Conditions: Behçet's Syndrome
Keywords: APREMILAST (CC-10004) CC-10004 Efficacy Safety Phase 3 Behçet's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 207
Healthy volunteers: no

Brief summary:
The main objective of this study is to evaluate the efficacy and safety of apremilast in the treatment of oral ulcers in adults with active Behçet's disease (BD).

Detailed description:
Behçet's disease, is a rare disorder that causes inflammation in blood vessels throughout the body. The signs and symptoms of Behçet's disease may include mouth sores, eye inflammation, skin rashes and lesions, and genital sores that vary from person to person and may come and go on their own. The exact cause of Behçet's is unknown, but it may be an autoimmune disorder, which means the body's immune system mistakenly attacks some of its own healthy cells.

This study will evaluate if apremilast is better than placebo (inactive substance in the same form as the drug) for the treatment of oral ulcers in subjects with active Behçet's disease. Other manifestations of the disease will also be assessed, such as, pain and tenderness in joints, eye inflammation, genital ulcers, and skin disease. This study also will test how well the body tolerates apremilast. In addition, the second purpose of the study is to assess the safety of apremilast in patients with Behçet's disease.

This study is a randomized, placebo-controlled, parallel design. The placebo-controlled period will be 12 weeks long and participants will receive apremilast or placebo. After the 12-week placebo-controlled period, all participants will receive apremilast for 52 weeks in the active treatment period. All participants will have their final study visit 4 weeks after stopping apremilast treatment.

Participants in Germany will have the opportunity to enter an optional open-label extension phase after the 52-week active treatment phase (week 64 visit), and continue until apremilast is commercially available for Behçet's disease or until apremilast is found not to be acceptable for Behçet's disease, according to either the sponsor or health authority.

Arms:
arm 1: Participants randomized to this arm will receive placebo tablets twice daily by mouth for the first twelve weeks followed by 52 weeks of 30 mg apremilast tablets twice daily by mouth. arm 2: Participants randomized to this arm will receive 30 mg apremilast tablets twice daily by mouth for 64 weeks.

Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets for oral administration intervention 2: Tablets for oral administration

Protocol document:
Prot_002.pdf: 
Apremilast 
Protocol CC-10004-BCT-002 
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Confidential and Proprietary 
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TITLE PAGE 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP 
STUDY, FOLLOWED BY AN ACTIVE-TREATMENT 
PHASE TO EVALUATE THE EFFICACY AND SAFETY 
OF APREMILAST (CC-10004) IN THE TREATMENT OF 
SUBJECTS WITH ACTIVE BEHÇET’S DISEASE 
INVESTIGATIONAL PRODUCT (IP): 
Apremilast (CC-10004) 
PROTOCOL NUMBER: 
CC-10004-BCT-002
DATE FINAL: 
10 SEP 2014 
AMENDMENT 1: 
2 FEB 2016 
AMENDMENT 1.1 DE 
5 JUL 2017 
EudraCT NUMBER: 
2014-002108-25 
IND NUMBER: 
101761 
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.
NCT Number: NCT02307513
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION  
 
Contact Information: All regions – North America, Europe, APAC 
Name: 
, MD  
Title: Associate Medical Director, Pharmacovigilance, PPD 
Address: Business Center Megapark, 4th floor 
115 G Tsarigradsko Shosse Blvd. Sofia 1784, Bulgaria 
Phone: + 1 888 483 7729 
+ 0044 1223 374 240 
Toll-free: +0044 22 132 896 
For Japan: +0044 1223 374 240 
Toll-free Japan only: (010 or 0033+010) 800 3380 3380, access code 95479 
E-mail: PVGMedicalMonitorsadmin.SM@ppdi.com 
 
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: +1-877-501-7738 
 


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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE 
 
 
{See appended electronic signature page} 
 
 
Signature of Celgene Therapeutic Area Head 
 
dd mmm yyyy 
 
 
, MD – Therapeutic Area Head, Inflammation & Immunology, 
Clinical Research & Development 
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.   
 


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


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


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PROTOCOL SUMMARY 
Study Title 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Parallel Group Study, 
followed by an Active-Treatment Phase to Evaluate the Efficacy and Safety of Apremilast 
(CC-10004) in the Treatment of Subjects with Active Behçet’s Disease. 
Indication 
Behçet's disease (BD) is a chronic, relapsing, multisystemic inflammatory disorder characterized 
by recurrent oral and genital ulcers, which may be accompanied by cutaneous, ocular, articular, 
gastrointestinal, and/or central nervous system inflammatory lesions. In some cases, uncontrolled 
inflammation may lead to blindness, intestinal complications, stroke and even meningitis, which 
can be fatal. The main clinical feature of Behçet's disease is recurrent (exacerbations and 
remissions) painful oral ulcerations appearing either alone or in combination with painful ulcers 
of the genitals, as well as lesions of the skin and eyes, and involvement of joints and other 
organs. Oral ulcers are the most frequent sign at onset (Kone-Paut, 1998; Krause, 1999; Alpsoy, 
2007; Kerkeni, 2010; Atmaca, 2011) being observed in nearly every patient (range, 90% to 
100% of cases). Genital ulcerations are generally less frequent, occurring in about 80% of adults 
(range, 55% to 97% of cases). 
In BD, the pro-inflammatory mediators that are upregulated include the T cell derived cytokines 
interferon (IFN)-γ, interleukin (IL)-2 and IL-17 (Sugi-Ikai, 1998; Frassanito, 1999; Ahmed, 
2004, Hamzaoui, 2002, Hamzaoui, 2011), as well as IL-1β, IL-6, IL-8, IL-12 and tumor necrosis 
factor (TNF)-α (Hamzaoui, 1990; Ozoran 1995, Evereklioglu, 2002; Hamzaoui, 2002).  Elevated 
IL-12 and IL-17 levels in patients with active BD appear to correlate with disease activity 
(Frassanito, 1999; Hamzaoui, 2002; Turan, 1997; Hamzaoui, 2011).  Together, these data 
indicate that pro-inflammatory responses prevail in active BD, and that targeted inhibition of 1 or 
more of these mediators may be an effective treatment in BD. 
Apremilast (CC-10004), an oral small-molecule inhibitor of phosphodiesterase (PDE) 4, works 
intracellularly to modulate a network of pro-inflammatory and anti-inflammatory 
mediators.  Phosphodiesterase 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and 
the dominant PDE in inflammatory cells.  Phosphodiesterase 4 inhibition elevates intracellular 
cAMP levels, which in turn down-regulates the inflammatory response by modulating the 
expression of TNF-α, IL-23, IL-17, and other inflammatory cytokines.  Cyclic AMP also 
modulates levels of anti-inflammatory cytokines such as IL-10.  Apremilast has 
immunomodulatory activity and, therefore, has the potential to be effective in the treatment of 
BD. 
Objectives 
Primary Objective: 
• To evaluate the efficacy of apremilast for the treatment of oral ulcers in active Behçet’s 
disease 
Secondary Objectives: 
• To evaluate the efficacy of apremilast in subjects with active Behçet’s disease 


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• To evaluate the effect of apremilast on Patient Reported Outcomes (PROs) in subjects 
with active Behçet’s disease 
Safety Objective: 
• To evaluate the safety and tolerability of apremilast in subjects with active Behçet’s 
disease 
Exploratory 
 Objectives: 
Exploratory 
 Objective: 
 
Exploratory Objectives: 
Study Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study, followed by an active-treatment phase to evaluate the efficacy and safety of apremilast 
(CC-10004) in the treatment of subjects with active BD. The study consists of a Screening Phase 
of up to 6 weeks; a 12-week Double-blind Placebo-controlled Treatment Phase; a 52-week 
Active Treatment Phase, an optional Open-label Extension Phase; and a 4-week Posttreatment 
Observational Follow-up Phase.  
Subjects will have the opportunity to enter an optional Open-label Extension Phase after the 52-
week Active Treatment Phase (Week 64 visit). Subjects may continue in the optional Open-label 
Extension Phase until apremilast is commercially available for BD or until the benefit/risk of 
apremilast is found not to be acceptable for BD, according to either the sponsor or health 
authority.  
To estimate the treatment difference for the primary endpoint for the study, approximately 204 
eligible subjects will be randomized; stratified by gender, history of uveitis and region (Japan 
and Other). Subjects will be randomized 1:1 to receive apremilast 30 mg twice daily (BID) (APR 
30 BID), or identically-appearing placebo tablets BID for the 12-week Placebo-controlled 
Treatment Phase. 
Upon completion of the Week 12 visit, subjects initially randomized to placebo will transition to 
APR 30 BID, while subjects initially randomized to APR 30 BID will continue on the same 
treatment during the 52-week Active Treatment Phase.  
Subjects who complete Visit 14 of the 52-week Active Treatment Phase will have an opportunity 
to continue to receive APR 30 BID in an optional Open-label Extension Phase. Subjects who 


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choose to not enter the optional Open-label Extension Phase will complete the 4-week 
Posttreatment Observational Follow-up Phase. 
Subjects who discontinue at any time from the study for any reason, are to enter the 4-week 
Posttreatment Observational Follow-up Phase. 
Study Population 
Male and female subjects  18 years old at the time of consent, who have BD, meeting the 
International Study Group (ISG) criteria, without major organ involvement, and who have at 
least 2 oral ulcers at Visit 1 (Screening Visit) AND at least 2 oral ulcers at Visit 2 (day of 
randomization), when Visit 2 occurs at least 14 days after Visit 1 OR at least 3 oral ulcers at 
Visit 2 (day of randomization), when Visit 2 occurs at any time between 1 day and 42 days after 
Visit 1. 
Length of Study 
The study will consist of the following phases: 
• Screening Phase — up to 6 weeks 
• Double-blind, Placebo-controlled Treatment Phase — 12 weeks 
• Active Treatment Phase — 52 weeks 
• Optional Open-label Extension Phase until apremilast is commercially available for 
BD or until the benefit/risk of apremilast is found not to be acceptable for BD, 
according to either the sponsor or health authority.  
• Posttreatment Observational Follow-up Phase – 4 weeks after the last dose (if a 
subject early terminates or chooses not to enter the optional Open-label Extension 
Phase) 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the 
Statistical Analysis Plan, whichever is the later date. 
Study Treatments 
Double-blind, Placebo-controlled Treatment Phase: 
• Following a 7-day dose titration, apremilast (30 mg) and identically-appearing placebo 
tablets will be provided and administered orally BID  
Active Treatment Phase  
• Apremilast (30 mg) tablets will be provided and administered orally BID 
Optional Open-label Extension Phase: 
• Apremilast (30 mg) tablets will be provided and administered orally BID 
Overview of Efficacy Assessments 
• Oral ulcer count using area under the time curve (AUC) through Week 12 


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• Visual analogue scale (VAS) to assess pain of oral and genital ulcers separately 
• BD Quality of Life measure 
• BD Current Activity Form  
• Behçet’s Syndrome Activity Score (BSAS) 
• 
  
• Physician’s Global Assessment (PGA) of skin lesions 
• 
 
• BD-related inflammatory eye disease 
• 
• 
• 
• 
Overview of Safety Assessments 
• Adverse events 
• Vasculitis and psychiatric evaluations 
• Chest radiographs 
• Physical examinations 
• Vital signs 
• Weight measurements 
• Clinical laboratory safety evaluations 
• Manual 12-lead electrocardiograms (ECGs) 
• Pregnancy test 


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TABLE OF CONTENTS 
 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL SUMMARY ...............................................................................................................6 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
Behçet’s Disease .........................................................................................................17 
1.2. 
Apremilast ...................................................................................................................18 
1.2.1. 
Clinical Safety ............................................................................................................19 
1.3. 
Efficacy and Safety of Apremilast in Behçet’s Disease .............................................20 
1.4. 
Rationale for Dose Chosen .........................................................................................22 
2. 
STUDY OBJECTIVES ..............................................................................................23 
2.1. 
Primary Objective .......................................................................................................23 
2.2. 
Secondary Objectives .................................................................................................23 
2.3. 
Safety Objective ..........................................................................................................23 
2.4. 
Exploratory 
 Objectives ....................................23 
2.5. 
Exploratory 
 Objective ....................................................................23 
2.6. 
Exploratory Objective .................................................................................................23 
3. 
STUDY ENDPOINTS ................................................................................................24 
3.1. 
Primary Endpoint ........................................................................................................24 
3.2. 
Secondary Endpoints ..................................................................................................24 
3.3. 
Safety Endpoints .........................................................................................................25 
3.4. 
Exploratory 
 Endpoints ...................................25 
3.5. 
Exploratory 
 Endpoint .....................................................................25 
3.6. 
Exploratory Endpoint(s) .............................................................................................25 
4. 
OVERALL STUDY DESIGN ....................................................................................27 
4.1. 
Study Design ...............................................................................................................27 
4.1.1. 
Internal Celgene Safety Monitoring During the Apremilast Program: Role of 
the Safety Management Team ....................................................................................28 
4.1.2. 
External Safety and Efficacy Monitoring During Apremilast Program: Role 
of the Independent Data Monitoring Committee ........................................................28 
4.2. 
Study Design Rationale ..............................................................................................28 
4.3. 
Study Duration ............................................................................................................30 
4.4. 
End of Trial .................................................................................................................31 


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5. 
TABLE OF EVENTS .................................................................................................32 
6. 
PROCEDURES ..........................................................................................................38 
6.1. 
Informed Consent .......................................................................................................38 
6.2. 
Demographic Data ......................................................................................................38 
6.3. 
Complete Medical History ..........................................................................................38 
6.4. 
Inclusion/Exclusion Criteria .......................................................................................38 
6.5. 
Prior and Concomitant Medications ...........................................................................38 
6.6. 
Safety Assessments .....................................................................................................38 
6.6.1. 
Adverse Events ...........................................................................................................39 
6.6.1.1. 
Adverse Events of Special Interest .............................................................................39 
6.6.2. 
Vital Signs, Height and Weight ..................................................................................39 
6.6.3. 
Complete Physical Examinations ...............................................................................39 
6.6.4. 
Limited Physical Examinations ..................................................................................40 
6.6.5. 
Vasculitis Assessment ................................................................................................40 
6.6.6. 
Psychiatric Evaluation ................................................................................................40 
6.6.7. 
Clinical Laboratory Evaluations .................................................................................40 
6.6.7.1. 
Hematology .................................................................................................................41 
6.6.7.2. 
Serum Chemistry ........................................................................................................41 
6.6.7.3. 
Urinalysis ....................................................................................................................41 
6.6.7.4. 
Hepatitis Testing .........................................................................................................41 
6.6.8. 
Contraception Education ............................................................................................42 
6.6.9. 
Pregnancy Tests for Females of Childbearing Potential.............................................42 
6.6.10. 
Chest Radiograph ........................................................................................................42 
6.6.11. 
12-lead ECG ...............................................................................................................42 
6.7. 
Efficacy Assessments .................................................................................................43 
6.7.1. 
Number of Oral and Genital Ulcers ............................................................................43 
6.7.2. 
Pain VAS for Oral and Genital Ulcers .......................................................................43 
6.7.3. 
BD Current Activity Form ..........................................................................................43 
6.7.4. 
Behçet’s Disease Quality of Life Measure .................................................................43 
6.7.5. 
Behçet’s Syndrome Activity Score .............................................................................43 
......................................44 
6.7.7. 
Physician’s Global Assessment of Skin Lesions ........................................................44 
..............................................................................44 


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6.7.9. 
Assessment of Behçet’s Disease-related Inflammatory Eye Disease .........................44 
............................................................................45 
............................45 
........................................................45 
.......................................................................................46 
..........................................................................................................46 
......................................................................................................46 
.........................................................................................47 
6.8. 
Investigational Product ...............................................................................................47 
6.8.1. 
Study Medication Dispensing and Counting ..............................................................47 
6.8.2. 
Site Instructions for Dosing the Subject .....................................................................47 
6.9. 
Investigational Product Discontinuation .....................................................................47 
6.10. 
Early Termination Visit ..............................................................................................48 
6.10.1. 
Observational Follow-up Visit ...................................................................................48 
6.10.2. 
Lost to Follow-up .......................................................................................................48 
6.11. 
Study Completion .......................................................................................................48 
7. 
STUDY POPULATION .............................................................................................49 
7.1. 
Number of Subjects and Sites .....................................................................................49 
7.2. 
Inclusion Criteria ........................................................................................................49 
7.3. 
Exclusion Criteria .......................................................................................................51 
8. 
DESCRIPTION OF STUDY TREATMENTS ..........................................................53 
8.1. 
Description of Investigational Product .......................................................................53 
8.2. 
Description of Placebo ................................................................................................53 
8.3. 
Treatment Administration and Schedule ....................................................................53 
8.3.1. 
Dose Modification or Interruption ..............................................................................55 
8.3.2. 
Overdose .....................................................................................................................55 
8.4. 
Method of Treatment Assignment ..............................................................................55 
8.4.1. 
Placebo-controlled Treatment Phase (12 Weeks) .......................................................55 
8.4.2. 
Active Treatment Phase (52 Weeks) ..........................................................................55 
8.4.3. 
Optional Open-label Extension Phase ........................................................................55 
8.5. 
Packaging and Labeling ..............................................................................................56 
8.6. 
Investigational Product Accountability and Disposal .................................................56 
8.6.1. 
Investigational Product Accountability ......................................................................56 


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8.6.2. 
Record of Administration ...........................................................................................56 
8.7. 
Investigational Product Compliance ...........................................................................56 
9. 
CONCOMITANT MEDICATIONS AND PROCEDURES ......................................57 
9.1. 
Permitted Concomitant Medications and Procedures .................................................57 
9.2. 
Prohibited Concomitant Medications and Procedures ................................................57 
9.3. 
Required Concomitant Medications and Procedures ..................................................58 
10. 
STATISTICAL ANALYSES .....................................................................................59 
10.1. 
Overview .....................................................................................................................59 
10.2. 
Study Population Definitions ......................................................................................59 
10.3. 
Sample Size and Power Considerations .....................................................................59 
10.4. 
Background and Demographic Characteristics ..........................................................59 
10.5. 
Subject Disposition .....................................................................................................59 
10.6. 
Efficacy Analysis ........................................................................................................60 
10.6.1. 
Efficacy Evaluation for the Double-blind, Placebo-controlled Treatment 
Phase ...........................................................................................................................60 
10.6.1.1. 
Multiplicity .................................................................................................................60 
10.6.1.2. 
Primary Analysis for Primary Efficacy Endpoint .......................................................60 
10.6.1.3. 
Analysis for Secondary Efficacy and Exploratory Endpoints ....................................60 
10.6.2. 
Efficacy Evaluation for the Active Treatment Phase .................................................61 
10.7. 
Safety Analysis ...........................................................................................................61 
10.8. 
Interim Analysis ..........................................................................................................61 
10.9. 
Other Topics ...............................................................................................................61 
.......................................................................................................61 
.................................................................................62 
..................................................................................62 
11. 
ADVERSE EVENTS..................................................................................................63 
11.1. 
Monitoring, Recording and Reporting of Adverse Events .........................................63 
11.1.1. 
Monitoring, Recording and Reporting AEs of Diarrhea ............................................63 
11.2. 
Evaluation of Adverse Events ....................................................................................64 
11.2.1. 
Seriousness .................................................................................................................64 
11.2.2. 
Severity / Intensity ......................................................................................................65 
11.2.3. 
Causality .....................................................................................................................65 
11.2.4. 
Duration ......................................................................................................................66 


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11.2.5. 
Action Taken ..............................................................................................................66 
11.2.6. 
Outcome ......................................................................................................................66 
11.3. 
Abnormal Laboratory Values .....................................................................................66 
11.4. 
Pregnancy ...................................................................................................................67 
11.4.1. 
Females of Childbearing Potential..............................................................................67 
11.4.2. 
Male Subjects ..............................................................................................................67 
11.5. 
Reporting of Serious Adverse Events .........................................................................68 
11.5.1. 
Safety Queries .............................................................................................................68 
11.6. 
Expedited Reporting of Adverse Events .....................................................................68 
12. 
DISCONTINUATIONS .............................................................................................70 
13. 
EMERGENCY PROCEDURES ................................................................................71 
13.1. 
Emergency Contact .....................................................................................................71 
13.2. 
Emergency Identification of Investigational Products ...............................................71 
14. 
REGULATORY CONSIDERATIONS......................................................................72 
14.1. 
Good Clinical Practice ................................................................................................72 
14.2. 
Investigator Responsibilities .......................................................................................72 
14.3. 
Subject Information and Informed Consent ...............................................................73 
14.4. 
Confidentiality ............................................................................................................73 
14.5. 
Protocol Amendments ................................................................................................73 
14.6. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval .....................................................................................................................73 
14.7. 
Ongoing Information for Institutional Review Board / Ethics Committee ................74 
14.8. 
Closure of the Study ...................................................................................................74 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................76 
15.1. 
Data/Documents .........................................................................................................76 
15.2. 
Data Management .......................................................................................................76 
15.3. 
Record Retention ........................................................................................................76 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
16.1. 
Study Monitoring and Source Data Verification ........................................................78 
16.2. 
Audits and Inspections ................................................................................................78 
17. 
PUBLICATIONS .......................................................................................................79 
18. 
REFERENCES ...........................................................................................................80 
19. 
APPENDICES ............................................................................................................83 


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Appendix A: List of Behçet’s Disease Clinical Features ............................................................83 
Appendix B: Visual Analog Scales (VAS) for Pain of Oral and Genital Ulcers ........................84 
Appendix C: Behçet’s Disease Current Activity Form ...............................................................85 
Appendix D: Behçet’s Disease Quality of Life Measure ............................................................88 
Appendix E: Behçet’s Syndrome Activity Score (BSAS) ..........................................................90 
........................................92 
Appendix G: Static Physician’s Global Assessment of Skin Lesions .......................................100 
.........................103 
...................................................105 
..............106 
Appendix K: International Study Group Criteria For The Diagnosis Of Behçet's 
Disease (1990) ..........................................................................................................108 
 
 
 


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LIST OF TABLES 
Table 1: 
Table of Events (up to Week 64) ................................................................................32 
Table 2: 
Table of Events (Years 2 to 4) ....................................................................................36 
............................46 
Table 4: 
Treatment Schema for Dose Titration at Visit 2 .........................................................54 
Table 5: 
Treatment Schema for Dose Titration at Visit 9 .........................................................54 
 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................30 
 


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1. 
INTRODUCTION 
1.1. 
Behçet’s Disease  
Behçet's disease (BD) is a chronic, relapsing, multisystemic inflammatory disorder of unknown 
etiology characterized by four major symptoms (oral aphthous ulcers, genital ulcers, skin lesions, 
and ocular lesions) and occasionally by five minor symptoms (arthritis, gastrointestinal ulcers, 
epididymitis, vascular lesions, and central nervous system [CNS] symptoms) (Cho, 2012). 
The main clinical feature of BD is recurrent (exacerbations and remissions), painful oral 
ulcerations appearing either alone or in combination with painful ulcers of the genitals, as well as 
lesions of the skin, and eyes, and involvement of joints and other organs. Oral ulcers are the most 
frequent sign at onset (Kone-Paut, 1998; Krause, 1999; Alpsoy, 2007; Kerkeni, 2010; Atmaca, 
2011) being observed in nearly every patient (range, 90% to 100% of cases). These ulcers can be 
severe enough to interfere with normal diet and nutrition, leading to malnutrition and weight 
loss.  Due to their severity and frequency of reoccurrence, oral ulcers are an important aspect of 
the chronically debilitating nature of BD (Bang 1995; Davatchi, 2010).  Genital ulcerations 
generally occur less frequently (approximately 80% of adults, range, 55% to 97% of cases). Skin 
involvement, eg, nodosum-like lesions, papulopustular lesions, pathergy reaction and erythema 
multiforme ranges from 39% to 93% of cases in adults.  Ocular and joint involvement typically 
affects approximately 50% of patients (54.2% and 53.8% of cases, respectively), but there was 
significant variability between studies (Davatchi, 2010). Inflammatory disease of the eye 
manifesting as uveitis remains one of the leading causes of blindness in some parts of the world 
(Cho, 2012).  Classification criteria for the diagnosis of BD were established by the International 
Study Group (ISG) (ISGBD, 1990).  The diagnosis of BD is based on a manifestation of 
recurrent oral ulcerations plus 2 of the following criteria: recurrent genital ulceration, eye 
lesions, skin lesions, or positive pathergy test. 
In BD, the pro-inflammatory mediators that are upregulated include the T cell derived cytokines 
interferon (IFN)-γ, interleukin (IL)-2 and IL-17 (Sugi-Ikai, 1998; Frassanito, 1999; Ahmed, 
2004; Hamzaoui, 2002; Hamzaoui, 2011), as well as IL-1β, IL-6, IL-8, IL-12 and tumor necrosis 
factor (TNF)-α (Hamzaoui, 1990; Ozoran 1995, Evereklioglu, 2002; Hamzaoui, 2002).  Elevated 
IL-12 and IL-17 levels in patients with active BD appear to correlate with disease activity 
(Frassanito, 1999; Hamzaoui, 2002; Turan, 1997; Hamzaoui, 2011), and BD is also associated 
with an imbalance in numbers of Th17 and regulatory T cells (Tregs) (Direskeneli, 2011). 
Together, these data indicate that pro-inflammatory responses prevail in active BD, and that 
targeted inhibition of one or more of these mediators may be an effective treatment in BD. 
Treatment 
The treatment of BD is generally empirical and the drug of choice is based on specific clinical 
manifestations in each patient (Fresko, 2008; Hatemi, 2008; Davatchi, 2010; Yazici 2010).  The 
aim of treatment is to control symptoms, suppress inflammation and prevent end-organ damage.  
It is also important to avoid exacerbations of mucocutaneous and joint involvement, which may 
affect quality of life (Hatemi, 2008).  To achieve these aims, the European League Against 
Rheumatism (EULAR) recommendations for the management of BD were developed by a 
multidisciplinary expert committee (Hatemi, 2008).  These recommendations focus on the 


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treatment of Behçet-related eye disease, major vessel involvement, gastrointestinal involvement, 
arthritis, central nervous system involvement and mucocutaneous ulceration. 
For isolated oral and genital ulcers, the most prevalent manifestations of BD, topical 
corticosteroids are the first line treatment of choice based on the EULAR guidelines (Hatemi, 
2008).  Corticosteroids have a significant side effect profile, especially when used for a long 
period of time.  The most common side effects of oral mucosal application of topical 
corticosteroids include oral candidiasis, dry mouth, mouth burning, hypogeusia, sore throat, 
gingival atropy, halitosis and nausea (Thongprasom, 2008; Gonzalez-Moles, 2010). In addition 
to topical corticosteroids, supportive care including lidocaine gel and/or chlorhexidine are also 
used for oral ulcers, and sucralfate for genital lesions (Fresko, 2008; Hatemi, 2008).  The most 
that these topical treatments offer is short-term symptomatic relief.  Although oral and genital 
ulcers do not cause organ damage, it is important to avoid their exacerbations and recurrence, 
since they affect the patients’ quality of life (Fresko, 2008; Hatemi, 2008). Systemic therapy may 
be required in a substantial number of cases with more severe manifestations. Colchicine has 
been widely used, however, there is no definitive evidence to show that it is beneficial for all 
mucocutaneous lesions (Aktulga, 1980, Yurdakul, 2001).  Side effects associated with colchicine 
use include nausea, vomiting, diarrhea and abdominal pain, neuropathy, as well as bone marrow 
suppression, which has been reported with long-term usage (Colchicine SmPC).  Other rare 
adverse events (AEs) include peripheral neuritis, myopathy, purpura, dermatosis, alopecia and 
reversible azospermia. Other oral systemic treatments, such as azathioprine, and biologic 
parenteral therapies such as IFN-α and TNF-α antagonists have been used off-label for the more 
recalcitrant manifestations of BD (Fresko, 2008; Hatemi, 2008).  TNF-α antagonists include anti-
TNF monoclonal antibodies (infliximab and adalimumab) and the soluble TNF receptor blocker 
(etanercept).  The level of evidence regarding the effectiveness of these oral and biologic 
systemic treatments for the treatment of BD is limited, and their use is associated with hepatic, 
renal, metabolic, endocrinologic, and hematologic adverse events.  Increased susceptibility to 
infections and development of malignancies are also known to occur (Hatemi, 2008). As such, 
there is an unmet medical need for a medication with a more acceptable safety profile in BD. 
1.2. 
Apremilast 
Apremilast (CC-10004), an oral small-molecule inhibitor of phosphodiesterase (PDE) 4, works 
intracellularly to modulate a network of pro-inflammatory and anti-inflammatory 
mediators.  PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant 
PDE in inflammatory cells.  PDE4 inhibition elevates intracellular cAMP levels, which in turn 
down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 
and other inflammatory cytokines.  Cyclic AMP also modulates levels of anti-inflammatory 
cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the 
potential to be effective in the treatment of BD. 
The pharmacologic profile of apremilast suggests a potential therapeutic benefit in the treatment 
of BD by a mechanism that involves restraining pro-inflammatory cytokine levels that occurs in 
active BD, through modulation of TNF-α, IL-2, IL-8, IL-12, IL-17 and IFN-γ production. 


