Clinical trial NCT02576678
Conditions: Psoriasis
Keywords: Psoriasis Moderate to Severe Plaque Psoriasis Plaque Psoriasis CC-10004 Apremilast Pharmacokinetics Open-label Safety Pediatric
Sponsor: Amgen
Start date: 2015-10-13; Completion date: 2019-07-29
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, multicenter, open-label study in subjects with moderate to severe plaque psoriasis aged 6 to 17 years, inclusive, intended to assess the safety, tolerability, and PK of apremilast with 2 weeks of oral apremilast treatment followed by a 48-week extension of apremilast treatment. Moderate to severe plaque psoriasis is defined as Psoriasis Area Severity Index (PASI) ≥ 12, Body Surface Area (BSA) ≥ 10%, and static Physician Global Assessment (sPGA) of ≥ 3. The total study duration for each subject will last for up to a total of 107 weeks which includes screening, treatment (including the PK portion of the study and the extension treatment period), two short-term follow-up periods and a long-term follow-up period.

Detailed description:
Each subject will undergo a screening period of up to 5 weeks, a treatment period of 2 weeks with PK sample collection, and an extension treatment period of 48 weeks, to allow subjects access to apremilast treatment if medically appropriate (following the completion of the 2 week PK portion). Regardless of when they stop treatment, subjects should complete two post treatment follow-up visits at approximately 4 and 8 weeks after the last dose. All subjects should complete the final follow-up visit at Week 102 or at a timepoint 52 weeks after the last dose of apremilast was taken in subjects who have withdrawn at any time prior to Week 50. At least 32 subjects will be enrolled into this study to provide an adequate PK profile and safety assessment in subjects of different ages and body weight ranges. Subjects will be divided into 2 age groups (adolescents \[ages 12 to 17 years, inclusive\] and children \[ages 6 to 11 years, inclusive\]), with at least 16 subjects in each group. Apremilast treatment will start in older and heavier subjects.

Group 1 (ages 12 to 17 years, inclusive; weight ≥ 35 kg)

* The data collected from the first 8 subjects will be reviewed by an independent data monitoring committee (DMC) to determine if it is appropriate to proceed with dosing the balance of Group 1 subjects and to proceed with dosing in the Group 2 subjects.

and an evaluation of these data by the DMC has been completed.

Group 2 (ages 6 to 11 years, inclusive; weight ≥ 15 kg)

* The dose regimens (dose strength and/or dose frequency) for these first 8 subjects will be based upon the PK and safety assessments from the first 8 subjects in Group 1.
* For the remaining subjects in Group 2, the dose (dose strength and/or dose frequency) will be based upon the subject weight as determined by the PK and safety assessments. The dose strength and/or dose frequency will be adjusted for any safety concerns or for unexpected changes in exposure. In the event of a dose regimen adjustment after the second PK and safety assessment, the first 8 subjects in Group 2 will return to the site for the appropriate dosing adjustment.

Arms: arm 1: Apremilast doses of 10-mg, 20-mg or 30-mg tablets have been selected to determine the dose range in adolescents and children with moderate to severe plaque psoriasis. These pediatric dosages are expected to achieve exposures similar to those achieved in adult psoriasis and psoriatic arthritis (PsA) subjects treated with apremilast 30 mg orally twice daily (BID).

A staggered, stepwise approach by age range and weight (starting with older and heavier subjects) is considered appropriate for this first-time-in-children study. Doses for younger and lower body weight subjects will be adjusted based on safety and PK data from older and heavier subjects.

Subjects will be divided into 2 age groups with at least 16 subjects in each group. Dosing within and between groups will be staggered, based on PK data collected and on a minimum of 2 weeks of safety data.
Interventions: intervention 1: Apremilast
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
1
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
TITLE PAGE
A PHASE 2, MULTICENTER, OPEN-LABEL STUDY TO 
ASSESS THE SAFETY, TOLERABILITY AND 
PHARMACOKINETICS OF APREMILAST (CC-10004) 
IN PEDIATRIC SUBJECTS WITH MODERATE TO 
SEVERE PLAQUE PSORIASIS
PROTOCOL NUMBER:
CC-10004-PPSO-001
DATE FINAL:
09 Mar 2015
AMENDMENT 1 DATE FINAL:
17 Aug 2015
AMENDMENT 2 DATE FINAL:
29 Apr 2016
EudraCT NUMBER:
2015-003314-24
IND NUMBER:
070270
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
2
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address: 86 Morris Ave., Summit, NJ 07901
Telephone:
E-mail:
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24 hour Global Emergency Contact Call Center: 
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
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 protocol and find its content to be 
acceptable.
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
4
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
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
Celgene representatives, the Declaration of Helsinki, International Conference on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
5
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
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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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
6
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
PROTOCOL SUMMARY
Study Title
A Phase 2, Multicenter, Open-label Study to Assess the Safety, Tolerability and 
Pharmacokinetics of Apremilast (CC-10004) in Pediatric Subjects with Moderate to Severe 
Plaque Psoriasis
Indication
The indication is moderate to severe plaque psoriasis in adolescents (ages 12 to 17 years, 
inclusive) and in children (ages 6 to 11 years, inclusive).
Objectives
Primary Objective:
!
To select a pediatric dose of apremilast based on the safety, tolerability, and 
pharmacokinetics (PK) of apremilast (APR) in adolescents and children with 
moderate to severe plaque psoriasis.
Secondary Objective:
!
To evaluate the taste and acceptability of apremilast tablet using a faces Likert Scale.
Exploratory Objective:
!
To evaluate the effect of apremilast on psoriasis in adolescents and children as 
measured by the Psoriasis Area and Severity Index (PASI).
Study Design
This is a Phase 2, multicenter, open-label study of apremilast in subjects aged 6 to 17 years,
inclusive, with moderate to severe plaque psoriasis. The study will assess the safety, tolerability, 
and PK of apremilast during the first 2 weeks of treatment.  At least 32 subjects will be enrolled.  
Subjects will be divided into 2 age groups (adolescents [ages 12 to 17 years, inclusive] and 
children [ages 6 to 11 years, inclusive]), with at least 16 subjects in each group.  Apremilast 
treatment will start in older and heavier subjects.  Subjects will complete the first 2 weeks of 
treatment with apremilast for PK analysis and then continue treatment for 48 weeks in the 
extension period that will explore the safety and efficacy of apremilast. 
This Study will be conducted in compliance with International Conference on Harmonisation 
(ICH) Good Clinical Practices (GCPs).
Study Population
This study will be conducted in subjects aged 6 to 17 years, inclusive, with chronic moderate to 
severe plaque psoriasis, defined as Psoriasis Area Severity Index (PASI) ≥12, Body Surface 
Area (BSA) ≥10%, and static Physician Global Assessment (sPGA) of ≥ 3 (moderate to severe)
[See Appendix A], diagnosed at least 6 months prior to Screening.  Subjects whose psoriasis is 
inadequately controlled by or inappropriate for topical psoriasis therapy will be included.  
Previous treatment with one systemic agent will be allowed but subjects treated with more than 
one systemic agent will be excluded.  Subjects must be able to swallow apremilast tablets.
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
7
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Length of Study
The study will last for up to a total of 107 weeks which includes screening, treatment (PK 
portion of the study and the extension treatment period), two short-term follow-up periods and a 
long-term follow-up period.
Each subject will undergo a screening period of up to 5 weeks, an initial treatment period of 
2 weeks, and an extension treatment period of 48 weeks, that will allow subjects access to 
apremilast treatment if medically appropriate (following the completion of the 2 week PK 
portion). Regardless of when they stop treatment, subjects should complete the post treatment 
follow-up visits at 4 and at 8 weeks after the last dose.  An additional long-term follow-up should 
be performed 52 weeks after the last dose of apremilast.  All subjects should complete the final 
follow-up visit at Week 102 or at a timepoint 52 weeks after the last dose of apremilast was 
taken in subjects who have withdrawn at any time prior to Week 50.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
Apremilast doses of 10-mg, 20-mg or 30-mg tablets have been selected to determine the dose 
range in adolescents and children with moderate to severe plaque psoriasis.  These pediatric 
dosages are expected to achieve exposures similar to those achieved in adult psoriasis and
psoriatic arthritis (PsA) subjects treated with apremilast 30 mg orally twice daily (BID).
A staggered, stepwise approach by age range and weight (starting with older and heavier 
subjects) is considered appropriate for this first-time-in-children study.  Doses for younger and 
lower body weight subjects will be adjusted based on safety and PK data from older and heavier 
subjects.  
Subjects will be divided into 2 age groups with at least 16 subjects in each group.  Dosing within 
and between groups will be staggered as described below, based on PK data collected and on a 
minimum of 2 weeks of safety data:
Group 1 (ages 12 to 17 years, inclusive; weight ≥ 35 kg)
!
At least 8 subjects will initially be enrolled into Group 1 and will weigh ≥ 35 kg. 
∀
Dosing for subjects with a weight ≥ 35 kg to < 70 kg will be a 20 mg BID dose 
regimen (10 mg BID less than the maximum adult dose). 
∀
Dosing for subjects with a weight ≥ 70 kg will be a 30 mg BID dose regimen 
(same as for adults). 
!
Dose regimens (dose strength and/or dose frequency) for the remaining subjects in 
Group 1 will be determined based on the initial 2 week PK and safety assessments
from the first 8 subjects in Group 1 to complete this period. These data will be 
reviewed by an independent data monitoring committee (DMC) to determine if it is 
appropriate to proceed with dosing the balance of Group 1 subjects and to proceed 
with dosing in the Group 2 subjects. In the event of a dose regimen adjustment, some 
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
8
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
or all of the first 8 subjects in Group 1, depending on weight, will return to the site for 
the appropriate dosing adjustment.
!
For the remaining subjects in Group 1, the dose strength and/or dose frequency will 
be adjusted for any safety concerns or for unexpected changes in exposure. 
!
Group 2 will be open to enrollment once at least 8 subjects from Group 1 have 
completed the first 2 weeks of apremilast dosing, PK data analysis, and safety 
assessments and an evaluation of these data by the DMC has been completed.
Group 2 (ages 6 to 11 years, inclusive; weight ≥ 15 kg)
!
At least 8 subjects will initially be enrolled into Group 2 and will weigh ≥ 15 kg. The 
dose regimens (dose strength and/or dose frequency) for these first 8 subjects will be 
based upon the PK and safety assessments from the first 8 subjects in Group 1.  If PK 
and safety are not affected by age and body weight, 20 mg BID will be administered 
to Group 2 children.
!
Dose regimens (dose strength and/or dose frequency) for the remaining subjects in 
Group 2 will be determined based on PK and safety assessments from the data 
collected from the first 8 subjects in each group. These data will be reviewed by an
independent DMC to determine if it is appropriate to proceed with dosing the balance 
of Group 2 subjects. In the event of a dose regimen adjustment after the second PK 
and safety assessment, the first 8 subjects in Group 2 will return to the site for the 
appropriate dosing adjustment.
!
For the remaining subjects in Group 2, the dose (dose strength and/or dose frequency) 
will be based upon the subject’s weight as determined by the PK and safety 
assessments.  The dose strength and/or dose frequency will be adjusted for any safety 
concerns or for unexpected changes in exposure.
An independent DMC will review available safety and PK data at the following timepoints:
1. After the first 8 subjects in Group 1 have completed the 2 weeks of apremilast dosing, 
PK, and safety assessments.
2. After the first 8 subjects in Group 2 have completed the 2 weeks of apremilast dosing, 
PK, and safety assessments.
Overview of Safety Assessments
Safety will be monitored throughout the study.  The following will be used to assess safety:
!
Adverse events (AEs)
!
Physical examinations
!
Vital sign measurements
!
Clinical laboratory safety tests
!
12-lead electrocardiograms (ECGs)
!
Concomitant medications / procedures
!
Pregnancy tests
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
9
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Overview of Pharmacokinetic Assessments
Blood samples, with volumes appropriate for the weight of the child, will be collected at pre-
specified times to determine levels of apremilast in plasma/blood. The following PK parameters 
will be estimated for apremilast using a non-compartmental approach if data permit:
!
Maximum observed plasma concentration (Cmax)
!
Time to Cmax (tmax)
!
Area under the plasma concentration-time curve from time zero to 12 hours postdose 
(AUC0-12)
!
Area under the plasma concentration-time curve from time zero to the last 
quantifiable concentration (AUC0-t)
!
Apparent total plasma clearance when dosed orally (CL/F)
!
Apparent total volume of distribution when dosed orally, based on steady-state 
(Vss/F) or the terminal phase (Vz/F)
!
Terminal-phase elimination half-life (t1/2)
The following population PK parameters will be determined as appropriate:
!
CL/F
!
Apparent total volume of distribution when dosed orally (V/F)
!
Absorption rate constant (first-order; Ka)
!
Lag (if applicable)
Overview of Secondary Objective of Tablet Taste and Acceptability
!
Apremilast tablet palatability will be assessed at Visit 2 (Day1) using a faces 
Likert Scale
Overview of Exploratory Efficacy Assessments
!
Psoriasis Area Severity Index 
Percent change in the PASI score from the Baseline Visit at Weeks 2, 4, 8, 16, 24, 
32, 40 and 50
Statistical Methods
No formal sample size calculation is performed. A sample size of at least 16 subjects per group 
has been selected to provide an adequate PK profile and safety assessment in subjects of 
different ages and body weight ranges.  If needed, dropouts will be replaced to ensure that 
evaluable PK data from at least 32 subjects is collected.
Pharmacokinetic analyses will be based on the pharmacokinetic population, defined as all 
enrolled subjects who take at least one dose of the investigational product (ie, apremilast) and 
have evaluable pharmacokinetic (PK) data. Pharmacokinetic data is considered evaluable if 
there are measurable drug levels of apremilast in plasma from at least 3 time points which extend 
over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a 
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Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
dose. Pharmacokinetic parameters will be calculated using non-compartmental methods, plasma 
concentrations and actual blood sampling times from the intensive sampling schedule.  
Pharmacokinetic parameters and plasma concentrations for apremilast will be presented using 
descriptive statistics.  Population PK analyses will be performed using non-linear mixed effect 
modeling (NONMEM).  Covariate analysis will be performed to identify relevant covariates.
Safety and efficacy analyses will be based on the safety population, defined as all enrolled 
subjects who take at least one dose of apremilast.  Safety endpoints, including adverse events, 
laboratory data and vital sign measurements, will be summarized using descriptive statistics.  
Adverse events will be coded using Medical Dictionary for Drug Regulatory Activities 
(MedDRA) dictionary. Exploratory efficacy endpoints will be summarized using descriptive 
statistics.  
No formal interim analysis is planned for this study. However, an analysis of the PK and 2 weeks 
of safety data from the initial 8 adolescent subjects enrolled into Group 1 will be used to model 
the most appropriate dose for subsequently enrolled subjects.  Similarly, 2 week PK and safety 
data from the first 8 subjects from Group 2 will be used to model the most appropriate dose for 
subsequently enrolled subjects.
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................18
1.1.
Apremilast..............................................................................................................18
1.2.
Psoriasis .................................................................................................................18
1.3.
Human Pharmacology.............................................................................................19
1.4.
Clinical Efficacy and Safety Data ...........................................................................20
1.6.
Risks/Benefits of Investigational Product and Safety Population.............................22
2.
STUDY OBJECTIVES...........................................................................................24
2.1.
Primary Objective...................................................................................................24
2.2.
Secondary Objectives .............................................................................................24
2.3.
Exploratory Objectives ...........................................................................................24
3.
STUDY ENDPOINTS............................................................................................25
3.1.
Primary Endpoint(s) ...............................................................................................25
3.2.
Secondary Endpoint(s)............................................................................................26
3.3.
Exploratory Endpoint(s)..........................................................................................26
4.
OVERALL STUDY DESIGN ................................................................................27
4.1.
Study Design ..........................................................................................................27
4.2.
Study Design Rationale ..........................................................................................31
4.3.
Study Duration .......................................................................................................32
4.4.
End of Trial ............................................................................................................33
5.
TABLE OF EVENTS.............................................................................................34
6.
PROCEDURES......................................................................................................37
6.1.
Informed Consent and Subject Assent.....................................................................37
6.2.
Inclusion/Exclusion Criteria....................................................................................37
6.3.
Demographic Data..................................................................................................37
6.4.
Complete Medical History......................................................................................37
6.5.
Prior and Concurrent Therapies and Procedures......................................................37
6.6.
Safety Assessments.................................................................................................38
6.6.1.
Adverse Events.......................................................................................................38
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6.6.2.
Contraception Education.........................................................................................38
6.6.3.
Serum and Urine Pregnancy Tests for Females of Childbearing Potential ...............38
6.6.4.
Complete Physical Examinations............................................................................38
6.6.5.
Abbreviated Physical Examination .........................................................................38
6.6.6.
Hepatitis B and C Testing .......................................................................................39
6.6.7.
Vital Signs, Height, Weight and Body Mass Index..................................................39
6.6.8.
Clinical Laboratory Evaluations..............................................................................39
6.6.8.1.
Hematology............................................................................................................39
6.6.8.2.
Serum Chemistry....................................................................................................39
6.6.8.3.
Urinalysis ...............................................................................................................40
6.6.8.4.
Vaccinations...........................................................................................................40
6.6.9.
Twelve-lead Electrocardiogram ..............................................................................40
6.7.
Tablet Taste and Acceptability Testing ...................................................................40
6.8.
Oral Dose of Apremilast .........................................................................................40
6.9.
Apremilast Drug Accountability .............................................................................41
6.10.
Stool Diary .............................................................................................................41
6.11.
Tanner Staging .......................................................................................................41
6.12.
Worsening Psoriasis and Rebound Assessments......................................................41
6.13.
Psychiatric Evaluation ............................................................................................41
6.14.
Clinic Visits............................................................................................................42
6.14.1.
Unscheduled Visits.................................................................................................42
6.15.
Blood Collection for Pharmacokinetic Analysis......................................................42
6.16.
Exploratory Assessments........................................................................................44
6.16.1.
Psoriasis Area Severity Index (PASI)......................................................................44
7.
STUDY POPULATION.........................................................................................45
7.1.
Number of Subjects and Sites .................................................................................45
7.2.
Inclusion Criteria....................................................................................................45
7.3.
Exclusion Criteria...................................................................................................47
8.
DESCRIPTION OF STUDY TREATMENTS........................................................49
8.1.
Description of Investigational Product(s)................................................................49
8.2.
Treatment Administration and Schedule .................................................................49
8.2.1.
Overdose ................................................................................................................49
8.3.
Method of Treatment Assignment...........................................................................49
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8.1.
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8.4.
Packaging and Labeling..........................................................................................50
8.5.
Investigational Product Accountability and Disposal ..............................................50
8.6.
Investigational Product Compliance........................................................................50
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................52
9.1.
Permitted Concomitant Medications and Procedures...............................................52
9.2.
Prohibited Concomitant Medications and Procedures..............................................52
9.3.
Required Concomitant Medications and Procedures................................................53
10.
STATISTICAL ANALYSES..................................................................................54
10.1.
Overview................................................................................................................54
10.2.
Study Population Definitions ..................................................................................54
10.3.
Sample Size and Power Considerations...................................................................54
10.4.
Background and Demographic Characteristics........................................................54
10.5.
Subject Disposition.................................................................................................54
10.6.
Exploratory Efficacy Analysis ................................................................................54
10.7.
Safety Analysis.......................................................................................................55
10.7.1.
Internal Celgene Safety Monitoring During the Apremilast Program: Role of 
the Safety Management Team.................................................................................55
10.7.2.
External Safety Monitoring During Apremilast Program: Role of the 
Independent Data Monitoring Committee ...............................................................55
10.8.
Pharmacokinetic Analysis.......................................................................................55
10.9.
Interim Analysis .....................................................................................................56
10.10.
Other Topics...........................................................................................................56
10.10.1.
Investigational Product Compliance (Tablets).........................................................56
10.10.2.
Concomitant Therapy .............................................................................................56
10.10.3.
Taste and Acceptability ..........................................................................................57
11.
ADVERSE EVENTS..............................................................................................58
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................58
11.2.
Evaluation of Adverse Events.................................................................................58
11.2.1.
Seriousness.............................................................................................................58
11.2.2.
Severity / Intensity..................................................................................................59
11.2.3.
Causality ................................................................................................................60
11.2.4.
Duration .................................................................................................................60
11.2.5.
Action Taken..........................................................................................................61
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2 3


