baseline definition for all safety endpoints is given in Section 5.1. Change from baseline 
is calculated as post-baseline visit value minus the baseline value. Handling of time 
points is described in Section 5.2. 
5.4.1 
Treatment-emergent Adverse Event 
An AE is a treatment-emergent AE (TEAE) if the AE start date is 
• 
On or after the date of the first dose of IP and no later than 28 days after the last 
dose of IP for subjects who have completed study treatment or have discontinued early 
by the time of database cut, or 
• 
On or after the date of the first dose of IP for subjects who are ongoing with study 
treatment at the time of database cut. 
If the treatment-emergent status of an AE is unclear due to a missing/incomplete start 
date, it will always be considered treatment-emergent, unless shown otherwise by data. 
Date imputation rules for missing AE start dates are described in Appendix C. 
For the Placebo-controlled Phase (Weeks 0-16), TEAEs include adverse events started 
on or after the first IP dose date and prior to the first dose date of the Apremilast 
Extension Phase for subjects who also received treatment in the Apremilast Extension 
Phase or within 28 days of the last dose date for subjects who received treatment only in 
the Placebo-controlled Phase.  


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For the Apremilast Extension Phase (Weeks 16-52), TEAEs include adverse events 
started on or after the first dose date of the Apremilast Extension Phase and within 28 
days of the last dose date.  
For the Apremilast-exposure Period, TEAEs include adverse events started on or after 
the first Apremilast dose date and within 28 days of the last Apremilast dose date. 
Adverse event started more than 28 days after the last dose of IP will not be considered 
as a treatment-emergent AE. 
5.4.2 
Treatment-emergent Adverse Events Leading to Drug Withdrawal, 
Leading to Drug Interruption, and Leading to Death, and Drug-
related Treatment-emergent Adverse Events 
A TEAE leading to drug withdrawal is a TEAE for which the investigator indicates that 
the action taken with respect to IP is withdrawn permanently. A TEAE leading to drug 
interruption is a TEAE for which the investigator indicates that the action taken with 
respect to IP is interrupted. A TEAE leading to death is a TEAE for which the outcome is 
fatal. Relationship to IP is based on the investigator's causality judgment; that is, a drug-
related AE is an AE indicated by the investigator to have a suspected relationship to IP. 
5.4.3 
Stool Diary for Diarrhea 
Subjects and their parent/guardian will be supplied with paper diaries that will be filled 
out daily to record and describe any diarrhea, including duration, frequency, treatment, 
and associated symptoms. Subjects and their parent/guardian will complete the Stool 
Diary every day beginning after the first dose of apremilast, up to the 4-week post last 
dose follow-up visit. 
5.4.4 
Psychiatric Evaluation 
Subjects will complete the Columbia-Suicide Severity Rating Scale (C-SSRS) 
assessment. This questionnaire is suitable for assessment of suicidal ideation and 
behavior in clinical and research settings. The assessment will be completed at 
screening, baseline, and at post-baseline visits. 
Any subject that answers ‘Yes’ to any question on the C-SSRS at any time during the 
study will be immediately withdrawn from study treatment. 
5.4.5 
Psoriasis Flare and Psoriasis Rebound 
Psoriasis flare was considered an AE (and was to be recorded as an AE) and represents 
an atypical or unusual worsening of disease during treatment. It was defined as a 
sudden intensification of psoriasis requiring medical intervention or a diagnosis of new 


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generalized erythrodermic, inflammatory, or pustular psoriasis. A more typical, gradual 
worsening of plaque psoriasis was not to be recorded as an AE. 
Rebound was considered as AE and was defined as a severe and sudden worsening of 
disease that occurred after treatment had been discontinued. This exacerbation is 
characterized by PASI ≥ 125% of baseline or a new generalized pustular, erythrodermic, 
or more inflammatory psoriasis after stopping therapy. 
Psoriasis adverse events will be selected as those containing the word “psoriasis” in the 
coded preferred term. A psoriasis flare is defined as a psoriasis adverse event started 
during treatment with IP. A psoriasis rebound is defined as a psoriasis adverse event 
started after the last dose of IP. 
5.4.6 
Body Weight, Height and Body Mass Index (BMI) 
Body weight (kg) and Height (cm) will be measured and recorded at study visits. The 
BMI (kg/m2) is calculated as BMI = Weight / (Height/100)2. The variables include the 
observed value, change and percent change from baseline over time. 
It is now common practice to express child growth status in the form of the BMI standard 
deviation scores (Z-score). The LMS method provides a way of obtaining normalized 
growth centile standards. It assumes that the data can be normalized by using a power 
transformation, which stretches one tail of the distribution and shrinks the other, 
removing the skewness. The LMS parameters are the power in the Box-Cox 
transformation (L), the median (M), and the generalized coefficient of variation (S).  
For a given value of BMI of a boy or girl with known age, the corresponding z-score (Z) 
can be calculated as:  
Z = [(BMI/M)L – 1]/LS,  
where the coefficients L, M, S are from the BMI percentile values in Data Tables of BMI-
for-age Charts (CDC 2000). The tables list L, M, S values for boys or girls with age 
ranging from 2 to 20 years old.  
BMI are classified using z-score (Z) as:  
• 
Underweight: Percentile < 5 
• 
Healthy Weight: Percentile ≥ 5 to < 85 
• 
Overweight: Percentile ≥ 85 to < 95 
• 
Obesity: Percentile ≥ 95 


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5.4.7 
Vital Signs 
Vital signs include:  
• 
Observed value and change from baseline over time in vital signs (temperature, 
pulse, and blood pressure) 
• 
Shifts from baseline to post-baseline timepoints 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) 
5.4.8 
Clinical Laboratory Evaluations 
Laboratory evaluations include:  
• 
Observed value and change from baseline over time in hematology and serum 
chemistry parameters 
• 
Laboratory marked abnormalities 
• 
Shifts from baseline to post-baseline time points and to the worst post-baseline 
value in terms of normal/abnormal (low or high) in hematology and serum chemistry 
parameters 
6. 
Analysis Sets 
6.1 
Intent-to-treat Population 
The intent-to-treat (ITT) population will consist of all subjects who are randomized 
regardless of whether or not the subject received IP. Subjects will be included in the 
treatment group to which they are randomized. 
6.2 
Safety Analysis Set 
6.2.1 
Placebo-controlled Phases (Weeks 0 to16) 
The safety population will consist of all subjects who are randomized and received at 
least one dose of investigational product (IP).  Subjects will be included in the treatment 
group corresponding to the IP they actually received (apremilast or placebo) for the 
analyses and summaries using the safety population. 
6.2.2 
Apremilast Extension Phase (Weeks 16 to 52) 
Safety analyses will be based on subjects who are treated in the phase, ie, who receive 
at least one dose of apremilast in the extension phase. At Week 16, subjects will 
continue apremilast treatment or will switch to apremilast treatment from placebo. 


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6.2.3 
Apremilast-exposure Period 
The safety analyses for the Apremilast-exposure Period will be based on the apremilast 
subjects as treated population, which includes all subjects who are randomized to (at 
Week 0/Visit 2) or treated with (at Week 16/Visit 7) apremilast, and receive at least one 
dose of apremilast after randomization or Week 16. 
6.3 
Per Protocol Set(s) 
The per protocol (PP) population will consist of all subjects included in the ITT population 
who receive at least one dose of IP, have both baseline and at least one post-treatment 
sPGA assessment, and have no important protocol deviations (IPD) which may affect 
efficacy assessments in the Placebo-controlled Phase. 
6.4 
Health-related Quality-of-Life or Health Economics Analyses Set(s) 
Not applicable. 
6.6 
Interim Analyses Set(s) 
Not applicable. 
6.7 
Study-specific Analysis Sets 
Not applicable. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis will be conducted. 
After all subjects have completed Week 16 (Visit 7), or discontinued from the study, a 
Week 16 database lock will be performed; the primary data analysis will be conducted 
and a Week 16 Clinical Study Report will be generated. Study investigators and subjects 
will remain blinded to treatment assignments until the final database lock at the 
conclusion of the study. The blind also should be maintained for persons responsible for 
the ongoing conduct of the study. Blinded persons may include but are not limited to: 
clinical research physician, clinical research scientist, clinical trial manager, study 
statistician, data manager, programmer, and clinical research associate. At the end of 
the study, after all subjects have either completed the Observational Follow-up Phase, or 
have been discontinued from the Apremilast Extension Phase (Weeks 16 to 52) or the 