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1.2.1. 
Clinical Safety 
As of the clinical cutoff date of 10 May 2014, apremilast had been administered at daily doses 
ranging from 10 to 100 mg/day to approximately 5200 subjects in Celgene-sponsored studies, 
Phase 1 to 3 studies, including 4180 subjects who received apremilast in Phase 2 or Phase 3 
studies in psoriasis, psoriatic arthritis (PsA), or rheumatoid arthritis (RA). 
In total, 26 clinical studies have been completed, including 18 Phase 1 studies (14 studies in 
healthy subjects, 1 study in subjects with moderate or severe hepatic impairment, 1 study in 
subjects with severe renal impairment, 1 study in subjects with mild to moderate renal 
impairment, and 1 study in subjects with PsA or RA) and 8 Phase 2 studies (4 studies in subjects 
with psoriasis, 1 study in subjects with PsA, 1 study in subjects with RA, 1 study in subjects with 
BD, and 1 study in subjects with asthma).  More than 4500 subjects have been enrolled in 2 
ongoing Phase 2 studies (both in subjects with psoriasis) and in 9 ongoing Phase 3 studies (5 in 
subjects with PsA, 3 in subjects with psoriasis, and 1 in subjects with AS).  The most commonly 
observed treatment-emergent adverse events (TEAEs) (ie, those reported in > 5% of subjects) 
have been diarrhea, nausea, headache (including tension headache), upper respiratory tract 
infections, and nasopharyngitis.  The majority of reported AEs were mild or moderate in severity 
and resolved while subjects continued apremilast treatment.  
Based on the pooled data from the ongoing Phase 3 PsA studies, as of the data cutoff date of 
01 Mar 2013, the incidence of withdrawal from investigational product (IP) due to these 
common AEs was low (≤ 2.1% for the individual AE).  The most frequently reported AEs that 
led to IP withdrawal were diarrhea (0.4%, 1.2%, and 2.1%, for the placebo, apremilast 20 mg 
BID, and apremilast 30 mg BID treatment groups, respectively), nausea (0.4%, 1.0%, and 2.0%, 
for the placebo, apremilast 20 mg BID, and apremilast 30 mg BID treatment groups, 
respectively), and headache (0.3%, 0.5%, and 1.4%, for the placebo, apremilast 20 mg BID, and 
apremilast 30 mg BID treatment groups, respectively).   
Based on the pooled data from the ongoing Phase 3 psoriasis studies, as of the data cutoff date of 
11 Jan 2013, the incidence of withdrawal from IP due to these common AEs was low (≤ 1.4% for 
the individual AE).  The most frequently reported AEs that led to IP withdrawal were nausea 
(0.2% and 1.4%, for the placebo and apremilast 30 mg BID treatment groups, respectively), 
diarrhea (0.2% and 0.9%, for the placebo and apremilast 30 mg BID treatment groups, 
respectively), and psoriasis (1.0% and 0.9%, for the placebo and apremilast 30 mg BID treatment 
groups, respectively).   
The incidence of SAEs was low and comparable between apremilast and placebo treatment 
groups in the placebo-controlled periods and was not driven by any single preferred term or any 
specific individual organ toxicity.  The safety profile of apremilast is comparable in the psoriasis 
and PsA indications.   
Ten deaths have been reported as of 10 May 2014, including two deaths in completed Celgene-sponsored 
studies, seven deaths in ongoing Celgene-sponsored studies, and one death in an ongoing investigator-
initiated study.  Among nine deaths in Celgene-sponsored studies, four subjects were taking apremilast 30 
mg BID, two subjects were taking apremilast 20 mg BID, and three were taking placebo at the time of 
death.  One subject whose death was reported in an investigator-initiated study died 20 months after the 
last dose of apremilast.  


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Detailed information concerning the available pharmacology, toxicology, drug metabolism, 
clinical studies, and AE profile of apremilast can be found in the Investigator’s Brochure. 
1.3. 
Efficacy and Safety of Apremilast in Behçet’s Disease 
Apremilast has been studied for the treatment of BD in one completed Phase 2 study. 
Study CC-10004-BCT-001 was a Phase 2, multicenter, randomized, placebo-controlled, double-
blind, parallel-group study that assessed the safety and efficacy of apremilast in the treatment of 
Behçet's disease. The study consisted of 4 phases: a 12-week Screening Phase; a 12-week, 
Placebo-controlled Treatment Phase; a 12-week Dose Blinded Extension Phase; and a 4-week 
Posttreatment Observational Follow-up Phase. 
A total of 111 subjects were randomized and treated with placebo or apremilast 30 mg twice 
daily (BID) (APR 30 BID) for 84 days. A total of 100 subjects completed the Double-blind 
Phase and opted to continue to the 12-week period of active treatment with APR 30 BID. 
In the BCT-001 study, apremilast demonstrated a treatment benefit in subjects with BD with the 
achievement of the primary endpoint as subjects randomized to the APR 30 BID group had 
statistically significantly fewer oral ulcers on Day 85 compared with the placebo group.  The 
mean oral ulcer counts at baseline were 2.7 and 2.9 in the APR 30 BID and placebo groups, 
respectively.  On Day 85, the least squares (LS) mean oral ulcer counts were 0.4 and 2.0 in the 
APR 30 BID and placebo groups, respectively, yielding an LS mean difference (2-sided 95% 
confidence interval [CI]) of -1.6 (-2.4, -0.9) (p < 0.0001). 
The analyses of the secondary endpoints supported the results of the primary analysis.  A 
significantly greater proportion of subjects in the APR 30 BID group achieved complete (oral 
ulcer-free) response at Day 85 compared with the placebo group (70.9% APR 30 BID; 28.6% 
placebo; p < 0.0001).  Similarly, a significantly greater proportion of subjects in the APR 30 BID 
group achieved partial (≥ 50% reduction in oral ulcer number [including oral ulcer-free]) 
response at Day 85 compared with the placebo group (89.1% APR 30 BID group; 50.0% placebo 
group; p < 0.0001).  The area under the curve at Day 85 (AUC85) for oral ulcer count, average 
daily AUC85, and average number of ulcers from Day 1 to Day 85 were more than 2-fold lower 
in the APR 30 BID group compared with the placebo group. 
The mean oral ulcer counts in subjects randomized to the APR 30 BID group decreased sharply, 
reaching maximum reduction on Day 15 (first postbaseline assessment), and remained reduced 
for up to 24 weeks on treatment.  In subjects randomized to the placebo group, the mean oral 
ulcer counts were consistently higher than in subjects randomized to the APR 30 BID group 
during the Treatment Phase.  When the placebo subjects were transitioned to APR 30 BID in the 
Extension Phase, a reduction in mean oral ulcer counts was observed that was similar to those in 
the APR 30 BID-treated subjects.  The oral ulcer counts increased in both treatment groups 
during the Observational Follow-up Phase when apremilast treatment was stopped. 
Oral ulcer pain visual analog scale (VAS) scores in APR 30 BID- and placebo-treated subjects 
showed a pattern of change over time that was similar to that of oral ulcer counts.  At Day 85, 
there was a more than 2-fold greater improvement (indicating decreased pain) in VAS scores 
from baseline in the APR 30 BID group compared with the placebo group (nominal p < 0.0001).  
When the placebo subjects were transitioned to APR 30 BID in the Extension Phase, an 
improvement in oral ulcer pain VAS scores was observed that was similar to the APR 30 BID-


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treated subjects.  During the Observational Follow-up Phase, recurrence of pain was noted when 
apremilast treatment was stopped. 
A small number of subjects had genital ulcers at baseline. Therefore, formal statistical 
comparisons between the APR 30 BID and placebo treatment groups were not done.  However, a 
complete genital ulcer response (genital ulcer-free at Day 85) was achieved by all 10 (100%) 
subjects with baseline lesions in the APR 30 BID group versus 3 (50.0%) subjects with baseline 
lesions in the placebo group.  Further, only 1 subject in the APR 30 BID group who did not have 
genital ulcers at baseline developed a single, new genital ulcer at Day 85, compared with 
6 subjects in the placebo group. 
In addition to demonstrating efficacy in the treatment of mucocutaneous ulcers associated with 
BD, the use of APR 30 BID also significantly reduced overall disease activity compared to 
placebo as measured by the BD Current Activity Form (BDCAF) and Behçet’s Syndrome 
Activity Score (BSAS).  Aside from mucocutaneous ulcers, these validated instruments also take 
into account the involvement of other organ systems, such as the skin, joints, gastrointestinal 
tract, vascular, and nervous systems.  Significantly greater reductions (improvements) in the 
BDCAF from baseline were observed at Day 85 in the APR 30 BID group compared with the 
placebo group with an LS mean change of -1.2 and -0.1, respectively (nominal p = 0.0007).  
Similarly, BSAS mean scores were significantly reduced (improved) from baseline at Day 85 in 
the APR 30 BID group compared with the placebo group (p < 0.0001). 
Significant improvements in physical function and quality of life (QoL) measured by the 
SF-36v2 Physical Component Score (PCS) and the BD QoL questionnaires, were also observed 
with APR 30 BID treatment compared to placebo.  At Day 85, the SF-36v2 PCS mean scores 
were significantly higher relative to baseline (improved physical functioning) in the APR 30 BID 
group compared with the placebo group (LS mean APR 30 BID, 4.12; placebo, -1.10; 
p = 0.0011).  The improvement observed in the APR 30 BID treatment group at Day 85 
exceeded the minimal clinically important difference (MCID) of a 2.5-point increase from 
baseline.  Similarly, at Day 85, the BD QoL mean scores were significantly reduced (improved) 
from baseline in the APR 30 BID group compared with the placebo group (LS mean APR 30 
BID group, -4.3; placebo group, -1.8; p = 0.0397). 
Overall, the improvements seen at Week 12 were maintained through Week 24 for subjects who 
remained on apremilast treatment during the Treatment and Extension Phases, thus 
demonstrating persistence of response. 
During the Placebo-controlled Phase, the majority of subjects reported at least 1 TEAE, 89.3% of 
subjects in the placebo group and 89.1% of subjects in the APR 30 BID group. Severe TEAEs 
were reported in less than 10% of subjects, 8.9% of subjects in the placebo group and 9.1% of 
subjects in the APR 30 BID group. Serious TEAEs were reported in 3 subjects in the placebo 
group and 2 subjects in the APR 30 BID group. None of the serious TEAEs in the APR 30 BID 
group were considered related to investigational product (IP). One subject in the APR 30 BID 
group had IP interrupted due to a TEAE. Less than 10% of subjects had IP withdrawn due to 
TEAEs, ie, 8.9% of subjects in the placebo group and 7.3% of subjects in the APR 30 BID 
group. The proportion of subjects with TEAEs, drug-related TEAEs, severe TEAEs, serious 
TEAEs and TEAEs leading to IP interruption or withdrawal was similar in the placebo and APR 
30 BID groups. No deaths were reported in this study. 


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The most common TEAEs in the APR 30 BID group, in decreasing order of frequency, were 
headache, nausea, Behçet’s syndrome/flare, and diarrhea. The most common TEAEs in the 
Placebo group, in decreasing order of frequency, were Behçet’s syndrome/flare, headache, 
nausea, and abdominal pain. 
The design of the Study CC-10004-BCT-002 is guided by the design of, and results from 
CC-10004-BCT-001. 
1.4. 
Rationale for Dose Chosen 
Apremilast 
Based on the safety and efficacy results of 3 completed Phase 2 studies in psoriasis and PsA, the 
dose of APR 30 BID was chosen for the BCT-001 study (Section 1.3), to minimize the number 
of subjects required to evaluate this rare disorder and to maximize the opportunity to demonstrate 
efficacy.  Since apremilast is known to be associated with gastrointestinal side effects and 
headaches, the dose was escalated gradually to 30 mg BID over the first week of treatment, and 
subjects who could not tolerate the full dose of IP were allowed to reduce their dose to 20 mg 
BID. During the placebo-controlled period, 2 subjects in the APR 30 BID group dose-reduced. 
During the apremilast-exposure period, 2 subjects in the APR 30 BID/APR 30 BID group dose-
reduced; thus although dose reduction was allowed, it was infrequent. 
Data from the BCT-001 study indicated that APR 30 BID effectively reduced the number of oral 
and genital ulcers, decreased oral and genital ulcer pain, and improved physical function and 
quality of life in subjects with BD. Apremilast exhibited a safety profile in BD that was 
consistent with those observed in other inflammatory diseases in which apremilast was evaluated 
(eg, psoriasis and psoriatic arthritis). Taken together, these data demonstrate that APR 30 BID 
has an acceptable benefit/risk ratio profile in subjects with BD. 
Based on this rationale, APR 30 BID will be investigated in this BD study. 
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• The primary objective of the study is to evaluate the efficacy of apremilast in the 
treatment of oral ulcers in active Behçet’s disease. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the efficacy of apremilast in subjects with active Behçet’s disease 
• To evaluate the effect of apremilast on Patient Reported Outcomes (PROs) in subjects 
with active Behçet’s disease 
2.3. 
Safety Objective 
• To evaluate the safety and tolerability of apremilast in subjects with active Behçet’s 
disease 
2.4. 
Exploratory 
 Objectives 
The exploratory 
 objectives of the study are: 
2.5. 
Exploratory 
 Objective 
2.6. 
Exploratory Objective 
The exploratory objective of the study is: 
Data from exploratory objectives will be included in the Clinical Study Report or a separate report. 
 


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3. 
STUDY ENDPOINTS 
3.1. 
Primary Endpoint 
• Area under the curve (AUC) for the number of oral ulcers from baseline through 
Week 12 
3.2. 
Secondary Endpoints 
• Complete response rate for oral ulcers at Week 12 
− A complete response is defined as the proportion of subjects who are oral ulcer- 
free.  
• Change from baseline in the pain of oral ulcers as measured by VAS at Week 12 
• Complete response rate for genital ulcers at Week 12 for subjects who had genital 
ulcers at Baseline 
− A complete response is defined as the proportion of subjects who are genital 
ulcer-free. 
• Change from baseline in the pain of genital ulcers, as measured by VAS at Week 12 
in subjects who had genital ulcers at baseline 
• Change from baseline in disease activity as measured by Behçet’s Disease Current 
Activity scores (BD Current Activity Form) at Week 12 
• Change from baseline in the BD QoL score at Week 12 
• Change from Baseline in Behçet’s Syndrome Activity Score (BSAS) at Week 12 
• Time to oral ulcer resolution (complete response), ie, the first instance when a subject 
has a complete response, during the Placebo-controlled Treatment Phase 
• Proportion of subjects with no oral ulcers following complete response, ie, the first 
time when a subject has a complete response, during the Placebo-controlled 
Treatment Phase 
• Number of oral ulcers following loss of complete response, ie, the first instance when 
a subject has a reappearance of oral ulcers following a complete response, during the 
Placebo-controlled Treatment Phase 
• Time to recurrence of oral ulcers following loss of complete response, ie, the first 
instance when a subject has a reappearance of oral ulcers following a complete 
response, during the Placebo-controlled Treatment Phase 
• Change from baseline in the total score of the Static Physician’s Global Assessment 
(PGA) of skin lesions (acne-like lesions, folliculitis and erythema nodosum) of BD at 
Week 12 in subjects who had BD skin lesions at baseline 
• Proportion of subjects achieving an oral ulcer complete response (oral ulcer-free) by 
Week 6, after start of dosing, and who remain oral ulcer free for at least 6 additional 
weeks during the 12-week Placebo-controlled Treatment Phase 


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3.3. 
Safety Endpoints 
Safety and tolerability as defined by the following: 
• Type, frequency, severity, and relationship of the AEs to apremilast 
• Number of subjects who prematurely discontinue IP due to any AE 
• Frequency of clinically significant changes in vital signs, and/or laboratory findings 
3.4. 
Exploratory 
 Endpoints 
3.5. 
Exploratory 
 Endpoint 
3.6. 
Exploratory Endpoint(s) 


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4. 
OVERALL STUDY DESIGN  
4.1. 
Study Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study, followed by an active-treatment phase to evaluate the efficacy and safety of apremilast 
(CC-10004) in the treatment of subjects with active BD. 
Approximately 204 eligible subjects will be randomized 1:1 (102 subjects per group) to receive 
apremilast (APR 30 BID) or identically-appearing placebo tablets BID for the 12-week Placebo-
controlled Treatment Phase. Subjects will be stratified by gender, history of uveitis and region 
(Japan and Other).  
Upon completion of the Week 12 visit, subjects initially randomized to placebo will transition to 
APR 30 BID, while subjects initially randomized to APR 30 BID will continue on the same 
treatment during the 52-week Active Treatment Phase.  
Subjects who complete Visit 14 of the 52-week Active Treatment Phase will have an opportunity 
to continue to receive APR 30 BID in an optional Open-label Extension Phase. Subjects who 
choose to not enter the optional Open-label Extension Phase will complete the 4-week 
Posttreatment Observational Follow-up Phase.   
Subjects who discontinue at any time from the study for any reason, are to enter the 4-week 
Posttreatment Observational Follow-up Phase. 
 
The study will include the following (Figure 1): 
• Screening Phase: up to 6 weeks 
• Double-blind, Placebo-controlled Treatment Phase: 12 weeks 
− APR 30 BID 
− Placebo  
• Active Treatment Phase:  52 weeks 
− APR 30 BID 
• Optional Open-label Extension Phase until apremilast is commercially available for 
BD or until the benefit/risk of apremilast is found not to be acceptable for BD, 
according to either the sponsor or health authority.  
− APR 30 BID 
• Posttreatment Observational Follow-up Phase – 4 weeks after the last dose (if a 
subject early terminates or chooses not to enter the optional Open-label Extension 
Phase) 


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4.1.1. 
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 blinded AEs, serious adverse events (SAEs), discontinuations, and 
laboratory findings are reviewed internally by a Safety Management Team (SMT) at Celgene. 
The review follows the Council for International Organizations for Medical Sciences, Working 
Group VI (CIOMS 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 the SMT charter. 
4.1.2. 
External Safety and Efficacy Monitoring During Apremilast Program: Role of 
the Independent Data Monitoring Committee 
Monitoring is also performed by an independent, external Data Monitoring Committee (DMC) 
that will assess both safety and efficacy, as outlined in the DMC charter (available upon request). 
The DMC will review data in a blinded manner, but reserves the right to unblind data for safety 
or efficacy reasons. 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 is 
convened approximately every 12 months, or ad hoc, at the request of the SMT. The DMC’s 
scope, conduct, processes, and accountabilities are specified in its charter. Recommendations of 
the DMC, based on the overall benefit/risk evaluation, may include proceeding with the study 
according to the protocol, proceeding with the study with modification, or study suspension. 
4.2. 
Study Design Rationale 
The design of this study was guided by the results from a Phase 2 study in Behçet’s disease 
(Section 1.3).  
The safety profile of apremilast in Behçet’s disease was consistent with its known safety profile 
as demonstrated in the overall development program. 
The primary purpose of the CC-10004-BCT-002 study is to evaluate the efficacy of apremilast in 
the treatment of mucocutaneous manifestations in subjects with Behçet's disease.  The primary 
endpoint will be the AUC for the number of oral ulcers from Day 1 through Week 12. Oral 
ulcers have spontaneous flares and remissions; thus, using an AUC for the number of oral ulcers 
from baseline through Week 12 provides a better representation of the effect of apremilast on the 
number of oral ulcers the subject experiences during the Placebo-controlled Treatment Phase 
rather than at one point in time, such as Day 85, the primary endpoint, in the CC-10004-BCT-
001 study. 
Active Treatment Phase 
Establishing the long-term safety and tolerability benefit/risk profile of any new therapy, 
especially one with a new and novel mechanism of action, is a critical aspect of drug 
development.  The 52-week active treatment, wherein all subjects including those initially 
randomized to placebo receive apremilast, will support the assessment of the long term safety 
profile of apremilast. 


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Optional Open-label Extension Phase 
Subjects who complete Visit 14 of the 52-week Active Treatment Phase will have an opportunity 
to continue to receive APR 30 BID in an optional Open-label Extension Phase. 
Further to and consistent with the principles of the Declaration of Helsinki, study subjects should 
also share in any benefit arising from the study, which may include access to treatments 
identified as being beneficial.  For these reasons, a longer active treatment phase and optional 
Extension Phase, compared to the CC-10004-BCT-001 study, has been included. 
 
 
 


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Figure 1: 
Overall Study Design 
 
 
 
* Subjects will have an opportunity to enter an Optional Open-label Extension Phase until apremilast is 
commercially available for BD or until the benefit/risk of apremilast is found not to be acceptable for BD, 
according to either the sponsor or health authority.  
 
4.3. 
Study Duration  
The study will consist of the following phases: 
• Screening Phase – up to 6 weeks 
• Double-blind, Placebo-controlled Treatment Phase – 12 weeks 
• Active Treatment Phase – 52 weeks 
• Optional Open-label Extension Phase until apremilast is commercially available for 
BD or until the benefit/risk of apremilast is found not to be acceptable for BD, 
according to either the sponsor or health authority.  
• Posttreatment Observational Follow-up Phase – 4 weeks after the last dose (if a 
subject early terminates or chooses not to enter the optional Open-label Extension 
Phase) 
Screening
Up to
6 Weeks
-6
Weeks
Week 0
Week 12
Primary
endpoint
Week 
64
Week 
68
Double-blind, Placebo-
controlled Treatment
12 Weeks
Active Treatment
52 Weeks
Posttreatment
Observational
Follow-up
4 Weeks
Apremilast 30 mg BID 
Apremilast 30 mg BID
Apremilast 30 mg BID
Placebo
Optional, 
Open-label, 
Long-term 
Extension* 


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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 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the 
Statistical Analysis Plan, whichever is the later date. 


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5. 
TABLE OF EVENTS 
Table 1: 
Table of Events (up to Week 64) 
Phases 
Screening 
Phase 
Double-blind, Placebo-controlled Treatment Phase 
(12 weeks) 
Active Treatment Phase 
(52 weeks) 
Post- 
treatment 
Observational 
FU Visit 
(4 weeks after 
last dose of IP) a 
Early 
Termination 
(ET)b 
Visit Number 
1 
2 
Randomization 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week 
-6 to 0 
0 
1 
2 
4 
6 
8 
10 
12 
16 
 28 
40 
52 
64 
68 
Day 
 -42 to 0 
1 
8±
1 
15 
±1 
29 
±3 
43
±3 
57 
±3 
71 
±3 
85 
±3 
113 
±7 
197 
±7 
281 
±7 
365 
±7 
449 
±7 
476 
±7 
Informed Consent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demography 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical History including BD historyc 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion/Exclusion Criteria 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Prior/Concomitant Medicationsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vasculitis and Psychiatric Evaluationse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Examinationg 
X 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X 
- 
X 
Limited Physical Examinationh 
- 
X 
- 
- 
X 
- 
X 
- 
- 
X 
X 
X 
X 
- 
X 
- 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyi 
X 
X 
- 
- 
X 
- 
- 
- 
X 
X 
- 
X 
X 
X 
X 
X 
Serum Chemistryj 
X 
X 
- 
- 
X 
- 
- 
- 
X 
X 
- 
X 
X 
X 
X 
X 
Urinalysisk 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Pregnancy Testingl 
X 
X 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
X 
Contraception Educationm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 1: 
Table of Events (Continued) 
Phases 
Screening 
Phase 
Double-blind, Placebo-Controlled Treatment Phase 
(12 weeks) 
Active Treatment Phase 
(52 weeks) 
Post- 
treatment 
Observational 
FU Visit 
(4 weeks after 
last dose of IP) 
a) a 
Early 
Termination 
(ET)b 
Visit Number 
1 
2 
Randomization 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week 
-6 to 0 
0 
1 
2 
4 
6 
8 
10 
12 
16 
 28 
40 
 52 
64 
68 
Day 
-42 to 0 
1 
8 
±1 
15 
±1 
29 
±3 
43
±3 
57 
±3 
71 
±3 
85 
±3 
113 
±7 
197 
±7 
281 
±7 
365 
±7 
449 
±7 
476 
±7 
Chest Radiographn 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
12-lead ECGo 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Efficacy Assessments 
Number of Oral Ulcers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Number of Genital Ulcers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain VAS for Oral Ulcers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain VAS for Genital Ulcers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BD Current Activity Form 
- 
X 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
X 
BD Quality of Life Measure 
- 
X 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
X 
BSAS 
- 
X 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
X 
Physician’s Global Assessment of 
Skin Lesionsp 
- 
X 
X 
X 
X 
- 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of BD-related 
Inflammatory Eye Diseaser 
X 
- 
- 
- 
- 
- 
- 
- 
X  
- 
- 
- 
- 
X 
- 
X 


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Table 1: 
Table of Events (Continued) 
Phases 
Screening 
Phase 
Double-blind, Placebo-Controlled Treatment Phase 
(12 weeks) 
Active Treatment Phase 
(52 weeks) 
Post- 
treatment 
Observational 
FU Visit 
(4 weeks after 
last dose of IP) a 
Early 
Termination 
(ET)b 
Visit Number 
1 
2 
Randomization 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week 
-6 to 0 
0 
1 
2 
4 
6 
8 
10 
12 
16 
 28 
40 
 52 
64 
68 
Day 
-42 to 0 
1 
8 
±1 
15
±1 
29 
±3 
43 
±3 
57 
±3 
71 
±3 
85 
±3 
113 
±7 
197 
±7 
281 
±7 
365 
±7 
449 
±7 
476 
±7 
Investigational Productw 
Dispense IP 
- 
X 
- 
- 
X 
- 
X 
- 
X 
X 
X 
X 
X 
Xx 
- 
- 
IP Accountability 
- 
- 
X 
X 
X 
- 
X 
- 
X 
X 
X 
X 
X 
X 
- 
X 
 BD = Behçet’s disease; BSAS = Behçet’s Syndrome Activity Score; ECG = electrocardiogram; FU = follow-up; IP = investigational product; 
 
 VAS = visual analog scale. 
 
a Observational Follow-up Visit - Subjects who discontinue at any time from the study for any reason and subjects who do choose to not enter the optional Open-label Extension 
Phase are to enter the 4-week Posttreatment Observational Follow-up Phase. 
b  ET assessments are to be completed when a subject withdraws from any of the treatment phases. 
c Medical history and BD-related history (as listed in Appendix A) will be captured.  
d See Section 6.5 for details. 
e A vasculitis assessment (Section 6.6.5) and psychiatric evaluation (Section 6.6.6) are to be assessed as appropriate. Evaluate the need for referral to a psychiatrist and other 
actions, including discontinuation, as required in Section 6.6.6. Please answer the question in the eCRF as Yes/No for whether the subject was sent for a psychiatric evaluation. 
f Vital signs include temperature, pulse, respiratory rate, and seated blood pressure.   
g Complete physical examinations include height (Visit 1), weight (street clothes; no shoes), skin, nasal cavities, eyes, ears, lymph nodes, genitalia, and respiratory, cardiovascular, 
gastrointestinal, neurological and musculoskeletal systems evaluations. 