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11.2.6.
Outcome.................................................................................................................61
11.3.
Abnormal Laboratory Values..................................................................................61
11.4.
Pregnancy...............................................................................................................61
11.4.1.
Females of Childbearing Potential ..........................................................................61
11.4.2.
Male Subjects.........................................................................................................62
11.5.
Reporting of Serious Adverse Events......................................................................62
11.5.1.
Safety Queries ........................................................................................................62
11.6.
Expedited Reporting of Adverse Events..................................................................63
12.
DISCONTINUATIONS .........................................................................................64
13.
EMERGENCY PROCEDURES.............................................................................65
13.1.
Emergency Contact.................................................................................................65
13.2.
Emergency Identification of Investigational Products .............................................65
14.
REGULATORY CONSIDERATIONS...................................................................66
14.1.
Good Clinical Practice............................................................................................66
14.2.
Investigator Responsibilities ...................................................................................66
14.3.
Informed Consent and Subject Assent.....................................................................67
14.4.
Confidentiality........................................................................................................67
14.5.
Protocol Amendments.............................................................................................67
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................67
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................68
14.8.
Termination of the Study ........................................................................................68
15.
DATA HANDLING AND RECORDKEEPING.....................................................69
15.1.
Data/Documents .....................................................................................................69
15.2.
Data Management...................................................................................................69
15.3.
Record Retention....................................................................................................69
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................71
16.1.
Study Monitoring and Source Data Verification......................................................71
16.2.
Audits and Inspections............................................................................................71
17.
PUBLICATIONS ...................................................................................................72
18.
REFERENCES.......................................................................................................73
19.
APPENDICES........................................................................................................75
Appendix A:
Static Physician Global Assessment (sPGA)......................................................75
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17.7


Apremilast
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Celgene Corporation
Confidential and Proprietary
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Appendix B:
Stool Diary ........................................................................................................76
Appendix C:
Example of a Faces Likert Scale ........................................................................77
Appendix D:
Tanner Stages....................................................................................................78
Appendix E1:
Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Baseline/Screening: ................................................................................................79
Appendix E2:
Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s Since 
Last Visit:...............................................................................................................82
Appendix F:
Apremilast Plasma and Dried Blood Spot for Pharmacokinetic Sample 
Handling Instructions..............................................................................................85
Appendix G:
Psoriasis Area Severity Index ............................................................................87
Appendix H:
List of Abbreviations and Definition of Terms...................................................88
82
82
...........
..... 85
8
.............
............
..............
............


Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
16
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
LIST OF TABLES
Table 1:
Table of Events.......................................................................................................34
Table 2:
Acceptable Time Windows for Pharmacokinetic Blood Sampling...........................43
&(/*(1(35235,(7$5<,1)250$7,21


Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
17
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................29
Figure 2:
Subject Treatment Groups ......................................................................................30


Apremilast
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Celgene Corporation
Confidential and Proprietary
18
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
1.
INTRODUCTION 
1.1.
Apremilast
Apremilast (APR) (also called CC-10004), an oral small-molecule inhibitor of phosphodiesterase
4 (PDE4), works intracellularly to modulate a network of pro- and anti-inflammatory mediators.  
Phosphodiesterase 4 is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase 
(PDE) and the dominant PDE in inflammatory cells.  Inhibition of PDE4 elevates intracellular 
cAMP levels, which in turn downregulates the inflammatory response by modulating the 
expression of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-23, and other inflammatory 
cytokines.  Elevation of cAMP also increases anti-inflammatory cytokines such as IL-10.  These 
pro- and anti-inflammatory mediators have been implicated in psoriasis and psoriatic arthritis 
(PsA) (Claveau, 2004; Schafer, 2010; Hamzaoui, 2011).
Apremilast is approved for the treatment of psoriasis and PsA in adults in the United States (US), 
Canada, European Union (EU), Switzerland, Australia and Israel. Apremilast is being developed 
for use in the treatment of other immune-mediated inflammatory conditions such as 
 
 ulcerative colitis, Behçet’s Disease, 
.  
1.2.
Psoriasis
Psoriasis is a chronic, inflammatory skin disorder estimated to affect up to 2.5% of the world’s
population (Christophers, 2001). Plaque-type psoriasis is the most common form of the disease 
in both adults and children (Fan, 2007; Mallbris, 2005; Morris, 2001). The prevalence of 
psoriasis in children in the United States from birth to age 18 is 1%, with an incidence of 40.8 
per 100,000 (Tollefson, 2010). Psoriasis is characterized by thickened, well-demarcated 
erythematous plaques of skin covered with silvery scales. 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). For mild plaque psoriasis, which comprises the majority of pediatric cases, 
the disease can be treated with topical therapies. Phototherapy is not recommended for fair-
skinned or younger children and psoralens and long-wave ultraviolet radiation (PUVA) is not 
recommended for use in pediatric psoriasis patients at all, due to the increased risk of 
malignancies (Ståhle, 2010). Most pediatric patients present with mild, localized psoriasis that is 
treated primarily with topical medications. Systemic medications are typically reserved for more 
extensive or refractory disease. Management of psoriasis in children can be challenging owing to 
a paucity of data and lack of standardized guidelines specific to the pediatric population. (Vogel,
2012).
Approved therapies for moderate to severe psoriasis in children are very limited.  As a 
consequence, some pediatric patients are treated off-label with the same systemic agents 
prescribed for adults. In children, these treatments are reserved for severe psoriasis due to the 
risks of hepatic, renal, and neurological toxicities that often require routine clinical and 
laboratory monitoring, as well as an increased risk of infections and malignancies.  Pediatric 
psoriasis tends to be less severe than that seen in adults and may also be more responsive to 
treatment than in adults (Paller, 2008); therefore, it is important that the severity of the disease 
justifies the risks of treatment for the pediatric population. 
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Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
1.3.
Human Pharmacology
To date, no studies with apremilast have been conducted in subjects < 18 years of age.
In healthy adult subjects under fasting conditions, apremilast is rapidly absorbed following oral 
administration.  Apremilast demonstrates linear pharmacokinetics, with area under the plasma 
concentration-time curve (AUC) increasing in a dose-proportional manner through 50 mg BID or 
80 mg once daily.  Co-administration with food does not affect the PK bioavailability of 
apremilast (CC-10004-CP-022).  Apremilast is primarily eliminated as metabolites formed via 
both cytochrome P450 (CYP)-mediated oxidative metabolism (and subsequent glucuronidation) 
and non-CYP-mediated hydrolysis, with less than 3% excreted unchanged in urine (CC-10004-
PK-002).  Only 2 minor human apremilast metabolites retain pharmacologic activity, indicating 
that the in vivo pharmacological activity of apremilast is attributed to the parent compound.  The 
plasma clearance of apremilast is on average about 10 L/hr in healthy subjects (CC-10004-CP-
012), with a terminal elimination half-life of approximately 6 to 9 hours.  CYP3A4, CYP1A2, 
and CYP2A6 all participate in apremilast metabolism.  Co-administration with ketoconazole 
increased mean apremilast area under the plasma concentration-time curve from time zero to 
infinity (AUC0-∞) and maximum plasma concentration of the drug (Cmax) by approximately 36% 
and 5%, respectively, but did not alter the elimination half-life of apremilast (CC-10004-PK-
005).  Co-administration of multiple oral doses of rifampin increased apremilast apparent 
clearance by about 9.6 L/h to 34.5 L/h, which resulted in a decrease in apremilast mean AUC 
(approximately 72% lower) and Cmax (approximately 43% lower) relative to that of apremilast 
given alone (CC-10004-CP-025).  Methotrexate (MTX), a commonly prescribed anti-
inflammatory drug, does not affect apremilast PK exposure.  Apremilast does not affect the PK 
exposure of MTX and its metabolite, 7-OH MTX (CC-10004-PK-010).  Hepatic impairment 
does not affect apremilast exposure (CC-10004-CP-011), and thus no dose adjustment is 
necessary for subjects with hepatic impairment. In the subjects with mild renal impairment, there 
were no clinically meaningful differences in the PK of apremilast relative to the matched healthy 
group. There were an ~22% higher AUC0-∞and ~13% lower Cmax of apremilast noted in the 
moderate renal impairment group relative to the matched healthy subject group, however, the 
differences noted were not statistically significant. Moreover, when compared to the healthy 
subjects matched to the mild renal impairment group, the mean AUC from moderate renal 
impaired subjects were comparable and the mean Cmax was 18% lower. Thus, the numerical 
differences noted in the moderate renal impairment group are likely within the between-subject 
variability of apremilast exposure and are not clinically meaningful (CC-10004-CP-029). In 
subjects with severe renal impairment, a single oral dose administration of a 30-mg apremilast 
tablet resulted in an increase in overall mean exposure (AUC0-∞) by approximately 88% (CC-
10004-CP-019).  Apremilast PK and exposure are comparable across ethnic groups of Caucasian, 
Japanese and Chinese subjects (CC-10004-CP-018).  Analyses showed apremilast exposure is 
also similar among Hispanic Caucasians, non-Hispanic Caucasians, and African Americans.  
Apremilast exposure (AUC) in elderly healthy subjects (70.5 ± 4.15 years of age [mean ± 
standard deviation (SD)]) was approximately 13% higher than that in young healthy subjects 
(34.3 ± 7.17 years of age [mean ± SD]; CC-10004-CP-024) although not statistically different.  
Young and elderly combined, apremilast AUC exposure was approximately 30% higher in 
females than in males.  
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Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
The metabolic profile of a single 20-mg oral dose of [14C]-apremilast was characterized in a 
healthy volunteer absorption/distribution/metabolism/excretion (ADME) study.  The mean total 
urinary and fecal radioactive recovery of apremilast (and its metabolites) was 97.1%, with mean 
contributions of 57.9% and 39.2% from urine and feces, respectively (CC-10004-PK-002).
Detailed information regarding the available pharmacology, toxicology, drug metabolism, 
clinical studies, and safety profile of apremilast are available in the Investigator’s Brochure.
 