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Observational Follow-up Phase, the final analysis will be performed and a final Clinical 
Study Report will be generated. 
7.2 
Primary Analysis 
The primary analysis will be conducted once all subjects have completed week 16 or 
terminated early from the study. At this time, the data will be cleaned, processed, and 
extracted, and restricted. The endpoints will be assessed at the time of the primary 
analysis. 
To maintain the blind at the site and subject level, the individual subject treatment 
assignments will not be revealed to the Investigators until after the final database lock 
following the study completion. 
7.3 
Final Analysis 
The final analysis will be conducted after study completion (end of study for the last 
subject) is reached and all study data are collected. 
7.4 
Analysis Phases or Periods 
For efficacy analysis, different phases will be used. For safety analysis, different phases 
and Apremilast-exposure Period will be used. 
7.4.1 
Analysis Phases 
Per protocol specification, data summary and analysis will be provided for the following 
phases. 
• 
Placebo-controlled Phase – Weeks 0 to16 
This phase starts on the day of randomization (Week 0/Visit 2), and stops on either: (1) 
the day the first IP for the next phase is dispensed at Week 16/Visit 7; or (2) the day of 
the discontinuation visit if the subject discontinued prior to or at Week 16/Visit 7; or (3) 
the last known study day if the subject is lost to follow-up prior to Week 16/Visit 7 during 
the phase. 
For safety analysis in subjects who continued treatment in Apremilast Extension Phase 
(Weeks 16 to 52), the phase stopped one day prior to the first dose date in Apremilast 
Extension Phase.  
• 
Apremilast Extension Phase – Weeks 16 to 52 
This phase starts on the next day the first IP is dispensed for the phase at Week 16/Visit 
7, and stops on either: (1) the day of Week 52/Visit 16; or (2) the day of the 
discontinuation visit if the subject discontinued prior to or at Week 52/Visit 16; or (3) the 


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last known study day if the subject lost to follow-up prior to Week 52/Visit 16 during the 
phase. 
For safety analysis, the phase started at the first dose date in the phase.  
• 
Observational Follow-up Phase – 14 weeks 
Subjects who choose not to participate in a separate Long-term Study (for up to 4 years 
or until approval, whichever comes first), or discontinue the study early, should return for 
observational follow-up visits four, eight and fourteen weeks after the last dose of study 
drug. The 14 weeks Observational Follow-up Phase starts at the next day after the 
completion or discontinuation visit and stops at the last follow-up visit or the last 
assessment date. 
7.4.2 
Apremilast-exposure Period for Safety Analysis 
In addition to the above defined phases, Apremilast-exposure Period will be used for 
safety analyses. 
• 
Apremilast-exposure Period: 
This period starts on the date of either: (1) the first dose of IP following randomization 
(Week 0/Visit 2) for subjects who are treated with apremilast from Week 0; or (2) the first 
dose of IP from the IP dispensed at Week16/Visit 7 for subjects who were originally 
treated with placebo and are treated with apremilast at Week 16. 
This period stops on either: (1) data cut-off date; or (2) the day of the treatment 
discontinuation if the subject discontinued prior to or at Week 52/Visit 16; or (3) the last 
known study day if the subject lost to follow-up prior to Week 52/Visit 16; or (4) Week 
52/Visit 16 visit date. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE 
database. 


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8.3 
Handling of Missing and Incomplete Data 
Missing values at Week 16 for efficacy endpoint will be imputed using the multiple 
imputation (MI) method based on similar subjects who remained in the study as the 
primary method. Sensitivity analysis will be conducted to account for missing data using 
the last observation carried forward (LOCF) method, the non-responder imputation (NRI) 
method and the tipping point analyses. A sensitivity analysis using the PP population will 
also be performed. 
The handling of incomplete and partial dates for adverse events and concomitant 
medications etc. will be described in Appendix C. 
8.4 
Detection of Bias 
The measures to Minimize Bias in this study are Randomization and Blinding. It is not 
expected that any study conduct procedures or statistical analysis will incur bias in the 
study results or conclusions. The potential sources of bias in this study are: 
a) Inadvertent breaking of the blind 
Break of blind should be rare and anticipated only if it is necessary for safety and 
treatment reasons. Should this happen in more than 5% of the subjects in the study, a 
sensitivity analysis may be conducted for the primary endpoint by excluding those 
patients who were unblinded. 
b) Protocol deviations 
A subject list of important protocol deviations will be finalized prior to the database lock 
and unblinding. The impact of protocol deviations on the study results will be 
investigated and a sensitivity analysis may be conducted if deemed necessary by 
comparing the results of the primary endpoint analysis on subjects with and without 
protocol deviations. 
8.5 
Outliers 
Various methods, including univariate summaries, histograms, scatter plots, box plots, 
and line graphs, may be used to identify outliers in key safety and efficacy variables.  
The primary analyses will include outliers in the data. Sensitivity analyses may be 
undertaken if extreme outliers for a variable are observed.  


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8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required, data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
The intent-to-treat principle will be used in statistical analyses for efficacy endpoints. For 
the Placebo-controlled Phase (Weeks 0-16), efficacy evaluations will be conducted using 
the intent-to-treat (ITT) population defined as all randomized subjects. Statistical 
comparisons will be made between the two treatment arms (placebo or apremilast). The 
apremilast arm will include both 20 mg BID and 30 mg BID, since subjects will receive 
weight-based apremilast doses which will provide comparable exposure to the adult 
subjects treated with 30 mg BID. For the Apremilast Extension Phase (Weeks 16-52), 
efficacy evaluations will be conducted using subjects who entered the phase from both 
treatment arms. 
Descriptive statistics (n, mean, SD, median, Q1, Q3, min, max) will be presented for 
appropriate endpoints at specified time points. Specifically, for continuous variables, 
descriptive statistics for assessment values and change (plus percentage change when 
specified) from baseline will be provided. Binary variables will be summarized with 
frequency tabulations.  
Statistical comparisons will be made between placebo arm and apremilast arm; the null 
hypothesis is that the effects of the two treatment arms (i.e., placebo vs. apremilast) 
have no difference. Statistical tests will be at the two-sided 0.05 significance level and 
the corresponding p-values and two-sided 95% confidence intervals will be reported. For 
the primary and the major secondary endpoints, the sequential approach will be used for 


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multiplicity adjustment to control the overall type I error rate. The primary approach for 
treating missing values will be multiple imputation (MI) methods. 
For binary endpoints, the two arms will be compared using Cochran–Mantel–Haenszel 
(CMH) test adjusted by stratification factors. For continuous endpoints, the analysis of 
covariance (ANCOVA) model will be performed. The ANCOVA model will have the 
change or percent change from baseline as the dependent variable and will include 
treatment arms and stratification factors as independent variables and the baseline value 
as a covariate variable. 
9.2 
Subject Accountability 
The number and percent of subjects who were screened, randomized, received study 
treatment, and completed the study will be summarized by treatment group. The number 
and percent of subjects who discontinued study treatment, and study will be tabulated, 
along with the reason for discontinuation. The number of subjects included in and 
excluded from each analysis set and reason for exclusion will also be summarized.  
Key study dates for the first subject enrolled, last subject enrolled, last subject’s end of 
IP, and last subject’s end of study will be presented. 
9.3 
Important Protocol Deviations 
Important protocol deviations will be categorized by Clinical Research Physician (CRP). 
A list of important protocol deviations for all subjects for week 16 analysis will be defined 
prior to the database lock and unblinding (i.e., prior to the unblinding of double-blind 
placebo-controlled phase data). The list of important protocol deviations for all subjects 
for final analysis will be finalized prior to the final database lock. This listing of important 
protocol deviation for week 16 analysis will also identify which subjects are to be 
excluded from the per-protocol population. 
Important protocol deviations will be summarized by treatment arm for Placebo-
controlled Phase (Weeks 0 to16) and Apremilast Extension Phase (Weeks 16 to 52). 
Summary tables showing the number and percent of subjects with at least one important 
protocol deviations and by each category of important protocol deviations will be 
provided. Listings of subjects with important protocol deviations will be provided. 
Additionally, protocol deviations and important protocol deviations related to COVID-19 
will be summarized. 