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h Limited physical examinations will include evaluations to assess the subject’s BD.  If a subject presents with symptoms other than BD, the Investigator should determine whether 
a complete physical examination should be performed.  
i See Section 6.6.7.1 for details. 
j See Sections 6.6.7.2 and 6.6.7.4 for details. 
k See Section 6.6.7.3 for details. 
l Urine pregnancy testing (females of childbearing potential [FCBP]) will be performed at Visit 2 (Baseline Visit; prior to randomization). At all other time points indicated in 
Section 5, a serum pregnancy test will be performed.  A urine pregnancy test(s) should be administered if the FCBP subject misses a menstrual period.   
m Contraception education is for males and FCBP. The Investigator will educate all FCBP and males about the different options of contraceptive methods and their correct use at 
Visits 1 and 2. The subject will be reeducated every time their contraceptive measures/methods or their ability to become pregnant changes. 
n A chest radiograph (posteroanterior [PA] and lateral views) should be taken prior to randomization at Visit 2 (Baseline Visit), when most of the eligibility criteria are met, so that 
results are available prior to randomization.  A PA view is required. An additional lateral view is strongly recommended but not required. Alternatively, PA or PA/lateral 
radiographs that were taken within the 12 weeks prior to Visit 1 will be accepted. 
 
Additional chest radiographs should be performed as indicated by local treatment guidelines or, if guidelines are not available/applicable, chest radiographs should be performed 
when clinically indicated (see Section 6.6.10). 
o A 12-lead ECG will be performed after the subject has been supine for 3 minutes. Results must be within normal limits or not clinically significant.  
p See Appendix G for details.  
r An ophthalmological exam should be completed during the Screening Phase, once the subject has met most of the eligibility criteria, after the chest radiograph and ECG, but 
prior to randomization at Visit 2 (Baseline Visit).  A complete evaluation of the eyes, including a slit lamp examination, must be performed by an ophthalmologist during the 
Screening Phase and at Visits 9, 14, ET, and at any time when the subject is suspected of new onset/worsening of Behçet's disease-related inflammatory eye disease, including 
uveitis, retinitis, ophthalmitis and iritis. If a subject has a report from his/her ophthalmologist, dated within 12 weeks of Visit 2 (Baseline Visit; day of randomization), stating 
that the subject does not have BD-related ophthalmological symptoms, then the subject will not be required to have an ophthalmological exam during Screening Phase unless 
there is an eye-related complaint during the Screening Phase. 
w See Sections 6.8, 8.3, and 8.6 for details. 
x Subjects who complete Visit 14 and choose to continue in the optional Open-label Extension Phase will be dispensed IP at Visit 14. 
 
 


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Table 2: 
Table of Events (Years 2 to 4) 
 
Optional Open-label Extension Phase 
Observational FU 
Visit 
(4 weeks ±7 days 
after last dose) a 
Early Termination 
(ET) b 
Year 
Year 2 
Year 3 
Year 4c 
 
 
Visit Number 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
 
 
Week  
76 
88 
100 
112 
124 
136 
148 
160 
172 
184 
196 
208 
Day 
533 
±7 
617 
±7 
701 
±7 
785 
±7 
869 
±7 
953 
±7 
1037 
±7 
1121 
±7 
1205 
±7 
1289 
±7 
1373 
±7 
1457 
±7 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Limited Physical Examinatione 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
- 
- 
Complete Physical Examinationf 
- 
- 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyg 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
Serum Chemistryh 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
Pregnancy Testingi 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
X 
Investigational Product 
Dispense IP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
IP Accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
BD = Behçet’s disease; ET = Early Termination; FCBP = female of child-bearing potential; FU = follow-up; IP = investigational product. 
a Observational Follow-up Visit - Subjects who discontinue at any time from the study for any reason and subjects who do not choose to enter the optional Open-label Extension 
Phase are to enter the 4-week Posttreatment Observational Follow-up Phase. 
b ET assessments are to be completed when a subject withdraws at any time from the Extension study. 
c After Year 4 – if apremilast is not commercially available the visits will repeat starting at Visit 16 until apremilast is commercially available for BD or until the benefit/risk of 
apremilast is found not to be acceptable for BD, according to either the sponsor or health authority.  


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d Vital signs include temperature, pulse, respiratory rate, and seated blood pressure. 
e Limited physical examinations will include evaluations to assess the subject’s BD.  If a subject presents with symptoms other than BD, the Investigator should determine whether 
a complete physical examination should be performed. 
f Complete physical examinations will include weight (street clothes; no shoes), skin, nasal cavities, eyes, ears, lymph nodes, genitalia, and respiratory, cardiovascular, 
gastrointestinal, neurological and musculoskeletal systems evaluations. 
g See Section 6.6.7.1 for details. 
h See Sections 6.6.7.2 and 6.6.7.4 for details. 
i A urine pregnancy test(s) should be administered if the FCBP subject misses a menstrual period. If a FCBP terminates the study early, a serum pregnancy test will be completed 
after the last dose of IP. 
 


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6. 
PROCEDURES 
Assessments, as detailed in the following sections, will be done at the intervals specified in the 
Table of Events, Section 5. 
6.1. 
Informed Consent  
An Informed Consent Document must be signed before any study related assessments are 
performed. 
6.2. 
Demographic Data 
The demographic data will include (but not be limited to) the subject’s initials (as allowed per 
local regulations), date of birth (as allowed per local regulations), age, gender, and race/ethnic 
origin.  The demographic profile will be recorded in the source documents and electronic case 
report form (eCRF). 
6.3. 
Complete Medical History 
Relevant medical history should be recorded, including previous relevant surgeries.  History of 
BD will be reported in the eCRF including diagnosis date and a detailed history of BD 
manifestations, as listed in Appendix A, and BD treatment history. 
6.4. 
Inclusion/Exclusion Criteria 
Subjects must meet all inclusion criteria (Section 7.2) and must not have any of the conditions 
specified in the exclusion criteria (Section 7.3).  The subject’s source documents must support 
his/her qualifications for the study (eg, if a female subject does not require pregnancy testing and 
birth control because of a hysterectomy, the date of the hysterectomy must be included in the 
medical history). 
6.5. 
Prior and Concomitant Medications 
All medications and therapies (including systemic and topical medications, prescription, and 
non-prescription, including 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.   
Previous biologic use should be recorded, including start and stop dates regardless of when it 
was administered. 
All medications and therapies being taken by the subjects, at any time during the study, must also 
be recorded. 
6.6. 
Safety Assessments 
The following safety assessments will be performed as outlined in Section 5. 


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6.6.1. 
Adverse Events 
The time frames for recording all AEs are indicated in Section 5.  It should be noted that during 
the first 64 weeks of the study worsening of a subject’s BD should be considered as worsening of 
the disease under study, and should not be captured as an AE. Worsening of disease will be 
captured on a separate BD activity page in the eCRF that lists each of the BD manifestations.  
Worsening of a subject’s BD will be captured on the AE eCRF for subjects who continue in the 
optional Open-label Extension Phase after Week 64. 
6.6.1.1. 
Adverse Events of Special Interest 
The PDE4 inhibitors, including apremilast, have been associated with AE reports of diarrhea.  
Diarrhea has not been well characterized in previous apremilast studies.  
Diarrhea is the passage of three or more loose or liquid stools per day, or more frequently than is 
normal for the individual (World Health Organization [WHO], 2013). Following the definition of 
diarrhea by the WHO and taking a more conservative approach, the AE of diarrhea in this 
protocol is defined as having two or more watery/liquid stools in a day.  
In order to better characterize diarrhea and to distinguish similar events coding to the Medical 
Dictionary of Regulatory Activities (MedDRA) preferred term of diarrhea, subjects reporting 
diarrhea or similar events (eg, frequent bowel movements, loose bowels, etc.) will be asked 
whether they have had two or more watery/liquid stools in a day.  Subjects who respond “yes” to 
this question will be further asked how often, on average, since their last visit have they 
experienced two or more watery/liquid stools in a day.  Subjects who respond “no” to the 
question will not be asked any further questions. 
6.6.2. 
Vital Signs, Height and Weight 
Weight (to be measured in street clothes, no shoes) and vital signs, including temperature, pulse, 
respiratory rate, and seated blood pressure, will be taken during the visits indicated in Section 5. 
Height will be recorded at Visit 1 only.  
Vital signs will be obtained after the subject has been in a comfortable position for at least 
5 minutes.  
If body temperature is measured orally, 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 of the measurement. Investigators are to report any clinically significant 
abnormal findings as AEs. 
6.6.3. 
Complete Physical Examinations 
Complete physical examinations, including height (Visit 1 only), skin, nasal cavities, eyes, ears, 
lymph nodes, genitalia, and respiratory, cardiovascular, gastrointestinal, neurological, and 
musculoskeletal systems evaluations will be performed as indicated in Section 5. 


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6.6.4. 
Limited Physical Examinations 
Limited physical examinations will include evaluations to assess the subject’s BD.  If a subject 
presents with symptoms other than BD, the Investigator should determine whether a complete 
physical examination should be performed. 
6.6.5. 
Vasculitis Assessment 
The PDE4 inhibitors, including apremilast, have been shown to produce inflammatory 
perivascular histopathological changes in animal studies (eg, rodent toxicology studies).  The 
Investigator should be watchful for any signs and symptoms of vasculitis at all times.  Any 
suspicion of vasculitis must be thoroughly investigated by taking pertinent subject history, doing 
a physical examination, reviewing AEs, and performing diagnostic procedures as clinically 
indicated.  A subject with signs and symptoms of possible vasculitis should receive a thorough 
evaluation as described above, managed as medically appropriate, and continued with follow-up 
until the signs and symptoms of vasculitis have resolved. If vasculitis is assessed as being BD-
related, then the vasculitis should be reported on the BD activity pages in the eCRF. 
6.6.6. 
Psychiatric Evaluation 
During the study (post randomization), any subject who is identified by the Investigator (and/or 
appropriate site staff) as having a suicide attempt, or major psychiatric illness requiring 
hospitalization, must be immediately withdrawn from the study and referred for further medical 
and/or psychiatric care.  If a subject is discontinued, the subject should return for the 
Posttreatment Observational Follow-up Phase Visit.  
At any time during the study (post randomization), the Investigator (and/or appropriate site staff) 
should evaluate any subject who reports thoughts of suicide to determine if the subject truly has 
suicide ideation.  In such a case, the subject will be referred to a psychiatrist for evaluation and 
treatment as appropriate.  The subject may remain on IP until after the psychiatric evaluation, 
which should be completed within 3 weeks of the referral time.  If the psychiatrist deems the 
subject not to be a risk for suicide, the subject may remain in the study, but if a risk of suicide is 
confirmed, the subject must be discontinued from the study.  If the subject is discontinued, the 
subject should return for the Posttreatment Observational Follow-up Phase Visit. 
A copy of the psychiatric evaluation report must be in the subject’s source document, especially 
if the subject is confirmed not to be at risk for suicide and is continuing in the study. 
A Yes/No question should be completed in the eCRF as to whether the subject was sent for a 
psychiatric evaluation.  
6.6.7. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed as indicated in Section 5. 
A central laboratory will be used for this study. The Principal Investigator (PI) or medically-
qualified designee will review and assess all clinical laboratory results for each subject 
participating at their sites, and indicate whether the results are clinically significant. The 
laboratory reports should be initialed and dated by the PI or medically-qualified designee to 
indicate that they have been reviewed. Abnormal laboratory results may be repeated to rule out 
laboratory errors. Any clinically significant abnormal laboratory result that is not part of a 


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clinical diagnosis AE should be reported as a separate AE and should be followed to resolution 
(ie, stabilizes, returns to baseline, or improves and considered as no longer clinically significant). 
Additional clinical safety laboratory evaluations should be performed if judged clinically 
appropriate by the PI 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. 
6.6.7.1. 
Hematology 
As indicated in Section 5, hematology laboratory evaluations will include complete blood count 
(red blood cell [RBC] count, hemoglobin, hematocrit, white blood cell (WBC) count (absolute 
and differential), and platelet count. 
6.6.7.2. 
Serum Chemistry 
During Visits 1 and 2, serum chemistry laboratory evaluations will include sodium, potassium, 
chloride, bicarbonate, calcium, blood urea nitrogen (BUN), creatinine, glucose, albumin, total 
protein, alkaline phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum 
glutamic oxaloacetic transaminase (AST/SGOT), and alanine aminotransferase/serum glutamate 
pyruvic transaminase (ALT/SGPT). 
At subsequent visits, as indicated in Section 5, serum chemistry laboratory evaluations will 
include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, alkaline 
phosphatase, bilirubin (total and direct), AST/SGOT, and ALT/SGPT. 
6.6.7.3. 
Urinalysis 
Urinalysis will be done at Visit 1 (Screening Visit) and as clinically necessary; dipstick 
urinalysis (specific gravity, pH, glucose, protein, ketones, bilirubin, and hemoglobin/blood) will 
be performed. A microscopic urinalysis (epithelial cells, casts, RBCs, and WBCs) will be 
performed in the event of a positive dipstick result. 
6.6.7.4. 
Hepatitis Testing 
Screening tests for hepatitis B and C antigen or antibodies for study inclusion/exclusion purposes 
will not be performed. A complete medical history must be taken and must include a query to 
rule out whether a subject has known active current or history of recurrent infections including 
hepatitis B and C (see Exclusion #13).  Subjects must be asymptomatic and their liver function 
test (ie, ALT/SGPT, AST/SGOT, and alkaline phosphatase) levels must be ≤ 1.5 x upper limit of 
normal (ULN) at baseline.  
At any time post randomization, a subject’s liver function tests should be repeated when 
ALT/SGPT, AST/SGOT, or alkaline phosphatase levels are ≥ 2.0 x ULN.  A viral hepatitis panel 
should be performed together with the repeat liver function tests. A viral hepatitis panel includes 
total hepatitis A virus antibody (HAV Ab), qualitative hepatitis B surface antibody (HBsAb) and 
hepatitis B surface antigen (HBsAg) with reflex confirmation, hepatitis B core antibody 
(HBcAb), and hepatitis C virus antibody (HCV Ab). 


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6.6.8. 
Contraception Education 
The risks to a fetus or to a nursing child from apremilast are not known at this time.  Results of 
the animal and in vitro studies can be found in the Investigator’s Brochure. 
Contraception education is for males and females of childbearing potential (FCBP)1. The 
Investigator will educate all FCBP and males about the different options of contraceptive 
methods and their correct use at Visits 1 and 2. All males and FCBP must use one of the 
approved contraceptive options as described in Section 7.2, while on IP and for at least 28 days 
after administration of the last dose of the IP. 
When a female subject’s childbearing potential changes due to a change in contraceptive 
measures or her 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 and the correct and 
consistent use of effective contraceptive methods in order to successfully prevent pregnancy. 
6.6.9. 
Pregnancy Tests for Females of Childbearing Potential 
For all FCBP,1 pregnancy testing will be performed during the study as indicated in Section 5.  A 
serum pregnancy test with a sensitivity of ≤ 25 mIU/mL will be required at Visit 1, Visit 9, after 
the last dose of IP (eg, the ET Visit), and at the Observational Follow-up Visit, (4 weeks after the 
last dose of IP). In addition, a local urine pregnancy test kit will be provided by the central 
laboratory and the test performed on all FCBP subjects at Visit 2 (Baseline Visit; day of 
randomization) at the site, prior to randomization. A urine pregnancy test(s) should be 
administered if the FCBP subject misses a menstrual period. 
6.6.10. 
Chest Radiograph 
Subjects must have an essentially normal chest radiograph. Results must be within normal limits 
or not clinically significant in order to allow a subject to enroll in the study. 
A chest radiograph (posteroanterior [PA] and lateral views) should be taken prior to Visit 2, 
when most of the eligibility criteria are met, so that results are available prior to randomization.  
A PA view is required. An additional lateral view is strongly recommended, but not required. 
Alternatively, PA or PA/lateral radiographs that were taken within the 12 weeks prior to Visit 1 
will be accepted for evaluation for participation in the study.   
Additional chest radiographs should be performed as indicated by local treatment guidelines or, 
if guidelines are not available/applicable, chest radiographs should be performed when clinically 
indicated. 
6.6.11. 
12-lead ECG 
A 12-lead ECG will be performed during the Screening Phase. 
                                                     
1 A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24 
consecutive months). 


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An ECG will be performed after the subject has been supine for approximately 3 minutes.  Sites 
are to use their own, local ECG machines for the study and the ECG readings will be interpreted 
by the Investigator by clinically correlating with the subject’s condition.  
The Investigator’s interpretation will be recorded in the ECG eCRF as: normal; abnormal, not 
clinically significant; or abnormal, clinically significant.  
Results must be within normal limits or not clinically significant in order to allow a subject to 
continue in the study. 
6.7. 
Efficacy Assessments 
The following efficacy assessments will be performed as indicated in Section 5. 
6.7.1. 
Number of Oral and Genital Ulcers 
The number of oral and genital ulcers will be counted. For females, both vulvar and vaginal 
ulcers will be counted for genital ulcers.  
6.7.2. 
Pain VAS for Oral and Genital Ulcers 
Pain VAS scales (100 mm) for oral and genital ulcers (Appendix B) will be evaluated separately. 
These will be completed by the subject on a secure, validated hand-held device.  Subjects will be 
asked to click on a the VAS line at the point that represents the severity of their pain during the 
previous week, with zero (the left-hand end of the scale) representing no pain and 100 mm (the 
right-hand end of the scale) representing the worst possible pain.   
6.7.3. 
BD Current Activity Form 
The BD Current Activity Form (BDCAF) was developed for the International Scientific 
Committee on Behçet’s disease for routine monitoring of subjects, as well as for clinical studies 
(Lawton, 2004; Appendix C).  The questionnaire is administered to the subject by the 
Investigator (Investigator will complete the form on a secure, validated hand-held device), and 
disease manifestations over the previous 4 weeks are quantified on a 12-point scale, with a 
higher score indicating higher level of activity. As a validated instrument, the BDCAF was found 
to be a reliable instrument for the classic mucocutaneous and articular manifestations of BD, as 
well as, for general complaints and non-mucocutaneous manifestations of BD. 
6.7.4. 
Behçet’s Disease Quality of Life Measure 
The BD QoL questionnaire was developed to measure the influence of BD on a subject’s life 
(Gilworth, 2004; Appendix D).  It consists of 30 self-completed items that measure disease-
related restrictions on the subject’s activities and the subject’s emotional response to these 
restrictions. The BD QoL Measure will be completed by the subject on a secure, validated hand-
held device. 
6.7.5. 
Behçet’s Syndrome Activity Score 
The Behçet’s Syndrome Activity Score (BSAS) (Forbess, 2008; Appendix E) contains 10 
questions, including ones that assess the number of new oral and genital ulcers and skin lesions; 
assess gastrointestinal (GI), CNS, vascular, and ocular involvement; and evaluates the subject’s 


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current level of discomfort.  The item scores are totaled to create a score ranging from 0 to 100. 
The BSAS will be completed by the subject on a secure, validated hand-held device. 
6.7.7. 
Physician’s Global Assessment of Skin Lesions 
Physician’s global assessment (PGA) of BD related skin lesions (on skin lesions except 
oral/genital ulcers) will be completed by the Investigators as described in Appendix G. 
6.7.9. 
Assessment of Behçet’s Disease-related Inflammatory Eye Disease 
An ophthalmological examination should be completed during the Screening Phase, once the 
subject has met most of the eligibility criteria, after the chest radiograph and ECG but prior to 
randomization at Visit 2, to determine whether the subject has BD-related uveitis.  If a subject 
has BD-related uveitis and only requires corticosteroid eye drops to manage the uveitis, then the 
subject will be allowed to enroll into the study. A complete evaluation of the eyes, including a 
slit lamp examination, should be performed by an ophthalmologist as indicated in Section 5 and 
at any time when the subject is suspected of new onset or worsening of BD-related inflammatory 
eye disease, such as uveitis, retinitis, ophthalmitis and iritis. If a subject has a report from an 
ophthalmologist, dated within 12 weeks of Visit 2, stating that the subject does not have BD-
related ophthalmological symptoms, then the subject will not be required to have an 
ophthalmological examination during Screening Phase unless there is an eye-related complaint 
during the Screening Phase. 


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6.8. 
Investigational Product 
6.8.1. 
Study Medication Dispensing and Counting 
After the subject has satisfied all eligibility criteria, IP will be dispensed as specified by the 
interactive response technology (IRT). The tear-off label from each blister card should be pasted 
into the drug accountability document. Subjects must be instructed to return all previously issued 
empty blister cards and/or unused IP at the time of their next visit at the site. A detailed record of 
tablets issued and returned at each visit must be maintained in the subject’s record. 
6.8.2. 
Site Instructions for Dosing the Subject 
At each visit that new IP is dispensed, the site staff should make every effort to witness the 
subject taking the first dose from the new blister card and should record the date and time in the 
subject’s source record 
If the subject is seen in the late afternoon or evening, the subject should take the AM tablets at 
the site, and should skip the PM tablets on that date if it is less than 7 hours before the subject’s 
scheduled bed time. Taking the AM tablets will ensure that subjects who are randomized to an 
apremilast dose group will receive the active dose from the dose titration card. 
6.9. 
Investigational Product Discontinuation 
Investigational product discontinuation is defined as the date when the subject took his/her last 
dose of IP prior to withdrawal or early discontinuation from the study (prior to Week 64).  
The date of IP discontinuation should be entered into the IRT as the end of dosing. Sites are 
requested to make every effort to determine and record the last day of dosing. 
When IP is discontinued early, an Early Termination Visit (see Section 6.10) should be 
scheduled as soon as possible. The Observational Follow-up Visit (see Section 6.11) should also 
be scheduled 4 weeks (± 7 days) after the subject’s last dose of IP, regardless of the reason for IP 
discontinuation. 


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6.10. 
Early Termination Visit 
The Early Termination Visit is based on the subject’s withdrawal from any time during the study. 
In addition, the investigator may discontinue the subject from the study at any time based on 
his/her assessment of clinical efficacy and/or safety. The decision to discontinue a subject 
remains the responsibility of the treating physician, which will not be delayed or refused by the 
sponsor.  
When a subject withdraws or is discontinued from the study, every effort should be made to 
complete as many safety and efficacy assessments as reasonably appropriate. Please see the 
Table of Events, Section 5, for the assessments to be performed at the Early Termination Visit. 
The Observational Follow-up Visit (see Section 6.11) should also be scheduled 4 weeks (± 7 
days) after the subject’s last dose of IP, regardless of the reason for IP discontinuation. 
6.10.1. 
Observational Follow-up Visit 
The Observational Follow-up Visit should occur 4 weeks after the last dose of IP for subjects 
who Early Terminate or for those subjects who decide to not continue in the optional Open-label 
Extension phase. Subjects who complete the optional Open-label Extension phase do not need to 
complete the Observational Follow-up Visit.  
6.10.2. 
Lost to Follow-up 
Subjects will be considered lost to follow-up when they fail to attend study visits without stating 
an intention to withdraw from the study. The investigator should show due diligence by 
documenting in the source documents the steps taken to contact the subject through at least two 
telephone calls and/or emails and one registered letter. After all reasonable attempts have been 
made to contact the subject, the subject should be recorded as “lost to follow-up” in the eCRF. 
6.11. 
Study Completion 
Study completion for an individual subject who decides to not continue in the optional Open-
label Extension phase is defined as reaching Visit 15 (Observational Follow-up Visit), following 
the completion of active treatment phase.  
Study completion for an individual subject who enters the optional Open-label Extension phase, 
is defined as completion of the optional Open-label Extension Phase.  
Subjects who do not meet these definitions are considered under Section 6.10, Early 
Terminations. All subjects who early terminate the study are to enter the Posttreatment 
Observational Follow-up Phase (Visit 15) approximately 4 weeks after the last dose of IP was 
taken. 
 