 
 
 
 
 
 
 
 
 
 However, when apremilast is given to subjects whose body 
weights range from 15 kg to < 70 kg, initial dosing regimens should be adjusted based on body 
weight.  As a result, the proposed dosing regimen in this study will be weight-based and a 
staggered, stepwise study design (starting enrollment with older and heavier adolescents) will 
guide dosing of subsequently enrolled subjects (younger and lower body weight children).
The PK and pharmacodynamics (PD) of apremilast in pediatric subjects have not been 
investigated.  Considering the similarity of the disease process between adult and pediatric 
patients, it is appropriate to choose the dose for the pediatric population that will provide overall 
drug exposure similar to that of the US Food and Drug Administration (FDA), Health Canada,
and the European Medicines Agency (EMA) approved adult dose in psoriasis, assuming a similar 
exposure and response relationship in adult and pediatric patients.
1.4.
Clinical Efficacy and Safety Data
At the time of protocol finalization, apremilast had been administered to adult subjects (≥18 
years of age) at daily doses ranging from 10 to 100 mg/day in completed Phase 1 and Phase 2 
clinical studies, and doses of 20 mg BID (APR 20 BID) to 30 mg BID (APR 30 BID) in ongoing 
Phase 2 and 3 clinical studies.
A dose ranging study in adult subjects with psoriasis has been performed to determine the 
optimal adult dose of apremilast (Study CC-10004-PSOR-005).  Apremilast dose regimens of 10 
mg, 20 mg and 30 mg BID were tested versus placebo.  Both the 20 mg and 30 mg BID doses 
were significantly better than placebo, with a 29% response in PASI-75 at 20 mg BID, and a 
41% response in PASI-75 for the 30 mg BID dose.  Furthermore, the safety profiles of the 20 mg 
and 30 mg BID regimens were acceptable and similar.  Based on these findings, apremilast 30 
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
21
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
mg BID was determined to be the optimal dose for treatment of psoriasis for the Phase 3 
registration trials.
The efficacy, safety, and tolerability of APR 30 BID were assessed in a total of approximately 
1250 adult subjects with moderate to severe plaque psoriasis who were candidates for 
phototherapy or systemic therapy in 2 pivotal Phase 3 studies (Study CC-10004-PSOR-008 and 
Study CC-10004-PSOR-009).  The baseline demographic characteristics of subjects were similar 
across both studies, generally well balanced across the treatment groups, and representative of 
the typical subject population in psoriasis clinical studies in adults.  Approximately 55% of the 
subjects had been treated previously with systemic therapy (ie, conventional systemic and/or 
biologics). Approximately 40% of subjects were previously treated with conventional systemic 
therapies, approximately 30% had prior exposure to biologics, and 17% to 29% had prior 
exposure to TNF blockers.
Apremilast demonstrated a treatment benefit in adult subjects with moderate and severe 
psoriasis, as both studies achieved the primary endpoint by demonstrating that a significantly
greater proportion of subjects randomized to APR 30 BID achieved a PASI-75 response at Week 
16 compared with placebo. In Study PSOR-008, 33.1% of subjects receiving APR 30 BID 
achieved a PASI-75 response at Week 16 compared with 5.3% of subjects receiving placebo (p < 
0.0001). In Study PSOR-009, 28.8% of subjects achieved a PASI-75 response at Week 16 
compared with 5.8% of subjects receiving placebo (p < 0.0001).
Clinically meaningful and statistically significant improvements were also observed with APR 
30 BID for many other efficacy endpoints in both studies, including the major secondary 
endpoint, sPGA clear (0) or almost clear (1), PASI-50 response, mean change in PASI, BSA, 
pruritus and skin discomfort/pain compared with placebo.  Clinical response to apremilast 
treatment was rapid, with significant improvement compared to placebo as early as Week 2.  
Maximal responses were generally achieved by Week 16, and sustained during ongoing 
treatment.  
The overall safety and tolerability profile of APR 30 BID is acceptable for the treatment of 
moderate to severe plaque psoriasis.  The most commonly reported adverse events in the 
psoriasis Phase 3 program were diarrhea, nausea and upper respiratory tract infection.  The most 
common adverse reactions leading to discontinuation for subjects taking apremilast were nausea, 
diarrhea, and headache.  The vast majority of subjects in the APR 30 BID group reported these 
events as mild or moderate in severity.  None of the most common events were reported as 
serious adverse events (SAEs).  
In 3 Phase 3 pivotal studies in adult subjects with active psoriatic arthritis despite prior treatment 
with small molecules or disease modifying anti-rheumatic drugs (DMARDs), evaluating 
apremilast 20 mg BID and 30 mg BID in a total of 1493 subjects (Studies CC-10004-PSA-002, 
CC-10004-PSA-003, and CC-10004-PSA-004), apremilast demonstrated a statistically 
significant response, as measured by American College of Rheumatology (ACR) 20 at Week 16, 
the primary endpoint, for both of the apremilast treatment groups, compared with placebo.  The 
studies were sized to demonstrate an approximate 20% treatment difference when comparisons 
are made between any active treatment group and placebo.  The ACR20 responses ranged from 
18.3% to 19.0% in the placebo group, 28.4% to 37.4% in the apremilast 20 mg BID treatment 
group (p ≤ 0.0295 versus placebo), and 32.1% to 40.7% in the apremilast 30 mg BID treatment 
group (p ≤ 0.0060 versus placebo).  In subjects who were DMARD-naïve (Study CC-10004-PSA 
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Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
005), the primary endpoint was met for both the APR 20 BID and APR 30 BID treatment groups, 
compared with placebo (28.0% and 30.7% versus 15.9%, respectively [p = 0.0062 and 0.0010, 
respectively]).  Among subjects who were initially randomized to apremilast, ACR20/50/70 
response rates were maintained through Week 52 across all the studies.  At Week 16 
improvements in the skin manifestations of psoriasis were seen in the apremilast-treated subjects.  
Among subjects who remained on the apremilast treatment to which they were randomized at 
study start, these improvements were maintained through Week 52.
Overall Safety Profile of Apremilast
The safety profile of apremilast has been well characterized on the basis of data from 4089 
subjects exposed to apremilast for a total of 3541 subject-years, including 1631 subjects exposed 
for 1 year or more. Apremilast was generally well tolerated, demonstrating an acceptable safety 
profile with long-term exposure (1 year or more). The most frequently observed adverse 
reactions were gastrointestinal (GI) disturbances, most commonly diarrhea and nausea. The vast
majority of these events were reported as mild or moderate in severity, and led to discontinuation
in a small proportion of subjects. In general, these events were self-limiting, did not require
intervention, and resolved with uninterrupted apremilast treatment.
 
 
 
 
 
 
 
 
 
 
 
1.6.
Risks/Benefits of Investigational Product and Safety Population
The safety and tolerability profiles of the apremilast 20 mg BID and 30 mg BID dose groups are 
both acceptable based on results from the clinical development program for apremilast. 
Treatment-emergent adverse events (TEAEs) associated with apremilast treatment were diarrhea, 
nausea, headache (including tension headache), and upper respiratory tract infection, which were 
usually mild or moderate in severity and often resolved while subjects continued to take 
apremilast. Diarrhea, nausea and headache tended to occur early in treatment. The overall 
discontinuation rate due to AEs was low and was most frequently due to nausea, diarrhea, or 
headache. Treatment with apremilast was associated with observed weight loss without overt 
clinical consequences. The results of pivotal Phase 3 clinical trials in psoriasis and PsA 
demonstrate that the 30 mg BID dose presents a favorable benefit/risk profile in adult subjects 
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
23
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
with moderate to severe psoriasis and PsA.  All apremilast approvals to date for both PsA and 
psoriasis have been for the 30 mg BID dose regimen.
Please refer to the IB for detailed information concerning the available pharmacology, 
toxicology, drug metabolism, clinical studies, and the safety profile of apremilast.
&(/*(1(35235,(7$5<,1)250$7,21


Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
24
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is to select a pediatric dose of apremilast based on the safety, 
tolerability, and PK of apremilast in adolescents and children with moderate to severe plaque 
psoriasis.
2.2.
Secondary Objectives
The secondary objective is to evaluate the taste and acceptability of apremilast tablet using a 
faces Likert Scale.
2.3.
Exploratory Objectives
The exploratory objective of the study is to evaluate the effect of apremilast on psoriasis in 
adolescents and children as measured by PASI.
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using a 
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ast on psori


Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
25
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint(s)
Safety
The safety (reported AEs) and laboratory findings of subjects in each age group will be described 
and evaluated in relation to the extent of exposure to apremilast.
The following will be monitored, evaluated, recorded, and reported:
!
Adverse events (AEs)
!
Physical examinations
!
Vital sign measurements
!
Clinical laboratory safety tests
!
12-lead electrocardiograms (ECGs)
!
Concomitant medications / procedures
!
Pregnancy tests
Pharmacokinetics
The following PK parameters will be estimated for apremilast using a non-compartmental 
approach if data permit:
!
Maximum observed plasma concentration (Cmax)
!
Time to Cmax (tmax)
!
Area under the plasma concentration-time curve from time zero to 12 hours postdose 
(AUC0-12)
!
Area under the plasma concentration-time curve from time zero to the last 
quantifiable concentration (AUC0-t)
!
Apparent total plasma clearance when dosed orally (CL/F)
!
Apparent total volume of distribution when dosed orally, based on steady-state 
(Vss/F) or the terminal phase (Vz/F)
!
Terminal-phase elimination half-life (t1/2)
The following population PK parameters will be determined as appropriate:
!
CL/F
!
Apparent total volume of distribution when dosed orally (V/F)
!
Absorption rate constant (first-order; Ka)
!
Lag (if applicable)
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!