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9.3.1 
Treatment Compliance 
As part of the routine recording of the amount of IP taken by each subject, the numbers 
of tablets dispensed and/or returned will be recorded at visits in treatment phases. 
These records will be used to calculate treatment compliance. 
The treatment compliance for each subject will be computed as 100 times the total 
number of tablets taken (the total number of tablets dispensed minus the total number of 
tablets returned) over the analysis phase or period divided by the intended total number 
of tablets that should have been taken over the same phase or period. 
Summary statistics for compliance (%) will be provided by treatment arm for each 
analysis phase or period. Frequency summary tables of compliance will also be 
presented with the following categories: < 75%, >= 75% to <= 120%, and > 120%. A 
subject data listing of drug accountability records will be provided. 
9.3.1.1 
Placebo-controlled Phase (Weeks 0 to 16) 
Treatment compliance will be calculated for the treatment duration in the phase specified 
in Section 9.6.1 and will be summarized by treatment arm for ITT population. 
9.3.1.2 
Apremilast Extension Phase (Weeks 16 to 52) 
Treatment compliance will be calculated for the treatment duration in the phase specified 
in Section 9.6.2 and will be summarized by treatment arm for the subset of ITT 
population who entered the phase. 
9.3.1.3 
Apremilast-exposure Period 
Treatment compliance will be calculated for the treatment duration in the period specified 
in Section 9.6.3 
Treatment compliance will be summarized for apremilast treatment for apremilast as 
treated population. 
9.4 
Subject Disposition 
The number of subjects screened, the number and percentage of subjects randomized 
(as recorded in the IVRS database) will be summarized. The failed inclusion/exclusion 
criteria of subjects who were screened and not randomized will be included in the 
summary. The above percentages will be based on the number of subjects screened. 
The number and percentage of subjects randomized will be tabulated by treatment arm, 
study site, country and region. The percentages will be based on the number of subjects 
randomized. 


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Subject disposition will be provided by treatment arm and phase: 
• 
Placebo-controlled Phase – Weeks 0 to16 
Summary will be based on subjects who are randomized. Tabulation of subjects 
included in the ITT, PP, and Safety populations, subjects who completed and 
discontinued early will be provided. The primary reasons for early discontinuation 
will also be tabulated. Subjects who completed include subjects who have IP 
dispensed at Week 16/Visit 7, discontinued early subjects include those who 
discontinued prior to the Week 16 visit window. 
• 
Apremilast Extension Phase – Weeks 16 to 52 
Summary will be based on subjects who entered the Apremilast Extension 
Phase, ie, who had IP dispensed for the Phase. Subjects who entered the phase, 
took at least one dose of IP, completed, discontinued early, and primary reason 
for discontinuation will be provided. 
• 
Observational Follow-up Phase (14 weeks)  
Summary will include subjects who entered Follow-up Phase. Subjects who 
entered the phase, completed, discontinued early, and primary reason for 
discontinuation will be provided. 
The primary reasons for discontinuation are collected in the screening disposition, 
treatment disposition and follow-up disposition eCRF using the following categories: 
• 
Adverse Event 
• 
Lack of efficacy 
• 
Withdrawal by subject 
• 
Withdrawal by parent/guardian 
• 
Death 
• 
Lost to follow-up 
• 
Non-compliance with IP 
• 
Protocol deviation 
• 
Pregnancy 
• 
Physician decision 


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• 
Study terminated by Sponsor 
• 
Other 
Discontinued reason due to COVID-19 controlled measure will also be provided. 
9.5 
Demographic and Baseline Characteristics 
Summaries for the demographics, baseline characteristics, prior medication/procedure, 
and concomitant medications/procedure will be presented for the ITT population by 
treatment group and overall.  
9.5.1 
Demographics 
Summary statistics will be provided for the following continuous variables: 
• 
Age (years) 
• 
Weight (kg) 
• 
Height (cm) 
• 
Baseline Body Mass Index (BMI; kg/m2) 
Number and percentage will be provided for the following categorical variables: 
• 
Sex (Male, Female) 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islanders, White, Other) 
• 
Age category (6-11, 12-17 years)  
• 
Baseline weight category (≥ 20 kg to < 50 kg, ≥ 50 kg) 
• 
Age and baseline weight category (6-11 years and ≥ 20 kg to < 50 kg, 6-11 
years and ≥ 50 kg, 12-17 years and ≥ 20 kg to < 50 kg,  12-17 years and ≥ 50 
kg) 
• 
Baseline BMI category (Underweight, Healthy Weight, Overweight, Obesity) 
• 
Geographical region (USA, Canada, Europe, Rest of the World) 
(Note: Subjects ≥ 20 kg to < 50 kg will receive apremilast 20 mg BID or placebo BID and 
subjects ≥ 50 kg will receive apremilast 30 mg BID or placebo BID. Baseline weight at 
randomization will be used to determine apremilast dose level for the whole study.) 


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9.5.2 
Baseline disease characteristics 
Baseline clinical characteristics will be summarized descriptively by treatment group, 
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 (< 1, ≥ 1 to < 2, ≥ 2 to <5, ≥ 5 years) 
• 
Baseline sPGA score: Moderate (3), Severe (4) 
• 
Baseline PASI score 
• 
Baseline PASI score category 
• 
Baseline BSA (%) score 
• 
Baseline BSA (%) score category 
• 
Baseline CDLQI total score 
• 
Baseline CDLQI total score category: No effect on child’s life (0-1); Small 
effect (2-6); Moderate effect (7-12); Very large effect (13-18); Extremely large 
effect (19-30) 
• 
Baseline FDLQI total score 
• 
Baseline ScPGA score 
• 
Baseline sPGA-G score 
• 
Baseline whole body itch NRS 
• 
Baseline whole body itch NRS category (0 to 4, 5 to 10) 
• 
Number of prior phototherapies  
• 
Number of failed prior phototherapies  
• 
Number of prior conventional systemic therapies  
• 
Number of failed prior conventional systemic therapies  
• 
Number of prior biologic therapies  
• 
Number of failed prior biologic therapies  
• 
Number of prior systemic therapies  
• 
Number of failed prior systemic therapies 


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9.5.3 
Medical History 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.0 or higher. A frequency summary (counts and percentage) of 
medical history will be presented by treatment group, system organ class (SOC), and 
preferred term (PT). 
9.5.4 
Concomitant Procedures 
Concomitant procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 24.0 or higher. Frequency summaries of concomitant 
procedures will be provided for the safety population by treatment group, SOC, and PT.  
A concomitant procedure is defined similarly as a TEAE. Concomitant procedures will be 
summarized similarly as TEAEs for (1) Placebo-controlled Phase (Weeks 0 to16), (2) 
Apremilast Extension Phase (Weeks 16 to 52), and (3) Observational Follow-up Phase 
(14 weeks). 
9.5.5 
Prior and Concomitant Medications 
The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health 
Organization Drug Dictionary (WHO DD version March 2020 or later) will be used to 
group prior and concomitant medications and prior psoriasis medications into relevant 
categories. Frequency summaries will be provided by treatment group, ATC level, and 
standardized medication name for the safety population. 
Prior medications are defined as those started before the first dose of IP (whether or not 
ended before the first dose of IP). Prior medications that continue after the first dose of 
IP will also be reported as concomitant medications. 
Prior psoriasis medications will also be classified as phototherapies, biologic therapies, 
conventional systemic therapies, systemic therapies (including both biologic therapies 
and conventional systemic therapies).  
For each of the two treatment phases, concomitant mediations are defined as non-study 
medications started during the phase, or started before the phase and ended or remain 
ongoing during the phase. The treatment phase for concomitant medications will start on 
the first dose date and end one day prior to the last dose date. For the Apremilast 
Exposure Period, concomitant mediations are similarly defined.  
Medications in the Follow-up Phase will include those medications started on or after the 
date of last dose of investigational product. 