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7. 
STUDY POPULATION 
7.1. 
Number of Subjects and Sites 
Approximately 204 subjects with BD will be enrolled with 1:1 randomization for approximately 
102 subjects in the APR 30 BID treatment group and 102 subjects in the placebo treatment 
group. Approximately 45 sites will be included in this study. This study will include sites in 
different regions including North America, Europe and Asia.  
7.2. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
General Patient Population: 
1. Understand and voluntarily sign an informed consent document prior to any study related 
assessments/procedures being conducted. 
1. Male and female subjects 18 years of age at the time of signing the informed consent 
document. 
2. Able to adhere to the study visit schedule and other protocol requirements. 
Disease Specific Parameters: 
3. Diagnosed with Behçet’s disease meeting the International Study Group (ISG) criteria 
(Appendix K). 
4. Oral ulcers that occurred at least 3 times in the previous 12-month period, including oral 
ulcers at the Screening Visit. 
5. Subjects must have at least 2 oral ulcers at Visit 1 (Screening Visit), and: 
a) at least 2 oral ulcers at Visit 2 (day of randomization), when Visit 2 occurs at 
least 14 days after Visit 1, 
OR 
b) at least 3 oral ulcers at Visit 2 (day of randomization), when Visit 2 occurs at 
any time between 1 day and 42 days after Visit 1. 
6. Have prior treatment with at least 1 non-biologic BD therapy, such as, but not limited to, 
topical corticosteroids, or systemic treatment. 
7. Candidate for systemic therapy, for the treatment of oral ulcers.  
a. A candidate for systemic therapy is a subject judged by the study Investigator as 
someone whose mucocutaneous ulcers are considered inappropriate for topical 
therapy based on the severity of disease and extent of the affected area, or whose 
oral ulcers cannot be adequately controlled by topical therapy. 
8. Laboratory Measures: Must meet the following laboratory measures: 
• Hemoglobin > 9 g/dL 


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• White blood cell (WBC) count ≥ 3000 /L (≥ 3.0 X 109/L) and  
 14,000/L ( 14 X 109/L) 
• Platelet count ≥ 100,000 /L (≥ 100 X 109/L)  
• Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L) 
• Total bilirubin  2.0 mg/dL 
• Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) and 
alanine transaminase (ALT [serum glutamate pyruvic transaminase, SGPT])  1.5 X 
ULN. Subjects who fail screening due to ≥ 1.5 X ULN AST/SGOT and/or 
ALT/SGPT will be allowed to repeat AST/SGOT and/or ALT/SGPT tests within the 
Screening Phase. Repeat test results should be ≤ ULN (within reference range) to be 
eligible. 
Laboratory tests will be allowed to be repeated 1 time if, in the Investigator’s clinical 
judgment, there is a reasonable possibility of the repeat tests not meeting the exclusion 
values, and with concurrence from the Medical Monitor. 
9. Contraception Requirements: 
All FCBP2 must use one of the approved contraceptive options as described below while 
taking apremilast and for at least 28 days after administration of the last dose of the 
apremilast.   
At the time of study entry, and at any time during the study when a FCBP’s contraceptive 
measures or ability to become pregnant changes, the Investigator will educate the subject 
regarding contraception options and the correct and consistent use of effective 
contraceptive methods in order to successfully prevent pregnancy. 
All FCBP must have a negative pregnancy test at Visits 1 and 2.  All FCBP subjects who 
engage in activity in which conception is possible must use one of the approved 
contraceptive options described below: 
Option 1:  Any one of the following highly effective methods:  hormonal contraception 
(oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal 
ligation; or partner’s vasectomy; 
OR 
Option 2:  Male or female condom (latex condom or non-latex condom NOT made out 
of natural [animal] membrane [for example, polyurethane]); PLUS one additional barrier 
method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or 
(c) contraceptive sponge with spermicide. 
Male subjects (including those who have had a vasectomy) who engage in activity in 
which conception is possible must use barrier contraception (latex or non-latex condoms 
                                                     
2 A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24 
consecutive months). 


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NOT made out of natural [animal] membrane [for example, polyurethane]) while on IP 
and for at least 28 days after the last dose of IP. 
7.3. 
Exclusion Criteria 
The presence of any of the following will exclude a subject from the study enrollment: 
Disease Specific Exclusions: 
1. Behçet’s disease-related active major organ involvement – pulmonary (eg, pulmonary 
artery aneurysm), vascular (eg, thrombophlebitis), gastrointestinal (eg, ulcers along the 
gastrointestinal tract), and central nervous systems (eg, meningoencephalitis) 
manifestations, and ocular lesions (eg, uveitis) requiring immunosuppressive therapy; 
however: 
• Previous major organ involvement is allowed if it occurred at least 1 year prior to 
Visit 1 (Screening Visit) and is not active at time of enrollment.  
• Subjects with mild BD-related ocular lesions not requiring systemic 
immunosuppressive therapy are allowed. 
• Subjects with BD-related arthritis and BD-skin manifestations are also allowed. 
Previous and Current Medications: 
2. Previous exposure to biologic therapies for the treatment of BD oral ulcers 
• Previous biologic therapy exposure is allowed for other indications, including 
other manifestations of BD 
3. Prior use of apremilast. 
4. Use of any investigational medication within 4 weeks prior to Visit 2 or  
5 pharmacokinetic/pharmacodynamic half-lives (whichever is longer). 
5. Current use of strong cytochrome P450 enzyme inducers (eg, rifampin, phenobarbital, 
carbamazepine, phenytoin)  
6. Having received concomitant immune modulating therapy (except oral or topical 
corticosteroids) within: 
• Seven days prior to Visit 2 (Baseline Visit; day of randomization) for colchicine 
• Ten days prior to Visit 2 (Baseline Visit; day of randomization) for azathioprine 
and mycophenolate mofetil  
• Four weeks (28 days) prior to Visit 2 (Baseline Visit; day of randomization) for 
cyclosporine, methotrexate, cyclophosphamide, thalidomide, and dapsone 
Note: Oral and topical corticosteroids must have been tapered as appropriate 
and discontinued prior to the day of Visit 2 (day of randomization). 
• At least 5 terminal half-lives for all biologics, including, but not limited to, those 
listed below; within: 
− Four weeks prior to Visit 2 (Baseline Visit; day of randomization) for etanercept 


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− Eight weeks prior to Visit 2 (Baseline Visit; day of randomization) for infliximab 
− Ten weeks prior to Visit 2 (Baseline Visit; day of randomization) for adalimumab, 
golimumab, certolizumab, abatacept, and tocilizumab 
− Six months prior to Visit 2 (Baseline Visit; day of randomization) for 
secukinumab 
7. Having received intra-articular or parenteral corticosteroids within 6 weeks (42 days) 
prior to Visit 2 (Baseline Visit; day of randomization). 
General Health: 
8. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study. 
9. Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study. 
10. Inability to provide voluntary consent.  
11. Pregnant women or breast feeding mothers. 
12. Systemic or opportunistic fungal infection. 
13. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or 
other infections (including but not limited to tuberculosis and atypical mycobacterial 
disease, hepatitis B and C and herpes zoster, histoplasmosis, coccidiomycosis, but 
excluding onychomycosis) or any major episode of infection requiring hospitalization or 
treatment with IV or oral antibiotics within 4 weeks of the Screening Phase. 
14. Clinically significant abnormality on chest radiograph. 
15. Clinically significant abnormality on 12-lead ECG. 
16. History of positive test for, or any clinical suspicion of, human immunodeficiency virus 
(HIV), or congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency disease). 
17. Malignancy or history of malignancy, except for: 
• treated (ie, cured) basal cell or squamous cell in situ skin carcinomas; 
• treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in situ of 
the cervix with no evidence of recurrence within the previous 5 years of Visit 1. 
18. Any condition that confounds the ability to interpret data from the study. 
19. Scheduled surgery or other interventions that would interrupt the subject’s participation 
in the study. 
20. Prior history of suicide attempt at any time in the subject’s lifetime prior to Visit 2 
(Baseline Visit; day of randomization) or major psychiatric illness requiring 
hospitalization within 3 years prior to Visit 2 (Baseline Visit; day of randomization). 
 


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8. 
DESCRIPTION OF STUDY TREATMENTS 
8.1. 
Description of Investigational Product 
The chemical name of apremilast (CC-10004) is N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl) ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl] acetamide. 
Apremilast is supplied for oral administration in tablets containing 10, 20, and 30 mg active 
ingredient. 
8.2. 
Description of Placebo 
Placebo tablets will be provided as identically appearing apremilast 10, 20, or 30 mg tablets. 
8.3. 
Treatment Administration and Schedule 
Beginning at Visit 2 (Baseline Visit; ie, at randomization day), APR 30 BID or placebo BID will 
be taken orally, approximately 12 hours apart, without respect to food or drink. To mitigate 
potential GI side effects dose titration will be implemented in the first week of this study 
(Table 4).  For dose titration, 10 mg, 20 mg and 30 mg apremilast tablets, or identically-
appearing placebo tablets, will be dispensed in dose titration cards at Week 0. IP will be 
dispensed as indicated in Section 5. 
• Weeks 0 to 12: Double-blind, Placebo-controlled Treatment Phase: APR 30 BID or 
placebo BID  
o Week 0 to 1: subjects will be dose titrated as described above 
• Weeks 12 to 64: Active Treatment Phase: APR 30 BID  
• After Week 64: Optional Open-label Extension Phase: APR 30 BID 
During Weeks 12 to 64, the IP will remain blinded, to prevent study personnel and subjects from 
knowing the IP assignment in the Placebo-controlled Treatment Phase. To maintain the blind 
regarding the initial treatment assignment, all subjects will receive dose titration cards at Visit 9 
(Table 5). Although only subjects initially randomized to placebo will be dose titrated during 
their first week of the Active Treatment Phase, all subjects entering the active treatment phase 
will receive identically-appearing titration/treatment cards. 
Any dose modifications outside of those described above are not permissible in this study. 
 
 


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Table 4: 
Treatment Schema for Dose Titration at Visit 2 
 
Week 0 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6-7 
 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
APR 30 
BID 
10mg A 
20mg P 
30mg P 
10mg P 
20mg P 
30mg P 
10mg A 
20mg P 
30mg P 
10mg A 
20mg P 
30mg P 
10mg A 
20mg P 
30mg P 
10mg P 
20mg A 
30mg P 
 
20mg A 
30mg P 
 
20mg A 
30mg P 
 
20mg A 
30mg P 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
Placebo 
10mg P 
20mg P 
30mg P 
10mg P 
20mg P 
30mg P 
10mg P 
20mg P 
30mg P 
10mg P 
20mg P 
30mg P 
10mg P 
20mg P 
30mg P 
10mg P 
20mg P 
30mg P 
 
20mg P 
30mg P 
 
20mg P 
30mg P 
 
20mg P 
30mg P 
 
20mg P 
30mg P 
 
20mg P 
30mg P 
 
20mg P 
30mg P 
A=Apremilast; BID= twice daily; P= Placebo. 
 
Table 5: 
Treatment Schema for Dose Titration at Visit 9 
 
Week 12 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6-7 
 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
APR 30 
BID 
10mg P 
20mg P 
30mg A 
10mg P 
20mg P 
30mg A 
10mg P 
20mg P 
30mg A 
10mg P 
20mg P 
30mg A 
10mg P 
20mg P 
30mg A 
10mg P 
20mg P 
30mg A 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
Placebo 
to APR 
30 BID 
10mg A 
20mg P 
30mg P 
10mg P 
20mg P 
30mg P 
10mg A 
20mg P 
30mg P 
10mg A 
20mg P 
30mg P 
10mg A 
20mg P 
30mg P 
10mg P 
20mg A 
30mg P 
 
20mg A 
30mg P 
 
20mg A 
30mg P 
 
20mg A 
30mg P 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
 
20mg P 
30mg A 
A=Apremilast; BID= twice daily; P= Placebo. 
 


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8.3.1. 
Dose Modification or Interruption 
Dose interruptions are not permitted except for safety reasons.  If a subject misses 4 or more 
consecutive days of dosing, Celgene should be contacted for further instructions. 
8.3.2. 
Overdose 
Overdose for this protocol, on a per dose basis, is defined as ingestion of 4 or more APR 30 BID 
(or matching placebo) tablets in any 24 hour period whether by accident or intentionally. On a 
schedule or frequency basis, an overdose is defined as complete dosing more than 4 times during 
any 24 hour period. 
Adverse events associated with an overdose must be collected on the AE page of the eCRF for 
all overdosed subjects, but the overdose itself is not considered an AE. Other required or optional 
non-study 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. 
8.4. 
Method of Treatment Assignment 
8.4.1. 
Placebo-controlled Treatment Phase (12 Weeks) 
At Visit 2, subjects who meet entry criteria will be randomized using a permuted block 
randomization in parallel 1:1 to receive either APR 30 BID or placebo, using a centralized 
IRT.  Eligible subjects will be stratified according to gender, history of uveitis, and region (Japan 
and Other). The detailed information is documented in the IRT (IVRS) System Requirements 
document.  
Designated research personnel at the investigational sites will be assigned password protected, 
coded identification numbers, which give them authorization to enter the IRT to randomize 
subjects.  The system will present a menu of questions by which the research center personnel 
will identify the subject and confirm eligibility.  When all questions have been answered, the 
IRT will assign a randomization identification number.  Confirmation of the randomization will 
be sent to the investigational site, Celgene, and/or its representative. 
During the study visits, the pharmacy or authorized study personnel at the investigational site 
will dispense coded IP kits in accordance with the randomization number assigned by the IRT. 
8.4.2. 
Active Treatment Phase (52 Weeks) 
All subjects who complete the Placebo-controlled Treatment Phase will be eligible to enter the 
Active Treatment Phase.  
8.4.3. 
Optional Open-label Extension Phase  
All subjects who complete Visit 14 will be eligible to enter the optional Open-label Extension 
Phase.  


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8.5. 
Packaging and Labeling 
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations. 
8.6. 
Investigational Product Accountability and Disposal  
8.6.1. 
Investigational Product Accountability 
The Investigator(s) or designee(s) is responsible for accounting for all IP that is issued to and 
returned by the subject during the course of the study. 
The Investigator(s) or designee(s) is responsible for taking an inventory of each shipment of IP 
received, and comparing it with the accompanying IP accountability form.  The Investigator(s) or 
designee(s) will verify the accuracy of the information on the form, sign and date it, retain a copy 
in the study file, and return a copy to Celgene. 
At the study site, all IP will be stored in a locked, safe area to prevent unauthorized access. 
The IP should be stored as directed on the package label. 
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for IP return, disposal, and/or destruction including responsibilities for the site versus Celgene 
(or designee).  
8.6.2. 
Record of Administration 
Accurate recording of all IP administration (including dispensing and dosing) will be made in the 
appropriate section of the subject’s eCRF and source documents. 
8.7. 
Investigational Product Compliance 
Study personnel will review the instructions printed on the package with the study subjects prior 
to dispensing the IP.  New IP will be dispensed as indicated in Section 5.  The subjects will be 
instructed to return the IP blister cards, including any unused IP, to the study site at each visit for 
pill counts and reconciliation.  Subjects will be asked whether they have taken their IP as 
instructed at each study visit. Any problems with IP compliance will be reviewed with the 
subject.  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.  Compliance 
is defined as taking between 75% and 120% of dispensed IP.  This definition of compliance is 
only for the purpose of study analysis, not study conduct. 
 


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9. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
9.1. 
Permitted Concomitant Medications and Procedures 
The following medications will be permitted: 
• Corticosteroid eye drops for BD-related or other ocular diseases are allowed at any 
time during this study. 
• Oral/topical analgesics (lidocaine gel), chlorhexidine, used according to product 
prescribing information, will be allowed throughout the study except for 24 hours 
prior to clinic visits to avoid interference with the pain assessments of oral or genital 
ulcers. 
• Use of topical corticosteroids for ulcers and skin disease will be allowed until the day 
of randomization AND/OR after the Week 12 visit (Visit 9) and assessments for any 
non-responders  
− Non-responders: subjects who fail to achieve at least a partial response ( 50% 
improvement [reduction] in the number of oral ulcers from baseline). 
• Use of colchicine will be allowed at any time after the Week 12 visit (Visit 9) and 
assessments for any non-responders (subjects who fail to achieve at least a partial 
response in the number of oral ulcers) or for any subjects who experience a worsening 
of BD (eg, arthritis, skin disease, uveitis, etc). 
• Chronic medication should be dosed on a stable regimen. For medications restricted 
by the protocol, see Section 7.3. For details about prohibited medications, see Section 
9.2. 
• Subjects may take any medication that is not restricted by the protocol or that does 
not confound the efficacy and safety assessments in the study. All medications 
(prescription and non-prescription), treatments, and therapies taken from Visit 1 
through the last visit, including the Posttreatment Observational Follow-up Phase 
Visit, must be recorded on the appropriate page of the eCRF. The dose, unit, 
frequency, route, indication, the date the medication was started, and the date the 
medication was stopped (if not ongoing) must be recorded. 
9.2. 
Prohibited Concomitant Medications and Procedures 
The following medications are prohibited. 
• Topical corticosteroids will be prohibited for ulcers and skin disease during the first 
12 week Placebo-controlled Treatment Phase of the study (through Visit 9). 
• Use of colchicine will be prohibited during the 12-week Placebo-controlled 
Treatment Phase of the trial (through Visit 9).  
• Systemic therapy, other than colchicine, including, but not limited to, systemic 
corticosteroids (including low doses), cyclosporine, methotrexate, cyclophosphamide, 
hydroxychloroquine, thalidomide, dapsone, azathioprine, and mycophenolate mofetil 
are prohibited for the Treatment Phases of the study. 


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• Biologic agents, including, but not limited to, adalimumab, infliximab, etanercept, 
and rituximab are prohibited for the Treatment Phases of the study. 
9.3. 
Required Concomitant Medications and Procedures 
Subjects must agree to maintain the same stable dose of background medication (or lack of 
medication) prior to Visit 2 (day of randomization) as described in the background medication 
inclusion criterion (see Section 7.2), except for a safety reason (eg, AEs). 
All required procedures for this study are described in Section 6. 
 


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10. 
STATISTICAL ANALYSES 
10.1. 
Overview 
This is a 12-week placebo-controlled study, followed by a 52-week Active Treatment Phase and 
optional Open-label Extension Phase, to evaluate the efficacy and safety of apremilast (CC-
10004) in the treatment of Behçet’s disease. The primary efficacy endpoint, AUC from baseline 
through Week 12 for the number of oral ulcers, will be assessed and the APR 30 BID group will 
be compared to the placebo group.  
A Statistical Analysis Plan (SAP), which includes detailed list of analyses, will be written based 
on this Statistical Analyses section. 
10.2. 
Study Population Definitions 
The safety population will include all randomized subjects who received at least one dose of IP.  
The analysis of safety data in this study will be based on the safety population and subjects will 
be included in the treatment group they actually received. 
The intent-to-treat (ITT) population will be defined as all randomized subjects who received at 
least one dose of IP. This ITT population will be used for the primary efficacy analysis. Subjects 
will be included in the treatment group to which they are randomized. 
The per protocol (PP) population will include all randomized subjects who received at least one 
dose of IP, have a baseline and at least one postbaseline oral ulcer evaluation, and have no 
important protocol violations during the 12-week Placebo-controlled Treatment Phase.  The final 
determination of important protocol violation criteria will be made prior to the unblinding of the 
database and will be documented separately.  
10.3. 
Sample Size and Power Considerations 
The sample size estimation is based on the consideration from the results of the Phase 2 study 
CC-10004-BCT-001. A two-sided t-test at a 0.05 significance level will have 90% power to 
detect a treatment difference of 66 in the AUC of oral ulcer counts from Day 1 through Week 12 
(AUC of placebo – drug = 66), the primary efficacy endpoint, when the sample size in each 
group is 102, assuming a common standard deviation of 144.  
10.4. 
Background and Demographic Characteristics 
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data will be summarized using frequency tabulations by system 
organ class and preferred term.  
10.5. 
Subject Disposition 
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percentage for placebo-
controlled, active treatment and follow-up phases.  Subject disposition for the optional Open-


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label Extension Phase will be reported separately. A summary of subjects enrolled by site will be 
provided. Protocol deviations will be summarized using frequency tabulations. 
10.6. 
Efficacy Analysis 
All efficacy analyses will be performed using the ITT population. In addition, analysis using the 
PP population will be provided for the primary efficacy endpoint.  
Efficacy results will be considered statistically significant after consideration of the control of 
multiplicity, as specified in Section 10.6.1.1.  All statistical tests will be conducted at the 
α = 0.05 (2-sided) level, and 2-sided p-values and CIs will be reported. 
10.6.1. 
Efficacy Evaluation for the Double-blind, Placebo-controlled Treatment Phase 
10.6.1.1. Multiplicity 
Statistical tests for comparing the APR 30 BID and placebo groups will be conducted for the 
primary endpoint and other efficacy endpoints as listed in Section 3. 
The multiplicity of the analyses of the primary and other efficacy endpoints will be adjusted 
using a Gate-Keeping Procedure. This procedure will preserve the Family Wise Error Rate of the 
multiple analyses. The analyses will be performed in sequence until one of the analyses has 
failed to show the significant difference or all analyses have been completed at a significance 
level of 0.05. The sequence of the analyses for the other efficacy endpoints will be specified in 
the statistical analysis plan (SAP).  
10.6.1.2. Primary Analysis for Primary Efficacy Endpoint 
The primary efficacy endpoint is the AUC for the number of oral ulcers from Day 1 through 
Week 12. It will be compared between the placebo and APR 30 BID groups using an analysis of 
covariance (ANCOVA) model with the AUC as the response variable, the treatment, gender and 
region as factors, and the number of oral ulcers at baseline as a covariate. Multiple imputation 
method will be used to impute missing oral ulcer counts when the AUC is derived. 
Sensitivity analyses including missing data imputations conducted for the primary efficacy 
endpoint to assess the robustness of the primary analysis will be detailed in the SAP. 
10.6.1.3. Analysis for Secondary Efficacy and Exploratory Endpoints 
Secondary efficacy endpoints and exploratory endpoints will be summarized and analyzed 
similarly to that described for the primary efficacy endpoint. For continuous endpoints, such as 
change from baseline in the pain VAS, descriptive statistics (N, mean, median, standard 
deviation, quartiles, minimum and maximum) will be provided by treatment group at specified 
visits per study phase. The endpoints at Week 12 will also be compared between the placebo and 
APR 30 BID groups using a similar ANCOVA model as described in Section 10.6.1.2. 
Frequency count and percentage will be provided for categorical variables such as ulcer 
responders. The proportions of subjects who achieve a response at Week 12 between the APR 30 
BID and placebo groups will be compared using the Cochran-Mantel-Haenszel (CMH) test at the 
0.05 level, controlling for stratification factors as specified in the SAP, using the ITT population. 


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Subjects who have discontinued early prior to Week 12, or who do not have data at Week 12, 
will be regarded as non-responders at Week 12. 
10.6.2. 
Efficacy Evaluation for the Active Treatment Phase 
For continuous endpoints, descriptive statistics (N, mean, median, standard deviation, quartiles, 
minimum and maximum) will be provided by treatment group at specified visits per study phase. 
Frequency count and percentage will be provided for categorical variables.  
The detailed analysis methods for each efficacy endpoint will be specified in the SAP. 
10.7. 
Safety Analysis 
The safety analyses will be performed using the Safety population as defined in Section 10.2. 
Safety will be assessed by clinical review of all relevant parameters including AEs, AEs of 
special interest (ie, diarrhea), laboratory tests, and vital signs; no inferential testing for statistical 
significance will be performed. 
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system.  All TEAEs will be summarized by system organ class, 
preferred term, severity and relationship to IP.  Adverse events leading to death or to 
discontinuation from treatment and SAEs will also be tabulated.  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 by visit descriptively.  In addition, shift tables showing the 
number of subjects with values low, normal, high compared to the normal ranges pretreatment 
versus posttreatment, together with the number determined to be clinically significant, will be 
provided. 
Vital sign measurements, including weight, will be summarized by visit descriptively.   
To account for the different exposure to the IP, AEs or marked laboratory abnormalities will also 
be summarized using the exposure adjusted incidence rate. 
Safety data collected during the optional Open-Label Extension Phase will be listed. 
The detailed safety analyses will be specified in the SAP. 
10.8. 
Interim Analysis 
None is planned. 
10.9. 
Other Topics 


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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.  
Worsening of a subject’s BD (any manifestation) should be considered as worsening of disease 
under study, and should not be captured as an AE, unless the event meets the definition of an 
SAE. Worsening of disease will be reported on the BD activity pages that lists each of the BD 
manifestations in the eCRF, and not captured in the AE eCRF. See 
 for more 
details.  
Worsening of a subject’s BD will be captured on the AE eCRF for subjects who continue in the 
optional Open-label Extension Phase after Week 64. Abuse, withdrawal, sensitivity or toxicity to 
an investigational product should be reported as an AE.  Overdose, accidental or intentional, 
whether or not it is associated with an AE should be reported on the overdose eCRF (see Section 
8.3.2 for the definition of overdose). Any sequela of an accidental or intentional overdose of an 
investigational product should be reported as an AE on the AE eCRF.  If the sequela of an 
overdose is an SAE, then the sequela must be reported on an SAE report form and on the AE 
eCRF.  The overdose resulting in the SAE should be identified as the cause of the event on the 
SAE report form and in the eCRF but should not be reported as an SAE itself. 
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for apremilast overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician. 
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures. 
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP and those SAEs made known to the investigator at any time 
thereafter that are suspected of being related to IP.  All AEs and SAEs will be recorded on the 
AE page of the CRF 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.   
11.1.1. 
Monitoring, Recording and Reporting AEs of Diarrhea 
The PDE4 inhibitors, including apremilast, have been associated with AE reports of diarrhea.  To 
better characterize and understand all reported AEs of diarrhea, further information will be 


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collected on a separate eCRF page. Please refer to Section 6.6.1.1 for further details on how to 
record such AEs. 
11.2. 
Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to:  
11.2.1. 
Seriousness  
A serious adverse event (SAE) is any AE occurring at any dose that: 
• Results in death; 
• Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE); 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
• Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions); 
• Is a congenital anomaly/birth defect; 
• Constitutes an important medical event. 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
Events not considered to be SAEs are hospitalizations for: 
• A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE.  
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• 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 CRF.  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. 


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If an AE is considered serious, the AE 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 IP, action taken regarding IP, and outcome. 
11.2.2. 
Severity / Intensity 
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event.  The 
following grading scale should be used to evaluate severity/intensity. 
Mild  
• Asymptomatic or mild symptoms; clinical or diagnostic observations only 
• Intervention not indicated 
• Activities of daily life (ADL) minimally or not affected 
• No or minimal intervention/therapy may be required  
Moderate  
• Symptom(s) cause moderate discomfort 
• Local or noninvasive intervention indicated 
• More than minimal interference with ADL but able to carry out daily social and 
functional activities. 
• Drug therapy may be required 
Severe (could be non-serious or serious)  
• Symptoms causing severe discomfort/pain 
• Symptoms requiring medical/surgical attention/intervention 
• Interference with ADL 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 IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 


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Not suspected: 
Means a causal relationship of the adverse event to IP 
administration is unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event. 
Suspected: 
Means there is a reasonable possibility that the administration 
of IP caused the adverse event.  ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the IP 
and the adverse event. 
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available. 
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by 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.  
The AE of diarrhea can be continuous or intermittent. For intermittent diarrhea, please capture 
the start and stop date for each episode of intermittent diarrhea in the eCRF. 
11.2.5. 
Action Taken 
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event.  
11.2.6. 
Outcome 
The Investigator will report the outcome of the event for both AEs and SAEs. 
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).  
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 IP dose, or any other therapeutic 
intervention; or 
• is judged to be of significant clinical importance. 


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Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.   
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  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 
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events. 
11.4.1. 
Females of Childbearing Potential 
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 IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events.  Investigational product 
is to be discontinued immediately and the subject instructed to return any unused portion of the 
IP to the Investigator.  The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to 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 will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form. 
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to 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 that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to 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 IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately.   


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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 CRF.  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 IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) or any 
SAE made known to the Investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the Informed Consent 
Form) 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 Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with 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 phone. 
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 (EEA), 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 
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• Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR). 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• In Japan, measures taken in foreign countries to ensure subject safety, study reports 
that indicate potential risk of cancer, etc., or annual SAE reports according to the 
local regulations. 
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects. 
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC (see Section 15.3 for record retention 
information). 
Celgene Drug Safety Contact Information: 
For Celgene Drug Safety 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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12. 
DISCONTINUATIONS 
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study: 
• Adverse event 
• Lack of efficacy  
• Non-compliance with IP 
• Withdrawal by subject 
• Death 
• Lost to follow-up 
• Protocol violation 
• Other 
The reason for discontinuation should be recorded in the eCRF and in the source documents. 
The decision to discontinue a subject 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 the 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 the 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 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 
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be discontinued if, in the opinion of the 
investigator, continuing IP can negatively affect the outcome of the subject’s treatment.  The 
subject must be withdrawn from the study once the treatment code for the subject has been 
unblinded. 
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor.  However, the investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject.  
The investigator should ensure that the code is broken only in accordance with the protocol.  The 
investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the investigator in the 
subject’s source documentation. 
Emergency unblinding should only be performed by the investigator through the IRT by using an 
emergency unblinding personal identification number (PIN), and the investigator should call the 
IRT for unblinding for the treatment group: APR 30 BID or placebo. 
 