Apremilast
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Celgene Corporation
Confidential and Proprietary
26
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
3.2.
Secondary Endpoint(s)
The taste and acceptability of apremilast tablet will be assessed using a faces Likert Scale on
Day 1, initial dosing.  
3.3.
Exploratory Endpoint(s)
The exploratory endpoint is the percent change in PASI scores from Baseline.
Measurements of PASI will be performed at Screening, Baseline, Weeks 2, 4, 8, 16, 24, 32, 40,
50,54, 58, Unscheduled visits, and Early Termination visits as indicated in the Table of Events 
(Section 5).
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
27
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is a Phase 2, multicenter, open-label study in subjects with moderate to severe plaque 
psoriasis aged 6 to 17 years, inclusive, intended to assess the safety, tolerability, and PK of 
apremilast with 2 weeks of oral apremilast treatment followed by a 48-week extension of 
apremilast treatment.  Moderate to severe plaque psoriasis is defined as Psoriasis Area Severity 
Index (PASI) ≥ 12, Body Surface Area (BSA) ≥ 10%, and static Physician Global Assessment 
(sPGA) of ≥ 3 (moderate to severe) [See Appendix A].  The total study duration for each subject 
will last for up to a total of 107 weeks which includes screening, treatment (including the PK 
portion of the study and the extension treatment period), two short-term follow-up periods and a 
long-term follow-up period (Figure 1).
Each subject will undergo a screening period of up to 5 weeks, a treatment period of 2 weeks 
with PK sample collection, and an extension treatment period of 48 weeks, to allow subjects 
access to apremilast treatment if medically appropriate (following the completion of the 2 week 
PK portion).  Regardless of when they stop treatment, subjects should complete two post
treatment follow-up visits at approximately 4 and 8 weeks after the last dose.  
All subjects should complete the final follow-up visit at Week 102 or at a timepoint 52 weeks 
after the last dose of apremilast was taken in subjects who have withdrawn at any time prior to 
Week 50.
At least 32 subjects will be enrolled into this study to provide an adequate PK profile and safety 
assessment in subjects of different ages and body weight ranges.  Subjects will be divided into 2 
age groups (adolescents [ages 12 to 17 years, inclusive] and children [ages 6 to 11 years, 
inclusive]), with at least 16 subjects in each group. Apremilast treatment will start in older and 
heavier subjects.  
A staggered, stepwise approach by age range and weight (starting with older and heavier 
subjects) is considered appropriate for this first-time-in-children study.  Doses for younger and 
lower body weight subjects will be adjusted based on safety and PK data from older and heavier 
subjects.  Dosing within and between groups will be staggered as described below, and in Figure 
2, based on PK data collected and a minimum of 2 weeks of safety data. 
Group 1 (ages 12 to 17 years, inclusive; weight ≥ 35 kg)
!
At least 8 subjects will initially be enrolled into Group 1 and will weigh ≥ 35 kg. 
∀
Dosing for subjects with a weight ≥ 35 kg to < 70 kg will be administered as a  20 
mg BID dose regimen (10 mg BID less than the adult dose). 
∀
Dosing for subjects with a weight ≥ 70 kg will be administered as a 30 mg BID 
dose regimen (same as for adults). 
!
Dose regimens (dose strength and/or dose frequency) for the remaining subjects in 
Group 1 will be determined based on PK and safety assessments from the first 8 
subjects in Group 1 to complete this period. These data will be reviewed by an
independent data monitoring committee (DMC) to determine if it is appropriate to 
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
proceed with dosing the balance of Group 1 subjects and to proceed with dosing in 
the Group 2 subjects.  
!
For the remaining subjects in Group 1, the dose strength and/or dose frequency will 
be adjusted for any safety concerns or for unexpected changes in exposure. In the 
event of a dose regimen adjustment, some or all of the first 8 subjects in Group 1, 
depending on weight, will return to the site for the appropriate dosing adjustment. 
Group 2 will open to enrollment once at least 8 subjects from Group 1 have 
completed the 2 weeks of apremilast dosing, PK data analysis, and safety assessments
and an evaluation of these data by the DMC has been completed.
Group 2 (ages 6 to 11 years, inclusive; weight ≥ 15 kg)
!
At least 8 subjects will initially be enrolled into Group 2 and will weigh ≥ 15 kg. The 
dose regimens (dose strength and/or dose frequency) for these first 8 subjects will be 
based upon the PK and safety assessments from the first 8 subjects in Group 1. If PK 
and safety are not affected by age and body weight, 20 mg BID will be administered 
to Group 2 children.  
!
Dose regimens (dose strength and/or dose frequency) for the remaining subjects in 
Group 2 will be determined based on PK and safety assessments from the data
collected from the first 8 subjects in each group. These data will be reviewed by an 
independent DMC to determine if it is appropriate to proceed with dosing the balance 
of Group 2 subjects.  
!
For the remaining subjects in Group 2, the dose (dose strength and/or dose frequency) 
will be based upon the subject weight as determined by the PK and safety 
assessments.  The dose strength and/or dose frequency will be adjusted for any safety 
concerns or for unexpected changes in exposure. In the event of a dose regimen 
adjustment after the second PK and safety assessment, the first 8 subjects in Group 2 
will return to the site for the appropriate dosing adjustment.
An independent DMC will review available safety and PK data at the following timepoints:
1. After the first 8 subjects in Group 1 have completed the first 2 weeks of apremilast 
dosing, PK, and safety assessments.
2. After the first 8 subjects in Group 2 have completed the first 2 weeks of apremilast 
dosing, PK, and safety assessments.
Treatment administration and schedule are discussed in Section 8.2.
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 anytime during the treatment (PK, or extension treatment period) of the 
study and require additional psoriasis medication including conventional systemic therapies such 
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Apremilast
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Celgene Corporation
Confidential and Proprietary
29
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
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 International Conference on Harmonisation 
(ICH) Good Clinical Practices (GCPs).
Figure 1:
Overall Study Design
&(/*(1(35235,(7$5<,1)250
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
30
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Figure 2:
Subject Treatment Groups
Group 1:
N=16
Ages: 12 to 17 years, inclusive
Weight:  ≥ 35 kg
Group 1:
Initial Dose:  
20 mg BID for subjects weighing ≥35 kg to < 70 kg
30 mg BID for subjects weighing ≥70 kg 
Group 1:
(Ages 12 to 17 years, inclusive)
(8 subjects with weight ≥35 kg)
Initial Dose:
20 mg BID (≥35 to < 70 kg)
30 mg BID (≥ 70 kg)
2 weeks PK 
and Safety 
Assessment
Begin Enrollment of 
subjects in Group 2
Enroll remaining subjects in 
Group 1
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
31
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Figure 2: Subject Treatment Groups (Continued)
Group 2:
N=16
Ages: 6 to 11 years, inclusive
Weight: ≥ 15 kg
Dose: Based upon completion of PK and safety data analysis from at least 8 subjects 
from Group 1. 
BID = twice daily; N = number of subjects; PK = pharmacokinetic; TBD = to be determined.
4.2.
Study Design Rationale
There is a paucity of treatments available for pediatric patients with moderate to severe psoriasis.  
Consequently, these subjects are treated off-label with the same systemic agents prescribed for 
adults.  The currently available systemic therapies for psoriasis are associated with significant 
cumulative toxicities and are associated with risks of hepatic, renal and neurological toxicities 
that often require routine clinical and laboratory monitoring, as well as an increased risk of 
infections and malignancies. Given the chronic nature of psoriasis, there is a need for medication 
that can be dosed chronically with less risk. It is, therefore, important for new medications to 
demonstrate both efficacy and safety with continuous use.  Apremilast provides a favorable 
Group 2:
(Ages 6 to 11 years, inclusive)
(8 subjects with weight ≥ 15 kg)
Initial Dose: TBD
Based on PK and safety from first 
8 subjects in Group 1 
2 weeks PK 
and Safety 
Assessment
Enroll remaining subjects in Group 2
based on PK and safety from first 8 
subjects in both groups
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Apremilast
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Celgene Corporation
Confidential and Proprietary
32
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
benefit/risk profile supporting the use of APR 30 BID in the treatment of adult patients with 
moderate to severe plaque psoriasis who are candidates for systemic and phototherapy.
Adolescents and children may differ from adults in their ADME of apremilast, hence evaluation 
of the safety and PK properties of apremilast in adolescents and children prior to initiation of an 
efficacy study in this subject population is warranted.  Although apremilast has only been 
investigated in adult subjects, it is known that there is a general similarity of disease process, as 
reflected in PD parameters, between adult and pediatric populations. Assuming a similar 
exposure-response relationship in adults compared to adolescents and children, it is appropriate 
to initiate dosing in the pediatric population at a dose of 20 or 30 mg BID, depending on weight, 
that will provide overall drug exposure similar to that associated with the selected optimal adult 
dose.
In CC-10004-PSOR-008-PK, the concentration versus time profile of apremilast was well 
described by a population PK model.  
 
 
 
 
 
 A comparable exposure in 
pediatric subjects is expected to achieve a similar clinical response seen in psoriasis adult 
patients following 30 mg BID.
This Phase 2 study will evaluate the clinical safety and PK of apremilast.  The proposed dosing 
regimen in this study will be weight-based and a staggered, stepwise study design (starting 
enrollment with older and heavier adolescents) will guide dosing of subsequently enrolled 
subjects (younger and lighter weight children) (Figure 2).  Efficacy of apremilast in the treatment 
of pediatric subjects with moderate to severe psoriasis will also be explored in this study.
4.3.
Study Duration
The study will last for up to a total of 107 weeks which includes screening, treatment, including 
the PK portion of the study and the extension treatment period, short-term follow-up and a long-
term follow-up.  
Each subject will undergo a screening period of up to 5 weeks, a treatment period of 2 weeks, 
and an extension treatment period of 48 weeks, to allow subjects access to apremilast treatment if 
medically appropriate (following the completion of the 2 week PK portion).
Regardless of when they stop treatment, subjects should complete two post treatment follow-up 
visits at approximately 4 and 8 weeks after the last dose.  
All subjects should complete the final follow-up visit at Week 102 or at a timepoint 52 weeks 
after the last dose of apremilast was taken in subjects who have withdrawn at any time prior to 
Week 50.
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
33
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
4.4.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
An abbreviated clinical study report will be written following analysis of the PK results. The 
results of the extension treatment period will be added once this portion of the study has been 
completed.
&(/*(1(35235,(7$5<,1)250$7,21


Apremilast
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Celgene Corporation
Confidential and Proprietary
34
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
5.
TABLE OF EVENTS
Table 1:
Table of Events
Procedure
Visit 1
Screening
Visit 2 
Baseline
Visit 3
Final 
PK
Visit 4-10
Extension 
Treatment
Visits 11 & 
12 Follow-
upa
Visit 13
Final 
Follow-upb
UNSc
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Week -5
Week 0
Week 2
Weeks 4, 8, 16, 
24, 32, 40, 50
Weeks 54
& 58
Week 102
Days -35 
to -1
Day 1
Day 14 
(+/-1)
Days 28, 56, 
112, 168, 224, 
280, 350 (+/-4)
Days 378
& 406
(+/-7)
Day 714
(+/-7)
Study Entry
Informed Consent / 
Assent
X
-
-
-
-
-
-
-
Inclusion/Exclusion 
Criteria
X
X
-
-
-
-
-
-
Demographic Data
X
-
-
-
-
-
-
-
Complete Medical 
History
X
-
-
-
-
-
-
-
Prior and Concurrent 
Therapies and 
Procedures
X
X
X
X
X
-
X
X
Stool Diary
Collectiond
-
-
X
X
X
-
X
X
Tanner Staging 
Assessment
-
X
-
-
Xe
-
-
-
Columbia-Suicide 
Severity Rating Scale 
(C-SSRS) Screening
Xf
-
-
-
-
-
-
-
Columbia-Suicide 
Severity Rating Scale 
(C-SSRS) Since Last 
Visit
-
Xg
Xg
Xg
Xg
-
Xg
Xg
Safety Assessments
Adverse Events
After signing ICF and until 28 days after the last dose
Pregnancy Test 
(FCBP only)h
X
X
-
X
X
-
-
X
Physical Examination
X
-
-
-
-
Xi
-
-
Abbreviated Physical 
Examination
-
Xj
Xj
Xj
Xj
-
Xj
Xj
Hepatitis B and C 
Testing
X
-
-
-
-
-
-
-
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52
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Table 1:
Table of Events (Continued)
Procedure
Visit 1
Screening
Visit 2 
Baseline
Visit 3
Final 
PK
Visit 4-10 
Extension 
Treatment
Visits 11 & 
12 Follow-
upa
Visit 13 
Final 
Follow-upb
UNSc
ET
Week -5
Week 0
Week 2
Weeks 4, 8, 16, 
24, 32, 40, 50
Weeks 54 
& 58
Week 102
Days -35 
to -1
Day 1
Day 14 
(+/-1)
Days 28, 56, 
112, 168, 224, 
280, 350 (+/-4)
Days 378 
& 406 (+/-
7)
Day 714
(+/-7)
Vital Signsk
X
X
X
X
X
-
X
X
Height
X
X
X
X
X
X
X
X
Weight 
X
X
X
X
X
X
X
X
Body Mass Index 
(BMI)
X
X
X
X
X
X
X
X
Hematology 
Laboratory Tests 
X
X
-
X
X
-
Xl
X
Serum Chemistry 
Laboratory Tests 
X
X
-
X
X
-
Xl
X
Urinalysis 
X
X
-
X
X
-
Xl
X
12-lead ECG
X
-
Xm
Xm
-
-
-
Xm
Apremilast
Tablet Taste and 
Acceptability Testing 
(via Likert Scale)
-
X
-
-
-
-
-
-
Oral Dose Apremilastn
-
X
X
X
-
-
-
-
Apremilast Drug 
Accountability
-
X
X
X
-
-
X
X
Drug Dispensation
-
X
X
Xo
-
-
-
-
Pharmacokinetic Assessments
Blood Collection for 
PKp
-
X
X
-
-
-
-
Xq
Exploratory Assessments
Psoriasis Area 
Severity Index (PASI)
X
X
X
X
X
-
X
X
ET = early termination; ECG = electrocardiogram; FCBP = females of childbearing potential; ICF = informed 
consent form; PK = pharmacokinetics; UNS = unscheduled visit.
a All subjects should complete the initial follow-up visits 4 and 8 weeks after taking their last dose of apremilast 
regardless of when they stop taking apremilast.
b All subjects should complete the final follow-up visit at Week 102 or at a timepoint 52 weeks after the last dose of 
apremilast was taken in subjects who have withdrawn at any time prior to Week 50.
c Refer to 6.14.1 for details.
d 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 11).
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X
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X
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X
50
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X
25
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25
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X
X
X
X
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35
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l


Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
e Tanner Staging assessment will be performed at Baseline and the 8 week post last dose of apremilast follow-up 
visit (Visit 12).
f Any subject, during screening or at baseline, 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.
g Any subject that answers ‘Yes’ to any question on the Columbia-Suicide Severity Rating Scale, at anytime during 
the study (post baseline) will be immediately withdrawn from study treatment and must be referred immediately 
for a psychiatric evaluation. 
h Serum and urine pregnancy testing will be required for FCBP at Baseline.  Urine pregnancy testing will be 
performed at Screening and at each visit during the extension period, the Week 54 and 58 Follow-up Visits, and 
the ET visit (if applicable).  If a urine test is positive, a serum test will be done for confirmation.
i Laboratory tests may be performed as clinically indicated based on the investigator’s medical judgment. The 
subject will be asked if he/she has used any investigational drug within the 52 weeks prior to the Week 102 visit.
j An abbreviated physical examination may be performed at the discretion of the Investigator, if clinically needed.
k Vital signs will be obtained after the subject has been in the supine position for at least 5 minutes.
l Urinalysis, hematology, and serum chemistry laboratory tests may be performed at the discretion of the 
Investigator, if clinically needed.
m Electrocardiogram (ECG) will be completed at Screening and after the last dose of investigational product (Week 
50/ET). If a subject withdraws from the study prior to entering the extension treatment period, an ECG should be 
completed at the Week 2 (Final PK) visit.
n Apremilast will be administered orally twice daily from Day 1 through the morning of Day 14.  Evening doses 
should be administered approximately 12 hours after the morning dose.  The evening dose taken on Day 14 must 
not be taken until AFTER the last PK blood sample is drawn. On PK days (Day 1 and Day 14), all subjects will be 
administered the morning dose of apremilast by mouth in the fasted state.  Food and beverages (except water) will 
be withheld from subjects for at least 8 hours prior to the morning dose until at least 2 hours after the morning 
dose on PK days (Day 1 and Day 14).  For all evening doses and all morning doses administered on non-PK days, 
apremilast tablets should be taken approximately 12 hours apart and without any food restrictions. NOTE: Dosing 
regimens may vary depending on dose strength/dose frequency determined from the Group 1 PK and safety data.
o No drug will be dispensed at Week 50.
p Group 1 (ages 12 to 17 years, inclusive, at the time of Screening): Day 1: 2 hours after the morning dose. Day 14 
(last dose of PK treatment period): Predose (prior to morning dose) and 1, 2, 3, 5, 8, and 12 hours post morning 
dose.  
Group 2 (ages 6 to 11 years, inclusive, at the time of Screening): Day 1: 2 hours after the morning dose. Day 14 
(last dose of PK treatment period): Predose (prior to morning dose) and 2, 5, and 12 hours after the morning dose.  
q Do not collect PK after Day 14.
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
37
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
6.
PROCEDURES
The following procedures will be conducted as outlined in the Table of Events, Section 5.
6.1.
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 again 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.
6.2.
Inclusion/Exclusion Criteria
Subjects must meet all eligibility criteria (Section 7.2 and Section 7.3) 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 reviewed again prior to first 
dose.
6.3.
Demographic Data
The demographic data will include (but not be limited to) the subject’s date of birth, age, gender, 
and race/ethnic origin.  The demographic profile will be recorded in the source documents and 
electronic case report form (eCRF).
6.4.
Complete Medical History
Relevant medical history should be recorded, including previous relevant surgeries.  Disease 
history should include history of plaque psoriasis.
6.5.
Prior and Concurrent Therapies 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 therapies being taken by the subject at any time during the study 
must also be recorded. The stop dates and the 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 electronic case report form (eCRF) Completion 
Guidelines.
Subjects are eligible for study participation if not previously exposed to more than one systemic 
agent for psoriasis. 
Refer to Section 9 for further details regarding permitted and prohibited concomitant medications 
and procedures.
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f


Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
6.6.
Safety Assessments
6.6.1.
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 11.  All AEs, whether reported by subjects 
spontaneously or when elicited by direct questioning, will be monitored and recorded from the 
time the subject signs the ICF until 28 days after the last dose of apremilast. Serious adverse 
events (SAEs) suspected of being related to apremilast and made known to the Investigator at 
any time will be monitored and recorded.
6.6.2.
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 7.2 while on investigational product and 
for at least 28 days after administration of the last dose of the investigational product.
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.
6.6.3.
Serum and Urine Pregnancy Tests for Females of Childbearing Potential
A serum pregnancy test with a sensitivity of ≤ 25 mIU/mL will be required for all FCBP at 
Baseline and as confirmation of any positive urine test. Urine pregnancy testing will be 
performed on all FCBP at Screening, Baseline and at the extension treatment period visits and 
the 4 and 8 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.
6.6.4.
Complete Physical Examinations
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.
6.6.5.
Abbreviated Physical Examination
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. 
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6.6
n ab


Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
6.6.6.
Hepatitis B and C Testing
Hepatitis testing will be performed at Screening and will include hepatitis B surface antigen and 
hepatitis C antibody.
6.6.7.
Vital Signs, Height, Weight and Body Mass Index
Vital signs, including temperature, respiratory rate, pulse, and seated blood pressure, will be 
taken during the visits indicated in the Table of Events, (Section 5).  Height, weight and body 
mass index will be measured and recorded at Screening and then as 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. 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.
6.6.8.
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.
6.6.8.1.
Hematology
Hematology laboratory evaluations will include red blood cells (RBCs), hemoglobin, hematocrit, 
white blood cells (WBCs), absolute and differential and platelet count.
6.6.8.2.
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. 
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
6.6.8.3.
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.
6.6.8.4.
Vaccinations
Apremilast’s effect on vaccinations has not been studied, therefore, a conservative approach will 
be taken and vaccinations will be withheld during the first 14 days of dosing.  Inactivated 
vaccines will be allowed during the extension treatment period, however, live vaccines are not 
allowed during active treatment with apremilast. 
6.6.9.
Twelve-lead Electrocardiogram
The timeframes for all 12-lead electrocardiograms (ECGs) are indicated in the Table of Events, 
Section 5.
An ECG will be performed after the subject has been supine for approximately 3 minutes. Sites 
are to utilize their own, local ECG machines for the study and the ECG readings will be further 
interpreted by the Investigator by clinically correlating with the subject’s condition.  The 
Investigator’s clinical interpretation will be recorded in the electronic Case Report Form (eCRF) 
as: normal; abnormal, not clinically significant; abnormal, clinically significant; indeterminate; 
or not evaluable. Any abnormal findings in the ECG reading should be recorded in the ECG 
eCRF. “Abnormal, clinically significant” results should be recorded in the Medical History 
eCRF if found predose or in the AE eCRF if found postdose of the investigational product. If a 
subject has an “abnormal, clinically significant” result at Screening, then he/she should be 
excluded. 
An ECG may be performed outside of the timeframes indicated in the Table of Events if the 
investigator feels that this is warranted based on medical evidence.
6.7.
Tablet Taste and Acceptability Testing
The taste and acceptability of apremilast tablet will be assessed using a faces Likert Scale on 
Day 1, initial dosing.  An example of a faces Likert Scale is illustrated in Section 19,
Appendix C.
6.8.
Oral Dose of Apremilast
Apremilast will be administered orally twice daily from Day 1 through the morning of Day 14
for pharmacokinetics assessment.  Evening doses should be administered approximately 12 hours 
after the morning dose.  The evening dose taken on Day 14 must not be taken until AFTER the 
last PK blood sample is drawn.  
Dosing regimens may vary depending on dose strength/dose frequency determined from the PK 
and safety data collected from the initial 8 subjects in Groups 1 and 2. See Section 8.2 for 
additional details concerning treatment administration. 
During the extension phase, apremilast will be administered orally twice daily. Evening doses 
will be administered approximately 12 hours after the morning dose.  
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Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
6.9.
Apremilast Drug Accountability
The Investigator(s) or designee(s) will account for all apremilast that is issued to and returned by 
the subject throughout the study.  
6.10.
Stool Diary
Diarrhea is the passage of three or more watery/liquid stools per day (WHO, 2015). 
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 (Appendix B). 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 11).
6.11.
Tanner Staging 
Assessments of sexual maturity (Tanner Staging) will be performed at baseline and the 8 week 
post last dose follow-up visit (Visit 12).  A description of each Tanner stage is provided in 
Appendix D (WHO, 2015).
6.12.
Worsening Psoriasis and Rebound Assessments
A worsening of plaque psoriasis, including flare, during treatment will not be collected as an 
adverse event unless it is considered a serious adverse event (SAE). Disease activity (worsening 
or improvement in severity) will be collected using PASI. 
Rebound is defined as a severe and sudden worsening of disease that occurs between the time of 
study treatment discontinuation and the 4 and 8 week Follow-up Visits. 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).
6.13.
Psychiatric Evaluation
Psoriasis has been associated with an increased risk of developing psychiatric disorders, 
including depression and anxiety in pediatric patients (Kimball, 2012). Depression has been 
reported in the apremilast clinical trials. 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 (Apremilast 
Investigator’s Brochure).
All subjects will complete the Columbia-Suicide Severity Rating Scale (C-SSRS) (Appendix E)
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.  Any subject that answers ‘Yes’ to any question on the C-SSRS at anytime 
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 
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Apremilast
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Celgene Corporation
Confidential and Proprietary
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Follow-up Visits four and eight weeks after Early Termination and the long-term follow-up visit 
52 weeks after the last dose.
A copy of the psychiatric evaluation report, if available, should be in the subject’s source 
document.
6.14.
Clinic Visits
Subjects will be expected to visit the clinic for Screening, at Baseline (which includes Day 1 
dosing and PK), at Day 14 (for AM dosing and PK), and 7 additional visits at Weeks 4, 8, 16, 24, 
32, 40, and 50, during the extension period and for the Follow-up Visits 4 and 8 weeks after the 
last dose of apremilast is taken (eg, at Weeks 54 & 58). The visit window for the Day 14 Visit is 
± 1 day.  The visit window for the Week 4, 8, 16, 24, 32, 40, and 50 visits is ± 4 days and for the
follow-up visits is ± 7 days.
All subjects should complete the two initial follow-up visits 4 and 8 weeks after taking their last 
dose of apremilast regardless of when they stop taking apremilast. 
All subjects should complete the final follow-up visit at Week 102 or at a timepoint 52 weeks 
after the last dose of apremilast was taken in subjects who have withdrawn at any time prior to 
Week 50.
6.14.1.
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 seated blood pressure) and 
weight
!
Record concomitant medications and AEs
!
Drug accountability
!
PASI
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, Section 5
!
Perform abbreviated physical examination
6.15.
Blood Collection for Pharmacokinetic Analysis
Blood samples will be collected through an indwelling venous cannula, by direct venipuncture or 
by finger sticks at pre-specified time points for measurement of apremilast in plasma and/or 
blood.  Concentrations of apremilast in plasma or blood will be measured using a validated liquid 
chromatography tandem mass spectrometry assay and dried blood spot (DBS) assay, 
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respectively.  Specific details regarding the collection, processing, storage, and shipment of all 
PK samples are provided in Section 19, Appendix F.
Pharmacokinetic blood draws will be performed at the following nominal time(s):
Group 1 (ages 12 to 17 years, inclusive): 
Day 1:  2 hours post morning dose.
Day 14 (last dose of PK treatment period):  Predose (prior to morning dose), 1, 2, 3, 5, 8, 
and 12 hours after the morning dose. 
Group 1 Notes: 
!
For Group 1 subjects, a DBS will be collected by fingerstick in parallel (each time 
point) to the standard plasma PK sample collection.  Detailed instructions for the 
collection and processing are provided in Section 19, Appendix F. Plasma 
sampling may be discontinued from the protocol procedure at anytime, per the 
direct instruction of the Sponsor, in the situation that the DBS sample collection 
method is comparable to the plasma sample collection method.
Group 2 (ages 6 to 11 years, inclusive): 
Day 1: 2 hours post morning dose.
Day 14 (last dose of PK treatment period): Predose (prior to morning dose), and 2, 5, and 
12 hours post morning dose. 
Group 2 Notes:
!
If the DBS assay using minimal blood volume is verified during Group 1 study 
conduct, the DBS assay may be used in place of the plasma PK sampling for the 
balance of Group 1 and any subject in Group 2.  If the DBS assay is not 
acceptable, DBS will be discontinued from the protocol procedure per the direct 
instruction of the Sponsor, and thus only the standard plasma PK sampling will be 
used for the duration of the study.
Actual PK blood sample collection times will 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 2.
All enrolled subjects who take at least one dose of apremilast and have evaluable PK data will be 
included in the PK analysis. Pharmacokinetic data is considered evaluable if there are 
measurable drug levels of apremilast in plasma from at least 3 time points which extend over a 
minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
Table 2:
Acceptable Time Windows for Pharmacokinetic Blood Sampling
Scheduled PK Blood Draw Time
Acceptable Time Window
Predose
Within 60 minutes prior to dosing
0 to 3 hours postdose (inclusive)
± 5 minutes
4 to 12 hours postdose (inclusive)
± 10 minutes
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Celgene Corporation
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6.16.
Exploratory Assessments
6.16.1.
Psoriasis Area Severity Index (PASI)
Psoriasis Area Severity Index scores will be determined for all subjects throughout the study. 
The PASI calculation is described in Appendix G.
The PASI is a measure of psoriatic disease severity taking into account qualitative lesion
characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on
defined anatomical regions. The PASI is a validated instrument that has become standard in
clinical trials for psoriasis.
Psoriasis Area Severity Index scores range from 0 to 72, with higher scores reflecting greater
disease severity (Fredriksson, 1978). Erythema, thickness, and scaling are scored on a scale of 0 
(none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower 
limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no 
involvement) to 6 (90% to 100% involvement). The total qualitative score (sum of erythema, 
thickness, and scaling scores) is multiplied by the degree of involvement for each anatomic 
region and then multiplied by a constant. These values for each anatomic region are summed to 
yield the PASI score.
Measurements of PASI will be performed at Screening, Baseline and all following visits as 
indicated in the Table of Events (Section 5).
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Apremilast
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7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
At least 32 subjects (16 subjects in Group 1 and 16 subjects in Group 2) with moderate to severe 
plaque psoriasis will be enrolled at approximately 20 sites in the United States, Canada and 
Europe.
7.2.
Inclusion Criteria
Subjects must satisfy all of the following criteria to be enrolled in the study:
1. Male or female subjects 6 to 17 years of age, inclusive, at the time the informed consent 
document is signed by the legal guardian
2. Group 1 Only:  ages 12 to 17 years, inclusive, and weighs ≥ 35 kg
3. Group 2 Only:  ages 6 to 11 years, inclusive, and weighs ≥ 15 kg
4. Subject is able to swallow the apremilast tablet
5. Able to sign an assent with a legal guardian who can understand and voluntarily sign an 
informed consent 
6. Able to adhere to the study visit schedule and other protocol requirements
7. Must agree to withhold vaccinations during the first 2 weeks of dosing. Inactivated 
vaccines will be allowed during the extension treatment period
8. Diagnosis of chronic plaque psoriasis for at least 6 months prior to Screening
9. Have 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) 
10. Disease inadequately controlled by or inappropriate for topical therapy for psoriasis
11. Candidate for systemic or phototherapy
12. Have not been exposed to any or have been exposed to no more than one systemic agent 
for psoriasis
13. At Screening, laboratory values must be within the following ranges:
!
White blood cell (WBC) count 
Age (yrs)
Males (x 103 /μL)
Females (x 103 /μL)
6-11
3.5 – 13.65
3.5 – 13.65
12-18
3.5 – 13.15
3.5 – 13.15
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Apremilast
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Celgene Corporation
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!
Platelet count 
Age (yrs)
Males (x 103 /μL)
Females (x 103 /μL)
6-11
117 – 394
117 - 394
12-18 
126 – 400
126 - 400
!
Serum creatinine ≤1.2 X upper limit of normal (ULN) for age and gender. Please see 
reference ranges of the central laboratory.
!
AST (SGOT) and ALT (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 
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 (yrs)
Males (g/dL)
Females (g/dL)
6-11 
10.0 – 15.5
10.0 – 15.5
12-18 
11.0 – 18.1
10.0 – 16.4
14. Male subjects who engage in activity in which conception is possible must use barrier 
contraception (male latex condom or nonlatex condom NOT made out of natural [animal] 
membrane [for example, polyurethane]) while on apremilast and for at least 28 days after 
the last dose of apremilast
15. 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 for at least 28 days after administration of the last dose of 
apremilast.  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
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 effective methods:  hormonal contraception (oral, 
injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal 
ligation; or partner’s vasectomy;
OR
Option 2:  Male or female condom (latex condom or nonlatex condom NOT made out of 
natural [animal] membrane [for example, polyurethane]; PLUS one additional barrier 
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method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or 
(c) contraceptive sponge with spermicide
* Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. History of or currently active inflammatory bowel disease
2. Major concurrent medical conditions, pregnancy or lactation
3. Any condition that confounds the ability to interpret data from the study
4. Guttate, erythrodermic, or pustular psoriasis
5. Psoriasis flare or rebound within 4 weeks prior to Screening
6. Evidence of skin conditions that would interfere with clinical assessments
7. History of human immunodeficiency virus infection, or positive result to hepatitis B 
surface antigen or hepatitis C antibodies at Screening
8. Clinically significant abnormality on 12-Lead ECG at Screening
9. History of active mycobacterial infection with any species (including Mycobacterium 
tuberculosis) within 3 years of the Screening Visit and without documentation of 
successful treatment
10. Congenital and acquired immunodeficiencies (eg, Common Variable Immunodeficiency), 
immunoglobulin A deficiency
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 15 cP, titanium dioxide, polydextrose FCC, 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-
glactose 4-epimerase, galactokinase or Fanconi Bickel syndrome, including congenital 
lactase deficiencies, and glucose-galactose malabsorption.
16. Any other significant medical condition, laboratory abnormality, or psychiatric illness 
that would prevent the subject from participating in the study or which places the subject 
at unacceptable risk if he/she were to participate in the study
17. Prior history of suicide attempt at any time in the subject’s lifetime prior to screening or 
enrollment in the study or major psychiatric illness requiring hospitalization within 3 
years
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18. Answering “Yes” to any question on the Columbia-Suicide Severity Rating Scale during 
screening or at baseline
19. Having received biologic therapy within 5 terminal half-lives, including but not limited to 
the following time periods:
!
Four weeks prior to baseline for etanercept
!
Ten weeks prior to baseline for adalimumab
!
Twenty-four weeks prior to baseline for ustekinumab
20. Topical therapy within 2 weeks of baseline (including but not limited to topical 
corticosteroids, topical retinoid or vitamin D analog preparations, tacrolimus, 
pimecrolimus, or anthralin/dithranol)
!
Exceptions: low-potency corticosteroids (please refer to the Investigators’ Manual) 
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
!
Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or 
salicylic acid scalp preparations on scalp lesions
!
An unmedicated skin moisturizer (eg, Eucerin®) will be also permitted for body 
lesions only.  Subjects should not use these topical treatments within 24 hours prior to 
the clinic visit
21. Systemic therapy for psoriasis within 4 weeks prior to baseline (including but not limited 
to cyclosporine, corticosteroids, methotrexate, oral retinoids, mycophenolate, 
thioguanine, hydroxyurea, sirolimus, sulfasalazine, azathioprine, and fumaric acid esters)
22. Use of phototherapy (ie, UVB, PUVA)within 4 weeks prior to baseline
23. Use of any investigational drug within 4 weeks prior to baseline, or 5 
pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer)
24. 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
25. Prior treatment with apremilast
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8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
Sufficient quantities of apremilast will be supplied by Celgene and should be stored as directed 
on the label.  Apremilast will be supplied in tablets with the following strengths: 10 mg, 20 mg 
and 30 mg for oral administration only.  All dose strengths will be supplied to the sites in bottles
or equivalent.  The excipients contained in the apremilast tablets used in this study are listed in 
Section 7.3 (exclusion criterion #14). Refer to the Investigator’s Brochure for additional detailed 
information regarding apremilast.
8.2.
Treatment Administration and Schedule
On PK days (Day 1 and Day 14), all subjects will be administered the morning dose of 
apremilast by mouth in the fasted state.  Food and beverages (except water) will be withheld 
from subjects for at least 8 hours prior to the morning dose until at least 2 hours after the 
morning dose. All apremilast administered while the subject is in the clinic will be administered 
by trained staff with approximately 240 mL of noncarbonated, room temperature water or as 
much as needed to ensure apremilast is swallowed.  The person responsible for dosing will check 
the subject’s mouth to ensure that the formulation has been swallowed intact. 
For all evening doses and all morning doses administered on non-PK days, apremilast tablets 
will be taken approximately 12 hours apart and without any food restrictions.  Apremilast tablets 
should always be taken with water as described in the previous paragraph.  Dosing regimens may 
vary depending on dose strength/dose frequency determined from the Group 1 and Group 2 PK 
and safety data. See Section 6.8 for additional details concerning oral dosing of apremilast.
The sponsor may provide financial assistance for overnight accommodations near the study site 
before and/or on PK blood draw visit days for the sake of subject convenience.
8.2.1.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of apremilast.
Overdose for this protocol, on a per dose basis, is defined as ingestion of greater than 100 mg of 
apremilast tablets in any specific dosing period (ie, 24 hours) whether by accident or 
intentionally. Adverse events associated with an overdose must be collected on the Adverse 
Events page of the eCRF (see Section 11.1) for all overdosed subjects, but the overdose itself is 
not considered an AE. Other required or optional nonstudy drugs intended for prophylaxis of 
certain side effects, etc, are excluded from this definition.
Detailed information about any Celgene drug overdose in this study, regardless of whether the 
overdose was accidental or intentional, should be reported on the drug exposure eCRF page.
8.3.
Method of Treatment Assignment
Prior to dosing, subjects will be identified by their unique screening number assigned by the 
clinical site.  On the morning of Day 1 and prior to receiving any apremilast, subjects who 
continue to be qualified for participation in the study will be enrolled and assigned a unique 
study number.  All subjects enrolled in this protocol will receive apremilast.  
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8.4.
Packaging and Labeling
The label(s) for apremilast will include Sponsor name, address and telephone number, the 
protocol number, apremilast name, dosage form and strength (where applicable), amount of 
apremilast 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.
8.5.
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 qualified designee(s), will verify the accuracy of the 
information on the form, sign and date it, retain a copy in the study file, and return a copy to 
Celgene, where it will be maintained in the trial master file.
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 bottle 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. 
Celgene (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
Celgene (or designee).
8.6.
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 Celgene’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
containers, 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 4 or more consecutive days of dosing, Celgene 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 Celgene. 
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Accurate recording of all apremilast administration (including dispensing and dosing) will be 
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9.
CONCOMITANT MEDICATIONS AND PROCEDURES
9.1.
Permitted Concomitant Medications and Procedures
Topical anesthetics will be permitted to prevent and control pain and discomfort associated with 
finger sticks during the DBS sample collection. Topical anesthetics (such as Eutectic Mixture of 
Local Anesthetics) should be administered as directed per the package insert. Prior to the blood 
collection procedure, fingers should be thoroughly wiped clean of the topical medication to avoid 
contamination of the PK blood sample. 
Only inactivated vaccines will be allowed during the extension treatment phase.
Furthermore, 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 2-week treatment 
phase.
All medications (prescription and non-prescription), treatments and therapies taken by the 
subject from Screening throughout the 50 weeks of treatment and the 4 and 8 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.
!
Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or salicylic 
acid soap preparations on scalp lesions
!
An unmedicated skin moisturizer (eg, Eucerin®) will also be permitted for body lesions 
only
Subjects should not use these topical treatments within 24 hours to the clinic visit.
9.2.
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: see Section 9.1)
voioid d
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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, or 
ustekinumab 
!
Prolonged sun exposure or use of tanning booths or other ultraviolet light sources
!
Use of an investigational drug
All vaccines will be withheld during the first 2 weeks of dosing. Live vaccines are not allowed at 
any time during active treatment with apremilast.  
Subjects who need to be treated with protocol-prohibited medication will be withdrawn from the 
study.
9.3.
Required Concomitant Medications and Procedures
Not applicable.
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10.
STATISTICAL ANALYSES
10.1.
Overview
Descriptive statistics (mean, standard deviation [SD], median, minimum and maximum, and 
sample size) will be provided for quantitative data. Frequency tabulations will be compiled for 
classification of qualitative data.  Graphical displays will be provided where useful to assist in 
the interpretation of results.
10.2.
Study Population Definitions
Two study populations will be analyzed:
!
Safety population: all enrolled subjects who take at least one dose of apremilast will 
be included in the safety population.  Safety and efficacy analyses will be based on 
this population.
!
Pharmacokinetic population: all enrolled subjects who take at least one dose of 
apremilast and have evaluable pharmacokinetic (PK) data will be included in the PK 
analysis. Pharmacokinetic data is considered evaluable if there are measurable drug 
levels of apremilast in plasma from at least 3 time points which extend over a 
minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a 
dose.
10.3.
Sample Size and Power Considerations
No formal sample size calculation is performed. A sample size of at least 16 subjects per group 
has been selected to provide an adequate PK profile and safety assessment in subjects of 
different ages and body weight ranges.  If needed, dropouts will be replaced to ensure that 
evaluable PK data from at least 32 subjects is collected.
10.4.
Background and Demographic Characteristics
Subjects’ age, height, and weight as baseline characteristics will be summarized using 
descriptive statistics.  Gender, race and other categorical variables will be provided using 
frequency tabulations.  Medical history data will be summarized using frequency tabulations by 
using the Medical Dictionary for Regulatory Activities (MedDRA) system organ class and 
preferred term classification system.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations.
10.6.
Exploratory Efficacy Analysis
Exploratory efficacy endpoint(s) will be summarized using descriptive statistics.
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10.7.
Safety Analysis
Safety analyses will be performed for all subjects who received at least one dose of apremilast. 
Adverse events will be classified using MedDRA. Treatment-emergent AEs will be summarized 
by system organ class, preferred term, severity, and relationship to apremilast. Adverse events 
leading to death or to discontinuation from treatment and SAEs will be listed. In the by-subject 
analysis, a subject having the same event more than once will be counted only once and by 
greatest severity. Laboratory data will be summarized descriptively by visit (n, mean, median, 
SD, minimum, and maximum). Vital sign measurements, by visit, including weight, and 
concomitant medications and procedures, will be summarized descriptively. Data from the
C-SSRS assessments and the stool diary will be summarized, respectively.
An independent DMC will review available safety and PK data at the following timepoints:
1. After the first 8 subjects in Group 1 have completed the 2 weeks of apremilast dosing, 
PK, and safety assessments.
2. After the first 8 subjects in Group 2 have completed the 2 weeks of apremilast dosing, 
PK, and safety assessments.
10.7.1.
Internal Celgene Safety Monitoring During the Apremilast Program: Role of the 
Safety Management Team
In addition to daily safety monitoring conducted by investigators and individual study personnel, 
cumulative and interval AEs, serious adverse events (SAEs), discontinuations and laboratory 
findings will be reviewed internally by a Safety Management Team (SMT) at Celgene. The 
review follows the Council for International Organizations for Medical Sciences, Working 
Group VI recommendations. The SMT is comprised of lead representatives from multiple 
Celgene functions engaged in the apremilast development program. The scope, conduct, 
processes, and accountabilities of the SMT are specified in an SMT charter.
10.7.2.
External Safety Monitoring During Apremilast Program: Role of the 
Independent 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 trialists and an independent external statistician 
for whom there is no identified conflict of interest. The DMC will meet as outlined in Section 
10.7 or ad hoc at the request of the SMT. 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.
10.8.
Pharmacokinetic Analysis
Pharmacokinetic parameters will be calculated using non-compartmental methods, plasma 
concentrations and actual blood sampling times from the intensive sampling schedule.  
Pharmacokinetic parameters and plasma concentrations for apremilast will be presented as 
descriptive statistics.  The descriptive statistics will include but will not be limited to the 
following: sample size [N], mean, SD, coefficient of variation [CV%] geometric mean, and 
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geometric CV%. Results will be presented in tabular and graphic formats as appropriate.  
Population PK analyses will be performed using non-linear mixed effect modeling (NONMEM).  
Covariate analysis will be performed to identify relevant covariates.  For all PK parameters, the 
population geometric mean will be estimated and provided.  The between-subject variability will 
be reported as an apparent coefficient of variation (ie, square root of the estimated variance) if 
data permits.  The following PK parameters will be determined:
!
Cmax
!
tmax
!
AUC0-12
!
AUC0-t
!
CL/F
!
Vss/F or Vz/F
!
t1/2
The following population PK parameters will be determined as appropriate:
!
CL/F
!
V/F
!
Ka 
!
Lag (if applicable)
10.9.
Interim Analysis
No formal interim analysis is planned for this study. However, an extract of the PK and 2 weeks 
of safety data from the initial 8 adolescent subjects enrolled into Group 1 will be used to model 
the most appropriate dose for subsequently enrolled subjects (such that the exposure will be 
similar to the exposures in adult subjects administered apremilast 30 mg BID).
Pharmacokinetic data and 2-week safety data from at least 8 Group 1 subjects will be utilized to 
determine the appropriate dosage (dose strength/dose frequency) for subjects enrolled into 
Group 2.
10.10.
Other Topics
10.10.1.
Investigational Product Compliance (Tablets)
Investigational product record information will be summarized. Overall compliance will be 
estimated by the proportion of subjects who take between 75% and 120% of the intended 
quantity of IP.
10.10.2.
Concomitant Therapy
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations. The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health 
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Organization (WHO) will be used to group medications into relevant categories for these 
tabulations. Separate data summaries of background medications will be provided.
10.10.3.
Taste and Acceptability
The taste and acceptability of apremilast tablet will be summarized.
&(/*(1(35235,(7$5<,1)250$7,21