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Summaries will be provided for prior psoriasis medications and prior medications, as well 
as for concomitant medications in: (1) Placebo-controlled Phase (Weeks 0 to16), (2) 
Apremilast Extension Phase (Weeks 16 to 52) , (3) Apremilast Exposure Period, and (4) 
Observational Follow-up Phase (14 weeks).  
The following two subsets of concomitant medications will also be listed separately and 
summarized for both treatment phases  and the Apremilast Exposure Period: 
• 
Moderate-to-high potency topical steroid preparations (early escape) or other 
protocol prohibited medications 
• 
Low potency topical corticosteroids 
9.6 
Treatment Duration 
Treatment duration will be summarized by treatment group for the analysis phases and 
for the Apremilast-exposure Period. Subjects who are treated in the corresponding 
phases or period will be used, i.e., the safety population for Placebo-controlled Phase 
(Weeks 0 to16), subjects who are treated in Apremilast Extension Phase (Weeks 16-52), 
and the apremilast subjects as treated population for the Apremilast-exposure Period. 
Summary statistics for treatment duration (in weeks), as well as a frequency summary of 
treatment duration categories (e.g., < 4, ≥ 4 - < 8 weeks, etc.), will be provided.  
9.6.1 
Placebo-controlled Phase (Weeks 0 to 16) 
Treatment duration (in weeks) is calculated from the date of the first dose of IP at Week 
0/Visit 2 to either the date one day prior to the first dose date in the Apremilast Extension 
phase for the IP dispense at Week 16/Visit 7, or the date of the last dose of IP in the 
study for subjects who discontinue in the phase. Imputation rule for partially or 
completely missing last dose date is specified in Appendix C. 
Treatment duration will be summarized by actual treatment (placebo or apremilast) for 
the safety population. 
9.6.2 
Apremilast Extension Phase (Weeks 16 to 52) 
Treatment duration is calculated from the first dose date in the Apremilast Extension 
phase for the IP dispense at Week 16/Visit 7 to the date of the last dose of IP in the 
study for subjects who discontinue in the phase or who complete the study at Week 
52/Visit 16. Imputation rule for partially or completely missing last dose date is specified 
in Appendix C. 


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9.6.3 
Apremilast-exposure Period 
Treatment duration for Apremilast-exposure Period is calculated from the date of the first 
dose of apremilast, which is the date of the first dose of apremilast after randomization at 
Week 0/Visit 2 or switched to apremilast at Week 16/Visit 7, to the last apremilast dose 
date for subjects who discontinue in the first 52 weeks or who complete the study at 
Week 52/Visit 16.  Imputation rule for partially or completely missing last dose date is 
specified in Appendix C. 
9.7 
Efficacy Analyses 
9.7.1 
Multiplicity Adjustment 
The primary and the major secondary efficacy endpoints will be hierarchically ranked for 
testing to control the overall type I error rate in claiming statistical significance at the two-
sided 0.05 significance level.  Specifically, for the primary efficacy endpoint (sPGA 
response at Week 16), if the two-sided p-value from the comparison between apremilast 
arm and placebo arm is below 0.05, the outcome will be considered statistically 
significant and apremilast will be declared effective. For the major secondary endpoint, 
statistical significance will be claimed only if its two-sided p-value is below 0.05 and tests 
for the primary endpoint is significant at the two-sided 0.05 level. The proposed test 
sequence for the primary and the major secondary efficacy endpoints is listed as the 
following: 
• 
Proportions of subjects who achieve sPGA response at Week 16 (defined as 
sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from 
baseline at Week 16) 
• 
Proportion of subjects who achieve PASI-75 response at Week 16 (defined as at 
least a 75% reduction in total PASI score from baseline at Week 16) 
For the other secondary efficacy endpoints, multiplicity adjustment will not be applied 
and statistical significance will not be claimed. 
9.7.2 
 Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
The primary endpoint is the proportions of subjects who achieving sPGA response at 
Week 16 (defined as sPGA score of clear (0) or almost clear (1) with at least a 2-point 
reduction from baseline at Week 16).  The estimand of primary interest is defined in 
terms of the following four attributes: 
A.  The population is defined through appropriate inclusion/exclusion criteria to 
reflect the targeted patient population for approval (e.g., ITT Population); 


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B.  The variable is the proportion of subjects who achieving sPGA response at Week 
16. Subjects who terminate early due to lack of efficacy or add moderate-to-high 
potency topical steroid preparations (early escape) or other protocol prohibited 
medications prior to Week 16 will be assigned as non-responders.  
C.  Potential intercurrent events are captured through the variable definition (B). 
D.  The summary measure is the difference in response proportions. 
Missing values at Week 16 for this estimand will be imputed using the multiple 
imputation (MI) method (SAS Institute Inc. 2011) based on similar subjects who 
remained in the study as the primary method. With this missing data handling approach, 
the estimand answers a clinically relevant question that compares the number of 
subjects who achieve the defined response criteria at Week 16 in the ITT population.  
The primary endpoint will be analyzed using the CMH (Cochran–Mantel–Haenszel) test 
adjusting for the stratification factor at randomization. The two-sided p-values from the 
CMH test, the adjusted treatment difference in proportion using the weighted average of 
the treatment differences across the strata with the CMH weights, along with the 
associated two-sided 95% confidence intervals (CIs) using a normal approximation to 
the weighted average will be provided. 
Sensitivity analysis will be conducted to account for missing data using the last 
observation carried forward (LOCF) method, the non-responder imputation (NRI) method 
and the tipping point analyses. A sensitivity analysis using the PP population will also be 
performed.  
For the multiple imputation method, the SAS procedure MI will be used to impute 
missing sPGA scores at the scheduled analysis visits in the Placebo-controlled Phase 
(Weeks 0-16) to create M=25 complete data sets. The sPGA assessment data will not 
be included in multiple imputation steps from subjects who terminate early due to lack of 
efficacy or added moderate-to-high potency topical steroid preparations (early escape) 
or other protocol prohibited medications prior to Week 16. The missing data patterns will 
be checked at the scheduled analysis visits, ie, Baseline (Week 0), and Weeks 2, 4, 8, 
12 and 16. If there are non-monotone missing patterns, two separate imputation 
procedures will be used to complete the imputation process.  
In the first step, the Markov Chain Monte Carlo (MCMC) method will be used with a 
single chain to impute missing scores by treatment and stratification factor to create 
M=25 imputed data sets with monotone missing patterns.  In case there are 


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convergence issues, a simple model will be used to impute the missing scores by 
treatment, with further simplification by dropping both treatment and stratification factor 
in imputation model if necessary. The seed will be set to 17813721. The imputed scores 
will be rounded to the nearest integer. The minimum and the maximum values for 
imputation will be 0 and 4, which correspond to the lowest and the highest sPGA scores.  
In the second step, the predictive mean matching method will be used to impute the 
remaining missing scores for the 25 data sets with monotone missing patterns. The 
imputation procedure will use monotone statement to create one complete data set for 
each of the monotone data set from the first step, and the variables will include 
treatment arm, stratification factor, and sPGA scores at scheduled analysis visits from 
baseline to Week 16. The seed will be set to 55218163.  
After the completion of imputation, sPGA response at Week 16 will be derived based on 
both observed and imputed scores. Data from subjects who terminate early due to lack 
of efficacy or add moderate-to-high potency topical steroid preparations (early escape) 
or other protocol prohibited medications prior to Week 16 as non-responders will be 
added to the 25 imputed data sets. The same CMH method will be used to analyze the 
25 complete data sets and the SAS procedure MIANALYZE will be used to combine the 
results for the statistical inferences.  
The primary endpoint will be assessed for site effect as specified in Section 9.7.6. 
9.7.3 
Analyses of Major Secondary Efficacy Endpoint(s) 
The major secondary efficacy endpoint is the proportions of subjects who achieve PASI-
75 response at Week 16 (defined as at least a 75% reduction in total PASI score from 
baseline at Week 16), which will be analyzed using the same approaches as the primary 
endpoint. The estimand of primary interest is defined in terms of the following four 
attributes: 
A.  The population is defined through appropriate inclusion/exclusion criteria to 
reflect the targeted patient population for approval (e.g., ITT Population); 
B.  The variable is the proportion of subjects who achieving PASI-75 response at 
Week 16. Subjects who terminate early due to lack of efficacy or add moderate-
to-high potency topical steroid preparations (early escape) or other protocol 
prohibited medications prior to Week 16 will be assigned as non-responders.  
C.  Potential intercurrent events are captured through the variable definition (B).  