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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 Harmonization (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 CRFs 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. 
Subject Information and Informed Consent 
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures. 
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original informed consent document signed and dated by the study 
subject and by the person consenting the study subject prior to the study subject’s entry into the 
study, must be maintained in the Investigator’s study files and a copy given to the study subject.  
In addition, if a protocol is amended and it impacts on the content of the informed consent, the 
informed consent document must be revised.  Study subjects participating in the study when the 
amended protocol is implemented must be re-consented with the revised version of the informed 
consent document.  The revised informed consent document signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.   
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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Investigational product 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 adverse events as soon as possible;  
• Periodic reports on the progress of the study; 
• Deviations from the protocol or anything that may involve added risk to subjects. 
14.8. 
Closure 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; 


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• 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 CRFs or CD-ROM. 
15.2. 
Data Management 
Data will be collected via eCRF, and a secure, validated hand-held device at the site, and entered 
into the clinical database. 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 the IP. The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer. Essential documents include, but are not limited to, the following: 
• Signed 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; 
• IP accountability records; 
• Record of any body fluids or tissue samples retained; 
• All other source documents (subject records, hospital records, laboratory records, 
etc.); 


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• All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial). 
The Investigator must notify 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, site’s secure, validated hand-held device, 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 standard operating procedures (SOPs) to evaluate 
compliance with Good Clinical Practice guidelines and regulations. 
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, US 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 
The results of this study may be published in a medical publication, journal, or may be used for 
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.  Selection of first authorship 
will be based on several considerations, including, but not limited to study participation, 
contribution to the protocol development, and analysis and input into the manuscript, related 
abstracts, and presentations in a study. 
 


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18. 
REFERENCES 
Ahmed MB, Houman H, Miled M, Dellagi K, Louzir H. Involvement of chemokines and Th1 
cytokines in the pathogenesis of mucocutaneous lesions of Behçet’s disease. Arthritis Rheum 
2004;50(7):2291-5. 
Aktulga E, Altaç M, Müftuoglu A, Özyazgan Y, Pazarli H, Tüzün Y, et al. A double blind study 
of colchicine in Behçet’s disease. Haematologica 1980;65(3):399–402. 
Alpsoy E, Zouboulis CC, Ehrlich GE. Mucocutaneous lesions of Behçet's disease. Yonsei Med J 
2007;48(4):573-85. 
Atmaca L, Boyvat A, Yalçindağ FN, Atmaca-Sonmez P, Gurler A. Behçet disease in children. 
Ocul Immunol Inflamm 2011;19(2):103-7. 
Bang D, Hur W, Lee ES, Lee S. Prognosis and clinical relevance of recurrent oral ulceration in 
Behçet’s disease. J Dermatol 1995;22(12):926-9. 
Cho SB, Cho S, Bang D. New insights in the clinical understanding of Behçet's disease. Yonsei 
Med J 2012;53(1):35-42. 
Colchicine [summary of product characteristics]. Wrexham, UK: Wockhardt UK Ltd; 2010. 
Available from: http://www.medicines.org.uk/emc/medicine/21325/SPC. 
Davatchi F, Shahram F, Chams-Davatchi C, Shams H, Nadji A, Akhlaghi M, et al. Behçet’s 
disease: from east to west. Clin Rheumatol 2010 29(8):823-33. 
Direskeneli H, Fujita H, Akdis CA. Regulation of TH17 and regulatory T cells in patients with 
Behçet’s disease. J Allergy Clin Immunol 2011;128(3):665-6. 
Evereklioglu C, Er H, Türköz Y, Cekmen M. Serum levels of TNF-alpha, sIL-2R, IL-6, and IL-8 
are increased and associated with elevated lipid peroxidation in patients with Behçet’s disease. 
Mediators Inflamm 2002;11(2): 87-93. 
Forbess C, Swearingen C, Yazici Y.  Behçet’s syndrome activity score (BSAS):  a new disease 
activity assessment tool, composed of patient-derived measures only, is strongly correlated with 
the Behçet’s disease current activity form (BDCAF).  Presented at the Annual European 
Congress of Rheumatology, Paris, 11-14 Jun 2008; Abstract D 14. 
Frassanito MA, Dammacco R, Cafforio P, Dammacco F. Th1 polarization of the immune 
response in Behçet’s disease: a putative pathogenetic role of interleukin-12. Arthritis Rheum 
1999;42(9):1967-74. 
Fresko I, Yazici H. Treatment strategies for Behçet’s disease. Expert Opin Pharmacother 
2008;9(18):3211-9. 
Gilworth G, Chamberlain MA, Bhakta B, Haskard D, Silman A, Tennant A.  Development of the 
DB-QoL; a quality of life measure specific to Behçet’s disease.  J Rheumatol 2004;31:931-7. 
Gonzalez-Moles MA. The use of topical corticoids in oral pathology. Med Oral Patol Oral Cir 
Bucal 2010;15(6):e827-31. 
Hamzaoui K, Hamza M, Ayed K. Production of TNF-alpha and IL-1 in active Behçet 's disease. 
J Rheumatol 1990;17(10):1428-9. 


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Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza M, Ayed K. Cytokine profile in 
Behçet's disease patients. Relationship with disease activity. Scand J Rheumatol 2002;31(4):205-
10. 
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. 
Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gul A, et al. EULAR 
recommendations for the management of Behçet disease. Ann Rheum Dis 2008;67(12):1656-62. 
International Study Group for Behçet’s Disease. Criteria for diagnosis of Behçet’s 
disease.  Lancet 1990;335(8697):1078-80. 
Kerkeni N, Zaraa I, Ayachi J, El Euch D, Mokni M, Osman AB. Behçet’s disease: a profile of 
mucocutaneous features. Acta Dermatovenerol Alp Pannonica Adriat 2010;19(2):11-5. 
Koné-Paut I, Yurdakul S, Bahabri SA, Shafae N, Ozen S, Özdogen H, et al. Clinical features of 
Behçet's disease in children: an international collaborative study of 86 cases. J Pediatr 
1998;132(4):721-5. 
Krause I, Uziel Y, Guedj D, Mukamel M, Harel L, Molad Y, et al. Childhood Behçet's disease: 
clinical features and comparison with adult-onset disease. Rheumatology (Oxford) 
1999;38(5):457-62. 
Lawton G, Bhakta BB, Chamberlain MA, Tennant A.  The Behçet’s disease activity index.  
Rheumatol 2004;43:73-8. 
Ozoran K, Aydintuğ O, Tokgöz G, Düzgün N, Tutkak H, Gürler A. Serum levels of interleukin-8 
in patients with Behçet’s disease. Ann Rheum Dis 1995;54(7):610. 
 
 
 
Sugi-Ikai N, Nakazawa M, Nakamura S, Ohno S, Minami M. Increased frequencies of 
interleukin-2- and interferon-gamma-producing T cells in patients with active Behçet's disease. 
Invest Ophthalmol Vis Sci 1998;39(6):996-1004. 
Thongprasom K, Dhanuthai K. Steroids in the treatment of lichen planus: a review. J Oral Sci 
2008:50(4):377-85. 
Turan B, Gallati H, Erdi H, Gurler A, Michel BA, Villiger PM. Systemic levels of the T cell 
regulatory cytokines IL-10 and IL-12 in Behcet’s disease; soluble TNFR-75 as a biological 
marker of disease activity. J Rheumatol 1997;24(1):128-32. 
  
. 
World Health Organization (WHO). Diarrhoea. Available at: 
http://www.who.int/topics/diarrhoea/en/. Accessed November 27, 2013. 
Yazici Y. From the silk road to the states. tracking patient manifestations of Behçet’s syndrome 
around the world. The Rheumatologist. July 2010. Available from: http://www.the-
rheumatologist.org/details/article/863699/From_the_Silk_Road_to_the_States.html. 


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Yurdakul S, Mat C, Tüzün Y, Özyazgan Y, Hamuryudan V, Uysal Ö, et al. A double-blind trial 
of colchicine in Behçet’s syndrome. Arthritis Rheum 2001;44(11):2686-92. 
 


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19. 
APPENDICES 
Appendix A: List of Behçet’s Disease Clinical Features 
 
 
 
 
 
 
 
 
Behçet Syndrome Diagnostic Criteria 
Recurrent oral aphthous ulceration 
Skin Lesions 
Erythema nodosum 
Subcutaneous thrombophlebitis 
Papulopustular lesions 
Pseudofolliculitis 
Acneiform nodules 
Positive pathergy test 
Cutaneous hypersensitivity 
Eye Lesions 
Anterior uveitis, Iridocyclitis 
Posterior uveitis 
Chorioretinitis, retino-vasculitis 
Definite history of chorioretinitis or retino-vasculitis 
Genital Ulcers 
Arthritis without deformity and ankylosis 
Gastrointestinal lesions characterized by ileocecal ulcers 
Epididymitis 
Vascular lesions 
Central nervous system symptoms 


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Appendix B: Visual Analog Scales (VAS) for Pain of Oral and Genital Ulcers 
 
 
 
 
 
 
 


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Appendix C: Behçet’s Disease Current Activity Form 
 
 


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Appendix C: Behçet’s Disease Current Activity Form (Continued) 
 
 
 


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Appendix C: Behçet’s Disease Current Activity Form (Continued) 
 
 
 


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Appendix D: Behçet’s Disease Quality of Life Measure 
 
 
 


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Appendix D: Behçet’s Disease Quality of Life Measure (Continued) 
 
 


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Appendix E: Behçet’s Syndrome Activity Score (BSAS) 
 
 
 
 


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Appendix E: Behçet’s Syndrome Activity Score (BSAS) (Continued) 
 


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Appendix G: Static Physician’s Global Assessment of Skin Lesions 
For uniform assessment of BD skin lesions, investigators will use and follow the scoring system 
in the Physician’s Global Assessment of Behçet’s disease-related skin lesions described below.  
These skin lesions include erythema nodosum, pseudofolliculitis, papulopustular or acneiform 
lesions on the face, back, chest, shoulders, arms, femoral regions, pubis and buttocks. 
Acne-like lesions 
Two types of acne-like lesions are observed in BD: inflammatory (papules, pustules and cysts) 
and non inflammatory (comedones). 
Acne like lesions will be rated as described in the table below, on the face, upper back, chest and 
shoulders based on the Investigator’s judgment. 
Examples are presented for the mild (score of 1), moderate (score of 2), and severe (score of 3) 
acne-like lesions in the images below: 
 
 
 
Scoring for Acne-like lesions: 
 
 
 
Score 
Severity 
Description  
0 
Clear 
Clear skin 
1 
Mild 
Presence of 1 to 10 lesions (papules, pustules, cysts) at any 
anatomical site  
2 
Moderate 
Presence of 11 to 20 lesions (papules, pustules, cysts) at any 
anatomical site 
3 
Severe 
Presence of > 20 lesions (papules, pustules, cysts) at any 
anatomical site 
Mild (1) 
Moderate (2) 
Severe (3) 


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Appendix G: Static Physician’s Global Assessment of Skin Lesions 
(Continued) 
Folliculitis 
Folliculitis is localized at the face, chest, back, genital area, arms, buttocks, and legs, and is 
characterized by the following: 
• Pustules, more commonly form in the follicular lesions, and are surrounded by an 
erythematous halo. 
• Lesions typically heal within 2 to 3 days.  
• During the healing phase, pustules may rupture and a crust presents at the pustule site 
and erythema fades. 
• Healed lesions occasionally show pigmentation at the lesion site. 
• It is more common among males for pustules to occur at the hairy sites.  
Non follicular pustules are rare in BD subjects.   
Evaluations of folliculitis will be rated as described in the table below, based on the 
Investigator’s judgment. 
Examples are presented for mild (score of 1), moderate (score of 2), and severe (score of 3) 
follicular lesions in the images below: 
 
 
Scoring for Folliculitis: 
Score 
Severity 
Description  
0 
Clear 
Clear skin 
1 
Mild 
Presence of 1 to 10 lesions (intact and/or ruptured lesions) at any 
anatomical site 
2 
Moderate 
Presence of 11 to 20 lesions (intact and/or ruptured lesions) at any 
anatomical site 
3 
Severe 
Presence of > 20 lesions (intact and/or ruptured lesions) at any 
anatomical site 
Mild (1) 
Moderate (2) 
Severe (3) 


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Appendix G: Static Physician’s Global Assessment of Skin Lesions 
(Continued) 
Erythema nodosum 
Erythem nodosum is usually localized to the front of the legs beneath the knees; it may also be 
found on the arms. Erythema nodosum is characterized by the following: 
• Begins as red nodules on the shins and may be painful 
• After about a week, lesions may appear purple or blue in color and then fade to 
yellow; appearing like a bruise 
• Nodules may appear on the buttocks, thighs, arms, trunk, and ankles 
• Nodules or lumps may vary in dimension from 1 cm to 5 cm 
 
Scoring for Erythema nodosum: 
 
Total Score 
The total score is calculated as: 
Score for acne-like lesions + Score for follicultits + Score for erythema nodosum = Total Score 
 
 
 
Score 
Severity 
Description  
0 
Clear 
Clear skin 
1 
Mild 
Presence of 1 to 10 nodules/lesions at any anatomical site 
2 
Moderate 
Presence of 11 to 20 nodules/lesions at any anatomical site 
3 
Severe 
Presence of > 20 nodules/lesions at any anatomical site 


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Appendix K: International Study Group Criteria For The Diagnosis Of 
Behçet's Disease (1990) 
In the absence of other clinical explanations, subjects must have:  
Recurrent Oral Ulceration (aphthous or herpetiform) observed by the physician or subject 
recurring at least three times in one 12-month period. 
 
Plus at least two of the following criteria:  
 
Recurrent Genital Ulceration:  
Aphthous ulceration or scarring observed by physician or subject. 
Eye Lesions:  
Anterior uveitis, posterior uveitis, or cells in vitreous on slit-lamp examination;  
or: 
Retinal vasculitis observed by ophthalmologist. 
Skin Lesions:  
Erythema nodosum, pseudofolliculitis, or papulopustular lesions;  
or: 
Acneiform nodules in postadolescent subjects not on corticosteroid treatment. 
Positive Result on Pathergy Testing: 
Read by a physician at 24 to 48 hr. 
 


Apremilast 
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Protocol CC-10004-BCT-002 Amendment 1.1 DE Final 28 Jul 2017 
1. 
JUSTIFICATION FOR AMENDMENT 
 
Significant changes included in this amendment are summarized below: 
• Addition of an optional Open-label Extension Phase 
This amendment will allow subjects the opportunity to enter an optional Open-label Extension 
Phase after the 52-week Active Treatment Phase (Week 64 visit). Subjects may continue in the 
optional Open-label Extension Phase until apremilast is commercially available for BD or until 
the benefit/risk of apremilast is found not to be acceptable for BD, according to either the 
sponsor or health authority.  
Revised sections:  
• Protocol Summary 
• Section 4.1 – Study Design 
• Section 4.2 – Study Design Rationale (including Figure 1) 
• Section 4.3 – Study Duration 
• Section 5 – Table of Events (Table 2) 
• Section 6.6.1 – Adverse Events 
• Section 6.6.9 – Pregnancy Tests for Females of Childbearing Potential 
• 
 
• Section 6.10 – Early Termination Visit 
• Section 6.10.1 – Observational Follow-up Visit 
• Section 6.11 – Study Completion 
• Section 8.3 – Treatment Administration and Schedule 
• Section 8.4.3 – Optional Open-label, Extension Phase 
• Section 10.1 – Statistical Analysis Overview 
• Section 10.2 – Study Population Definitions 
• Section 10.5 – Subject Disposition 
• Section 10.7 – Safety Analysis 
• Section 11.1 – Monitoring, Recording and Reporting of Adverse Events 
 
Minor changes in this amendment are summarized below: 
• Minor editorial and administrative changes 
 
 


Apremilast 
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Protocol CC-10004-BCT-002 Amendment 1.1 JA Draft 2 Feb 2016 
1. 
JUSTIFICATION FOR AMENDMENT 
 
Significant changes included in this amendment are summarized below: 
1. Extending eligibility to patients previously exposed to biologic therapy (Sections 6.5,  
7.3) 
The amendment will allow inclusion of potential subjects who have been previously exposed to  
biologic therapies for indications other than oral ulcers, including other manifestations of 
Behçet’s Disease.  The last dose for biologic therapies must correspond to at least 5 terminal 
half-lives of the individual drugs.  
The greater availability of biologic therapies globally and the practice of prescribing them for 
specific indications in Behçet’s Disease (BD) have become more common.  While oral ulcers in 
BD are not typically treated with biologics, major organ manifestations such as gastrointestinal 
and CNS involvement and severe uveitis or retinal vasculitis may require treatment with 
biologics [eg, tumor necrosis factor (TNF)α antagonists and interferon (IFN)α].  Excluding BD 
patients who have had treatment with biologics regardless of the indications or the timing when 
treatment occurred has become unrealistic in terms of recruiting patients for the BCT002 study.  
The amendment will help improve recruitment while retaining the intent of enrolling a 
population with active BD who have 2 or 3 oral ulcers and no major organ involvement within 
one year of the screening visit (see number 3 below).  
2. Modifications related to previous and current medications (Sections 7.3, 9.1) 
a. Colchicine (Section 7.3 only) 
The amendment will allow patients to continue taking colchicine until 7 days 
prior to randomization. 
In a consultation meeting with PMDA held on 23 July 2014 on the design and conduct of the 
BCT002 Study of apremilast in Behçet’s disease, the PMDA recommended to enroll patients 
using colchicine after establishing an appropriate washout period, and to not allow colchicine as 
a concurrent medication until completion of the double blind period.  Celgene accepted this 
recommendation and subsequently implemented it in the protocol (Section 7.3, Exclusion #6, 3rd 
bullet).  Patients on colchicine were allowed to enter the study provided it had been at least four 
weeks (28 days) since the last dose of colchicine was taken prior to randomization.  
In the same meeting, Celgene recognized the clinical reality that in Japan colchicine has been 
used as a treatment for BD for many years.  Celgene understood that prohibiting use of 
colchicine for an extended period of time may not be ethically acceptable.  
For more than 14 months to date, the BCT002 study has been actively recruiting BD patients to 
participate in this clinical trial.   Enrollment has been challenging.  One of the reasons for the 
slow enrollment has been due to the reluctance of patients to discontinue taking colchicine from 
at least 4 weeks prior to randomization.  The patients taking colchicine are not necessarily oral 
ulcer-free, but  nonetheless feel that colchicine is having some positive impact on their disease.  
Patients feel that waiting for 4 weeks prior to randomization without colchicine would not be 
tolerable, and therefore would rather not participate in the BCT002 study. 


Apremilast 
Protocol CC-10004-BCT-002 
 
Celgene Corporation 
Confidential and Proprietary 
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Protocol CC-10004-BCT-002 Amendment 1.1 JA Draft 2 Feb 2016 
 
Celgene considers that amending the protocol  in terms of the required washout  period of 
colchicine prior to randomization will benefit patients who would consider enrolling in the study 
if colchicine is discontinued closer to randomization.  The maximal anti-inflammatory effects of 
colchicine develop over 24 to 48 hours, based on intraleukocyte accumulation where it reaches 
much higher concentrations compared to plasma (Slobodnick, 2015). Colchicine has been used 
in BD and has shown to improve oral ulcers, skin lesions, and arthralgia (Yardakul, 2001; 
Davatchi, 2009; Aktulga, 1980). Although the anti-inflammatory effects persist while taking 
colchicine, many BD patients continue to have oral ulcers.  The proposed modification to the 
protocol is to allow the use of colchicine until at least 7 days prior to randomization, based on 5 
elimination half lives of colchicine (t½ ~32 hours).  Celgene considers this amendment 
reasonable because the amendment will only allow subjects who continue to have oral ulcers 
(required by the protocol) despite recent use of colchicine. The 7 day washout period will still be 
sufficient to ensure that colchicine will not confound efficacy assessments of apremilast in this 
study.  
b. Oral and topical corticosteroids 
The amendment will allow for tapering of topical and oral corticosteroids and 
subsequent discontinuation close to the day of randomization. 
The modification to allow tapering of oral and topical corticosteroids with subsequent 
discontinuation close to randomization is not expected to confound assessments secondary to the 
potential carry over effects of corticosteroids on oral ulcers. The amendment will only allow 
subjects who continue to have oral ulcers (required by the protocol), despite continued use of 
oral and topical corticosteroids, until the day of randomization.   
3. Clarification for the required number of oral ulcers (Protocol Summary, Section 
7.2) 
The required number of oral ulcers at screening AND at baseline are clarified to eliminate 
misinterpretation.  All subjects must have at least 2 oral ulcers at Visit 1. Once 3 oral ulcers are 
observed, regardless of the time interval from the screening visit (ie, the interval of 2 weeks is 
not required) a subject is qualified to be randomized provided all other eligibility criteria are met. 
If only 2 oral ulcers are present at Visit 2, then at least 14 days must have passed since Visit 1 
before the subject may be randomized.  
4. Clarification on the Static Physician’s Global Assessment of Skin Lesions (Appendix 
G) 
The wording on scoring of severity of skin lesions as described in Appendix G, Static 
Physician’s Global Assessment of Skin Lesions is revised.  The protocol describes the scoring of 
the severity of skin lesions by the number of nodules/lesions present at one anatomical site. Since 
lesions can occur at different anatomical sites during the course of the study, it is more feasible 
to assess and score the lesions all together.  As such, scoring of the number of nodules/lesions 
will be based NOT on one anatomical site at a time but at any anatomical site with respect to the 
whole body. 


Apremilast 
Protocol CC-10004-BCT-002 
 
Celgene Corporation 
Confidential and Proprietary 
5 
Protocol CC-10004-BCT-002 Amendment 1.1 JA Draft 2 Feb 2016 
5. Hepatitis Testing (Section 6.6.7.4) 
Revised to allow the decision to perform laboratory screening and clinical interpretation of tests 
for hepatitis B and C antigen or antibodies for study inclusion/exclusion purposes, to be left to 
the Investigator’s discretion. 
 
Minor changes in this amendment are summarized below: 
• Change in Therapeutic Area Head (page 3, deleted 
 and added 
 
) 
• Section 14.2, updated investigator responsibilities and confidentiality requirements 
• Section 11.2.6, updated to ensure all serious adverse events (SAEs) will be followed 
until resolution or until the AE is no longer serious 
• Minor editorial and administrative changes (including changing document to form, 
and punctuation edits)  
 
References: 
Aktulga E, Altaç M, Müftuoglu A, Özyazgan Y, Pazarli H, Tüzün Y, et al. A double blind study 
of colchicine in Behçet’s disease. Haematologica 1980;65(3):399–402. 
Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, Shahram F, Nadji A, Shams H, et al. 
Colchicine versus placebo in Behçet’s disease: randomized, double blind, controlled crossover 
trial. Mod Rheumatol 2009;19(5):542-549. 
Slobodnick A, Shah B, Pillinger MH, Krasnokutsky S. Colchicine: old and new. Am J Med 
2015;128:461-470. 
Yurdakul S, Mat C, Tüzün Y, Özyazgan Y, Hamuryudan V, Uysal Ö, et al. A double-blind trial 
of colchicine in Behçet’s syndrome. Arthritis Rheum 2001;44(11):2686-92. 
 
 
 


Apremilast 
Protocol CC-10004-BCT-002 
 
Celgene Corporation 
Confidential and Proprietary 
3 
  Protocol CC-10004-BCT-002 Amendment 1 Final 2 Feb 2016 
1. 
JUSTIFICATION FOR AMENDMENT 
 
Significant changes included in this amendment are summarized below: 
1. Extending eligibility to patients previously exposed to biologic therapy (Sections 6.5, 
7.3) 
The amendment will allow inclusion of potential subjects who have been previously exposed to  
biologic therapies for indications other than oral ulcers, including other manifestations of 
Behçet’s Disease.  The last dose for biologic therapies must correspond to at least  5 terminal 
half-lives of the individual drugs.  
The greater availability of biologic therapies globally and the practice of prescribing them for 
specific indications in Behçet’s Disease (BD) have become more common.  While oral ulcers in 
BD are not typically treated with biologics, major organ manifestations such as gastrointestinal 
and CNS involvement and severe uveitis or retinal vasculitis may require treatment with 
biologics [eg, tumor necrosis factor (TNF)α antagonists and interferon (IFN)α].  Excluding BD 
patients who have had treatment with biologics regardless of the indications or the timing when 
treatment occurred has become unrealistic in terms of recruiting patients for the BCT002 study.  
The amendment will help improve recruitment while retaining the intent of enrolling a 
population with active BD who have 2 or 3 oral ulcers and no major organ involvement within 
one year of the screening visit (see number 3 below).  
2. Modifications related to previous and current medications (Sections 7.3, 9.1) 
a. Colchicine (Section 7.3 only) 
The amendment will allow patients to continue taking colchicine until 7 days 
prior to randomization. 
For more than 14 months to date, the BCT002 study has been actively recruiting BD patients to 
participate in this clinical trial.  Enrollment has been challenging.  One of the reasons for the 
slow enrollment has been due to the reluctance of patients to discontinue taking colchicine from 
at least 4 weeks prior to randomization.  The patients taking colchicine are not necessarily oral 
ulcer-free, but  nonetheless feel that colchicine is having some positive impact on their disease.  
Patients feel that waiting for 4 weeks prior to randomization without colchicine would not be 
tolerable, and therefore would rather not participate in the BCT002 study. 
Celgene considers that amending the protocol  in terms of the required washout  period of 
colchicine prior to randomization will benefit patients who would consider enrolling in the study 
if colchicine is discontinued closer to randomization.  The maximal anti-inflammatory effects of 
colchicine develop over 24 to 48 hours, based on intraleukocyte accumulation where it reaches 
much higher concentrations compared to plasma (Slobodnick, 2015). Colchicine has been used 
in BD and has shown to improve oral ulcers, skin lesions, and arthralgia (Yardakul, 2001; 
Davatchi, 2009; Aktulga, 1980). Although the anti-inflammatory effects persist while taking 
colchicine, many BD patients continue to have oral ulcers.  The proposed modification to the 
protocol is to allow the use of colchicine until at least 7 days prior to randomization, based on 5 
elimination half lives of colchicine (t½ ~32 hours).  Celgene considers this amendment 


Apremilast 
Protocol CC-10004-BCT-002 
 
Celgene Corporation 
Confidential and Proprietary 
4 
  Protocol CC-10004-BCT-002 Amendment 1 Final 2 Feb 2016 
reasonable because the amendment will only allow subjects who continue to have oral ulcers 
(required by the protocol) despite recent use of colchicine. The 7 day washout period will still be 
sufficient to ensure that colchicine will not confound efficacy assessments of apremilast in this 
study.  
b. Oral and topical corticosteroids 
The amendment will allow for tapering of topical and oral corticosteroids and 
subsequent discontinuation close to the day of randomization. 
The modification to allow tapering of oral and topical corticosteroids with subsequent 
discontinuation close to randomization is not expected to confound assessments secondary to the 
potential carry over effects of corticosteroids on oral ulcers.  The amendment will only allow 
subjects who continue to have oral ulcers (required by the protocol), despite continued use of 
oral and topical corticosteroids, until the day of randomization.   
3. Clarification for the required number of oral ulcers (Protocol Summary, Section 
7.2) 
The required number of oral ulcers at screening AND at baseline are clarified to eliminate 
misinterpretation.  All subjects must have at least 2 oral ulcers at Visit 1. Once 3 oral ulcers are 
observed, regardless of the time interval from the screening visit (ie, the interval of 2 weeks is 
not required) a subject is qualified to be randomized provided all other eligibility criteria are met. 
If only 2 oral ulcers are present at Visit 2, then at least 14 days must have passed since Visit 1 
before the subject may be randomized.  
4. Clarification on the Static Physician’s Global Assessment of Skin Lesions 
(Appendix G) 
The wording on scoring of severity of skin lesions as described in Appendix G, Static 
Physician’s Global Assessment of Skin Lesions is revised.  The protocol describes the scoring of 
the severity of skin lesions by the number of nodules/lesions present at one anatomical site. Since 
lesions can occur at different anatomical sites during the course of the study, it is more feasible 
to assess and score the lesions all together.  As such, scoring of the number of nodules/lesions 
will be based NOT on one anatomical site at a time but at any anatomical site with respect to the 
whole body. 
 