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11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (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 11.3), regardless of
etiology. Any worsening (ie, any clinically significant adverse change in the frequency or
intensity of a pre-existing condition) should be considered an AE. A diagnosis or syndrome
should be recorded on the AE page of the eCRF rather than the individual signs or symptoms of
the diagnosis or syndrome.
For this study, reports of overdose of apremilast that do not have an associated AE(s) should not 
be reported as an AE(s). These reports should be discussed in the study compliance section of 
clinical study reports. See Section 8.2.1 for the definition and collection of overdose.
All subjects will be monitored for AEs during the study. Assessments may include monitoring of 
any or all of the following parameters: the subject’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or findings from other tests 
and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent
until 28 days after the last dose of apremilast as well as those SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to apremilast. Adverse 
events and SAEs will be recorded on the AE page of the eCRF and in the subject’s source 
documents. All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the event by facsimile, or other appropriate method, using the SAE 
Report Form, or approved equivalent form.
11.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to: 
11.2.1.
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)
!
Results in a congenital anomaly/birth defect
!
Constitutes an important medical event.
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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.
!
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 starting of treatment on study); must 
be documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
!
An elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to apremilast, action taken regarding apremilast, and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event.
Mild
!
Asymptomatic or mild symptoms; clinical or diagnostic observations only
!
Intervention not indicated
!
Activities of daily living (ADLs) minimally or not affected
!
No or minimal intervention/therapy may be required
Moderate
!
Symptom(s) cause moderate discomfort
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!
Local or noninvasive intervention indicated
!
More than minimal interference with activities of daily living (ADLs), but able to 
carry out daily social and functional activities
!
Drug therapy may be required
Severe (nonserious 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.
11.2.3.
Causality 
The Investigator must determine the relationship between the administration of apremilast and 
the occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not Suspected:
Means a causal relationship of the AE to apremilast
administration is unlikely or remote, or other medications,
therapeutic interventions, or underlying conditions provide a
sufficient explanation for the observed event.
Suspected:
Means there is a reasonable possibility that the administration
of apremilast caused the AE. ‘Reasonable possibility’ means
there is evidence to suggest a causal relationship between 
apremilast and the AE.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional 
apremilast that has not been manufactured or provided by Celgene, please provide the name of 
the manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
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11.2.5.
Action Taken
The Investigator will report the action taken with apremilast as a result of an AE or SAE, as 
applicable (eg, discontinuation, interruption, or reduction of apremilast, as appropriate) and 
report if concomitant and/or additional treatments were given for the event. 
11.2.6.
Outcome
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered (death due to another 
cause) or death (due to the SAE). 
11.3.
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 apremilast dose, or any other 
therapeutic intervention; or
!
is judged to be of significant clinical importance.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE 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).
11.4.
Pregnancy
11.4.1.
Females of Childbearing Potential
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.
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on apremilast, or within 28 days
of the subject’s last dose of apremilast, are considered immediately reportable events.  
Investigational product is to be discontinued immediately.  The pregnancy, suspected pregnancy, 
or positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile, or 
other appropriate method, using the Pregnancy Initial Report Form, or approved equivalent form.  
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
The Investigator or designee will monitor the progress of the pregnancy of a female subject until 
completion of the pregnancy, and must notify Celgene Drug Safety, or designee, immediately 
about the outcome of the pregnancy (either normal or abnormal outcome) using the Pregnancy 
Follow-up Report Form, or approved equivalent form.
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If the outcome of the pregnancy was abnormal (eg, spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form.
All neonatal deaths (ie, occur within 28 days of birth) should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to apremilast should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking apremilast should notify the Investigator, and the pregnant female partner should 
be advised to call their healthcare provider immediately.  
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  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 apremilast) that occur during 
the study (from the time the subject signs informed consent to 28 days after the last dose of 
apremilast), or any SAE made known to the Investigator at anytime thereafter that are suspected 
of being related to apremilast.  Serious adverse events occurring prior to treatment (after signing 
the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the Investigator is responsible for informing the ethics 
committee (IRB/EC) of the SAE and providing them with all relevant initial and follow-up 
information about the event. The Investigator must keep copies of all SAE information on file 
including correspondence with Celgene and the IRB/EC.
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by telephone.
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11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to apremilast based on the Investigator’s Brochure.
In the United States, 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, Celgene or its authorized representative will 
report in an expedited manner to Regulatory Authorities and Ethics Committees concerned, 
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.
Celgene or its authorized representative shall notify the Investigator of the following 
information:
!
Any AE suspected of being related to the use of apremilast 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 Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Local Drug Safety Affiliate Office contact information, please refer to the Serious Adverse 
Event Report Form Completion Guidelines or to the Pregnancy Report Form Completion 
Guidelines.
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Protocol CC-10004-PPSO-001
Celgene Corporation
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12.
DISCONTINUATIONS
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 9.1 Permitted Concomitant Medications and Procedures) 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 
disease progression / disease flare.  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.
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product:
!
Adverse Event(s)
!
Lack of efficacy
!
Non-compliance with study drug
!
Study terminated by sponsor
!
Withdrawal of consent
!
Death
!
Lost to follow-up
!
Pregnancy
!
Protocol violation
The reason for discontinuation should be recorded in the eCRF and in the source documents.  
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
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13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the Investigator should 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, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page).This global Emergency 
Call Center is available 24 hours a day and 7 days a week. The representatives are responsible 
for obtaining your call-back information and contacting the on call Celgene/contract research 
organization (CRO) Medical Monitor, who will then contact you promptly.
Note: The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
13.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, apremilast will be identified on the package labeling.
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dent
dentified o
ified o