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D.  The summary measure is the difference in response proportions. 
The primary analysis for this estimand will use CMH (Cochran–Mantel–Haenszel) test 
adjusting for the stratification factor at randomization. Missing values at Week 16 will be 
imputed using the multiple imputation (MI) method (SAS Institute Inc. 2011) based on 
similar subjects who remained in the study. The two-sided p-values from the CMH test, 
the adjusted treatment difference in proportion using the weighted average of the 
treatment differences across the strata with the CMH weights, along with the associated 
two-sided 95% CIs using a normal approximation to the weighted average will be 
provided. 
Sensitivity analysis will be conducted to account for missing data using the last 
observation carried forward (LOCF) method, the non-responder imputation (NRI) 
method, and tipping point analyses. A sensitivity analysis using the PP population will 
also be performed. 
For using the multiple imputation method, the SAS procedure MI will be used to impute 
missing total PASI scores at the scheduled analysis visits in the Placebo-controlled 
Phase (Weeks 0-16) to create M=25 complete data sets. The PASI assessment data will 
not be included in multiple imputation steps from subjects who terminate early due to 
lack of efficacy or who add moderate-to-high potency topical steroid preparations (early 
escape) or other protocol prohibited medications prior to Week 16.  
The missing data patterns will be checked at the scheduled analysis visits, ie, Baseline 
(Week 0), and Weeks 2, 4, 8, 12 and 16. If there are non-monotone missing patterns, 
two separate imputation steps 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. In case there are convergence issues, a simple model 
will be used to impute the missing scores by treatment, with further simplification by 
dropping both treatment and stratification factor in imputation model if necessary. The 
minimum and the maximum values for imputation will be 0 and 72, which correspond to 
the lowest and the highest total PASI scores. The seed will be set to 17813721 and a 
single chain will be used to produce imputations. The imputed scores will be rounded to 
numbers with one digit (format xx.x).  
In the second step, the predictive mean matching method will be used to impute the 
remaining missing scores for the 25 data sets with monotone missing patterns. The 


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imputation procedure will use monotone statement to create one complete data set for 
each of the monotone data set from the first step, and the variables will include 
treatment arm, stratification factor, and total PASI scores at scheduled analysis visits 
from baseline to Week 16. The seed will be set to 55218163. 
After the completion of imputation, PASI-75 response at Week 16 will be derived based 
on both observed and imputed scores. Data from subjects who terminate early due to 
lack of efficacy or add moderate-to-high potency topical steroid preparations (early 
escape) or other protocol prohibited medications prior to Week 16 as non-responders 
will be added to the 25 imputed data sets. The same CMH method will be used to 
analyze the 25 complete data sets and the SAS procedure MIANALYZE will be used to 
combine the results for the statistical inferences. 
The major secondary endpoint will be assessed for site effect as specified in Section 
9.7.6. 
9.7.4 
Analyses of Other Secondary Efficacy Endpoint(s) 
The other secondary efficacy endpoints will be analyzed similarly as the primary and the 
major secondary endpoints. The main analysis will be based on the ITT population with 
missing values imputed using multiple imputation methods. The two-sided p-values and 
two-sided 95% confidence intervals (CIs) will be reported for treatment difference 
between placebo arm and apremilast arm. Multiplicity adjustment will not be applied and 
statistical significance will not be claimed. 
9.7.4.1 
Binary Variables 
The binary variables for secondary endpoints include the following: 
• 
Proportion of subjects who achieve PASI-50 response at Week 16 (defined as at 
least a 50% reduction in total PASI score from baseline at Week 16) 
• 
Proportion of subjects who achieve CDLQI (0/1) response at Week 16 (defined 
as CDLQI score 0 or 1 at Week 16) for subjects with baseline CDLQI score 2 or 
above 
For these two binary endpoints, the treatment difference between apremilast arm and 
placebo arm will be compared using CMH (Cochran–Mantel–Haenszel) test adjusting for 
the stratification factor at randomization. The two-sided p-values from the CMH test, the 
adjusted treatment difference in proportion using the weighted average of the treatment 
differences across the strata with the CMH weights, along with the associated two-sided 
95% CIs using a normal approximation to the weighted average will be provided. 


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Subjects who terminate early due to lack of efficacy or add moderate-to-high potency 
topical steroid preparations (early escape) or other protocol prohibited medications prior 
to Week 16 will be considered as non-responders. Missing values will be imputed using 
the similar MI method as the primary and major secondary endpoints, with sensitivity 
analysis using the LOCF method and NRI method. 
9.7.4.2 
Continuous Variables 
The continuous variables for secondary endpoints include the following: 
• 
Percent change from baseline in total PASI score at Week 16 
• 
Percent change from baseline in affected BSA at Week 16 
• 
Change from baseline in CDLQI score at Week 16 
The three continuous endpoints will be analyzed based on the ITT population using the 
analysis of covariance (ANCOVA) model. 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 and 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 two-sided 95% CIs, treatment 
differences in LS mean changes from baseline, and the associated two-sided 95% CIs 
and p-values, will be derived from the ANCOVA model.  Missing values at Week 16 will 
be imputed using the MI method, with sensitivity analysis using the LOCF method. The 
primary analysis will estimate treatment effect without additional psoriasis medications, 
ie, data from assessments after adding those medications will be removed before using 
MI method for subjects who add moderate-to-high potency topical steroid preparations 
(early escape) or other protocol prohibited medications prior to Week 16. A sensitivity 
analysis will be performed with all available data using MI method regardless whether 
subjects who add moderate-to-high potency topical steroid preparations (early escape) 
or other protocol prohibited medications prior to Week 16. 
9.7.5 
Analyses of Exploratory Efficacy Endpoint(s) 
Descriptive statistics will be provided for all endpoints by study phases. Data summaries 
will be provided for scheduled timepoints in each phase; and for an end of phase 
assessment in each treatment phase (the last assessment for each subject within the 
phase). Specifically, for continuous variables, descriptive statistics for assessment value 
and change or percent changes from baseline will be provided. Categorical variables will 


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be summarized with frequency tabulations for specified time points.  In addition, two-
sided 95% CIs will be provided for each treatment.  
For the exploratory endpoints evaluated at Week 16, statistical comparisons between 
the two treatment arms (apremilast versus placebo) will be performed using the ITT 
population when appropriate. No multiplicity adjustment will be pre-specified and 
nominal two-sided p-values will be presented. Missing values at Week 16 will be imputed 
using the LOCF method as the main approach. For binary endpoints, the treatment 
difference will be compared using CMH test adjusting for the stratification factor at 
randomization. For continuous endpoints, the analyses will use an analysis of 
covariance (ANCOVA) model with the change or percent change from baseline as the 
dependent variable and will include treatment group and stratification factor as 
independent variables and the baseline value as a covariate variable. 
9.7.5.1 
Study Phases 
The subjects included and the treatment arms for statistical analyses and summaries in 
each phase are described below in this section. The specific summaries are discussed 
in the following sections. 
• 
Placebo-controlled Phase (Weeks 0 to 16) 
Subjects in the ITT population will be put in the two treatment arms for analysis: 
- 
Placebo 
- 
Apremilast 
• 
Apremilast Extension Phase (Weeks 16 to 52) 
Subjects who entered the extension phase will be included in analysis, ie, who 
were initially randomized to apremilast and continued at Week 16 and who were 
initially randomized to placebo and switched to apremilast at Week 16. The two 
treatment arms are:  
- 
Placebo/Apremilast  
- 
Apremilast/Apremilast 
• 
Observational Follow-up Phase (14 weeks) 
For subjects who entered Follow-up Phase from Placebo-controlled Phase, 
summaries will be provided by their initial treatment arm:  
- 
Placebo 
- 
Apremilast 


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For subjects who entered Follow-up Phase from Apremilast Extension Phase, 
summaries will be provided by their treatment sequence:  
- 
Placebo/Apremilast  
- 
Apremilast/Apremilast 
9.7.5.2 
sPGA, PASI and BSA 
The endpoints include the following: 
• 
Proportion of subjects who achieve PASI-75, PASI-50, and PASI-90 response at 
all visits 
• 
Proportion of subjects who achieve sPGA (0/1) response at all visits 
• 
Percent changes from the baseline in total PASI score at all visits 
• 
Percent changes from the baseline in affected BSA at all visits 
All endpoints will be summarized by time point (ie, visit) using descriptive statistics. 
PASI-90 response at Week 16 will also be analyzed using CMH test. 
9.7.5.3 
ScPGA and Modified sPGA-G 
The endpoints include:  
• 
ScPGA: Proportion of subjects with scalp psoriasis with improvement of ScPGA 
of clear (0) or almost clear (1)  
• 
Modified sPGA-G: Proportion of subjects with genital psoriasis with improvement 
of sPGA-G of clear (0) or almost clear (1)  
The endpoints will be summarized by time point using descriptive statistics. Week 16 
proportions between the two arms will be compared using CMH test. 
In addition, shift tables will be provided from baseline to post-baseline visits for the 
corresponding full range of scores. 
9.7.5.4 
CDLQI and FDLQI 
The endpoints include:  
• 
CDLQI (0/1): Proportion of subjects who achieve CDLQI (0/1)  
• 
CDLQI: Change from baseline in CDLQI total score  
• 
FDLQI (0/1): Proportion of subjects achieving FDLQI (0/1)  
• 
FDLQI: Change from baseline in FDLQI total score 