Minor changes in this amendment are summarized below: 
• Change in Therapeutic Area Head (page 3, deleted 
 and added 
 
) 
• Section 14.2, updated investigator responsibilities and confidentiality requirements 
• Section 11.2.6, updated to ensure all serious adverse events (SAEs) will be followed 
until resolution or until the AE is no longer serious. 
• Minor editorial and administrative changes (including changing document to form, 
and punctuation edits)  
 


Apremilast 
Protocol CC-10004-BCT-002 
 
Celgene Corporation 
Confidential and Proprietary 
5 
  Protocol CC-10004-BCT-002 Amendment 1 Final 2 Feb 2016 
 
References: 
Aktulga E, Altaç M, Müftuoglu A, Özyazgan Y, Pazarli H, Tüzün Y, et al. A double blind study 
of colchicine in Behçet’s disease. Haematologica 1980;65(3):399–402. 
Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, Shahram F, Nadji A, Shams H, et al. 
Colchicine versus placebo in Behçet’s disease: randomized, double blind, controlled crossover 
trial. Mod Rheumatol 2009;19(5):542-549. 
Slobodnick A, Shah B, Pillinger MH, Krasnokutsky S. Colchicine: old and new. Am J Med 
2015;128:461-470. 
Yurdakul S, Mat C, Tüzün Y, Özyazgan Y, Hamuryudan V, Uysal Ö, et al. A double-blind trial 
of colchicine in Behçet’s syndrome. Arthritis Rheum 2001;44(11):2686-92. 
 
 


Apremilast 
Protocol CC-10004-BCT-002 
 
Celgene Corporation 
Confidential and Proprietary 
3 
CC-10004-BCT-002 Amendment 0.1 JA 27 OCT 2014 
1. 
JUSTIFICATION FOR AMENDMENT 
Significant changes included in this amendment are summarized below: 
• The Medical Monitor / Emergency Contact Information has been changed for Japan. 
• The following sections were updated to meet local regulatory requirements: Title 
Page, Protocol Summary, 7.2, 11.6, 14, 14.6, 14.8, 15.1, 15.3, and 16.2. 
In addition, minor editorial changes have been made.  
 
 
 

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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Parallel Group 
Study, followed by an Active-Treatment Phase to Evaluate the Efficacy and Safety of 
Apremilast (CC-10004) in the Treatment of Subjects with Active Behçet’s Disease.
STUDY DRUG:
Apremilast (CC-10004)
PROTOCOL NUMBER:
CC-10004-BCT-002
DATE FINAL:
25 Aug 2017
Prepared by:
On behalf of Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................10
3.
STUDY OBJECTIVES...........................................................................................11
3.1.
Primary Objective...................................................................................................11
3.2.
Secondary Objectives .............................................................................................11
3.3.
Safety Objective .....................................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.2.
Study Endpoints .....................................................................................................13
4.2.1.
Efficacy Endpoints .................................................................................................13
4.2.2.
Safety Endpoints.....................................................................................................15
4.2.5.
Derivations of Efficacy Endpoints ..........................................................................16
4.2.6.
Derivations of Safety Endpoints..............................................................................19
4.3.
Stratification, Randomization, and Blinding............................................................19
4.4.
Sample Size Determination.....................................................................................20
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................21
5.1.
Reporting Conventions ...........................................................................................21
5.2.
Analysis Periods.....................................................................................................21
5.3.
Baseline Definitions ...............................................................................................22
5.4.
Time points.............................................................................................................22
5.5.
Analysis Populations ..............................................................................................25
5.5.1.
Intent-to-Treat Population.......................................................................................25
5.5.2.
Safety Population....................................................................................................25
5.5.3.
Per-Protocol Population..........................................................................................25
5.5.4.
Apremilast Subjects as Treated Population .............................................................25
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
3
6.
SUBJECT DISPOSITION......................................................................................26
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................27
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................28
8.1.
Demographics.........................................................................................................28
8.2.
Baseline Disease Characteristics.............................................................................28
8.3.
Medical History......................................................................................................29
8.4.
Prior Therapy..........................................................................................................29
8.5.
Concomitant Medications and Procedures...............................................................30
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................31
9.1.
Treatment Duration.................................................................................................31
9.2.
Treatment Compliance............................................................................................32
10.
EFFICACY ANALYSIS ........................................................................................33
10.1.
General Approaches to Efficacy Analyses...............................................................33
10.2.
Efficacy Evaluation for the Double-blind, Placebo-controlled Treatment 
Phase......................................................................................................................33
10.2.1.
Multiplicity.............................................................................................................33
10.2.2.
Analysis of Primary Efficacy Endpoint...................................................................35
10.2.3.
Analyses of Secondary Efficacy Endpoints.............................................................36
10.3.
Efficacy Evaluation for the Active Treatment Phase in the Final Analysis ..............38
10.4.
Subgroup Analysis..................................................................................................39
10.5.
Assessing Study Center Effect and Treatment-by-Center Interaction.......................39
11.
SAFETY ANALYSES ...........................................................................................41
11.1.
General Approaches to Safety Analyses..................................................................41
11.2.
Adverse Events.......................................................................................................41
11.2.1.
Overall Summary of Adverse Events ......................................................................42
11.2.2.
All TEAEs..............................................................................................................42
11.2.3.
Common TEAEs ....................................................................................................42
11.2.4.
Drug-related TEAEs...............................................................................................43
11.2.5.
TEAEs by Maximum Severity................................................................................43
11.2.6.
Serious TEAEs.......................................................................................................43
11.2.7.
Severe TEAEs ........................................................................................................43
11.2.8.
TEAEs Leading to Drug Withdrawal ......................................................................43
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
4
11.2.9.
TEAEs Leading to Drug Interruption......................................................................43
11.2.10.
TEAEs of Special (Specific) Interests.....................................................................43
11.2.11.
TEAEs and Serious TEAEs by Subgroups ..............................................................44
11.2.12.
TEAEs Leading to Drug Withdrawal by Subgroups................................................44
11.2.13.
Deaths ....................................................................................................................44
11.3.
Clinical Laboratory Evaluations..............................................................................44
11.4.
Vital Signs and Weight...........................................................................................44
11.5.
Physical Examination .............................................................................................45
11.6.
Electrocardiogram ..................................................................................................45
12.
INTERIM ANALYSIS...........................................................................................46
14.
CHANGES TO THE STATISTICAL SECTION OF THE PROTOCOL ................49
15.
REFERENCES.......................................................................................................50
16.
APPENDICES........................................................................................................51
16.1.
Handling of Dates...................................................................................................51
16.1.1.
Calculation Using Dates .........................................................................................51
16.2.
Date Imputation Guideline......................................................................................52
16.2.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications.......................52
16.2.2.
Impute Missing Diagnosis Date for Behçet’s Disease .............................................53
16.3.
Marked (Atypical) Abnormalities Criteria...............................................................54
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2:
Definition of Visit Window for Study Visit.............................................................23
Table 3:
Mapping of Study Weeks for Placebo Subjects who Switched Treatment in 
Summary of Safety Data over Time........................................................................25
Table 4:
Rank of the Endpoints (Including Primary Efficacy Endpoint) in the 
Hierarchy of Multiplicity Adjustment .....................................................................34
Table 5:
Marked Abnormalities Criteria ...............................................................................54
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
7
Lead Product Safety Physician
Signature
{See appended electronic signature page}
Printed Name
Date
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
Adverse event
ALT (SGPT)
Alanine transaminase (serum glutamate pyruvic transaminase)
ANCOVA
Analysis of covariance
APR
Apremilast 
AST (SGOT)
Aspartate transaminase (serum glutamic oxaloacetic transaminase)
ATC
Anatomical Therapeutic Chemical
AUC
Area under the curve
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
AUC85
Area under the curve for the number of ulcers from baseline to Week 12/Day 85
BD
Behçet’s disease
BDCAF
Behçet’s disease Current Activity Form
BID
Twice daily
BMI
Body mass index
BSAS
Behçet’s Syndrome Activity Score
CI
Confidence interval
Cmax
Maximum observed plasma concentration
CMH
Cochran-Mantel-Haenszel (test or weights)
CRF
Case report form
DMC
Data Monitoring Committee
EAIR
Exposure-adjusted incidence rate
ECG
Electrocardiogram
ET
Early termination
GI
Gastrointestinal
IL
Interleukin
IP
Investigational product
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
9
IRT
Interactive Response Technology
ITT
Intent-to-Treat
LOCF
Last observation carried forward
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects model for repeated measures
PCS
Physical Component Summary
PGA
Physician’s Global Assessment
PP
Per Protocol
PRO
Patient Reported Outcome
PT
Preferred term
QOL
Quality-of-life
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error
SI
Standard international (unit)
SOC
System organ class
TEAE
Treatment-emergent adverse event
tmax
Time to maximum observed plasma concentration
ULN
Upper limit of normal
VAS
Visual analog scale
WHODD
World Health Organization Drug Dictionary
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-10004-BCT-002 “A Phase 3, Multicenter, Randomized, Double-blind, Placebo-
controlled Parallel Group Study, followed by an Active-Treatment Phase to Evaluate the 
Efficacy and Safety of Apremilast (CC-10004) in the Treatment of Subjects with Active 
Behçet’s Disease,” Amendment 1 and Amendment 1.1 DE, which were issued on 02 FEB 2016 
and 05 JUL 2017 (for German sites only), respectively.  It contains definitions of analysis 
populations, derived variables and statistical methods for the analysis of efficacy and safety.
Throughout this SAP, the treatment arms will be referred to as the 30 mg twice daily (BID) 
group and the placebo group.  The purpose of the SAP is to ensure the credibility of the study 
findings by pre-specifying the statistical approaches for the analyses of study data prior to 
database lock and the data analyses. This SAP will be finalized and signed prior to the clinical 
database lock for the first analysis (at 12 weeks).
These analyses include:
!
Week 12 data analyses: clinical efficacy and safety analyses based on a database cut 
at Week 12/Visit 9 after all subjects have completed Week 12/Visit 9 or have 
discontinued early at or prior to Week 12, including Early Termination and 
Observational Follow-up visits (referred as the 12-week database). The treatment 
comparisons during Placebo-controlled Treatment Phase and the safety analysis for 
the Placebo-controlled period will be based on this database lock;
!
Analyses of efficacy up to Week 28 and safety with at least 100 subjects with at least 
1 year of apremilast exposure (referred as the second database);
!
Week 68 analyses: clinical efficacy and safety analyses when all subjects have 
completed the Active Treatment Phase and/or 4-week Posttreatment Observational 
Follow-up Phase or have discontinued early;
In addition, for German sites only: 
!
Analyses for the optional Open-label Extension Phase for subjects from German sites
who choose to enter the optional Open-label Extension Phase after completing the 
Active Treatment Phase.
 
 
All statistical analyses detailed in this SAP will be conducted using SAS® 9.2 or higher.  
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
11
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective is to evaluate the efficacy of apremilast in the treatment of oral ulcers in 
active Behçet’s disease.
3.2.
Secondary Objectives
The secondary objectives of the study are:
!
To evaluate the efficacy of apremilast in subjects with active Behçet’s disease
!
To evaluate the effect of apremilast on Patient Reported Outcomes (PROs) in subjects 
with active Behçet’s disease
3.3.
Safety Objective
!
To evaluate the safety and tolerability of apremilast in subjects with active Behçet’s 
disease
 
 
 
 
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
12
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study, followed by an active-treatment extension phase to evaluate the efficacy and safety of 
apremilast (CC-10004) in the treatment of subjects with active Behçet’s disease (BD). 
Approximately 204 eligible subjects will be randomized 1:1 (102 subjects per group) to receive 
apremilast 30 mg BID (APR 30 BID), or identically-appearing placebo tablets BID for the 12-
week Placebo-controlled Treatment Phase. 
Upon completion of the Week 12 visit, subjects initially randomized to placebo will transition to 
APR 30 BID, while subjects initially randomized to APR 30 BID will continue on the same 
treatment during the 52-week Active Treatment Phase. 
Subjects from German sites who complete Visit 14 of the 52-week Active Treatment Phase will 
have an opportunity to continue to receive APR 30 BID in an optional Open-label Extension 
Phase. Subjects who choose not to enter the optional Open-label Extension Phase will complete 
the 4-week Posttreatment Observational Follow-up Phase. 
Subjects who discontinue at any time from the study for any reason are to enter the 4-week 
Posttreatment Observational Follow-up Phase. 
The study will include the following:
!
Screening Phase: up to 6 weeks
!
Double-blind, Placebo-controlled Treatment Phase: 12 weeks
∀
APR 30 BID
∀
Placebo
!
Active Treatment Phase: 52 weeks
∀
APR 30 BID
!
Optional Open-label Extension Phase for German Sites until apremilast is 
commercially available for BD or until the benefit/risk of apremilast is found not to 
be acceptable for BD, according to either the sponsor or health authority. 
∀ APR 30 BID
!
Posttreatment Observational Follow-up Phase: – 4 weeks after the last dose (if a 
subject early terminates or, for subjects from German sites, choose not to enter the 
optional Open-label Extension Phase). Subjects from German sites who complete the 
optional Open-label Extension Phase do not need to complete the Observational 
Follow-up Visit.
Screening Phase
Screening procedures must be performed no more than 6 weeks prior to the start of study 
investigational product (IP) at Visit 2 (Day 1).
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
13
Treatment Phase
Subjects who qualify for enrollment will be randomized 1:1 to receive APR 30 BID or 
identically-appearing placebo tablets BID for the 12-week Placebo-controlled Treatment Phase. 
To mitigate potential gastrointestinal (GI) side effects dose titration will be implemented in the 
first week of this study. For dose titration, 10 mg, 20 mg and 30 mg apremilast tablets, or 
identically appearing placebo tablets, will be dispensed in dose titration cards at Week 0.
Active Treatment Phase
All subjects who complete the Placebo-controlled Treatment Phase will be eligible to enter the 
Active Treatment Phase. Subjects initially randomized to placebo will transition to APR 30 BID, 
while subjects initially randomized to APR 30 BID will continue on the same treatment during 
the 52-week Active Treatment Phase. To maintain the blind regarding the initial treatment 
assignment, all subjects will receive dose titration cards at Visit 9 (Week 12). Although only 
subjects initially randomized to placebo will be dose titrated during their first week of the Active 
Treatment Phase, all subjects entering the Active Treatment Phase will receive identically-
appearing titration/treatment cards.
Posttreatment Observational Follow-up Phase
Subjects who discontinue at any time from the study for any reason are to enter the 4-week 
Posttreatment Observational Follow-up Phase to monitor changes in disease activity or safety 
parameters. 
Optional Open-label Extension Phase
Subjects from German sites who complete Visit 14 of the 52-week Active Treatment Phase will 
have an opportunity to continue to receive APR 30 BID in an optional Open-label Extension 
Phase.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary 
 analysis, as pre-specified in the protocol and/or the SAP, 
whichever is the later date.
4.2.
Study Endpoints
Study endpoints are described below, and the timing of when each assessment is to be collected 
is described in the protocol. 
4.2.1.
Efficacy Endpoints
4.2.1.1.
Primary Efficacy Endpoint
The primary endpoint is area under the curve (AUC) for the number of oral ulcers from baseline 
through Week 12.
4.2.1.2.
Secondary Efficacy Endpoints
!
Complete response rate for oral ulcers at Week 12
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352


Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
14
∀
A complete response is defined as the proportion of subjects who are oral ulcer-
free. 
!
Change from baseline in the pain of oral ulcers as measured by visual analog scale 
(VAS) at Week 12
!
Complete response rate for genital ulcers at Week 12 for subjects who had genital 
ulcers at baseline
∀
A complete response is defined as the proportion of subjects who are genital 
ulcer-free.
!
Change from baseline in the pain of genital ulcers, as measured by VAS at Week 12 
in subjects who had genital ulcers at baseline
!
Change from baseline in disease activity as measured by Behçet’s Disease Current 
Activity scores (BD Current Activity Form [BDCAF]) at Week 12
!
Change from baseline in the BD Quality-of-Life (QoL) score at Week 12
!
Change from baseline in Behçet’s Syndrome Activity Score (BSAS) at Week 12
!
Time to oral ulcer resolution (complete response), ie, the first instance when a subject 
has a complete response, during the Placebo-controlled Treatment Phase
!
Proportion of subjects with no oral ulcers following complete response, ie, the first 
time when a subject has a complete response, during the Placebo-controlled Phase 
(Note: this will be the proportion of subjects with no oral ulcers following subject’s 
first complete response during the Placebo-controlled Phase.)
!
Number of oral ulcers following loss of complete response, ie, the first instance when 
a subject has a reappearance of oral ulcers following a complete response, during the 
Placebo-controlled Treatment Phase (Note: this will be the number of oral ulcers 
reported at the time of the first loss of complete response during the Placebo-
controlled Phase.)
!
Time to recurrence of oral ulcers following loss of complete response, ie, the first 
instance when a subject has a reappearance of oral ulcers following a complete 
response, during the Placebo-controlled Treatment Phase
!
Change from baseline in the total score of the Static Physician’s Global Assessment 
(PGA) of skin lesions (acne-like lesions, folliculitis and erythema nodosum) of BD at 
Week 12 in subjects who had BD skin lesions at baseline
!
Proportion of subjects achieving an oral ulcer complete response (oral ulcer-free) by 
Week 6, after start of dosing, and who remain oral ulcer free for at least 6 additional 
weeks during the 12-week Placebo-controlled Treatment Phase
 
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&


Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
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15
 
 
 
 
 
 
 
 
 
 
 
4.2.2.
Safety Endpoints
Safety and tolerability as defined by the following:
!
Type, frequency, severity, and relationship of the AEs to apremilast
!
Number of subjects who prematurely discontinue IP due to any AE
!
Frequency of clinically significant changes in vital signs, and/or laboratory findings
 
 
 
 
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Apremilast
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Celgene Corporation
Confidential and Proprietary
16
 
 
4.2.5.
Derivations of Efficacy Endpoints
Efficacy assessments, as detailed in the following section, will be done at the intervals specified 
in the Table of Events, Table 1 in the protocol.
!
The number of oral ulcers and genital ulcers will be counted at each study visit, at ET 
and Observational Follow-up visits following the Placebo-controlled or Active 
Treatment Phase. For females, both vulvar and vaginal ulcers will be considered for 
genital ulcers.
!
The AUC from baseline to Week 12/Day 85 (AUC85) is the sum of the AUCs in each 
time interval specified by the dates of the visits. The individual AUC for any given 
time interval is calculated based on the linear trapezoidal method, which uses linear 
interpolation between data points to calculate the AUC. The AUC85 can be calculated 
as follows:
 =  ∗

 (C + C)(


t −t), k = 2, 3, ⋯, 8,
and
 =
()
( ! ") =
#
( ! ")  =
()
( ! ") =
#
( ! ").
where C2, C3, …, C9 are the number of ulcers at each visit from Visit 2/Baseline to 
Visit 9/Week 12, and t2, t3, …, t9 are the ulcer assessment dates for Visit 2/Baseline 
to Visit 9/Week 12. When Visit 9/Week 12 does not exactly coincide with Day 85, 
the AUC through Week 12 will be adjusted for the actual study duration by dividing 
the total AUC by total study duration (in days) and multiplying this quantity by 84
days. 
∀
The multiple imputation method will be used to impute missing oral ulcer counts 
when deriving the primary efficacy endpoint of AUC for the number of oral 
ulcers.
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Apremilast
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Celgene Corporation
Confidential and Proprietary
17
∀
AUC using a last observation carried forward (LOCF) approach to impute 
missing assessments at Week 12 will be used as a sensitivity analysis. If a subject 
has no post baseline ulcer assessment excluding the value obtained at the 
Observational Follow-up Visit, the baseline value will be carried forward for 
calculation. If there is a missing oral ulcer assessment between two visits or time 
points with assessments within a period, the AUC will be calculated based on the 
preceding and subsequent ulcers count.
!
The LOCF approach will also be used for all other efficacy endpoints based on oral or 
genital ulcers count including calculating the cumulative number of oral ulcers per 
subject at all scheduled visits from baseline to Week 12. Of note, the cumulative 
count does not distinguish new occurrence of ulcers or the same ulcers appeared 
previously.
!
The number of subjects who are oral ulcer-free (complete response) at Week 12 will 
be determined. Similarly, the complete response for genital ulcers at Week 12 will be 
determined for subjects who had genital ulcers at baseline. Subjects with missing data 
at Week 12 will be classified as non-responders. A sensitivity analysis with LOCF 
approach will also be conducted. 
!
 
!
The time to oral ulcer resolution is defined as the time interval in weeks from the date 
of first dose of IP to the date of first complete response with oral ulcer-free during the 
Placebo-controlled Treatment Phase. For subjects without any post-baseline oral ulcer 
assessment, the time to oral ulcer resolution will be censored to Day 1 of the placebo-
controlled period; for the rest of the subjects who have a post-baseline assessment but 
have not achieved the complete response during Placebo-controlled Treatment Phase, 
the time to event will be censored at the last oral ulcer assessment date during the 
Placebo-controlled Treatment Phase
 
 
!
Time to oral ulcer recurrence is defined as the time interval in weeks from the date of 
first complete response to the first reappearance of oral ulcers during the Placebo-
controlled Treatment Phase. This analysis will only be conducted for subjects who are 
complete responders prior to Week 12. For subjects without ulcers recurrence 
following a complete response during the Placebo-controlled Treatment Phase, the 
time to event will be censored to the last oral ulcer assessment date during the 
Placebo-controlled Treatment Phase; for subjects without any ulcer assessment 
following the first complete response, the time to event will be censored to the first 
complete response date.
 
!
For continuous endpoints including pain of ulcers as measured by VAS, BDCAF 
scores, total scores of PGA, BD QoL scores, and BSAS scores, the LOCF imputation 
approach will be used for subjects whose Week 12 assessment is unavailable. Similar 
to number of ulcers, if a subject has no post baseline assessment of endpoints above 
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Celgene Corporation
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18
excluding the value obtained at the Observational Follow-up Visit, the baseline value 
will be carried forward for calculation.
!
Additional derivations including 3 patient reported outcome (PRO) endpoints are 
provided below:
∀
Two separate pain VAS scales (100 mm) for oral and for genital ulcers will be 
completed by the subject and recorded on a secure, validated hand-held device. 
Subjects will be asked to click on the VAS line at the point that represents the 
severity of their pain during the previous week, with zero (the left-hand end of the 
scale) representing no pain and 100 mm (the right-hand end of the scale) 
representing the worst possible. The change from baseline will be determined. A 
negative change from baseline indicates improvement. 
∀
Behçet’s Disease Current Activity Form (BDCAF) was developed for the 
International Scientific Committee on Behçet’s Disease for routine monitoring of 
subjects, as well as for clinical studies (Lawton, 2004). The questionnaire is 
administered to the subjects by the investigator (Investigator will complete the 
form on a secure, validated hand-held device), and disease manifestations over the 
previous 4 weeks are quantified on a 12-point scale, with a higher score indicating 
higher level of activity, which is the sum score of 12 questions. A negative change 
from baseline indicates improvement.
∀
Physician’s global assessment (PGA) of BD related skin lesions (on skin lesions 
except oral/genital ulcers) will be completed by the investigators. 
∀
 
 
∀
The Behçet’s Disease Quality of Life (BD QoL) questionnaire was developed to 
measure the influence of BD on a subject’s life (Gilworth, 2004). It consists of 30 
self-completed items that measure disease-related restrictions on the subject’s 
activities and the subject’s emotional response to these restrictions. The BD QoL 
measure will be completed by the subject on a secure, validated hand-held device. 
The total score will be the summary of all 30 items (each yes scores 1 and each no 
scores 0). For possible missed items collected on the paper, the total score will be 
calculated using the following formula: [(sum of score of nonmissing items)/(total 
number of nonmissing items)]*total number of items on questionnaire. The total 
score ranges from 0-30, with zero representing no influence of BD on a subject’s 
quality of life, and 30 representing the most severe influence. A negative change 
from baseline indicates improvement.
∀
The Behçet’s Syndrome Activity Score (BSAS) ( Forbess, 2008) contains 10 
questions, including assessments of the number of new oral and genital ulcers and 
skin lesions; assessment of the GI, CNS, vascular, and ocular involvement; and 
the assessment of the subject’s current level of discomfort. The item scores are 
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Apremilast
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Celgene Corporation
Confidential and Proprietary
19
totaled to create a score ranging from 0 to 100, with a higher score indicating 
higher level of activity; a negative change from baseline indicates improvement. 
The BSAS will be completed by the subject on a secure, validated hand-held 
device. If any BSAS question has the missing answer, the total score will be 
calculated based on the same formula used for BD QoL.
∀
 
 
 
 
 
 
 
 
 
 
4.2.6.
Derivations of Safety Endpoints
Baseline definition for all safety endpoints is given in Section 5.3. Change from baseline is 
calculated as on-treatment value minus the baseline value. Handling of time points is described 
in Section 5.4.
4.2.6.1.
Treatment-emergent Adverse Event
A treatment-emergent adverse event (TEAE) is defined as any AE that begins or worsens on or 
after the date of the first dose of IP through 28 days after the last dose of IP for subjects who 
have completed the study or have discontinued early by the time of database cut, or on or after 
the date of the first dose of IP for subjects who are ongoing at the time of database cut.
If the treatment-emergent status of an AE is unclear due to a missing/incomplete start date, it will 
be defined as a TEAE, unless shown otherwise by data. Date imputation rules for partially 
missing AE start dates are described in Section 16.2.
Relationship to IP is based on the investigator's causality judgment; that is, a drug-related AE is 
an AE indicated by the investigator to have a suspected relationship to IP.
4.3.
Stratification, Randomization, and Blinding
At Visit 2, subjects who meet entry criteria will be randomized using a permuted block 
randomization in parallel 1:1 (102 subjects per group) to receive either APR 30 BID or 
identically-appearing placebo BID for the 12-week Placebo-controlled Treatment Phase, using a 
centralized Interactive Response Technology (IRT). Eligible subjects will be stratified according 
to sex, history of uveitis, and region (Japan and Other). 
This study will be conducted as a double-blind study for the Placebo-controlled Treatment Phase. 
During the Active Treatment Phase (Weeks 12 to 64), the IP will remain blinded, to prevent 
study personnel and subjects from knowing the IP assignment in the Placebo-controlled Phase. 
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To maintain the blind regarding the initial treatment assignment, all subjects will receive dose 
titration cards at Visit 9. Although only subjects initially randomized to placebo will be dose 
titrated during their first week of the Active Treatment Phase, all subjects entering the Active 
Treatment Phase will receive identically-appearing titration/treatment cards.
Data analyses and reporting will be performed after all subjects have completed Week 12/Visit 9 
or have discontinued early (the 12-week database). After medical/scientific review has been 
completed, protocol violations/deviations have been identified, and the data have been declared 
final and complete, the 12-week database will be extracted and restricted with the corresponding 
external data files in the appropriate location in the data repository. For 12-week database lock, 
Celgene personnel who have access to the unblinded data are not to discuss or make materials 
available that would unblind individual subjects data to the personnel involved in the study 
conduct. Blinding to treatment assignment will be maintained at all study sites prior to the Week 
68 database lock. 
4.4.
Sample Size Determination
The sample size estimation is based on the consideration from the results of the Phase 2 study 
CC-10004-BCT-001. A 2-sided t-test at a 0.05 significance level will have 90% power to detect 
a treatment difference of 66 in the AUC of oral ulcer counts from Day 1 through Week 12 
(AUC85 of placebo – drug = 66), the primary efficacy endpoint, when the sample size in each 
group is 102, assuming a common standard deviation of 144. 
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Celgene Corporation
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21
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
Summary statistics for continuous variables include sample size (n), mean, standard deviation 
(SD), median, minimum, the 25th (Q1) and 75th(Q3) percentiles, and maximum. All mean and 
median values will be formatted to one more decimal place than the measured value. SD values 
will be formatted to two more decimal places than the measured value. Minimum and maximum 
values will be presented to the same number of decimal places as the measured value. Frequency 
summary for categorical variables includes number and percentage. All percentages will be 
rounded to one decimal place. Number and percentage values will be presented as xx (xx.x%). 
All analysis and summary tables will have the population sample size for each treatment group in 
the column heading. P-values (2-sided) will be presented with 4 decimal places. All laboratory 
data will be reported using standard international (SI) units.
5.2.
Analysis Periods
For the purposes of data analysis and reporting, 2 analysis periods are defined as follows, unless 
otherwise defined for a specific tabulation. Data analysis and reporting for a specific analysis 
period will include all data measured or collected (based on date of measurement or date of 
specimen collection, as appropriate) during that analysis period. 
!
Placebo-controlled period:
This period starts on the date of the first dose of IP, and stops 
∀
on the date the first dose of apremilast is administered at the Week 12 visit (Visit 
9), or
∀
on the date of the last study visit (including the ET Visit and the Observational 
Follow-up Visit; i.e., all data after the start date will be included) for efficacy 
analyses, or 28 days after the last dose of IP or the date of death (if applicable), 
whichever comes first, for safety analyses, for whom IP is not dispensed at Week 
12
The start day is exclusive and the stop day is inclusive for efficacy, and safety analyses 
based on laboratory, vital signs, and weight. For AE analyses, the start day is inclusive, 
and the stop day under the first bullet is exclusive and the stop day under the second 
bullet is inclusive. 
!
Apremilast-exposure period:
This period starts
∀
on the date the first dose of apremilast is administered for subjects who are 
randomized to an apremilast dose group, or 
∀
on the date the first dose of apremilast is administered at the Week 12 (Visit 9) for 
subjects who were originally randomized to placebo and switched to the APR 30 
BID group, 
and this period stops 
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∀