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14.
REGULATORY CONSIDERATIONS
14.1.
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 Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International 
Conference on 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.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in
the local regulations. Celgene staff or an authorized representative will evaluate and approve all
Investigators who in turn will select their staff. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent
form (ICF) and are screened for entry into the study. Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during
monitoring visits to review data, resolve queries and allow direct access to subject records (eg,
medical records, office charts, hospital charts, and study-related charts) for source data
verification. The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the
information provided by Celgene on public registry websites) is considered Celgene confidential
information. Only information that is previously disclosed by Celgene on a public registry
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical
Trial Agreement. Celgene 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 Celgene. Information proposed for posting on the Investigator’s or their
institution’s website must be submitted to Celgene 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, Celgene will provide
Investigators with a summary of the results that is written for the lay person. The Investigator is
responsible for sharing these results with the subject and/or their caregiver as agreed by the
subject.
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14.3.
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.
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, subject’s legal guardian, and 
by the person facilitating the process, 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.  
14.4.
Confidentiality
Celgene 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). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene 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.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, 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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Apremilast can only be supplied to an Investigator by Celgene or its authorized representative 
after documentation on all ethical and legal requirements for starting the study has been received 
by Celgene 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 informed consent document 
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 Celgene and the 
IRB/EC prior to use.
14.7.
Ongoing Information for Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected AEs as soon as possible
!
Periodic reports on the progress of the study
!
Deviations from the protocol or anything that may involve added risk to subjects.
14.8.
Termination of the Study
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc...).
In addition, the Investigator or Celgene 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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15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
15.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene 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.
15.3.
Record Retention
Essential documents must be retained by the Investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of apremilast. 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 informed consent documents for all subjects
!
Subject identification code list, screening log (if applicable), and enrollment log
!
Record of all communications between the Investigator and the IRB/EC
!
Composition of the IRB/EC
!
Record of all communications between the Investigator, Celgene, 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
!
Apremilast accountability records
!
Record of any body fluids or tissue samples retained
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!
All other source documents (subject records, hospital records, laboratory records, 
etc.)
!
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 Celgene 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 Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents.
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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigator meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the eCRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, Food and Drug Administration 
[FDA], European Medicines Agency [EMA], Health Canada) and company authorized 
representatives.  The Investigator should make every effort to be available for the audits and/or 
inspections.  If the Investigator is contacted by any regulatory authority regarding an inspection, 
he/she should contact Celgene immediately.
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17.
PUBLICATIONS
As described in Section 14.2, all protocol- and amendment-related information, with the
exception of the information provided by Celgene on public registry websites, is considered
Celgene confidential information and is not to be used in any publications.  Celgene protocol 
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-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 external authorship, as well as selection of first authorship, will be based on
several considerations, including, but not limited to, contribution to protocol development, study
recruitment, data quality, participation in data analysis, participation in study steering committee
(when applicable) and contribution to abstract, presentation and/or publication development.
tific
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18.
REFERENCES
Benoit S, Hamm H. Childhood psoriasis. Clin Dermatol 2007;25(6):555-562.
Christophers E. Psoriasis - epidemiology and clinical spectrum. Clin Exp Dermatol 2001;26:314-
20.
Claveau D, Chen SL, O’Keefe S, Zaller DM, Styhler A, Liu S, et al.  Preferential inhibition of T 
helper 1, but not T helper 2, cytokines in vitro by L-826,141 [4-{2-(3,4-
Bisdifluromethoxyphenyl)-2-{4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl}-
3-methylpyridine-1-oxide], a potent and selective phosphodiesterase 4 inhibitor. J Pharmacol 
Exp Ther 2004 Aug;310(2):752-60.
Fan X, Xiao FL, Yang S, Liu JB, Yan KL, Liang YH, et al. Childhood psoriasis: a study of 277
patients from China. J Eur Acad Dermatol Venereol 2007;21:762–65. [PubMed: 17567304].
Fredriksson T, Pettersson U. Severe psoriasis: oral therapy with a new retinoid. Dermatologica
1978;157:238-44.
Gordon KB, Feldman SR, Koo JYM, Menter A, Rolstad T, Krueger G. Definitions of measures 
of effect duration for psoriasis treatments [editorial]. Arch Dermatol 2005 Jan;141(1):82-4.
Hamzaoui K, Bouali E, Ghorbel I, Khanfir M, Houman H, Hamzaoui A. Expression of Th-17 
and RORγt mRNA in Behçet’s disease. Med Sci Monit 2011;17(4):CR227-34.
Mallbris L, Larsson P, Bergqvist S, Vingard E, Granath F, Stahle M. Psoriasis phenotype at 
disease onset: clinical characterization of 400 adult cases. J Invest Dermatol 2005;124:499–504. 
[PubMed:15737189]
Morris A, Rogers M, Fischer G, Williams K. Childhood psoriasis: a clinical review of 1262 
cases. Pediatr Dermatol 2001;18:188–98. [PubMed: 11437997]
Paller AS, Siegfried EC, Langley RG, Gottleib AB, Pariser D, Landells I, et al. Etanercept 
treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008 Jan 
17;358(3):241-51.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: Initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry 2011 December;168(12):1266-
1277.
Raychaudhuri SP, Farber EM. The prevalence of psoriasis in the world. J Eur Acad Dermatol 
Venereol 2001 Jan;15(1):16-7.
Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, et al. Apremilast, a cAMP 
phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of 
psoriasis. British J Pharm 2010;159:842-55.
Ståhle M, Atakan N, Boehncke WH, Chimenti S, Dauden E, Giannetti A, et al. Juvenile psoriasis 
and its clinical management: a European expert group consensus. J Dtsch Dermatol Ges 2010 
Oct;8(10):812-18. 
&(/*(1(35235,(7$5<,1)250$7,21
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Tollefson MM, Crowson CS, McEvoy MT, Maradit Kremers H. Incidence of psoriasis in 
children: a population-based study. J Am Acad Dermatol 2010;62 (6):979-87.
Vogel SA, Yentzer B, Davis SA, Feldman SR, Cordoro KM. Trends in pediatric psoriasis 
outpatient health care delivery in the United States. Arch Dermatol 2012;148 (1):66-71.
Weinstein GD, Menter MA. An overview of psoriasis. In: eds. Weinstein GD, Gottlieb AB.
Therapy of moderate to severe psoriasis. New York, NY. National Psoriasis Foundation 2003; 
1-28.
World Health Organization (WHO). Diarrhea. Available at: 
http://www.who.int/topics/diarrhea/en/. Accessed August 5, 2015.
World Health Organization (WHO). Antiretroviral therapy for HIV infection in infants and 
children: towards universal access: recommendations for a public health approach: 2010 
Revision. Available at: 
http://apps.who.int/iris/bitstream/10665/164255/1/9789241599801_eng.pdf?ua=1. Accessed on 
August 12, 2015.
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
19.
APPENDICES
Appendix A:
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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Apremilast
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Confidential and Proprietary
76
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Appendix B:
Stool Diary
DAILY STOOL DIARY 
1. Did you have 3 or more liquid or watery stools today?
 No 
 Yes
2. If yes, did you take any medications for your liquid or watery stools?
 No 
 Yes
3. If yes, type the medication name(s) below:
-----------------------------------------------------
4. 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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these symp
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ubjec


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77
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Appendix C:
Example of a Faces Likert Scale 
1
2
3
4
5
Dislike
very 
much
Dislike
a little
Not 
sure
Like
a little
Like
very 
much
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much


Apremilast
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Appendix D:
Tanner Stages
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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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
79
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Appendix E1: Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Baseline/Screening:
50$7,21
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
80
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
&(/*(1(35235,(7$5<,1)250$7,21
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
81
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
&(/*(1(35235,(7$5<,1)250$7,21
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
82
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Appendix E2: Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Since Last Visit: 
$7
0$7


Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
83
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
&(/*(1(35235,(7$5<,1)250$7,21
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Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
84
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016


Apremilast
Protocol CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
85
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Appendix F:
Apremilast Plasma and Dried Blood Spot for Pharmacokinetic
Sample Handling Instructions
Labels must contain the following information:
!
Protocol No.: CC-10004-PPSO-001
!
Subject ID number
!
Group: (1 or 2) 
!
Nominal Time: eg, 0.5 hours after dosing
!
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.
1. Blood Sample Collection for Plasma PK samples
!
Fill an ice bucket with a sufficient amount of wet ice and place blood collection tubes 
into the ice bath to pre-chill all collection tubes before blood draw
!
Collect approximately 1 mL of whole blood into a pre-chilled lithium heparin tube
!
Accurately record the time of blood collection
!
Gently invert the tube 3 to 5 times and immediately immerse it into the ice bath to 
prevent possible compound degradation at room temperature.
2. 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 min at 4°C to obtain plasma
!
Transfer approximately 0.5 mL of plasma into the pre-labeled, pre-chilled, citric 
acid-containing polypropylene storage tube (to be provided by Celgene) as primary 
sample
!
Gently invert the tube 3 to 5 times
!
Transfer approximately 0.2 mL of plasma from the primary sample into the 
pre-labeled, polypropylene storage tube as backup sample
!
Keep both the primary and backup sample 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 –20oC freezer, where they will remain stored until shipping
!
Immediately record the time of sample entry into the freezer.
NOTE: All secondary (backup) samples will be maintained at the Investigator site until they are 
requested by the Celgene representative to be shipped to the central laboratory (or another 
facility) or be destroyed at the Investigator site.
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Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
3. Blood Collection for DBS PK Samples
!
Load a fresh capillary onto the DBS pipette and collect approximately 50 μL of 
whole blood into the lithium heparin capillary tube
!
Accurately record the time of blood collection
!
Immediately spot one drop of blood (approximately 15 μL) onto the DBS card target 
area. Do not allow the capillary to touch the DBS target. Repeat for 2 more spots 
(there will be 4 targets on the card but only 3 targets will be used)
!
Eject the used capillary into the supplied container and reload a fresh capillary for the 
next sample collection
!
Dry the DBS card for 2 to 4 hours at room temperature. Place the DBS card in a 
plastic zip top bag along with a desiccant pouch. All DBS cards from a subject should 
be placed in a single zip top bag for storage at room temperature.
4. PK Sample Shipment
!
All PK sample label information on the storage tubes/DBS cards must be checked 
against the requisition form. The samples collected in storage tubes must be shipped 
frozen and on dry ice to the central laboratory. The DBS cards are to be shipped at 
room temperature.
!
The central lab must be contacted via email PRIOR TO shipping, and confirmation of 
receipt from the central laboratory must be documented at the site.
5. Sample Collection Documents to Accompany Shipment(s)
A copy of the completed specimen inventory log(s) must accompany the shipment, and must 
list the following information at a minimum:
!
Sponsor name: Celgene Corp
!
Celgene Study Number: CC-10004-PPSO-001
!
Subject ID Numbers
!
Group (1 or 2)
!
Collection Date (ie, 29 May 2013)
!
Nominal collection time point for plasma/DBS samples
!
Sample type (eg, Plasma or DBS)
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Apremilast
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Celgene Corporation
Confidential and Proprietary
87
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Appendix G:
Psoriasis Area Severity Index
Fredriksson, 1978.
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redriksson, 1


Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Appendix H:
List of Abbreviations and Definition of Terms
Abbreviation or Term
Explanation
AE(s)
Adverse Event(s)
ACR
American College of Rheumatology
ACR20
ACR criteria for 20% improvement
ACR50
ACR criteria for 50% improvement
ACR70
ACR criteria for 70% improvement
ADLs
Activities of daily living
ADME
absorption/distribution/metabolism/excretion
ALT (SGPT)
Alanine transaminase (serum glutamate pyruvic transaminase)
APR
Apremilast
AST (SGOT)
Aspartate transaminase (serum glutamic oxaloacetic transaminase)
AUC
Area under the plasma concentration-time curve
AUC0-∞
Area under the plasma concentration-time curve from time zero extrapolated to 
infinity
AUC0-12
Area under the plasma concentration-time curve from time zero to 12 hours 
postdose
AUC0-t
Area under the plasma concentration-time curve from time zero to the last 
quantifiable concentration
AUC0-τ,ss
The area under the plasma drug concentration–time curve over
the dosing interval τ at steady state
BID
Twice daily
BSA
Body surface area
cAMP
Cyclic adenosine monophosphate
CFR
Code of federal regulations
CL/F
Apparent total plasma clearance when dosed orally
Cmax
Peak (maximum) observed plasma concentration of drug
C-SSRS
Columbia-Suicide Severity Rating Scale
CV%
Coefficient of variation
CYP
Cytochrome p-450
DBS
Dried blood spot
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Apremilast
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Celgene Corporation
Confidential and Proprietary
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CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Abbreviation or Term
Explanation
DMARD(s)
Disease modifying anti-rheumatic drug(s)
DMC
Data Monitoring Committee
ECG(s)
Electrocardiogram(s)
eCRF
Electronic case report form
EMA
European Medicines Agency
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
GCP(s)
Good Clinical Practice(s)
GI
Gastrointestinal
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IL
Interleukin
IND 
Investigational New Drug Application
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MTX
Methotrexate
NOAEL
No observed adverse effect level
NONMEM
Non-linear mixed effect modeling
PASI
Psoriasis Area and Severity Index
PASI-50
At least a 50% reduction in PASI
PASI-75
At least a 75% reduction in PASI
PDE4
Phosphodiesterase four
PD
Pharmacodynamic
PK
Pharmacokinetics
PI
Principal investigator
PsA
Psoriatic arthritis
PUVA
Psoralens and long-wave ultraviolet radiation
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Apremilast
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Celgene Corporation
Confidential and Proprietary
90
CC-10004-PPSO-001 Amendment 2 Final: 29 Apr 2016
Abbreviation or Term
Explanation
RBC(s)
Red blood cell(s)
SAE(s)
Serious adverse event(s)
SD
Standard deviation
SMT
Safety management team
sPGA 
Static Physician Global Assessment
SOP(s)
Standard operating procedure(s)
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal-phase elimination half-life
TEAE(s)
Treatment-emergent adverse event(s)
tmax
Time to maximum plasma concentration
TNF-α
Tumor necrosis factor alpha
ULN
Upper limit of normal
US
United States
V/F
Apparent total volume of distribution when dosed orally
Vss/F
Apparent total volume of distribution when dosed orally, based on steady-state 
Vz/F
Apparent total volume of distribution when dosed orally, based on the terminal 
phase
UVB
Ultraviolet light B
WBC(s)
White blood cell(s)
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This is a representation of an electronic record that was signed electronically in Livelink.
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the organizations electronic signature policies and procedures.
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Apremilast
Summary of Changes CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PPSO-001  Amendment 2 Final:  29 Apr 2016
1.
JUSTIFICATION FOR AMENDMENT
 
1. Revised white blood cell (WBC) levels, platelet count, and hemoglobin for subject 
eligibility (Section 7.2, Inclusion Criterion #13) 
The amendment provides allowance for laboratory values that are lower than the lower limit of 
normal (LLN) reference ranges used by 
 the Central Laboratory for the PPSO-001 
study. The revised eligibility criteria are gender- and age-specific and would allow for up to 
10% lower than the LLN for hemoglobin and platelet count levels, and for up to 20% lower for 
the WBC count, to adjust for the effects in blood cells of inflammatory conditions such as 
psoriasis and for certain medications used to treat it, without compromising the safety of subjects 
participating in the study. 
2. Added the excipients of apremilast to screen for potential sensitivity (Section 7.3, 
Exclusion Criterion #14)
The excipients of apremilast are specified and listed in the exclusion criteria to inform subjects 
of all ingredients/contents of the investigational product to properly identify or rule out during 
screening a potential allergy or intolerance that may arise from any of the ingredients.
3. Added an exclusion criterion for deficiencies in lactose metabolism (Section 7.3, 
Exclusion Criterion #15)
Because the investigational product formulation contains lactose, an exclusion was added for
subjects who may have an allergy to lactose. 
Minor changes, 
 in this amendment 
include:
!
Modified “highly effective” to “effective” in the Option 1 description of contraception 
methods for females (Section 7.2, Inclusion Criterion #15), which is consistent with the
type of contraceptive described.
!
Added a reference to Section 7.3 for the list of excipients of apremilast formulation 
(Section 8.1).
Other significant changes in this amendment include: 
1. Extended eligibility to patients previously exposed to biologic therapy (Protocol 
Summary, Section 6.5, Section 7.2. Inclusion Criteria #12 and #13, Section 7.3,
Exclusion Criteria #19, Section 9.2)
The amendment will allow inclusion of potential subjects who have been previously exposed to a 
systemic biologic therapy for psoriasis or other indication provided that the last dose was given 
at least 5 terminal half-lives prior to randomization. The greater availability of biologic therapies 
globally and the practice of prescribing them for a number of diseases including plaque psoriasis 
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235


Apremilast
Summary of Changes CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
4
CC-10004-PPSO-001  Amendment 2 Final:  29 Apr 2016
in children have become more common. Excluding patients who have had treatment with 
biologics has become unrealistic in terms of recruiting patients for the PPSO-001 study. The 
amendment will help improve recruitment while retaining the intent of enrolling a pediatric 
population with active moderate-to-severe plaque psoriasis. Systemic therapy with biologics will 
be counted in the maximum total number (1) of systemic therapies for eligibility purposes.  
Inclusion #12 is modified for this reason. Exclusion #19 was added to specify required washout 
periods for previous biologic therapies.
2. Removal of the 24-hour post-Day 14 dosing pharmacokinetics (PK) blood draw time
point (Section 5, Table 1 footnotes, Section 6.15, Table 2)
The amendment will remove the last blood draw (24 hours after the Day 14 dose) that was 
included in the intensive PK assessments for Group 1 subjects.  Inclusion of this last time point 
for the adolescent subjects was deemed, via study site feedback, to be a major factor in 
dissuading prospective subjects from participating in the study because of time away from school 
and activities, as well as parents’ time away from work. Analysis of the intensive PK results can 
be performed without the 24-hour post-dose blood sample.
Other minor changes in this amendment include:
!
The PK endpoint for area under the concentration-time curve from last dose to infinity 
(AUC0-∞) was removed from the Protocol Summary, Section 3.1, and Section 10.8 
because removal of the 24-hour post-dose blood draw requirement eliminates the data to 
accurately determine terminal elimination phase or lambda, which is used to calculate 
AUC0-∞.
!
A statement was added in Section 1.4 to show the percentage of subjects in studies 
PSOR-008 and 009, that had prior exposure to biologic therapy to illustrate that previous 
exposure to biologics was common and was allowed in adult psoriasis studies.
!
A bullet point for “Pregnancy test” was added to the Section 3.1 list of primary 
endpoints. Although it already appeared in the Protocol Summary Section, this addressed 
the omission.
!
A reminder to take the Day 14 dose only after the 12-hour post-dose blood draw was 
added for clarification to Section 5, Table 1 footnotes and Section 6.8.
!
Since the 24-hour post-last dose blood draw was removed, text indicating that there 
would be no Day 14 evening dose was removed as well from Section 5, Table 1, Section 
6.8, and Section 6.15.
!
Additional text was included in Section 6.1 to clarify that the consenting/assenting 
process must be repeated for any subject who fails screening and returns to be rescreened.
!
Text was added to Section 6.15, Group 2 Notes, to clarify that not all 16 subjects in 
Group 1 will need to have both the dried blood spot (DBS) assay and a venous blood 
draw if the DBS method of blood sample analysis is validated before all Group 1 subjects 
have blood taken using both methods.
!
More sites will be added to the study so an update of the approximate number of sites 
was entered in Section 7.1.
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Apremilast
Summary of Changes CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
5
CC-10004-PPSO-001  Amendment 2 Final:  29 Apr 2016
!
Text describing the shipping of PK samples was clarified in Appendix F.
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Apremilast
Summary of Changes CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
3
CC-10004-PPSO-001 Amendment 1 Final: 17 Aug 2015
1.
JUSTIFICATION FOR AMENDMENT
 
Primary Objective: (Protocol Summary, Section 2)
The exact description of the primary objective was clarified to reflect that the study is being 
conducted to select a pediatric dose of apremilast.
Age ranges of two subject groups: (Protocol Summary, Section 4.1, Figure 2, Sections 6.15 and 
7.2, Table 1 footnotes)
 an adjustment of age groups from Group 1- ages 13 to 17 years; and 
Group 2 – ages 6 to 12 years to: Group 1- ages 12 to 17 years; and Group 2 – ages 6 to 11 years.
Added questionnaire: (Table 1 and footnotes, Sections 10.7, 6.13, 7.3, Appendix E1, E2 and H)
The Columbia-Suicide Severity Rating Scale (C-SSRS) was added at screening and baseline as 
well as all visits (except Week 102 final follow up). An exclusion criterion was added which 
mandates ineligibility if any question is answered YES at screening. A YES answer to any 
question during the study is cause for immediate withdrawal from study medication.
Psychiatric Evaluation Section: (Sections 6.13, 7.3, 10.7, and 18, Appendices E1 and E2)
This section was updated to explain the use of the C-SSRS.
Tanner Staging Assessment: Table 1and footnotes, Sections 6.11and 18, Appendix D
Added in Tanner Staging section (6.11) along with a description of the stages (Appendix D) and 
when to perform the assessments in Table 1. 
 
Extension Treatment Period: (Protocol Summary, Figure 1, Table 1and footnotes, Sections 4.1 
and 4.3, 4.4, 6.14, 6.6.3, 6.6.8.4, 7.2)
Optional  open label  was deleted from participation in the extension treatment period and the 50 
week treatment extension period was changed to a 48 week treatment extension period. Sections
3.3, 4.1, 4.3, Table 1 and footnotes, Sections 6.14, and 9.1 were updated to show 50 weeks of 
treatment instead of 52 weeks. The total length of the study (in weeks) was also shortening to 
107 weeks from 109 weeks.
Number of Visits: (Protocol Summary, Section 3.3, Table 1, and Section 6.14)
Two additional visits, at Week 24 and Week 40, were added to comply with the request for more 
frequent safety assessments. Language was updated in Section 6.14 from “5 additional visits” to 
“7 additional visits”. The study days were updated in Table 1 to reflect the addition of the two 
visits.
Follow-up Visits: (Protocol Summary, Section 4.1, Figure 1, Section 4.3, Table 1, Table 1 and 
footnotes, Sections 6.6.3, 6.12, 6.14, 9.1,)
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35


Apremilast
Summary of Changes CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
4
CC-10004-PPSO-001 Amendment 1 Final: 17 Aug 2015
Short-term follow-up was adjusted to 4 weeks and 8 weeks after the last dose of apremilast. The 
original Week 56 short-term follow-up visit is now Weeks 54 and 58.
Number of Study Subjects: (Protocol Summary and Sections 4.1, 7.1, 10.3)
A change from “approximately 32 subjects”  to “at least 32 subjects” and  “at least 16 subjects in 
each group” instead of  “approximately” was made. Text of “minimum of 24 evaluable subjects” 
was deleted.
Daily Stool Diary: (Sections 6.10, 10.7, 18, Table 1 and footnotes, Appendix B)
This was added in a protocol section as well as to the appendix to monitor any diarrhea 
symptoms and treatment.
Frequency of Height Measurement:  (Table 1)
Height is now measured at each visit.
Study Timeline Schematic: (Figure 1)
This was updated to reflect 
 changes which included length of extension treatment period, 
addition of a post 8 week follow-up, and adjustment to length of study.
The amendment also includes several other minor clarifications and corrections:
!
Two additional possible ECG interpretations were added to be in alignment with the new 
CRF structure (Section 6.6.9)
!
Psoriasis flare and rebound are now under Section 6 (Procedures) as they are no longer to 
be considered as adverse events (Section 6.12)
!
Canada was added as a participating country (Section 7.1)
!
Prior treatment with apremilast was added as an exclusion criterion (Section 7.3)
!
Preganacy was added as a possible reason for withdrawal (Section 12)
!
Added “Moderate to Severe” to the protocol title (title page, Protocol Summary)
!
Updated EudraCT Number and IND Number (title page).
!
Removed text that described use of a subject pill diary since daily pill monitoring will not 
be done in this study (Section 8.6, 
!
Added “using a faces Likert Scale” to Secondary Objective (Protocol Summary)
!
Updated Exploratory Objective in Protocol Summary to match Section 2.3 (Protocol 
Summary)
!
The word “Screening” was added to the last sentence in Section 6.16.1 to match the 
information in Table 1 (Section 5)
!
Added abbreviation “C-SSRS” for the Columbia-Suicide Severity Rating Scale was 
added to Appendix H
!
“Psoriasis Flare and Rebound” section title was changed to “Worsening Psoriasis and 
Rebound Assessments” since flare and rebound are not considered as AEs in Celgene 
studies. (Section 6.12)
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A


Apremilast
Summary of Changes CC-10004-PPSO-001
Celgene Corporation
Confidential and Proprietary
5
CC-10004-PPSO-001 Amendment 1 Final: 17 Aug 2015
!
Changed, “….two short-term follow-ups and a long-term follow-up” to “….two short-
term follow-up periods and a long-term follow-up period.” for clarity and readability
(Protocol Summary and Section 4.1)
!
Added three references:  Posner 2011. WHO 2010 and WHO 2015. Deleted one 
reference:  Carey 2006. (Section 18)
!
Deleted letter “A” from “Group 1A” in Figure 2 for clarity (Figure 2)
!
Deleted the sentence, “The actual dosing time will be recorded on each dosing day (via 
subject diary or equivalent)” since we will not be using a pill diary in the study. (Section 
6.8, 8.6)
!
Deleted the sentence, “Accountability will include a review of the subject diary (or 
equivalent)” since we will not be using a pill diary in the study (Section 6.9).
!
Collection of initials was removed from the protocol (Section 6.3, 8.3)
!
Added “pregnancy tests” to Overview of Safety Assessments in the Protocol Summary. 
This was an oversight in the original protocol. (Protocol Summary)
!
Two clarifying sentences were added to the dosing scenario. For Group 1, “In the event 
of a dose regimen adjustment, some or all of the first 8 subjects in Group 1, depending on 
weight, will return to the site for the appropriate dosing adjustment”. For Group 2, “In the 
event of a dose regimen adjustment after the second PK and safety assessment, the first 8 
subjects in Group 2 will return to the site for the appropriate dosing adjustment.” 
(Protocol Summary and Section 4.1)
!
An additional sentence was added to Section 12 (Discontinuations) in compliance with 
the Celgene protocol template. (Section 12)
Administrative Changes and Corrections
!
Table of Contents was expanded to include sections, “Stool Diary” and “Worsening 
Psoriasis and Rebound Assessments
!
The letter designations for the appendices were updated since two appendices were added
!
A number of “X” indicators were added in Table 1 for Height, Weight, and BMI  
. One “X” was added to the PASI row as well to align with 
text in the protocol
!
Table 1 footnote letter designations were updated due to the addition of 3 new footnotes
!
The numbering of sections in Section 6 was updated due to the addition of a new section 
and movement of others
!
In Section 6.14, text was added for clarity: “….the two initial…” 
!
Added Switzerland, Australia and Israel as countries where apremilast is approved for 
PsA and Psoriasis. Made clear that apremilast is approved for both PsA and psoriasis.
(Section 1.1)
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