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All endpoints will be summarized by time point using descriptive statistics. CDLQI (0/1) 
response at Week 16 will also be analyzed using CMH test. Change from baseline for 
CDLQI total score at Week 16 will be analyzed using ANCOVA model. 
9.7.5.5 
Modified Whole Body Itch Numeric Rating Scale (NRS) 
The endpoints include:  
• 
NRS response: Proportion of subjects with ≥4-point reduction (improvement) 
from baseline in whole body itch NRS score  
• 
Change from baseline in whole body itch NRS score  
The two endpoints will be summarized by time point using descriptive statistics. NRS 
response at Week 16 will also be analyzed using CMH test. Change from baseline in 
whole body itch NRS score at Week 16 will be analyzed using ANCOVA model. 
9.7.6 
Assessing Study Site Effect 
This study is a multicenter study and planned to have more than 100 study sites to enroll 
at least 230 subjects. A single site may not have sufficient number of subjects to allow 
meaningful within-site analysis; therefore, study sites will be pooled for the analysis. The 
primary and the major secondary efficacy endpoints will be further analyzed adjusting for 
the stratification factor and the pooled site and examining whether the treatment 
differences are consistent with those from the primary analysis.  
In addition, the consistency of the treatment effect across individual study sites (or 
pooled sites) will also be assessed by performing a subgroup-type analysis with 
individual study sites (or pooled sites) treated as subgroups. Listings of response rates 
will be provided by individual study site and by pooled site. The treatment difference for 
each of the individual study sites (or pooled sites) will be reviewed to evaluate the effect 
among the individual study sites (or pooled sites).  
In pooling sites for analysis, the minimum cell size of 5 randomized subjects will be 
used. With five subjects per treatment arm (placebo arm or apremilast arm) per stratum 
of age group (6-11 or 12-17 years old), there is an approximately 67% chance to 
observe at least one sPGA responder per stratum for the apremilast arm (assuming a 
20% responder rate) and 23% chance to observe at least one sPGA responder per 
stratum for the placebo arm (assuming a 5% responder rate).  
Site will be pooled within the 4 geographical regions (USA, Canada, Europe, Rest of the 
World). In each region, the smallest sites will be pooled first until the pooled site has a 


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minimum cell size of 5 for all four cells. The remaining unpooled sites will be pooled with 
the smallest pooled site within the region.  
The 4 geographical regions will be ranked from the smallest to the largest according to 
the total number of randomized subjects. If the smallest region can’t reach a minimum 
cell size of 5 for all four cells, all sites in that region will be pooled with the smallest 
pooled site in the next region.  
In analysis using CMH method, if a pooled site does not have a responder in one of the 
age groups (6-11 or 12-17 years old), that pooled site will be further pooled with the next 
pooled site in the region. 
9.8 
Safety Analyses 
Safety will be assessed via descriptive statistics and point estimates. Unless otherwise 
specified, all safety analyses described in this section will be performed for both the 
Placebo-controlled Phase and the Apremilast-exposure Period. The safety analyses for 
the Placebo-controlled Phase will be based on the safety population and presented by 
treatment group (placebo arm or apremilast arm).The safety analyses for the Apremilast-
exposure Period will be based on the apremilast subjects as treated population and 
presented for both groups (subjects who were initially treated with placebo and switched 
to apremilast at Week 16, or subjects who were initially treated with apremilast from 
Week 0), and for overall apremilast group irrespective of the start time of apremilast 
exposure (at Week 0 or 16). For apremilast treatment groups, the further refined 
summaries for both dose levels (20 mg BID or 30 mg BID) will also be provided. 
For the analyses of AEs and marked abnormalities, the following point estimates are 
distinguished: 
• 
Subject incidence: Subject incidence (i.e., percentage [%] used in a frequency 
summary) is defined as the number of subjects with the specific event divided by 
the number of subjects included in the analysis. Subjects with multiple 
occurrences of the specific event in the specific analysis period will be counted 
only once in the numerator. 
• 
Exposure-adjusted incidence rate (EAIR) per 100 subject-years: The EAIR per 
100 subject-years is defined as 100 times the number of subjects with the 
specific event divided by the total exposure time (in years) among subjects 
included in the analysis. Subjects with multiple occurrences of the specific event 
in the specific analysis period will be counted only once in the numerator. The 


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exposure time for a subject without the specific event is the treatment duration, 
whereas the exposure time for a subject with the specific event is the treatment 
duration up to the start date (inclusive) of the first occurrence of the specific 
event. For subject only having the specific event started after and within the 28 
days of the last dose date, the exposure time will be calculated to the last dose 
date. The total exposure time in years is calculated by dividing the sum of 
exposure time in days over all subjects included in the analysis by 365.25. The 
EAIR per 100 subject-years is interpreted as the expected number of subjects 
with at least one occurrence of the specific event per 100 subject-years of 
exposure to the IP. 
AEs and marked abnormalities will be summarized by subject incidence and EAIR for 
the Placebo-controlled Phase (Weeks 0 to16) and for the Apremilast-exposure Period. In 
addition, selected summaries for the first 16 weeks in the Apremilast Extension Phase 
(Weeks 16 to 52) and for the Observational Follow-up Phase (14 weeks) after 28 days of 
the last dose date will be presented. Selected summaries will also be presented for the 
first 16 weeks in Apremilast-exposure Period for apremilast group irrespective of the 
start time of apremilast exposure (at Week 0 or 16). 
Descriptive statistics will be provided for vital signs, weight, height and BMI, tanner 
staging of sexual development, stool diary for diarrhea, Columbia-Suicide Severity 
Rating Scale (C-SSRS), laboratory values (continuous measurements) by treatment and 
visit, including the end of treatment visits. The baseline value, value at the time point, 
and change from baseline will be summarized for subjects who have values at baseline 
and at the time point. 
Shift tables, that is, tables that summarize the baseline categories (normal, abnormal) 
versus the category at the end of the respective periods or versus the worst post-
baseline category, include subjects who have values at baseline and at least one post-
baseline value. Similarly, in frequency summaries of shifts from baseline at scheduled 
study weeks per protocol, only subjects who have values at baseline and at the time 
point will be included. 
9.8.1 
 Adverse Events 
AEs will be coded according to the MedDRA version 24.0 or higher. Unless otherwise 
specified, AEs will be summarized by SOC and PT, with SOCs presented in the 
standard international order and PTs within SOCs will be presented in descending order 
of subject incidence. 


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9.8.1.1 
Overall Summary of TEAEs 
An overall summary of the following TEAE categories will be provided for the Placebo-
controlled Phase (Weeks 0 to16) for subjects with: 
• 
Any TEAE 
• 
Any drug-related TEAE 
• 
Any severe TEAE 
• 
Any serious TEAE 
• 
Any serious drug-related TEAE 
• 
Any TEAE leading to drug interruption 
• 
Any TEAE leading to drug withdrawal 
• 
Any TEAE leading to death 
In addition, for Apremilast Extension Phase (Weeks 16 to 52), Observational Follow-up 
Phase (14 weeks) and Apremilast Exposure Period overall summary of TEAEs will also 
be provided. 
9.8.1.2 
All TEAEs 
All TEAEs will be summarized by SOC and PT as well as by PT only (in descending 
order of subject incidence). In addition to the Placebo-controlled Phase (Weeks 0 to16) 
and the Apremilast-exposure Period, summaries will also be provided for the Apremilast 
Extension Phase (Weeks 16 to 52).  
New events of all TEAEs by exposure interval (≤ 1, > 1 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12, and 
> 12 Weeks) will be summarized for the Placebo-controlled Phase. Each subject is 
counted once for either subject incidence or EAIR for each applicable specific TEAE in 
each exposure interval where an event started. The denominator of a subject incidence 
is the number of subjects with treatment duration exceeding the lower bound of the 
particular exposure interval, while the denominator of an EAIR is the sum of the 
exposure time during the exposure interval (up to the first event start date for subjects 
with at least one event starting in the interval) among the same number of subjects as in 
the denominator of the corresponding subject incidence. 
In addition, new events of all TEAEs by exposure interval (≤ 1, > 1 to ≤ 8, > 8 to ≤ 16, > 
16 to ≤ 24, > 24 to ≤ 32, > 32 to ≤ 40, > 40 to ≤ 48, > 48 Weeks) will be summarized for 
the Apremilast-exposure Period. 