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∀
For efficacy analyses, on the date of the last study visit (including the ET visit and 
the Observational Follow-up Visit; i.e., all data after the start date of the 
apremilast-exposure period will be included), or
∀
For safety analysis, 28 days after the last dose of apremilast for subjects who have 
completed the study or have discontinued early, or the date of death (if 
applicable), whichever comes first. 
The start day is exclusive and stop date is inclusive for efficacy analyses, and safety 
analyses of laboratory, vital signs, and weight. For AE analyses, both the start date and 
stop date are inclusive.
5.3.
Baseline Definitions
For all efficacy analyses and the data tabulation of baseline disease characteristics, baseline is 
defined as the last value measured on or before the day of the first dose of IP. For the summaries 
of laboratory parameters, vital signs, and weight, baseline is defined as the last value measured 
on or before the day of the first dose of IP in the summaries for the placebo-controlled period, 
and defined as the last value measured on or before the start day (defined in Section 5.2) of the 
apremilast-exposure period in the summaries for the apremilast-exposure period.
5.4.
Time points
Assessments will be done at the intervals specified in the Table of Events, Section 5 in protocol. 
During the trial, assessments can occur outside protocol specified intervals (i.e., Early 
Termination Visit or unscheduled visits). For the purpose of data analysis and reporting, all 
assessments will be assigned to analysis visits according to a visit window schema (See Table 2
and Table 3), which is defined as the study day ranges relative to either the date of first dose of 
IP or apremilast 30 mg for placebo subjects who switch to the APR 30 BID group at Week 12.
If more than one assessment of a particular efficacy or safety variable occurs in the same study 
visit window (due to unscheduled visits or Early Termination visit), the assessment within given 
visit window that is closest to the target Study Day will be used for the analysis; in the case of 
ties, the later assessment will be used. 
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l be used


Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
23
Table 2:
Definition of Visit Window for Study Visit
Visit 
Number
Week 
Analysis 
Time 
Point
Target 
Study 
Day
Start 
(Study 
Day)
End (Study Day)
Visit 2
Week 0
Baseline
1
1
Visit 3
Week 1
Week 1
8
2
11
Visit 4
Week 2
Week 2
15
12
22
Visit 5
Week 4
Week 4
29
23
36
Visit 6
Week 6
Week 6
43
37
50
Visit 7
Week 8
Week 8
57
51
64
Visit 8
Week 10
Week 10
71
65
78
Visit 9
Week 12
Week 12
85
79
1) Last measure on or prior to first 
APR dose date on Visit 9 or 
2) 1 day prior to date of Follow-up 
Visit if subjects discontinue 
study prior to Visit 9 and 
complete Follow-up visits or 
3) ET visit if performed or date of 
treatment discontinuation if 
subjects discontinue study and 
have no Observational Follow-
up Visits, whichever is later.
Visit 10
Week 16
Week 16
113
First APR 
dose date 
on Visit 9 
+ 1
155
Visit 11
Week 28
Week 28
197
156
239
Visit 12
Week 40
Week 40
281
240
323
Visit 13
Week 52
Week 52
365
324
407
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(1


Apremilast
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Celgene Corporation
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Visit 
Number
Week 
Analysis 
Time 
Point
Target 
Study 
Day
Start 
(Study 
Day)
End (Study Day)
Visit 14
Week 64
Week 64
449
408
For subjects entering Active Treatment 
Phase but not entering optional Open-
label Extension Phase:
1) 1 day prior to date of 
Observational Follow-up Visit if 
Observational Follow-up Visit 
performed or 
2) ET visit if performed or 
3) Date of APR treatment 
discontinuation if subjects 
discontinue study and have no 
Observational Follow-up visits, 
whichever is later. 
For subjects from German sites entering 
the optional Open-label Extension 
Phase, the end day is when the IP is 
administered at Visit 14
APR = Apremilast; ET = Early termination. 
The time points for analyses of efficacy data will be assigned according to visit window scheme 
in Table 2 which are set up as the continuous and mutually exclusive, from midpoint to midpoint 
between each successive part of scheduled visits or otherwise specified.
The time points for summaries of safety data (laboratory parameters, vital signs, and weight) will 
be assigned as defined above for both placebo-controlled and apremilast-exposure period for 
subjects who are randomized as APR30 BID; and for placebo-control period only (through Week 
12) for placebo subjects. For all placebo subjects who switch to the APR 30 BID group at Week 
12, safety data within apremilast-exposure period will be mapped to reflect the Study Days 
relative to the first dose of apremilast (see Table 3 below). In addition, safety analysis on the end 
of treatment will be included, which is defined as the last visit among all the scheduled and 
unscheduled visits and, if applicable, the Early Termination visit, all within the same analysis 
period. The baseline visit and the Observational Follow-up Visit are not included in the 
derivation of the end-of-treatment value.
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Confidential and Proprietary
25
Table 3:
Mapping of Study Weeks for Placebo Subjects who Switched Treatment in 
Summary of Safety Data over Time
Visit
Week 
Mapped Analysis Time 
Point
Target APR
Day
Start 
(APR
Day)
End (APR Day)
Visit 9
Week 12
Baseline
1
Last measure prior to 
First APR Dose Date(≤
1 APR day)
Visit 10
Week 16
Week 4
29
2
71
Visit 11
Week 28
Week 16
113
72
155
Visit 12
Week 40
Week 28
197
156
239
Visit 13
Week 52
Week 40
281
240
323
Visit 14
Week 64
Week 52
365
324
407
Note: APR Day is the study day relative to the first apremilast dose date on Visit 9.
5.5.
Analysis Populations
5.5.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population will be defined as all randomized subjects who received at 
least one dose of IP. This ITT population will be used for the primary efficacy analysis. Subjects 
will be included in the treatment group to which they are randomized.
5.5.2.
Safety Population
The safety population will include all randomized subjects who received at least one dose of IP.  
The analysis of safety data in this study will be based on the safety population and subjects will 
be included in the treatment group to which they actually received.
5.5.3.
Per-Protocol Population
The per protocol (PP) population will include all randomized subjects who received at least one 
dose of IP, have a baseline and at least one post-baseline oral ulcer evaluation, and have no 
important protocol violations during the 12-week Placebo-controlled Treatment Phase.  The final 
determination of important protocol violation criteria will be made prior to the unblinding of the 
database and will be documented separately.
5.5.4.
Apremilast Subjects as Treated Population
Safety analyses for the apremilast-exposure period will be based on the apremilast subjects as 
treated population, which will include all subjects who actually receive 30 mg BID at the 
randomization visit or switched (at the Week 12 visit) to the APR 30 BID. Subjects will be 
included in the treatment sequence they actually received. 
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
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6.
SUBJECT DISPOSITION
The number of subjects screened, the number and percentage of subjects randomized and not 
randomized among all subjects screened, and the reasons for not being randomized will be 
summarized. The above percentages will be calculated using the number of subjects screened as 
the denominator.
The number and percentage of subjects who entered, completed, and discontinued each study 
phase (Placebo-controlled Treatment Phase, Active Treatment Phase, and Observational Follow-
up Phase), and the number and percentage of primary reasons for discontinuation of each study 
phase (except for the Observational Follow-up Phase) will be summarized by treatment group at 
randomization. For the Placebo-controlled Treatment Phase, the summary of the number and 
percentage of subjects who completed and entered or completed but did not enter the Active 
Treatment Phase will be provided separately. 
The primary reasons for discontinuation are collected in the Discontinuation eCRF and will be 
summarized with the following categories:
!
Adverse event
!
Lack of efficacy 
!
Non-compliance with IP
!
Withdrew by subject
!
Death
!
Lost to follow-up
!
Study terminated by sponsor
!
Protocol violation
!
Pregnancy
!
Other
The number of subjects randomized, and the number and percentage of subjects included in the 
ITT, PP,  Safety and Apremilast as Treated analysis populations will be summarized by 
treatment group (placebo and 30 mg BID) at randomization. The percentages will be based on 
the number of subjects randomized. A listing of subject eligibility/analysis population and a 
listing of subjects who discontinue the study early and reasons for discontinuation will be 
provided. A listing of subjects excluded from the per protocol population, with the reasons for 
exclusions, will also be provided.
The number and percentage of subjects by region, country, study site and treatment group will be 
tabulated based on the ITT population.
Subject disposition for the optional Open-label Extension Phase will be presented in a separate 
listing.
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7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol deviations/violations will be identified and assessed by clinical research physician 
or designee following company standard operational procedure. 
The number and percentage of protocol violations and deviations will be summarized for the ITT 
population from Weeks 0 to 12 by treatment group at randomization, and after Week 12 by 
treatment sequence and the total for subjects who enter the Active Treatment Phase. 
A listing of subjects with protocol deviations/violations in the ITT population will be provided.
&(/*(1(35235,(7$5<,1)250$7,21


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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics and baseline characteristics will be summarized for the ITT population. The 
demographics and baseline clinical characteristics will also be summarized for subjects who 
discontinued study early within the ITT population. Individual subject listings will be provided 
to support the summary tables.
8.1.
Demographics
Summary statistics will be provided by treatment group for the following continuous variables:
!
Age (years)
!
Weight (kg)
!
Height (cm)
!
Body mass index (BMI; kg/m2)
Number and percentage will be provided by treatment group for the following categorical
variables:
!
Age category (< 65, ≥ 65 years; < 40, ≥ 40 to < 65, ≥ 65 years)
!
Sex (female, male)
!
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islanders, White, Other)
!
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
!
Region (Japan, Other; Europe, North America, Asia, Rest of the World) 
!
Weight category (< 50, ≥50 to 60, ≥60 to 70, ≥70 to < 85, ≥85 kg) 
!
BMI category (< 18.5, ≥18.5 to < 25, ≥25 to < 30, ≥30 kg/m2)
The body mass index (BMI) will be calculated as 
BMI (kg/m2) = baseline weight (in kilograms) / height² (in meters).
!
Alcoholic beverage intake (yes [<1 drink per week, 1-14 drinks per week, >14 drinks 
per week], no)
!
Tobacco use (current user, past user, non-user).
8.2.
Baseline Disease Characteristics
Variables indicated below will be summarized descriptively:
!
Duration of disease (time [in years] from first diagnosis to the informed consent date)
!
Duration of disease (≤ 2, > 2 to ≤6, > 6 to ≤ 10, > 10 years)
!
History of uveitis from IRT data
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!
History of uveitis from clinical data, defined as having a history of ‘Anterior uveitis, 
iridocyclitis’, ‘Cells in vitreous’, ‘Chorioretinitis, retinovasculitis’, and/or ‘Posterior 
uveitis’, which are collected on screening and randomization visit BD manifestation 
activity history
!
Behçet’s syndrome diagnostic criteria
!
Ophthalmologic examination for presence of uveitis
!
Chest Radiograph (Normal, Abnormal [Not Clinically Significant, Clinically 
Significant]) 
!
Electrocardiogram (ECG) (Normal, Abnormal [Not Clinically Significant, Clinically 
Significant])
!
Baseline BD activities as measured by number of oral ulcers, number of genital 
ulcers (non-zero for subjects who had genital ulcers at baseline), pain of oral ulcers as 
measured by VAS , pain of genital ulcers as measured by VAS (non-zero), BD
Current Activity Index score, BD QOL total score, BSAS score, total score of PGA of 
BD skin lesions (non-zero),
 
. 
!
Baseline oral ulcers category (≥ 2 to ≤ 5, > 5 to ≤ 10, > 10)
!
Prior use of immunosuppressants (Yes, No)
!
Prior use of colchicines (Yes, No) 
!
Prior use of oral corticosteroids (Yes, No)
!
Prior use of topical corticosteroids (Yes, No)
!
Prior use of biologics (Yes, No)
!
Prior use of NSAIDs (Yes, No)
!
Prior use of analgesics/anesthetics (Different from NSAIDs) (Yes, No)
8.3.
Medical History
Medical history will be coded according to Medical Drug Regulatory Activities (MedDRA). A 
frequency summary table of medical history will be presented by treatment group, system organ 
class (SOC) and preferred term (PT).
8.4.
Prior Therapy
Prior medications are defined as therapies that were started before the start of the study treatment 
(whether or not ended before the start of the study treatment). Prior therapies that continue into 
study treatment period(s) will be also reported as concomitant medications. The Anatomical 
Therapeutic Chemical (ATC) coding scheme of the World Health Organization Drug Dictionary 
(WHODD) will be used to group medications into relevant categories. A frequency summary of 
prior medications will be provided by treatment group, ATC1 level, and standardized medication 
name.
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8.5.
Concomitant Medications and Procedures
Concomitant medications/procedures are defined as non-study medications or procedures that are 
started after the start but before the end of the study treatment (of each study period), or started 
before the start of the study treatment and ended or remain ongoing during the study treatment.
All concomitant treatments documented during the placebo-controlled period and apremilast-
exposure period will be summarized respectively in frequency tabulations. The Anatomical 
Therapeutic Chemical (ATC) coding scheme of the WHODD will be used to group medications 
into relevant categories. A frequency summary of concomitant medications for each analysis 
period will be provided by treatment group, ATC1 level, and standardized medication name. 
Concomitant medications in the Posttreatment Observational Follow-up Phase will be 
summarized for all subjects who enter the phase. In addition, concomitant medications initiated 
in the Posttreatment Observational Follow-up Phase will be summarized separately and a 
corresponding listing will be provided. 
A frequency summary table for concomitant procedures will be presented for each analysis 
period by presented by treatment group, MedDRA SOC, and PT.
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Apremilast
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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Treatment duration will be summarized by treatment group for the placebo-controlled period 
using the safety population, and for the apremilast-exposure period using the apremilast subjects 
as treated population. Subjects whose treatments are switched to active therapy will have the 
following treatment group designation: Placebo/APR 30 BID in the apremilast-exposure period. 
A subject data listing of study drug administration will be provided.
Treatment duration (in weeks) is calculated as (the date of the last dose of IP – the date of the 
first dose of IP + 1) / 7 during each period and rounded to one decimal place. Summary statistics 
for subject years, treatment duration (in weeks), as well as a frequency summary of treatment 
duration categories (e.g., ≥ 1 day, < 2 weeks, ≥ 2 to < 6 weeks, etc.), will be provided.
The specific definitions of the first and last dose dates for the Placebo-controlled and Apremilast-
exposure periods are given below:
!
Placebo-controlled period:
∀
First dose date: The date of the first dose of IP.
∀
Last dose date: 
o
1 day before the date of first dose of apremilast administered at the Week 
12/Visit 9, or 
o
The date of the last dose of IP in the study for subjects who discontinue the 
study on or prior to Week 12/Visit 9.
!
Apremilast-exposure period:
∀
First dose date: 
o
The date the first dose of apremilast is administered for subjects who receive 
apremilast at randomization, or 
o
The date the first dose of apremilast is administered at the Week 12 (Visit 9) 
for subjects who originally received placebo during the Placebo-controlled
Treatment Phase and switched to the APR 30 BID group when entering 
Active Treatment Phase. 
∀
Last dose date: 
o
The date of the last dose of apremilast during Active Treatment Phase for 
subjects who have either completed or discontinued Active Treatment Phase
by the time of database lock or study close, or
o
The latest date out of scheduled visit dates, AE event dates or study drug 
administration dates for treatment ongoing subjects at time of database lock
(ie, the second database in Section 2). 
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9.2.
Treatment Compliance 
Subjects are instructed to return the IP blister cards, including any unused IP, to the study site at 
each post-baseline visit for pill counts and reconciliation. The number of tablets dispensed and 
returned will be recorded at visits specified in the Table of Events, Table 1 in the protocol.
The compliance rate (%) will be calculated for each subject as 100 times the total number of 
tablets taken (total number of tablets dispensed minus the total number of tablets returned) over 
the period divided by the intended total number of tablets that should have been taken over the 
same period.
It is assumed that from the first dose date through the last dose date, a subject takes the first 3 
rows of tablets (6 tablets per row/day) on each complete blister card before taking the remaining 
rows (4 tablets per row/day), and completes all 33 rows and then starts a new blister card if 
multiple cards are dispensed. It is also assumed that a subject takes the full day’s tablets from a 
new blister card on a study drug dispense date.
The intended total number of tablets is calculated as follows. First order the first dose date, the 
second dispense date, the third dispense date, etc., and the last dose date. The first and last dose 
dates are defined in the same way as those defined for treatment duration calculations. The 
intended number of tablets between any 2 consecutive dates is calculated as 
4 × n + 2 × int[(n + 32) / 33] + 2 × int[(n + 31) / 33] + 2 × int[(n + 30) / 33],
where n denotes the number of days between the 2 consecutive dates (i.e., the second date minus 
the first date for all pairs of consecutive dates, and the second date minus the first date plus 1 for 
the last pair), and “int” denotes the integer part of the result. Then the intended total number of 
tablets is the sum of all intended numbers of tablets as calculated above from the first dose date 
through the last dose date.
Of note, compliance rate will not be calculated for subjects (if existent) who have only the 
dispense record at Week 0/Visit 2 and no other drug accountability records.
Compliance will be summarized using descriptive statistics for the placebo-controlled period and 
apremilast-exposure period. The acceptable range for compliance is defined as between 75%-
120%.  The number and percentage of subjects will be summarized by category < 75%, ≥ 75% to 
≤120%, and > 120%.
A subject data listing of drug accountability records will be provided.
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drug a


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10.
EFFICACY ANALYSIS
10.1.
General Approaches to Efficacy Analyses
The efficacy analyses will be based on the ITT population, and analyses of the primary efficacy 
endpoint will also be provided using the PP population. Statistical comparisons will be made 
between the apremilast group and the placebo group using 2-sided tests and the overall 
significance level will be maintained at 0.05.
All efficacy endpoints will be summarized by time points per the report conventions in Section 
5.1. Analyses of the primary endpoint, secondary 
 endpoints assessed during the 
Placebo-controlled Period will be presented by randomized treatment group, Placebo and 30 mg 
BID. During the Active Treatment Phase, data will be presented by treatment sequence, i.e., 
Placebo/30 mg BID, or 30 mg BID/30 mg BID. 
Efficacy results that will be considered statistically significant are described in Section 10.2.1. 
All statistical tests will be conducted at the α = 0.05 (2-sided) level, and 2-sided p-values will be 
reported.
10.2.
Efficacy Evaluation for the Double-blind, Placebo-controlled 
Treatment Phase
10.2.1.
Multiplicity
Planned statistical tests will be conducted between APR 30 BID and placebo for the primary 
endpoint, and selected secondary endpoints evaluated at Week 12.  
The multiplicity of the analyses of the primary and selected secondary efficacy endpoints will be 
adjusted using a gatekeeping Procedure. This procedure will preserve the Family Wise Error 
Rate of the multiple analyses. The analyses will be performed in sequence until one of the 
analyses has failed to show the significant difference or all analyses have been completed at a 
significance level of 0.05. The sequence of the analyses for the selected secondary efficacy 
endpoints are listed below:
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ses will b
ficant differ
ficant dif
quence of th
quence of


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Table 4:
Rank of the Endpoints (Including Primary Efficacy Endpoint) in the 
Hierarchy of Multiplicity Adjustment 
Endpoints
Rank of Endpoints in 
Multiple Testing 
Sequence
AUC for the number of oral ulcers from baseline through Week 12
1
Change from baseline in the pain of oral ulcers as measured by VAS at 
Week 12
2
Change from baseline in Behçet’s Syndrome Activity Score (BSAS) at 
Week 12
3
Change from baseline in disease activity as measured by Behçet’s Disease 
Current Activity scores (BD Current Activity Form) at Week 12
4
Proportion of subjects achieving an oral ulcer complete response (oral 
ulcer-free) by Week 6, after start of dosing, and who remain oral ulcer free 
for at least 6 additional weeks during the 12-week Placebo-controlled 
Treatment Phase
5
Time to oral ulcer resolution (complete response), ie, the first instance when 
a subject has a complete response, during the Placebo-controlled Treatment 
Phase
6
Complete response rate for oral ulcers at Week 12
7
Change from baseline in the BD QoL score at Week 12
8
Complete response rate for genital ulcers at Week 12 for subjects who had 
genital ulcers at baseline
9
Proportion of subjects with no oral ulcers following complete response, ie, 
the first time when a subject has a complete response, during the Placebo-
controlled Treatment Phase
10
Time to recurrence of oral ulcers following loss of complete response, ie, 
the first instance when a subject has a reappearance of oral ulcers following 
a complete response, during the Placebo-controlled Treatment Phase
11
Number of oral ulcers following loss of complete response, ie, the first 
instance when a subject has a reappearance of oral ulcers following a 
complete response, during the Placebo-controlled Treatment Phase
12
Change from baseline in the total score of the Static Physician’s Global 
Assessment (PGA) of skin lesions (acne-like lesions, folliculitis and 
erythema nodosum) of BD at Week 12 in subjects who had BD skin lesions 
at baseline
13
Change from baseline in the pain of genital ulcers as measured by VAS at 
Week 12 in subjects who had genital ulcers at baseline
14
For example, formal comparison with respect to the first secondary endpoint to be tested 
(Change from baseline in the pain of oral ulcers as measured by VAS at Week 12) will be 
conducted conditional on the test results for primary efficacy endpoint. If the test of AUC is 
&(
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statistically significant, (i.e., two sided p-value ≤ 0.05), then the comparison for change from 
baseline in the pain of oral ulcers as measured by VAS at Week 12 will be performed at α = 0.05. 
If the test result of AUC is not statistically significant, the formal statistical tests will not be 
performed for change from baseline in the pain of oral ulcers as measured by VAS at Week 12 
and for the remaining of secondary/
endpoints. 
For planned statistical tests that are not formally performed as a result of aforementioned 
multiplicity adjustment strategy, nominal 2-sided p-values (without adjustment for multiplicity) 
will still be computed as a measure of the strength of the association between the endpoints and
the treatment effect rather than formal test of hypotheses. In addition, nominal 2-sided p-values 
may also be computed for other efficacy analysis. 
10.2.2.
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint is the AUC for the number of oral ulcers from Day 1 through
Week 12/Day 85 (AUC85). The AUC85 will be compared between the placebo and APR 30 BID 
groups using a two-tailed parametric ANCOVA test at the 0.05 level. The model will include 
AUC85 as the response variable; treatment, sex and region as factors; and the number of oral 
ulcers at baseline as a covariate. Within-group least-squares (LS) means, the associated standard 
errors (SE), and treatment differences in LS means, the associated SE, and associated 2-sided 
95% CIs and 2-sided p-values will be derived from the model. The primary efficacy analysis will 
be performed using the ITT and PP population. 
To derive AUC85, the multiple imputation (MI) method will be used to impute missing oral ulcer 
counts on study visits from Day 1 through Week 12 with 3 steps: 
!
Check missing data patterns;
!
If there are non-monotone patterns, then use the Markov Chain Monte Carlo 
(MCMC) with a single chain method to impute sufficient missing oral ulcer counts by 
treatment to make 25 data sets having monotone patterns only. The seed will be set to 
37851. When the imputed oral ulcer count post-baseline is negative, the value of 0
will be assigned. 
!
For the monotone datasets, use the predictive mean matching method with treatment, 
sex, region, and oral ulcer counts from previous visits as covariate to impute the 
remaining missing oral ulcer counts to make datasets complete. The MONOTONE 
REGPMM statement will be used with a seed of 37951. 
In this MI approach, instead of filling in a single value for each missing value, SAS® procedure 
PROC MI performs MI by replacing each missing value with a set of plausible values. The 
missing data will be filled in multiple times to generate multiple complete data sets. A supportive 
analysis based on PP population will be performed using MI approach with the same seed 
number on PP population.
Missing data patterns will be provided in a separate table. The results obtained from parametric 
ANCOVA models (one for each imputation) will then be combined to derive valid statistical 
inference through the SAS® procedure PROC MIANALYZE. The complete-data degrees of 
freedom for parameter estimate specified in the PROC MIANALYZE option will be pulled from 
degree of freedom from parametric ANCOVA models.
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Parametric ANCOVA modeling AUC85 will also be performed for ITT and PP populations using 
an LOCF approach, and for subjects who complete Week 12 assessment based on observed data 
as sensitivity analyses.
Additional sensitivity analyses for AUC85 will be conducted for ITT population for subjects who 
complete each scheduled assessment from baseline through Week 12 based on observed data and 
for subjects who missed at most 2 scheduled oral ulcer assessments from baseline through Week 
12 based on MI imputed data. 
10.2.3.
Analyses of Secondary Efficacy Endpoints
Frequency counts and percentages will be provided for categorical variables including oral ulcer 
complete responders at Week 12, and genital ulcer complete responders at Week 12 for subjects 
who had genital ulcers at baseline. The proportions of complete responders in the two study 
treatment groups will be compared using a 2-sided Cochran-Mantel-Haenszel (CMH) test with 
significance level of 0.05, controlling for stratification factors including sex (male, female) and 
region (Japan, Other). Subjects who have discontinued early prior to Week 12 or who do not 
have data at Week 12 will be regarded as non-responders at Week 12. A sensitivity analysis 
using LOCF approach will be performed. The complete response rate based on the approach of 
NRI, or LOCF or the observed data will be provided for each time point during Placebo-
controlled Treatment Phase.
Similarly, the proportion of subjects with no oral ulcers or no genital ulcers following subject’s 
first complete response during Placebo-controlled Treatment Phase will be analyzed. The 
subjects who have a complete response prior to Week 12 but have no oral ulcers or genital ulcers
assessment following subject’s first complete response through Week 12 assessment will be
excluded when summarizing each endpoint. The treatment comparison will only be conducted if 
appropriate.
The proportion of subjects achieving an oral ulcer complete response (oral ulcer-free) by Week 
6, after the start of dosing, and who remain oral ulcer free for at least 6 additional weeks during 
the 12-week Placebo-controlled Treatment Phase will be analyzed similarly as the complete 
response rate as described above. Only those subjects who are oral ulcer-free by Week 6 and 
remain oral ulcer free for at least 6 consecutive weeks during the 12-week Placebo-controlled 
Treatment Phase will be considered as a responder; otherwise, subjects will be considered as 
non-responders. In case an oral ulcer assessment is missing at a visit, the LOCF approach will be 
used to impute missing assessments up to the ET visit or the last scheduled visit on or prior to 
date of treatment discontinuation, whichever is later. 
The number of oral ulcers following subject’s first loss of a complete response will be 
summarized for subjects who have a complete response prior to Week 12. The number of oral 
ulcers will be summarized as zero for subjects who had no reappearance of oral ulcers following 
a complete response prior to Week 12. The comparison between two treatment groups will be 
performed using ANCOVA model with the treatment, sex and region as factors and baseline 
number of oral ulcers as a covariate. Within-group LS means, the associated SEs, and treatment 
differences in LS means, the associated SE, and associated 2-sided 95% CIs and 2-sided p-values 
will be derived from the model. The treatment comparison will only be conducted if appropriate.
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f


Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
37
The summary tables with descriptive statistics for number of oral ulcers and general ulcers will 
be presented by treatment group at all applicable analysis visits.
Summary tables for change from baseline with descriptive statistics will be presented for 
continuous variables including pain VAS of oral ulcers, pain VAS of genital ulcers, BD Current 
Activity Form Scores, BD QoL scores, BSAS scores, 
 
, and total score of the Static PGA of skin lesions by treatment group 
at all applicable visits per study period. For the PGA, only subjects who had BD skin lesions at 
baseline will be included. For the pain VAS of genital ulcers, only subjects who had genital 
ulcers at baseline will be included.
The LOCF approach will be used to impute the missing assessment at Week 12 for the following 
endpoints: pain VAS of oral ulcers, pain VAS of genital ulcers, BD Current Activity Form 
Scores, BD QoL, and BSAS. The change from baseline at Week 12 (LOCF approach) will be 
compared between the placebo and the APR 30 BID group using ANCOVA model with change 
from baseline at Week 12 as the response variable, treatment, sex and region as factors and 
baseline value as a covariate. Within-group LS means, the associated SEs, and treatment 
differences in LS means, the associated SE, and associated 2-sided 95% CIs and 2-sided p-values 
will be derived from the model. A sensitivity analysis for change from baseline in the pain VAS 
of oral ulcers at Week 12 will be conducted using mixed-effects model for repeated measures 
(MMRM) with treatment, visit, treatment-by-visit interaction, sex and region as factors and 
baseline value as a covariate. An unstructured covariance matrix that is homogeneous across 
treatment groups is to be used.
The frequency distributions for categorical changes from baseline for VAS (-100 to 100 
inclusive in 25 increment for each interval) , BD QoL (< -20 to ≥ 10 in 5 increment for each 
interval), BD BSAS (< -60 to ≥ 40 in 20 increment for each interval)
 
will be 
summarized by time point A shift table from baseline to applicable analysis visits will be 
provided for number of oral ulcers, genital ulcers, the Behçet’s disease activity index (0 to 3, 4 to 
8 and 9 to 12), and PGA of skin lesions scales components (None, Mild, Moderate, and Severe).
Analyses of time to oral ulcer resolution and time to recurrence of oral ulcers following the first 
complete response during the Placebo-controlled Treatment Phase will use Kaplan-Meier method 
to estimate the median resolution/ recurrence time and its 2-sided 95% CIs. The stratified log-
rank test will be used for calculating 2-sided p-values for treatment comparison. The hazard ratio 
and 2-sided 95% CIs will be estimated using a stratified Cox model. For the time to oral ulcer 
resolution, the baseline number of oral ulcers will be included as covariate in the Cox model. The 
treatment comparison will only be conducted if appropriate.
Kaplan-Meier curves for time to event endpoints will be provided by treatment group.
 
 
 
 
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
38
 
 
 
 
 
 
 
 
 
 
10.3.
Efficacy Evaluation for the Active Treatment Phase in the Final 
Analysis
All subjects entering into the Active Treatment Phase of the study will be included in the 
analysis. Descriptive summaries for the endpoints as listed below will be performed at each 
applicable study visits based on the observed data by treatment sequence. 
!
Complete response
rate for oral ulcers
!
Complete response rate for genital ulcers for subjects who had genital ulcers at 
baseline
!
Number of oral ulcers
!
Number of genital ulcers
!
Change from baseline in the pain of oral ulcers as measured by VAS 
!
Change from baseline in the pain of genital ulcers, as measured by VAS in subjects 
who had genital ulcers at baseline
!
Change from baseline in disease activity as measured by BD Current Activity scores 
(BD Current Activity Form) 
!
Change from baseline in the BD QoL score 
!
Change from baseline in Behçet’s Syndrome Activity Score (BSAS)
!
Change from baseline in the total score of the Static Physician’s Global Assessment 
(PGA) of skin lesions (acne-like lesions, folliculitis and erythema nodosum) of BD in 
subjects who had BD skin lesions at baseline
 
 
 
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
39
10.4. Subgroup Analysis
The focus of subgroup analyses will be limited to the stratification factor and baseline 
characteristics as listed below and will be conducted on the ITT population for AUC85:
!
Sex (male, female)
!
Race (White, non-White)
!
Age (< 40, ≥ 40 to < 65, ≥ 65 years years)
!
Region (Japan, Other; Europe, North America, Asia, Rest of the World)
!
Baseline weight category (< 50, ≥50 to < 60, ≥60 to < 70, ≥ 70 to < 85, ≥ 85 kg)
!
Baseline BMI category (< 18.5, ≥ 18.5 to < 25, 25 to < 30, ≥30 kg/m2)
!
Alcoholic beverage intake (yes, no)
!
Tobacco use (current user, past user, never user).
!
Duration of disease (≤ 2, > 2 to ≤6, > 6 to ≤ 10, > 10 years)
!
Baseline oral ulcers category (≥ 2 to ≤ 5, > 5 to ≤ 10, ≥ 10)
!
Prior use of colchicines (Yes, No) 
!
Prior use of oral corticosteroids (Yes, No) 
The consistency of the treatment effect across subgroups will be assessed in the context of the 
primary methods used for the analyses. For AUC85, sex or region will not be included as a factor 
for the sex or region subgroup analysis, respectively, in the ANCOVA model. 
Forest plots will be provided based on the treatment differences for each subgroup estimated as 
described above for AUC85.
10.5.
Assessing Study Center Effect and Treatment-by-Center Interaction
This study is a multicenter study. As site enrollment caps are imposed in this study, no single site 
will have a sufficient number of subjects felt to allow a meaningful within-site analysis of 
treatment differences in AUC85 stratified by sex, therefore, study site effects will be assessed by 
pooling sites on a geographic basis to help interpret the results should potential site effects be 
suspected. In pooling sites for analysis purposes, values around 5 are often chosen as the 
minimum cell size in models containing interaction terms for a continuous endpoint. In this 
study, a minimum of 5 ITT subjects per treatment group per stratum of sex is chosen. The 
detailed pooling strategy for the stratified analyses is described in 4 steps as follows:
!
Sites will first be pooled within each country according to their rank based on site-
specific sample size, starting with the smallest sites; i.e., within a country, the 
smallest sites will first be pooled until the pooled site has a minimum cell size of 5. 
!
The remaining unpooled sites will then be pooled within a region (as defined in the 
subgroup analysis by region) in a similar fashion.
!
The remaining unpooled sites will then be pooled across regions in a similar fashion.
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Si
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Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
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40
!
The remaining unpooled sites will finally be pooled with the smallest pooled site. 
Study site effects will be assessed for the primary efficacy endpoint by stratifying the analysis 
based on both sex and pooled sites and examining whether the treatment differences, adjusted for 
pooled site, are consistent with those from the primary analysis.
In addition, the consistency of the treatment effect across pooled sites will also be assessed by 
performing a subgroup-type analysis with respect to the primary endpoint, with pooled sites 
treated as subgroups (see Section 10.4). A table summarizing AUC85 values by multiple 
imputation approach will be provided by individual study site and treatment group.
&(/*(1(35235,(7$5<,1)250$7,21


Apremilast
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Celgene Corporation
Confidential and Proprietary
41
11.
SAFETY ANALYSES
11.1.
General Approaches to Safety Analyses
Safety analyses will be performed for both the placebo-controlled and apremilast-exposure 
periods (see Section 5.2), based on the safety population and the apremilast subjects as treated 
population respectively. Summary tables during the placebo-controlled period are presented by 
treatment group, Placebo and 30 mg BID. During the apremilast-exposure period, data are 
presented by treatment sequence, i.e., Placebo/30 mg BID, 30 mg BID as Initiated, and a total 
column of 30 mg BID as Treated.
Unless otherwise specified, the analyses of AEs and marked abnormalities (laboratory
parameters and vital signs) for both the placebo-controlled and apremilast-exposure periods will 
include the subject incidence rate (i.e. percentage [%] used in a frequency summary), which is 
defined as the number of subjects with the specific event divided by the number of subjects 
included in the analysis. Subjects with multiple occurrences of the specific event in the specific 
analysis period will be counted only once in the numerator. 
To account for the different exposure to the IP, AEs and laboratory marked abnormalities will 
also be analyzed using exposure-adjusted incidence rate (EAIR) per 100 subject-years as defined 
below: 
!
The EAIR per 100 subject-years is defined as 100 times the number of subjects with 
the specific event divided by the total exposure time (in years) among subjects 
included in the analysis. Subjects with multiple occurrences of the specific event in 
the specific analysis period will be counted only once in the numerator. The exposure 
time for a subject without the specific event is the treatment duration, whereas the 
exposure time for a subject with the specific event is the treatment duration up to the 
start date (inclusive) of the first occurrence of the specific event. The total exposure 
time in years is calculated by dividing the sum of exposure time in days over all 
subjects included in the analysis by 365.25. The EAIR per 100 subject-years is 
interpreted as the expected number of subjects with at least one occurrence of the 
specific event per 100 subject-years of exposure to the study drug.
Summaries of vital signs, weight, and laboratory parameters over time (e.g., summary statistics
of observed value and changes from baseline and shifts from baseline to post-baseline time 
points in terms of normal/abnormal or grade) will be provided. In summaries for a post-baseline 
time point, subjects who have both values at baseline and at the time point will be included; for 
end of period and shifts from baseline to the end of period and to the worst post-baseline value, 
subjects who have a baseline value and at least one post-baseline value will be included. 
Safety data collected during the optional Open-Label Extension Phase will be listed.
11.2.
Adverse Events
AEs will be classified using the MedDRA. Unless otherwise specified, AEs will be summarized 
by system organ class (SOC) and preferred term (PT), with SOCs presented in the standard 
international order and PTs within each SOC in descending order of subject incidence.
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periods wil
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per 100 subj
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ure time (in
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ult
ultipiple occu
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unted only o
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fic event is 
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the specifi
rst occurren
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by
by dividing
dividing
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pected num
pected num
100 subjec
100 subjec
, wei
, weight, an
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changes fr
changes fr
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11.2.
1.2.
A
AEs wi
AEs w


Apremilast
Statistical Analysis Plan. Protocol CC-10004-BCT-002
Celgene Corporation
Confidential and Proprietary
42
A subject data listing of all AEs (including TEAEs and non-TEAEs) sorted by subject ID and AE 
start date will be provided based on the safety population, irrespective of analysis periods; this 
listing will include a “non-treatment-emergent” flag and the date of the last IP dose. Only TEAEs 
will be included in the AE summaries as described below.
11.2.1.
Overall Summary of Adverse Events
An overall summary of the following AE categories will be provided:
!
Subjects with any TEAE
!
Subjects with any drug-related TEAE
!
Subjects with any severe TEAE 
!
Subjects with any serious TEAE
!
Subjects with any serious drug-related TEAE
!
Subjects with any TEAE leading to drug interruption
!
Subjects with any TEAE leading to drug withdrawal
!
Subjects with any TEAE leading to death
Specific TEAEs under each of the above categories will be summarized.
11.2.2.
All TEAEs
All TEAEs will be summarized by
!
SOC and PT
!
PT only (in descending order of subject incidence)
New events of all TEAEs by exposure interval (≤1, >1 to ≤ 2, > 2 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12 
and > 12 weeks) will be summarized for the placebo-controlled period and for the apremilast-
exposure period (≤1, >1 to ≤ 2, > 2 to ≤ 4, > 4 to ≤ 8, > 8 to ≤ 12, >12 to ≤ 16, > 16 to ≤ 28, > 28 
to ≤ 40, > 40 to ≤ 52, > 52 to ≤ 64 and > 64 weeks); an event with a start date falling within an 
exposure interval is considered a new event for that interval. Each subject is counted once in the 
numerator of a subject incidence or EAIR for each applicable specific TEAE in each exposure 
interval where an event started. The denominator of a subject incidence is the number of subjects 
with treatment duration exceeding the lower bound of the particular exposure interval, while the 
denominator of an EAIR is the sum of the exposure time during the exposure interval (up to the 
first event start date subjects with at least one event starting in the interval) among the same 
number of subjects as in the denominator of the responding subject incidence. 
11.2.3.
Common TEAEs
TEAEs with subject incidence ≥ 5% in any treatment group will be summarized by SOC and PT 
as well as by PT only in descending order of subject incidence.
Summaries about the most frequent TEAEs will include onset day of the most frequent TEAE, 
and the duration of those most frequent TEAE. The most frequent TEAEs will be those 
identified in the ≥ 5% summaries noted above.
summarize
ummarize
of subject i
of subject i
e interval (
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ed for the p
> 2 to ≤ 4,
> 2 to ≤ 4,
o ≤ 64 and >
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dered a new
dered a 
incidence 
incidence 
vent started
nt started
urati
uration e
on exc
xc
f an EAIR
f an EAIR
start date su
tart date su
of subjects
of subject
2.3.
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TEAEs w
TEAEs w
wel
wel


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Celgene Corporation
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11.2.4.
Drug-related TEAEs
Drug-related TEAEs will be summarized by SOC and PT.
11.2.5.
TEAEs by Maximum Severity
All TEAEs will be summarized by maximum severity (mild, moderate, and severe). If a subject 
reports multiple occurrences of a specific event within a specific analysis period, the subject will 
be counted only once by the maximum severity. 
11.2.6.
Serious TEAEs
Serious TEAEs and serious drug-related TEAEs will be summarized by SOC and PT. Serious 
TEAEs will also be summarized by PT only (in descending order of subject incidence). 
A subject data listing of all serious AEs (both TEAEs and non-TEAEs) will be listed.
11.2.7.
Severe TEAEs
Severe TEAEs will be summarized by SOC and PT.
A subject data listing of all severe AEs (both TEAEs and non-TEAEs) will be listed.
11.2.8.
TEAEs Leading to Drug Withdrawal
All TEAEs leading to drug withdrawal will be summarized by SOC and PT as well as by PT 
only (in descending order of subject incidence). 
A subject data listing of TEAEs leading to drug withdrawal will be provided.
11.2.9.
TEAEs Leading to Drug Interruption
All TEAEs leading to drug interruption will be summarized by SOC and PT.
11.2.10.
TEAEs of Special (Specific) Interests
The diarrhea characterization CRF collects information at each visit: what event occurred, if the 
event meets protocol definition (yes or no), and frequency of watery/liquid stools (Daily, 5 – 6 
days per week, 2 – 4 days per week, Once every other week to once a week, Once a month or 
less). Protocol-defined diarrhea refers to diarrhea adverse events that have two or more watery 
or liquid stools in a day.
Summarization will include:
!
Subject incidence of protocol-defined diarrhea TEAE; 
!
Total number of diarrhea event and protocol-defined diarrhea TEAE;
!
Protocol-defined diarrhea TEAE characteristics of highest frequency of watery/liquid 
stools, duration and onset day of the event, 
The summaries will be provided for the placebo-controlled period, and for the apremilast-
exposure period.
A listing for diarrhea events will be provided. 
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on (yes or 
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s per week,
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11.2.11.
TEAEs and Serious TEAEs by Subgroups 
All TEAEs and serious TEAEs will be summarized by sex (male, female), age category (< 65, ≥ 
65 years), race (White, non-White), and region (Japan, other; Europe, North America, Asia, and 
Rest of the World), provided sufficient subjects are enrolled into these categories.
11.2.12.
TEAEs Leading to Drug Withdrawal by Subgroups
All TEAEs leading to drug withdrawal will be summarized by sex (male, female), age category 
(< 65, ≥ 65 years), race (White, non-White), and region (Japan, other; Europe, North America, 
Asia, and Rest of the World)), provided sufficient subjects are enrolled into these categories.
11.2.13.
Deaths
All TEAEs leading to death will be summarized by SOC and PT. A subject data listing of deaths 
will be provided.
All TEAEs occurring after the date of the last dose of IP and up to 28 days after the last dose of 
IP will also be summarized by SOC and PT for subjects who enter the Observational Follow-up 
Phase. The EAIR will not be provided in this summary. 
11.3.
Clinical Laboratory Evaluations
Laboratory parameters as specified in protocol 6.6.7 will be included. 
Laboratory marked abnormalities (see Section 16.3) will be summarized using subject incidence 
and EAIR for each marked abnormality based on subjects with a baseline value and at least one 
post-baseline value for criteria requiring baseline or subjects with at least one post-baseline value 
for criteria not requiring baseline. Laboratory marked abnormalities will also be summarized for 
subjects with normal values at baseline and for subjects with abnormal values at baseline 
separately. For the purposes of these summaries, subjects with abnormal (normal) values at 
baseline are defined as those whose baseline value is low (not low) for criteria concerning low 
values and those whose baseline value is high (not high) for criteria concerning high values; both 
low and high are relative to the laboratory normal range.
Summary statistics of observed values and changes from baseline in continuous laboratory 
parameters will be provided by time points. Numeric values reported as less than (<) or greater 
than (>) a laboratory-defined limit will be included with the “<” or “>” signs ignored. Frequency 
summaries of shifts from baseline category to the category of post-baseline time points, the end
of treatment and to the worst post-baseline category in terms of normal/abnormal (low or high) 
or grade will be provided in the above hematology and serum chemistry parameters.
A subject data listing of all laboratory data sorted by subject ID and date of sample collection 
will be provided based on the safety population, irrespective of analysis periods.
11.4.
Vital Signs and Weight
Summary statistics of observed values and changes from baseline in vital signs (including 
weight, for which percent change from baseline will also be summarized) will be provided over 
time. Frequency summaries (shift tables) of shifts from baseline to post-baseline time points and 
to the worst post-baseline value in terms of normal/abnormal will be provided for pulse, 
&(/*(1(35235,(7$5<,1)250$7,21
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baseline val
baseline 
value is high
alue is high
laboratory
laboratory
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11.4.
11.4
umm
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Celgene Corporation
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45
respiratory rate and blood pressure. The normal ranges are defined as: 60-100 beats/minute for 
pulse, 12 to 16 breaths/minutes for respiratory rate, 90-140 mmHg for systolic blood pressure, 
and 60-90 mmHg for diastolic blood pressure).
Vital sign abnormalities will be summarized in a manner similar to laboratory marked 
abnormalities. A subject data listing of vital sign abnormalities will be provided. Frequency 
summaries of change and percent change in weight from baseline to the end of the period will be 
provided by baseline BMI category (< 18.5, ≥ 18.5 to < 25, # 25 to < 30, # 30 kg/m2) and by 
baseline weight category (<50, ≥50 to 60, ≥60 to < 70, # 70 to < 85, # 85 kg). The categories of 
weight change (kg) and percent change (%) are < -20, # -20 to < -10, # -10 to < -5, # -5 to < 0, 0, 
> 0 to ≤ 5, > 5 to ≤ 10, > 10 to ≤ 20, and > 20. The end-of-period value is the last post-baseline 
value in the analysis period (excluding the value obtained at the follow-up visit, if applicable) up 
to 28 days after the last dose of IP in the study.
A subject data listing of all vital signs and weight data sorted by subject ID and date of 
measurement will be provided based on the safety population, irrespective of analysis periods.
11.5.
Physical Examination
Physical examination results will not be summarized.
11.6.
Electrocardiogram
A 12-lead ECG will be performed during the Screening Phase. The site will use its own, local 
ECG machines for the study. ECG reading will be interpreted by the investigator and recorded
as: normal; abnormal, not clinically significant; or abnormal, clinically significant. 
A subject data listing of all ECG data sorted by subject ID and date of measurement will be 
provided based on the safety population, irrespective of analysis periods.
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12.
INTERIM ANALYSIS
No interim analysis is planned prior to the analysis of the primary efficacy endpoint and the 
planned analyses are stated in Section 2.
&(/*(1(35235,(7$5<,1)250$7,21


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Statistical Analysis Plan. Protocol CC-10004-BCT-002
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Confidential and Proprietary
47
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.
CHANGES TO THE STATISTICAL SECTION OF THE 
PROTOCOL
No change has been made to the statistical section of the protocol. 
The following additional endpoints, described in Section 4.2.1.3, will be analyzed as described in 
Section 10.2.4 and Section 10.3.
 
 
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15.
REFERENCES
Forbess C, Swearingen C, Yazici Y. Behçet’s syndrome activity score (BSAS): A new disease 
activity assessment tool, composed of patient-derived measures only, is strongly correlated with 
the Behçet’s disease current activity form (BDCAF). Presented at the Annual European Congress 
of Rheumatology, Paris, 11-14 June 2008; Abstract D 14.
Gilworth G, Chamberlain MA, Bhatia B, Haskard D, Silman A, Tennant A. Development of the 
DB-QoL; A quality of life measure specific to Behçet’s disease. J Rheumatol. 2004;31:931- 937.
Lawton G, Bhakta BB, Chamberlain MA, Tennant A. The Behçet’s disease activity index. 
Rheumatol. 2004;43:73-78.
 
.
Stokes, Davis, Koch (2000) Categorical Data Analysis Using the SAS Program, Page 174-179.
 
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16.
APPENDICES 
16.1.
Handling of Dates 
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. datetime format in SAS).  Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedure are 
performed.  They include the dates of laboratory testing, physical examinations, 
tumor scans, etc.  They should be present whenever data for a protocol-specified 
procedure are present and should only be missing when a procedure are marked as 
NOT DONE in the database.  Procedure dates will not be imputed.
!
Log Dates are dates recorded in CRF data logs.  Specifically, they are the start and 
end dates for adverse events and concomitant medications/procedures.  They should 
not be missing unless an event or medication is marked as ongoing in the database.  
Otherwise, incomplete log dates will be imputed according to the rules in Appendix 
16.2 (ie, for duration or cycle assignment, etc). However, in listings, log dates will be 
shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc.  They should not be 
missing if the milestone occurs for a subject.  They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc.  In most cases they are derived either from a milestone (eg, the 
survival date is derived from the death date), or a procedure date (eg, the progression 
date is derived from the date of the tumor scan that was used to determine 
progression).  They may be subject to endpoint-specific censoring rules if the 
outcome did not occur, but are not otherwise subject to imputation.
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth.  They may be subject to variable-specific censoring and imputation 
rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
16.1.1.
Calculation Using Dates
Calculations using dates (ie, subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions: 
!
Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study drug (e.g, 
lenalidomide) plus 1 day. The generalized calculation algorithm for relative day is the 
following: 
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o
If TARGET DATE ≥DSTART then STUDY DAY = (TARGET DATE –
DSTART) + 1; 
o
Else use STUDY DAY = TARGET DATE – DSTART.
Note that Study Day 1 is the first day of treatment of study drug. Negative study days 
are reflective of observations obtained during the baseline/screening period.  Note: 
Partial dates for the first study drug are not imputed in general. All effort should be 
made to avoid incomplete study drug start dates. 
!
Age (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1.  In 
practice, age will be transformed to years by dividing the difference by 365.25 days, 
then truncating.
∀
Preference is for using calculated age from clinical database. When not available, 
calculated age from CRF or IVRS may be used
∀
Partial birth date: impute missing day as 15th of the month; impute missing month 
as July; set missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS /30.4167
16.2.
Date Imputation Guideline
16.2.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications 
Incomplete Start Date:
Missing day and month
!
If the year is the same as the year of the first dosing date, then the day and month of 
the first doing date will be assigned to the missing fields.
!
If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.
!
If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 
!
If the month and year are the same as the year and month of first dosing date, then the 
first doing date will be assigned to the missing day.
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!
If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial 
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.
!
If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.
!
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
Missing day, month, and year
!
No imputation is needed, the corresponding AE will be included as TEAE. 
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date but 
is the same as the year of the first dosing date, then the first dosing date will be 
assigned to the missing date. 
!
If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 
!
If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day. 
16.2.2.
Impute Missing Diagnosis Date for Behçet’s Disease
Partial missing BD diagnosis date will be imputed in the ADaM dataset for the purpose of 
calculating duration of BD history. The 16th of the month will be used to impute a partially 
missed diagnosis date that has only the day missing, that July 1st will be used to impute a 
partially missed diagnosis date that has both the month and day missing. If the above imputation 
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inappropriately results in a diagnosis date on or after the informed consent date, then the 
incomplete date will be assigned to the day prior to the informed consent date.
16.3.
Marked (Atypical) Abnormalities Criteria
Table 5:
Marked Abnormalities Criteria
Category / Analyte
SI Units
Criteria
Chemistry /
Alanine Aminotransferase (SGPT)
U/L
> 3 xULN  
Albumin
Kg/m3
< 25
Alkaline Phosphatase
U/L
> 400  
Aspartate Aminotransferase (SGOT)
U/L
> 3 x ULN  
Total Bilirubin
μmol/L
> 1.8 x ULN  
Blood Urea Nitrogen
mmol/L
> 15
Calcium 
mmol/L
< 1.8
> 3.0
Creatinine 
μmol/L 
> 1.7 x ULN 
Glucose
mmol/L
< 2.8
> 13.9
Hemoglobin A1C
%
> 9
Lactate Dehydrogenase
U/L
> 3 x ULN
Magnesium
mmol/L
> 1.2
Phosphate
mmol/L
< 0.64
> 1.60
Potassium
mmol/L
< 3.0
> 5.5
Sodium
mmol/L
< 130
> 150
Urate
μmol/L
Male: > 590; Female: > 480
Hematology /
Hemoglobin
g/L
Male: < 105, Female: < 85 
Male: > 185, Female: > 170 
Leukocytes
10^9/L 
< 1.5
Lymphocytes
10^9/L
< 0.8
Neutrophils
10^9/L
< 1.0
Platelets
10^9/L
< 75
> 600
Vital Signs /
Systolic Blood Pressure
mmHg
Increase > 10 but ≤ 15 (mild)
Increase > 15 but ≤ 20 (moderate)
Increase > 20 (severe)
Diastolic Blood Pressure
mmHg
Increase > 5 but ≤10 (mild)
Increase > 10 but ≤15 (moderate)
Increase > 15 (severe)
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