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All TEAEs will be summarized by age category (6-11, 12-17 years), sex, and race. All 
TEAEs will also be summarized by patients using or not using low potency topical 
corticosteroids.  
All TEAEs occurring after the date of the last dose of IP will also be summarized by SOC 
and PT for the Observational Follow-up Phase (14 weeks). The EAIR will not be 
provided in this summary. 
9.8.1.3 
Common TEAEs 
TEAEs with subject incidence ≥ 5% (or another cut-off if justified) in any treatment group 
will be summarized by SOC and PT as well as by PT only in descending order of subject 
incidence. 
9.8.1.4 
Drug-related TEAEs 
Drug-related TEAEs will be summarized and new events of drug-related TEAEs by 
exposure interval (see Section 9.8.1.2) will be summarized. 
9.8.1.5 
TEAEs by Maximum Severity 
All TEAEs will be summarized by maximum severity (mild, moderate, severe, and, if 
needed, missing). If a subject reports multiple occurrences of a specific event within a 
specific analysis phase or period, the subject will be counted only once by the maximum 
severity. If the severity is missing for one or more of the occurrences, the maximum 
severity of the remaining occurrences will be used. If the severity is missing for all of the 
occurrences, the subject will be counted only once in the “missing” category of severity. 
9.8.1.6 
Serious TEAEs 
Serious TEAEs and serious drug-related TEAEs will be summarized.  
New events of serious TEAEs and serious drug-related TEAEs by exposure interval will 
be summarized for Placebo-controlled Phase (Weeks 0 to16). 
Serious TEAEs will be summarized by age category (6-11, 12-17 years), sex.  
A subject data listing of all serious AEs (both TEAEs and non-TEAEs) will be provided. 
9.8.1.7 
TEAEs Leading to Drug Interruption and TEAEs Leading to Drug 
Withdrawal 
TEAEs leading to drug interruption and TEAEs leading to drug withdrawal will be 
summarized. 
TEAEs leading to drug withdrawal will also be summarized by age category (6-11, 12-17 
years), sex, and patients using or not using low potency topical corticosteroids. 


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A subject data listing of TEAEs leading to drug withdrawal will be provided. 
9.8.1.8 
Deaths 
TEAEs leading to death will be summarized. A subject data listing of all deaths will be 
provided. 
9.8.1.9 
Onset and duration 
For selected TEAE events, categories for onset (start) day from the first dose date and 
event duration (from start date to end date) will be summarized. 
9.8.2 
Laboratory Test Results 
Summary statistics of observed values and changes from baseline in laboratory 
parameters will be provided over time. Frequency summaries (shift tables) of shifts from 
baseline to post-baseline time points and to the worst post-baseline value in terms of 
normal/abnormal will be provided. 
Laboratory marked abnormalities will be summarized; subject incidence and EAIR for 
each abnormality will be calculated based on subjects with a baseline value and at least 
one post-baseline value 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 will be provided. 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. 
Subject data listings for clinical laboratory data, including hematology, serum chemistry 
and urinalysis, will be provided. 
9.8.3 
Vital Signs 
Summary statistics of observed values and changes from baseline in vital signs will be 
provided over time. Frequency summaries (shift tables) of shifts from baseline to post-
baseline time points and to the worst post-baseline value in terms of normal/abnormal 
will be provided for pulse and blood pressure. 
A subject data listing of all vital signs will be provided. 


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9.8.4 
Physical Measurements 
The protocol specified that physical examination findings of clinical significance (as 
defined by the investigator) are to be reported as AEs. No summary of physical 
examination findings will be provided. 
9.8.5 
Electrocardiogram 
Not applicable. 
9.8.6 
Antibody Formation 
Not applicable.  
9.8.7 
Exposure to Concomitant Medication 
The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health 
Organization Drug Dictionary (WHO DD version March 2020 or later) will be used to 
group prior and concomitant medications and prior psoriasis medications into relevant 
categories. Frequency summaries will be provided by treatment group, ATC level, and 
standardized medication name for the safety population. 
Summaries will be provided for prior psoriasis medications and prior medications, as well 
as for concomitant medications in: (1) Placebo-controlled Phase (Weeks 0 to16), (2) 
Apremilast Extension Phase (Weeks 16 to 52), (3) Apremilast Exposure Period, and (4) 
Observational Follow-up Phase (14 weeks).  
9.8.8 
Exposure to Concomitant Procedures 
Concomitant procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 24.0 or higher. Frequency summaries of concomitant 
procedures will be provided for the safety population by treatment group, SOC, and PT.  
Concomitant procedures will be summarized similarly as concomitant medication for (1) 
Placebo-controlled Phase (Weeks 0 to16), (2) Apremilast Extension Phase (Weeks 16 to 
52),  (3) Apremilast Exposure Period, and (4) Observational Follow-up Phase (14 
weeks).  
9.8.9 
Stool Diary for Diarrhea 
Subjects and their parent/guardian will be supplied with paper diaries that will be filled 
out daily to record and describe any diarrhea, including duration, frequency, treatment, 
and associated symptoms. Subjects and their parent/guardian will complete the Stool 
Diary every day beginning after the first dose of apremilast, up to the 4-week post last 
dose follow-up visit. 
Summary and subject data listing of stool diary entries will be provided.  


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9.8.10 
Psychiatric Evaluation 
Subjects will complete the Columbia-Suicide Severity Rating Scale (C-SSRS) 
assessment. This questionnaire is suitable for assessment of suicidal ideation and 
behavior in clinical and research settings. The assessment will be completed at 
screening, baseline, and at post-baseline visits.  
Summary and subject data listing of psychiatric evaluation results will be provided. 
9.8.11 
Tanner Staging of Sexual Development 
Assessments of sexual maturity (Tanner Staging) will be performed at baseline and at 
the end of treatment for boys and girls. Summary and subject data listing of Tanner 
Staging assessment findings will be provided. 
9.8.12 
Psoriasis Flare and Rebound 
Subjects with psoriasis flare or rebound will be summarized for the two treatment phases 
and for the Apremilast-Exposure Period. Subject data listing will be presented for 
psoriasis adverse events. 
9.8.13 
Weight, Height and BMI 
Body weight and height will be measured by study visit. BMI will be calculated using 
weight and height.  
Body weight, height and BMI will be summarized using change and percent change from 
baseline. Weight change (kg) and percent change (%) from baseline will also be 
summarized using categories as < -20, ≥ -20 to < -10, ≥-10 to < -5, ≥-5 to < 0, 0, > 0 to ≤ 
5, > 5 to ≤ 10, > 10 to ≤ 20, and > 20 at the end of treatment phase or period.  
The categories of weight change (kg) and percent change (%) are < -20, ≥ -20 to < -10, 
≥ -10 to < -5, ≥- 5 to < 0, 0, > 0 to ≤ 5, > 5 to ≤ 10, > 10 to ≤ 20, and > 20. The 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.BMI will also be summarized for 
shifting from baseline to post-baseline timepoints using the four categories as 
underweight, healthy weight, overweight or obesity.  
Data listing will be provided for weight, height and BMI. Subjects with weight decrease 
from baseline ≥ 10% will be listed separately. 
9.9 
Other Analyses 
9.9.1 
Analyses of COVID-19 impacted data 
Analyses will be performed to assess the impact of COVID-19 on the amount of data 
collected for the study.  


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10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
11. 
Literature Citations / References 
Basra MKA, Sue-Ho R, Finlay AY. The Family Dermatology Life Quality Index; 
measuring the secondary impact of skin disease. Br J Dermatol 2007; 156: 528-538. 
Erratum: British Journal of Dermatology 2007; 156: 791 (Correct FDLQI given here). 
Basra M K A, Finlay A Y. The family impact of skin diseases: the greater patient concept. 
Br J Dermatol 2007; 156: 929-937. 
Cole TJ, Green PJ (1992). Smoothing reference centile curves: the LMS method and 
penalized likelihood. Statistics in Medicine, 11:1305–1319.  
Lewis-Jones MS, Finlay AY. The Children’s Dermatology Life Quality Index (CDLQI): 
Initial validation and practical use. British Journal of Dermatology, 1995; 132: 942-949. 
Mehrotra, DV, and Railkar, R. Minimum risk weights for comparing treatments in 
stratified binomial trials. Statist. Med., 2000; 19: 811–825. 
MKA Basra, O Edmunds, MS Salek, AY Finlay. Measurement of family impact of skin 
disease: further validation of the Family Dermatology Life Quality Index (FDLQI). J Eur 
Acad Dermatol Venereol 2008. 22: 813-821. 
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. 


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Rigby RA, Stasinopoulos DM (2004). Smooth centile curves for skew and kurtotic data 
modelled using the Box-Cox power exponential distribution. Statistics in Medicine, 
23:3053–3076.  
SAS Institute Inc. 2011. SAS/STAT® 9.3 User’s Guide. Cary, NC: SAS Institute Inc.  
Centers for Disease Control (CDC) National Center for Health Statistics Clinical Growth 
Charts, Modified 2000: https://www.cdc.gov/growthcharts/clinical_charts.htm. 
Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC growth charts for the United 
States: Methods and development. National Center for Health Statistics.Vital Health Stat 
11(246). 2002. 
12. 
Prioritization of Analyses 
Not applicable. 
13. 
Data Not Covered by This Plan 


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14. 
Appendices 
 
 


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


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Category / Analyte 
SI Units  
Criteria  
  Platelets 
10^9/L 
<100 
>500 
 
 
 


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Appendix B. Analytical Windows 
Post baseline time points in all analyses will be captured based on analysis visit window 
(range of study days) around the target day for each analysis visit, based on the actual 
day of evaluation relative to a reference date. Appropriate dates will be used to calculate 
the study day, e.g., date of measurement or date of specimen collection will first be 
used, and then the date of visits/study weeks as recorded in the database will be used. 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 1. Table for Visit Mapping for by Time Point Analysis 
Analysis visit 
Target Day 
Visit Window 
Placebo-controlled Phase 
  Week 0 (Baseline) 
1 
<= 1 
  Week 2 
15 
2 to 21 
  Week 4 
29 
22 to 42 
  Week 8 
57 
43 to 70 
  Week 12 
85 
71 to 98 
  Week 16 
113 
99 to End of Phase 
  
  
  
Apremilast Extension Phase 
  Week 20 
141 
(End of Previous Phase + 
1) to 154 
  Week 24 
169 
155 to 182 
  Week 28 
197 
183 to 210 
  Week 32 
225 
211 to 238 
  Week 36 
253 
239 to 266 
  Week 40 
281 
267 to 294 
  Week 44 
309 
295 to 322 
  Week 48 
337 
323 to 350 
  Week 52 
365 
351 to End of Phase 
Note: Target day and visit window are relative to the date of Visit 2/Week 0 (Day 1) 
randomization date. For efficacy and safety analysis, definitions for start or end dates for 
a phase or period are specified in Section 5.3. 
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 visits. Appropriate dates (e.g., date of measurement or date of specimen 


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collection) will first be used to ensure only data (including data from scheduled, 
unscheduled, discontinuation, and observational follow-up visits) measured or collected 
within the specific analysis phase 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. 
For the Apremilast-exposure Period, the scheduled study weeks for placebo subjects 
who are treated with apremilast 20 or 30 mg BID at Week 16/Visit 7 will be mapped to 
reflect the study weeks relative to the first dose of apremilast for summaries of safety 
data (laboratory parameters, vital signs, etc). 
Table 2. Adjustment of Study Weeks for Placebo Subjects Who Are Treated with 
Apremilast 20 or 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 
Week 0 (Baseline) 
Week 20 
Week 4 
Week 24 
Week 8 
Week 28 
Week 12 
Week 32 
Week 16 
Week 36 
Week 20 
Week 40 
Week 24 
Week 44 
Week 28 
Week 48 
Week 32 
Week 52 
Week 36 
 
 
 


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Appendix C. Partially Missing Date Imputation 
Adverse Events 
Partially missing AE start dates will be imputed in the ADaM dataset for AEs, but partially 
missing AE end dates will not be imputed in the same dataset. If the AE end date is 
complete with no missing year, month, or day, and the partially missing start date 
imputed by the rules below is after the AE end date, then the start date will be imputed 
by the AE end date. 
Subjects who were treated with apremilast at Week 0/Visit 2 
The principle of the imputation rules for subjects who were treated with apremilast 
initially is to treat the AE as treatment-emergent, i.e., occurring on or after the date of the 
first dose of IP, if possible. 
Let an AE start date be represented as “DEvent/MEvent/YEvent”, and the date of the first dose 
of IP as “DIP/MIP/YIP”. The following table gives the imputation rules for partially missing 
AE start dates for subjects who were treated with apremilast initially. 
Table 3. Imputation Rules for Partially Missing AE Start Dates for Subjects Who 
Were Treated with Apremilast Initially 
Scenario 
Condition 
Imputation Rule 
Partially missing date includes year only (both month and day are missing) 
1 
YEvent < YIP 
12/31/YEvent 
2 
Otherwise, i.e., YIP ≤ YEvent 
Max (date of first dose of IP, 
1/1/YEvent) 
Partially missing date includes both year and month (only day is missing) 
1 
YEvent < YIP, or (YEvent = YIP and MEvent 
< MIP) 
Last date of MEvent/YEvent 
2 
Otherwise, i.e., YIP < YEvent, or (YIP = 
YEvent and MIP ≤ MEvent)  
Max (date of first dose of IP, 
1/MEvent/YEvent) 
Subjects who were treated with placebo at Week 0/Visit 2 
The principle of the imputation rules for subjects who were treated with placebo initially 
and started apremilast treatment at Week 16 is to consider the AE starting on or after the 
date of the first dose of apremilast, if possible; if the partially missing start date suggests 
that it is prior to the date of the first dose of apremilast, the AE will be considered starting 
on or after the date of the first dose of IP, if possible. 
The following are 4 scenarios considered in the imputation rules: 


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


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3 
YEvent = YAPR and MEvent = MAPR 
Date of first dose of apremilast 
following Week 16 
4 
Otherwise, i.e., YIP < YEvent < YAPR, or  
(YIP = YEvent < YAPR and MIP ≤ MEvent), 
or  
(YIP = YEvent = YAPR and MIP ≤ MEvent < 
MAPR), or (YIP < YEvent = YAPR and 
MEvent < MAPR) 
Max (date of first dose of IP, 
1/MEvent/YEvent) 
 
 
 


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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. 
 
 


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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. 
 
 


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Treatment Duration 
Partially or completely missing last dose dates will be imputed in the ADaM dataset for 
treatment duration.  
When partially missing last dose date is available, set last dose date to the maximum of 
[the earliest possible date given the non-missing field(s) of last dose date, the minimum 
of (the latest possible date given the non-missing field(s) of last dose date, last known 
date in database, first non-missing Early Termination (ET) visit date)] 
When last dose date is completely missing, set last dose date to the minimum of (last 
known date in database, first non-missing Early Termination (ET) visit date) 
Last known date in database is defined as maximum of (last visit date, lab, vital signs, 
ECG assessment date, AE start or end dates, concomitant medications start or end 
dates, concomitant procedure date, last dose date from 'Disposition- Treatment' page, 
treatment exposure start or end dates where doses were completely or partially taken, 
death date). 
 
 


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Appendix D. Reporting conventions 
· 
Summary tabulation will be provided by treatment arm (e.g., Placebo vs. 
Apremilast for the Placebo-controlled Phase; Placebo/Apremilast vs. Apremilast 
/Apremilast for the Apremilast Extension Phase; Apremilast for Apremilast-exposure 
Period); 
· 
Statistical test of the treatment difference will use two-sided significance level 
0.05 for significance or nominal significance.  
· 
P-values will be rounded to 4 decimal places. p-values that round to 0.0000 will 
be presented as ‘<0.0001’ and p-values that round to 1.000 will be presented as 
‘>0.9999’; 
· 
Confidence intervals (CIs) will be presented as two-sided 95% CIs unless 
specified differently in specific analysis; 
· 
Summary statistics will consist of the number and percentage of subjects in each 
category for discrete variables, the sample size, mean, median, standard deviation (SD), 
minimum, and maximum for continuous variables, the 25th (Q1) and 75th (Q3) 
percentiles will also be applied to efficacy continuous variables; 
· 
Mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal places 
than the measured value. Minimum and maximum values will be presented to the same 
number of decimal places as the measured value; 
· 
Percentages will be rounded to one decimal place. The number and percentage 
of responses will be presented in the form xx (xx.x), where the percentage is in the 
parentheses; 
· 
Analysis and summary tables will have the analysis population sample size (i.e., 
number of subjects) in the column header; 
· 
Subject data listings will be provided to support the tables and graphs. Listings 
will be sorted for presentation in order of subject number and date of procedure or event.